Imidazolidazines as regulators of IL-17

Abstract

This application is filed under R 1 , R 2 , R 3 , R 4 , and R 5 discloses compounds having the following formula (I), as defined herein, or pharmaceutically acceptable salts thereof, and methods of making and using the compounds disclosed herein for treating or ameliorating syndromes, disorders, and / or diseases mediated by IL-17. [Formula 1] TIFF2023524018001564.tif30128

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 017,682, filed April 30, 2020, the entire disclosure of which is incorporated herein by reference under 35 U.S.C. §119(e).

[0002] (Reference to electronically submitted sequence listing) This application contains a Sequence Listing, which has been submitted electronically via EFS-Web as an ASCII format Sequence Listing with filename "716604_NTT-6306PC-SEQ-TEXT-FILE.txt" created on April 27, 2021, and has a size of 5 KB. The Sequence Listing submitted via EFS-Web is a part of the present specification and is incorporated by reference in its entirety herein.

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

[0004] Interleukin-17 ("IL-17"), also known as IL-17A, and CTLA-8 are produced primarily by CD4+ Th17 cells, and also by other immune cells such as CD8+ T cells, γδ T cells, NK cells, NKT cells, and innate lymphoid cells (ILCs). IL-17A exists as a homodimer (A / A) or as a heterodimer with IL-17F (A / F) and signals through binding to the dimeric receptor complex IL-17RA and IL-17RC. IL-17RA is ubiquitously expressed at particularly high levels by hematopoietic cell types, while IL-17RC is preferentially expressed by non-hematopoietic cells (Gaffen, S. Structure and signaling in the IL-17 receptor family. Nat. Rev. Immunol. 2009, 9, 556-567). IL-17A / IL-17R signaling induces de novo gene transcription by inducing NF-kB, C / EBP, and MAPK pathways through ACT1-TRAF6-TRAF4. It can also stabilize target mRNA transcription through the ACT1-TRAF2-TRAF5 complex (Amatya N.et al.,Trends in Immunology,2017,38,310-322). IL-17A stimulates the release of inflammatory mediators, including IL-6, IL-8, G-CSF, TNF-α, and IL-1β, which recruit and activate lymphocytes to sites of injury or inflammation and maintain a proinflammatory state.

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

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

[0007] In psoriatic arthritis (PsA): IL-17A is mechanistically linked to PsA through NFκB activation, which induces the transcription of several PsA-related genes, including the receptor activator of nuclear factor κB ligand (RANKL). RANKL induces the differentiation of osteoclast precursor cells into activated osteoclasts, resulting in bone resorption and subsequent joint deformation in PsA (Adamopoulos I.and Mellins E.Nature reviews Rheumatology 2015;11:189-94). PsA joints are enriched for IL-17+CD8+T cells, and the levels of this T cell subset correlate with disease activity (Menon B.et al.,Arthritis&Rheumatology 2014;66:1272-81). Synovial fibroblasts isolated from PsA patients also contain elevated IL-17R expression ex vivo and secrete increased IL-6, CXCL8, and MMP3 compared to osteoarthritis patients. Both secukinumab and ixekizumab are FDA-approved drugs for PsA. In a matched-adjusted indirect comparison analysis, secukinumab was associated with higher ACR20 / 50 / 70 response rates than anti-TNFα antibodies in patients with active PsA (Mease P. et al., Eur. J. Rheumatol. 2019 Jul1;6(3):113-121; Strand V. et al., J. Comp. Eff. Res. 2019,8(7):497-510; Nash P. et al., Rheumatol. Ther. 2018,5(1):99-122). In a recent head-to-head study, ixekizumab was superior to adalimumab in achieving simultaneous improvement in joint and skin disease (ACR50 and PASI100) in patients with PsA and inadequate response to conventional synthetic disease-modifying antirheumatic drugs (Mease, P. et al. Ann Rheum Diss 2020;79:123-131).By attacking the same target, IL-17A small molecule inhibitor compounds may exert similar or better efficacy than biologics, where small molecules generally appear to have better tissue penetration.

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

[0009] In the case of Ankylosing Spondylitis (AS): Various studies have reported an increase in IL-17A and Th17, as well as other cells that produce IL-17, in blood samples from AS (Wendling D. et al., Joint Bone Spine. 2007; 74: 304-305; Shen H. et al., Arthritis Rheum. 2009; 60 (6): 1647-56; Zhang L. et al., PLoS One. 2012; 7 (4): e31000; Jansen D. et al., Rheumatology (Oxford). 2015 Apr; 54 (4): 728-735). In situ analysis of AS spines has revealed increased IL-17A-producing cells in the bone of the facet (articular) joints (Appel H. et al., Arthritis Res. Ther. 2011;13(3):R95). Two advanced IL-17A neutralizing antibodies, FDA approved secukinumab and ixekizumab, for AS, have shown efficacy over placebo, even in anti-TNF poor responders. In contrast, anti-IL-23 p40 and p19 biologics failed to show beneficial effects (Deodhar A. et al., Arthritis Rheumatol. 2019, 71(2):258-270; Baeten D. et al., Ann. Rheum. Dis. 2018, 77(9):1295-1302), indicating different underlying mechanisms along the IL-23 / IL-17 pathway in AS and providing strong evidence to support the continued development of IL-17A inhibitors.

[0010] In the case of hidradenitis suppurativa (HS): In skin lesions of HS patients, an increase in IL-17 and IL-17-producing T helper cells has been reported, and molecular proteomic and gene expression data indicate that the IL-23 / Th17 pathway is upregulated in HS lesions (Schlapbach C. et al., J. Am. Acad. Dermatol. 2011; 65(4): 790; Kelly G. et al., British J. Dermatol. 2015 Dec; 173(6): 1431-9; Moran B. et al., J. Invest. Dermatol. 2017; 137(11): 2389; Thomi R. et al., JAMA Dermatol. 2018; 154(5): 592). Seven out of nine (78%) patients with moderate-to-severe HS achieved HiSCR in an open-label pilot study with secukinumab (Prussick L. et al., British J. Dermatol. 2019 Sep;181(3):609-611), and further clinical trials with anti-IL-17 mAbs in HS are ongoing.

[0011] In bullous pemphigoid (BP): IL-17 is elevated in blister fluid and perilesional skin of BP patients. (Le Jan 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 12 IL-17-related genes in one third of patients, providing a genetic link 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 L J Autoimmun. 2019,96:104-112). Phase 2 of ixekizumab in treatment-naïve and refractory BP patients is ongoing (NCT03099538).

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

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

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

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

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

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

[0018] In multiple myeloma (MM): IL-17A serum levels are significantly higher in MM patients, and also in those with advanced stages compared to healthy subjects (Lemancewicz D. et al., Med. Sci. Monit. 2012; 18(1): BR54-BR59). In the SCIDhu model of human myeloma, weekly administration of secukinumab for 4 weeks after the first detection of tumors in mice resulted in a significant inhibition of tumor growth and reduced bone damage compared to isotype control mice (Prabhala R. et al., Leukemia. 2016 February; 30(2): 379-389).

[0019] In the case of systemic lupus erythematosus (SLE): Increased serum or plasma IL-17 levels, proliferation of IL-17-producing T cells in peripheral blood, and infiltration of Th17 cells in target organs such as the kidney were 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 was observed in SLE patients, including in the quiescent phase (Ma J. et al., Clin. Rheumatol. 2010; 29(11): 1251-1258, Dolff S. et al., Clin. Immunol. 2011, 141(2): 197-204). Overexpression of IL-17A using adenovirus improved the severity of lupus nephritis, whereas blocking IL-17A using neutralizing antibodies resulted in a decrease in the severity of lupus nephritis (Wen, Z. et al., PLoS One. 2013, 8: e58161). In a phase 2 study, ustekinumab, an anti-IL-12 / 23p40 monoclonal antibody that blocks the IL-23 / IL-17 pathway, showed efficacy in SLE patients (van Vollenhoven R.et al.,Lancet 2018;392:1330-39). Human expression studies, animal models, and clinical trials indicate that IL-17 blockade may be a promising therapeutic strategy for SLE (Koga T.et al.,Expert Rev.Clin.Immunol.2019,15(6)629-637).

[0020] In summary, animal and human studies indicate that IL-17A plays an important role in the pathogenesis of multiple diseases and / or conditions discussed above. The importance of targeting IL-17A is shown by the transformative efficacy of IL-17A neutralizing antibodies in patients. Although no oral small molecule IL-17A inhibitors have yet progressed to late-stage clinical trials, they are an attractive area of ​​discovery because their development could expand treatment options for many patients who do not have access to biologics. In addition, safe and effective small molecule IL-17A inhibitors could provide significant benefits to patients, such as convenient dosing regimens and cost savings, which could in turn provide effective long-term disease management. Summary of the Invention

[0021] Thus, there is a need for new small molecule IL-17A modulators (eg, inhibitors).

[0022] The present application relates to a compound of formula I:

[0023] [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (1~6) Alkyl, -C (0~2) Alkyl C (3~6) cycloalkyl, or 5- to 6-membered heterocyclyl having 1 to 2 nitrogen atoms; -C (1~6) Alkyl is unsubstituted or has 1 to 6 R 1a is substituted with a group, -C (0~2) Alkyl C (3~6) Cycloalkyl is unsubstituted or has 1 to 6 R 1b is substituted with a group, The 5- to 6-membered heterocyclyl is unsubstituted or has 1 to 3 R 1c is substituted with a group, R 2 But, H, -C (3~5)Cycloalkyl or -C (1~4) Alkyl, -C (1~4) Alkyl is unsubstituted or has 1 to 6 R 2a is substituted with a group, R 1a , R 1b , and R 2a each independently represents fluorine, -C (3~5) Cycloalkyl, -CN, -OH, -OC (1~3) Alkyl or -OC (3~4) Cycloalkyl, -OC (1~3) Alkyl and -OC (3~4) the cycloalkyl group is unsubstituted or substituted with 1 to 3 fluorine atoms; Each R 1c But independently, -OCH 3 , -OCF 3 , -OCHF 2 or unsubstituted or substituted with 1 to 6 fluorine atoms -C (1~4) is alkyl, R 3 But -C (0~1) Alkyl C (3~6) Cycloalkyl, -C (3~6) Alkyl or -C (1~2) Alkyl-OC (1~3) Alkyl, -C (0~1) Alkyl C (3~6) Cycloalkyl, -C (3~6) Alkyl, and -C (1~2) Alkyl-OC (1~3) Alkyl is unsubstituted or substituted with fluorine, -CH 3 -CHF 2 , -CF 3 1 to 5 R independently selected from , OH, and ═O; 3a is substituted with a group, R 4 But -C (3~6) cycloalkyl, phenyl, or 5-6 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S; C (3~6) Cycloalkyl is unsubstituted or is halogen, -OC (1~3) Alkyl, and -C(1~4) 1 to 3 R independently selected from alkyl 4a is substituted with the group -OC (1~3) Alkyl and -C (1~4) Alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms; Alternatively, two R's attached to the same ring atom 4a The groups, in combination with the atoms to which they are attached, form C (3~6) may form a cycloalkyl, Phenyl is unsubstituted or is selected from the group consisting of 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) 1 to 3 R independently selected from alkyl, and 3 to 6-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; 4b is substituted with the group -OC (1~3) Alkyl, -C (0~2) Alkyl-C (3~4) Cycloalkyl, and -C (1~4) the alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms, the heterocyclyl is unsubstituted or substituted with one oxo; The 5- to 6-membered heteroaryl is unsubstituted or has one or two R 4c is substituted with a group, 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 3-6 membered heterocyclyl having 1-2 heteroatoms selected from N and O; (0~2) Alkyl C (3~6) Cycloalkyl, -C (1~4)Alkyl, -OC (1~3) Alkyl and heterocyclyl groups are unsubstituted or have 1 to 6 R 4d is substituted with a group, Alternatively, two R's attached to adjacent ring atoms 4c The groups combine to form C (4~6) may form a cycloalkyl, 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 3-6 membered heterocyclyl having 1-2 heteroatoms selected from N and O; (1~3) Alkyl, -OC (1~3) Alkyl, -OC (3~4) cycloalkyl and heterocyclyl groups are unsubstituted or substituted with 1 to 3 fluorine atoms; R 4c1 , R 4c2 , R 4d1 , and R 4d2 each independently represents H or -C (1~3) Alkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 6 groups selected from fluorine and chlorine; Or, R 4d1 and R 4d2 may combine with the atom to which they are attached to form a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, the heterocyclyl being unsubstituted or substituted with 1 to 4 fluorine atoms; R 5 is hydrogen or halogen; R 4 When R is 1,2,4-triazolyl, 4 but,

[0024] [ka] and R 4 Disclosed are compounds, or pharma- ceutically acceptable salts thereof, where is a substituted 6-membered heteroaryl, where the substituted heteroaryl is unsubstituted at the para position.

[0025] This 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.

