Imidazopyridazines as IL-17 modulators

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 017,682, filed April 30, 2020, the disclosure of which is incorporated herein by reference in its entirety.

[0003] Reference sequence listing submitted electronically

[0004] This application contains a sequence listing, which is submitted electronically via EFS-Web as an ASCII formatted sequence listing with a file name of "716604_NTT-6306PC-SEQ-TEXT-FILE.txt", a creation date of April 27, 2021, and a size of 5 KB. This sequence listing submitted via EFS-Web is part of this specification and is incorporated herein by reference in its entirety. Technical Field

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

[0006] Interleukin-17 ("IL-17"), also known as IL-17A and CTLA-8, is primarily produced by CD4+ Th17 cells and is also produced 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 (A / F) with IL-17F and signals by binding to the dimeric receptor complexes IL-17RA and IL-17RC. IL-17RA is ubiquitously expressed at particularly high levels in hematopoietic cell types, while IL-17RC is preferentially expressed in non-hematopoietic cells (Gaffen, S., "Structure and signaling in the IL-17 receptor family", Nat. Rev. Immunol. 2009, 9, 556-567). IL-17A / IL-17R signaling triggers NF-kB, C / EBP, and MAPK pathways through ACT1-TRAF6-TRAF4 to induce nascent gene transcription. It can also stabilize target mRNA transcripts through the ACT1-TRAF2-TRAF5 complex (Amatya N. et al., Trends in Immunology, 2017, 38, 310-322). IL-17A stimulates the release of inflammatory mediators, including IL-6, IL-8, G-CSF, TNF-α, and IL-1β, which recruit and activate lymphocytes to sites of injury or inflammation and maintain a pro-inflammatory state.

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

[0008] For psoriasis: IL-17A mRNA and / or protein levels are elevated in the lesional skin and blood of patients with psoriasis and correlate with disease severity. IL-17A directly synergizes with other cytokines on keratinocytes (such as TNFα, IFNγ or IL-22), triggering a self-amplifying inflammatory response in the skin and leading to the formation of psoriasis plaques. Blocking IL-17A by antibodies to IL-17A or IL-23 results in a complete reversal of molecular and clinical disease features in most psoriasis patients, indicating a significant role for IL-17A and IL-17-producing T cells in the immune pathogenesis of psoriasis. (Hawkes et al., "Psoriasis Pathogenesis and the Development of Novel, Targeted Immune Therapies", J Allergy Clin Immunol. 2017, 140(3): 645-653). The development and approval of IL-17 monoclonal antibodies (such as secukinumab, ixekizumab, and brodalumab) and their transformative efficacy in psoriasis have demonstrated that IL-17A is a valid target for psoriasis treatment (Blauvelt A. and Chiricozzi A., "The Immunologic Role of IL-17 in Psoriasis and Psoriatic Arthritis Pathogenesis", Clin Rev Allergy Immunol. 2018, 55(3): 379-390).

[0009] For psoriatic arthritis (PsA): IL-17A is mechanistically associated with PsA through NFκB activation, which triggers the transcription of several PsA-related genes, including receptor activator of nuclear factor κB ligand (RANKL). RANKL triggers 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 rich in IL-17+CD8+ T cells, and the level of this T cell subset is correlated with disease activity (Menon B. et al., Arthritis & Rheumatology 2014; 66: 1272-81). Synovial fibroblasts isolated from PsA patients also contain elevated IL-17R expression and secrete increased IL-6, CXCL8, and MMP3 in vitro compared to osteoarthritis patients. Both secukinumab and ixekizumab are FDA-approved PsA drugs. In a matched-adjusted indirect comparison analysis, secukinumab was associated with higher ACR 20 / 50 / 70 response rates in patients with active PsA compared with anti-TNFα antibodies (Mease P. et al., Eur. J. Rheumatol. 20019 Jul 1, 6(3): 113-121; Strand V. et al., J. Comp. Eft. Res. 2019, 8(7): 497-510; Nash P. et al., Rheumatol. Ther. 2018, 5(1): 99-122). In a recent head-to-head study, ixekizumab was superior to adalimumab in achieving simultaneous improvement in joint and skin disease (ACR50 and PASI100) in patients with PsA who had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (Mease, P. et al., Ann Rheum Diss 2020;79:123-131). Given that small molecules generally have better tissue penetration, IL-17A small molecule inhibitor compounds may exert similar or better efficacy than biologics by engaging the same target.

[0010] For rheumatoid arthritis (RA): IL-17A has been recognized to be crucial for the progression of rheumatoid arthritis. "The recognition of IL-17 as a pro-inflammatory T cell derived cytokine, and its abundance within rheumatoid joints, provides the strongest candidate mechanism to date throughout 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 rheumatoid arthritis, IL-17A acts locally on synoviocytes and osteoclasts, leading to synovitis and joint destruction. Robert and Miossec have proposed the use of synovial biopsy tissue and / or biomarkers to accurately identify patients who respond to IL-17A inhibition. Their work concluded that IL.17 inhibitors should now be considered in the development of precision medicine for RA. (Robert M. and Miossec P., Front. Med., 2019, 5: 364)

[0011] For ankylosing spondylitis (AS): Various studies have reported elevated IL-17A and Th17 and other IL-17-producing cells in AS blood samples (Wendling D. et al., Joint Bone Spine. 2007; 74: 304-305; Shen H. et al., Arthritis Rheum. 2009; 60(6): 1647-56; Zhang L. et al., PLoS One. 2012; 7(4): e31000; Jansen D. et al., Rheumatology (Oxford). 2015 Apr; 54(4): 728-735). In situ analysis of AS spines revealed an increase in IL-17A-producing cells in the facet joint bones (Appel H. et al., Arthritis Res. Ther. 2011; 13(3): R95). Two advanced IL-17A neutralizing antibodies, secukinumab and ixekizumab, which are FDA-approved for AS, have demonstrated superior efficacy to placebo even in anti-TNF inadequate responders. In contrast, anti-IL-23p40 and p19 biologics failed to demonstrate beneficial effects (Deodhar A. et al., Arthritis Rheumatol. 2019, 71(2): 258-270; Baeten D. et al., Ann. Rheum. Dis. 2018, 77(9): 1295-1302), indicating a mechanism underlying differentiation along the IL-23 / IL-17 pathway in AS and providing strong evidence to support continued development of IL-17A inhibitors.

[0012] For hidradenitis suppurativa (HS): IL-17 and IL-17-producing T helper cells have been reported to be increased in skin lesions of HS patients, and molecular proteomic and gene expression data suggest that the IL-23 / Th17 pathway is upregulated in HS lesions (Schlapbach 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 of nine patients (78%) with moderate to severe HS achieved HiSCR in an open-label pilot trial with secukinumab (Prussick L. et al., British J. Dermatol. 2019 Sep; 181(3): 609-611), and more clinical trials of anti-IL-17 mAbs in HS are ongoing.

[0013] For bullous pemphigoid (BP): IL-17 is elevated in the blister fluid and perilesional skin of BP patients. (LeJan S. et al., J. Invest. Dermatol. 2014; 134(12): 2908-2917.; Chakievska L. J Autoimmun. 2019, 96: 104-112). Exome sequencing of BP patients revealed mutations in twelve IL-17-related genes in one-third of patients, providing a genetic connection between the IL-17 pathway and BP (Chakievska L. J Autoimmun. 2019, 96: 104-112). In experimental murine BP, IL-17A- / - mice were protected, and anti-IL-17A treatment significantly reduced skin lesions in wild-type mice (Chakievska LJ Autoimmun. 2019, 96: 104-112). A phase 2 trial of ixekizumab in patients with treatment-naive and refractory BP is ongoing (NCT03099538).

[0014] For atopic dermatitis (AD): IL-17 was found to be elevated in the peripheral blood and lesions of AD patients, and the infiltration of Th17 cells in acute lesions was more obvious than in chronic lesions, indicating that it plays a role in the acute phase of AD (Koga C. et al., J. Invest. Dermatol. 2008, 128, 2625-2630). Molecular profiling analysis from the ustekinumab phase II study suggests that the IL-23 / Th1 7 / IL-17 pathway may play a role in AD (Khattri S. et al., Exp. Dermatol. 2017 January, 26(1): 28-35).

[0015] For vitiligo: Many studies on vitiligo patients have demonstrated that increased frequencies of Th17 cells in both the circulation and lesions, as well as elevated IL-17 levels, are positively correlated with disease duration, severity, and activity (Singh R. et al., Autoimmun. Rev, April 2016, 15(4): 397-404). Studies in mice have demonstrated that depigmentation is associated with elevated IL-17 expression / secretion, which regulates vitiligo development (Eb y J. et al., Pigment Cell & Melanoma Res. 2014 Nov, 27(6): 1075-85).

[0016] For 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 enriched in active MS lesions ((Tzartos, J. et al., Am. J. Pathol. 2008, 172: 146-155; Willing A. et al., J. Hmmunol. 2018, 200(3): 974-982). IL-17A levels are elevated in the CSF of patients with relapsing-remitting MS (RRMS) and correlate with the CSF / serum albumin quotient, a measure of blood-brain barrier (BBB) ​​dysfunction, as well as in vitro data showing that IL-17A combined with IL-6 reduced the expression of tight junction-related genes and disrupted the monolayer integrity in BBB cell lines, highlighting the potential importance of targeting IL-17A to maintain BBB integrity in RRMS (Setiadi et al., 2018). AF et al., J Neuroimmunol. 2019, 332: 147-154). Secukinumab first showed promising results in a proof-of-concept study in MS patients (Havrdová, E. et al., J. Neurol. 2016, 263: 1287-1295).

[0017] For asthma: IL-17 expression is increased in the lungs, sputum, bronchoalveolar lavage fluid, and serum of patients with asthma, and the severity of airway hyperresponsiveness is positively correlated with IL-17 expression levels. (Chakir J. et al., J. Allergy Clin. Immunol. 2003, 111(6):1293-8). IL-17 is 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 modulate 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).

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

[0019] For uveitis: IL-17 promotes the release of inflammatory mediators from retinal pigment epithelial cell lines, disrupting the retinal pigment epithelial barrier function (Chen Y. et al., PLoS One. 2011; 6: e18139). IL-17 levels are elevated in the serum or aqueous humor of patients with uveitis (El-Asrar 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. Ophthahnol. 2011; 152(2): 177-182.). Anti-IL-17 antibodies delayed the onset of ocular inflammation in rats and significantly inhibited the development of experimental autoimmune uveitis (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 that secukinumab had a beneficial effect in reducing the use of concomitant immunosuppressive medications (Dick A. et al., Ophthalmology 2013, 120(4):777-87). Subsequent studies of intravenous secukinumab in uveitis demonstrated that the efficacy of intravenous secukinumab was superior to sc administration, suggesting that optimal exposure is required for efficacy and confirming the therapeutic potential of IL-17A inhibition (Letko E. et al., Ophthalmology 2015, 122(5), 939-948). It has also been reported that ustekinumab, which blocks the IL-23 / IL-17 pathway, successfully treated patients with severe non-infectious uveitis associated with psoriasis and PsA who were unable to respond to conventional immunosuppressants (Mugheddu C. et al., Dermatol. Ther. 2017 Sep, 30(5); e12527.).

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

[0021] For systemic lupus erythematosus (SLE): Elevated IL-17 levels in serum or plasma, expansion of IL-17-producing T cells in peripheral blood, and infiltration of Th17 cells in target organs (such as the kidney) are 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 is observed in SLE patients, 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 enhanced the severity of lupus nephritis, while blocking IL-17A using neutralizing antibodies resulted in a reduction in the severity of lupus nephritis (Wen, Z. et al., PLoS One. 2013, 8: e58161). In a phase 2 study, ustekinumab, an anti-IL-12 / 23p40 monoclonal antibody that blocks the IL-23 / IL-17 pathway, has been shown to be effective in SLE patients (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).

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

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

[0024]

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

[0026] R 1 -C (1-6) Alkyl, -C (0-2) Alkyl C (3-6) a cycloalkyl group, or a 5- to 6-membered heterocyclic group having 1 to 2 nitrogen atoms;

[0027] Where -C (1-6) The alkyl group is unsubstituted or substituted with one to six R 1a group substitution;

[0028] Where -C (0-2) Alkyl C (3-6) The cycloalkyl group is unsubstituted or substituted with one to six R 1b group substitution; and

[0029] and

[0030] The 5-membered to 6-membered heterocyclic group is unsubstituted or replaced by one to three R 1c group substitution;

[0031] R 2 H, -C (3-5) Cycloalkyl or -C (1-4) Alkyl; wherein -C (1-4) The alkyl group is unsubstituted or substituted with one to six R 2a group substitution;

[0032] R 1a 、R 1b and R 2a are each independently fluorine, -C (3-5)Cycloalkyl, -CN, -OH, -OC (1-3) Alkyl or -OC (3-4) Cycloalkyl, where -OC (1-3) Alkyl and -OC (3-4) The cycloalkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0033] Each R 1c is independently -OCH3, -OCF3, -OCHF2, or -C (1-4) alkyl;

[0034] R 3 -C (0-1) Alkyl C (3-6) Cycloalkyl, -C (3-6) Alkyl or -C (1-2) Alkyl-OC (1-3) Alkyl, where -C (0-1) Alkyl C (3-6) Cycloalkyl, -C (3-6) Alkyl and -C (1-2) Alkyl-OC (1-3) The alkyl group is unsubstituted or is independently selected from one to five R 3a Group substitution: fluorine, -CH3-CHF2, -CF3, OH and =O;

[0035] R 4 -C (3-6) cycloalkyl, phenyl, or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from N, O, and S;

[0036] Among them C (3-6) The cycloalkyl group is unsubstituted or is independently selected from one to three R 4a Group substitution: halogen, -OC (1-3) Alkyl and -C (1-4) Alkyl, where -OC (1-3) Alkyl and -C (1-4) The alkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0037] Alternatively, two R attached to the same ring atom 4a Groups can combine with the atoms to which they are attached to form C (3-6) Cycloalkyl;

[0038] wherein the phenyl group is unsubstituted or is substituted by one to three R 4b Group substitution: halogen, -CN, -C (0-2) Alkyl-C (3-4) Cycloalkyl, -OC (0-2) Alkyl-C (3-4)Cycloalkyl, -OC (1-3) Alkyl, -C (1-4) Alkyl and 3- to 6-membered heterocyclic groups having 1 to 2 heteroatoms selected from N and O, wherein -OC (1-3) Alkyl, -C (0-2) Alkyl-C (3-4) Cycloalkyl and -C (1-4) The alkyl group is unsubstituted or substituted with one to three fluorine atoms, and the heterocyclyl group is unsubstituted or substituted with one oxo group;

[0039] wherein the 5- to 6-membered heteroaryl group is unsubstituted or replaced by one or two R 4c group substitution;

[0040] Each R 4c are independently halogen, -CN, -OH, -N(R 4c1 )(R 4c2 ),-C (0-2) Alkyl C (3-6) Cycloalkyl, -OC (0-2) Alkyl-C (3-4) Cycloalkyl, -C (1-4) Alkyl, -OC (1-3) alkyl, or a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms selected from N and O, wherein -C (0-2) Alkyl C (3-6) Cycloalkyl, -C( 1-4 )alkyl, -OC (1-3) The alkyl and heterocyclic groups are unsubstituted or substituted with one to six R 4d group substitution;

[0041] Alternatively, two R attached to adjacent ring atoms 4c Groups can be combined to form C (4-6) Cycloalkyl;

[0042] Each R 4d are independently fluorine, -CN, -OH, oxo, -C (1-3) Alkyl, -OC (1-3) Alkyl, -OC (3-4) Cycloalkyl, -C (0-2) Alkyl-N(R 4d1 )(R 4d2 ),-C (0-2) Alkyl-N(C (1-4 )alkyl)C(O)(C (1-4 ) alkyl), or a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms selected from N and O, wherein -C (1-3) Alkyl, -OC (1-3) Alkyl, -OC (3-4) Cycloalkyl and heterocyclyl groups are unsubstituted or substituted with one to three fluorine atoms;

[0043] R 4c1 、R 4c2 、R 4d1 and R 4d2 Each independently is H or -C (1-3) Alkyl, where -C (1-3) The alkyl group is unsubstituted or substituted with one to six groups selected from fluorine and chlorine;

[0044] Alternatively, R 4d1 and R 4d2 can combine with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1 to 4 fluorine atoms; and

[0045] R 5 is hydrogen or halogen;

[0046] in

[0047] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0048] and

[0049] When R 4 When it is a substituted 6-membered heteroaryl, the substituted heteroaryl is not substituted at the para position.

[0050] The present application also discloses compounds of Formula I'. All compounds of Formula I are compounds of Formula I'. Some compounds of Formula I' are compounds of Formula I.

[0051] Therefore, disclosed herein is a compound of formula I':

[0052]

[0053] or a pharmaceutically acceptable salt thereof, wherein:

[0054] R 1 -C (1-6) Alkyl, -C (0-2) Alkyl C (3-6) Cycloalkyl, -C (0-2) Alkyl-cyclopropyl-C (1-3) a perfluoroalkyl group, or a 5- to 6-membered heterocyclic group having 1 to 2 nitrogen atoms;

[0055] Where -C (1-6) The alkyl group is unsubstituted or substituted with one to six R 1a group substitution;

[0056] Where -C (0-2) Alkyl C(3-6) The cycloalkyl group is unsubstituted or substituted with one to six R 1b group substitution; and

[0057] and

[0058] The 5-membered to 6-membered heterocyclic group is unsubstituted or replaced by one to three R 1c group substitution;

[0059] R 2 H, -C (3-5) Cycloalkyl, -C (1-4) alkyl, or a 6-membered heterocyclic ring having 1 to 2 oxygen atoms; wherein -C (1-4 ) alkyl is unsubstituted or substituted by one to six R 2a and wherein -C (3-5) Cycloalkyl is unsubstituted or substituted with -CN;

[0060] R 1a 、R 1b and R 2a are each independently fluorine, -C (3-5) Cycloalkyl, -CN, -OH, -OC (1-3) Alkyl or -OC (3-4) Cycloalkyl, where -OC (1-3) Alkyl and -OC (3-4) The cycloalkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0061] Each R 1c is independently -OCH3, -OCF3, -OCHF2, or -C (1-4) alkyl;

[0062] R 3 -C (0-1) Alkyl C (3-6) Cycloalkyl, -C (3-6) Alkyl or -C (1-2) Alkyl-OC (1-3) Alkyl, where -C (0-1) Alkyl C (3-6) Cycloalkyl, -C (3-6) Alkyl and -C (1-2) Alkyl-OC (1-3) The alkyl group is unsubstituted or is independently selected from one to five R 3a Group substitution: fluorine, -CH3-CHF2, -CF3, OH and =O;

[0063] R 4 -C (3-6) cycloalkyl, phenyl, or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from N, O, and S;

[0064] Among them C (3-6) The cycloalkyl group is unsubstituted or is independently selected from one to three R 4a Group substitution: halogen, -OC (1-3) Alkyl and -C (1-4) Alkyl, where -OC (1-3) Alkyl and -C (1-4) The alkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0065] Alternatively, two R attached to the same ring atom 4a Groups can combine with the atoms to which they are attached to form C (3-6) Cycloalkyl;

[0066] wherein the phenyl group is unsubstituted or is substituted by one to three R 4b Group substitution: halogen, -CN, -C (0-2) Alkyl-C (3-4) Cycloalkyl, -OC (0-2) Alkyl-C (3-4) Cycloalkyl, -OC (1-3) Alkyl, -C (1-4) Alkyl and 3- to 6-membered heterocyclic groups having 1 to 2 heteroatoms selected from N and O, wherein -OC (1-3) Alkyl, -C (0-2) Alkyl-C (3-4) Cycloalkyl and -C (1-4) The alkyl group is unsubstituted or substituted with one to three fluorine atoms, and the heterocyclyl group is unsubstituted or substituted with one oxo group;

[0067] wherein the 5- to 6-membered heteroaryl group is unsubstituted or replaced by one or two R 4c group substitution;

[0068] Each R 4c are independently halogen, -CN, -OH, -N(R 4c1 )(R 4c2 ),-C (0-2) Alkyl C (3-6) Cycloalkyl, -OC (0-2) Alkyl-C (3-4) Cycloalkyl, -C (1-4) Alkyl, -OC (1-3) alkyl, or a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms selected from N and O, wherein -C (0-2) Alkyl C (3-6) Cycloalkyl, -C (1-4) Alkyl, -OC (1-3) The alkyl and heterocyclic groups are unsubstituted or substituted with one to six R 4d group substitution;

[0069] Alternatively, two R attached to adjacent ring atoms 4c Groups can be combined to form C (4-6) Cycloalkyl;

[0070] Each R 4d are independently fluorine, -CN, -OH, oxo, -C (1-3) Alkyl, -OC (1-3) Alkyl, -OC (3-4) Cycloalkyl, -C (0-2) Alkyl-N(R 4d1 )(R 4d2 ),-C (0-2) Alkyl-N(C (1-4 )alkyl)C(O)(C (1-4) alkyl), or a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms selected from N and O, wherein -C (1-3) Alkyl, -OC (1-3) Alkyl, -OC (3-4) Cycloalkyl and heterocyclyl groups are unsubstituted or substituted with one to three fluorine atoms;

[0071] R 4c1 、R 4c2 、R 4d1 and R 4d2 Each independently is H or -C (1-3) Alkyl, where -C (1-3) The alkyl group is unsubstituted or substituted with one to six groups selected from fluorine and chlorine;

[0072] Alternatively, R 4d1 and R 4d2 can combine with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1 to 4 fluorine atoms; and

[0073] R 5 is hydrogen or halogen;

[0074] in:

[0075] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0076] and

[0077] When R 4 When it is a substituted 6-membered heteroaryl, the substituted heteroaryl is not substituted at the para position.

[0078] 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.

[0079] Also described herein is a method for treating and / or ameliorating IL-17A-mediated inflammatory syndromes, disorders, or diseases (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, etc.), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, disclosed herein is the use of a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof for treating and / or ameliorating IL-17A-mediated inflammatory syndromes, disorders, or diseases (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, etc.).

[0081] In some embodiments, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or ameliorating IL-17A-mediated inflammatory syndromes, disorders, or diseases (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, etc.).

[0082] In some embodiments, provided herein are methods and intermediates disclosed herein that are useful for preparing compounds of Formula I or pharmaceutically acceptable salts thereof.

[0083] 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.

[0084] Also described herein is a method for treating and / or ameliorating IL-17A-mediated inflammatory syndromes, disorders, or diseases (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, etc.), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, disclosed herein is the use of a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof for treating and / or ameliorating IL-17A-mediated inflammatory syndromes, disorders, or diseases (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, etc.).

[0086] In some embodiments, disclosed herein is the use of a compound of Formula I' or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or ameliorating IL-17A-mediated inflammatory syndromes, disorders or diseases (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, etc.).

[0087] In some embodiments, provided herein are methods and intermediates disclosed herein that are useful for preparing compounds of Formula I' or pharmaceutically acceptable salts thereof.

[0088] The present disclosure also provides compounds or methods as described herein. DETAILED DESCRIPTION

[0089] definition

[0090] Various publications, articles, and patents are cited or described in the Background and throughout the specification; each of these references is incorporated herein by reference in its entirety. The discussion of documents, acts, materials, devices, articles, and the like included in this specification is intended to provide a context for the present invention. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any invention disclosed or claimed.

[0091] 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. Otherwise, certain terms used herein have the meanings set forth in this specification. All patents, published patent applications, and publications cited herein are incorporated by reference as if fully set forth herein.

[0092] It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0093] In order to help the reader of the application, the description is divided into each paragraph or chapter, or relates to each embodiment of the application. These divisions should not be considered as the essence of paragraphs or chapters or embodiments being separated from the essence of another paragraph or chapter or embodiment. On the contrary, it will be understood by those skilled in the art that this description has a wide range of applications and contains all combinations of conceivable chapters, paragraphs and sentences. The discussion of any embodiment is only intended to be exemplary, and is not intended to show that the scope of the disclosure (including claims) is limited to these examples.

[0094] With respect to the methods of the present invention, the term "administering" means a method of therapeutically or prophylactically preventing, treating, or ameliorating a syndrome, disorder, or disease as described herein by using a compound of the present invention, or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof. Such methods include administering a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof at different times during the course of treatment, or administering simultaneously or sequentially as a combination therapy.

[0095] The term "subject" refers to a patient, which may be an animal, preferably a mammal, most preferably a human, who will be or has been treated by a method according to an embodiment of the present application. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) (such as monkeys or apes), humans, etc., and more preferably include humans.

[0096] The term "therapeutically effective amount" or "effective amount" means that amount of an active compound or agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, including preventing, treating or ameliorating the symptoms of the syndrome, disorder or disease being treated.

[0097] As used herein, "IL-17" or "IL-17A" refers to interleukin 17A. It is also designated as IL17, CTLA8, and CTLA-8. Interleukin 17A is a proinflammatory cytokine. This cytokine is produced by a group of immune cells in response to stimulation of the immune cells. An exemplary amino acid sequence of human IL-17 is set forth in GenBank Accession No. NP_0021811, which can be encoded by a nucleic acid sequence, such as the nucleic acid sequence in GenBank Accession No. NM_002190.3.

[0098] As used herein, the term "modulator" refers to any agent or molecule, including small molecule compounds, that is capable of binding to IL-17.

[0099] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0100] As used herein, in one embodiment, the term "treating" of any disease, condition, syndrome or disorder refers to ameliorating the disease, condition, syndrome or disorder (i.e., slowing or arresting or slowing the development of at least one of the disease or its clinical symptoms). In another embodiment, "treating" refers to alleviating or improving at least one physiological or biochemical parameter associated with or causing the disease, condition, syndrome or disorder, including parameters that may not be discernible to the patient. In another embodiment, "treating" refers to modulating the disease, condition, syndrome or disorder physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing physical parameters), or both. In yet another embodiment, "treating" refers to preventing or delaying the onset or development or progression of a disease, condition, syndrome or disorder.

[0101] As used herein, the term "QD" means once daily.

[0102] As used herein, the term "BID" means twice daily.

[0103] The term "alkyl" is a straight or branched chain saturated hydrocarbon. For example, an alkyl group may have 1 to 12 carbon atoms (i.e., (C1-C 12 ) alkyl) or 1 to 6 carbon atoms (i.e., (C1-C6) alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), isopropyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-bu, n-butyl, -CH2CH2CH2CH3), 2-butyl (s-bu, s-butyl, -CH(CH3)CH2CH3), tert-butyl (t-bu, t-butyl, -CH(CH3)3), 1-pentyl (n-pentyl, -CH2CH2 CH2CH2CH3), 2-pentyl (-CH(CH3)2CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), heptyl (-(CH2)6CH3), octyl (-(CH2)7CH3), 2,2,4-trimethylpentyl (-CH2C(CH3)2CH2CH(CH3)2), nonyl (-(CH2)8CH3), decyl (-(CH2)9CH3), undecyl (-(CH2) 10 CH3) and dodecyl (-(CH2) 11 CH3). Any alkyl group may be unsubstituted or substituted.

[0104] Term "C (a-b)"" (where a and b are integers indicating the number of carbon atoms) refers to an alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl group, or to the alkyl portion of a group wherein alkyl appears as a prefix root and has from a to b carbon atoms, inclusive. For example, C (1-4) represents a group having 1, 2, 3 or 4 carbon atoms.

[0105] The term "perfluoroalkyl" refers to an alkyl group as defined herein in which all carbon-hydrogen bonds have been replaced by carbon-fluorine bonds. For example, a perfluoroalkyl group may have from 1 to 6 carbon atoms (i.e., (C 1-6 ) perfluoroalkyl) or 1 to 3 carbon atoms (ie, (C 1-3 )perfluoroalkyl). Examples of perfluoroalkyl groups include, but are not limited to, trifluoromethyl (-CF3), pentafluoroethyl (-CF2CF3), heptafluoropropyl (-CF2CF2CF3), and heptafluoroisopropyl (-CF(CF3)2).

[0106] The term "heterocycle" or "heterocyclyl" refers to a single saturated or partially unsaturated ring having at least one atom other than a carbon atom in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen, and sulfur. Exemplary heterocycles include, but are not limited to, oxetanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholinyl.

[0107] The term "cycloalkyl" refers to a group having 3 to 8 carbon atoms (ie, C(3 - 8) cycloalkyl) and preferably 3 to 6 carbon atoms (ie, C (3-6) All saturated or partially unsaturated carbocyclic ring systems of cycloalkyl (cycloalkyl), wherein the cycloalkyl ring system has a single ring or multiple rings in the form of a spirocycle or a bicyclic ring. Exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise specified in this specification, cycloalkyls may be unsubstituted or substituted. Some cycloalkyls may exist as spirocycloalkyls, in which two cycloalkyl rings are fused via a single carbon atom; for example, but not limited to, spiropentyl is exemplified by For example, but not limited to, examples of spirohexyl groups include For example, but not limited to, examples of cycloheptyl groups include For example, but not limited to, examples of cyclooctyl groups include Unless otherwise specified in the specification, a spirocycloalkyl group may be unsubstituted or substituted. Bicyclic cycloalkyl ring systems also include

[0108] The term "heteroaryl" refers to a single aromatic ring having at least one atom other than a carbon atom in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen, and sulfur. The term "heteroaryl" includes single aromatic rings having from 1 to 6 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Exemplary heteroaryl ring systems include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, Azolyl, Oxazolyl, iso oxazolyl, triazolyl, imidazolyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl or furyl.