[0026] Thus, disclosed herein is a compound of formula I':

[0027] [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (1~6) Alkyl, -C (0~2) Alkyl C (3~6) Cycloalkyl, -C (0~2) Alkyl-cyclopropyl-C (1~3) perfluoroalkyl, or a 5- to 6-membered heterocyclyl having 1 to 2 nitrogen atoms; -C (1~6) Alkyl is unsubstituted or has 1 to 6 R 1a is substituted with a group, -C (0~2) Alkyl C (3~6) Cycloalkyl is unsubstituted or has 1 to 6 R 1b is substituted with a group, The 5- to 6-membered heterocyclyl is unsubstituted or has 1 to 3 R 1c is substituted with a group, R 2 But, H, -C (3~5) Cycloalkyl, -C (1~4) alkyl or a 6-membered heterocycle having 1 to 2 oxygen atoms; (1~4)Alkyl is unsubstituted or has 1 to 6 R 2a is substituted with a -C (3~5) cycloalkyl is unsubstituted or substituted with -CN; R 1a , R 1b , and R 2a each independently represents fluorine, -C (3~5) Cycloalkyl, -CN, -OH, -OC (1~3) Alkyl or -OC (3~4) Cycloalkyl, -OC (1~3) Alkyl and -OC (3~4) the cycloalkyl group is unsubstituted or substituted with 1 to 3 fluorine atoms; Each R 1c But independently, -OCH 3 , -OCF 3 , -OCHF 2 or unsubstituted or substituted with 1 to 6 fluorine atoms -C (1~4) is alkyl, R 3 But -C (0~1) Alkyl C (3~6) Cycloalkyl, -C (3~6) Alkyl or -C (1~2) Alkyl-OC (1~3) Alkyl, -C (0~1) Alkyl C (3~6) Cycloalkyl, -C (3~6) Alkyl, and -C (1~2) Alkyl-OC (1~3) Alkyl is unsubstituted or substituted with fluorine, -CH 3 -CHF 2 , -CF 3 1 to 5 R independently selected from , OH, and ═O; 3a is substituted with a group, R 4 But -C (3~6) cycloalkyl, phenyl, or 5-6 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S; C (3~6) Cycloalkyl is unsubstituted or is halogen, -OC (1~3) Alkyl, and -C(1~4) 1 to 3 R independently selected from alkyl 4a is substituted with the group -OC (1~3) Alkyl and -C (1~4) Alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms; Alternatively, two R's attached to the same ring atom 4a The groups, in combination with the atoms to which they are attached, form C (3~6) may form a cycloalkyl, Phenyl is unsubstituted or is selected from the group consisting of 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) 1 to 3 R independently selected from alkyl, and 3 to 6-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; 4b is substituted with the group -OC (1~3) Alkyl, -C (0~2) Alkyl-C (3~4) Cycloalkyl, and -C (1~4) the alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms, the heterocyclyl is unsubstituted or substituted with one oxo; The 5- to 6-membered heteroaryl is unsubstituted or has one or two R 4c is substituted with a group, 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 3-6 membered heterocyclyl having 1-2 heteroatoms selected from N and O; (0~2) Alkyl C (3~6) Cycloalkyl, -C (1~4)Alkyl, -OC (1~3) Alkyl and heterocyclyl groups are unsubstituted or have 1 to 6 R 4d is substituted with a group, Alternatively, two R's attached to adjacent ring atoms 4c The groups combine to form C (4~6) may form a cycloalkyl, 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 3-6 membered heterocyclyl having 1-2 heteroatoms selected from N and O; (1~3) Alkyl, -OC (1~3) Alkyl, -OC (3~4) cycloalkyl and heterocyclyl groups are unsubstituted or substituted with 1 to 3 fluorine atoms; R 4c1 , R 4c2 , R 4d1 , and R 4d2 each independently represents H or -C (1~3) Alkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 6 groups selected from fluorine and chlorine; Or, R 4d1 and R 4d2 may combine with the atom to which they are attached to form a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, the heterocyclyl being unsubstituted or substituted with 1 to 4 fluorine atoms; R 5 is hydrogen or halogen; R 4 When R is 1,2,4-triazolyl, 4 but,

[0028] [ka] and R 4 When is a substituted 6-membered heteroaryl, the substituted heteroaryl is unsubstituted at the para position.

[0029] In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0030] Also disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, etc.), comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof.

[0031] In some embodiments, disclosed herein is the use of a therapeutically effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, etc.).

[0032] In some embodiments, disclosed herein is the use of a compound of formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, etc.).

[0033] In some embodiments, provided herein are processes and intermediates disclosed herein that are useful for preparing a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0034] In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of formula I', or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0035] Also disclosed herein is a method for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, etc.), comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of formula I' or a pharma- ceutically acceptable salt thereof.

[0036] In some embodiments, disclosed herein is the use of a therapeutically effective amount of a compound of formula I' or a pharma- ceutically acceptable salt thereof for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, etc.).

[0037] In some embodiments, disclosed herein is the use of a compound of formula I' or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, etc.).

[0038] In some embodiments, provided herein are processes and intermediates disclosed herein that are useful for preparing a compound of formula I' or a pharma- ceutically acceptable salt thereof.

[0039] The disclosure also provides compounds or methods described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] definition Various publications, articles and patents are cited or described in the Background and throughout this specification, and each of these references is incorporated herein by reference in its entirety. Any discussion of documents, operations, materials, devices, articles and the like which is included in the specification is for the purpose of providing a context for the invention. Such discussion is not an admission that any or all of these items constitute part of the prior art to any invention disclosed or claimed.

[0041] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Unless otherwise specified, specific terms used herein have the meanings described herein. All patents, published patent applications and publications cited herein are incorporated by reference as if set forth herein in their entirety.

[0042] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise.

[0043] To aid the reader in the present application, the description is divided into various paragraphs or sections or directed to various embodiments of the present application. These divisions should not be considered as separating the substance of a paragraph or section or embodiment from the substance of another paragraph or section or embodiment. On the contrary, those skilled in the art will understand that the description herein has broad application and encompasses all combinations of the various paragraphs, paragraphs, and sentences that may be conceived. Discussion of any embodiment is meant to be merely illustrative and is not intended to suggest that the scope of the present disclosure, including the claims, is limited to these examples.

[0044] The term "administration" with respect to the methods of the present invention means a method for therapeutically or prophylactically preventing, treating, or ameliorating a syndrome, disorder, or disease described herein by using a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, composition thereof, or pharmaceutical preparation thereof. Such methods include administering a therapeutically effective amount of a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, composition thereof, or pharmaceutical preparation thereof, either simultaneously or sequentially at different times during the course of treatment or as a combination therapy.

[0045] The term "subject" refers to a patient, which may be an animal, preferably a mammal, most preferably a human, who will be or has been treated by a method according to an embodiment of the present application. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs), such as monkeys or apes, humans, and the like, more preferably humans.

[0046] The term "therapeutically effective amount" or "effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits the biological or medical response sought by a researcher, veterinarian, physician, or other clinician in a tissue system, animal, or human that prevents, cures, or ameliorates the symptoms of the syndrome, disorder, or disease being treated.

[0047] As used herein, "IL-17" or "IL-17A" refers to interleukin 17A. "IL-17" or "IL-17A" is also referred to as IL17, CTLA8, CTLA-8. Interleukin 17A is a pro-inflammatory cytokine. This cytokine is produced by a group of immune cells in response to their stimulation. An exemplary amino acid sequence of human IL-17 is shown in GenBank Accession No. NP_002181.1, which can be encoded by a nucleic acid sequence such as that in GenBank Accession No. NM_002190.3.

[0048] As used herein, the term "modulator" refers to any agent or molecule capable of binding to IL-17, including small molecule compounds.

[0049] As used herein, the term "composition" is intended to encompass a product containing specified ingredients in specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in specified amounts.

[0050] As used herein, the terms "treat", "treating", or "treatment" of any disease, condition, syndrome, or disorder, in one embodiment, refer to ameliorating the disease, condition, syndrome, or disorder (i.e., delaying or arresting or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treat", "treating", or "treatment" refers to alleviating or improving at least one physiological or biochemical parameter associated with or causing the disease, condition, syndrome, or disorder, including those that may not be discernible by the patient. In a further embodiment, "treat", "treating", or "treatment" refers to modulating the disease, condition, syndrome, or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treat", "treating", or "treatment" refers to preventing or delaying the onset or development or progression of the disease, condition, syndrome, or disorder.

[0051] As used herein, the term "QD" means once daily.

[0052] As used herein, the term "BID" means twice a day.

[0053] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon. For example, an alkyl group may be one having 1 to 12 carbon atoms (i.e., (C 1 ~C 12 ) alkyl) or 1 to 6 carbon atoms (i.e., (C1 ~C 6 Examples of alkyl groups include methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-Butyl (n-bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-butyl (s-bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-bu, t-butyl, -CH(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), heptyl (-(CH 2 ) 6 CH 3 ), octyl (-(CH 2 ) 7 CH 3 ), 2,2,4-trimethylpentyl (-CH 2 C(CH 3 ) 2 CH 2 CH(CH 3 )2 ), nonyl (-(CH 2 ) 8 CH 3 ), Decyl (-(CH 2 ) 9 CH 3 ), undecyl (-(CH 2 ) 10 CH 3 ), and dodecyl (-(CH 2 ) 11 CH 3 Any alkyl group can be unsubstituted or substituted.

[0054] The term “C (a~b) " (where a and b are integers referring to the indicated number of carbon atoms) refers to an alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl radical or radical portion of alkyl represented as a prefix root where alkyl contains a through b carbon atoms, inclusive. For example, C (1~4) represents a radical containing 1, 2, 3, or 4 carbon atoms.

[0055] The term "perfluoroalkyl" refers to an alkyl group, as defined herein, in which all carbon-hydrogen bonds have been replaced with carbon-fluorine bonds. For example, a perfluoroalkyl group can be a fluoroalkyl group having 1 to 6 carbon atoms (i.e., (C 1~6 ) perfluoroalkyl) or 1 to 3 carbon atoms (i.e., (C 1~3 ) perfluoroalkyl). An example of a perfluoroalkyl group is trifluoromethyl (-CF 3 ), pentafluoroethyl (-CF 2 CF 3 ), heptafluoropropyl (-CF 2 CF 2 CF 3 ), and heptafluoroisopropyl (-CF(CF 3 ) 2 ), but are not limited to these.

[0056] The term "heterocycle" or "heterocyclyl" refers to a single saturated or partially unsaturated ring having at least one atom other than carbon in the ring, the atom being selected from the group consisting of oxygen, nitrogen, and sulfur. Exemplary heterocycles include, but are not limited to, oxetanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholinyl.

[0057] The term "cycloalkyl" refers to any saturated or partially unsaturated carbocyclic ring system having 3 to 8 carbon atoms (i.e., C (3~8) cycloalkyl), preferably having 3 to 6 carbon atoms (i.e., C (3~6) "cycloalkyl" refers to a cycloalkyl ring system having a single ring or multiple rings in a spirocyclic or bicyclic form. Exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise specifically stated in the specification, cycloalkyl groups can be unsubstituted or substituted. Some cycloalkyl groups can exist as spirocycloalkyls, where two cycloalkyl rings are fused through a single carbon atom, for example, but not limited to, an example of a spiropentyl group is:

[0058] [ka] For example, but not limited to, examples of spirohexyl groups include:

[0059] [ka] For example, but not limited to, examples of cycloheptyl groups include:

[0060] [ka] For example, but not limited to, examples of cyclooctyl groups include:

[0061] [ka] Unless stated otherwise specifically in the specification, siprocycloalkyl groups can be unsubstituted or substituted. Bicyclic cycloalkyl ring systems also include:

[0062] [ka] Examples include:

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

[0064] The terms "ortho," "meta," and "para" have their art-recognized meanings and are used herein to denote the location of a substituent on a phenyl or 6-membered heteroaryl ring relative to the point of attachment of the ring. For example, the following structure has X in the ortho position: 1 Substituent, X in meta position 2 Substituents and X at para position 3 substituted with 3-pyridinyl:

[0065] [ka]

[0066] The term "halogen" refers to bromo (-Br), chloro (-Cl), fluoro (-F), or iodo (-I).

[0067] When the compounds disclosed herein contain at least one stereocenter, they may accordingly exist as enantiomers or diastereomers, and it is understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0068] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0069] "Enantiomers" are a pair of stereoisomers that are not superimposable mirror images of each other. A "racemic" mixture is a 1:1 mixture of a pair of enantiomers. A "scalomic" mixture of enantiomers is a mixture of enantiomers in a ratio other than 1:1.

[0070] When the process for preparing the compounds according to the invention gives rise to a mixture of stereoisomers, these isomers can be separated by conventional methods such as preparative chromatography. The compounds can be prepared in racemic form, and the scalemic mixtures or individual enantiomers can be prepared either by enantioselective synthesis or resolution. The compounds can be resolved into their constituent enantiomers by standard techniques such as forming diastereomeric pairs by salt formation with optically active acids such as (-)-di-p-toluoyl-D-tartaric acid and / or (+)-di-p-toluoyl-L-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds can also be resolved by forming diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be resolved using chiral column vial HPLC or SFC. In some cases, 1 leading to complex multiplets and peak integrals in H NMR spectra, 1Rotamers of the compounds may exist, observable by 1 H NMR.

[0071] Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. Chiral centers whose absolute configuration is known are labeled with the prefixes R and S, assigned by standard sequence rule procedures, and preceded, where necessary, by the appropriate locant (Pure & Appl. Chem. 45, 1976, 11-30). Certain examples are (R*) or (S * (R * ) or (S * When (R ) is used in the name of a compound or in the chemical description of a compound, it is intended to convey that the compound is a pure single isomer at that stereocenter. However, the absolute configuration of that stereocenter has not been established. Thus, (R * A compound designated as (R) or (S) refers to a compound that is a single isomer pure at that stereocenter, having either the (R) or (S) absolute configuration; * ) refers to a compound that is a single isomer pure at its stereocenter with either the (R) or (S) absolute configuration. For example, N-((S)-(7-((S*)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide:

[0072] [ka] refers to a compound that is either:

[0073] [ka]

[0074] Pseudochiral asymmetric centers are treated in the same manner as chiral centers but are given the lower case symbol r or s (Angew. Chem. Int. Ed. Engl. 1982, 21, 567-583).

[0075] During any of the processes for preparing the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. JFW MacOmie, Plenum Press, 1973, and TW Greene & PG M Huts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups can be removed at a subsequent convenient stage using methods well known in the art.

[0076] Additionally, within the scope of the present invention, particularly when reference is made to the compounds of the present disclosure or pharma- ceutically acceptable salts thereof, any element is intended to include all isotopes and isotopic mixtures of that element, either occurring in nature or synthetically produced, either in natural abundance or in isotopically enriched form. For example, a reference within the scope to hydrogen is: 1 H, 2 H (i.e., deuterium or D), and 3 H (i.e., tritium or T). In some embodiments, the compounds described herein include 2 H (i.e., deuterium) isotopes. For example, -C (1~6) A group designated as alkyl is -CH 3 Not just CDs 3 Also includes CH 2 CH 3 Not just CDs 2 CD 3 Similarly, the references to carbon and oxygen within those ranges respectively include 12 C. 13 C, and14 C, and 15 O, and 16 O, and 17 O, and 18 Such isotopes may be radioactive or non-radioactive isotopes. The radiolabeled compounds of the present disclosure include 3 H, 11 C. 18 F, 35 S, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br, and 82 The radioisotope may be selected from the group including Br. Preferably, the radioisotope is 3 H, 11 C, and 18 F.