[0109] The terms "ortho," "meta," and "para" have their meanings as understood in the art and are used herein to indicate the position of substituents on a phenyl or 6-membered heteroaryl ring relative to the point of attachment to the ring. For example, the structure below is depicted as a 3-pyridyl group having an X1 substituent in the ortho position, an X2 substituent in the meta position, and an X3 substituent in the para position:

[0110]

[0111] The term "halogen" refers to bromo (-Br), chloro (-Cl), fluoro (-F), or iodo (-I).

[0112] When the compounds disclosed herein have at least one stereocenter, they may exist as enantiomers or diastereomers, respectively. It should be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0113] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of one another.

[0114] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A "racemic" mixture is a 1:1 mixture of a pair of enantiomers. A "non-racemic" mixture of enantiomers is a mixture of enantiomers in a ratio other than 1:1.

[0115] If the method for preparing the compound according to the present invention produces a mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. These compounds can be prepared in racemic form, non-racemic mixtures, or can be synthesized by enantiomer specificity or prepared by splitting a single enantiomer. For example, standard techniques can be used, such as by forming a diastereomeric pair with an optically active acid (such as (-)-di-p-toluoyl-D-tartaric acid and / or (+)-di-p-toluoyl-L-tartaric acid), followed by fractional crystallization and regeneration of the free base, thereby splitting these compounds into their component enantiomers. These compounds can also be split by forming diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, these compounds can be split using chiral column bottles HPLC or SFC. In some cases, there may be rotational isomers of the compound, which can be separated by 1 H NMR observations, leading to 1 Complex multiplets and peak integration in H NMR spectra.

[0116] Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. It is known that the chiral center of the absolute configuration is marked by the prefixes R and S specified using a standard sequence rule program, and when necessary, by appropriate position priority (Pure & Appl. Chem. 45, 1976, 11-30). Some examples contain chemical structures depicted or labeled as (R *) or (S *). When (R *) or (S *) are used in the name of a compound or in the chemical representation of a compound, it is intended to represent that the compound is a pure single isomer at the stereo center; However, the absolute configuration of the stereo center has not yet been determined. Therefore, the compound designated as (R *) refers to a compound of a pure single isomer at the stereo center with an absolute configuration of (R) or (S), and the compound designated as (S *) refers to a compound of a pure single isomer at the stereo center with an absolute configuration of (R) or (S). For example, N-((S)-(7-((S*)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4- -- (fluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide:

[0117] means one of the following compounds:

[0118]

[0119] Although pseudoasymmetric stereogenic centers are treated in the same manner as chiral centers, they are given lower case letter symbols, r or s (Angew. Chem. Int. Ed. Engl. 1982, 21, 567-583).

[0120] During any of the processes for preparation of the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups in any of the molecules concerned. This can be achieved by conventional protecting groups such as those described in: Protective Groups in Organic . Chemistry ″, JFW McOmie, ed., Plenum Press, 1973; and TW Greene and PGM Wuts, ″ Protective Groups in Organic Synthesis ", John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known in the art.

[0121] Furthermore, within the scope of the present invention, any element, particularly when referenced to a compound of the present disclosure or a pharmaceutically acceptable salt thereof, is intended to encompass all isotopes or isotopic mixtures of said element (naturally occurring or synthetically produced) in its natural abundance or in its isotopically enriched form. For example, a reference to hydrogen includes within its scope 1 H. 2 H (i.e. deuterium or D) and 3 H (ie, tritium or T). In some embodiments, the compounds described herein include 2 H (i.e. deuterium) isotopes. For example, -C (1-6) Alkyl groups include not only -CH3 but also CD3; not only CH2CH3 but also CD2CD3, etc. Similarly, references to carbon and oxygen include within their scope 12 C. 13 C and 14 C, and 15 O and 16 O and 17 O and 18 O. The isotope may be radioactive or non-radioactive. The radiolabeled compounds of the present disclosure may include a radioisotope selected from the group consisting of: 3 H. 11 C. 18 F. 35 S. 122 I. 123 I. 125 I. 131 I. 75 Br, 76 Br,77 Br and 82 Br. Preferably, the radioisotope is selected from the group consisting of 3 H. 11 C and 18 F's group.

[0122] Compounds of the present disclosure

[0123] The present application discloses a compound of formula I:

[0124]

[0125] or a pharmaceutically acceptable salt thereof, wherein:

[0126] R 1 -C (1-6) Alkyl, -C (0-2) Alkyl C (3-6) a cycloalkyl group, or a 5- to 6-membered heterocyclic group having 1 to 2 nitrogen atoms;

[0127] Where -C (1-6) The alkyl group is unsubstituted or substituted with one to six R 1a group substitution;

[0128] Where -C (0-2) Alkyl C (3-6) The cycloalkyl group is unsubstituted or substituted with one to six R 1b group substitution; and

[0129] and

[0130] The 5-membered to 6-membered heterocyclic group is unsubstituted or replaced by one to three R 1c group substitution;

[0131] R 2 H, -C (3-5) Cycloalkyl or -C (1-4) Alkyl; wherein -C (1-4) The alkyl group is unsubstituted or substituted with one to six R 2a group substitution;

[0132] R 1a 、R 1b and R 2a are each independently fluorine, -C (3-5) Cycloalkyl, -CN, -OH, -OC (1-3) Alkyl or -OC (3-4) Cycloalkyl, where -OC (1-3) Alkyl and -OC (3-4) The cycloalkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0133] Each R 1cis independently -OCH3, -OCF3, -OCHF2, or -C (1-4) alkyl;

[0134] R 3 -C (0-1) Alkyl C (3-6) Cycloalkyl, -C (3-6) Alkyl or -C (1-2) Alkyl-OC (1-3 )alkyl, wherein -C (0-1) Alkyl C (3-6) Cycloalkyl, -C (3-6) Alkyl and -C (1-2) Alkyl-OC (1-3) The alkyl group is unsubstituted or is independently selected from one to five R 3a Group substitution: fluorine, -CH3-CHF2, -CF3, OH and =O;

[0135] R 4 -C (3-6) cycloalkyl, phenyl, or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from N, O, and S;

[0136] Among them C (3-6) The cycloalkyl group is unsubstituted or is independently selected from one to three R 4a Group substitution: halogen, -OC (1-3) Alkyl and -C (1-4) Alkyl, where -OC (1-3) Alkyl and -C (1-4) The alkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0137] Alternatively, two R attached to the same ring atom 4a Groups can combine with the atoms to which they are attached to form C (3-6) Cycloalkyl;

[0138] wherein the phenyl group is unsubstituted or is substituted by one to three R 4b Group substitution: halogen, -CN, -C (0-2) Alkyl-C (3-4) Cycloalkyl, -OC (0-2) Alkyl-C (3-4) Cycloalkyl, -OC (1-3) Alkyl, -C (1-4) Alkyl and 3- to 6-membered heterocyclic groups having 1 to 2 heteroatoms selected from N and O, wherein -OC (1-3) Alkyl, -C (0-2) Alkyl-C (3-4) Cycloalkyl and -C (1-4)The alkyl group is unsubstituted or substituted with one to three fluorine atoms, and the heterocyclyl group is unsubstituted or substituted with one oxo group;

[0139] wherein the 5- to 6-membered heteroaryl group is unsubstituted or replaced by one or two R 4c group substitution;

[0140] Each R 4c are independently halogen, -CN, -OH, -N(R 4c1 )(R 4c2 ),-C (0-2) Alkyl C (3-6) Cycloalkyl, -OC (0-2) Alkyl-C (3-4) Cycloalkyl, -C (1-4) Alkyl, -OC (1-3) alkyl, or a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms selected from N and O, wherein -C (0-2) Alkyl C (3-6) Cycloalkyl, -C (1-4) Alkyl, -OC (1-3) The alkyl and heterocyclic groups are unsubstituted or substituted with one to six R 4d group substitution;

[0141] Alternatively, two R attached to adjacent ring atoms 4c Groups can be combined to form C (4-6) Cycloalkyl;

[0142] Each R 4d are independently fluorine, -CN, -OH, oxo, -C (1-3) Alkyl, -OC (1-3) Alkyl, -OC (3-4) Cycloalkyl, -C (0-2) Alkyl-N(R 4d1 )(R 4d2 ),-C (0-2) Alkyl-N(C (1-4) alkyl)C(O)(C (1-4) alkyl), or a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms selected from N and O, wherein -C (1-3) Alkyl, -OC (1-3) Alkyl, -OC (3-4) Cycloalkyl and heterocyclyl groups are unsubstituted or substituted with one to three fluorine atoms;

[0143] R 4c1 、R 4c2 、R 4d1 and R 4d2 Each independently is H or -C (1-3) Alkyl, where -C (1-3)The alkyl group is unsubstituted or substituted with one to six groups selected from fluorine and chlorine;

[0144] Alternatively, R 4d1 and R 4d2 can combine with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1 to 4 fluorine atoms; and

[0145] R 5 is hydrogen or halogen;

[0146] in

[0147] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0148] and

[0149] When R 4 When it is a substituted 6-membered heteroaryl, the substituted heteroaryl is not substituted at the para position.

[0150] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0151] R 1 -C (1-6) Alkyl, -C (0-2) Alkyl C (3-6) Cycloalkyl or piperidinyl;

[0152] Where -C (1-6) The alkyl group is unsubstituted or substituted with one to six R 1a group substitution;

[0153] Where -C (0-2) Alkyl C (3-6) The cycloalkyl group is unsubstituted or substituted with one to six R 1b group substitution; and

[0154] and

[0155] wherein the piperidinyl group is unsubstituted or replaced by one to three R 1c group substitution;

[0156] R 1a and R 1b Each is independently -OH, -OCH3, -OCF3, -OCHF2 or fluorine;

[0157] Each R 1c is independently unsubstituted or substituted with one to three fluorine atoms -C (1-2) alkyl;

[0158] R 2 H, -C (3-5) Cycloalkyl or -C (1-4) alkyl;

[0159] R 3 is unsubstituted or substituted with one or two fluorine atoms -C(5 - 6) cycloalkyl;

[0160] R 4 -C (3-4) cycloalkyl, phenyl, or a 5-membered heteroaryl group having 1 to 4 heteroatoms selected from N, O, and S;

[0161] Among them C (3-6) The cycloalkyl group is unsubstituted or is independently selected from one to three R 4a Group substitution: halogen and C unsubstituted or substituted with one to three fluorine atoms (1-4) alkyl;

[0162] Alternatively, two R attached to the same ring atom 4a Groups can combine with the atoms to which they are attached to form C (3-6) Cycloalkyl;

[0163] wherein the phenyl group is unsubstituted or is substituted by one or two R 4b Group substitution: halogen, -CN, -C (0-2) Alkyl-C (3-4) Cycloalkyl, -OC (0-2) Alkyl-C (3-4) Cycloalkyl, -OC (1-3) .Alkyl, C (1-4) Alkyl and 3- to 6-membered heterocyclic groups having 1 to 2 heteroatoms selected from N and O, wherein -OC (1-3) Alkyl, -C (0-2) Alkyl-C (3-4) Cycloalkyl and -C (1-4) The alkyl group is unsubstituted or substituted with one to three fluorine atoms, and the heterocyclyl group is unsubstituted or substituted with one oxo group.

[0164] replace;

[0165] The 5-membered heteroaryl group is unsubstituted or replaced by one or two R 4c group substitution;

[0166] Each R 4c are independently halogen, -CN, -C (0-2) Alkyl C (3-6) Cycloalkyl, -OC (0-2) Alkyl-C (3-4) Cycloalkyl, -C (1-4) Alkyl, -OC(1-3) alkyl, or a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms selected from N and O, wherein -C (0-2) Alkyl C (3-6) Cycloalkyl, -C (1-4) Alkyl, -OC (1-3) The alkyl and heterocyclic groups are unsubstituted or substituted with one to six R 4d group substitution;

[0167] Each R 4d are independently fluorine, -CN, oxo, -C (1-3) Alkyl, -OC (1-3) Alkyl, -OC (3-4) Cycloalkyl, -C (0-2) Alkyl-N(R 4d1 )(R 4d2 ), or -C (0-2) Alkyl-N(C (1-4) alkyl)C(O)(C (1-4) alkyl), wherein -C (1-3) Alkyl, -OC (1-3) Alkyl and -OC (3-4) The cycloalkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0168] R 4d1 and R 4d2 Each independently is H or -C (1-3) Alkyl, where -C (1-3) The alkyl group is unsubstituted or substituted with one to six groups selected from fluorine and chlorine;

[0169] Alternatively, R 4d1 and R 4d2 can combine with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1 to 4 fluorine atoms; and

[0170] R 5 is hydrogen or fluorine;

[0171] in

[0172] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0173]

[0174] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0175] R 1 -C (1-6) Alkyl, -CH2C(3-6) Cycloalkyl or piperidinyl;

[0176] Where -C (1-6) The alkyl group is unsubstituted or substituted with one to six R 1a group substitution;

[0177] Among them -CH2C (3-6) The cycloalkyl group is unsubstituted or substituted with one to four fluorine atoms; and

[0178] Wherein the piperidinyl group is unsubstituted or replaced by -C (1-2) Alkyl substitution, the -C (1-2) The alkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0179] Each R 1a are independently -OH, -OCH3, -OCF3, -OCHF2 or fluorine;

[0180] R 2 H, -C (3-5) Cycloalkyl or -C (1-3) alkyl;

[0181] R 3 is a cyclohexyl group which is unsubstituted or substituted with one to two fluorine atoms;

[0182] R 4 -C (3-4) Cycloalkyl, spiropentanyl, spirohexanyl, spiroheptanyl, spirooctanyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, Azolyl, Oxazolyl, iso oxazolyl, triazolyl, imidazolyl or thiadiazolyl;

[0183] Where -C (3-4) The cycloalkyl group is unsubstituted or substituted by one to three groups selected from the group consisting of halogen and C (1-2) alkyl;

[0184] wherein phenyl, pyridyl, pyrimidinyl and pyrazinyl are unsubstituted or substituted by one or two groups selected from the group consisting of halogen and C (1-2) alkyl;

[0185] Among them, pyrazolyl, Azolyl, Oxazolyl, iso Azolyl, triazolyl, imidazolyl and thiadiazolyl are replaced by one or two R 4c group substitution;

[0186] Each R 4c Independently -C(0-2) Alkyl C (3-6) Cycloalkyl or -C (1-4) Alkyl, where -C (0-2) Alkyl C (3-6) Cycloalkyl and -C (1-4) The alkyl group is unsubstituted or substituted with one to four R 4d group substitution;

[0187] Each R 4d is independently -OCH3, -OCF3, -OCHF2 or fluorine; and

[0188] R 5 is hydrogen or fluorine.

[0189] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0190] R 1 -C (3-5) alkyl,

[0191] Where -C (3 - 5) The alkyl group is unsubstituted or substituted with one to six R 1a group substitution;

[0192] in is unsubstituted or substituted with one to four fluorine atoms; and

[0193] in Not replaced or replaced by -C (1-2) Alkyl substitution, the -C (1-2) The alkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0194] Each R 1a are independently -OH or fluorine;

[0195] R 2 is H, cyclopropyl, methyl or isopropyl;

[0196] R 3 is cyclohexyl or

[0197] R 4 is cyclopropyl, spiropentanyl, spirohexanyl, phenyl, pyridyl, pyrazolyl, Azolyl, iso oxazolyl, triazolyl, imidazolyl or 1,2,3-thiadiazolyl;

[0198] wherein the cyclopropyl group is unsubstituted or substituted by one to three groups selected from the group consisting of: fluorine and unsubstituted

[0199] C substituted or substituted by one to three fluorine atoms (1-2) alkyl;

[0200] Wherein phenyl and pyridyl are unsubstituted or substituted by one to two groups selected from the following: chlorine

[0201] and C unsubstituted or substituted with one to three fluorine atoms (1-2) alkyl;

[0202] Wherein 1,2,3-thiadiazolyl is unsubstituted or replaced by C (1-3) Alkyl substituted, where C (1-3) Alkyl

[0203] is substituted or replaced by one to three fluorine atoms;

[0204] Among them, pyrazolyl, Azolyl, iso Azolyl, triazolyl and imidazolyl are unsubstituted or replaced by one or two R 4c group substitution;

[0205] Each R 4c Independently -C (0-1) Alkyl C (3-4) Cycloalkyl or -C (1-4) Alkyl, where -C (0-1) Alkyl C (3-4) Cycloalkyl and -C (1-4) The alkyl group is unsubstituted or substituted with one to four R 4d group substitution;

[0206] Each R 4d is independently -OCH3, -OCF3, -OCHF2 or fluorine; and

[0207] R 5 is hydrogen or fluorine.

[0208] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0209] R 1 -C (1-6) Alkyl, -CH2C (3-6) Cycloalkyl or piperidinyl;

[0210] Where -C (1-6) The alkyl group is unsubstituted or substituted with one to six R 1a group substitution;

[0211] Among them -CH2C (3-6) The cycloalkyl group is unsubstituted or substituted with one to four fluorine atoms; and

[0212] Wherein the piperidinyl group is unsubstituted or replaced by -C(1-2) Alkyl substitution, the -C (1-2) The alkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0213] Each R 1a are independently -OH, -OCH3, -OCF3, -OCHF2 or fluorine;

[0214] R 2 H, -C (3-5) Cycloalkyl or -C (1-3) alkyl;

[0215] R 3 is a cyclohexyl group which is unsubstituted or substituted with one to two fluorine atoms;

[0216] R 4 -C (3-4) Cycloalkyl, spiropentanyl, spirohexanyl, spiroheptanyl, spirooctanyl, phenyl, pyrrolyl, pyrazolyl, Azolyl, Oxazolyl, iso oxazolyl, triazolyl, tetrazolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl or thiadiazolyl; wherein -C (3-4) The cycloalkyl group is unsubstituted or substituted by one to three groups selected from the group consisting of halogen and C (1-2) alkyl;

[0217] Wherein phenyl is unsubstituted or substituted by one or two groups selected from the following: halogen, -CN, -C (0-2) Alkyl-C (3-4) Cycloalkyl, -OC (0-2) Alkyl-C (3-4) Cycloalkyl, -OC (1-3) Alkyl, C (1-4) Alkyl and 3- to 6-membered heterocyclic groups having 1 to 2 heteroatoms selected from N and O, wherein -OC (1-3) Alkyl, -C (0-2) Alkyl-C (3-4) Cycloalkyl and -C (1-4) The alkyl group is unsubstituted or substituted with one to three fluorine atoms, and the heterocyclyl group is unsubstituted or substituted with one oxo group;

[0218] Among them, pyrazolyl, Azolyl, Oxazolyl, iso Azolyl, triazolyl, tetrazolyl, imidazolyl, thiazolyl, isothiazolyl and thiadiazolyl are replaced by one or two R 4c group substitution;

[0219] Each R 4c are independently halogen, -CN, -C(0-2) Alkyl C (3-6) Cycloalkyl, -OC (0-2) Alkyl-C (3-4) Cycloalkyl, -C (1-4 Alkyl, -OC (1-3) alkyl, or a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms selected from N and O, wherein -C (0-2) Alkyl C (3-6) Cycloalkyl, -C (1-4) Alkyl, -OC (1-3) Alkyl and heterocyclic groups are unsubstituted or substituted with one to four R 4d group substitution;

[0220] Each R 4d is independently -OCH3, -OCF3, -OCHF2 or fluorine; and

[0221] R 5 is hydrogen or fluorine;

[0222] in

[0223] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0224]

[0225] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0226] R 1 -C (3-5) alkyl,

[0227] Where -C (3-5) The alkyl group is replaced by one to six R 1a group substitution;

[0228] in is substituted with two fluorine atoms; and

[0229] in Replaced by -CF3;

[0230] Each R 1a are independently -OH or fluorine;

[0231] R 2 is H, cyclopropyl, methyl or isopropyl;

[0232] R 3 is cyclohexyl or

[0233] R 4is cyclopropyl, spiropentanyl, spirohexanyl, phenyl, pyridyl, pyrazolyl, Azolyl, iso oxazolyl, triazolyl, imidazolyl or 1,2,3-thiadiazolyl;

[0234] wherein the cyclopropyl group is substituted by one or two groups selected from the group consisting of fluorine and unsubstituted or trisubstituted

[0235] C substituted with fluorine atoms (1) alkyl;

[0236] Wherein the phenyl group is unsubstituted or replaced by -C1 or -C (1-2) Alkyl substitution;

[0237] The pyridyl group is C (1-2) Alkyl substitution, the C (1-2) The alkyl group is unsubstituted or substituted with one to three fluorine

[0238] Atomic substitution;

[0239] The 1,2,3-thiadiazolyl group is C (2-3) Alkyl substitution;

[0240] Among them, pyrazolyl, Azolyl, iso Azolyl, triazole and imidazolyl groups are replaced by one or two

[0241] R 4c group substitution;

[0242] Each R 4c Independently -C (0-1) Alkyl C (3-4) Cycloalkyl or -C (1-3) Alkyl, where -C (0-1) Alkyl C (3-4) Cycloalkyl and -C (1-3) The alkyl group is unsubstituted or substituted with one to four R 4d group substitution;

[0243] Each R 4d is independently -OCH3, -OCF3, -OCHF2 or fluorine; and

[0244] R 5 For hydrogen.

[0245] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0246] R 1 -C (3-5) alkyl,

[0247] Where -C (3-5)The alkyl group is unsubstituted or substituted with one to six R 1a group substitution;

[0248] in unsubstituted or substituted with one to four fluorine atoms;

[0249] in is unsubstituted or substituted with one to four fluorine atoms; and

[0250] in Not replaced or replaced by -C (1-2) Alkyl substitution, the -C (1-2) The alkyl group is unsubstituted or

[0251] substituted by one to three fluorine atoms;

[0252] Each R 1a are independently -OH or fluorine;

[0253] R 2 is H, methyl, isopropyl or cyclopropyl;

[0254] R 3 is cyclohexyl or

[0255] R 4 is cyclopropyl, spiropentanyl, spirohexanyl, phenyl, pyrazolyl, Azolyl, iso Azolyl, 1.2.5- oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl or 1,2,5-thiadiazolyl;

[0256] wherein the cyclopropyl group is unsubstituted or substituted by one to three groups selected from the group consisting of fluorine and C (1-2) alkyl;

[0257] wherein the phenyl group is unsubstituted or substituted by one to two groups selected from the group consisting of: chlorine and unsubstituted

[0258] C substituted or substituted by one to three fluorine atoms (1-2) alkyl;

[0259] Wherein 1,2,3-thiadiazolyl is unsubstituted or replaced by C (1-3) Alkyl substituted, where C (1-3) Alkyl

[0260] is substituted or replaced by one to three fluorine atoms;

[0261] Among them, pyrazolyl, Azolyl, iso Azolyl, 1,2,5- The oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, thiazolyl, isothiazolyl or 1,2,5-thiadiazolyl groups are unsubstituted or substituted with one or two R 4c group substitution;

[0262] Each R 4c Independently -C (0-1) Alkyl C (3-4) Cycloalkyl or -C (1-4) Alkyl, where -C (0-1) Alkyl C (3-4) Cycloalkyl and -C (1-4) The alkyl group is unsubstituted or substituted with one to four R 4d group substitution;

[0263] Each R 4d is independently -OCH3, -OCF3, -OCHF2 or fluorine; and

[0264] R 5 is hydrogen or fluorine;

[0265] in

[0266] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0267]

[0268] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0269] R 1 -C (3-5) alkyl,

[0270] Where -C (3-5) The alkyl group is replaced by one to six R 1a group substitution;

[0271] in unsubstituted or substituted with one to two fluorine atoms;

[0272] in is substituted with two fluorine atoms; and

[0273] in Replaced by -CF3;

[0274] Each R 1a are independently -OH or fluorine;

[0275] R 2 is H, methyl, isopropyl or cyclopropyl;

[0276] R3 is cyclohexyl or

[0277] R 4 is cyclopropyl, spiropentanyl, spirohexanyl, phenyl, pyrazolyl, Azolyl, iso Azolyl, oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, 1,2,3-thiadiazolyl or 1,2,5-thiadiazolyl;

[0278] wherein the cyclopropyl group is substituted by one or two groups selected from the group consisting of fluorine and unsubstituted or trisubstituted

[0279] C substituted with fluorine atoms (1) alkyl;

[0280] Wherein the phenyl group is unsubstituted or replaced by -C1 or -C (1-2) Alkyl substitution;

[0281] Among them, 1,2,3-thiadiazolyl and 1,2,5-thiadiazolyl are C (2-3) Alkyl substitution;

[0282] Among them, pyrazolyl, Azolyl, iso Azolyl, Oxazolyl, triazolyl, tetrazolyl and imidazolyl are replaced by one or two R 4c group substitution;

[0283] Each R 4c Independently -C (0-1) Alkyl C (3-4) Cycloalkyl or -C (1-3) Alkyl, where -C (0-1) Alkyl C (3-4) Cycloalkyl and -C (1-3) The alkyl group is unsubstituted or substituted with one to four R 4d group substitution;

[0284] Each R 4d is independently -OCH3, -OCF3, -OCHF2 or fluorine; and

[0285] R 5 is hydrogen;

[0286] in

[0287] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0288]

[0289] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0290] R 1 -C (3-6) Alkyl, -C (0-2) Alkyl C (3-6) a cycloalkyl group, or a 6-membered heterocyclic group having 1 to 2 nitrogen atoms;

[0291] Where -C (1-6) The alkyl group is unsubstituted or substituted with one to six R 1a group substitution;

[0292] Where -C (0-2) Alkyl C (3-6) The cycloalkyl group is unsubstituted or substituted with one to three R 1b group substitution; and

[0293] and

[0294] The 6-membered heterocyclic group is replaced by an R 1c group substitution;

[0295] Each R 1a are independently fluorine or -OH;

[0296] Each R 1b are independently fluorine;

[0297] R 1c -C substituted by one to three fluorine atoms (1-4) alkyl.

[0298] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 for:

[0299]

[0300] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 for:

[0301]

[0302]

[0303] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 for:

[0304]

[0305] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 for In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 for In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 1 for

[0306] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is H, methyl, isopropyl or cyclopropyl.

[0307] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is H. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 It is cyclopropyl.

[0308] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 2 is an unsubstituted cyclopropyl group.

[0309] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ia:

[0310]

[0311] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 3 -C is unsubstituted or substituted with one or two fluorine atoms (0-1) Alkyl C (3-6) In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 3 It is a cyclohexyl group which is unsubstituted or substituted by one to two fluorine atoms.

[0312] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 3 for

[0313] In some embodiments, disclosed herein is a compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ib:

[0314]

[0315] where R 3a is fluorine, and n is 0, 1 or 2.

[0316] In some embodiments, disclosed herein is a compound of Formula I, Ia, or Ib, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ib-1:

[0317]

[0318] where R 3a is fluorine, and n is 2.

[0319] In some embodiments, disclosed herein is a compound of Formula I, Ia, Ib, or Ib-1, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ib-2a:

[0320]

[0321] where R 3a is fluorine, and n is 2.

[0322] In some embodiments, disclosed herein is a compound of Formula I, Ia, Ib, or Ib-1, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ib-2b:

[0323]

[0324] where R 3a is fluorine, and n is 2.

[0325] In some embodiments, disclosed herein is a compound of Formula I, Ia, Ib, Ib-1, or Ib-2a, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ib-3a:

[0326]

[0327] In some embodiments, disclosed herein is a compound of Formula I, Ia, Ib, Ib-1, or Ib-2b, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ib-3b:

[0328]

[0329] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 3 for

[0330] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0331] R 4 is unsubstituted or replaced by one to three R 4a -C substituted with a group (3-6) cycloalkyl; and

[0332] Each R 4a Independently selected from halogen, -OC (1-3) Alkyl and -C (1-4) Alkyl, where -OC (1-3) Alkyl and -C (1-4) The alkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0333] Alternatively, two R attached to the same ring atom 4a Groups can combine with the atoms to which they are attached to form C (3-6) Cycloalkyl.

[0334] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4a The group is fluorine, methyl or -CF3, or two R attached to the same ring atom 4a The groups can combine with the atoms to which they are attached to form a cyclopropyl, cyclobutyl, or cyclopentyl group.

[0335] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is cyclopropyl which is unsubstituted or substituted by one to three groups selected from fluorine, CH3 and CF3.

[0336] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is cyclopropyl which is unsubstituted or substituted by one to two groups selected from fluorine, CH3 and CF3.

[0337] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for

[0338]

[0339] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 It is spiropentanyl or spirohexanyl.

[0340] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0341]

[0342] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0343]

[0344] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0345] R 4 is unsubstituted or replaced by one or two R 4b a phenyl group substituted with a phenyl group; and

[0346] Each R 4b are independently selected from chloro, fluoro, -CN, cyclopropyl, -OCH2-cyclopropyl, -OC (1-2) Alkyl, -C (1-2) Alkyl and pyrrolidin-2-one, including cyclopropyl, -OC (1-2) Alkyl and C (1-2) The alkyl group is unsubstituted or substituted with one to three fluorine atoms.

[0347] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein each R 4b The groups are independently H, fluorine, chlorine, -CN, methyl, ethyl, -CHF2, -CH2CF3, -OCHF2, -OCH2CHF2, -OCH2CF3, cyclopropyl,

[0348]

[0349] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is phenyl which is unsubstituted or substituted by halogen (eg chlorine), -CH3 or -CH2CH3.

[0350] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is phenyl which is unsubstituted or substituted by chlorine, -CH3 or -CH2CH3.