[0077] Compounds of the Disclosure The present application relates to a compound of formula I:

[0078] [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (1~6) Alkyl, -C (0~2) Alkyl C (3~6) cycloalkyl, or 5- to 6-membered heterocyclyl having 1 to 2 nitrogen atoms; -C (1~6) Alkyl is unsubstituted or has 1 to 6 R 1a is substituted with a group, -C (0~2) Alkyl C (3~6) Cycloalkyl is unsubstituted or has 1 to 6 R 1b is substituted with a group, The 5- to 6-membered heterocyclyl is unsubstituted or has 1 to 3 R 1c is substituted with a group, R 2 But, H, -C (3~5)Cycloalkyl or -C (1~4) Alkyl, -C (1~4) Alkyl is unsubstituted or has 1 to 6 R 2a is substituted with a group, R 1a , R 1b , and R 2a each independently represents fluorine, -C (3~5) Cycloalkyl, -CN, -OH, -OC (1~3) Alkyl or -OC (3~4) Cycloalkyl, -OC (1~3) Alkyl and -OC (3~4) the cycloalkyl group is unsubstituted or substituted with 1 to 3 fluorine atoms; Each R 1c But independently, -OCH 3 , -OCF 3 , -OCHF 2 or unsubstituted or substituted with 1 to 6 fluorine atoms -C (1~4) is alkyl, R 3 But -C (0~1) Alkyl C (3~6) Cycloalkyl, -C (3~6) Alkyl or -C (1~2) Alkyl-OC (1~3) Alkyl, -C (0~1) Alkyl C (3~6) Cycloalkyl, -C (3~6) Alkyl, and -C (1~2) Alkyl-OC (1~3) Alkyl is unsubstituted or substituted with fluorine, -CH 3 -CHF 2 , -CF 3 1 to 5 R independently selected from , OH, and ═O; 3a is substituted with a group, R 4 But -C (3~6) cycloalkyl, phenyl, or 5-6 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S; C (3~6) Cycloalkyl is unsubstituted or is halogen, -OC (1~3) Alkyl, and -C(1~4) 1 to 3 R independently selected from alkyl 4a is substituted with the group -OC (1~3) Alkyl and -C (1~4) Alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms; Alternatively, two R's attached to the same ring atom 4a The groups, in combination with the atoms to which they are attached, form C (3~6) may form a cycloalkyl, Phenyl is unsubstituted or is selected from the group consisting of 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) 1 to 3 R independently selected from alkyl, and 3 to 6-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; 4b is substituted with the group -OC (1~3) Alkyl, -C (0~2) Alkyl-C (3~4) Cycloalkyl, and -C (1~4) the alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms, the heterocyclyl is unsubstituted or substituted with one oxo; The 5- to 6-membered heteroaryl is unsubstituted or has one or two R 4c is substituted with a group, 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 3-6 membered heterocyclyl having 1-2 heteroatoms selected from N and O; (0~2) Alkyl C (3~6) Cycloalkyl, -C (1~4)Alkyl, -OC (1~3) Alkyl and heterocyclyl groups are unsubstituted or have 1 to 6 R 4d is substituted with a group, Alternatively, two R's attached to adjacent ring atoms 4c The groups combine to form C (4~6) may form a cycloalkyl, 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 3-6 membered heterocyclyl having 1-2 heteroatoms selected from N and O; (1~3) Alkyl, -OC (1~3) Alkyl, -OC (3~4) cycloalkyl and heterocyclyl groups are unsubstituted or substituted with 1 to 3 fluorine atoms; R 4c1 , R 4c2 , R 4d1 , and R 4d2 each independently represents H or -C (1~3) Alkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 6 groups selected from fluorine and chlorine; Or, R 4d1 and R 4d2 may combine with the atom to which they are attached to form a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, the heterocyclyl being unsubstituted or substituted with 1 to 4 fluorine atoms; R 5 is hydrogen or halogen; R 4 When R is 1,2,4-triazolyl, 4 but,

[0079] [ka] and R 4 Disclosed are compounds, or pharma- ceutically acceptable salts thereof, where is a substituted 6-membered heteroaryl, where the substituted heteroaryl is unsubstituted at the para position.

[0080] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (1~6) Alkyl, -C (0~2) Alkyl C (3~6) cycloalkyl, or piperidinyl; -C (1~6) Alkyl is unsubstituted or has 1 to 6 R 1a is substituted with a group, -C (0~2) Alkyl C (3~6) Cycloalkyl is unsubstituted or has 1 to 6 R 1b is substituted with a group, Piperidinyl is unsubstituted or has one to three R 1c is substituted with a group, R 1a and R 1b Each independently represents -OH, -OCH 3 , -OCF 3 , -OCHF 2 or fluorine, Each R 1c are independently unsubstituted or substituted with 1 to 3 fluorine atoms; (1~2) is alkyl, R 2 But, H, -C (3~5) Cycloalkyl or -C (1~4) is alkyl, R 3 is unsubstituted or substituted with 1 to 2 fluorine atoms; (5~6) is cycloalkyl, R 4 But -C(3~4) cycloalkyl, phenyl, or a 5-membered heteroaryl having 1 to 4 heteroatoms selected from N, O, and S; C (3~6) Cycloalkyl is unsubstituted or substituted with halogen and unsubstituted or substituted with 1 to 3 fluorine atoms. (1~4) 1 to 3 R independently selected from alkyl 4a is substituted with a group, Alternatively, two R's attached to the same ring atom 4a The groups, in combination with the atoms to which they are attached, form C (3~6) may form a cycloalkyl, Phenyl is unsubstituted or is selected from the group consisting of 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) one or two R independently selected from alkyl, and 3- to 6-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; 4b is substituted with the group -OC (1~3) Alkyl, -C (0~2) Alkyl-C (3~4) Cycloalkyl, and -C (1~4) the alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms, the heterocyclyl is unsubstituted or substituted with one oxo; The 5-membered heteroaryl is unsubstituted or contains one or two R 4c is substituted with a group, 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 3-6 membered heterocyclyl having 1-2 heteroatoms selected from N and O; (0~2) Alkyl C(3~6) Cycloalkyl, -C (1~4) Alkyl, -OC (1~3) Alkyl and heterocyclyl groups are unsubstituted or have 1 to 6 R 4d is substituted with a group, 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), and -C (1~3) Alkyl, -OC (1~3) Alkyl and -OC (3~4) the cycloalkyl group is unsubstituted or substituted with 1 to 3 fluorine atoms; R 4d1 and R 4d2 each independently represents H or -C (1~3) Alkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 6 groups selected from fluorine and chlorine; Or, R 4d1 and R 4d2 may combine with the atom to which they are attached to form a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, the heterocyclyl being unsubstituted or substituted with 1 to 4 fluorine atoms; R 5 is hydrogen or fluorine, R 4 When R is 1,2,4-triazolyl, 4 but,

[0081] [ka] or a pharma- ceutically acceptable salt thereof.

[0082] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (1~6) Alkyl, -CH 2 C (3~6) cycloalkyl, or piperidinyl -C (1~6) Alkyl is unsubstituted or has 1 to 6 R 1a is substituted with a group, -CH 2 C (3~6) cycloalkyl is unsubstituted or substituted with 1 to 4 fluorine atoms; Piperidinyl is unsubstituted or unsubstituted or substituted with 1 to 3 fluorine atoms -C (1~2) is substituted with alkyl, Each R 1a are independently -OH, -OCH 3 , -OCF 3 , -OCHF 2 or fluorine, R 2 But, H, -C (3~5) Cycloalkyl or -C (1~3) is alkyl, R 3 is unsubstituted or substituted with 1 to 2 fluorine atoms, R 4 But -C (3~4) cycloalkyl, spiropentanyl, spirohexanyl, spiroheptanyl, spirooctanyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, imidazolyl, or thiadiazolyl; -C (3~4) Cycloalkyl is unsubstituted or substituted with halogen and unsubstituted or substituted with 1 to 3 fluorine atoms. (1~2) substituted with 1 to 3 groups selected from alkyl; Phenyl, pyridinyl, pyrimidinyl, and pyrazinyl are unsubstituted or substituted with halogen and unsubstituted or substituted with 1 to 3 fluorine atoms. (1~2) substituted with one or two groups selected from alkyl, Pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, imidazolyl, and thiadiazolyl are each independently selected from the group consisting of one or two R 4c is substituted with a group, Each R 4c But independently, -C (0~2) Alkyl C (3~6) Cycloalkyl or -C (1~4) Alkyl, -C (0~2) Alkyl C (3~6) Cycloalkyl and -C (1~4) The alkyl group is unsubstituted or has 1 to 4 R 4d is substituted with a group, Each R 4d But independently, -OCH 3 , -OCF 3 , -OCHF 2 or fluorine, R 5 is hydrogen or fluorine.

[0083] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (3~5) Alkyl,

[0084] [ka] and -C (3~5) Alkyl is unsubstituted or has 1 to 6 R 1a is substituted with a group,

[0085] [ka] is unsubstituted or substituted with 1 to 4 fluorine atoms,

[0086] [ka] is unsubstituted or unsubstituted or substituted with 1 to 3 fluorine atoms, (1~2) is substituted with alkyl, Each R 1a is independently -OH or fluorine; R 2 is H, cyclopropyl, methyl, or isopropyl; R 3 is cyclohexyl, or

[0087] [ka] and R 4 is cyclopropyl, spiropentanyl, spirohexanyl, phenyl, pyridinyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, imidazolyl, or 1,2,3-thiadiazolyl; Cyclopropyl is unsubstituted or substituted with fluorine and unsubstituted or substituted with 1 to 3 fluorine atoms. (1~2) substituted with 1 to 3 groups selected from alkyl; Phenyl and pyridinyl are unsubstituted or substituted with chlorine and unsubstituted or substituted with 1 to 3 fluorine atoms. (1~2) substituted with 1 to 2 groups selected from alkyl; 1,2,3-Thiadiazolyl is unsubstituted or (1~3) Alkyl-substituted, C (1~3) alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms; Pyrazolyl, oxazolyl, isoxazolyl, triazolyl, and imidazolyl are unsubstituted or contain one or two R 4c is substituted with a group, Each R 4c But independently, -C (0~1) Alkyl C (3~4)Cycloalkyl or -C (1~4) Alkyl, -C (0~1) Alkyl C (3~4) Cycloalkyl and -C (1~4) The alkyl group is unsubstituted or has 1 to 4 R 4d is substituted with a group, Each R 4d But independently, -OCH 3 , -OCF 3 , -OCHF 2 or fluorine, R 5 is hydrogen or fluorine.

[0088] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (1~6) Alkyl, -CH 2 C (3~6) cycloalkyl, or piperidinyl -C (1~6) Alkyl is unsubstituted or has 1 to 6 R 1a is substituted with a group, -CH 2 C (3~6) cycloalkyl is unsubstituted or substituted with 1 to 4 fluorine atoms; Piperidinyl is unsubstituted or unsubstituted or substituted with 1 to 3 fluorine atoms -C (1~2) is substituted with alkyl, Each R 1a are independently -OH, -OCH 3 , -OCF 3 , -OCHF 2 or fluorine, R 2 But, H, -C (3~5) Cycloalkyl or -C (1~3) is alkyl, R 3 is unsubstituted or substituted with 1 to 2 fluorine atoms, R 4 But -C (3~4)cycloalkyl, spiropentanyl, spirohexanyl, spiroheptanyl, spirooctanyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, or thiadiazolyl; (3~4) Cycloalkyl is unsubstituted or substituted with halogen and unsubstituted or substituted with 1 to 3 fluorine atoms. (1~2) substituted with 1 to 3 groups selected from alkyl; Phenyl is unsubstituted or is selected from the group consisting of 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) substituted with one or two groups selected from alkyl, and 3- to 6-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; (1~3) Alkyl, -C (0~2) Alkyl-C (3~4) Cycloalkyl, and -C (1~4) the alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms, the heterocyclyl is unsubstituted or substituted with one oxo; Pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, imidazolyl, thiazolyl, isothiazolyl, and thiadiazolyl are each independently selected from the group consisting of one or two R 4c is substituted with a group, 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 3-6 membered heterocyclyl having 1-2 heteroatoms selected from N and O; (0~2) Alkyl C (3~6) Cycloalkyl, -C(1~4) Alkyl, -OC (1~3) The alkyl and heterocyclyl groups are unsubstituted or have 1 to 4 R 4d is substituted with a group, Each R 4d But independently, -OCH 3 , -OCF 3 , -OCHF 2 or fluorine, R 5 is hydrogen or fluorine, R 4 When R is 1,2,4-triazolyl, 4 but,

[0089] [ka] It is.

[0090] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (3~5) Alkyl,

[0091] [ka] and -C (3~5) Alkyl is 1 to 6 R 1a is substituted with a group,

[0092] [ka] is substituted with two fluorine atoms,

[0093] [ka] But -CF 3 is replaced by Each R 1a is independently -OH or fluorine; R 2is H, cyclopropyl, methyl, or isopropyl; R 3 is cyclohexyl, or

[0094] [ka] and R 4 is cyclopropyl, spiropentanyl, spirohexanyl, phenyl, pyridinyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, imidazolyl, or 1,2,3-thiadiazolyl; Cyclopropyl is fluorine and unsubstituted or substituted with three fluorine atoms (1) substituted with 1 to 2 groups selected from alkyl; Phenyl is unsubstituted or is -chlorine or -C (1~2) is substituted with alkyl, Pyridyl is unsubstituted or substituted with 1 to 3 fluorine atoms. (1~2) is substituted with alkyl, 1,2,3-Thiadiazolyl is C (2~3) is substituted with alkyl, Pyrazolyl, oxazolyl, isoxazolyl, triazolyl, and imidazolyl are each independently selected from the group consisting of one or two R 4c is substituted with a group, Each R 4c But independently, -C (0~1) Alkyl C (3~4) Cycloalkyl or -C (1~3) Alkyl, -C (0~1) Alkyl C (3~4) Cycloalkyl and -C (1~3) The alkyl group is unsubstituted or has 1 to 4 R 4d is substituted with a group, Each R 4d But independently, -OCH 3 , -OCF 3 , -OCHF 2 or fluorine, R 5 is hydrogen.

[0095] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (3~5) Alkyl,

[0096] [ka] and -C (3~5) Alkyl is unsubstituted or has 1 to 6 R 1a is substituted with a group,

[0097] [ka] is unsubstituted or substituted with 1 to 4 fluorine atoms,

[0098] [ka] is unsubstituted or substituted with 1 to 4 fluorine atoms,

[0099] [ka] is unsubstituted or unsubstituted or substituted with 1 to 3 fluorine atoms, (1~2) is substituted with alkyl, Each R 1a is independently -OH or fluorine; R 2 is H, methyl, isopropyl, or cyclopropyl; R 3 is cyclohexyl, or

[0100] [ka] and R 4is cyclopropyl, spiropentanyl, spirohexanyl, phenyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, or 1,2,5-thiadiazolyl; Cyclopropyl is unsubstituted or substituted with fluorine and unsubstituted or substituted with 1 to 3 fluorine atoms. (1~2) substituted with 1 to 3 groups selected from alkyl; Phenyl is unsubstituted or substituted with chlorine and unsubstituted or substituted with 1 to 3 fluorine atoms; (1~2) substituted with 1 to 2 groups selected from alkyl; 1,2,3-Thiadiazolyl is unsubstituted or (1~3) Alkyl-substituted, C (1~3) alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms; Pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, thiazolyl, isothiazolyl, or 1,2,5-thiadiazolyl is unsubstituted or has one or two R 4c is substituted with a group, Each R 4c But independently, -C (0~1) Alkyl C (3~4) Cycloalkyl or -C (1~4) Alkyl, -C (0~1) Alkyl C (3~4) Cycloalkyl and -C (1~4) The alkyl group is unsubstituted or has 1 to 4 R 4d is substituted with a group, Each R 4d But independently, -OCH 3 , -OCF 3 , -OCHF 2 or fluorine, R 5 is hydrogen or fluorine, R 4 When R is 1,2,4-triazolyl,4 but,

[0101] [ka] It is.

[0102] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (3~5) Alkyl,

[0103] [ka] and -C (3~5) Alkyl is 1 to 6 R 1a is substituted with a group,

[0104] [ka] is unsubstituted or substituted with 1 to 2 fluorine atoms,

[0105] [ka] is substituted with two fluorine atoms,

[0106] [ka] But -CF 3 is replaced by Each R 1a is independently -OH or fluorine; R 2 is H, methyl, isopropyl, or cyclopropyl; R 3 is cyclohexyl, or

[0107] [ka] and R 4 is cyclopropyl, spiropentanyl, spirohexanyl, phenyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, 1,2,3-thiadiazolyl, or 1,2,5-thiadiazolyl; Cyclopropyl is fluorine and unsubstituted or substituted with three fluorine atoms (1) substituted with 1 to 2 groups selected from alkyl; Phenyl is unsubstituted or is -chlorine or -C (1~2) is substituted with alkyl, 1,2,3-Thiadiazolyl and 1,2,5-Thiadiazolyl are C (2~3) is substituted with alkyl, Pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, and imidazolyl are each independently selected from the group consisting of one or two R 4c is substituted with a group, Each R 4c But independently, -C (0~1) Alkyl C (3~4) Cycloalkyl or -C (1~3) Alkyl, -C (0~1) Alkyl C (3~4) Cycloalkyl and -C (1~3) The alkyl group is unsubstituted or has 1 to 4 R 4d is substituted with a group, Each R 4d But independently, -OCH 3 , -OCF 3 , -OCHF 2 or fluorine, R 5 is hydrogen, R 4 When R is 1,2,4-triazolyl, 4 but,

[0108] [ka] It is.

[0109] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (3~6) Alkyl, -C (0~2) Alkyl C (3~6) cycloalkyl or a 6-membered heterocyclyl having 1 to 2 nitrogen atoms; -C (1~6) Alkyl is unsubstituted or has 1 to 6 R 1a is substituted with a group, -C (0~2) Alkyl C (3~6) Cycloalkyl is unsubstituted or has 1 to 3 R 1b is substituted with a group, 6-membered heterocyclyl is one R 1c is substituted with a group, Each R 1a is independently fluorine or -OH; Each R 1b are independently fluorine; R 1c is substituted with 1 to 3 fluorine atoms -C (1~4) It is an alkyl.

[0110] In some embodiments, disclosed herein are compounds of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 1 but,

[0111] [ka] It is.

[0112] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 1 but,

[0113] [ka] It is.

[0114] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 1 but,

[0115] [ka] It is.

[0116] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 1 but,

[0117] [ka] It is.

[0118] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 1 but,

[0119] [ka] It is.

[0120] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 1 but,

[0121] [ka] It is.

[0122] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 2 is H, methyl, isopropyl, or cyclopropyl.

[0123] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 2 is H or cyclopropyl. In some embodiments, disclosed herein are compounds of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 2 is H. In some embodiments, disclosed herein are compounds of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 2 is cyclopropyl.

[0124] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 2 is unsubstituted cyclopropyl.

[0125] In some embodiments, disclosed herein is a compound of formula I, which is a compound of formula Ia, or a pharma- ceutically acceptable salt thereof:

[0126] [ka]

[0127] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 3 is unsubstituted or substituted with 1 to 2 fluorine atoms; (0~1) Alkyl C (3~6) In some embodiments, disclosed herein are compounds of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 3 is unsubstituted or cyclohexyl substituted with 1 to 2 fluorine atoms.

[0128] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 3 but,

[0129] [ka] It is.

[0130] In some embodiments, disclosed herein is a compound of formula I or Ia, or a pharma- ceutically acceptable salt thereof, which is a compound of formula Ib:

[0131] [ka] In the formula, R 3a is fluorine and n is 0, 1, or 2.

[0132] In some embodiments, disclosed herein is a compound of Formula I, Ia, or Ib, which is a compound of Formula Ib-1, or a pharma- ceutically acceptable salt thereof:

[0133] [ka] In the formula, R 3a is fluorine and n is 2.

[0134] In some embodiments, disclosed herein is a compound of Formula I, Ia, Ib, or Ib-1, which is a compound of Formula Ib-2a, or a pharma- ceutically acceptable salt thereof:

[0135] [ka] In the formula, R 3a is fluorine and n is 2.

[0136] In some embodiments, disclosed herein is a compound of Formula I, Ia, Ib, or Ib-1, which is a compound of Formula Ib-2b, or a pharma- ceutically acceptable salt thereof:

[0137] [ka] In the formula, R 3a is fluorine and n is 2.

[0138] In some embodiments, disclosed herein is a compound of Formula I, Ia, Ib, Ib-1, or Ib-2a, which is a compound of Formula Ib-3a, or a pharma- ceutically acceptable salt thereof:

[0139] [ka] In some embodiments, disclosed herein is a compound of Formula I, Ia, Ib, Ib-1, or Ib-2b, which is a compound of Formula Ib-3b, or a pharma- ceutically acceptable salt thereof:

[0140] [ka] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 3 but,

[0141] [ka] It is.

[0142] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 4 is unsubstituted or 1 to 3 R 4a -C substituted with group (3~6) is cycloalkyl, Each R 4a are independently halogen, -OC (1~3) Alkyl, and -C (1~4) alkyl, -OC (1~3) Alkyl and -C (1~4) Alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms; Alternatively, two R's attached to the same ring atom 4a The groups, in combination with the atoms to which they are attached, form C (3~6)It may also form a cycloalkyl.

[0143] In some embodiments, disclosed herein are compounds of formula I, or a pharma- ceutically acceptable salt thereof, wherein each R 4a The group is fluorine, methyl, or -CF 3 or two R attached to the same ring atom 4a The groups may combine with the atom to which they are attached to form a cyclopropyl, cyclobutyl, or cyclopentyl.

[0144] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 is unsubstituted or fluorine, CH 3 , and C.F. 3 and cyclopropyl substituted by 1 to 3 groups selected from the group consisting of:

[0145] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 is unsubstituted or fluorine, CH 3 , and C.F. 3 is cyclopropyl substituted by 1 to 2 groups selected from

[0146] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0147] [ka] It is.

[0148] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 In some embodiments, disclosed herein are compounds of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4is spiropentanyl or spirohexanyl.

[0149] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0150] [ka] It is.

[0151] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0152] [ka] It is.

[0153] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 4 is unsubstituted or has 1-2 R 4b phenyl substituted with a group; Each R 4b are independently chlorine, fluorine, -CN, cyclopropyl, -OCH 2 -Cyclopropyl, -OC (1~2) Alkyl, -C (1~2) alkyl, and pyrrolidin-2-one; cyclopropyl, -OC (1~2) Alkyl, and C (1~2) The alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms.

[0154] In some embodiments, disclosed herein are compounds of formula I, or a pharma- ceutically acceptable salt thereof, wherein each R 4b The groups are independently H, fluorine, chlorine, -CN, methyl, ethyl, -CHF 2 , -CH 2 CF 3, -OCHF 2 , -OCH 2 CHF 2 , -OCH 2 CF 3 , cyclopropyl,

[0155] [ka] It is.

[0156] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 is unsubstituted or halogen (e.g., chlorine), CH 3 , or -CH 2 CH 3 is a phenyl substituted with

[0157] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 is unsubstituted or chlorine, -CH 3 , or -CH 2 CH 3 is a phenyl substituted with

[0158] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0159] [ka] It is.

[0160] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0161] [ka] It is.

[0162] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0163] [ka] It is.

[0164] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 4 But one or two R 4c is a 5-6 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S, substituted with a group; 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 3-6 membered heterocyclyl having 1-2 heteroatoms selected from N and O; (0~2) Alkyl C (3~6) Cycloalkyl, -C (1~4) Alkyl, -OC (1~3) Alkyl and heterocyclyl groups are unsubstituted or have 1 to 6 R 4d is substituted with a group, Alternatively, two R's attached to adjacent ring atoms 4c The groups combine to form C (4~6) may form a cycloalkyl, 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), and -C (1~3) Alkyl, -OC (1~3) Alkyl and -OC (3~4) the cycloalkyl group is unsubstituted or substituted with 1 to 3 fluorine atoms; R 4d1 and R 4d2 each independently represents H or -C (1~3) Alkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 6 groups selected from fluorine and chlorine; Or, R 4d1 and R 4d2 may combine with the atom to which they are attached to form a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, the heterocyclyl being unsubstituted or substituted with 1 to 4 fluorine atoms; R 4 When R is 1,2,4-triazolyl, 4 is 1H-1,2,4-triazolyl; R 4 When is a 6-membered heteroaryl, the heteroaryl is unsubstituted at the para position.

[0165] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: Each R 4c are independently fluorine, -CN, methyl, ethyl, isopropyl, -CD 2 CD 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3, -CF 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH(CH 3 )CF 3 , -CH(CH 2 F) 2 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 O.C.H.F. 2 , -CH 2 CH 2 OCF 3 , -OCHF 2 , -OCH 2 CHF 2 , -OCH 2 CF 3 , cyclopropyl, cyclobutyl, cyclopentyl, -CH 2 -cyclopropyl, -O-cyclopropyl, -O-cyclobutyl,

[0166] [ka] or Alternatively, two R's attached to adjacent ring atoms 4c The groups may combine to form the following groups:

[0167] [ka]

[0168] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 4 But one or two R 4cis a 5-membered heteroaryl ring having 1 to 4 heteroatoms selected from N, O, and S, substituted with a group; R 4 When R is 1,2,4-triazolyl, 4 but,

[0169] [ka] It is.

[0170] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 4 But one or two R 4c pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, or thiadiazolyl substituted by a group; R 4 When R is 1,2,4-triazolyl, 4 but,

[0171] [ka] It is.

[0172] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 But one or two R 4c and 1,3,4-thiadiazolyl, substituted with a group selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thienyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl.

[0173] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 But one or two R 4c and 1,2,5-thiadiazolyl, substituted by a group selected from the group consisting of pyrazolyl, imidazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, thienyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, and 1,2,5-thiadiazolyl.

[0174] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 4 But one or two R 4c oxazolyl, isoxazolyl, or oxadiazolyl substituted with a group; Each R 4c But independently, C (3~5) Cycloalkyl, -C (1~3) Alkyl, or

[0175] [ka] and C (3~5) Cycloalkyl and -C (1~3) The alkyl group is unsubstituted or is -OCH 3 Or substituted with 1 to 3 fluorine atoms.

[0176] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 4 But one or two R 4c a group or a substituted oxazolyl, isoxazolyl, or thiadiazolyl (e.g., 1,2,3-thiadiazolyl); Each R 4c are independently cyclopropyl or -C (1~3)alkyl, cyclopropyl and -C (1~3) The alkyl group is unsubstituted or substituted with 1 to 3 fluorine atoms.

[0177] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but, each independently represents methyl, ethyl, isopropyl, -CF 3 , -CH 2 CH 2 F, -CH 2 CH 2 CF 3 , -CH 2 -OCH 3 , cyclopropyl, cyclopentyl, or

[0178] [ka] One or two R 4c isoxazolyl substituted with a group; oxazolyl substituted with one isopropyl; or It is an oxadiazolyl substituted with one methyl or ethyl.

[0179] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 But one -C (1~3) It is an alkyl substituted oxadiazolyl.

[0180] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0181] [ka] It is.

[0182] In some embodiments, disclosed herein is a compound of formula I, which is a compound of formula Ic, or a pharma- ceutically acceptable salt thereof:

[0183] [ka] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, which is a compound of formula Ic-1:

[0184] [ka] In the formula, R 3a is fluorine and n is 2.

[0185] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0186] [ka] It is.

[0187] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0188] [ka] It is.

[0189] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 4 is unsubstituted or has one or two R 4c pyrazolyl or imidazolyl substituted with a group; Each R 4c are independently fluorine or unsubstituted or -CHF 2 , -CF3 , -OCHF 2 , -OCF 3 and fluorine; (1~3) It is an alkyl.

[0190] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 is unsubstituted or has one or two R 4c pyrazolyl or imidazolyl, each R 4c is independently unsubstituted or -CHF 2 , -CF 3 , -OCHF 2 , -OCF 3 and -C substituted with 1 to 3 groups selected from fluorine (1~3) It is an alkyl.

[0191] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 But one or two R 4c pyrazolyl or imidazolyl, each R 4c is independently unsubstituted or -CHF 2 , -CF 3 , -OCHF 2 , -OCF 3 and -C substituted with 1 to 3 groups selected from fluorine (1~3) It is an alkyl.

[0192] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but, Each independently is methyl, ethyl, isopropyl, -CD 2 CD 3 , fluorine, -CHF 2 , -CF 3 , -CH 2 CHF 2 , -CH 2 CF 3 , -CH(CH3 )CF 3 , -CH(CH 2 F) 2 , -CH 2 CH 2 O.C.H.F. 2 , or -CH 2 CH 2 OCF 3 One or two R 4c pyrazolyl substituted with a group, or It is an imidazolyl substituted with one isopropyl.

[0193] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 But one -C (1~3) It is an alkyl substituted pyrazolyl.

[0194] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0195] [ka] It is.

[0196] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0197] [ka] It is.

[0198] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0199] [ka] It is.

[0200] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0201] [ka] It is.

[0202] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0203] [ka] It is.

[0204] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0205] [ka] It is.

[0206] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 4 is unsubstituted or has one or two R 4c is a triazolyl substituted with a group; Each R 4c But independently, C (0~1) Alkyl C (3~4) Cycloalkyl, -C (1~3) Alkyl,

[0207] [ka] and -C (0~1)Alkyl C (3~4) Cycloalkyl and -C (1~3) The alkyl group is unsubstituted or has 1 to 4 R 4d is substituted with a group, Each R 4d But independently, -OCH 3 , -OCF 3 , -OCHF 2 , fluorine,

[0208] [ka] and R 4 When R is 1,2,4-triazolyl, 4 but,

[0209] [ka] It is.

[0210] Or, R 4 When R is 1,2,4-triazolyl, 4 is 1H-1,2,4-triazolyl.

[0211] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 4 is unsubstituted or has one or two R 4c is a triazolyl substituted with a group; Each R 4c But independently, -C (0~1) Alkyl C (3~4) Cycloalkyl or -C (1~3) Alkyl, -C (0~1) Alkyl C (3~4) Cycloalkyl and -C (1~3) The alkyl group is unsubstituted or has 1 to 4 R 4d is substituted with a group, Each R 4d But independently, -OCH 3 , -OCF 3, or -OCHF 2 , or fluorine.