[0351] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0352]

[0353] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0354]

[0355] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0356]

[0357] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0358] R 4 is a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from N, O and S, the heteroaryl group being surrounded by one or two R 4c group substitution;

[0359] Each R 4c are independently halogen, -CN, -C (0-2) Alkyl C (3-6) Cycloalkyl,

[0360] -OC (0-2) Alkyl-C (3-4) Cycloalkyl, -C (1-4) Alkyl, -OC (1-3) alkyl, or a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms selected from N and O, wherein -C (0-2) Alkyl C (3-6) Cycloalkyl, -C (1-4) Alkyl, -OC (1-3) The alkyl and heterocyclic groups are unsubstituted or substituted with one to six R 4d group substitution;

[0361] Alternatively, two R attached to adjacent ring atoms 4c Groups can be combined to form C (4-6) Cycloalkyl;

[0362] Each R 4d are independently fluorine, -CN, oxo, -C (1-3) Alkyl, -OC (1-3) Alkyl, -OC (3-4) Cycloalkyl, -C (0-2) Alkyl-N(R 4d1 )(R 4d2 ), or -C (0-2) Alkyl-N(C (1-4) alkyl)C(O)(C (1-4) alkyl), wherein -C (1-3)Alkyl, -OC (1-3) Alkyl and -OC (3-4) The cycloalkyl group is unsubstituted or substituted with one to three fluorine atoms; and

[0363] R 4d1 and R 4d2 Each independently is H or -C (1-3) Alkyl, where -C (1-3) The alkyl group is unsubstituted or substituted with one to six groups selected from fluorine and chlorine;

[0364] Alternatively, R 4d1 and R 4d2 may combine with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1 to 4 fluorine atoms;

[0365] in

[0366] When R 4 When it is 1,2,4-triazolyl, then R 4 is 1H-1,2,4-triazolyl, and

[0367] When R 4 When it is a 6-membered heteroaryl group, the heteroaryl group is not substituted at the para position.

[0368] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0369] Each R 4c are independently fluorine, -CN, methyl, ethyl, isopropyl, -CD2CD3, -OCH3, -OCH2CH3, -OCH(CH3)2, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CF2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH(CH3)CF3, -CH(CH2F)2, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCHF2, -CH2CH2OCF3, -OCHF2, -OCH2CHF2, -OCH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -O-cyclopropyl, -O-cyclobutyl,

[0370]

[0371] Alternatively, two R attached to adjacent ring atoms 4c Groups can be combined to form groups:

[0372]

[0373] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0374] R 4 is a 5-membered heteroaryl ring having 1 to 4 heteroatoms selected from N, O and S, the heteroaryl ring being surrounded by one or two R 4c Group substitution,

[0375] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0376]

[0377] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0378] R 4 For one or two R 4c substituted pyrrole, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, Azolyl, iso Azolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl or thiadiazolyl,

[0379] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0380]

[0381] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 For one or two R 4c substituted pyrrolyl, pyrazolyl, imidazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, tetrazolyl, furyl, Azolyl, iso Azolyl, 1,2,3- oxadiazole, 1,2,4- oxadiazole, 1,2,5- oxadiazole, 1,3,4- oxadiazolyl, thienyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl or 1,3,4-thiadiazolyl.

[0382] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 For one or two R4c substituted pyrazolyl, imidazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, tetrazolyl, Azolyl, iso Azolyl, 1,2,5- oxazolyl, thienyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl or 1,2,5-thiadiazolyl.

[0383] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0384] R 4 For one or two R 4c Group substituted Azolyl, iso Azolyl or oxadiazole,

[0385] Each R 4c Independently C (3-5) Cycloalkyl, -C (1-3) Alkyl or

[0386]

[0387] Among them C (3-5) Cycloalkyl and -C (1-3) The alkyl group is unsubstituted or substituted with -OCH3 or one to three fluorine atoms.

[0388] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0389] R 4 For one or two R 4c Group substituted Azolyl, iso oxazolyl or thiadiazolyl (e.g., 1,2,3-thiadiazolyl),

[0390] Each R 4c are independently cyclopropyl or -C (1-3) Alkyl, among which cyclopropyl and -C (1-3) The alkyl group is unsubstituted or substituted with one to three fluorine atoms.

[0391] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for

[0392] are each independently one or both of the following R 4c Group-substituted iso Azolyl: methyl, ethyl, isopropyl, -CF3, -CH2CH2F, -CH2CH2CF3, -CH2-OCH3, cyclopropyl, cyclopentyl or

[0393]

[0394] Substituted with an isopropyl group azole, or

[0395] Substituted with a methyl or ethyl group Oxazolyl.

[0396] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 For being a -C (1-3) Alkyl substituted Oxazolyl.

[0397] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0398]

[0399]

[0400] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ic:

[0401]

[0402] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ic-1:

[0403]

[0404] where R 3a is fluorine, and n is 2.

[0405] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0406]

[0407]

[0408] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0409]

[0410] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0411] R 4 is unsubstituted or replaced by one or two R 4c a pyrazolyl or imidazolyl group substituted with a group,

[0412] Each R 4c is independently fluorine, or -C (1-3) Alkyl: -CHF2, -CF3, -OCHF2, -OCF3 and fluorine.

[0413] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is unsubstituted or replaced by one or two R 4c a pyrazolyl or imidazolyl group substituted with a group, wherein each R 4c is independently unsubstituted or substituted by one to three groups selected from the following -C (1-3) Alkyl: -CHF2, -CF3, -OCHF2, -OCF3 and fluorine.

[0414] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 For one or two R 4c a pyrazolyl or imidazolyl group substituted with a group, wherein each R 4c is independently unsubstituted or substituted by one to three groups selected from the following -C (1-3) Alkyl: -CHF2, -CF3, -OCHF2, -OCF3 and fluorine.

[0415] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for

[0416] One or two R groups are each independently methyl, ethyl, isopropyl, -CD2CD3, fluorine, -CHF2, -CF3, -CH2CHF2, -CH2CF3, -CH(CH3)CF3, -CH(CH2F)2, -CH2CH2OCHF2 or -CH2CH2OCF3. 4c substituted pyrazolyl, or

[0417] Imidazolyl substituted by an isopropyl group.

[0418] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 For being a -C(1-3) Alkyl-substituted pyrazolyl.

[0419] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0420]

[0421] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0422]

[0423]

[0424] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0425]

[0426] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for

[0427] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for

[0428] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for

[0429] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0430] R 4 is unsubstituted or replaced by one or two R 4c a triazole group substituted with a group;

[0431] Each R 4c Independently -C (0-1) Alkyl C (3-4) Cycloalkyl, -C (1-3) alkyl,

[0432]

[0433] Where -C (0-1) Alkyl C (3-4) Cycloalkyl and -C(1-3) The alkyl group is unsubstituted or substituted with one to four R 4d group substitution; and

[0434] Each R 4d are independently -OCH3, -OCF3, -OCHF2, fluorine,

[0435]

[0436] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0437]

[0438] Alternatively, when R 4 When it is 1,2,4-triazolyl, then R 4 It is 1H-1,2,4-triazolyl.

[0439] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein

[0440] R 4 is unsubstituted or replaced by one or two R 4c A triazole group substituted with a group wherein:

[0441] Each R 4c Independently -C (0-1) Alkyl C (3-4) Cycloalkyl or -C (1-3) Alkyl, where -C (0-1) Alkyl C (3-4) Cycloalkyl and -C (1-3) The alkyl group is unsubstituted or substituted with one to four R 4d group substitution; and

[0442] Each R 4d is independently -OCH3, -OCF3 or -OCHF2 or fluorine.

[0443] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0444] R 4 is unsubstituted or replaced by one or two R 4c a triazole group substituted with a group; and

[0445] Each R 4care independently methyl, ethyl, isopropyl, -CH2CH2OCH3, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2OCHF2, -CH2CH2OCF3, cyclopropyl, -CH2-cyclopropyl,

[0446]

[0447] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0448]

[0449] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0450]

[0451]

[0452] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0453]

[0454]

[0455] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 For the -C (1-4) Alkyl-substituted tetrazolyl.

[0456] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is a tetrazolyl group substituted by a methyl group or an isopropyl group.

[0457] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0458]

[0459] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 For each of them (1-3) Alkyl or -C (3-6)Cycloalkyl-substituted thienyl, thiazolyl, isothiazolyl or thiadiazolyl.

[0460] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 is thienyl, thiazolyl, isothiazolyl or thiadiazolyl, each of which is substituted by methyl, isopropyl or cyclopropyl.

[0461] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for

[0462] thienyl substituted by isopropyl,

[0463] isothiazolyl substituted by methyl,

[0464] thiazolyl substituted by isopropyl, or

[0465] Thiadiazolyl substituted by methyl, isopropyl or cyclopropyl.

[0466] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0467]

[0468] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0469] R 4 is a 6-membered heteroaryl group having 1 to 2 heteroatoms selected from N, the heteroaryl group being separated by one or two R 4c group substitution; and

[0470] Each R 4c The groups are independently fluorine, -CN, pyrrolidin-2-one, C (3-4) Cycloalkyl, -OC (3-4) Cycloalkyl, -OC (1-3) Alkyl or C (1-3) Alkyl, where -OC (1-3) Alkyl and C (1-3) The alkyl group is unsubstituted or substituted by -OCH3 or one to three fluorine atoms,

[0471] Alternatively, two R attached to adjacent ring atoms 4c Groups can be combined to form C (4-6) Cycloalkyl;

[0472] wherein the heteroaryl group is unsubstituted at the para position.

[0473] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein when R 4 When it is a substituted 6-membered heteroaryl, R 4 for

[0474]

[0475] and

[0476] Each R 4c The groups are independently fluorine, -CN, pyrrolidone, C (3-4) Cycloalkyl, -OC (3-4) Cycloalkyl, -OC (1-3) Alkyl or C (1-3) Alkyl, where -OC (1-3) Alkyl and C (1-3) The alkyl group is unsubstituted or substituted by -OCH3 or one to three fluorine atoms,

[0477] Alternatively, two R attached to adjacent ring atoms 4c Groups can be combined to form C (4-6) Cycloalkyl.

[0478] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0479] R 4 For one or two R 4c a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl substituted with a group; and

[0480] Each R 4c The groups are independently fluorine, -CN, pyrrolidin-2-one, C (3-4) Cycloalkyl, -OC (3-4) Cycloalkyl, -OC (1-3) Alkyl or C (1-3) Alkyl, where -OC (1-3) Alkyl and C (1-3) The alkyl group is unsubstituted or substituted with -OCH3 or one to three fluorine atoms;

[0481] Alternatively, two R attached to adjacent ring atoms 4c Groups can be combined to form C (4-6) Cycloalkyl;

[0482] wherein the heteroaryl group is unsubstituted at the para position.

[0483] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0484] R 4is unsubstituted or replaced by 1 to 2 R 4c a pyridyl group substituted with a group; and

[0485] Each R 4c The groups are independently fluorine, -CN, pyrrolidin-2-one, C (3-4) Cycloalkyl, -OC (3-4) Cycloalkyl, -OC (1-3) Alkyl or C (1-3) Alkyl, where -OC (1-3) Alkyl and C (1-3) The alkyl group is unsubstituted or substituted with -OCH3 or one to three fluorine atoms;

[0486] Alternatively, two R attached to adjacent ring atoms 4c Groups can be combined to form C (4-6) Cycloalkyl;

[0487] The pyridyl group is not substituted at the para position.

[0488] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 Not replaced or replaced by C (1-2) Alkyl substituted pyridyl, the C (1-2) The alkyl group is unsubstituted or substituted with one to three fluorine atoms, wherein the pyridyl group is unsubstituted at the para position. In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 Not replaced or replaced by C (1-2) Alkyl substituted pyridyl, the C (1-2) The alkyl group is unsubstituted or substituted with one to three fluorine atoms.

[0489] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0490] R 4 is unsubstituted or replaced by 1 to 2 R 4c a pyridyl group substituted with a group; and

[0491] Each R 4c The groups are independently fluoro, -CN, pyrrolidone, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -OMe, -OEt, -O-isopropyl, -OCHF2, -OCH2CHF2, -OCH2CF3, methyl, ethyl, isopropyl, -CH2-OCH3, -CHF2, -CF3, -C(CH3)F2, -CH2CHF2, -CH2CF3 or -CH2CH2CHF2;

[0492] Alternatively, two R attached to adjacent ring atoms 4cThe groups may combine to form a cyclopentyl group,

[0493] The pyridyl group is not substituted at the para position.

[0494] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein when R 4 When it is a substituted 6-membered heteroaryl, R 4 for:

[0495]

[0496] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0497]

[0498]

[0499] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0500] R 4 is pyridazinyl, pyrimidinyl or pyrazinyl, each of which is unsubstituted or substituted by one or two R 4c group substitution;

[0501] Each R 4c Independently selected from -C (3-4) Cycloalkyl, -OC (1-3) Alkyl and -C (1-4) Alkyl, where -C (1-4) The alkyl group is unsubstituted or substituted with one to three fluorine atoms,

[0502] The pyridazinyl, pyrimidinyl and pyrazinyl groups are not substituted at the para position.

[0503] In some embodiments, disclosed herein are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein:

[0504] R 4 is pyridazinyl, pyrimidinyl or pyrazinyl, each of which is unsubstituted or substituted by one or two R 4c group substitution; and

[0505] Each R 4c independently selected from methyl, isopropyl, -OMe, cyclopropyl, -CHF2 and -CF3,

[0506] The pyridazinyl, pyrimidinyl and pyrazinyl groups are not substituted at the para position.

[0507] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein when R 4 When it is a substituted 6-membered heteroaryl, R 4 for:

[0508]

[0509] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0510] pyridazinyl which is unsubstituted or substituted by -OCH3 or -CH3,

[0511] pyrimidinyl which is unsubstituted or substituted by methyl, isopropyl, -OCH3 or cyclopropyl, wherein the methyl group is unsubstituted or substituted by one to three fluorine atoms, or

[0512] pyrazinyl which is unsubstituted or substituted by -OCH3, -CH3 or -CF3,

[0513] The pyridazinyl, pyrimidinyl and pyrazinyl groups are not substituted at the para position.

[0514] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0515]

[0516] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0517]

[0518] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein: R 5 is hydrogen or halogen.

[0519] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein: R 5 is hydrogen or fluorine.

[0520] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein: R 5 For hydrogen.

[0521] In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein: R 5 In some embodiments, disclosed herein are compounds of Formula I or pharmaceutically acceptable salts thereof, wherein: R5 For fluorine.

[0522] Table 1A

[0523]

[0524]

[0525]

[0526] Table 1B

[0527]

[0528]

[0529]

[0530] Table 1C

[0531]

[0532]

[0533]

[0534]

[0535] Table 1D

[0536]

[0537]

[0538]

[0539] Table 1E

[0540]

[0541]

[0542]

[0543] Table 1F

[0544]

[0545]

[0546]

[0547] Table 1G

[0548]

[0549]

[0550]

[0551] Table 1H

[0552]

[0553]

[0554]

[0555] Table II

[0556]

[0557]

[0558]

[0559] Table 1J

[0560]

[0561] In some embodiments, disclosed herein is a compound of Formula I, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, Table 1H, Table II, and Table 1J.

[0562] In some embodiments, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof selected from the group consisting of:

[0563]

[0564] In some embodiments, disclosed herein are compounds of Formula I, which are or a pharmaceutically acceptable salt thereof.

[0565] In some embodiments, disclosed herein are compounds of Formula I, which are or a pharmaceutically acceptable salt thereof.

[0566] In some embodiments, disclosed herein are compounds of Formula I, which are or a pharmaceutically acceptable salt thereof.

[0567] In some embodiments, disclosed herein are compounds of Formula I, which are or a pharmaceutically acceptable salt thereof.

[0568] In some embodiments, disclosed herein are compounds of Formula I, which are or a pharmaceutically acceptable salt thereof.

[0569] In some embodiments, disclosed herein are compounds of Formula I, which are or a pharmaceutically acceptable salt thereof.

[0570] In some embodiments, disclosed herein are compounds of Formula I, which are or a pharmaceutically acceptable salt thereof.

[0571] In some embodiments, disclosed herein are compounds of Formula I, which are or a pharmaceutically acceptable salt thereof.

[0572] In some embodiments, disclosed herein are compounds of Formula I, which are or a pharmaceutically acceptable salt thereof.

[0573] In some embodiments, disclosed herein are compounds of Formula I, which are or a pharmaceutically acceptable salt thereof.

[0574] In some embodiments, disclosed herein are compounds of Formula I, which are or a pharmaceutically acceptable salt thereof.

[0575] In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration (e.g., tablets or capsules).

[0576] In some embodiments, disclosed herein is a pharmaceutical composition prepared by mixing a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0577] In some embodiments, disclosed herein is a method for preparing a pharmaceutical composition comprising mixing a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0578] The present application also discloses compounds of Formula I'. All compounds of Formula I are compounds of Formula I'. Some compounds of Formula I' are compounds of Formula I.

[0579] Therefore, disclosed herein is a compound of formula I':

[0580]

[0581] or a pharmaceutically acceptable salt thereof, wherein:

[0582] R 1 -C (1-6) Alkyl, -C (0-2) Alkyl C (3-6) Cycloalkyl, -C (0-2) Alkyl-cyclopropyl-C (1-3) a perfluoroalkyl group, or a 5- to 6-membered heterocyclic group having 1 to 2 nitrogen atoms;

[0583] Where -C (1-6) The alkyl group is unsubstituted or substituted with one to six R 1a group substitution;

[0584] Where -C (0-2) Alkyl C (3-6) The cycloalkyl group is unsubstituted or substituted with one to six R 1b group substitution; and

[0585] The 5-membered to 6-membered heterocyclic group is unsubstituted or replaced by one to three R 1c group substitution;

[0586] R 2 H, -C (3-5) Cycloalkyl, -C (1-4) alkyl, or a 6-membered heterocyclic ring having 1 to 2 oxygen atoms; wherein -C (1-4) The alkyl group is unsubstituted or substituted with one to six R 2a and wherein -C (3-5) Cycloalkyl is unsubstituted or substituted with -CN;

[0587] R 1a 、R 1b and R 2a are each independently fluorine, -C (3-5) Cycloalkyl, -CN, -OH, -OC (1-3) Alkyl or -OC (3-4) Cycloalkyl, where -OC (1-3)Alkyl and -OC (3-4) The cycloalkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0588] Each R 1c is independently -OCH3, -OCF3, -OCHF2, or -C (1-4) alkyl;

[0589] R 3 -C (0-1) Alkyl C (3-6) Cycloalkyl, -C (3-6) Alkyl or -C (1-2) Alkyl-OC (1-3) Alkyl, where -C (0-1) Alkyl C (3-6) Cycloalkyl, -C (3-6) Alkyl and -C (1-2) Alkyl-OC (1-3) The alkyl group is unsubstituted or is independently selected from one to five R 3a Group substitution: fluorine, -CH3-CHF2, -CF3, OH and =O;

[0590] R 4 -C (3-6) cycloalkyl, phenyl, or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from N, O, and S;

[0591] Among them C (3-6) The cycloalkyl group is unsubstituted or is independently selected from one to three R 4a Group substitution: halogen, -OC (1-3) Alkyl and -C (1-4) Alkyl, where -OC (1-3) Alkyl and -C (1-4) The alkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0592] Alternatively, two R attached to the same ring atom 4a Groups can combine with the atoms to which they are attached to form C (3-6) Cycloalkyl;

[0593] wherein the phenyl group is unsubstituted or is substituted by one to three R 4b Group substitution: halogen, -CN, -C (0-2) Alkyl-C (3-4) Cycloalkyl, -OC (0-2) Alkyl-C (3-4) Cycloalkyl, -OC (1-3) Alkyl, -C (1-4) Alkyl and 3- to 6-membered heterocyclic groups having 1 to 2 heteroatoms selected from N and O, wherein -OC(1-3) Alkyl, -C (0-2) Alkyl-C (3-4) Cycloalkyl and -C (1-4) The alkyl group is unsubstituted or substituted with one to three fluorine atoms, and the heterocyclyl group is unsubstituted or substituted with one oxo group;

[0594] wherein the 5- to 6-membered heteroaryl group is unsubstituted or replaced by one or two R 4c group substitution;

[0595] Each R 4c are independently halogen, -CN, -OH, -N(R 4c1 )(R 4c2 ),-C (0-2 )alkyl C (3-6) Cycloalkyl, -OC (0-2) Alkyl-C (3- 4 ) Cycloalkyl, -C (1-4) Alkyl, -OC (1-3) alkyl, or a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms selected from N and O, wherein -C (0-2) Alkyl C (3-6) Cycloalkyl, -C (1-4) Alkyl, -OC (1-3) The alkyl and heterocyclic groups are unsubstituted or substituted with one to six R 4d group substitution;

[0596] Alternatively, two R attached to adjacent ring atoms 4c Groups can be combined to form C (4-6) Cycloalkyl;

[0597] Each R 4d are independently fluorine, -CN, -OH, oxo, -C (1-3) Alkyl, -OC (1-3) Alkyl, -OC (3-4) Cycloalkyl, -C (0-2) Alkyl-N(R 4d1 )(R 4d2 ),-C (0-2) Alkyl-N(C (1-4) alkyl)C(O)(C (1-4) alkyl), or a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms selected from N and O, wherein -C (1-3) Alkyl, -OC (1-3) Alkyl, -OC (3-4 ) Cycloalkyl and heterocyclyl are unsubstituted or substituted with one to three fluorine atoms;

[0598] R 4c1 、R 4c2 、R 4d1and R 4d2 Each independently is H or -C (1-3) Alkyl, where -C (1-3) The alkyl group is unsubstituted or substituted with one to six groups selected from fluorine and chlorine;

[0599] Alternatively, R 4d1 and R 4d2 can combine with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1 to 4 fluorine atoms; and

[0600] R 5 is hydrogen or halogen;

[0601] in:

[0602] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0603] and

[0604] When R 4 When it is a substituted 6-membered heteroaryl, the substituted heteroaryl is not substituted at the para position.

[0605] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0606] R 1 -C (1-6) Alkyl, -C (0-2) Alkyl C (3-6) Cycloalkyl, -C (0-2) Alkyl-cyclopropyl-C (1-3) perfluoroalkyl, pyrrolidinyl or piperidinyl;

[0607] Where -C (1-6) The alkyl group is unsubstituted or substituted with one to six R 1a group substitution;

[0608] Where -C (0-2) Alkyl C (3-6) The cycloalkyl group is unsubstituted or substituted with one to six R 1b group substitution; and

[0609] Wherein the piperidinyl and pyrrolidinyl groups are unsubstituted or replaced by one to three R 1c group substitution;

[0610] R 1a and R 1b Each is independently -OH, -OCH3, -OCF3, -OCHF2 or fluorine;

[0611] Each R 1c is independently unsubstituted or substituted with one to three fluorine atoms -C (1-2) alkyl;

[0612] R 2 H, -C (3-5) Cycloalkyl, -C (1-4) alkyl or a 6-membered heterocyclic ring having 1 to 2 oxygen atoms; wherein -C (3-5) Cycloalkyl is unsubstituted or substituted with -CN;

[0613] R 3 -C is unsubstituted or substituted with one or two fluorine atoms (5-6) Cycloalkyl;

[0614] R 4 -C (3-4) cycloalkyl, phenyl, or a 5-membered heteroaryl group having 1 to 4 heteroatoms selected from N, O, and S;

[0615] Among them C (3-6) The cycloalkyl group is unsubstituted or is independently selected from one to three R 4a Group substitution: halogen and C unsubstituted or substituted with one to three fluorine atoms (1-4) alkyl;

[0616] Alternatively, two R attached to the same ring atom 4a Groups can combine with the atoms to which they are attached to form C (3-6) Cycloalkyl;

[0617] wherein the phenyl group is unsubstituted or is substituted by one or two R 4b Group substitution: halogen, -CN, -C (0-2) Alkyl-C (3-4) Cycloalkyl, -OC (0-2) Alkyl-C (3-4) Cycloalkyl, -OC (1-3) Alkyl, C (1-4) Alkyl and 3- to 6-membered heterocyclic groups having 1 to 2 heteroatoms selected from N and O, wherein -OC (1-3) Alkyl, -C (0-2) Alkyl-C (3-4) Cycloalkyl and -C (1-4) The alkyl group is unsubstituted or substituted with one to three fluorine atoms, and the heterocyclyl group is unsubstituted or substituted with one oxo group;

[0618] The 5-membered heteroaryl group is unsubstituted or replaced by one or two R 4c group substitution;

[0619] Each R 4care independently halogen, -CN, -C (0-2) Alkyl C (3-6) Cycloalkyl, -OC (0-2) Alkyl-C (3-4) Cycloalkyl, -C (1-4) Alkyl, -OC (1-3) alkyl, or a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms selected from N and O, wherein -C (0-2) Alkyl C (3-6) Cycloalkyl, -C (1-4) Alkyl, -OC (1-3) The alkyl and heterocyclic groups are unsubstituted or substituted with one to six R 4d group substitution;

[0620] Each R 4d are independently fluorine, -CN, oxo, -C (1-3) Alkyl, -OC (1-3) Alkyl, -OC (3-4) Cycloalkyl, -C (0-2) Alkyl-N(R 4d1 )(R 4d2 ), or -C (0-2) Alkyl-N(C (1-4) alkyl)C(O)(C (1-4) alkyl), wherein -C (1-3) Alkyl, -OC (1-3) Alkyl and -OC (3-4) The cycloalkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0621] R 4d1 and R 4d2 Each independently is H or -C (1-3) Alkyl, where -C (1-3) The alkyl group is unsubstituted or substituted with one to six groups selected from fluorine and chlorine;

[0622] Alternatively, R 4d1 and R 4d2 can combine with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1 to 4 fluorine atoms; and

[0623] R 5 is hydrogen or fluorine;

[0624] in

[0625] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0626]

[0627] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0628] R 1 -C (1-6) Alkyl, -C (0-2) Alkyl C (3-6) Cycloalkyl, -C (0-2) Alkyl-cyclopropyl-C (1-3) perfluoroalkyl, pyrrolidinyl or piperidinyl;

[0629] Where -C (1-6) The alkyl group is unsubstituted or substituted with one to six R 1a group substitution;

[0630] Where -C (0-2) Alkyl C (3-6) The cycloalkyl group is unsubstituted or substituted with one to six R 1b group substitution; and

[0631] wherein pyrrolidinyl and piperidinyl are unsubstituted or replaced by one to three R 1c group substitution;

[0632] R 1a and R 1b Each is independently -OH, -OCH3, -OCF3, -OCHF2 or fluorine;

[0633] Each R 1c is independently unsubstituted or substituted with one to three fluorine atoms -C (1-2) alkyl;

[0634] R 2 H, -C (3-5) Cycloalkyl or -C (1-4) Alkyl; wherein -C (3-5) Cycloalkyl is unsubstituted or substituted with -CN;

[0635] R 3 -C is unsubstituted or substituted with one or two fluorine atoms (5-6) Cycloalkyl;

[0636] R 4 -C (3-4) cycloalkyl, phenyl, or a 5-membered heteroaryl group having 1 to 4 heteroatoms selected from N, O, and S;

[0637] Among them C (3-6) The cycloalkyl group is unsubstituted or is independently selected from one to three R 4a Group substitution: halogen and C unsubstituted or substituted with one to three fluorine atoms (1-4) alkyl;

[0638] Alternatively, two R attached to the same ring atom 4a Groups can combine with the atoms to which they are attached to form C (3-6) Cycloalkyl;

[0639] wherein the phenyl group is unsubstituted or is substituted by one or two R 4b Group substitution: halogen, -CN, -C (0-2) Alkyl-C (3-4) Cycloalkyl, -OC (0-2) Alkyl-C (3-4) Cycloalkyl, -OC (1-3) Alkyl, C (1-4) Alkyl and 3- to 6-membered heterocyclic groups having 1 to 2 heteroatoms selected from N and O, wherein -OC (1-3) Alkyl, -C (0-2) Alkyl-C (3-4) Cycloalkyl and -C (1-4) The alkyl group is unsubstituted or substituted with one to three fluorine atoms, and the heterocyclyl group is unsubstituted or substituted with one oxo group;

[0640] The 5-membered heteroaryl group is unsubstituted or replaced by one or two R 4c group substitution;

[0641] Each R 4c are independently halogen, -CN, -C (0-2) Alkyl C (3-6) Cycloalkyl, -OC (0-2) Alkyl-C (3-4) Cycloalkyl, -C (1-4) Alkyl, -OC (1-3) alkyl, or a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms selected from N and O, wherein -C (0-2) Alkyl C (3-6) Cycloalkyl, -C (1-4) Alkyl, -OC (1-3) The alkyl and heterocyclic groups are unsubstituted or substituted with one to six R 4d group substitution;

[0642] Each R 4d are independently fluorine, -CN, oxo, -C (1-3) Alkyl, -OC (1-3) Alkyl, -OC (3-4) Cycloalkyl, -C (0-2) Alkyl-N(R 4d1 )(R 4d2 ), or -C (0-2) Alkyl-N(C (1-4) alkyl)C(O)(C (1-4) alkyl), wherein -C (1-3)Alkyl, -OC (1-3) Alkyl and -OC (3-4) The cycloalkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0643] R 4d1 and R 4d2 Each independently is H or -C (1-3) Alkyl, where -C (1-3) The alkyl group is unsubstituted or substituted with one to six groups selected from fluorine and chlorine;

[0644] Alternatively, R 4d1 and R 4d2 can combine with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1 to 4 fluorine atoms; and

[0645] R 5 is hydrogen or fluorine;

[0646] in

[0647] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0648]

[0649] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0650] R 1 -C (1-6) Alkyl, -C (1-2) Alkyl C (3-6) Cycloalkyl, -C (0-2) Alkyl-cyclopropyl-CF3, pyrrolidinyl or piperidinyl:

[0651] Where -C (1-6) The alkyl group is unsubstituted or substituted with one to six R 1a group substitution;

[0652] Where -C (1-2) Alkyl C (3-6) The cycloalkyl group is unsubstituted or substituted with one to four fluorine atoms; and