[0212] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 4 is unsubstituted or has one or two R 4c is a triazolyl substituted with a group; Each R 4c are independently methyl, ethyl, isopropyl, -CH 2 CH 2 OCH 3 ,-CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 O.C.H.F. 2 , -CH 2 CH 2 OCF 3 , cyclopropyl, -CH 2 -cyclopropyl,

[0213] [ka] and R 4 When R is 1,2,4-triazolyl, 4 but,

[0214] [ka] It is.

[0215] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0216] [ka]

[0217] [ka] It is.

[0218] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0219] [ka] It is.

[0220] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 But -C (1~4) It is an alkyl substituted tetrazolyl.

[0221] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 is tetrazolyl substituted with methyl or isopropyl.

[0222] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0223] [ka] It is.

[0224] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 But -C (1~3) Alkyl or -C (3~6) and thienyl, thiazolyl, isothiazolyl, or thiadiazolyl, each substituted with cycloalkyl.

[0225] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 is thienyl, thiadiazolyl, isothiazolyl, or thiadiazolyl, each substituted with methyl, isopropyl, or cyclopropyl.

[0226] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but, isopropyl substituted thienyl, methyl substituted isothiazolyl; isopropyl-substituted thiazolyl, or Thiadiazolyl substituted with methyl, isopropyl, or cyclopropyl.

[0227] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0228] [ka] It is.

[0229] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 4 But one or two R 4c is a 6-membered heteroaryl having 1 to 2 heteroatoms selected from N, substituted with a group; Each R 4cThe 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, -OC (1~3) Alkyl and C (1~3) Alkyl is unsubstituted or -OCH 3 or substituted with 1 to 3 fluorine atoms, Alternatively, two R's attached to adjacent ring atoms 4c The groups combine to form C (4~6) may form a cycloalkyl, The heteroaryl is unsubstituted at the para position.

[0230] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 When is a substituted 6-membered heteroaryl, R 4 but,

[0231] [ka] and 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, -OC (1~3) Alkyl and C (1~3) Alkyl is unsubstituted or -OCH 3 or substituted with 1 to 3 fluorine atoms, Alternatively, two R's attached to adjacent ring atoms 4c The groups combine to form C (4~6) It may also form a cycloalkyl.

[0232] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 4 But one or two R 4c pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl substituted with a group; 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, -OC (1~3) Alkyl and C (1~3) Alkyl is unsubstituted or -OCH 3 or substituted with 1 to 3 fluorine atoms, Alternatively, two R's attached to adjacent ring atoms 4c The groups combine to form C (4~6) may form a cycloalkyl, The heteroaryl is unsubstituted at the para position.

[0233] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 4 is unsubstituted or has 1-2 R 4c pyridyl substituted with a group; 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, -OC (1~3) Alkyl and C (1~3) Alkyl is unsubstituted or -OCH 3 or substituted with 1 to 3 fluorine atoms, Alternatively, two R's attached to adjacent ring atoms 4c The groups combine to form C (4~6) may form a cycloalkyl, The pyridyl is unsubstituted at the para position.

[0234] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 is unsubstituted, or unsubstituted or substituted with 1 to 3 fluorine atoms, (1~2) In some embodiments, disclosed herein are compounds of Formula I, or pharma- ceutically acceptable salts thereof, wherein R 4 is unsubstituted, or unsubstituted or substituted with 1 to 3 fluorine atoms, (1~2) It is pyridinyl substituted with alkyl.

[0235] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 4 is unsubstituted or has 1-2 R 4c pyridyl substituted with a group; Each R 4c The groups are independently selected from the group consisting of fluorine, -CN, pyrrolidin-2-one, cyclopropyl, cyclobutyl, -O-cyclopropyl, -O-cyclobutyl, -OMe, -OEt, -O-isopropyl, and -OCHF. 2 , -OCH 2 CHF 2 , -OCH 2 CF 3 , methyl, ethyl, isopropyl, -CH 2 -OCH 3 , -CHF 2 , -CF 3 , -C(CH 3 )F 2 , -CH 2 CHF 2 , -CH 2 CF 3 , or -CH 2 CH 2 CHF 2 or Alternatively, two R's attached to adjacent ring atoms 4c The groups may combine to form a cyclopropyl; The pyridyl is unsubstituted at the para position.

[0236] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 When is a substituted 6-membered heteroaryl, R 4 but,

[0237] [ka] It is.

[0238] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0239] [ka] It is.

[0240] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 4 is pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted or contains one or two R 4c is substituted with a group, Each R 4c But independently, -C (3~4) Cycloalkyl, -OC (1~3) Alkyl, and -C (1~4) alkyl, -C (1~4) the alkyl group is unsubstituted or substituted with 1 to 3 fluorine atoms; Pyridazinyl, pyrimidinyl, and pyrazinyl are unsubstituted at the para position.

[0241] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein: R 4is pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted or contains one or two R 4c is substituted with a group, Each R 4c are independently methyl, isopropyl, -OMe, cyclopropyl, -CHF 2 , and -CF 3 is selected from Pyridazinyl, pyrimidinyl, and pyrazinyl are unsubstituted at the para position.

[0242] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 When is a substituted 6-membered heteroaryl, R 4 but,

[0243] [ka] It is.

[0244] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but, Unsubstituted or -OCH 3 or -CH 3 pyridazinyl substituted with Unsubstituted or methyl, isopropyl, -OCH 3 or pyrimidinyl substituted with isopropyl, wherein the methyl is unsubstituted or substituted with 1 to 3 fluorine atoms; Unsubstituted or -OCH 3 , -CH 3 , or -CF 3 is pyrazinyl substituted with Pyridazinyl, pyrimidinyl, and pyrazinyl are unsubstituted at the para position.

[0245] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0246] [ka] It is.

[0247] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0248] [ka] It is.

[0249] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 5 is hydrogen or halogen.

[0250] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 5 is hydrogen or fluorine.

[0251] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 5 is hydrogen.

[0252] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 5 In some embodiments, disclosed herein are compounds of formula I, or a pharma- ceutically acceptable salt thereof, wherein R 5 is fluorine.

[0253] [Table 1-1]

[0254] [Table 1-2]

[0255]

Table 1-3

[0256]

Table 2-1

[0257]

Table 2-2

[0258]

Table 2-3

[0259]

Table 3-1

[0260]

Table 3-2

[0261]

Table 3-3

[0262]

Table 4-1

[0263]

Table 4-2

[0264]

Table 4-3

[0265]

Table 5-1

[0266]

Table 5-2

[0267]

Table 6-1

[0268]

Table 6-2

[0269]

Table 6-3

[0270]

Table 7-1

[0271]

Table 7-2

[0272]

Table 7-3

[0273]

Table 8-1

[0274]

Table 8-2

[0275] [Table 8-3]

[0276] [Table 9-1]

[0277] [Table 9-2]

[0278] [Table 9-3]

[0279] [Table 10]

[0280] In some embodiments, disclosed herein is a compound of formula I, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of the compounds of Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, Table 1F, Table 1G, Table 1H, Table 1I, and Table 1J.

[0281] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0282] [ka] or a pharma- ceutically acceptable salt thereof.

[0283] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0284] [ka] or a pharma- ceutically acceptable salt thereof.

[0285] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0286] [ka] or a pharma- ceutically acceptable salt thereof.

[0287] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0288] [ka] or a pharma- ceutically acceptable salt thereof.

[0289] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0290] [ka] or a pharma- ceutically acceptable salt thereof.

[0291] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0292] [ka] or a pharma- ceutically acceptable salt thereof.

[0293] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0294] [ka] or a pharma- ceutically acceptable salt thereof.

[0295] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0296] [ka] or a pharma- ceutically acceptable salt thereof.

[0297] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0298] [ka] or a pharma- ceutically acceptable salt thereof.

[0299] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0300] [ka] or a pharma- ceutically acceptable salt thereof.

[0301] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0302] [ka] or a pharma- ceutically acceptable salt thereof.

[0303] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0304] [ka] or a pharma- ceutically acceptable salt thereof.

[0305] In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of Formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration (e.g., a tablet or capsule).

[0306] In some embodiments, disclosed herein is a pharmaceutical composition made by mixing a compound of formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0307] In some embodiments, disclosed herein is a process for making a pharmaceutical composition comprising mixing a compound of formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0308] This 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.

[0309] Thus, disclosed herein is a compound of formula I':

[0310] [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (1~6) Alkyl, -C (0~2) Alkyl C (3~6) Cycloalkyl, -C (0~2) Alkyl-cyclopropyl-C (1~3) perfluoroalkyl, or a 5- to 6-membered heterocyclyl having 1 to 2 nitrogen atoms; -C (1~6) Alkyl is unsubstituted or has 1 to 6 R 1a is substituted with a group, -C (0~2) Alkyl C (3~6) Cycloalkyl is unsubstituted or has 1 to 6 R 1bis substituted with a group, The 5- to 6-membered heterocyclyl is unsubstituted or has 1 to 3 R 1c is substituted with a group, R 2 But, H, -C (3~5) Cycloalkyl, -C (1~4) alkyl or a 6-membered heterocycle having 1 to 2 oxygen atoms; (1~4) Alkyl is unsubstituted or has 1 to 6 R 2a is substituted with a -C (3~5) cycloalkyl is unsubstituted or substituted with -CN; R 1a , R 1b , and R 2a each independently represents fluorine, -C (3~5) Cycloalkyl, -CN, -OH, -OC (1~3) Alkyl or -OC (3~4) Cycloalkyl, -OC (1~3) Alkyl and -OC (3~4) the cycloalkyl group is unsubstituted or substituted with 1 to 3 fluorine atoms; Each R 1c But independently, -OCH 3 , -OCF 3 , -OCHF 2 or unsubstituted or substituted with 1 to 6 fluorine atoms -C (1~4) is alkyl, R 3 But -C (0~1) Alkyl C (3~6) Cycloalkyl, -C (3~6) Alkyl or -C (1~2) Alkyl-OC (1~3) Alkyl, -C (0~1) Alkyl C (3~6) Cycloalkyl, -C (3~6) Alkyl, and -C (1~2) Alkyl-OC (1~3) Alkyl is unsubstituted or substituted with fluorine, -CH 3 -CHF 2 , -CF 3 1 to 5 R independently selected from , OH, and ═O; 3ais substituted with a group, R 4 But -C (3~6) cycloalkyl, phenyl, or 5-6 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S; C (3~6) Cycloalkyl is unsubstituted or is halogen, -OC (1~3) Alkyl, and -C (1~4) 1 to 3 R independently selected from alkyl 4a is substituted with the group -OC (1~3) Alkyl and -C (1~4) Alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms; Alternatively, two R's attached to the same ring atom 4a The groups, in combination with the atoms to which they are attached, form C (3~6) may form a cycloalkyl, Phenyl is unsubstituted or is selected from the group consisting of 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) 1 to 3 R independently selected from alkyl, and 3 to 6-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; 4b is substituted with the group -OC (1~3) Alkyl, -C (0~2) Alkyl-C (3~4) Cycloalkyl, and -C (1~4) the alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms, the heterocyclyl is unsubstituted or substituted with one oxo; The 5- to 6-membered heteroaryl is unsubstituted or has one or two R 4c is substituted with a group, 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 3-6 membered heterocyclyl having 1-2 heteroatoms selected from N and O; (0~2) Alkyl C (3~6) Cycloalkyl, -C (1~4) Alkyl, -OC (1~3) Alkyl and heterocyclyl groups are unsubstituted or have 1 to 6 R 4d is substituted with a group, Alternatively, two R's attached to adjacent ring atoms 4c The groups combine to form C (4~6) may form a cycloalkyl, 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 3-6 membered heterocyclyl having 1-2 heteroatoms selected from N and O; (1~3) Alkyl, -OC (1~3) Alkyl, -OC (3~4) cycloalkyl and heterocyclyl groups are unsubstituted or substituted with 1 to 3 fluorine atoms; R 4c1 , R 4c2 , R 4d1 , and R 4d2 each independently represents H or -C (1~3) Alkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 6 groups selected from fluorine and chlorine; Or, R 4d1 and R 4d2may combine with the atom to which they are attached to form a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, the heterocyclyl being unsubstituted or substituted with 1 to 4 fluorine atoms; R 5 is hydrogen or halogen; During the ceremony, R 4 When R is 1,2,4-triazolyl, 4 but,

[0311] [ka] and R 4 When is a substituted 6-membered heteroaryl, the substituted heteroaryl is unsubstituted at the para position.

[0312] In some embodiments, disclosed herein is a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (1~6) Alkyl, -C (0~2) Alkyl C (3~6) Cycloalkyl, -C (0~2) Alkyl-cyclopropyl-C (1~3) perfluoroalkyl, pyrrolidinyl, or piperidinyl; -C (1~6) Alkyl is unsubstituted or has 1 to 6 R 1a is substituted with a group, -C (0~2) Alkyl C (3~6) Cycloalkyl is unsubstituted or has 1 to 6 R 1b is substituted with a group, Piperidinyl and pyrrolidinyl are unsubstituted or have one to three R 1c is substituted with a group, R 1a and R 1b Each independently represents -OH, -OCH 3 , -OCF 3 , -OCHF 2or fluorine, Each R 1c are independently unsubstituted or substituted with 1 to 3 fluorine atoms; (1~2) is alkyl, R 2 But, H, -C (3~5) Cycloalkyl, -C (1~4) alkyl or a 6-membered heterocycle having 1-2 oxygen atoms, C (3~5) cycloalkyl is unsubstituted or substituted with -CN; R 3 is unsubstituted or substituted with 1 to 2 fluorine atoms; (5~6) is cycloalkyl, R 4 But -C (3~4) cycloalkyl, phenyl, or a 5-membered heteroaryl having 1 to 4 heteroatoms selected from N, O, and S; C (3~6) Cycloalkyl is unsubstituted or substituted with halogen and unsubstituted or substituted with 1 to 3 fluorine atoms. (1~4) 1 to 3 R independently selected from alkyl 4a is substituted with a group, Alternatively, two R's attached to the same ring atom 4a The groups, in combination with the atoms to which they are attached, form C (3~6) may form a cycloalkyl, Phenyl is unsubstituted or is selected from the group consisting of 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) one or two R independently selected from alkyl, and 3- to 6-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; 4b is substituted with the group -OC (1~3) Alkyl, -C (0~2) Alkyl-C (3~4) Cycloalkyl, and -C (1~4)the alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms, the heterocyclyl is unsubstituted or substituted with one oxo; The 5-membered heteroaryl is unsubstituted or contains one or two R 4c is substituted with a group, 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 3-6 membered heterocyclyl having 1-2 heteroatoms selected from N and O; (0~2) Alkyl C (3~6) Cycloalkyl, -C (1~4) Alkyl, -OC (1~3) Alkyl and heterocyclyl groups are unsubstituted or have 1 to 6 R 4d is substituted with a group, 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), and -C (1~3) Alkyl, -OC (1~3) Alkyl and -OC (3~4) the cycloalkyl group is unsubstituted or substituted with 1 to 3 fluorine atoms; R 4d1 and R 4d2 each independently represents H or -C (1~3) Alkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 6 groups selected from fluorine and chlorine; Or, R 4d1 and R 4d2may combine with the atom to which they are attached to form a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, the heterocyclyl being unsubstituted or substituted with 1 to 4 fluorine atoms; R 5 is hydrogen or fluorine, R 4 When R is 1,2,4-triazolyl, 4 but,

[0313] [ka] It is.

[0314] In some embodiments, disclosed herein is a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (1~6) Alkyl, -C (0~2) Alkyl C (3~6) Cycloalkyl, -C (0~2) Alkyl-cyclopropyl-C (1~3) perfluoroalkyl, pyrrolidinyl, or piperidinyl; -C (1~6) Alkyl is unsubstituted or has 1 to 6 R 1a is substituted with a group, -C (0~2) Alkyl C (3~6) Cycloalkyl is unsubstituted or has 1 to 6 R 1b is substituted with a group, Pyrrolidinyl and piperidinyl are unsubstituted or have one to three R 1c is substituted with a group, R 1a and R 1b Each independently represents -OH, -OCH 3 , -OCF 3 , -OCHF 2 or fluorine, Each R 1c are independently unsubstituted or substituted with 1 to 3 fluorine atoms; (1~2) is alkyl, R 2 But, H, -C (3~5) Cycloalkyl or -C (1~4) Alkyl, C (3~5) cycloalkyl is unsubstituted or substituted with -CN; R 3 is unsubstituted or substituted with 1 to 2 fluorine atoms; (5~6) is cycloalkyl, R 4 But -C (3~4) cycloalkyl, phenyl, or a 5-membered heteroaryl having 1 to 4 heteroatoms selected from N, O, and S; C (3~6) Cycloalkyl is unsubstituted or substituted with halogen and unsubstituted or substituted with 1 to 3 fluorine atoms. (1~4) 1 to 3 R independently selected from alkyl 4a is substituted with a group, Alternatively, two R's attached to the same ring atom 4a The groups, in combination with the atoms to which they are attached, form C (3~6) may form a cycloalkyl, Phenyl is unsubstituted or is selected from the group consisting of 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) one or two R independently selected from alkyl, and 3- to 6-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; 4b is substituted with the group -OC (1~3) Alkyl, -C (0~2) Alkyl-C (3~4) Cycloalkyl, and -C (1~4) the alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms, the heterocyclyl is unsubstituted or substituted with one oxo; The 5-membered heteroaryl is unsubstituted or contains one or two R 4cis substituted with a group, 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 3-6 membered heterocyclyl having 1-2 heteroatoms selected from N and O; (0~2) Alkyl C (3~6) Cycloalkyl, -C (1~4) Alkyl, -OC (1~3) Alkyl and heterocyclyl groups are unsubstituted or have 1 to 6 R 4d is substituted with a group, 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), and -C (1~3) Alkyl, -OC (1~3) Alkyl and -OC (3~4) the cycloalkyl group is unsubstituted or substituted with 1 to 3 fluorine atoms; R 4d1 and R 4d2 each independently represents H or -C (1~3) Alkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 6 groups selected from fluorine and chlorine; Or, R 4d1 and R 4d2 may combine with the atom to which they are attached to form a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, the heterocyclyl being unsubstituted or substituted with 1 to 4 fluorine atoms; R5 is hydrogen or fluorine, R 4 When R is 1,2,4-triazolyl, 4 but,

[0315] [ka] It is.

[0316] In some embodiments, disclosed herein is a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (1~6) Alkyl, -C (1~2) Alkyl C (3~6) Cycloalkyl, -C (0~2) Alkyl-cyclopropyl-CF 3 , pyrrolidinyl, or piperidinyl: -C (1~6) Alkyl is unsubstituted or has 1 to 6 R 1a is substituted with a group, -C (1~2) Alkyl C (3~6) cycloalkyl is unsubstituted or substituted with 1 to 4 fluorine atoms; Pyrrolidinyl and piperidinyl are unsubstituted or unsubstituted or substituted with 1 to 3 fluorine atoms -C (1~2) is substituted with alkyl, Each R 1a are independently -OH, -OCH 3 , -OCF 3 , -OCHF 2 or fluorine, R 2 But, H, -C (3~5) Cycloalkyl or -C (1~3) Alkyl, C (3~5) cycloalkyl is unsubstituted or substituted with -CN; R 3 is unsubstituted or substituted with 1 to 2 fluorine atoms, R 4 But -C(3~4) cycloalkyl, spiropentanyl, spirohexanyl, spiroheptanyl, spirooctanyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, or thiadiazolyl; (3~4) Cycloalkyl is unsubstituted or substituted with halogen and unsubstituted or substituted with 1 to 3 fluorine atoms. (1~2) substituted with 1 to 3 groups selected from alkyl; Phenyl is unsubstituted or is selected from the group consisting of 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) substituted with one or two groups selected from alkyl, and 3- to 6-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; (1~3) Alkyl, -C (0~2) Alkyl-C (3~4) Cycloalkyl, and -C (1~4) the alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms, the heterocyclyl is unsubstituted or substituted with one oxo; Pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, imidazolyl, thiazolyl, isothiazolyl, and thiadiazolyl are each independently selected from the group consisting of one or two R 4c is substituted with a group, 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 3-6 membered heterocyclyl having 1-2 heteroatoms selected from N and O; (0~2) Alkyl C (3~6)Cycloalkyl, -C (1~4) Alkyl, -OC (1~3) The alkyl and heterocyclyl groups are unsubstituted or have 1 to 4 R 4d is substituted with a group, Each R 4d But independently, -OCH 3 , -OCF 3 , -OCHF 2 or fluorine, R 5 is hydrogen or fluorine, R 4 When R is 1,2,4-triazolyl, 4 but,

[0317] [ka] It is.

[0318] In some embodiments, disclosed herein is a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (3~5) Alkyl,

[0319] [ka] and -C (3~5) Alkyl is unsubstituted or has 1 to 6 R 1a is substituted with a group,

[0320] [ka] is unsubstituted or substituted with 1 to 4 fluorine atoms,

[0321] [ka] is unsubstituted or substituted with 1 to 4 fluorine atoms,

[0322] [ka] is unsubstituted or substituted with 1 to 4 fluorine atoms,

[0323] [ka] is unsubstituted or unsubstituted or substituted with 1 to 3 fluorine atoms, (1~2) is substituted with alkyl, Each R 1a is independently -OH or fluorine; R 2 is H, methyl, isopropyl, cyclopropyl, or cyclobutyl, wherein cyclopropyl and cyclobutyl are unsubstituted or substituted by -CN; R 3 is cyclohexyl, or

[0324] [ka] and R 4 is cyclopropyl, spiropentanyl, spirohexanyl, phenyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, or 1,2,5-thiadiazolyl; Cyclopropyl is unsubstituted or substituted with fluorine and unsubstituted or substituted with 1 to 3 fluorine atoms. (1~2) substituted with 1 to 3 groups selected from alkyl; Phenyl is unsubstituted or substituted with chlorine and unsubstituted or substituted with 1 to 3 fluorine atoms; (1~2) substituted with 1 to 2 groups selected from alkyl; 1,2,3-Thiadiazolyl is unsubstituted or (1~3) Alkyl-substituted, C (1~3)alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms; Pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, thiazolyl, isothiazolyl, or 1,2,5-thiadiazolyl is unsubstituted or has one or two R 4c is substituted with a group, Each R 4c But independently, -C (0~1) Alkyl C (3~4) Cycloalkyl or -C (1~4) Alkyl, -C (0~1) Alkyl C (3~4) Cycloalkyl and -C (1~4) The alkyl group is unsubstituted or has 1 to 4 R 4d is substituted with a group, Each R 4d But independently, -OCH 3 , -OCF 3 , -OCHF 2 or fluorine, R 5 is hydrogen or fluorine, R 4 When R is 1,2,4-triazolyl, 4 but,

[0325] [ka] It is.

[0326] In some embodiments, disclosed herein is a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (3~5) Alkyl,

[0327] [ka] and -C (3~5) Alkyl is 1 to 6 R 1a is substituted with a group,

[0328] [ka] is unsubstituted or substituted with 1 to 2 fluorine atoms,

[0329] [ka] is unsubstituted or substituted with 1 to 4 fluorine atoms,

[0330] [ka] is substituted with two fluorine atoms,

[0331] [ka] But -CF 3 is replaced by Each R 1a is independently -OH or fluorine; R 2 is H, methyl, isopropyl, cyclopropyl, or cyclobutyl, wherein cyclopropyl and cyclobutyl are unsubstituted or substituted by -CN; R 3 is cyclohexyl, or

[0332] [ka] and R 4 is cyclopropyl, spiropentanyl, spirohexanyl, phenyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, 1,2,3-thiadiazolyl, or 1,2,5-thiadiazolyl; Cyclopropyl is fluorine and unsubstituted or substituted with three fluorine atoms (1) substituted with 1 to 2 groups selected from alkyl; Phenyl is unsubstituted or is -chlorine or -C (1~2) is substituted with alkyl, 1,2,3-Thiadiazolyl and 1,2,5-Thiadiazolyl are C (2~3) is substituted with alkyl, Pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, triazolyl, tetrazolyl, and imidazolyl are each independently selected from the group consisting of one or two R 4c is substituted with a group, Each R 4c But independently, -C (0~1) Alkyl C (3~4) Cycloalkyl or -C (1~3) Alkyl, -C (0~1) Alkyl C (3~4) Cycloalkyl and -C (1~3) The alkyl group is unsubstituted or has 1 to 4 R 4d is substituted with a group, Each R 4d But independently, -OCH 3 , -OCF 3 , -OCHF 2 or fluorine, R 5 is hydrogen, R 4 When R is 1,2,4-triazolyl, 4 but,

[0333] [ka] It is.

[0334] All embodiments described herein above with respect to compounds of formula I are incorporated herein by reference with respect to compounds of formula I'. Thus, the variable R 1 , R 2 , R 3 , R 4 , and / or R 5 Any definitions for also apply to Formula I'. Certain embodiments of compounds of Formula I' are also provided below.

[0335] In some embodiments, disclosed herein is a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (1~6) Alkyl, -C (0~2) Alkyl C (3~6) Cycloalkyl, -C (0~2) Alkyl-cyclopropyl-C (1~3) perfluoroalkyl, pyrrolidinyl, or piperidinyl; -C (1~6) Alkyl is unsubstituted or has 1 to 6 R 1a is substituted with a group, -C (0~2) Alkyl C (3~6) Cycloalkyl is unsubstituted or has 1 to 6 R 1b is substituted with a group, Pyrrolidinyl and piperidinyl are unsubstituted or have one to three R 1c is substituted with a group.

[0336] In some embodiments, disclosed herein is a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (1~6) Alkyl, -C (0~2) Alkyl C (3~6) Cycloalkyl, -CH 2 -Cyclopropyl-C (1~3) perfluoroalkyl, pyrrolidinyl, or piperidinyl; -C (1~6) Alkyl is unsubstituted or has 1 to 6 R 1a is substituted with a group, -C (0~2) Alkyl C (3~6) Cycloalkyl is unsubstituted or has 1 to 6 R 1b is substituted with a group, Pyrrolidinyl and piperidinyl are unsubstituted or have one to three R 1c is substituted with a group.

[0337] In some embodiments, disclosed herein is a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (3~6) Alkyl, -C (0~2) Alkyl C (3~6) Cycloalkyl, -C (0~2) Alkyl-cyclopropyl-C (1~3) perfluoroalkyl, pyrrolidinyl, or piperidinyl; -C (1~6) Alkyl is unsubstituted or has 1 to 6 R 1a is substituted with a group, -C (0~2) Alkyl C (3~6) Cycloalkyl is unsubstituted or has 1 to 4 R 1b is substituted with a group, Pyrrolidinyl and piperidinyl are each independently one R 1c is substituted with a group, Each R 1a are independently fluorine, -CN, -OH, -OC (1~3) Alkyl or -OC (3~4) Cycloalkyl, -OC (1~3) Alkyl and -OC (3~4) the cycloalkyl group is unsubstituted or substituted with 1 to 3 fluorine atoms; Each R 1b are independently fluorine; R 1c is substituted with 1 to 3 fluorine atoms -C (1~4) It is an alkyl.

[0338] In some embodiments, disclosed herein is a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein: R 1 But -C (3~6) Alkyl, -C (1~2) Alkyl C (3~6) Cycloalkyl or -C (1~2) Alkyl-cyclopropyl-CF 3 and -C (1~6)Alkyl is unsubstituted or has 1 to 6 R 1a is substituted with a group, -C (1~2) Alkyl C (3~6) Cycloalkyl is unsubstituted or contains one or two R 1b is substituted with a group, Each R 1a are independently fluorine; Each R 1b are independently fluorine.

[0339] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 1 is unsubstituted or 1 to 3 R 1b -C substituted with group (0~2) Alkyl C (3~6) cycloalkyl, and each R 1b is independently fluorine. In some embodiments, disclosed herein are compounds of formula I' or a pharma- ceutically acceptable salt thereof, wherein R 1 is unsubstituted or 1 to 3 R 1b CH substituted with group 2 C (3~6) cycloalkyl, and each R 1b are independently fluorine.

[0340] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 1 but,

[0341] [ka]

[0342] [ka] It is.

[0343] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 1 but,

[0344] [ka] It is.

[0345] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 1 but,

[0346] [ka] It is.

[0347] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 1 but,

[0348] [ka] It is.

[0349] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 1 but,

[0350] [ka] It is.

[0351] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 1 but,

[0352] [ka] It is.

[0353] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 1 but,

[0354] [ka] It is.

[0355] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 1 but,

[0356] [ka] It is.

[0357] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 2 H, cyclopropyl, cyclobutyl, -C (1~3) alkyl, or tetrahydropyran; cyclopropyl and cyclobutyl are unsubstituted or substituted with -CN; -C (1~3) Alkyl is 1 to 3 R 2a is substituted with a group, Each R 2a are independently fluorine, -C (3~4) Cycloalkyl, -CN, -OH, or -OC (1~3) It is an alkyl.

[0358] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 2 is H, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, tetrahydropyranyl,

[0359] [ka] It is.