[0653] Wherein pyrrolidinyl and piperidinyl are unsubstituted or replaced by -C (1-2) Alkyl substitution, the -C (1-2) The alkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0654] Each R 1a are independently -OH, -OCH3, -OCF3, -OCHF2 or fluorine;

[0655] R 2 H, -C (3-5) Cycloalkyl or -C (1-3) Alkyl; wherein -C (3-5) Cycloalkyl is unsubstituted or substituted with -CN;

[0656] R 3 is a cyclohexyl group which is unsubstituted or substituted with one to two fluorine atoms;

[0657] R 4 -C (3-4) Cycloalkyl, spiropentanyl, spirohexanyl, spiroheptanyl, spirooctanyl, phenyl, pyrrolyl, pyrazolyl, Azolyl, Oxazolyl, iso oxazolyl, triazolyl, tetrazolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl or thiadiazolyl; wherein -C (3-4) The cycloalkyl group is unsubstituted or substituted by one to three groups selected from the group consisting of halogen and C (1-2) alkyl;

[0658] Wherein phenyl is unsubstituted or substituted by one or two groups selected from the following: halogen, -CN, -C (0-2) Alkyl-C (3-4) Cycloalkyl, -OC (0-2) Alkyl-C (3-4) Cycloalkyl, -OC (1-3) Alkyl, C (1-4) Alkyl and 3- to 6-membered heterocyclic groups having 1 to 2 heteroatoms selected from N and O, wherein -OC (1-3) Alkyl, -C (0-2) Alkyl-C (3-4) Cycloalkyl and -C (1-4) The alkyl group is unsubstituted or substituted with one to three fluorine atoms, and the heterocyclyl group is unsubstituted or substituted with one oxo group;

[0659] Among them, pyrazolyl, Azolyl, Oxazolyl, iso Azolyl, triazolyl, tetrazolyl, imidazolyl, thiazolyl, isothiazolyl and thiadiazolyl are replaced by one or two R 4c group substitution;

[0660] Each R 4c are independently halogen, -CN, -C (0-2) Alkyl C (3-6) Cycloalkyl, -OC (0-2) Alkyl-C (3-4) Cycloalkyl, -C (1-4) Alkyl, -OC(1-3) alkyl, or a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms selected from N and O, wherein -C (0-2) Alkyl C (3-6) Cycloalkyl, -C (1-4) Alkyl, -OC (1-3) Alkyl and heterocyclic groups are unsubstituted or substituted with one to four R 4d group substitution;

[0661] Each R 4d is independently -OCH3, -OCF3, -OCHF2 or fluorine; and

[0662] R 5 is hydrogen or fluorine;

[0663] in

[0664] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0665]

[0666] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0667] R 1 -C (3-5) alkyl,

[0668] Where -C (3-5) The alkyl group is unsubstituted or substituted with one to six R 1a group substitution;

[0669] in unsubstituted or substituted with one to four fluorine atoms;

[0670] in unsubstituted or substituted with one to four fluorine atoms;

[0671] in is unsubstituted or substituted with one to four fluorine atoms; and

[0672] in Not replaced or replaced by -C (1-2) Alkyl substitution, the -C (1-2) The alkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0673] Each R 1a are independently -OH or fluorine;

[0674] R 2is H, methyl, isopropyl, cyclopropyl or cyclobutyl; wherein cyclopropyl and cyclobutyl are unsubstituted or substituted by -CN;

[0675] R 3 is cyclohexyl or

[0676] R 4 is cyclopropyl, spiropentanyl, spirohexanyl, phenyl, pyrazolyl, Azolyl, iso Azolyl, 1,2,5- oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl or 1,2,5-thiadiazolyl;

[0677] wherein the cyclopropyl group is unsubstituted or substituted by one to three groups selected from the group consisting of fluorine and C (1-2) alkyl;

[0678] wherein the phenyl group is unsubstituted or substituted by one to two groups selected from the group consisting of chlorine and C (1-2) alkyl;

[0679] Wherein 1,2,3-thiadiazolyl is unsubstituted or replaced by C (1-3) Alkyl substituted, where C (1-3) The alkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0680] Among them, pyrazolyl, Azolyl, iso Azolyl, 1,2,5- The oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, thiazolyl, isothiazolyl or 1,2,5-thiadiazolyl groups are unsubstituted or substituted with one or two R 4c group substitution;

[0681] Each R 4c Independently -C (0-1) Alkyl C (3-4) Cycloalkyl or -C (1-4) Alkyl, where -C (0-1) Alkyl C (3-4) Cycloalkyl and -C (1-4) The alkyl group is unsubstituted or substituted with one to four R 4d group substitution;

[0682] Each R 4d is independently -OCH3, -OCF3, -OCHF2 or fluorine; and

[0683] R 5 is hydrogen or fluorine;

[0684] in

[0685] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0686]

[0687] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0688] R 1 -C (3-5) alkyl,

[0689] Where -C (3-5) The alkyl group is replaced by one to six R 1a group substitution;

[0690] in unsubstituted or substituted with one to two fluorine atoms;

[0691] in unsubstituted or substituted with one to four fluorine atoms;

[0692] in is substituted with two fluorine atoms; and

[0693] in Replaced by -CF3;

[0694] Each R 1a are independently -OH or fluorine;

[0695] R 2 is H, methyl, isopropyl, cyclopropyl or cyclobutyl; wherein cyclopropyl and cyclobutyl are unsubstituted or substituted by -CN;

[0696] R 3 is cyclohexyl or

[0697] R 4 is cyclopropyl, spiropentanyl, spirohexanyl, phenyl, pyrazolyl, Azolyl, iso Azolyl, 1,2,5- oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, 1,2,3-thiadiazolyl or 1,2,5-thiadiazolyl;

[0698] wherein the cyclopropyl group is substituted by one or two groups selected from the group consisting of fluorine and C (1) alkyl;

[0699] Wherein the phenyl group is unsubstituted or replaced by -Cl or -C (1-2)Alkyl substitution;

[0700] Among them, 1,2,3-thiadiazolyl and 1,2,5-thiadiazolyl are C (2-3) Alkyl substitution;

[0701] Among them, pyrazolyl, Azolyl, iso Azolyl, 1,2,5- Oxazolyl, triazolyl, tetrazolyl and imidazolyl are replaced by one or two R 4c group substitution;

[0702] Each R 4c Independently -C (0-1) Alkyl C (3-4) Cycloalkyl or -C (1-3) Alkyl, where -C (0-1) Alkyl C (3-4) Cycloalkyl and -C (1-3) The alkyl group is unsubstituted or substituted with one to four R 4d group substitution;

[0703] Each R 4d is independently -OCH3, -OCF3, -OCHF2 or fluorine; and

[0704] R 5 is hydrogen;

[0705] in

[0706] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0707]

[0708] All embodiments described above with respect to compounds of Formula I are incorporated herein by reference with respect to compounds of Formula I'. 1 、R 2 、R 3 、R 4 and / or R 5 Any definition of applies to both Formula I and Formula I'. Certain embodiments of compounds of Formula I' are also provided below.

[0709] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0710] R 1 -C (1-6) Alkyl, -C (0-2) Alkyl C (3-6) Cycloalkyl, -C (0-2) Alkyl-cyclopropyl-C(1-3) perfluoroalkyl, pyrrolidinyl or piperidinyl;

[0711] Where -C (1-6) The alkyl group is unsubstituted or substituted with one to six R 1a group substitution;

[0712] Where -C (0-2) Alkyl C (3-6) The cycloalkyl group is unsubstituted or substituted with one to six R 1b group substitution; and

[0713] wherein pyrrolidinyl and piperidinyl are unsubstituted or replaced by one to three R 1c Group substitution.

[0714] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0715] R 1 -C (1-6) Alkyl, -C (0-2) Alkyl C (3-6) Cycloalkyl, -CH2-cyclopropyl-C (1-3) perfluoroalkyl, pyrrolidinyl or piperidinyl;

[0716] Where -C (1-6) The alkyl group is unsubstituted or substituted with one to six R 1a group substitution;

[0717] Where -C (0-2) Alkyl C (3-6) The cycloalkyl group is unsubstituted or substituted with one to six R 1b group substitution; and

[0718] wherein pyrrolidinyl and piperidinyl are unsubstituted or replaced by one to three R 1c Group substitution.

[0719] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0720] R 1 -C (3-6) Alkyl, -C (0-2) Alkyl C (3-6) Cycloalkyl, -C (0-2) Alkyl-cyclopropyl-C (1-3) perfluoroalkyl, pyrrolidinyl or piperidinyl;

[0721] Where -C (1-6) The alkyl group is unsubstituted or substituted with one to six R 1a group substitution;

[0722] Where -C (0-2)Alkyl C (3-6) The cycloalkyl group is unsubstituted or substituted by one to four R 1b group substitution; and

[0723] Wherein the pyrrolidinyl and piperidinyl groups are replaced by an R 1c group substitution;

[0724] Each R 1a are independently fluorine, -CN, -OH, -OC (1-3) Alkyl or -OC (3-4) Cycloalkyl, where -OC (1-3) Alkyl and -OC (3-4) The cycloalkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0725] Each R 1b are independently fluorine;

[0726] R 1c -C substituted by one to three fluorine atoms (1-4) alkyl.

[0727] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0728] R 1 -C (3-6) Alkyl, -C (1-2) Alkyl C (3-6) Cycloalkyl, or -C (1-2) Alkyl-cyclopropyl-CF3;

[0729] Where -C (1-6) The alkyl group is unsubstituted or substituted with one to six R 1a group substitution;

[0730] Where -C (1-2) Alkyl C (3-6) The cycloalkyl group is unsubstituted or substituted by one or two R 1b group substitution;

[0731] Each R 1a are independently fluorine;

[0732] Each R 1b are independently fluorine.

[0733] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 1 is unsubstituted or replaced by one to three R 1b -C substituted with a group (0-2) Alkyl C (3-6) Cycloalkyl, wherein each R 1bIn some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 1 is unsubstituted or replaced by one to three R 1b -CH2C substituted with a group (3-6) Cycloalkyl, wherein each R 1b are independently fluorine.

[0734] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 1 for:

[0735]

[0736]

[0737] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 1 for:

[0738]

[0739] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 1 for:

[0740]

[0741] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 1 for:

[0742]

[0743] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 1 for:

[0744]

[0745] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 1 for:

[0746]

[0747] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 1 for:

[0748]

[0749] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 1 for:

[0750]

[0751] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 2 is H, cyclopropyl, cyclobutyl, -C (1-3) Alkyl or tetrahydropyran,

[0752] wherein cyclopropyl and cyclobutyl are unsubstituted or substituted with -CN;

[0753] Where -C (1-3) The alkyl group is replaced by one to three R 2a group substitution; and

[0754] Each R 2a are independently fluorine, -C (3-4) Cycloalkyl, -CN, -OH or -OC (1-3) alkyl.

[0755] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 2 is H, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, tetrahydropyranyl,

[0756]

[0757] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 2 is H, methyl, isopropyl, cyclopropyl, cyclobutyl or tetrahydropyran; wherein cyclopropyl and cyclobutyl are unsubstituted or substituted by -CN.

[0758] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 2 is H, methyl, isopropyl, cyclopropyl or cyclobutyl; wherein cyclopropyl and cyclobutyl are unsubstituted or substituted by -CN.

[0759] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 2 is cyclopropyl or cyclobutyl, wherein cyclopropyl and cyclobutyl are unsubstituted or substituted by -CN.

[0760] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 2In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 2 In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 2 for:

[0761]

[0762] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 2 In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 2 In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 2 for:

[0763]

[0764] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula I'a:

[0765]

[0766] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula I'b:

[0767]

[0768] where R 3a is fluorine, and n is 0, 1 or 2. In some embodiments, R 3a is fluorine, and n is 2.

[0769] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula I'b-1:

[0770]

[0771] where R 3a is fluorine, and n is 2.

[0772] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula I'b-2a:

[0773]

[0774] where R3a is fluorine, and n is 2.

[0775] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula I'b-2b:

[0776]

[0777] where R 3a is fluorine, and n is 2.

[0778] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula I'b-3a:

[0779]

[0780] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula I'b-3b:

[0781]

[0782] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula I'c:

[0783]

[0784] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula I'd:

[0785]

[0786] where R 3a is fluorine, and n is 0, 1 or 2. In some embodiments, R 3a is fluorine, and n is 2.

[0787] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula 1'd-1:

[0788]

[0789] where R 3a is fluorine, and n is 2.

[0790] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula I'd-2a:

[0791]

[0792] where R 3a is fluorine, and n is 2.

[0793] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula I'd-2b:

[0794]

[0795] where R 3a is fluorine, and n is 2.

[0796] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula I'd-3a:

[0797]

[0798] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula I'd-3b:

[0799]

[0800] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 3 C (3-6) Cycloalkyl, -C (3-6) Alkyl or -CH2-OC (1-3) Alkyl, where C (3-6) Cycloalkyl, -C (3-6) Alkyl and -CH2-OC (1-3) The alkyl group is unsubstituted or is independently selected from one to three R 3a Group substitution: fluorine, -CH3 and -CF3.

[0801] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 3 for:

[0802] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 3 for

[0803] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 3 for

[0804] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 3 for

[0805] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula I'e:

[0806]

[0807] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0808] R 4 is unsubstituted or replaced by one to three R 4a -C substituted with a group (3-6) cycloalkyl; and

[0809] Each R 4a independently selected from fluorine and -C (1-4) Alkyl, where -C (1-4) The alkyl group is unsubstituted or substituted with one to three fluorine atoms;

[0810] Alternatively, two R attached to the same ring atom 4a Groups can combine with the atoms to which they are attached to form C (3-6) Cycloalkyl.

[0811] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0812] R 4 is unsubstituted or replaced by one to three R 4a -C substituted with a group (3-6) cycloalkyl; and

[0813] Each R 4a independently selected from fluorine, CH3, CH2F, CF2H and CF3;

[0814] Alternatively, two R attached to the same ring atom 4a The groups can combine with the atoms to which they are attached to form a cyclopropyl, cyclobutyl, or cyclopentyl group.

[0815] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0816]

[0817] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0818] R 4 is a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms selected from N, O and S, the heteroaryl group being surrounded by one or two R 4c group substitution;

[0819] Each R 4c are independently halogen, -CN, -NH2, -N(CH3)2, -C (0-2) Alkyl C (3-6) Cycloalkyl, -OC (0-2) Alkyl-C (3-4) Cycloalkyl, -C (1-4) Alkyl, -OC (1-3) alkyl, or a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms selected from N and O, wherein -C (0-2) Alkyl C (3-6) Cycloalkyl, -C (1-4) Alkyl, -OC (1-3) The alkyl and heterocyclic groups are unsubstituted or substituted with one to six R 4d group substitution;

[0820] Alternatively, two R attached to adjacent ring atoms 4c Groups can be combined to form C (4-6) Cycloalkyl;

[0821] Each R 4d are independently fluorine, -CN, -OH, oxo, -C (1-3) Alkyl, -OC (1-3) Alkyl, -OC (3-4) Cycloalkyl, -C (0-2) Alkyl-N(R 4d1 )(R 4d2 ),-C (0-2) Alkyl-N(C (1-4) alkyl)C(O)(C (1-4) alkyl), or a 3- to 6-membered heterocyclic group having 1 to 2 heteroatoms selected from N and O, wherein -C (1-3) Alkyl, -OC (1-3) Alkyl, -OC (3-4) The cycloalkyl and heterocyclyl groups are unsubstituted or substituted with one to three fluorine atoms; and

[0822] R 4d1 and R 4d2 Each independently is H or -C (1-3) Alkyl, where -C (1-3) The alkyl group is unsubstituted or substituted with one to six groups selected from fluorine and chlorine;

[0823] Alternatively, R 4d1 and R 4d2may combine with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1 to 4 fluorine atoms;

[0824] in

[0825] When R 4 When it is 1,2,4-triazolyl, then R 4 is 1H-1,2,4-triazolyl, and

[0826] When R 4 When it is a 6-membered heteroaryl group, the heteroaryl group is not substituted at the para position.

[0827] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0828] Each R 4c are independently fluorine, -CN, -OH, -NH2, N(CH3)2, methyl, ethyl, isopropyl, -CD3, -CD2CD3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OC(CH3)3, CH(CH3)OH, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CF2CH3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH(CH 3) CHF2, -CH(CH3)CF3, -CH(CH2F)2, -CH2CF2CH3, -CH2CH2CF2CH3, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCHF2, -CH2CH2OCF3, -CH2OCHF2, -OCHF2, -OCH2CHF2, -OCH2CH2F, -OCH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -O-cyclopropyl, -O-cyclobutyl,

[0829]

[0830] Alternatively, two R attached to adjacent ring atoms 4c Groups can be combined to form groups:

[0831]

[0832] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0833] R 4 For one or two R 4c Group substituted Azolyl, iso Azolyl or oxadiazole,

[0834] Each R 4c are independently -OH, -NH2, -N(CH3)2, -C (0-1) Alkyl C (3-5) Cycloalkyl, -OC (3-4) Cycloalkyl, -C (1-3) Alkyl, -OC (1-3) alkyl,

[0835]

[0836] Where -C (0-1) Alkyl C (3-5) Cycloalkyl, -C (1-3) Alkyl and -OC (1-3) The alkyl group is unsubstituted or substituted with one to three groups selected from the group consisting of -OH, -OCH3, -OCHF2, -CH3 and fluorine.

[0837] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0838] R 4 is unsubstituted or replaced by one or two R 4c Group substituted Azolyl, iso Azolyl or Oxazolyl (e.g., 1,2,5- oxadiazole),

[0839] Each R 4c are independently cyclopropyl, -C (1-3) Alkyl or -OC (1-3) Alkyl, including cyclopropyl, -C (1-3) Alkyl and -OC (1-3) The alkyl group is unsubstituted or substituted with one to three fluorine atoms.

[0840] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0841] are each independently one or both of the following R 4c Group-substituted iso Azolyl: methyl, ethyl, isopropyl, -CF3, -CH2CH2F, -CH2CH2CF3, -CH2OCH3, cyclopropyl, cyclopentyl or

[0842]

[0843] Substituted with an isopropyl group azole, or

[0844] Substituted with a methyl, ethyl, -OCH2CHF2 or cyclopropyl group Oxazolyl.

[0845] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 1,2,5- Oxazolyl.

[0846] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0847]

[0848] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0849]

[0850] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0851]

[0852] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0853]

[0854] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0855]

[0856] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0857]

[0858] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0859]

[0860] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula I'f:

[0861]

[0862] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula I'g:

[0863]

[0864] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula I'h:

[0865]

[0866] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, which is a compound of Formula I'i:

[0867]

[0868] where R 3a is fluorine, n is 2 and m is 1 or 2.

[0869] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0870] R 4 is unsubstituted or replaced by one or two R 4c a pyrazolyl or imidazolyl group substituted with a group,

[0871] Each R 4c are independently fluoro, cyclopropyl or -C (1-3) Alkyl, where -C (1-3) The alkyl group is unsubstituted or substituted with one to three groups selected from the group consisting of -CHF2, -CF3, -OCHF2, -OCF3 and fluorine.

[0872] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 For one or two R 4c a pyrazolyl or imidazolyl group substituted with a group, wherein each R 4c is independently unsubstituted or substituted by one to three groups selected from the following -C (1-3) Alkyl: -CHF2, -CF3, -OCHF2, -OCF3 and fluorine.

[0873] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0874] One or two R each independently selected from cyclopropyl, methyl, ethyl, isopropyl, -CD3, -CD2CD3, fluorine, -CHF2, -CF3, -CH2CHF2, -CH2CF3, -CH(CH3)CF3, -CH(CH2F)2, -CH2CH2OCHF2 or -CH2CH2OCF3 4c substituted pyrazolyl, or

[0875] Imidazolyl substituted by one methyl or isopropyl group.

[0876] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 For being a -C (1-3) In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 is pyrazolyl substituted by isopropyl, -CD3 or -CD2CD3.

[0877] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0878]

[0879] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0880]

[0881] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for

[0882] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for

[0883] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for

[0884] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for

[0885] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0886] R 4 is unsubstituted or replaced by one or two R 4c a triazole group substituted with a group;

[0887] Each R 4c Independently -C (0-1) Alkyl C (3-4) Cycloalkyl, -C (1-4) alkyl,

[0888]

[0889] Where -C (0-1) Alkyl C (3-4) Cycloalkyl and -C (1-3) The alkyl group is unsubstituted or substituted with one to four R 4d group substitution; and

[0890] Each R 4d are independently -OCH3, -OCF3, -OCHF2, fluorine,

[0891]

[0892] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0893]

[0894] Alternatively, when R 4 When it is 1,2,4-triazolyl, then R 4 It is 1H-1,2,4-triazolyl.

[0895] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein:

[0896] R 4 is unsubstituted or replaced by one or two R 4c a triazole group substituted with a group; and

[0897] Each R 4care independently methyl, ethyl, isopropyl, -CH2CH2OCH3, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH(CH3)CHF2, -CH(CH3)CF3, -CH2CF2CH3, -CH2CH2CF2CH3, -CH2CH2OCHF2, -CH2CH2OCF3, cyclopropyl, -CH2-cyclopropyl,

[0898]

[0899] When R 4 When it is 1,2,4-triazolyl, then R 4 for

[0900]

[0901] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0902]

[0903]

[0904] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 is thienyl, thiazolyl or thiadiazolyl, each of which is substituted by methyl, isopropyl or cyclopropyl.

[0905] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0906] thienyl substituted by isopropyl,

[0907] thiazolyl substituted by isopropyl, or

[0908] Thiadiazolyl substituted by methyl, isopropyl or cyclopropyl.

[0909] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for:

[0910]

[0911] In some embodiments, disclosed herein are compounds of Formula I' or pharmaceutically acceptable salts thereof, wherein R 4 for

[0912] Table 2A

[0913]

[0914]

[0915]

[0916] Table 2B

[0917]

[0918]

[0919]

[0920] Table 2C

[0921]

[0922]

[0923]

[0924] Table 2D

[0925]

[0926]

[0927]

[0928] Table 2E

[0929]

[0930]

[0931]

[0932] Table 2F

[0933]

[0934]

[0935]

[0936] Table 2G

[0937]

[0938]

[0939]

[0940] Table 2H

[0941]

[0942]

[0943]

[0944] Table 2I

[0945]

[0946]

[0947]

[0948] Table 2J

[0949]

[0950]

[0951]

[0952] Table 2K

[0953]

[0954]

[0955]

[0956] Table 2L

[0957]

[0958]

[0959]

[0960] Table 2M

[0961]

[0962] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof selected from the group consisting of compounds in Table 2A, Table 2B, Table 2C, Table 2D, Table 2E, Table 2F, Table 2G, Table 2H, Table 2I, Table 2J, Table 2K, and Table 2M.

[0963] In some embodiments, disclosed herein is a compound of Formula I' or a pharmaceutically acceptable salt thereof selected from the group consisting of:

[0964] In some embodiments, disclosed herein are compounds of Formula I', which are or a pharmaceutically acceptable salt thereof.

[0965] In some embodiments, disclosed herein are compounds of Formula I', which are or a pharmaceutically acceptable salt thereof.

[0966] In some embodiments, disclosed herein are compounds of Formula I', which are or a pharmaceutically acceptable salt thereof.

[0967] In some embodiments, disclosed herein are compounds of Formula I', which are or a pharmaceutically acceptable salt thereof.

[0968] In some embodiments, disclosed herein are compounds of Formula I', which are or a pharmaceutically acceptable salt thereof.

[0969] In some embodiments, disclosed herein are compounds of Formula I', which are or a pharmaceutically acceptable salt thereof.

[0970] In some embodiments, disclosed herein are compounds of Formula I', which are or a pharmaceutically acceptable salt thereof.

[0971] In some embodiments, disclosed herein are compounds of Formula I', which are or a pharmaceutically acceptable salt thereof.

[0972] In some embodiments, disclosed herein are compounds of Formula I', which are or a pharmaceutically acceptable salt thereof.

[0973] In some embodiments, disclosed herein are compounds of Formula I', which are or a pharmaceutically acceptable salt thereof.

[0974] In some embodiments, disclosed herein are compounds of Formula I', which are or a pharmaceutically acceptable salt thereof.

[0975] In some embodiments, disclosed herein are compounds of Formula I', which are or a pharmaceutically acceptable salt thereof.

[0976] In some embodiments, disclosed herein are compounds of Formula I', which are or a pharmaceutically acceptable salt thereof.

[0977] 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 (eg, tablet or capsule).

[0978] In some embodiments, disclosed herein is a pharmaceutical composition prepared by mixing a compound of Formula I' or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0979] In some embodiments, disclosed herein is a method for preparing a pharmaceutical composition comprising mixing a compound of Formula I' or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0980] III. Therapeutic Uses

[0981] The present application also relates to a method for treating and / or improving IL-17-mediated inflammatory syndromes, disorders or diseases, which comprises administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, a composition thereof or a medicament thereof to a subject in need thereof.

[0982] The present application also relates to a method for treating and / or improving IL-17-mediated inflammatory syndromes, disorders or diseases, which comprises administering an effective amount of a compound of formula I' or a pharmaceutically acceptable salt thereof, a composition thereof or a medicament thereof to a subject in need thereof.

[0983] In some embodiments, disclosed herein are methods for treating or ameliorating IL-17A-mediated inflammatory syndromes, disorders, or diseases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0984] In some embodiments, disclosed herein are methods for treating or ameliorating IL-17A-mediated inflammatory syndromes, disorders, or diseases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof.

[0985] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disease, multiple myeloma, and systemic lupus erythematosus.

[0986] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disease, multiple myeloma, and systemic lupus erythematosus.

[0987] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is psoriasis.

[0988] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is psoriasis.

[0989] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis.

[0990] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis.

[0991] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is rheumatoid arthritis.

[0992] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is rheumatoid arthritis.

[0993] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is ankylosing spondylitis.

[0994] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is ankylosing spondylitis.

[0995] 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.

[0996] 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.

[0997] 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.

[0998] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is bullous pemphigoid.

[0999] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is atopic dermatitis.

[1000] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is atopic dermatitis.

[1001] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is vitiligo.

[1002] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is vitiligo.

[1003] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is multiple sclerosis.

[1004] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is multiple sclerosis.

[1005] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.

[1006] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.

[1007] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is asthma.

[1008] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is asthma.

[1009] 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.

[1010] 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.

[1011] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is chronic obstructive pulmonary disease.

[1012] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is chronic obstructive pulmonary disease.

[1013] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is multiple myeloma.

[1014] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is multiple myeloma.

[1015] 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 disease, multiple myeloma, and systemic lupus erythematosus, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally (e.g., as a tablet or capsule).

[1016] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disease, multiple myeloma, and systemic lupus erythematosus, wherein the compound of Formula I' or a pharmaceutically acceptable salt thereof is administered orally (e.g., as a tablet or capsule).

[1017] 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 disease, multiple myeloma, and systemic lupus erythematosus, wherein the therapeutically effective amount is a dose of about 10 mg to 300 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 20 mg to 200 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 50 mg to 100 mg QD.

[1018] 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 disease, multiple myeloma, and systemic lupus erythematosus, wherein the therapeutically effective amount is a dose of about 10 mg to 300 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 20 mg to 200 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 50 mg to 100 mg QD.

[1019] 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 disease, multiple myeloma, and systemic lupus erythematosus, 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.

[1020] 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 disease, multiple myeloma, and systemic lupus erythematosus, 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.

[1021] In some embodiments, disclosed herein is the use of a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disease, multiple myeloma, and systemic lupus erythematosus.

[1022] In some embodiments, disclosed herein is the use of a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disease, multiple myeloma, and systemic lupus erythematosus.

[1023] In some embodiments, disclosed herein is the use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disease, multiple myeloma, and systemic lupus erythematosus.

[1024] In some embodiments, disclosed herein is the use of a compound of Formula I' or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disease, multiple myeloma, and systemic lupus erythematosus.

[1025] In some embodiments, disclosed herein are methods for treating and / or ameliorating IL-17-mediated inflammatory syndromes, disorders, or diseases, 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.

[1026] In some embodiments, disclosed herein are methods for treating and / or ameliorating IL-17-mediated inflammatory syndromes, disorders, or diseases, 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.

[1027] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17-mediated inflammatory syndrome, disorder, or disease, wherein the syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, atopic dermatitis, vitiligo, multiple sclerosis, asthma, allergic asthma, steroid-resistant asthma, neutrophilic asthma, chronic obstructive pulmonary disease, uveitis, multiple myeloma, and systemic lupus erythematosus, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

[1028] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17-mediated inflammatory syndrome, disorder, or disease, wherein the syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, atopic dermatitis, vitiligo, multiple sclerosis, asthma, allergic asthma, steroid-resistant asthma, neutrophilic asthma, chronic obstructive pulmonary disease, uveitis, multiple myeloma, and systemic lupus erythematosus, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

[1029] In some embodiments, disclosed herein is a method for treating or ameliorating an IL-17-mediated inflammatory syndrome, disorder, or disease, wherein the syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, and ankylosing spondylitis, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

[1030] In some embodiments, disclosed herein is a method for treating or ameliorating an IL-17-mediated inflammatory syndrome, disorder, or disease, wherein the syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, and ankylosing spondylitis, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

[1031] 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.

[1032] 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.

[1033] Also disclosed herein are methods of inhibiting interleukin-17 production, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[1034] Also disclosed herein are methods of inhibiting interleukin-17 production, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof.

[1035] IV. Combination Therapy

[1036] The compound of formula I or its pharmaceutically acceptable salt, composition or medicament thereof can also be used in combination with one or more additional therapeutic agents. Similarly, the compound of formula I' or its pharmaceutically acceptable salt, composition or medicament thereof can be used in combination with one or more additional therapeutic agents.