[0360] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 2 is H, methyl, isopropyl, cyclopropyl, cyclobutyl, or tetrahydropyran, where cyclopropyl and cyclobutyl are unsubstituted or substituted with -CN.

[0361] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 2 is H, methyl, isopropyl, cyclopropyl, or cyclobutyl, where cyclopropyl and cyclobutyl are unsubstituted or substituted with -CN.

[0362] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 2 is cyclopropyl or cyclobutyl, where cyclopropyl and cyclobutyl are unsubstituted or substituted with -CN.

[0363] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 2 In some embodiments, disclosed herein are compounds of formula I' or a pharma- ceutically acceptable salt thereof, wherein R 2 is cyclopropyl substituted with -CN. In some embodiments, disclosed herein are compounds of formula I' or a pharma- ceutically acceptable salt thereof, wherein R 2 but,

[0364] [ka] It is.

[0365] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 2 In some embodiments, disclosed herein are compounds of formula I' or a pharma- ceutically acceptable salt thereof, wherein R 2 is cyclobutyl substituted with -CN. In some embodiments, disclosed herein are compounds of formula I' or a pharma- ceutically acceptable salt thereof, wherein R 2 but,

[0366] [ka] It is.

[0367] In some embodiments, disclosed herein is a compound of formula I', which is a compound of formula I'a, or a pharma- ceutically acceptable salt thereof:

[0368] [ka] In some embodiments, disclosed herein is a compound of formula I', or a pharma- ceutically acceptable salt thereof, which is a compound of formula I'b:

[0369] [ka] In the formula, R 3a is fluorine and n is 0, 1, or 2. In some embodiments, R 3a is fluorine and n is 2.

[0370] In some embodiments, disclosed herein is a compound of formula I', or a pharma- ceutically acceptable salt thereof, which is a compound of formula I'b-1:

[0371] [ka] In the formula, R 3ais fluorine and n is 2.

[0372] In some embodiments, disclosed herein is a compound of formula I', or a pharma- ceutically acceptable salt thereof, which is a compound of formula I'b-2a:

[0373] [ka] In the formula, R 3a is fluorine and n is 2.

[0374] In some embodiments, disclosed herein is a compound of formula I', or a pharma- ceutically acceptable salt thereof, which is a compound of formula I'b-2b:

[0375] [ka] In the formula, R 3a is fluorine and n is 2.

[0376] In some embodiments, disclosed herein is a compound of formula I', which is a compound of formula I'b-3a, or a pharma- ceutically acceptable salt thereof:

[0377] [ka] In some embodiments, disclosed herein is a compound of formula I', which is a compound of formula I'b-3b, or a pharma- ceutically acceptable salt thereof:

[0378] [ka] In some embodiments, disclosed herein is a compound of formula I', which is a compound of formula I'c, or a pharma- ceutically acceptable salt thereof:

[0379] [ka] In some embodiments, disclosed herein is a compound of formula I', or a pharma- ceutically acceptable salt thereof, which is a compound of formula I'd:

[0380] [ka] In the formula, R 3a is fluorine and n is 0, 1, or 2. In some embodiments, R 3a is fluorine and n is 2.

[0381] In some embodiments, disclosed herein is a compound of formula I', or a pharma- ceutically acceptable salt thereof, which is a compound of formula I'd-1:

[0382] [ka] In the formula, R 3a is fluorine and n is 2.

[0383] In some embodiments, disclosed herein is a compound of formula I', or a pharma- ceutically acceptable salt thereof, which is a compound of formula I'd-2a:

[0384] [ka] In the formula, R 3a is fluorine and n is 2.

[0385] In some embodiments, disclosed herein is a compound of formula I', or a pharma- ceutically acceptable salt thereof, which is a compound of formula I'd-2b:

[0386] [ka] In the formula, R 3a is fluorine and n is 2.

[0387] In some embodiments, disclosed herein is a compound of formula I', which is a compound of formula I'd-3a, or a pharma- ceutically acceptable salt thereof:

[0388] [ka] In some embodiments, disclosed herein is a compound of formula I', which is a compound of formula I'd-3b, or a pharma- ceutically acceptable salt thereof:

[0389] [ka] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 3 But, C (3~6) Cycloalkyl, -C (3~6) Alkyl or -CH 2 -OC (1~3) and C (3~6) Cycloalkyl, -C (3~6) Alkyl, and -CH 2 -OC (1~3) The alkyl groups are unsubstituted or each independently selected from fluorine, -CH 3 , and -CF 3 1 to 3 R selected from 3a is substituted with a group.

[0390] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 3 but,

[0391] [ka] It is.

[0392] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 3 but,

[0393] [ka] It is.

[0394] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 3 but,

[0395] [ka] It is.

[0396] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 3 but,

[0397] [ka] It is.

[0398] In some embodiments, disclosed herein is a compound of formula I', which is a compound of formula I'e, or a pharma- ceutically acceptable salt thereof:

[0399] [ka] In some embodiments, disclosed herein is a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein: R 4 is unsubstituted or 1 to 3 R 4a -C substituted with group (3~6) is cycloalkyl, Each R 4a are independently fluorine and - (1~4) alkyl, -C (1~4) Alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms; Alternatively, two R's attached to the same ring atom 4a The groups, in combination with the atoms to which they are attached, form C(3~6) It may also form a cycloalkyl.

[0400] In some embodiments, disclosed herein is a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein: R 4 is unsubstituted or 1 to 3 R 4a -C substituted with group (3~6) is cycloalkyl, Each R 4a are independently fluorine, CH 3 , C.H. 2 F, C.F. 2 H, and CF 3 Selected from or Alternatively, two R's attached to the same ring atom 4a The groups may combine with the atom to which they are attached to form a cyclopropyl, cyclobutyl, or cyclopentyl.

[0401] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0402] [ka] It is.

[0403] In some embodiments, disclosed herein is a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein: R 4 But one or two R 4c is a 5-6 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S, substituted with a group; Each R 4c are independently halogen, -CN, -NH 2 , -N(CH 3 ) 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 3-6 membered heterocyclyl having 1-2 heteroatoms selected from N and O; (0~2) Alkyl C (3~6) Cycloalkyl, -C (1~4) Alkyl, -OC (1~3) Alkyl and heterocyclyl groups are unsubstituted or have 1 to 6 R 4d is substituted with a group, Alternatively, two R's attached to adjacent ring atoms 4c The groups combine to form C (4~6) may form a cycloalkyl, 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 3-6 membered heterocyclyl having 1-2 heteroatoms selected from N and O; (1~3) Alkyl, -OC (1~3) Alkyl, -OC (3~4) cycloalkyl and heterocyclyl groups are unsubstituted or substituted with 1 to 3 fluorine atoms; R 4d1 and R 4d2 each independently represents H or -C (1~3) Alkyl, -C (1~3) alkyl is unsubstituted or substituted with 1 to 6 groups selected from fluorine and chlorine; Or, R 4d1 and R 4d2 may combine with the atom to which they are attached to form a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, the heterocyclyl being unsubstituted or substituted with 1 to 4 fluorine atoms; R 4 When R is 1,2,4-triazolyl, 4 is 1H-1,2,4-triazolyl; R 4 When is a 6-membered heteroaryl, the heteroaryl is unsubstituted at the para position.

[0404] In some embodiments, disclosed herein is a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein: Each R 4c are independently fluorine, -CN, -OH, -NH 2 , N(CH 3 ) 2 , methyl, ethyl, isopropyl, -CD 3 , -CD 2 CD 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OC(CH 3 ) 3 , CH(CH 3 )OH, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH(CH 3 )CHF 2 , -CH(CH 3 )CF 3 , -CH(CH 2 F) 2 , -CH 2 CF 2 CH 3, -CH 2 CH 2 CF 2 CH 3 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 O.C.H.F. 2 , -CH 2 CH 2 OCF 3 , -CH 2 O.C.H.F. 2 , -OCHF 2 , -OCH 2 CHF 2 , -OCH 2 CH 2 F, -OCH 2 CF 3 , cyclopropyl, cyclobutyl, cyclopentyl, -CH 2 -cyclopropyl, -O-cyclopropyl, -O-cyclobutyl,

[0405] [ka] or Alternatively, two R's attached to adjacent ring atoms 4c The groups may combine to form the following groups:

[0406] [ka]

[0407] In some embodiments, disclosed herein is a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein: R 4 But one or two R 4c oxazolyl, isoxazolyl, or oxadiazolyl substituted with a group; Each R 4c are independently -OH, -NH 2 , -N(CH 3 ) 2 , -C(0~1) Alkyl C (3~5) Cycloalkyl, -OC (3~4) Cycloalkyl, -C (1~3) Alkyl, -OC (1~3) Alkyl,

[0408] [ka] and -C (0~1) Alkyl C (3~5) Cycloalkyl, -C (1~3) Alkyl and OC (1~3) The alkyl group is unsubstituted or is selected from the group consisting of -OH, -OCH 3 , -OCHF 2 , -CH 3 and fluorine.

[0409] In some embodiments, disclosed herein is a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein: R 4 is unsubstituted or has one or two R 4c oxazolyl, isoxazolyl, or oxadiazolyl (e.g., 1,2,5-oxadiazolyl), substituted with a group; Each R 4c are independently cyclopropyl, C (1~3) Alkyl or -OC (1~3) Alkyl, cyclopropyl, -C (1~3) Alkyl and -OC (1~3) The alkyl group is unsubstituted or substituted with 1 to 3 fluorine atoms.

[0410] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but, each independently represents methyl, ethyl, isopropyl, -CF 3 , -CH 2 CH 2 F, -CH 2 CH 2 CF3 , -CH 2 OCH 3 , cyclopropyl, cyclopentyl, or

[0411] [ka] One or two R 4c isoxazolyl substituted with a group; oxazolyl substituted with one isopropyl; or One methyl, one ethyl, one -OCH 2 CHF 2 or oxadiazolyl substituted with cyclopropyl.

[0412] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 is a cyclopropyl-substituted 1,2,5-oxadiazolyl.

[0413] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0414] [ka]

[0415] [ka] It is.

[0416] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0417] [ka] It is.

[0418] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0419] [ka] It is.

[0420] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0421] [ka] It is.

[0422] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0423] [ka] It is.

[0424] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0425] [ka] It is.

[0426] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0427] [ka] It is.

[0428] In some embodiments, disclosed herein is a compound of formula I', which is a compound of formula I'f, or a pharma- ceutically acceptable salt thereof:

[0429] [ka]

[0430] In some embodiments, disclosed herein is a compound of formula I', which is a compound of formula I'g, or a pharma- ceutically acceptable salt thereof:

[0431] [ka]

[0432] In some embodiments, disclosed herein is a compound of formula I', which is a compound of formula I'h, or a pharma- ceutically acceptable salt thereof:

[0433] [ka]

[0434] In some embodiments, disclosed herein is a compound of formula I', or a pharma- ceutically acceptable salt thereof, which is a compound of formula I'i:

[0435] [ka] In the formula, R 3a is fluorine, n is 2, and m is 1 or 2.

[0436] In some embodiments, disclosed herein is a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein: R 4 is unsubstituted or has one or two R 4cpyrazolyl or imidazolyl substituted with a group; Each R 4c are independently fluorine, cyclopropyl, or -C (1~3) Alkyl, -C (1~3) The alkyl is unsubstituted or -CHF 2 , -CF 3 , -OCHF 2 , -OCF 3 and fluorine.

[0437] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 But one or two R 4c pyrazolyl or imidazolyl, each R 4c is independently unsubstituted or -CHF 2 , -CF 3 , -OCHF 2 , -OCF 3 and -C substituted with 1 to 3 groups selected from fluorine (1~3) It is an alkyl.

[0438] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but, each independently being cyclopropyl, methyl, ethyl, isopropyl, -CD 3 , -CD 2 CD 3 , fluorine, -CHF 2 , -CF 3 , -CH 2 CHF 2 , -CH 2 CF 3 , -CH(CH 3 )CF 3 , -CH(CH 2 F) 2 , -CH 2 CH 2 O.C.H.F. 2 , or -CH 2 CH 2 OCF3 One or two R 4c pyrazolyl substituted with a group, or Imidazolyl substituted with one methyl or isopropyl.

[0439] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 But one -C (1~3) In some embodiments, disclosed herein are compounds of formula I' or a pharma- ceutically acceptable salt thereof, wherein R 4 But isopropyl, -CD 3 , or -CD 2 CD 3 and pyrazolyl substituted with

[0440] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0441] [ka] It is.

[0442] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0443] [ka] It is.

[0444] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0445] [ka] It is.

[0446] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0447] [ka] It is.

[0448] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0449] [ka] It is.

[0450] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0451] [ka] It is.

[0452] In some embodiments, disclosed herein is a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein: R 4 is unsubstituted or has one or two R 4c is a triazolyl substituted with a group; Each R 4c But independently, C (0~1) Alkyl C (3~4) Cycloalkyl, -C (1~4) Alkyl,

[0453] [ka] and -C(0~1) Alkyl C (3~4) Cycloalkyl and -C (1~3) The alkyl group is unsubstituted or has 1 to 4 R 4d is substituted with a group, Each R 4d But independently, -OCH 3 , -OCF 3 , -OCHF 2 , fluorine,

[0454] [ka] and R 4 When R is 1,2,4-triazolyl, 4 but,

[0455] [ka] It is.

[0456] Or, R 4 When R is 1,2,4-triazolyl, 4 is 1H-1,2,4-triazolyl.

[0457] In some embodiments, disclosed herein is a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein: R 4 is unsubstituted or has one or two R 4c is a triazolyl substituted with a group; Each R 4c are independently methyl, ethyl, isopropyl, -CH 2 CH 2 OCH 3 , -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 CH2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH(CH 3 )CHF 2 , -CH(CH 3 )CF 3 -CH 2 CF 2 CH 3 , -CH 2 CH 2 CF 2 CH 3 , -CH 2 CH 2 O.C.H.F. 2 , -CH 2 CH 2 OCF 3 , cyclopropyl, -CH 2 -cyclopropyl,

[0458] [ka] and R 4 When R is 1,2,4-triazolyl, 4 but,

[0459] [ka] It is.

[0460] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0461] [ka]

[0462] [ka] It is.

[0463] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 is thienyl, thiadiazolyl, or thiadiazolyl, each substituted with methyl, isopropyl, or cyclopropyl.

[0464] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but, isopropyl substituted thienyl, isopropyl-substituted thiazolyl, or Thiadiazolyl substituted with methyl, isopropyl, or cyclopropyl.

[0465] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0466] [ka] It is.

[0467] In some embodiments, disclosed herein are compounds of formula I′ or a pharma- ceutically acceptable salt thereof, wherein R 4 but,

[0468] [ka] It is.