[1037] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of an anti-inflammatory agent, an immunomodulatory agent, and an immunosuppressive agent.

[1038] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of:

[1039] Anti-TNFα agents, such as infliximab Adalimumab Certolizumab Golimumab Etanercept Thalidomide Lenalidomide and pomalidomide

[1040] Anti-p40 antibody agents, such as ustekinumab and

[1041] Anti-p19 antibody agents, such as guselkumab Ilumya TM / Ilumetri), Risanizumab (Skyrizi TM ) and migizone.

[1042] 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 an anti-inflammatory agent, an immunomodulator, or an immunosuppressant), wherein the syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, atopic dermatitis, vitiligo, multiple sclerosis, asthma, allergic asthma, steroid-resistant asthma, neutrophilic asthma, chronic obstructive pulmonary disease, uveitis, multiple myeloma, and systemic lupus erythematosus.

[1043] In some embodiments, disclosed herein is a method 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 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.

[1044] In some embodiments, disclosed herein are methods for treating and / or improving an IL-17-mediated inflammatory syndrome, disorder, or disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, a composition thereof, or a combination therapy with one or more additional therapeutic agents (such as an anti-inflammatory agent or an immunosuppressant), wherein the syndrome, disorder, or disease is psoriasis, psoriatic arthritis, 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.

[1045] 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, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I' or a pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof in combination with one or more additional therapeutic agents (such as an anti-inflammatory agent or an immunosuppressant), wherein the syndrome, disorder, or disease is psoriasis, psoriatic arthritis, 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.

[1046] Dosage regimen

[1047] When used as IL-17A modulators, the compounds disclosed herein can be administered in an effective amount within a dosage range of about 0.5 mg to about 1 g, preferably about 0.5 mg to about 500 mg, in a single dose or divided daily doses. In some embodiments, the dosage is about 5 mg to 400 mg. In some embodiments, the dosage is about 10 mg to 300 mg. In some embodiments, the dosage is about 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 300 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, or 400 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, or 500 mg of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 10 mg to 300 mg.In some embodiments, the dosage is about 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg of a compound of Formula I' or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage is about 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg of a compound of Formula I' or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg or 300 mg of a compound of Formula I' or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg or 400 mg of a compound of Formula I' or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg or 500 mg of a compound of Formula I' or a pharmaceutically acceptable salt thereof.

[1048] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof can be administered in an effective amount within a dosage range of about 10 mg to 300 mg QD. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof can be administered in an effective amount within a dosage range of about 20 mg to 200 mg QD. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof can be administered in an effective amount within a dosage range of about 50 mg to 100 mg QD.

[1049] In some embodiments, the compound of Formula I' or a pharmaceutically acceptable salt thereof can be administered in an effective amount within a dosage range of about 10 mg to 300 mg QD. In some embodiments, the compound of Formula I' or a pharmaceutically acceptable salt thereof can be administered in an effective amount within a dosage range of about 20 mg to 200 mg QD. In some embodiments, the compound of Formula I' or a pharmaceutically acceptable salt thereof can be administered in an effective amount within a dosage range of about 50 mg to 100 mg QD.

[1050] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof can be administered in an effective amount within a dosage range of about 10 mg to 300 mg BID. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof can be administered in an effective amount within a dosage range of about 20 mg to 200 mg BID. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof can be administered in an effective amount within a dosage range of about 50 mg to 100 mg BID.

[1051] In some embodiments, the compound of Formula I' or a pharmaceutically acceptable salt thereof can be administered in an effective amount within a dosage range of about 10 mg to 300 mg BID. In some embodiments, the compound of Formula I' or a pharmaceutically acceptable salt thereof can be administered in an effective amount within a dosage range of about 20 mg to 200 mg BID. In some embodiments, the compound of Formula I' or a pharmaceutically acceptable salt thereof can be administered in an effective amount within a dosage range of about 50 mg to 100 mg BID.

[1052] The dosage administered 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 and unrelated treatments.

[1053] It will also be apparent to those skilled in the art that the therapeutically effective dose of the compound of the present invention or its pharmaceutical composition will vary depending on the desired effect. Thus, one skilled in the art can easily determine the optimal dose to be administered, and the optimal dose will vary with the specific compound used, the mode of administration, the strength of the formulation, and the progression of the disease condition. In addition, factors related to the specific subject being treated, including subject age, weight, diet, and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level. Therefore, the above-mentioned doses are examples of general circumstances. Of course, there may be individual cases where a higher or lower dosage range should be used, and such cases are also within the scope of the present invention.

[1054] Pharmaceutically acceptable salts

[1055] Pharmaceutically acceptable acidic salts / anionic salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camphorsulfonate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycolylaminophenylarsonic acid salt, hexylresorcinol salt, hydrazine, hydrobromide, hydrochloride, The organic or inorganic acid also includes, but is not limited to, hydroiodic acid, perchloric acid, sulfuric acid, phosphoric acid, propionic acid, glycolic acid, methanesulfonic acid, oxalic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, saccharinic acid or trifluoroacetic acid.

[1056] Pharmaceutically acceptable basic / cationic salts include, but are not limited to, aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (also known as tris(hydroxymethyl)aminomethane, tromethamine, or "TRIS"), ammonia, benzathine, t-butylamine, calcium, calcium gluconate, calcium hydroxide, chloroprocaine, choline, choline bicarbonate, choline chloride, cyclohexylamine, diethanolamine, ethylenediamine, lithium, LiOMe, L-lysine, magnesium, meglumine, NH3, NH4OH, N-methyl-D-glucamine, piperidine, potassium, potassium t-butoxide, potassium hydroxide (aqueous solution), procaine, quinine, sodium, sodium carbonate, sodium 2-ethylhexanoate, sodium hydroxide, triethanolamine, or zinc.

[1057] Pharmaceutical composition

[1058] The compound of Formula I or a pharmaceutically acceptable salt thereof can be formulated into a pharmaceutical composition comprising any known pharmaceutically acceptable carrier. The compound of Formula I' or a pharmaceutically acceptable salt thereof can also be formulated into a pharmaceutical composition comprising any known pharmaceutically acceptable carrier. Exemplary carriers include, but are not limited to, any suitable solvent, dispersion medium, coating, antibacterial and antifungal agent, and isotonic agent. Exemplary excipients that can also serve as formulation components include fillers, binders, disintegrants, and lubricants.

[1059] The pharmaceutically acceptable salt of the compound of formula I comprises conventional non-toxic salt or quaternary ammonium salt formed by inorganic or organic acid or alkali. Similarly, the pharmaceutically acceptable salt of the compound of formula I ' also comprises conventional non-toxic salt or quaternary ammonium salt formed by inorganic or organic acid or alkali. The example of this type of acid addition salt comprises acetate, adipate, benzoate, benzenesulfonate, citrate, camphorate, lauryl sulfate, hydrochloride, hydrobromide, lactate, maleate, mesylate, nitrate, oxalate, pivalate, propionate, succinate, sulfate and tartrate. Alkali salt comprises ammonium salt, alkali metal salt such as sodium salt and potassium salt, alkaline earth metal salt such as calcium salt and magnesium salt, organic base salt such as dicyclohexylamine salt and amino acid such as arginine salt. In addition, the basic nitrogen-containing group can be quaternized with for example alkyl halide.

[1060] The pharmaceutical compositions of the present invention can be administered in any manner that achieves its intended purpose. Examples include administration by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, oral or ocular routes. Alternatively or concurrently, administration can be by oral route. Preparations suitable for parenteral administration include aqueous solutions of water-soluble forms of the active compound (e.g., water-soluble salts), acidic solutions, alkaline solutions, aqueous dextrose solutions, isotonic carbohydrate solutions, and cyclodextrin inclusion complexes.

[1061] Also disclosed herein is a method for preparing a pharmaceutical composition, comprising mixing a pharmaceutically acceptable carrier with any one of the compounds of Formula I or a pharmaceutically acceptable salt thereof. Also disclosed herein is a method for preparing a pharmaceutical composition, comprising mixing a pharmaceutically acceptable carrier with any one of the compounds of Formula I' or a pharmaceutically acceptable salt thereof. Additionally, the present application includes a pharmaceutical composition prepared by mixing a pharmaceutically acceptable carrier with any one of the compounds of the present invention.

[1062] Example

[1063] abbreviation

[1064] Herein and throughout this application, the following abbreviations may be used.

[1065] angstrom

[1066] Ac acetyl

[1067] acac acetylacetone

[1068] ACN acetonitrile

[1069] BAST Bis(2-methoxyethyl)aminosulfur trifluoride

[1070] Boc tert-butyloxycarbonyl

[1071] br broad peak

[1072] Bs 4-Bromophenylsulfonyl (Bromophenylsulfonyl)

[1073] Butyl

[1074] Bz benzoate

[1075] CAM Cerium Ammonium Molybdate

[1076] COD or cod cyclooctadiene

[1077] δ NMR chemical shift (parts per million downfield relative to the standard)

[1078] d Twin Peaks

[1079] d day

[1080] DAST (diethylamino)sulfur trifluoride

[1081] dba dibenzylideneacetone

[1082] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[1083] DCM dichloromethane

[1084] DEA Diethylamine

[1085] DIAD Diisopropyl azodicarboxylate

[1086] DIBAL-H Diisobutylaluminum hydride

[1087] DIPEA N,N-diisopropylethylamine (Hünig's base)

[1088] DMA N,N-dimethylacetamide

[1089] DMAP 4-(dimethylamino)pyridine

[1090] DME 1,2-dimethoxyethane

[1091] DMF N,N-dimethylformamide

[1092] DMP Dess-Martin Periodinane

[1093] DMSO dimethyl sulfoxide

[1094] DPPE Ethylene bis(diphenylphosphine)

[1095] dpPf 1,1′-bis(diphenylphosphino)ferrocene

[1096] ELSD Evaporative Light Scattering Detector

[1097] EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[1098] ESI electrospray ionization

[1099] Et ethyl

[1100] EtOAc

[1101] Fmoc fluorenylmethoxycarbonyl

[1102] g grams

[1103] h hour

[1104] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[1105] HOAt 1-Hydroxy-7-azabenzotriazole

[1106] HOBt 1-Hydroxybenzotriazole

[1107] HPLC High-pressure liquid chromatography

[1108] Hz Hertz

[1109] i different

[1110] J coupling constant (NMR spectrum)

[1111] L liter

[1112] LC liquid chromatography

[1113] LDA lithium diisopropylamide

[1114] m milli- or multiplet

[1115] m / z mass-to-charge ratio

[1116] M + Parent molecular ion

[1117] M moles per liter (mol / L)

[1118] Me methyl

[1119] MeCN Acetonitrile

[1120] min

[1121] μ micro

[1122] Ms Methylsulfonyl

[1123] MS

[1124] MTBE methyl tert-butyl ether

[1125] NCS N-chlorosuccinimide

[1126] Normal

[1127] n Na

[1128] N standard (equivalent concentration)

[1129] NMM N-Methylmorpholine

[1130] NMR Nuclear Magnetic Resonance

[1131] NPA n-propylamine

[1132] Pd / C Palladium on Carbon

[1133] Ph Phenyl

[1134] PPTS Pyridinium p-Toluenesulfonate

[1135] Pr Propyl

[1136] Psi pounds per square inch

[1137] Pd(dtbpf)Cl2 [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride

[1138] q quartet

[1139] Rochelle Salt Potassium Sodium Tartrate

[1140] rt room temperature

[1141] RuPhos PD G3 (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate

[1142] s single peak

[1143] SFC Supercritical Fluid Chromatography

[1144] Uncle T

[1145] t Triplet

[1146] TBAT Tetrabutyldifluorotriphenylammonium silicate

[1147] TBD Triazabicyclodecene

[1148] TEA triethylamine

[1149] TFA trifluoroacetic acid

[1150] THF Tetrahydrofuran

[1151] TLC thin layer chromatography

[1152] TMP Tetramethylpiperidinyl

[1153] Ts p-Toluenesulfonyl (toluenesulfonyl)

[1154] XPhos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[1155] XPhos Pd G1 (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride, (XPhos)phenylethylaminepalladium(II) chloride, (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride

[1156] (Diethylamino)difluorosulfonium tetrafluoroborate

[1157] In some embodiments, provided herein are methods and intermediates disclosed herein that can be used to prepare the compounds of the present disclosure or pharmaceutically acceptable salts thereof.

[1158] General approach :

[1159] Solution 1

[1160]

[1161] Certain compounds of formula I-aa of the present invention can be prepared, for example, according to Scheme 1. Cyanidation of AI using a reagent such as zinc cyanide in the presence of a catalyst such as Pd2(dba)3 affords nitrile A-II. Removal of the Boc group under acidic conditions such as aqueous hydrochloric acid affords an amine, which is then coupled with a carboxylic acid using a coupling agent such as HATU or EDCI in the presence of a base such as DIPEA in a solvent such as DMF, MeCN, or DCM with or without an additive such as HOBt to produce an amide A-III. Reduction of the nitrile of A-III with hydrogen in the presence of a catalyst such as Raney nickel affords the corresponding primary amine A-IV, which can be coupled with a carboxylic acid in a manner similar to that used to convert A-II to A-III to afford compounds of the general structure I-aa shown in Scheme 1.

[1162] Option 2a

[1163]

[1164] Option 2b

[1165]

[1166] Certain compounds of general structure I-aa-1 and I-aa of the present invention can also be prepared according to Schemes 2a and 2b, respectively. Removal of the Boc group of compounds of type A-Ia or type A-Ib under acidic conditions (such as aqueous hydrochloric acid or TFA) yields amines of type AV (e.g., A-Va and A-Vb). Amides of formula A-VIa and A-VIb can be formed from A-Va and A-Vb, respectively, in a manner similar to the conversion of A-II to A-III (see Scheme 1). The conversion of compounds of type A-VI to compounds of type A-VII is carried out using a mixture of reagents capable of transferring vinyl groups (such as potassium trifluoro(vinyl)borate) in the presence of a catalyst such as Pd(dtbpf)Cl2. Compounds of general structure A-VII can be converted to compounds of structure A-VIII by oxidative cleavage of the vinyl substituent using reagents such as sodium periodate in the presence of a catalyst such as potassium osmate in a solvent such as 1,4-dioxane aqueous solution. Subsequently, compounds of general structure A-VIII are condensed with (S)-(-)-2-methyl-2-propanesulfenamide to provide the corresponding sulfenimine, which upon addition of a nucleophilic carbon-containing reagent such as an alkylmagnesium halide, produces the sulfenimine of general structure A-IX. The conversion of compounds of structure A-IX to compounds of structure AX can be carried out under acidic conditions such as aqueous hydrochloric acid and subsequently converted to compounds of general structures I-aa-1 and I-aa in a manner similar to the conversion of A-II to A-III. Compounds of general structure I-aa, obtained as a mixture of isomers, are subjected to additional purification techniques, such as HPLC or SFC using a column with a chiral stationary phase, to provide single isomeric products I-aa-1 and I-aa.

[1167] Option 2c

[1168]

[1169] Compound I-aa-2 can be prepared by the reaction shown in Scheme 2c. Treatment of N-oxide IA with trimethyl phosphite in toluene yields compound I-aa-2.

[1170] Plan 2d

[1171]

[1172] Compounds I-aa-3 can be prepared as shown in Scheme 2d. Hydration of the olefin in IAI using reagents such as Co(acac)2, (cobalt(II) acetylacetonate) and PhSiH3 (phenylsilane) in THF under an oxidizing atmosphere provides compounds I-aa-3.

[1173] Option 3

[1174]

[1175] Compounds of Formula I-aa of the present invention can also be prepared according to Scheme 3, wherein the relative order of transformations is reversed compared to Scheme 2b. Aldehydes of Formula A-XI can be formed from Al (e.g., A-Ib) in a manner similar to the conversion of A-VI to A-VIII. Similarly, compounds of general structure A-XII can be formed from A-XI in a manner similar to the conversion of A-VIII to A-IX. Selective removal of the sulfenyl imide functional group from compounds of general structure A-XII under acidic conditions, such as aqueous hydrochloric acid in EtOAc, yields amines of general structure A-XIII. Acylation of A-XIII, followed by removal of the Boc group and amide formation, can be carried out as described in the previous schemes to provide compounds of general structure I-aa, although in some cases these compounds are prepared by: (i) using an acyl chloride in a solvent such as DCM; (ii) direct conversion of the ester to the amide by heating with Al(CH3)3 in a solvent such as toluene; or (iii) conversion of the N-hydroxysuccinate in the presence of DIPEA in a solvent such as acetonitrile.

[1176] Option 3a

[1177]

[1178] Compounds of general structure A-XXXI can be prepared as shown in Scheme 3a. Following a sequence similar to that shown in Scheme 3, chloride A-1a can be converted to the corresponding aldehyde A-XIa in a two-step sequence. Compound A-XIa is condensed with (R)-2-methyl-2-propanesulfenamide or (S)-2-methyl-2-propanesulfenamide to give the corresponding sulfenyl imine A-XXX. A Grignard reagent such as R is reacted with a 2-hydroxy-2-hydroxy-2-hydroxy-3-hydroxy-4-propanesulfenamide in a solvent such as DCM. 2MgX (X = halide) is added to A-XXX (method a) to produce a compound of the general formula A-XXXI. A nucleophilic carbon-containing reagent such as TMSCF3 is added to A-XXX in a solvent such as THF in the presence of a reagent such as TBAF (method b) to produce a compound of the general formula A-XXXI. Alternatively, a nucleophilic carbon-containing reagent such as TMSCHF2 is added in a solvent such as THF in the presence of a reagent such as potassium tert-butoxide (method c) to give a compound of the general formula A-XXXI. Trimethylsilylacetonitrile can be metallated using a reagent such as tetrabutylammonium phenol in a solvent such as THF (method d) to give a sulfenyl imine of the general structure A-XXXI. Cycloalkyl nitrile can be deprotonated using a base such as LiHMDS in a solvent such as THF (method e) and, after the cycloalkyl nitrile is added to A-XXX, compound A-XXXI is provided. Addition of an indium reagent to A-XXX, such as allylindium formed by in situ treatment of allyl bromide and indium in THF (Method f), provides compounds A-XXXI.

[1179] Option 3b

[1180]

[1181] Compounds of formula A-XXXIV can be prepared according to Scheme 3b. Ketones of formula A-XXXIII can be formed from A-Ia by using a vinyl transfer agent such as 4,4,5,5-tetramethyl-vinyl-1,3,2-dioxaborolane (J-III) in the presence of a catalyst such as RuPhos Pd G3; followed by oxidative cleavage of the vinyl substituent using a reagent such as sodium periodate in a solvent such as 1,4-dioxane aqueous solution in the presence of a catalyst such as potassium osmate. Reductive amination using a reagent such as ammonium formate and an additive such as acetic acid in the presence of a reducing agent such as sodium cyanoborohydride in a solvent such as methanol produces amines of general structure A-XXXIV.

[1182] Option 3c

[1183]

[1184] Amides of structure A-XVIIa can be prepared as shown in Scheme 3c. Amide formation from amine A-XIIIa can be carried out as described in the previous scheme to provide A-XVa. Oxidative cleavage of the olefin in A-XVa using reagents such as sodium periodate and potassium permanganate in solvents such as 1,4-dioxane and water gives the corresponding aldehyde A-XVIa. Treatment of A-XVIa then yields the corresponding difluorinated products A-XVIIa. These products can then be converted to analogs 1-aa using the sequence shown in Scheme 3.

[1185] Plan 3d

[1186]

[1187] Compounds of formula A-Xaa can be prepared using the sequence shown in Scheme 3d. In the presence of DIPEA, the amine in A-XIIIa is protected using FmocCl in a solvent such as DCM to obtain carbamate A-XVIIIa. The Boc group is deprotected using an acid such as HCl in a solvent such as EtOAc to obtain the corresponding amine hydrochloride A-XIXa. Sequential amide bond formation is performed using the above conditions, and Fmoc deprotection is performed using a reagent such as piperidine in a solvent such as DCM to obtain amine A-Xaa.

[1188] Option 3e

[1189]

[1190] Compounds I-aa, such as I-aa-4, can be prepared as shown in Scheme 3e. Amide bond formation using cyanoacetic acid using the conditions described above yields amide A-XX. Treatment of A-XX with NaNO2 in the presence of HCl in a solvent such as acetonitrile yields oxime A-XXI. Subsequent treatment of A-XXI with hydroxylamine in THF then yields Oxidation of the amine in A-XXII using Na2WO4·2H2O in the presence of hydrogen peroxide and sulfuric acid then produces the nitro compound A-XXIII. Replacement of the nitro group in A-XXIII with a hydroxyl group can be achieved using sodium hydroxide in a solvent such as THF / H2O to give A-XXIV is obtained by treating the amine A-XXII with NaNO2 in the presence of LiCl in a solvent such as water and CH3CN to give the chloride A-XXIVa. 4cc OH treatment of chloride A-XXIVa affords compound I-aa-4, wherein R 4cc C (1-3) Alkyl or C (0-2) Alkyl-C (3-4) cycloalkyl, and wherein R 4cc Not replaced or replaced by one to six R 4d Group substitution.

[1191] Plan 3f

[1192]

[1193] Additional content Analogs of oxadiazoles can be prepared by the route shown in Scheme 3f. Amine A-XIIIa is treated with lactone I-XI in a solvent such as DCM or in the presence of triazabicyclodecene and in a solvent such as THF to provide amide A-XXV. In the case where A-XXV contains a primary alcohol, oxidation with DMP can produce the corresponding aldehyde A-XXVI. Treatment of A-XXVI with DAST in a solvent such as DCM then provides compound I-aa-5.

[1194] Plan 3g

[1195]

[1196] Amides of general formula A-XXVII can be prepared by the method described in Scheme 3g. Treatment of amine A-XIIIa with diazo-1-(3-fluorobicyclo[1.1.1]pentan-1-yl)ethan-1-one JI in the presence of DIPEA and silver benzoate (AgBz) in CH3CN provides the homologous amide A-XXVII.

[1197] Option 4

[1198]

[1199] Compounds of formula AI can be prepared according to the pathway in Scheme 4. Chloromethyl ketone BI is converted to the corresponding iodomethyl ketone B-II under conditions of halide interconversion (such as sodium iodide in acetone). Cyclocondensation with 5-chloropyridazin-3-amine then affords the imidazopyridazine AI.

[1200] Option 4a

[1201]

[1202] Compounds of formula A-Ia can be prepared according to the route in Scheme 4a. In the presence of a catalyst such as chlorocyclopentadienylbis(triphenylphosphine)ruthenium(II), in the presence of an additive such as sodium trifluoromethanesulfonate and Cyclocondensation of ylides of general structure CX with 5-chloropyridazin-3-amine in the presence of molecular sieves in a solvent such as toluene affords imidazopyridazines A-Ia.

[1203] Option 4b

[1204]

[1205] Compounds of general structure A-XVII can be prepared as shown in Scheme 4b. In the presence of molecular sieves, aminopyridazine GI undergoes cyclocondensation with iodone B-Ic to give compound A-XVII. Alternatively, under similar conditions, chlorinated compound G-Ia can be cyclocondensed with iodone B-Ic to produce chlorinated aminopyridazine A-XVIIb. Hydrogenation using palladium catalysis in the presence of hydrogen and ammonium formate in ethanol, or in the presence of hydrogen and acetic acid in a solvent such as THF, then produces compound A-XVII.

[1206] Option 5

[1207]

[1208] Alternatively, AI (e.g., A-Ib) can be prepared as shown in Scheme 5. 4,4-difluorocyclohexyl ketone is treated with methyl 2-((tert-butoxycarbonyl)amino)-2-(dimethoxyphosphoryl)acetate and a base such as DBU to provide the corresponding tetrasubstituted olefin B-III. Reduction of B-III with a hydrogen source such as hydrogen gas in the presence of a catalyst such as Pd / C produces racemic B-IV. 6 Treatment of B-IV with (-(1,2,5,6-η)-1,5-cyclooctadiene)-diiridium bis ...

[1209] Option 6

[1210]

[1211] Chloromethyl ketone B-Ia can also be prepared by the route described in Scheme 6. Treatment of (S)-methyl 2-amino-2-cyclohexylacetate with di-tert-butyl dicarbonate in the presence or absence of a base such as TEA in a solvent such as DCM provides B-VI, which can then be converted to chloromethyl ketone B-Ia upon treatment with LDA-treated chloroiodomethane in an aprotic solvent such as THF.

[1212] Option 7

[1213]

[1214] Alternatively, compounds of general structure B-Ib can be prepared according to Scheme 7. (S)-2-amino-2-(4-hydroxyphenyl)acetic acid can be converted to CI by the following method: acidifying the acid under acidic conditions (such as thionyl chloride in anhydrous methanol) and subsequently treating with di-tert-butyl dicarbonate in a solvent mixture (such as water and 1,4-dioxane) in the presence of a weak base such as potassium carbonate. Reducing the phenyl ring of CI using a hydrogen source such as hydrogen and a catalyst such as platinum (IV) oxide in a solvent such as HOAc gives C-II. Oxidizing the alcohol of C-II with an oxidant such as DMP gives ketone C-III. Converting C-III to a paired difluoride B-IV can be achieved by treating with a deoxyfluorination reagent such as BAST (bis(2-methoxyethyl)aminosulfur trifluoride) in a solvent such as DCM. The ester is saponified using a base such as lithium hydroxide to give the corresponding acid C-IV, which is converted to a mixed anhydride by treatment with a reagent such as isobutyl chloroformate followed by addition of diazomethane to produce the corresponding diazoketone CV. CV can be converted to B-Ib by treatment with aqueous hydrochloric acid.

[1215] Option 7b

[1216]

[1217] Compounds of general formula B-Ic and C-IX can be prepared as shown in Scheme 7b. Aldehyde H-II is condensed with (S)-(-)-2-methyl-2-propanesulfenamide to provide the corresponding sulfenyl imine C-VI. Cyanidation using TMSCN in the presence of scandium trifluoromethanesulfonate then provides nitrile C-VII. Subsequent treatment with HCl in methanol then provides ester C-VIII. Simultaneous ester saponification and Boc protection of the amine then produce C-IX. Activation of the carboxylic acid in C-IX using reagents such as CDI or isobutyl chloroformate in the presence of a base such as potassium tert-butoxide in a solvent such as THF then produces the ylide of structure CX. Treatment of the ylide CX with methanesulfonic acid in the presence of lithium chloride in a solvent such as THF then provides the chloromethyl ketone B-Ib, which can be converted to the corresponding iodide by treatment with sodium iodide in acetone to produce compound B-Ic. Alternatively, acid C-IX can be prepared from nitrile C-VII by treatment of the nitrile with aqueous HCl and subsequent treatment of the resulting amino acid C-XI with sodium hydroxide and Boc anhydride to afford the protected amino acid C-IX.

[1218] Option 8

[1219]

[1220] Trans-1-(tert-Butoxycarbonyl)-3-(trifluoromethyl)piperidine-2-carboxylic acid DI can be prepared as shown in Scheme 8. Esterification of 3-(trifluoromethyl)picolinic acid in acidic methanol produces ester D-II. Reduction of the pyridine ring D-II using a hydrogen source such as ammonium formate in the presence of a catalyst such as palladium on carbon gives the racemic piperidine D-III. DI can then be prepared by epimerization of the 2-position of D-III under basic conditions (such as sodium methoxide in methanol), followed by treatment with di-tert-butyl dicarbonate with a base such as aqueous sodium bicarbonate, followed by conversion of the ester to the corresponding acid under basic conditions, such as in a solvent such as THF with aqueous LiOH.

[1221] Option 9

[1222]

[1223] Substituted 1,2,3-triazole-5-carboxylic acid E-II can be prepared as shown in scheme 9.In a solvent such as DMF, 1H-1,2,3-triazole-5-carboxylic acid methyl esters or ethyl ester can be alkylated by processing ester with alkali (such as potassium carbonate or sodium hydride) and alkylating agent (such as alkyl bromide, p-bromobenzenesulfonate or toluenesulfonate), to produce 1,2,3-triazole-5-carboxylic acid esters alkylated at N1, N2 or N3 position EI, the mixture can be separated by silica gel chromatography. Alternatively, in a solvent such as THF, 1H-1,2,3-triazole-5-carboxylic acid methyl esters or ethyl ester can be processed with alcohol to realize alkylation, and EI is provided. In a solvent such as THF or EtOH, ester is hydrolyzed with aqueous base (such as sodium hydroxide or potassium hydroxide), to produce carboxylic acid E-II.

[1224] Plan 10

[1225]

[1226] Scheme 10 shows that substituted 1,2,4-triazole-5-carboxylic acids E-IV can be prepared in a similar sequence as described in Scheme 9 using methyl 1,2,4-triazole-5-carboxylate as the starting material, where PCy3 is tricyclohexylphosphine.

[1227] Plan 11

[1228]

[1229] 5-substituted iso Oxazole-4-carbonyl chloride EV can be prepared as described in Scheme 11. The 5-substituted isocyanate is treated with excess thionyl chloride. oxazole-4-carboxylic acid, and concentrated to give the corresponding acid chloride EV.

[1230] Plan 12

[1231]

[1232] Scheme 12 shows that substituted 1,2-pyrazole-4-carboxylic acids E-VII can be prepared in a similar sequence as described in Scheme 9.

[1233] Plan 13

[1234]

[1235] 3-substituted iso Oxazole-4-carboxylic acids EX can be prepared as shown in Scheme 13. Condensation of 4,4,4-trifluorobutyraldehyde with hydroxylamine hydrochloride in a solvent such as ethanol produces the corresponding oxime E-VIII. Subsequent treatment with NCS and cycloaddition with ethyl-3-(diethylamino)acrylate in a solvent such as chloroform gives ester E-IX. Saponification of the ester with a reagent such as sodium hydroxide in aqueous ethanol gives isocyanate. Oxazole-4-carboxylic acid EX.

[1236] Plan 13a

[1237]

[1238] 3-substituted iso Oxazole-4-carboxylates E-IXa can be prepared as shown in Scheme 13a. Condensation of aldehydes with hydroxylamine hydrochloride in solvents such as ethanol produces the corresponding oxime E-VIIIa. Subsequent treatment with NCS and cycloaddition with ethyl-3-(diethylamino)acrylate in solvents such as THF gives ester E-IXa.

[1239] Plan 13b

[1240]

[1241] different Oxazole E-Xa can be prepared by the method described in Scheme 13b. The appropriate nitroalkane is treated with phenyl isocyanate in the presence of EtN, followed by treatment with 3-pyrrolidin-1-yl-ethyl acrylate in a solvent such as benzene in the presence of triethylamine to give the corresponding ester E-IXa. Subsequent saponification in aqueous ethanol using reagents such as LiOH or NaOH produces the corresponding acid E-Xa.

[1242] Plan 13c

[1243]

[1244] different Oxazole esters E-XIII and E-XV can be prepared by the approach shown in Scheme 13c. Ester E-XI is desilylated using TBAF to give alcohol E-XII. Difluoromethylation using 2,2-difluoro-2-(fluorosulfonyl)acetic acid in a solvent such as CHCN in the presence of an additive such as CuI and a base such as EtN gives ester E-XIII. 3-hydroxyisothioic acid can be reacted with iodoalkyl in a solvent such as DMF in the presence of sodium hydride. Alkylation of oxazole-4-carboxylic acid ethyl ester E-XIV affords ether E-XV. Alternatively, 3-hydroxyisothiazolinone is treated with an aliphatic alcohol and a reagent such as triphenylphosphine and DIAD in a solvent such as THF. Ethyl oxazole-4-carboxylate E-XIV provides ether E-XV.

[1245] Plan 13d

[1246]

[1247] different Oxazole acids E-XVI can be prepared by the route shown in Scheme 13d. 4-Hydroxyisothiazolinone is prepared by alkyl iodide in the presence of a base such as cesium carbonate in a solvent such as DMF. The oxazole-3-carboxylic acid ethyl ester is alkylated to give the corresponding ester. Subsequent saponification using a reagent such as LiOH in a solvent mixture such as THF and water gives the isocyanate. Azolic acid E-XVI.

[1248] Plan 13e

[1249]

[1250] 4-substituted isocyanate of general formula E-XVIII Oxazole-3-carboxylic acids can be prepared as shown in Scheme 13e. In the presence of pyrrolidine, the appropriate aldehyde is condensed with ethyl 2-chloro-2-(hydroxyimino)acetate in a solvent such as DCM and a base such as triethylamine to produce compound E-XVII. Oxidation of the pyrrolidine in E-XVII using a reagent such as mCPBA in a solvent such as DCM then yields the corresponding isocyanate. Oxazole-3-carboxylate (structure not shown), the iso Saponification of oxazole-3-carboxylates using reagents such as aqueous LiOH in solvents such as THF provides compounds of formula E-XVIII.

[1251] Plan 14

[1252]

[1253] With R 5 =F compound I-ab can be prepared as shown in Scheme 14. Compound A-XIV (prepared from A-VIII as shown in Scheme 3) can be treated with a fluorinating agent such as 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) in a solvent such as acetonitrile to give a compound with R 5 = F. Subsequent amide bond formation is performed as previously described to then provide compound I-ab.

[1254] Plan 15

[1255]

[1256] Functionalized tetrazines can be prepared as shown in Scheme 15. Treatment of 3,6-dichloro-1,2,4,5-tetrazine with (4-methoxyphenyl)methanamine in the presence of a reagent such as DIPEA in a solvent such as MTBE yields the aminated product (not shown). Subsequent dechlorination reduction using palladium catalysis and Boc protection of the amine affords tetrazine FI.

[1257] Plan 16

[1258]

[1259] Aminopyridazines of general structure GI can be prepared by the route shown in Scheme 16. The Boc-protected amino acid is converted to the corresponding aldehyde via a two-step process involving Weinreb amide formation and subsequent reduction using a hydride reagent such as DIBAL-H in a solvent such as THF to provide aldehyde G-II. Treatment of aldehyde G-II with dimethyl (1-diazo-2-oxopropyl)phosphonate in the presence of a base such as potassium carbonate in a solvent such as methanol then provides alkyne G-III. Deprotection of the Boc group using hydrochloric acid in methanol provides amine G-IV. Subsequent amide bond formation with a carboxylic acid using a reagent such as HATU in a solvent such as DCM in the presence of an additive such as DIPEA then produces amide GV. Condensation of GV with tetrazine FI under thermal conditions (60°C to 115°C) produces compound G-VI. Deprotection of the Boc with HCl in methanol provides G-VII, and subsequent deprotection of the 4-methoxybenzyl group with TFA then provides aminopyridazine GI.

[1260] Plan 17

[1261]

[1262] Aminopyridazines of general structure G-Ia can be prepared via the route shown in Scheme 17. Treatment of 6-chloropyridazin-3-amine with pivaloyl chloride in DCM in the presence of pyridine then produces amide G-VIII. Metallation of amide G-VIII using reagents such as TMPMgCl·LiCl in solvents such as THF, followed by treatment with sulfenyl imine HI, then provides sulfenyl amide G-IX. Removal of the sulfenyl imine and pivaloyl groups by acidic hydrolysis using reagents such as aqueous hydrochloric acid then provides diamine GX. Subsequent amide bond formation produces aminopyridazine G-Ia.

[1263] Plan 18

[1264]

[1265] Sulfenyl imines HI are prepared as shown in Scheme 18. Aldehydes are condensed with sulfenamides (such as (S)-2-methylpropane-2-sulfenamide) in the presence of reagents such as copper sulfate and PPTS in solvents such as DCM, THF and / or toluene to produce sulfenyl imines HI.

[1266] Plan 19

[1267]

[1268] Aldehydes of general structure H-II are prepared as shown in Scheme 19. In some cases, carboxylic acid esters H-III can be reduced using reagents such as DIBAL-H in solvents such as DCM to provide aldehydes H-II. Carboxylic acids H-IV can be converted to the corresponding amides HV by treatment with N,O-dimethylhydroxylamine in a solvent such as DCM in the presence of reagents such as HATU or CDI and additives such as DIPEA. Amides HV are reduced using reducing agents such as DIBAL-H or lithium aluminum hydride in solvents such as DCM or diethyl ether to provide the corresponding aldehydes H-II. Terminal olefins H-VI can be cleaved to provide H-II by treatment with reagents such as ozone in DCM under oxidizing conditions, followed by treatment with dimethyl sulfide. Alternatively, H-VI is treated with reagents such as potassium osmate dihydrate and sodium periodate in solvents such as THF and water to provide aldehydes H-II.

[1269] Plan 20

[1270]

[1271] 5-substituted Oxadiazole-4-carbonyl chloride (I-II) and N-hydroxysuccinate (I-III) can be prepared as described in Scheme 20. Treatment of acid II with a chlorinating agent such as excess thionyl chloride and concentration affords the corresponding acid chloride I-II. Subsequent reaction with N-hydroxysuccinimide affords the corresponding ester I-III.

[1272] Plan 21

[1273]

[1274] The oxadiazole acids IV can be prepared as shown in Scheme 21. Treatment of the αβ-unsaturated aldehyde with sodium nitrite in a solvent such as acetic acid affords the corresponding 1,2,5-oxadiazole Oxidation of I-IV with a reagent such as Jones reagent in a solvent such as acetone provides the carboxylic acid IV.

[1275] Plan 22

[1276]

[1277] Formula II Oxadiazole acids can be prepared as shown in Scheme 22. Acid IV is treated with aniline to give amide I-VI. Reduction with trimethyl phosphite in a solvent such as toluene then gives compound I-VII. Subsequent treatment of I-VII with di-tert-butyl dicarbonate in a solvent such as DCM in the presence of DMAP gives compound I-VIII. Treatment of I-VIII with LiOH in THF / water then produces acid II.

[1278] Plan 23

[1279]

[1280] Amides I-IX can be prepared by the route shown in Scheme 23. Lactones I-XI can be prepared using the procedures described in Pollet, P.; Gelin, S., "Tetronic Acids and Derivatives", Part VI, "A Convenient Synthesis of New 4-Oxo-2-phenyl-2H-4,6-dihydrofuro[3,4-d]triazoleand 4-Oxo-4,6-dihydrofuro[3,4-c]furazan Systems", Synthesis. 1979, 12, 977. Treatment of lactone I-XI with aniline in a solvent mixture such as DMF and EtOH then provides amides I-IX.

[1281] Plan 24

[1282]

[1283] Oxadiazole amides can be prepared as shown in Scheme 24. Treatment of alcohol I-IXa with copper(I) iodide and 2-(fluorosulfonyl)acetic acid in a solvent such as acetonitrile provides the corresponding difluoromethyl ether I-XII. Activation of the hydroxyl group in I-IXa using methanesulfonyl chloride in the presence of EtN in a solvent such as DCM provides I-XIII. Treatment of I-XIII with DIPEA present at the 3-position in a solvent such as DCM provides I-XIV.

[1284] Plan 25

[1285]

[1286] Oxadiazole amides I-IXb and I-IXc can be prepared as shown in Scheme 25. Chloro-N-phenyl-1,2,5-dioxane is treated with certain amines in the presence of DIPEA in 1,4-dioxane or in the presence or absence of sodium hydride in THF. Similarly, in the presence of sodium hydride in THF, or in the presence of R in methanol, 4cc =Me, sodium methoxide, chloro-N-phenyl-1,2,5- Oxadiazole-3-carboxamide, yielding amide I-IXc.

[1287] Plan 26

[1288]

[1289] Diazoketone JI can be prepared as shown in Scheme 26. In the presence of DMF, 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid is reacted with oxalyl chloride in a solvent such as DCM to give the corresponding acid chloride J-II. Subsequent treatment of J-II with (trimethylsilyl)diazomethane in THF and acetonitrile then affords diazoketone JI.

[1290] intermediates

[1291] Intermediate 1

[1292] Methyl 3-(trifluoromethyl)picolinate

[1293]

[1294] Methanol (600mL) is cooled to 0 DEG C in an ice bath, then AcCl (95g, 1.2mol) is added dropwise at a rate keeping the internal temperature below 10 DEG C. After the addition is complete, the resulting solution is warmed to room temperature. Pure 3- (trifluoromethyl) pyridine-2-carboxylic acid (30g, 160mmol) is then added, and the resulting solution is heated at reflux temperature for 16h. After this, the reaction mixture is cooled to room temperature and then concentrated. By EtOAc and saturated NaHCO3 aqueous solution dilution of residue, each layer is mixed, then separated, and the water layer is extracted with EtOAc. The organic layers are merged, dried and concentrated with anhydrous MgSO4 to give the title compound as a yellow oil.

[1295] Intermediate 2

[1296] Methyl (cis-2,3)-3-(trifluoromethyl)piperidine-2-carboxylate

[1297]

[1298] Under nitrogen atmosphere, methyl 3-(trifluoromethyl)picolinate (20 g, 97 mmol, intermediate 1), HCO2NH4 (37 g, 0.58 mol) and Pd / C (9.0 g, 20% w / w, 17 mmol) were added to a reactor containing DMF (260 mL), and the resulting mixture was stirred at room temperature for 3 h. Afterwards, the mixture was filtered and the filter cake was washed with MTBE. The combined filtrate and washings were diluted with water. The layers were mixed, then separated, and the aqueous layer was extracted twice with MTBE. The organic layers were combined and then concentrated to give the title compound as a yellow oil.

[1299] Intermediate 3

[1300] (trans-2,3)-1-(tert-Butoxycarbonyl)-3-(trifluoromethyl)piperidine-2-carboxylic acid

[1301]

[1302] Sodium methoxide (2.6 g, 47 mmol) is added to a solution of (cis-2,3)-3-(trifluoromethyl)piperidine-2-carboxylic acid methyl ester (10 g, 47 mmol, intermediate 2) in anhydrous MeOH (100 mL), and the resulting solution is kept at room temperature for 1 h. The solution is then warmed to 45 ° C and kept at this temperature overnight. The solution is then cooled to room temperature and kept at this temperature for another 24 h. Thereafter, an HCl aqueous solution (80 mL, 1.0 M, 80 mmol) is added, and the mixture is partially concentrated to remove most of MeOH. The resulting concentrated aqueous solution is diluted with water (220 mL), followed by addition of Boc O (46 g, 0.21 mol) and NaHCO (18 g, 0.21 mol). The resulting mixture is stirred at room temperature for 20 h. Thereafter, the pH of the reaction mixture is adjusted to pH 6-7 with a 1N HCl aqueous solution. The mixture is then diluted with THF (250 mL). Lithium hydroxide (3.95 g, 165 mmol) and water (75 mL) were added, and the resulting mixture was stirred at room temperature for 16 h. Afterwards, a 1N aqueous HCl solution was added to make the mixture acidic. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The organic layers were combined and then concentrated to give a colorless solid. This solid was crystallized from EtOAc / n-heptane (250 mL, 1: 4 v / v) to give the title compound as a colorless crystalline solid.

[1303] Intermediate 4

[1304] (S)-2-((tert-Butoxycarbonyl)amino)-2-cyclohexylacetate

[1305]

[1306] Di-tert-Butyl dicarbonate (200mL, 870mmol) is added into the mixture of (S)-methyl-2-amino-2-cyclohexyl acetic acid hydrochloride (120g, 578mmol) and TEA (240mL, 1.73mol) in DCM (1.5L), and gained mixture is stirred at room temperature for 16h.After this, the pH of the mixture is adjusted to pH 5 by adding saturated citric acid aqueous solution.Then the mixture is poured into water (1L), and extracted three times with DCM.Organic extract is merged, through anhydrous Na2SO4 drying, filtered and concentrated.Residue is ground with petroleum ether (350mL), then separated by filtration, obtain the title compound as colorless solid.

[1307] Intermediate 5

[1308] tert-Butyl (S)-(3-chloro-1-cyclohexyl-2-oxopropyl)carbamate

[1309]

[1310] The solution of LDA is prepared by the following method:N-BuLi (194mL, 2.5M hexane solution, 485mmol) is added dropwise to -70 DEG C of solution of diisopropylamine (62.0mL, 441mmol) in THF (80mL), and the resulting solution is then warmed to 0 DEG C (ice bath) in 30min. The solution is then added dropwise to -70 DEG C of solution of methyl (S) -2- ((tert-butoxycarbonyl) amino) -2- cyclohexyl acetate (20g, 74mmol, intermediate 4) and chloroiodomethane (21.6mL, 295mmol) in THF (120mL). The resulting mixture is stirred at -70 DEG C for 3h, then quenched with saturated NH4Cl aqueous solution (200mL) and warmed to room temperature. The resulting mixture is extracted three times with EtOAc. The organic extracts are combined, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (20:1 to 5:1 petroleum ether / EtOAc) to give the title compound as a black oil.

[1311] Intermediate 6

[1312] tert-Butyl (S)-(1-cyclohexyl-3-iodo-2-oxopropyl)carbamate

[1313]

[1314] Sodium iodide (11.0g, 73.4mmol) is added to a solution of (S)-(3-chloro-1-cyclohexyl-2-oxopropyl) tert-butyl carbamate (35.0g, 121mmol, intermediate 5) in acetone (150mL), and the resulting mixture is stirred at room temperature for 48h. The mixture is then concentrated, and residue is diluted with EtOAc (150mL). The resulting suspension is filtered, and the filter cake is washed with EtOAc. The filtrate and washings are merged and concentrated to give the title compound, which is directly used in the next step without further purification.

[1315] Intermediate 7

[1316] (S)-2-Amino-2-(4-hydroxyphenyl)acetic acid methyl ester hydrochloride

[1317]

[1318] Thionyl chloride (711 g, 5.98 mol) was added to a solution of (S)-2-amino-2-(4-hydroxyphenyl)acetic acid (500 g, 2.99 mol) in MeOH (2.0 L) at 0° C. After the addition was complete, the mixture was stirred at 80° C. for 12 h. Afterwards, the mixture was cooled to room temperature and then concentrated to give the title compound as a yellow solid.

[1319] Intermediate 8

[1320] (S)-methyl 2-((tert-Butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate

[1321]

[1322] A solution of KCO (508 g, 3.68 mol) in water (2.0 L) was added to a suspension of (S)-2-amino-2-(4-hydroxyphenyl)acetic acid methyl ester hydrochloride (400 g, 1.84 mol, intermediate 7) in 1,4-dioxane (1.0 L), and the mixture was cooled to 0 ° C. Di-tert-butyl dicarbonate (421 g, 1.93 mol) was then added, and the mixture was warmed to 18 ° C and stirred for 12 h. After this, the mixture was diluted with EtOAc, and the layers were mixed and then separated. The organic layer was washed with brine, dried over anhydrous NaSO, filtered, and then concentrated to give the title compound as a colorless solid.

[1323] Intermediate 9

[1324] (S)-methyl 2-((tert-Butoxycarbonyl)amino)-2-(4-hydroxycyclohexyl)acetate

[1325]

[1326] Platinum dioxide (7.50 g, 33.1 mmol) was added to a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate (100 g, 355 mmol, Intermediate 8) in acetic acid (1.0 L), and the resulting mixture was stirred at 30 ° C. under a H atmosphere (48 psi) for 96 h. Afterwards, the reaction mixture was filtered and the filtrate was concentrated to give a yellow oil. The oil was purified by silica gel chromatography (10: 1 to 1: 1 petroleum ether / EtOAc) to give the title compound as a colorless oil.

[1327] Intermediate 10

[1328] (S)-methyl 2-((tert-Butoxycarbonyl)amino)-2-(4-oxocyclohexyl)acetate

[1329]

[1330] Dess-Martin periodinane (442 g, 1.04 mol) was added to a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-2-(4-hydroxycyclohexyl)acetate (200 g, 696 mmol, Intermediate 9) in DCM (2.0 L) at 0°C, and the resulting mixture was stirred at 10°C for 12 h. Afterwards, a solution of NaSO (400 g, 3.2 mol) in water (5 L) was added. The layers were mixed and then separated. The organic layer was washed with saturated aqueous NaHCO, then with brine, dried over anhydrous NaSO, filtered, and then concentrated to give the title compound as a yellow oil.

[1331] Intermediate 11

[1332] (S)-methyl 2-((tert-Butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetate

[1333]

[1334] At 0 ° C, bis (2-methoxyethyl) aminosulfur trifluoride (85.6 g, 387 mmol) was added dropwise to a solution of (S) -2- ((tert-butoxycarbonyl) amino) -2- (4- oxocyclohexyl) acetate (30.0 g, 105 mmol, intermediate 10) in DCM (300 mL), and the resulting solution was stirred at 10 ° C for 12 h. Afterwards, a cold saturated aqueous NaHCO solution was added with stirring until the pH of the aqueous layer remained at pH 7. The layers were then separated, and the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and then concentrated to give a yellow oil. The oil was purified by silica gel chromatography (10: 1 petroleum ether / EtOAc) to give the title compound as a yellow solid.

[1335] Intermediate 12

[1336] (S)-2-((tert-Butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid

[1337]

[1338] A solution of LiOH HO (21.8 g, 520 mmol) in water (250 mL) was added to a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetate (80.0 g, 260 mmol, intermediate 11) in THF (500 mL), and the mixture was stirred at 10 ° C for 3 h. After this, DCM (500 mL) was added, and the layers were mixed and then separated. The organic layer was discarded. The pH of the aqueous layer was adjusted to pH 2 with 1M HCl aqueous solution, and the resulting mixture was extracted three times with DCM. The organic extracts were combined, dried over anhydrous NaSO4, filtered and concentrated to give the title compound as a yellow solid.

[1339] Intermediate 13

[1340] tert-Butyl (S)-(3-diazo-1-(4,4-difluorocyclohexyl)-2-oxopropyl)carbamate

[1341]

[1342] Isobutyl chloroformate (25.6 g, 187 mmol) was added dropwise to a solution of (S)-2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid (50.0 g, 170.4 mmol, Intermediate 12) and 4-methylmorpholine (18.9 g, 187 mmol) in THF (500 mL) at -20°C, and the resulting mixture was stirred at -20°C for 30 min. Afterwards, the mixture was filtered. A solution of freshly prepared diazomethane in Et2O* (1.8 L, approximately 3 equivalents) was then added to the filtrate at 0°C, and the resulting solution was maintained at 0°C for 12 h. Afterwards, the solution was partially concentrated to remove excess diazomethane, washed with water, dried over anhydrous Na2SO4, filtered, and concentrated to give a yellow solid. The solid was purified by silica gel chromatography (20:1 petroleum ether / EtOAc) to give the title compound as a light yellow solid.

[1343] *Prepared according to de Boer, Th. J.; Backer, HJ Org. Synth. 1956, 36, 16.

[1344] Intermediate 14

[1345] (S)-tert-Butyl (3-chloro-1-(4,4-difluorocyclohexyl-2-oxopropyl)carbamate

[1346]

[1347] A solution of HCl in EtOAc (7.80 mL, 4.0 M, 31.2 mmol) was added to a solution of tert-butyl (S)-(3-diazo-1-(4,4-difluorocyclohexyl)-2-oxopropyl)carbamate (9.00 g, 28.3 mmol, intermediate 13) in EtOAc (100 mL), and the mixture was stirred at 10 ° C for 2 h. The mixture was then washed with saturated aqueous NaHCO 3 solution, dried over anhydrous Na 2 SO 4, filtered and concentrated. The residue was purified by silica gel chromatography (10: 1 petroleum ether / EtOAc) to give a colorless solid. The solid was triturated with petroleum ether (200 mL), then filtered, and the filter cake was dried in vacuo to give the title compound as a colorless solid.

[1348] Intermediate 15

[1349] (S)-tert-Butyl(1-(4,4-difluorocyclohexyl)-3-iodo-2-oxopropyl)carbamate

[1350]

[1351] The title compound was prepared as described for the synthesis of Intermediate 6 using (S)-tert-butyl(3-chloro-1-(4,4-difluorocyclohexyl)-2-oxopropyl)carbamate (Intermediate 14) instead of (S)-tert-butyl(3-chloro-1-cyclohexyl-2-oxopropyl)carbamate.

[1352] Intermediate 16

[1353] N-(5-chloropyridazin-3-yl)-1,1-diphenylmethanamine

[1354]

[1355] The stirred mixture of CsCO (875 g, 2.68 mol), dppf (59.5 g, 107 mmol) and Pd(dba) (49.2 g, 53.7 mmol) in DME (1.4 L) was warmed to 40 ° C, and then a solution of 3,5-dichloropyridazine (200 g, 1.34 mol) and benzophenone imine (243 g, 1.34 mol) in DME (600 mL) was added dropwise while maintaining the internal temperature at 40 to 45 ° C. When the addition was complete, the resulting mixture was stirred at 85 ° C for 16 h. Thereafter, the reaction mixture was cooled to room temperature and then filtered. The filter cake was washed with EtOAc, and the filtrate and washings were combined and concentrated. The residue was diluted with EtOAc (600 mL), and the resulting slurry was stirred at room temperature for 3 h. The mixture was filtered, and the filter cake was dried by suction to obtain the title compound as a brown solid.

[1356] Intermediate 17

[1357] 5-Chloropyridazin-3-amine

[1358]

[1359] N-(5-chloropyridazine-3-yl)-1,1-diphenylmethane (297g, 84%w / w, 0.85mol, intermediate 16) is diluted with EtOAc (1.0L) and water (700mL).Then at 20°C, the HCl aqueous solution (300mL, 5.0N, 1.5mol) is added dropwise, and the resulting mixture is stirred at 20°C for 30min.After this, the mixture is filtered, and the filter pad is washed with 1N HCl aqueous solution (100mL). The layers of the combined filtrate and washings are separated, and the water layer is washed three times with EtOAc. The water layer is merged, and the pH is adjusted to pH 8-9 using the 5N NaOH aqueous solution. After stirring for 1h at 10°C to 20°C, the precipitate is collected by filtration and washed with water to obtain the thick title compound (134g, 71%w / w) as a brown solid. This material was combined with another batch (36.2 g, 56% w / w) obtained in a similar manner. The combined batch was diluted with aqueous HCl (2.0 L, 1.0 N, 2.0 mol) and stirred at room temperature for 30 min. Undissolved impurities were removed by filtration and the filter pad was washed with water (100 mL). Mercaptan (20 g) was added to the combined filtrate and washings, and the resulting mixture was stirred at 40° C. for 2 h and then filtered. The thiol was treated twice more as described above. The pH of the final filtrate was adjusted to pH 9-10 using 5N aqueous NaOH and the resulting mixture was stirred at 10°C to 20°C for 1 h. The precipitate was isolated by filtration and then dried in vacuo to afford the title compound as an off-white solid.

[1360] Intermediate 18

[1361] Methyl 2-((tert-Butoxycarbonyl)amino)-2-(4,4-difluorocyclohexylidene)acetate

[1362]

[1363] A solution of 4,4-difluorocyclohexan-1-one (250g, 1.86mol) in DCM (500mL) is added dropwise to a stirred solution of 2-((tert-butoxycarbonyl)amino)-2-(dimethoxyphosphoryl)methyl acetate (582g, 1.96mol) and DBU (289g, 1.90mol) at 0°C (ice bath) in DCM (2.0L) at a rate keeping the internal temperature below 10°C. The reactant is then warmed to 20°C and kept at this temperature for 16h. Thereafter, water (800mL) is added, and the mixture is stirred for 30min. Each layer is separated, and the organic layer is washed three times with water, then concentrated. The residue is diluted with n-heptane (1L), and the resulting slurry is stirred and then filtered. The filter cake is dried in vacuo at 50°C to give the title compound as an off-white solid.

[1364] Intermediate 19

[1365] Methyl 2-((tert-Butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetate

[1366]

[1367] Under a nitrogen atmosphere, 2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexylidene)methyl acetate (750.0g, 2.46mol, intermediate 18) and Pd / C (75.0g, 10%w / w, 71mmol) are added to a reactor containing THF (6.0L). The resulting mixture is hydrogenated at room temperature for 18h using H2 balloon. After this, the reaction mixture is filtered, and the filter cake is rinsed with THF (1.5L). The filtrate and the rinse are combined and concentrated. The residue is diluted with n-heptane (3.75L), and the resulting slurry is stirred and then filtered. The filter cake is dried in vacuo at 50°C to give the title compound as an off-white solid.

[1368] Intermediate 20

[1369] (1-(4,4-difluorocyclohexyl)-3-(dimethyl(oxo)-λ 6 -sulfydene)-2-oxopropyl)carbamic acid tert- Butyl ester

[1370]

[1371] By trimethyl thionyl chloride (552g, 4.29mol) and potassium tert-butoxide (386g, 3.44mol) in THF (2.64L) suspension at 10 DEG C to 20 DEG C stirred 2h.After this, 2-((tert-butoxycarbonyl) amino)-2-(4,4-difluorocyclohexyl) methyl acetate (660g, 2.15mol, intermediate 19) in THF (2.64L) was added dropwise at a rate keeping the internal temperature below 20 DEG C. After the addition was completed, the resulting mixture was stirred at 10 DEG C to 20 DEG C for 48h. After this, saturated NH4Cl aqueous solution (1.32L) was added dropwise. The resulting mixture was diluted with water (1.32L) and stirred for 30min. Then the mixture was partially concentrated to remove THF, and the precipitate was separated by filtration. The filter cake was suspended in water (1L) and stirred for 2h. The mixture was filtered and the filter cake was dried in vacuo at 50 °C to give the title compound as an off-white solid.

[1372] Intermediate 21

[1373] tert-Butyl N-[(S)-(7-chloroimidazo[1,2-b]pyridazin-2-yl)-(4,4-difluorocyclohexyl)methyl]carbamate ester

[1374]

[1375] 5-Chloropyridazin-3-amine (15.0 g, 116 mmol, Intermediate 17), (1-(4,4-difluorocyclohexyl)-3-(dimethyl(oxo)-λ 6 -sulfonylidene)-2-oxopropyl)carbamic acid tert-butyl ester (46.8 g, 127 mmol, intermediate 20), K3PO4 (1.23 g, 5.80 mmol) and A mixture of molecular sieves (3.0 g) in toluene (500 mL) was stirred at room temperature for 30 min. Then under a nitrogen atmosphere, [Ir (cod) Cl] 2 (1.56 g, 2.32 mmol) was added, and the resulting mixture was heated to 95 ° C and stirred at this temperature for 16 h. Thereafter, the reaction mixture was cooled to 30 ° C and then filtered. The filter pad was washed with EtOAc, and the combined filtrate and washings were concentrated. The residue was purified by silica gel chromatography (5: 1 petroleum ether / EtOAc) to give the title compound as a light yellow solid. The solid was purified by SFC on a chiral stationary phase (Daicel Purification on AS-H, 60:40 2 mM NH in MeOH / CO2 (1% NH3 / 60%) afforded the S enantiomer as the second eluting isomer. The desired fractions were concentrated, diluted with n-heptane (2.5 volumes), and stirred at room temperature for 1 hour. The product was isolated by filtration and then dried under vacuum to afford the title compound as a colorless solid.

[1376] Alternative synthesis of intermediate 21

[1377] (S)-tert-Butyl (1-(4,4-difluorocyclohexyl)-3-iodo-2-oxopropyl)carbamate (500 mg, 1.98 mmol, intermediate 15), 5-chloropyridazin-3-amine (171 mg, 1.32 mmol), NaHCO (302 mg, 3.60 mmol) and t-BuOH (20 mL) were added to a 50 L round-bottom flask. The resulting mixture was stirred at 135 ° C for 20 h. Thereafter, the reactant was cooled to room temperature, then triturated with EtOAc (50 mL), filtered, and the filtrate was concentrated to dryness under reduced pressure to give the crude title product, which was purified by silica gel chromatography (10%-100% petroleum ether: ethyl acetate) to give the title compound as a white solid.

[1378] Intermediate 22

[1379] tert-Butyl (S)-((7-chloroimidazo[1,2-b]pyridazin-2-yl)(cyclohexyl)methyl)carbamate

[1380]

[1381] 5-Chloropyridazin-3-amine (1.5 g, 12 mmol, Intermediate 17) was added to a solution of (S)-tert-butyl (1-cyclohexyl-3-iodo-2-oxopropyl)carbamate (13.2 g, 34.6 mmol, Intermediate 6) and NaHCO3 (3.89 g, 46.3 mmol) in t-BuOH (30 mL). The mixture was then stirred at 130 ° C for 48 h. Thereafter, the mixture was cooled to room temperature and then washed with water. The product was filtered through a pad of 4% paraffin wax. The pad was rinsed with EtOAc, and the rinse was combined with the filtrate and diluted with water (50 mL). The layers were separated, and the aqueous layer was extracted three times with EtOAc. The organic extracts were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (1:0 to 4:1 petroleum ether / EtOAc) to give the title compound as a brown oil.

[1382] Intermediate 23

[1383] tert-Butyl (S)-((7-cyanoimidazolo[1,2-b]pyridazin-2-yl)(cyclohexyl)methyl)carbamate

[1384]

[1385] A mixture of (S)-tert-butyl (7-chloroimidazo[1,2-b]pyridazin-2-yl)(cyclohexyl)methyl)carbamate (800 mg, 2.19 mmol, intermediate 22), Zn(CN)2 (644 mg, 5.48 mmol) and zinc powder (29 mg, 0.44 mmol) in DMA (8.0 mL) was bubbled with argon for 5 min, and then Pd2(dba)3 (405 mg, 0.442 mmol) and XPhos (420 mg, 0.881 mmol) were added. The mixture was bubbled with argon for another 5 min. The mixture was then stirred at 120 ° C for 2 h under microwave irradiation. Thereafter, the mixture was cooled to room temperature and then purified by The product was filtered through a pad of 4% paraffin wax. The pad was rinsed with EtOAc, and the rinse was combined with the filtrate and diluted with water (30 mL). The layers were separated, and the aqueous layer was extracted three times with EtOAc. The organic extracts were combined, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (2:1 petroleum ether / EtOAc) to give the title compound as a brown oil.

[1386] Intermediate 24

[1387] (S)-2-(Amino(cyclohexyl)methyl)imidazo[1,2-b]pyridazine-7-carbonitrile hydrochloride

[1388]

[1389]

[0266] HCl solution (5.5 mL, 4.0 M in EtOAc, 22 mmol) was added to a 0°C solution of tert-butyl (S)-((7-cyanoimidazolo[1,2-b]pyridazin-2-yl)(cyclohexyl)methyl)carbamate (500 mg, 1.41 mmol, Intermediate 23) and EtOAc (5 mL), and the resulting mixture was stirred at 0°C for 4 h. The mixture was then concentrated to give the title compound as a colorless solid.

[1390] Intermediate 25

[1391] (S)-N-((7-cyanoimidazolo[1,2-b]pyridazin-2-yl)(cyclohexyl)methyl)benzamide

[1392]

[1393] Pure HATU (156 mg, 0.410 mmol) was added to a 0°C mixture of (S)-2-(amino(cyclohexyl)methyl)imidazo[1,2-b]pyridazine-7-carbonitrile hydrochloride (100 mg, 0.343 mmol, Intermediate 24), benzoic acid (50 mg, 0.41 mmol) and DIPEA (0.20 mL, 1.1 mmol) in DCM (2.0 mL), and the resulting mixture was stirred at 0°C for 2 h. The mixture was then poured into water (10 mL) and extracted three times with DCM. The organic extracts were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (1:0 to 3:1 DCM / EtOAc) to give the title compound as a yellow oil.

[1394] Intermediate 26

[1395] (S)-N-((7-(Aminomethyl)imidazo[1,2-b]pyridazin-2-yl)(cyclohexyl)methyl)benzamide

[1396]

[1397] Will -nickel (193 mg, slurry in water) was added to a mixture of (S)-N-((7-cyanoimidazolo[1,2-b]pyridazin-2-yl)(cyclohexyl)methyl)benzamide (191 mg, 0.531 mmol, Intermediate 25) and aqueous NH4OH (1.0 mL, 28% w / w ammonia, 15 mmol) in EtOH (10 mL). The reaction mixture was stirred at room temperature under H2 (15 psi) for 2 h. Thereafter, the mixture was passed through The mixture was filtered through a pad of Celite® and the pad was washed with EtOH. The filtrate and washings were combined and concentrated to give the title compound as a brown oil.

[1398] Intermediate 27

[1399] (trans-2,3)-2-(((2-((S)-Benzamido(cyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl) tert-Butyl (methyl)carbamoyl)-3-(trifluoromethyl)piperidine-1-carboxylate

[1400]

[1401] To a solution of (S)-N-((7-(aminomethyl)imidazo[1,2-b]pyridazin-2-yl)(cyclohexyl)methyl)benzamide (350 mg, 0.963 mmol, Intermediate 26), (trans-2,3)-1-(tert-butoxycarbonyl)-3-(trifluoromethyl)piperidine-2-carboxylic acid (273 mg, 0.918 mmol, Intermediate 3) and DIPEA (0.47 mL, 2.7 mmol) in DCM (5 mL) was added neat HATU (399 mg, 1.05 mmol) at 0°C, and the resulting mixture was stirred at 0°C for 2 h. The mixture was poured into water (30 mL) and extracted three times with DCM. The organic extracts were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (1 :0 to 1 :2 petroleum ether / EtOAc) to give the title compound as a diastereomeric mixture as a yellow solid.

[1402] Intermediate 28

[1403] (trans-2R*,3R*)-2-(((2-((S)-Benzamido(cyclohexyl)methyl)imidazo[1,2-b]pyridazine- tert-Butyl (7-yl)methyl)carbamoyl)-3-(trifluoromethyl)piperidine-1-carboxylate

[1404]

[1405] Intermediate 29

[1406] (trans-2S*,3S*)-2-(((2-((S)-Benzamido(cyclohexyl)methyl)imidazo[1,2-b]pyridazine- tert-Butyl (7-yl)methyl)carbamoyl)-3-(trifluoromethyl)piperidine-1-carboxylate

[1407]

[1408] Tert-butyl (trans-2,3)-2-(((2-((S)-benzamido(cyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)carbamoyl)-3-(trifluoromethyl)piperidine-1-carboxylate (Intermediate 27) was purified by SFC using a chiral stationary phase (Daicel Purification by IC, 45:55 EtOH (containing 0.1% (v / v) of 25% NH3 in water) / CO2) gave a pair of diastereomers. The first eluting isomer was Intermediate 28, and the second eluting isomer was Intermediate 29.

[1409] Intermediate 30

[1410] (trans-2,3)-2-(((2-((S)-cyclohexyl(1-methyl-1H-pyrazole-5-carboxamido)methyl)imidazo tert-Butyl [1,2-b]pyridazin-7-yl)methyl)carbamoyl)-3-(trifluoromethyl)piperidine-1-carboxylate

[1411]

[1412] The title compound was prepared as described for the synthesis of intermediate 27 using 1-methyl-1H-pyrazole-5-carboxylic acid instead of benzoic acid to give the title compound as a brown solid.

[1413] Intermediate 31

[1414] (trans-2R*,3R*)-2-(((2-((S)-cyclohexyl(1-methyl-1H-pyrazole-5-carboxamido)methyl)imidazole tert-Butyl (1,2-b]pyridazin-7-yl)methyl)carbamoyl)-3-(trifluoromethyl)piperidine-1-carboxylate

[1415]

[1416] Tert-butyl (trans-2,3)-2-(((2-((S)-cyclohexyl(1-methyl-1H-pyrazole-5-carboxamido)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)carbamoyl)-3-(trifluoromethyl)piperidine-1-carboxylate (Intermediate 30) was purified by SFC using a chiral stationary phase (Daicel Purification by IC, 45:55 i-PrOH (25% aqueous NH3 containing 0.1% (v / v)) / CO2) afforded the title compound as the first eluting isomer.

[1417] Intermediate 32

[1418] (S)-(7-chloroimidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methanamine

[1419]

[1420] Trifluoroacetic acid (8.0mL, 100mmol) is added to N-[(S)-(7-chloroimidazo[1,2-b]pyridazine-2-yl)-(4,4-difluorocyclohexyl)methyl]t-butyl carbamate (2.00g, 4.99mmol, intermediate 21), and the mixture is stirred at room temperature for 10min. After this, the resulting solution is concentrated, then diluted with saturated NaHCO3aqueous solution and EtOAc. Each layer is mixed, then separated, and the water layer is extracted twice with EtOAc. The organic layers are merged, washed with salt water, dried with anhydrous MgSO4, filtered, then concentrated to obtain the title compound as a pale solid.

[1421] Intermediate 33

[1422] (S)-N-((7-chloroimidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoromethyl)- (fluoropropyl)-1H-pyrazole-4-carboxamide

[1423]

[1424] Hünig's base (0.52 mL, 3.0 mmol) was added to a mixture of (S)-(7-chloroimidazo[1,2-b]pyridazine-2-yl)(4,4-difluorocyclohexyl)methanamine (750 mg, 2.49 mmol, intermediate 32), 1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxylic acid (523 mg, 2.54 mmol) and HOBt (337 mg, 2.49 mmol) in MeCN (13 mL), and the suspension was stirred for 10 min. EDCI (478 mg, 2.49 mmol) was then added and the mixture was stirred at room temperature for 3 h. Thereafter, the suspension was filtered and the filter cake was washed with MeCN / water (20 mL, 1: 1 v / v) and then with water (20 mL). The filtrate became isomeric with the introduction of water, combined with the filter cake and refiltered. The new filter cake was washed with water and then dried by suction. The filter cake was diluted with acetone (about 10 mL) and then filtered. The filtrate was then concentrated to give the title compound as an off-white solid.

[1425] Intermediate 34

[1426] (S)-N-((4,4-difluorocyclohexyl)(7-vinylimidazo[1,2-b]pyridazin-2-yl)methyl)-1-(3,3, 3-(Trifluoropropyl)-1H-pyrazole-4-carboxamide

[1427]

[1428] (S)-N-((7-chloroimidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide (790 mg, 1.37 mmol, 85% w / w, Intermediate 33), potassium trifluoro(vinyl)borate (275 mg, 2.05 mmol), Pd(dtbpf)Cl2 (180 mg, 0.27 mmol) and K3PO4 (870 mg, 4.1 mmol) were combined in a reactor, which was evacuated and backfilled with nitrogen three times. The mixture was then diluted with 1,4-dioxane and water (15 mL, 4:1 v / v), and the resulting mixture was bubbled with argon for 15 min. The mixture was then stirred at 100°C for 2.5 h. Thereafter, the reaction mixture was cooled to room temperature and then diluted with water and EtOAc. In the mixture of 4-nitro-2-nitro-1-oxo-2-nitropropene, 4-nitro-1-nitropropene, 4-nitro-2 ...

[1429] Intermediate 35

[1430] (S)-N-((4,4-difluorocyclohexyl)(7-formylimidazo[1,2-b]pyridazin-2-yl)methyl)-1-(3,3, 3-(Trifluoropropyl)-1H-pyrazole-4-carboxamide

[1431]

[1432] A solution of NaIO4 (1.1 g, 5.2 mmol) in water (25 mL) was added to a solution of (S)-N-((4,4-difluorocyclohexyl)(7-vinylimidazo[1,2-b]pyridazin-2-yl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide (500 mg, 1.04 mmol, Intermediate 34) in 1,4-dioxane (25 mL), followed by the addition of K2OsO4·2HO (76 mg, 0.21 mmol), and the resulting mixture was stirred at room temperature for 1.5 h. Thereafter, the resulting thick suspension was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give a brown residue. The residue was purified by silica gel chromatography (30% to 100% acetone / hexanes) to give the title compound as a colorless solid.

[1433] Intermediate 36

[1434] N-((S)-(7-((E)-(((S)-tert-butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazine-2-yl 4-(2-( ...methyl-1-thiazolyl)methyl)-1H-pyrazole-4-carboxamide))-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide)

[1435]

[1436] Copper (II) sulfate (311 mg, 1.95 mmol) and PPTS (15 mg, 0.061 mmol) were then added sequentially to a solution of (S)-N-((4,4-difluorocyclohexyl)(7-formylimidazo[1,2-b]pyridazin-2-yl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide (310 mg, 0.61 mmol, Intermediate 35) and (S)-(-)-2-methyl-2-propanesulfenamide (77 mg, 0.64 mmol) in THF (2 mL), and the mixture was stirred at room temperature for 18 h. Thereafter, an additional portion of CuSO4 (311 mg, 1.95 mmol) was added, and the mixture was stirred at 55°C for 8 h and then at 45°C for another 16 h. Thereafter, an additional portion of 1,2-difluoro-4-(7-formylimidazo[1,2-b]pyridazin-2-yl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide was added. The mixture was filtered. The pad was washed with DCM, and the filtrate and washings were combined and concentrated to give the title compound as a brown solid.

[1437] Intermediate 37

[1438] N-((1S)-(7-((((S)-tert-butylsulfinyl)amino)(cyclopropyl)methyl)imidazo[1,2-b]pyridazine- 2-amino)(4,4-difluorocyclohexylmethyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[1439]

[1440] Cyclopropylmagnesium bromide solution (2.0 mL, 0.92 M in 2-MeTHF, 1.8 mmol) was added dropwise to a stirred solution of N-((S)-(7-((((S)-tert-butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide (360 mg, 0.61 mmol, intermediate 36) in DCM (6.5 mL) at -78 °C, and the resulting solution was slowly warmed to 0 °C over 1 h. After this, saturated NH4Cl aqueous solution was added, followed by water. The layers were mixed and then separated. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated to give a brown foam. Purify the foam by silica gel chromatography (50% to 100% acetone / hexanes) to provide the title compound as a colorless film. 1 H NMR analysis showed a 4:1 mixture of diastereomers.

[1441] Intermediate 38

[1442] N-((1S)-(7-(amino(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl) methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[1443]

[1444] To a solution of N-((1S)-(7-((((S)-tert-butylsulfinyl)amino)(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide (292 mg, 91% w / w, 0.420 mmol, Intermediate 37) in 1,4-dioxane (3.0 mL) was added HCl solution (0.32 mL, 4.0 M in dioxane, 1.3 mmol) and the mixture was stirred for 1.5 h. Thereafter, the resulting solution was concentrated. The residue was diluted with EtOAc and water. The layers were mixed and then separated, and the aqueous layer was washed with EtOAc. The organic layers were combined, extracted with water, and then discarded. The aqueous layers were combined, made basic with 15% aqueous NaOH, and extracted three times with EtOAc. The organic extracts were combined, dried over anhydrous MgSO 4 , filtered and concentrated to give the title compound as a diastereomeric mixture as an off-white solid.

[1445] Intermediate 39

[1446] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4, 4-(4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[1447]

[1448] A mixture of N-((1S)-(7-(amino(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide (117 mg, 0.210 mmol, 96% w / w, Intermediate 38), 4,4,4-trifluorobutyric acid (34 mg, 0.24 mmol) and HOBt (29 mg, 0.21 mmol) was diluted with MeCN (1.2 mL). Hünig's base (0.044 mL, 0.26 mmol) was added followed by EDCI (41 mg, 0.21 mmol) and the resulting solution was maintained at room temperature for 30 min and then at 45° C. for 2 h. After this time, water and EtOAc were added. The layers were separated and the aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated. The residue was purified by silica gel chromatography (40% to 100% acetone / hexanes) to give the title compound as a diastereomeric mixture as a colorless film.

[1449] Intermediate 40

[1450] N-((1S)-(7-(cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-b]pyridazine- 2-amino)(4,4-difluorocyclohexylmethyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[1451]

[1452] The title compound was prepared as described for the synthesis of intermediate 39 using 2-(3,3-difluorocyclobutyl)acetic acid instead of 4,4,4-trifluorobutyric acid to afford the title compound as a colorless solid as a diastereomeric mixture.

[1453] Intermediate 41

[1454] N-((1S)-(7-(cyclopropyl(4,4,4-trifluoro-3-(trifluoromethyl)butanamido)methyl)imidazo[1,2-b] Pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[1455]

[1456] The title compound was prepared as described for the synthesis of intermediate 39 using 1-isopropyl-1H-pyrazole-5-carboxylic acid instead of 1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxylic acid and 4,4,4-trifluoro-3-(trifluoromethyl)butanoic acid instead of 4,4,4-trifluorobutyric acid to give the title compound as a colorless solid as a diastereomeric mixture.

[1457] Intermediate 42

[1458] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4, 4-(4-Difluorocyclohexyl)methyl)benzamide

[1459]

[1460] The title compound was prepared as described for the synthesis of intermediate 39 using benzoic acid instead of 1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxylic acid to give the title compound as a colorless solid as a diastereomeric mixture.

[1461] Intermediate 43

[1462] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4, (4-(difluorocyclohexyl)methyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[1463]

[1464] The title compound was prepared as described for the synthesis of intermediate 58 using 1-isopropyl-1H-pyrazole-5-carboxylic acid instead of 1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxylic acid to give the title compound as a colorless solid as a diastereomeric mixture.

[1465] Intermediate 44

[1466] N-((1S)-(7-(cyclopropyl(4,4,4-trifluoro-3-(trifluoromethyl)butanamido)methyl)imidazo[1,2-b] Pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)benzamide

[1467]

[1468] The title compound was prepared as described for the synthesis of intermediate 39 using benzoic acid instead of 1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxylic acid and 4,4,4-trifluoro-3-(trifluoromethyl)butanoic acid instead of 4,4,4-trifluorobutyric acid to give the title compound as a colorless solid as a diastereomeric mixture.

[1469] Intermediate 45

[1470] tert-(S)-((4,4-difluorocyclohexyl)(7-vinylimidazo[1,2-b]pyridazin-2-yl)methyl)carbamic acid Butyl ester

[1471]

[1472] Under positive nitrogen pressure, tert-butyl N-[(S)-(7-chloroimidazo[1,2-b]pyridazin-2-yl)-(4,4-difluorocyclohexyl)methyl]carbamate (9.00 g, 22.5 mmol, intermediate 21), potassium trifluoro(vinyl)borate (4.51 g, 33.7 mmol) and K3PO4 (14.3 g, 67.4 mmol) were added to a reactor containing 1,4-dioxane and water (250 mL, 5:1 v / v, sparged with argon before use). The mixture was heated to reflux temperature (88°C) and then a solution of RuPhosPdG3 (470 mg, 0.56 mmol) in 1,4-dioxane (5 mL) was added and the mixture was stirred at reflux temperature for 1.5 h. Afterwards, the mixture was cooled to room temperature and then concentrated to remove most of the 1,4-dioxane. The residue was diluted with EtOAc and water, the layers were separated, and the aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give the title compound as a brown foam.

[1473] Intermediate 46

[1474] tert-(S)-((4,4-difluorocyclohexyl)(7-formylimidazo[1,2-b]pyridazin-2-yl)methyl)carbamic acid Butyl ester

[1475]

[1476] A solution of NaIO4 (24.0 g, 112 mmol) in water (540 mL) was added to a solution of tert-butyl (S)-((4,4-difluorocyclohexyl)(7-vinylimidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (8.81 g, 22.5 mmol, Intermediate 45) in 1,4-dioxane (540 mL), followed by the addition of K2OsO4·2H2O (827 mg, 2.25 mmol). The reaction immediately began to heat up, so the reactor was placed in an ice bath for 15 min to maintain the temperature close to 30°C. Thereafter, the reaction mixture was stirred at room temperature for 1.75 h. Thereafter, the resulting thick suspension was passed through The 1-Hydroxy-2-nitropropene was added to 4-nitropropene (2-nitropropene)-2 ...

[1477] Intermediate 47

[1478] ((S)-(7-((((S)-tert-Butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4, tert-Butyl (4-difluorocyclohexyl)methyl)carbamate

[1479]

[1480] A mixture of (S)-tert-butyl((4,4-difluorocyclohexyl)(7-formylimidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (7.65 g, 19.4 mmol, Intermediate 46), (S)-(-)-2-methyl-2-propanesulfenamide (2.47 g, 20.4 mmol), CuSO4 (9.91 g, 62.1 mmol) and PPTS (488 mg, 1.94 mmol) was diluted with THF (64 mL), and the mixture was stirred at 55° C. overnight. Thereafter, the mixture was diluted with DCM and added The mixture was filtered. The filter pad was washed with DCM, and the filtrate and washings were combined and concentrated to give the title compound as an orange foam.

[1481] Intermediate 48

[1482] ((S)-(7-((R)-(((S)-tert-Butylsulfinyl)amino)(cyclopropyl)methyl)imidazo[1,2-b]pyridinium tert-Butyl (2-oxazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[1483]

[1484] A solution of tert-butyl ((S)-(7-((((S)-tert-butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (9.65 g, 19.4 mmol, intermediate 47) in DCM (205 mL) was cooled to -78 ° C. A solution of cyclopropylmagnesium bromide in 2-MeTHF (51 mL, 0.88 M, 45 mmol) was then added at a rate to keep the internal temperature below -60 ° C. When the addition was complete, the resulting solution was moved to an ice bath and allowed to slowly warm to 0 ° C over 1 h. Thereafter, saturated aqueous NH4Cl was added. Sufficient water was then added to dissolve the precipitate formed upon addition of the NH4Cl solution, and the layers were mixed and then separated. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, filtered, and then concentrated to give a brown foam. The residue was purified twice by silica gel chromatography (30% to 70% acetone / hexanes) to provide the title compound as a colorless foam.

[1485] Intermediate 49

[1486] ((S)-(7-((R)-amino(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl) tert-Butyl methylcarbamate

[1487]

[1488] A solution of HCl in 1,4-dioxane (6.7 mL, 4.0 M, 27 mmol) was added to a solution of tert-butyl ((S)-(7-((R)-(((S)-tert-butylsulfinyl)amino)(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (6.64 g, 11.7 mmol, Intermediate 48) in EtOAc (58 mL), and the solution was stirred at room temperature for 20 h. After this time, additional HCl in 1,4-dioxane (0.29 mL, 4.0 M, 1.2 mmol) was added to the resulting suspension, and stirring was continued for 24 h. The suspension was then diluted with water (40 mL), and the layers were mixed and then separated. The organic layer was extracted twice with water (2×10 mL), and all the aqueous layers were combined and washed with EtO (25 mL). The Et2O washings were discarded. The aqueous layer was made basic with 15% aqueous NaOH and then extracted three times with EtOAc. The organic extracts were combined, dried over anhydrous MgSO4, filtered, and concentrated to afford the title compound as a tan foam.

[1489] Intermediate 50

[1490] ((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-b]pyridazin-2-yl) tert-Butyl (4,4-difluorocyclohexyl)methyl)carbamate

[1491]

[1492] A flask was charged with a stirrer, tert-butyl ((S)-(7-((R)-amino(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (500 mg, 1.11 mmol, Intermediate 49), 4,4,4-trifluorobutyric acid (171 mg, 1.17 mmol), HOBt (158 mg, 1.17 mmol), acetonitrile (50 mL) and Hünig's base (0.29 mL, 1.67 mmol) and the solution was stirred until homogeneous (approximately 5 min). EDCI (224 mg, 1.17 mmol) was added to the solution and the mixture was stirred for 30 min. The reaction was heated to 45 °C and stirred for 1 h. The reaction was cooled to room temperature and quenched by the addition of water and ethyl acetate. The layers were separated and the aqueous phase was further extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated to give the title compound as a white solid.

[1493] Intermediate 51

[1494] N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)(cyclopropyl (4-(2-Methyl)-4,4,4-trifluorobutyramide)

[1495]

[1496] A vial was charged with a stirrer, tert-butyl ((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate (600 mg, 1.072 mmol, intermediate 50) and TFA (3 mL, 39.2 mmol) and stirred for 5 min. The reaction was condensed to a yellow oil and quenched by careful addition of saturated aqueous NaHCO3. The basic aqueous phase was extracted with ethyl acetate (2 x 15 mL). The combined organics were washed with brine, dried over anhydrous MgSO4, filtered and condensed to give the title compound as an off-white foam.

[1497] Intermediate 52

[1498] (S)-N-((7-chloroimidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoromethyl)- (2-(2-fluoropropyl)-2H-1,2,3-triazole-4-carboxamide)

[1499]

[1500] A flask was charged with a stirrer, (S)-(7-chloroimidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methanamine (0.5 g, 1.48 mmol, Intermediate 32), 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylic acid (0.34 g, 1.63 mmol, Intermediate 76), HOBt (0.21 g, 1.56 mmol), acetonitrile (45 mL) and Hünig's base (1.02 mL, 0.75 g / mL, 5.93 mmol). The reaction was stirred for 5 min, and then EDCI (0.298 g, 1.56 mmol) was added to the solution. The reaction was stirred overnight. The reaction was partitioned between water and ethyl acetate. The layers were separated, and the aqueous phase was further extracted with ethyl acetate (3×3 mL). The combined organics were washed with brine, dried over anhydrous MgSO 4 , filtered and condensed to give the title compound as an off-white foam.

[1501] Intermediate 53

[1502] (S)-N-((4,4-difluorocyclohexyl)(7-vinylimidazo[1,2-b]pyridazin-2-yl)methyl)-2-(3,3, 3-(trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide

[1503]

[1504] A microwave vial was charged with a stirrer, (S)-N-((7-chloroimidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide (460 mg, 0.935 mmol, intermediate 52), potassium trifluoro(vinyl)borate (188 mg, 1.40 mmol), K PO (596 mg, 2.81 mmol), and 1,4-dioxane and water (10 mL, 5: 1 v / v). The reaction mixture was bubbled with argon for 5 min, then Pd(dtbpf)Cl (122 mg, 0.187 mmol) was added and the mixture was bubbled with argon for an additional 5 min. The vial was sealed and heated to 100° C. using microwave radiation and stirred for 2 h. Thereafter, the reaction was cooled to room temperature and diluted with water and ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate (3 x 5 mL). The combined organics were washed with brine, dried over anhydrous MgSO4, filtered and condensed to a brown oil. The crude material was purified by silica gel chromatography (0-100% ethyl acetate / hexanes) to give the title compound as a tan solid.

[1505] Intermediate 54

[1506] (S)-N-((4,4-difluorocyclohexyl)(7-formylimidazo[1,2-b]pyridazin-2-yl)methyl)-2-(3,3, 3-(trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide

[1507]

[1508] A flask was charged with a stirrer, (S)-N-((4,4-difluorocyclohexyl)(7-vinylimidazo[1,2-b]pyridazin-2-yl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide (350 mg, 0.724 mmol, Intermediate 53), 1,4-dioxane and water (60 mL, 1:1 v / v) and K2OsO4·2H2O (53.3 mg, 0.145 mmol). NaIO4 (0.774 g, 3.62 mmol) was added to the solution and the reaction was stirred at room temperature for 1 h. After this time, the resulting thick suspension was diluted with additional water and extracted with ethyl acetate (3×20 mL). The combined organics were washed with brine, dried over anhydrous MgSO4, filtered and condensed to a brown residue. The crude material was purified by silica gel chromatography (10%-100% ethyl acetate / hexanes) to provide the title compound as an off-white solid.

[1509] Intermediate 55

[1510] N-((S)-(7-((E)-(((S)-tert-butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazine-2-yl 4-(4-(2-(4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide

[1511]

[1512] A vial was charged with a stirrer, N-((S)-(7-((E)-(((S)-tert-butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide (280 mg, 0.57 mmol, Intermediate 54), (S)-2-methylpropane-2-sulfinamide (141 mg, 1.17 mmol), PPTS (39 mg, 0.15 mmol), copper(II) sulfate (956 mg, 5.99 mmol) and THF (2.5 mL). The vial was sealed and stirred at 75° C. overnight. The mixture was cooled to room temperature and added The mixture was filtered and washed with DCM. The filtrate and combined washings were condensed to give the title compound as a glassy yellow solid.

[1513] Intermediate 56

[1514] N-((1S)-(7-((((S)-tert-butylsulfinyl)amino)(cyclopropyl)methyl)imidazo[1,2-b]pyridazine- 2-(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide

[1515]

[1516] A flask was charged with N-((S)-(7-((E)-(((S)-tert-butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide (180 mg, 0.306 mmol, Intermediate 55) and THF (3.25 mL). The flask was cooled to 0°C and a solution of cyclopropylmagnesium bromide (0.950 mL, 1 M in 2-methyltetrahydrofuran, 0.948 mmol) was added dropwise. The reaction was allowed to warm to room temperature over 30 min. The reaction was poured into saturated aqueous NH4Cl and further diluted with water and ethyl acetate. The layers were separated and the aqueous phase was extracted once more with ethyl acetate (10 mL). The combined organics were washed with brine, dried over anhydrous MgSO 4 , filtered and condensed to give the title compound as an off-white foam. 1 H NMR analysis showed a 3:1 mixture of diastereomers.

[1517] Intermediate 57

[1518] N-((1S)-(7-(amino(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl) methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide

[1519]

[1520] A flask was charged with a stirrer, N-((1S)-(7-((((S)-tert-butylsulfinyl)amino)(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide (175 mg, 0.27 mmol, Intermediate 56), 1,4-dioxane (2 mL), and HCl (0.21 mL, 4 M in dioxane). The reaction was stirred for 10 min and then condensed to an off-white residue. The crude material was taken up in water and washed with hexanes (2×5 mL). The aqueous layer was made basic by the addition of 1 N aqueous NaOH and then extracted with ethyl acetate (3×5 mL). The combined organics were washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated to give the title compound as an off-white foam as a diastereomeric mixture.

[1521] Intermediate 58

[1522] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4, 4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide

[1523]

[1524] A vial was charged with a stirrer, 4,4,4-trifluorobutyric acid (40 mg, 0.27 mmol), HATU (105 mg, 0.27 mmol), and DMF (1 mL), then stirred for 5 min. To the stirred homogeneous solution was added N-((1S)-(7-(amino(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide (110 mg, 0.21 mmol, Intermediate 57) and Hünig's base (0.072 mL, 0.42 mmol). The reaction was stirred for a further 10 min, then poured into water and diluted with ethyl acetate. The layers were separated, and the aqueous phase was further extracted with ethyl acetate (2 x 5 mL). The combined organics were washed with 10% aqueous lithium chloride solution, then brine, dried over anhydrous MgSO4, filtered and condensed to a glassy residue. The crude material was purified by silica gel chromatography (0-100% (10% MeOH in ethyl acetate) / hexanes) to give a mixture of diastereomers as an off-white foam.

[1525] Intermediate 59

[1526] N-((1S)-(7-(cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-b]pyridazine- 2-yl)(4,4-difluorocyclohexylmethyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxamide

[1527]

[1528] The title compound was prepared as described for the synthesis of intermediate 58 using 1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxylic acid instead of 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylic acid and 2-(3,3-difluorocyclobutyl)acetic acid instead of 4,4,4-trifluorobutyric acid to give the title compound as a glassy solid as a mixture of diastereoisomers.

[1529] Intermediate 60

[1530] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4, 4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxamide

[1531]

[1532] The title compound was prepared as described for the synthesis of intermediate 59 using 4,4,4-trifluorobutyric acid instead of 2-(3,3-difluorocyclobutyl)acetic acid to afford the title compound as a glassy solid as a diastereomeric mixture.

[1533] Intermediate 61

[1534] N-((1S)-(7-(cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-b]pyridazine- 2-(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide

[1535]

[1536] The title compound was prepared as described for the synthesis of intermediate 58 using 2-(3,3-difluorocyclobutyl)acetic acid instead of 4,4,4-trifluorobutyric acid to afford the title compound as a glassy solid as a diastereomeric mixture.

[1537] Intermediate 62

[1538] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4, 4-(4-difluorocyclohexyl)methyl)-1-methyl-1H-pyrazole-5-carboxamide

[1539]

[1540] The title compound was prepared as described for the synthesis of intermediate 58 using 1-methyl-1H-pyrazole-5-carboxylic acid instead of 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylic acid to give the title compound as a glassy solid as a mixture of diastereomers.

[1541] Intermediate 63

[1542] N-((1S)-(7-(cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-b]pyridazine- 2-yl)(4,4-difluorocyclohexylmethyl)-1-methyl-1H-pyrazole-5-carboxamide

[1543]

[1544] The title compound was prepared as described for the synthesis of intermediate 62 using 2-(3,3-difluorocyclobutyl)acetic acid instead of 4,4,4-trifluorobutyric acid to afford the title compound as a glassy solid as a mixture of diastereomers.

[1545] Intermediate 64

[1546] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4, 4-(difluorocyclohexyl)methyl)-2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxamide

[1547]

[1548] The title compound was prepared as described for the synthesis of Intermediate 58 using 2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxylic acid (Intermediate 106) instead of 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylic acid to give the title compound as a glassy solid as a mixture of diastereomers.

[1549] Intermediate 65

[1550] N-((1S)-(7-(cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-b]pyridazine- 2-(4,4-difluorocyclohexyl)methyl)-2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxamide

[1551]

[1552] The title compound was prepared as described for the synthesis of intermediate 64 using 2-(3,3-difluorocyclobutyl)acetic acid instead of 4,4,4-trifluorobutyric acid to afford the title compound as a glassy solid as a mixture of diastereomers.

[1553] Intermediate 66

[1554] N-((1S)-7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4, 4-(4-difluorocyclohexyl)methyl)-2-(2,2,2-trifluoroethyl)-2H-1,2,3-triazole-4-carboxamide

[1555]

[1556] The title compound was prepared as described for the synthesis of intermediate 58 using 2-(2,2,2-trifluoroethyl)-2H-1,2,3-triazole-4-carboxylic acid (intermediate 104) instead of 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylic acid to give the title compound as a glassy solid as a mixture of diastereomers.

[1557] Intermediate 67

[1558] N-((1S)-(7-(cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-b]pyridazine- 2-(4,4-difluorocyclohexyl)methyl)-2-(2,2,2-trifluoroethyl)-2H-1,2,3-triazole-4-carboxamide

[1559]

[1560] The title compound was prepared as described for the synthesis of intermediate 66 using 2-(3,3-difluorocyclobutyl)acetic acid instead of 4,4,4-trifluorobutyric acid to afford the title compound as a glassy solid as a mixture of diastereomers.

[1561] Intermediate 68

[1562] N-((1S)-(7-(cyclopropyl((R)-2-hydroxy-3,3-dimethylbutanamido)methyl)imidazo[1,2-b]pyridinium oxazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxamide

[1563]

[1564] The title compound was prepared as described for the synthesis of intermediate 64 using (R)-2-hydroxy-3,3-dimethylbutanoic acid in place of 4,4,4-trifluorobutanoic acid to afford the title compound as a glassy solid as a mixture of diastereomers.

[1565] Intermediate 69

[1566] N-((1S)-(7-(cyclopropyl(4,4,4-trifluoro-2-hydroxybutyramido)methyl)imidazo[1,2-b]pyridazine- 2-(4,4-difluorocyclohexyl)methyl)-2-(2,2,2-trifluoroethyl)-2H-1,2,3-triazole-4-carboxamide

[1567]

[1568] The title compound was prepared as described for the synthesis of intermediate 66 using 4,4,4-trifluoro-2-hydroxybutyric acid in place of 4,4,4-trifluorobutyric acid to afford the title compound as a glassy solid as a mixture of diastereomers.

[1569] Intermediate 70

[1570] (S)-N-((7-cyanoimidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(3,3,3- (trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide

[1571]

[1572] A microwave vial was charged with a stirrer, (S)-N-((7-chloroimidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide (1520 mg, 3.09 mmol, Intermediate 52), dicyanozinc (363 mg, 3.09 mmol), XPhos (76 mg, 0.155 mmol), XPhos Pd G1 (122 mg, 0.155 mmol) and NMP (15 mL). The vial was purged with argon for 5 min, sealed, heated to 110° C. with microwave irradiation, and stirred for 2 h. The reaction was cooled to room temperature and then poured into water. The resulting suspension was stirred for 30 min and then collected by filtration. The solid was dissolved in ethyl acetate, washed with brine, dried over anhydrous MgSO 4 , filtered and condensed. The crude residue was purified by silica gel chromatography (0-100% (10% methanol in ethyl acetate) / hexanes) to provide the title compound as an off-white solid.

[1573] Intermediate 71

[1574] (S)-N-((7-(aminomethyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2- (3,3,3-Trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide

[1575]

[1576] The flask was charged with a stirrer, (S)-N-((7-cyanoimidazolo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide (400 mg, 0.83 mmol, intermediate 70), Nickel (340 mg, 2.9 mmol), NH3 (8 mL, 28% aqueous solution) and ethanol (24 mL). The flask was evacuated and backfilled with nitrogen three times, then the flask was evacuated and placed under a hydrogen atmosphere. The reaction was stirred at room temperature overnight. The reaction was stirred overnight. The combined filtrate and organic washes were condensed to a glassy brown solid. Prep C18 OBD TM This material was purified using a 5 μm, 30 mm x 250 mm column, 0-100% acetonitrile (0.05% TFA) / water (0.05% TFA) to afford the title compound as an off-white solid.

[1577] Intermediate 72

[1578] (4,4,4-Trifluorobutyryl)-D-leucine methyl ester

[1579]

[1580] A flask was charged with a stirrer, D-leucine methyl ester (500 mg, 2.75 mmol), 4,4,4-trifluorobutyric acid (423 mg, 2.89 mmol), MeCN (50 mL), HOBt (390 mg, 2.89 mmol) and Hünig's base (1.2 mL, 6.88 mmol). The reaction was stirred for 10 min, then EDCI (555 mg, 2.89 mmol) was added. The reaction was stirred at 45 ° C for 2 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO4 and condensed to a clear oil. The clear oil was purified by silica gel chromatography (0-100% ethyl acetate / hexane, ELSD detection, CAM staining for TLC visualization) to obtain the title compound as a clear oil.

[1581] Intermediate 73

[1582] (4,4,4-Trifluorobutyryl)-D-leucine

[1583]

[1584] A flask was charged with a stirrer, (4,4,4-trifluorobutyryl)-D-leucine methyl ester (650 mg, 2.40 mmol, intermediate 72), ethanol (1 mL), water (1 mL) and lithium hydroxide (289 mg, 12.1 mmol). The reaction was stirred at room temperature overnight. The reaction was condensed to remove ethanol and further diluted with water. The reaction was made acidic (pH 5) by adding acetic acid. The aqueous phase was extracted with ethyl acetate (3 x 5 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered and condensed to give the title compound as a white solid.

[1585] Intermediate 74

[1586] 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylic acid methyl ester

[1587]

[1588] To a mixture of 1H-1,2,3-triazole-4-carboxylic acid methyl ester (5 g, 38.2 mmol), K2CO3 (5.27 g, 38.2 mmol) and DMF (49 mL) was added 3-bromo-1,1,1-trifluoropropane (4.07 mL, 38.2 mmol), and the resulting mixture was stirred at room temperature for 17 h. Thereafter, the mixture was passed through The product was filtered through a pad of 4% paraffin wax, rinsed with EtOAc and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous solution was further extracted with EtOAc (2 × 50 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (0 to 75% EtOAc / hexane; second eluting isomer) to provide the title compound as a white solid.

[1589] Intermediate 75

[1590] 1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxylic acid methyl ester

[1591]

[1592] The title compound was prepared as described for the synthesis of intermediate 74 and was isolated as the first eluting isomer as a clear, colorless oil.

[1593] Intermediate 76

[1594] 2-(3,3,3-Trifluoropropyl)-2H-1,2,3-triazole-4-carboxylic acid

[1595]

[1596] To a mixture of methyl 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylate (4.28 g, 19.2 mmol, intermediate 74) in THF (58 mL) was added 2M NaOH aqueous solution (58 mL, 115 mmol), and the mixture was stirred at room temperature for 15 h. Afterwards, the mixture was concentrated to remove THF and then washed with EtOAc (2 × 50 mL). The aqueous layer was then acidified to pH 3 by adding 1N HCl aqueous solution and extracted with 2-MeTHF (3 × 50 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous NaSO, filtered and concentrated to dryness to provide the title compound as a white solid.

[1597] Intermediate 77

[1598] 1-(3,3,3-Trifluoropropyl)-1H-1,2,3-triazole-5-carboxylic acid

[1599]

[1600] The title compound was prepared as described for the synthesis of Intermediate 76 using methyl 1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxylate (Intermediate 75) instead of methyl 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylate to afford the title compound as a white solid.

[1601] Intermediate 78

[1602] 1-(3,3-difluoropropyl)-1H-1,2,4-triazole-5-carboxylic acid methyl ester

[1603]

[1604] In a microwave vial, 1H-1,2,4-triazole-3-carboxylic acid methyl esters (1.25g, 9.64mmol), 3,3-difluoropropan-1-ol (1.39g, 14.5mmol), PPh3(2.76g, 10.5mmol) and THF (16mL) were added. Then, DIAD (2mL, 10.5mmol) was added and the resulting mixture was stirred at room temperature for 1h. The reaction mixture was concentrated to dryness, and the residue was purified by silica gel chromatography (0 to 100% EtOAc / hexane), and the title compound was provided as a light yellow oil.

[1605] Intermediate 79

[1606] 1-(3-Fluoropropyl)-1H-1,2,4-triazole-5-carboxylic acid methyl ester

[1607]

[1608] The title compound was prepared as described for the synthesis of intermediate 78 using 3-fluoropropan-1-ol instead of 3,3-difluoropropan-1-ol and cooling the mixture to 0 °C before adding DIAD to afford the title compound as a clear colorless oil.

[1609] Intermediate 80

[1610] 1-(3-Fluoropropyl)-1H-1,2,4-triazole-5-carboxylic acid

[1611]

[1612] A solution of 1- (3- fluoropropyl) -1H-1,2,4- triazole -5- carboxylic acid methyl ester (300 mg, 1.6 mmol, intermediate 79) in THF (1.6 mL) was cooled to 0 ° C, and then 1M LiOH aqueous solution (1.76 mL, 1.76 mmol) was slowly added. The resulting mixture was stirred for 1 h at 0 ° C. Afterwards, the mixture was concentrated to remove THF and then washed with EtOAc (2 × 15 mL). The aqueous layer was acidified to pH 1.5 by adding 1N HCl aqueous solution, and a precipitate was formed. The precipitate was collected by filtration, rinsed with water and dried in vacuo to provide the title compound as a white solid.

[1613] Intermediate 81

[1614] 1-(Cyclopropylmethyl)-1H-1,2,3-triazole-5-carboxylic acid methyl ester

[1615]

[1616] The title compound was prepared as described for the synthesis of intermediate 74 using (bromomethyl)cyclopropane instead of 3-bromo-1,1,1-trifluoropropane to provide the title compound as a yellow oil.

[1617] Intermediate 82

[1618] 1-(Cyclopropylmethyl)-1H-1,2,3-triazole-5-carboxylic acid

[1619]

[1620] The title compound was prepared as described for the synthesis of Intermediate 76 using methyl 1-(cyclopropylmethyl)-1H-1,2,3-triazole-5-carboxylate (Intermediate 81) instead of methyl 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylate to afford the title compound as a white solid.

[1621] Intermediate 83

[1622] 1-(3,3-difluoropropyl)-1H-1,2,3-triazole-5-carboxylic acid ethyl ester

[1623]

[1624] The title compound was prepared as described for the synthesis of intermediate 78 using ethyl 1H-1,2,3-triazole-4-carboxylate instead of methyl 1H-1,2,4-triazole-3-carboxylate, cooling the mixture to 0°C before adding DIAD, and stirring at room temperature for 2.5 h instead of 1 h to afford the title compound as a yellow oil.

[1625] Intermediate 84

[1626] 1-(3,3-Difluoropropyl)-1H-1,2,3-triazole-5-carboxylic acid

[1627]

[1628] The title compound was prepared as described for the synthesis of Intermediate 76 using ethyl 1-(3,3-difluoropropyl)-1H-1,2,3-triazole-5-carboxylate (Intermediate 83) instead of methyl 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylate and stirring at room temperature for 5 days instead of 15 h to afford the title compound as a white solid.

[1629] Intermediate 85

[1630] (S)-N-((7-chloroimidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-5-methyl-1-(3, 3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[1631]

[1632] A mixture of (S)-(7-chloroimidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methanamine (75 mg, 0.25 mmol, intermediate 32), 5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxylic acid (67 mg, 0.29 mmol), HOBt (35 mg, 0.26 mmol), DIPEA (52 μL, 0.3 mmol) and ACN (2.8 mL) was stirred until homogeneous. Then, EDCI (50 mg, 0.26 mmol) was added and the resulting mixture was stirred at room temperature for 3.5 h. Thereafter, water was added to the mixture and the solution was extracted with EtOAc (2×15 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness to provide the title compound as a light brown solid.

[1633] Intermediate 86

[1634] (S)-N-((4,4-difluorocyclohexyl)(7-vinylimidazo[1,2-b]pyridazin-2-yl)methyl)-5-methyl- 1-(3,3,3-Trifluoropropyl)-1H-pyrazole-4-carboxamide

[1635]

[1636] To a microwave vial was added (S)-N-((7-chloroimidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide (985 mg, 1.95 mmol, Intermediate 85), potassium trifluoro(vinyl)borate (392 mg, 2.93 mmol), K3PO4 (1.24 g, 5.85 mmol) and 1,4-dioxane / water (5 / 1, 17 mL total), and the mixture was sparged with nitrogen for 10 min. Then, Pd(dtbpf)Cl2 (257 mg, 0.39 mmol) was added, and the mixture was sparged with nitrogen for 5 min. The vial was capped and stirred at 100°C for 2 h. Thereafter, the mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3×25 mL). The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness. The residue was purified by silica gel chromatography (0 to 100% EtOAc / hexanes) to provide the title compound as an amber oil.

[1637] Intermediate 87

[1638] (S)-N-((4,4-difluorocyclohexyl)(7-formylimidazo[1,2-b]pyridazin-2-yl)methyl)-5-methyl- 1-(3,3,3-Trifluoropropyl)-1H-pyrazole-4-carboxamide

[1639]

[1640] To a mixture of (S)-N-((4,4-difluorocyclohexyl)(7-vinylimidazo[1,2-b]pyridazin-2-yl)methyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide (580 mg, 1.17 mmol, Intermediate 86) and K2OsO4·2HO (86 mg, 0.23 mmol) in 1,4-dioxane / water (1:1, 30 mL) was added NaIO4 (1.25 g, 5.84 mmol), and the resulting mixture was stirred at room temperature for 1.5 h. Afterwards, another portion of K2OsO4·2HO (86 mg, 0.23 mmol) was added, and the mixture was stirred at 37°C for 30 min. Afterwards, the mixture was cooled to room temperature, diluted with water (25 mL), and extracted with EtOAc (3×20 mL). The organic layers were combined, washed with brine (25 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness. The residue was purified by silica gel chromatography (0 to 100% EtOAc / hexanes) to provide the title compound as a yellow foam.

[1641] Intermediate 88

[1642] N-((S)-(7-((E)-(((S)-tert-butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazine-2-yl 4-(3-(4-(difluorocyclohexyl)methyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxylate amine

[1643]

[1644] To a sealed tube was added (S)-N-((4,4-difluorocyclohexyl)(7-formylimidazo[1,2-b]pyridazin-2-yl)methyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide (418 mg, 0.84 mmol, Intermediate 87), 4-methylbenzenesulfonate pyridinium (56 mg, 0.22 mmol), copper(II) sulfate (1.39 g, 8.72 mmol), (S)-(-)-2-methyl-2-propanesulfenamide (206 mg, 1.7 mmol) and THF (10.5 mL). The tube was capped and stirred at 80° C. for 16 h. Afterwards, the mixture was cooled to room temperature and filtered through a column of HPLC. The filtrate was concentrated to dryness and the resulting residue was purified by silica gel chromatography (0 to 100% EtOAc / hexanes) to provide the title compound as a yellow oil.

[1645] Intermediate 89

[1646] N-((1S)-(7-((((S)-tert-butylsulfinyl)amino)(cyclopropyl)methyl)imidazo[1,2-b]pyridazine- 2-yl)(4,4-difluorocyclohexylmethyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[1647]

[1648] Cyclopropylmagnesium bromide solution (1.9 mL, 1 M in 2-MeTHF, 1.9 mmol) was added dropwise to a stirred solution of N-((S)-(7-((E)-(((S)-tert-butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide (368 mg, 0.61 mmol, Intermediate 88) in DCM (6.5 mL) at -78 °C, and the resulting solution was slowly warmed to 0 °C over 1 h. The solution was then warmed to room temperature over 1.5 h. Thereafter, saturated aqueous NH4Cl solution (25 mL) was added, followed by water (10 mL). The layers were mixed and then separated. The aqueous layer was extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (0 to 100% (10% 2M NH3 / MeOH in DCM) / DCM) to provide the title compound as a light yellow oil.

[1649] Intermediate 90

[1650] N-((1S)-(7-(amino(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl) methyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[1651]

[1652] To a solution of N-((1S)-(7-((((S)-tert-butylsulfinyl)amino)(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide (270 mg, 0.42 mmol, Intermediate 89) in EtOAc (4.5 mL) was added HCl solution (0.21 mL, 4.0 M in dioxane, 0.4 mmol), and the mixture was stirred for 30 min. Another aliquot of HCl solution (0.1 mL, 4.0 M in dioxane, 0.4 mmol) was added, and the solution was stirred at room temperature for 3 h. After this time, the resulting solution was concentrated, water (20 mL) was added, and the mixture was washed with hexanes (2×20 mL). The aqueous layer was made basic by the addition of 1N aqueous NaOH and then extracted with EtOAc (2 x 25 mL). The organic layers were combined, washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness to provide the title compound as a yellow oil as a diastereomeric mixture.

[1653] Intermediate 91

[1654] N-((1S)-(7-(cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-b]pyridazine- 2-yl)(4,4-difluorocyclohexylmethyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[1655]

[1656] A mixture of N-((1S)-(7-(amino(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide (102 mg, 0.19 mmol, intermediate 90), 2-(3,3-difluorocyclobutyl)acetic acid (34 mg, 0.22 mmol), HOBt (27 mg, 0.2 mmol), DIPEA (39 μL, 0.23 mmol) and ACN (2.1 mL) was stirred until homogeneous. EDCI (38 mg, 0.2 mmol) was then added and the resulting mixture was stirred at room temperature for 2 h. Thereafter, water was added and the mixture was extracted with EtOAc (2×20 mL). The organic layers were combined, washed with brine (25 mL), dried over anhydrous NaSO, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (0 to 100% (10% 2M NH 3 in MeOH / DCM) / DCM) to provide the title compound as a diastereomeric mixture as a cream solid.

[1657] Intermediate 92

[1658] N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutyramido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4, 4-(4-difluorocyclohexyl)methyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[1659]

[1660] The title compound was prepared as described for the synthesis of intermediate 91 using 4,4,4-trifluorobutyric acid instead of 2-(3,3-difluorocyclobutyl)acetic acid and heating the mixture to 40°C for 1.5 h after stirring at room temperature to give the title compound as a cream solid as a diastereomeric mixture.

[1661] Intermediate 93

[1662] 1-(Cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylic acid methyl ester

[1663]

[1664] The title compound was prepared as described for the synthesis of intermediate 74 using methyl 1H-1,2,4-triazole-3-carboxylate instead of methyl 1H-1,2,3-triazole-4-carboxylate and (bromomethyl)cyclopropane instead of 3-bromo-1,1,1-trifluoropropane to afford the title compound as a light yellow oil.

[1665] Intermediate 94

[1666] 1-(Cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylic acid

[1667]

[1668] To a mixture of 1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylic acid (500 mg, 2.76 mmol, intermediate 93) in THF (2.76 mL) was added 2M NaOH aqueous solution (2.76 mL, 5.52 mmol), and the mixture was stirred at room temperature for 2 h. Afterwards, the mixture was concentrated to remove THF and then washed with EtOAc (2 × 15 mL). The aqueous layer was then acidified to a pH of 1-2 by adding 1N HCl aqueous solution and a precipitate was formed. The mixture was filtered, and the filter cake was rinsed with water and dried in vacuo to provide the title compound as a white solid.

[1669] Intermediate 95

[1670] 1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazole-5-carboxylic acid methyl ester

[1671]

[1672] The title compound was prepared as described for the synthesis of intermediate 78 using 3,3,3-trifluoropropan-1-ol instead of 3,3-difluoropropan-1-ol and stirring in the microwave at 120 °C instead of room temperature for 2 h to afford the title compound as a clear colorless oil.

[1673] Intermediate 96

[1674] 1-(3,3,3-Trifluoropropyl)-1H-1,2,4-triazole-5-carboxylic acid

[1675]

[1676] The title compound was prepared as described for the synthesis of Intermediate 94 using methyl 1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazole-5-carboxylate (Intermediate 95) instead of methyl 1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylate to afford the title compound as a white solid.

[1677] Intermediate 97

[1678] Ethyl 1-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxylate

[1679]

[1680] To a mixture of ethyl 1H-pyrazole-4-carboxylate (650 mg, 4.64 mmol), KCO (641 mg, 4.64 mmol) and DMF (11 mL) was added 1-bromo-2-(trifluoromethoxy)ethane (0.56 mL, 4.64 mmol) and the resulting mixture was stirred at room temperature for 20 h. Afterwards, the mixture was partitioned between EtOAc (30 mL) and water (30 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 30 mL). The organic layers were combined, washed with water (30 mL), then washed with brine (30 mL), dried over anhydrous NaSO, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (0 to 75% EtOAc / hexane) to provide the title compound as a white solid.

[1681] Intermediate 98

[1682] 1-(2-(Trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxylic acid

[1683]

[1684] The title compound was prepared as described for the synthesis of Intermediate 76 using ethyl 1-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxylate (Intermediate 97) instead of methyl 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylate and stirring at room temperature for 19 h followed by stirring at 90° C. for 2 h to afford the title compound as a white solid.

[1685] Intermediate 99

[1686] Ethyl 1-(2-(difluoromethoxy)ethyl)-1H-pyrazole-4-carboxylate

[1687]

[1688] The title compound was prepared as described in the synthesis of Intermediate 97 using 1-bromo-2-(difluoromethoxy)ethane instead of 1-bromo-2-(trifluoromethoxy)ethane to provide the title compound as a white solid.

[1689] Intermediate 100

[1690] 1-(2-(Difluoromethoxy)ethyl)-1H-pyrazole-4-carboxylic acid

[1691]

[1692] The title compound was prepared as described for the synthesis of Intermediate 76 using ethyl 1-(2-(difluoromethoxy)ethyl)-1H-pyrazole-4-carboxylate (Intermediate 99) instead of methyl 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylate and stirring at room temperature for 19 h followed by stirring at 90° C. for 3 h to afford the title compound as a white solid.

[1693] Intermediates 101

[1694] Ethyl 2-(3,3-difluoropropyl)-2H-1,2,3-triazole-4-carboxylate

[1695]

[1696] The title compound was prepared as described for the synthesis of intermediate 78 using ethyl 1H-1,2,3-triazole-4-carboxylate instead of methyl 1H-1,2,4-triazole-3-carboxylate and cooling the mixture to 0°C and stirring at room temperature for 2.5 h instead of 1 h before adding DIAD to afford the title compound as a clear, colorless oil.

[1697] Intermediate 102

[1698] 2-(3,3-Difluoropropyl)-2H-1,2,3-triazole-4-carboxylic acid

[1699]

[1700] The title compound was prepared as described for the synthesis of Intermediate 76 using ethyl 2-(3,3-difluoropropyl)-2H-1,2,3-triazole-4-carboxylate (Intermediate 101) instead of methyl 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylate and stirring at room temperature for 2 h instead of 15 h to afford the title compound as a white solid.

[1701] Intermediate 103

[1702] 2-(2,2,2-trifluoroethyl)-2H-1,2,3-triazole-4-carboxylic acid ethyl ester

[1703]

[1704] To a mixture of 1H-1,2,3-triazole-4-carboxylic acid ethyl ester (1 g, 6.73 mmol), Cs2CO3 (2.19 g, 6.73 mmol) and DMF (8.6 mL) was added 2-iodo-1,1,1-trifluoroethane (0.67 mL, 6.73 mmol) and the resulting mixture was stirred at 40°C for 2.5 h. Thereafter, another aliquot of 2-iodo-1,1,1-trifluoroethane (0.67 mL, 6.73 mmol) was added and the mixture was stirred at 60°C for 3 d. Thereafter, the mixture was stirred at 80°C for 3 d. Thereafter, the mixture was cooled to room temperature and purified by The product was filtered through a pad of 4% paraffin wax, rinsed wit...

Claims

1. A compound selected from: or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1, having the following structure: or a pharmaceutically acceptable salt thereof. 15 . A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating and / or ameliorating IL-17A-mediated inflammatory syndrome, disorder or disease.

17. The use according to claim 16, wherein the IL-17A mediated inflammatory syndrome, disorder or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disease, multiple myeloma and systemic lupus erythematosus.

18. The use according to claim 16, wherein the compound or a pharmaceutically acceptable salt thereof is administered orally.

19. The use according to claim 16, wherein the compound or a pharmaceutically acceptable salt thereof is administered as a tablet or a capsule.

20. The compound of claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1, having the following structure: or a pharmaceutically acceptable salt thereof.

24. The use according to claim 16, wherein the IL-17A mediated inflammatory syndrome, disorder or disease is systemic lupus erythematosus.

25. The use according to claim 16, wherein the IL-17A mediated inflammatory syndrome, disorder or disease is psoriatic arthritis.

26. The use according to claim 16, wherein the IL-17A mediated inflammatory syndrome, disorder or disease is psoriasis.

27. The use according to claim 16, wherein the IL-17A mediated inflammatory syndrome, disorder or disease is atopic dermatitis.

28. The use according to claim 16, wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent.

29. The use according to claim 28, wherein the compound or a pharmaceutically acceptable salt thereof is administered simultaneously with another therapeutic agent.

30. The use according to claim 28, wherein the compound or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered sequentially.

31. The compound of claim 1 having the following structure:

32. The compound of claim 1 having the following structure:

33. The compound of claim 1 having the following structure:

34. The compound of claim 1 having the following structure:

35. The compound of claim 1 having the following structure:

36. The compound of claim 1 having the following structure:

37. The compound of claim 1 having the following structure:

38. The compound of claim 1 having the following structure:

39. The compound of claim 1 having the following structure:

40. The compound of claim 1 having the structure:

41. The compound of claim 1 having the following structure:

42. The compound of claim 1 having the structure:

43. The compound of claim 1 having the structure:

44. The compound of claim 1 having the structure:

45. The compound of claim 1 having the structure:

46. ​​The compound of claim 1 having the structure:

47. The compound of claim 1 having the structure:

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