[0469] [Table 11-1]

[0470] [Table 11-2]

[0471]

Table 11-3

[0472]

Table 12-1

[0473]

Table 12-2

[0474]

Table 12-3

[0475]

Table 13-1

[0476]

Table 13-2

[0477]

Table 13-3

[0478]

Table 14-1

[0479]

Table 14-2

[0480]

Table 14-3

[0481]

Table 15-1

[0482]

Table 15-2

[0483]

Table 15-3

[0484]

Table 16-1

[0485]

Table 16-2

[0486]

Table 16-3

[0487]

Table 17-1

[0488]

Table 17-2

[0489]

Table 17-3

[0490]

Table 18-1

[0491]

Table 18-2

[0492]

Table 18-3

[0493]

Table 19-1

[0494]

Table 19-2

[0495]

Table 19-3

[0496]

Table 20-1

[0497]

Table 20-2

[0498]

Table 20-3

[0499]

[0500]

Table 21-1

[0501]

Table 21-2

[0502] [Table 21-3]

[0503] [Table 22-1]

[0504] [Table 22-2]

[0505] [Table 22-3]

[0506] [Table 23]

[0507] In some embodiments, disclosed herein is a compound of formula I', or a pharma- ceutically acceptable salt thereof, selected from the group consisting of the compounds of 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.

[0508] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0509] [ka]

[0510] [ka] or a pharma- ceutically acceptable salt thereof.

[0511] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0512] [ka] or a pharma- ceutically acceptable salt thereof.

[0513] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0514] [ka] or a pharma- ceutically acceptable salt thereof.

[0515] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0516] [ka] or a pharma- ceutically acceptable salt thereof.

[0517] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0518] [ka] or a pharma- ceutically acceptable salt thereof.

[0519] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0520] [ka] or a pharma- ceutically acceptable salt thereof.

[0521] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0522] [ka] or a pharma- ceutically acceptable salt thereof.

[0523] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0524] [ka] or a pharma- ceutically acceptable salt thereof.

[0525] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0526] [ka] or a pharma- ceutically acceptable salt thereof.

[0527] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0528] [ka] or a pharma- ceutically acceptable salt thereof.

[0529] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0530] [ka] or a pharma- ceutically acceptable salt thereof.

[0531] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0532] [ka] or a pharma- ceutically acceptable salt thereof.

[0533] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0534] [ka] or a pharma- ceutically acceptable salt thereof.

[0535] In some embodiments, disclosed herein is a method for treating a pulmonary circulation disorder comprising:

[0536] [ka] or a pharma- ceutically acceptable salt thereof.

[0537] In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound of formula I' or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration (e.g., a tablet or capsule).

[0538] In some embodiments, disclosed herein is a pharmaceutical composition made by mixing a compound of formula I' or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

[0539] In some embodiments, disclosed herein is a process for making a pharmaceutical composition, comprising mixing a compound of formula I' or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

[0540] III. Therapeutic Use The present application is also directed to a method for treating and / or ameliorating an IL-17 mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration an effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof, a composition thereof, or a medicament thereof.

[0541] The present application is also directed to a method for treating and / or ameliorating an IL-17 mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration an effective amount of a compound of formula I' or a pharma- ceutically acceptable salt thereof, a composition thereof, or a pharmaceutical preparation thereof.

[0542] In some embodiments, disclosed herein are methods for treating or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment or amelioration a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0543] In some embodiments, disclosed herein is a method for treating or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment or amelioration a therapeutically effective amount of a compound of formula I' or a pharma- ceutically acceptable salt thereof.

[0544] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0545] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0546] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is psoriasis.

[0547] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is psoriasis.

[0548] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is psoriatic arthritis.

[0549] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is psoriatic arthritis.

[0550] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is rheumatoid arthritis.

[0551] 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 of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is rheumatoid arthritis.

[0552] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is ankylosing spondylitis.

[0553] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is ankylosing spondylitis.

[0554] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is hidradenitis suppurativa.

[0555] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is hidradenitis suppurativa.

[0556] 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 of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutical acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is bullous pemphigoid.

[0557] 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 of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is bullous pemphigoid.

[0558] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is atopic dermatitis.

[0559] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is atopic dermatitis.

[0560] 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 of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutical acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is vitiligo.

[0561] 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 of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is vitiligo.

[0562] In some embodiments, disclosed herein is a method for treating or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutical acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is multiple sclerosis.

[0563] In some embodiments, disclosed herein is a method for treating or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment or amelioration a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is multiple sclerosis.

[0564] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is systemic lupus erythematosus.

[0565] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is systemic lupus erythematosus.

[0566] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is asthma.

[0567] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is asthma.

[0568] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is uveitits.

[0569] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is uveitis.

[0570] 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 of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is chronic obstructive pulmonary disorder.

[0571] 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 of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is chronic obstructive pulmonary disorder.

[0572] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is multiple myeloma.

[0573] In some embodiments, disclosed herein is a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is multiple myeloma.

[0574] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus, and wherein the compound of formula I, or a pharma- ceutically acceptable salt thereof, is administered orally (e.g., as a tablet or capsule).

[0575] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus, and wherein the compound of formula I' or a pharma- ceutically acceptable salt thereof is administered orally (e.g., as a tablet or capsule).

[0576] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus, and wherein the therapeutically effective amount is a dose of about 10 mg to 300 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 20 mg to 200 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 50 mg to 100 mg QD.

[0577] 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 of treatment and / or amelioration a therapeutically effective amount of a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus, and wherein the therapeutically effective amount is a dose of about 10 mg to 300 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 20 mg to 200 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 50 mg to 100 mg QD.

[0578] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus, and wherein the therapeutically effective amount is a dose of about 10 mg to 300 mg BID. In some embodiments, the therapeutically effective amount is a dose of about 20 mg to 200 mg BID. In some embodiments, the therapeutically effective amount is a dose of about 50 mg to 100 mg BID.

[0579] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of formula I' or a pharma- ceutically acceptable salt thereof, wherein the IL-17A-mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus, and wherein the therapeutically effective amount is a dose of about 10 mg to 300 mg BID. In some embodiments, the therapeutically effective amount is a dose of about 20 mg to 200 mg BID. In some embodiments, the therapeutically effective amount is a dose of about 50 mg to 100 mg BID.

[0580] In some embodiments, disclosed herein is the use of a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof for treating and / or ameliorating an IL-17A-mediated inflammatory syndrome, disorder, or disease selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0581] In some embodiments, disclosed herein is the use of a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof for treating and / or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0582] In some embodiments, disclosed herein is the use of a compound of Formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating and / or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0583] In some embodiments, disclosed herein is the use of a compound of Formula I' or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating and / or ameliorating an IL-17A mediated inflammatory syndrome, disorder, or disease selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

[0584] In some embodiments, disclosed herein are methods for treating and / or ameliorating an IL-17 mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of formula I or a pharma- ceutical acceptable salt thereof, a composition thereof, or a medicament thereof.

[0585] In some embodiments, disclosed herein is a method for treating and / or ameliorating an IL-17 mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of formula I' or a pharma- ceutically acceptable salt thereof, a composition thereof, or a pharmaceutical preparation thereof.

[0586] In some embodiments, disclosed herein are methods of treating and / or ameliorating an IL-17 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof, composition thereof, or medicament thereof, wherein the syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, atopic dermatitis, vitiligo, multiple sclerosis, asthma, allergic asthma, steroid-resistant asthma, neutrophilic asthma, chronic obstructive pulmonary disease, uveitis, multiple myeloma, and systemic lupus erythematosus.

[0587] In some embodiments, disclosed herein are methods of treating and / or ameliorating an IL-17 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, composition thereof, or medicament thereof, wherein the syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, atopic dermatitis, vitiligo, multiple sclerosis, asthma, allergic asthma, steroid-resistant asthma, neutrophilic asthma, chronic obstructive pulmonary disease, uveitis, multiple myeloma, and systemic lupus erythematosus.

[0588] In some embodiments, disclosed herein is a method of treating or ameliorating an IL-17 mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment or amelioration a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof, a composition thereof, or a medicament thereof, wherein the syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, and ankylosing spondylitis.

[0589] In some embodiments, disclosed herein is a method of treating or ameliorating an IL-17 mediated inflammatory syndrome, disorder, or disease, comprising administering to a subject in need of treatment or amelioration a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, a composition thereof, or a medicament thereof, wherein the syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, and ankylosing spondylitis.

[0590] In some embodiments, disclosed herein are methods of modulating IL-17 activity in a mammal by administering a therapeutically effective amount of at least one compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0591] In some embodiments, disclosed herein are methods of modulating IL-17 activity in a mammal by administering a therapeutically effective amount of at least one compound of formula I' or a pharma- ceutically acceptable salt thereof.

[0592] Also disclosed herein is a method of inhibiting the production of interleukin-17, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0593] Also disclosed herein is a method of inhibiting the production of interleukin-17, comprising administering to a subject in need of treatment and / or amelioration a therapeutically effective amount of a compound of formula I' or a pharma- ceutically acceptable salt thereof.

[0594] IV. Combination Therapy The compound of formula I or a pharma- ceutically acceptable salt thereof, composition thereof, or medicament thereof may also be used in combination with one or more additional therapeutic agents.Similarly, the compound of formula I' or a pharma- ceutically acceptable salt thereof, composition thereof, or medicament thereof may be used in combination with one or more additional therapeutic agents.

[0595] In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of anti-inflammatory agents, immunomodulatory agents, and immunosuppressants.

[0596] In some embodiments, the one or more additional therapeutic agents are Anti-TNF alpha agents such as infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), golimumab (Simponi®), etanercept (Enbrel®), thalidomide (Immunoprin® / lenalidomide (Revlimid®), and pomalidomide (Pomalyst® / Imnovid®); anti-p40 antibody agents such as ustekinumab (Stelara®); and selected from the group consisting of anti-p19 antibody agents such as guselkumab (Tremfya®), tildrakizumab (Ilumya™ / Ilumetri), risankizumab (Skyrizi™), and mirikizumab.

[0597] In some embodiments, disclosed herein are methods of treating and / or ameliorating an IL-17 mediated inflammatory syndrome, disorder, or disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof, composition thereof, or medicament thereof, in combination therapy with one or more additional therapeutic agents, such as anti-inflammatory agents, immunomodulatory agents, or immunosuppressants, wherein the syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, atopic dermatitis, vitiligo, multiple sclerosis, asthma, allergic asthma, steroid-resistant asthma, neutrophilic asthma, chronic obstructive pulmonary disease, uveitis, multiple myeloma, and systemic lupus erythematosus.

[0598] In some embodiments, disclosed herein are methods of treating and / or ameliorating an IL-17 mediated inflammatory syndrome, disorder, or disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, composition thereof, or medicament thereof, in combination therapy with one or more additional therapeutic agents, such as anti-inflammatory agents, immunomodulatory agents, or immunosuppressants, wherein the syndrome, disorder, or disease is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, atopic dermatitis, vitiligo, multiple sclerosis, asthma, allergic asthma, steroid-resistant asthma, neutrophilic asthma, chronic obstructive pulmonary disease, uveitis, multiple myeloma, and systemic lupus erythematosus.

[0599] In some embodiments, disclosed herein are methods of treating and / or ameliorating an IL-17 mediated inflammatory syndrome, disorder, or disease in a subject in need of such treatment and / or amelioration, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharma- ceutically acceptable salt thereof, composition thereof, or medicament thereof, in combination therapy with one or more additional therapeutic agents, such as anti-inflammatory agents or immunosuppressants, wherein the syndrome, disorder, or disease is psoriasis, psoriatic arthritis, ankylosing spondylitis. In some embodiments, the IL-17 mediated inflammatory syndrome, disorder, or disease is psoriasis. In some embodiments, the IL-17 mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis. In some embodiments, the IL-17 mediated inflammatory syndrome, disorder, or disease is ankylosing spondylitis.

[0600] In some embodiments, disclosed herein are methods of treating and / or ameliorating an IL-17 mediated inflammatory syndrome, disorder, or disease in a subject in need of such treatment and / or amelioration, comprising administering to the subject a therapeutically effective amount of a compound of Formula I' or a pharma- ceutically acceptable salt thereof, composition thereof, or medicament thereof, in combination therapy with one or more additional therapeutic agents, such as anti-inflammatory agents or immunosuppressants, wherein the syndrome, disorder, or disease is psoriasis, psoriatic arthritis, ankylosing spondylitis. In some embodiments, the IL-17 mediated inflammatory syndrome, disorder, or disease is psoriasis. In some embodiments, the IL-17 mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis. In some embodiments, the IL-17 mediated inflammatory syndrome, disorder, or disease is ankylosing spondylitis.

[0601] Dosing regimen When used as an IL-17A modulator, the compounds disclosed herein may be administered in an effective amount within the range of about 0.5 mg to about 1 g, preferably about 0.5 mg to about 500 mg, in single or divided daily doses. In some embodiments, the dosage is about 5 mg to 400 mg. In some embodiments, the dosage is about 10 mg to 300 mg. In some embodiments, the dosage is about 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage is about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage is about 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage is about 300, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage is about 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage is about 10 mg to 300 mg. In some embodiments, the dosage is about 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of a compound of formula I' or a pharma- ceutically acceptable salt thereof.In some embodiments, the dosage is about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of a compound of formula I' or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage is about 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg of a compound of formula I' or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage is about 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg of a compound of formula I' or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage is about 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 mg of a compound of formula I' or a pharma- ceutically acceptable salt thereof.

[0602] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 10 mg to 300 mg QD. In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 20 mg to 200 mg QD. In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 50 mg to 100 mg QD.

[0603] In some embodiments, the compound of formula I' or a pharma- ceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 10 mg to 300 mg QD. In some embodiments, the compound of formula I' or a pharma- ceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 20 mg to 200 mg QD. In some embodiments, the compound of formula I' or a pharma- ceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 50 mg to 100 mg QD.

[0604] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 10 mg to 300 mg BID. In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 20 mg to 200 mg BID. In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 50 mg to 100 mg BID.

[0605] In some embodiments, the compound of formula I' or a pharma- ceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 10 mg to 300 mg BID. In some embodiments, the compound of formula I' or a pharma- ceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 20 mg to 200 mg BID. In some embodiments, the compound of formula I' or a pharma- ceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 50 mg to 100 mg BID.

[0606] The dosage administered will be affected by factors such as the route of administration, the health, weight, and age of the recipient, frequency of treatment, and the presence of concurrent, unrelated treatments.

[0607] It is also obvious to those skilled in the art that the therapeutically effective amount of the compound of the present invention or its pharmaceutical composition varies according to the desired effect.Thus, the optimal dosage can be easily determined by those skilled in the art and varies according to the specific compound used, the administration method, the strength of the preparation, and the progress of the condition.In addition, factors related to the specific subject being treated, including the subject's age, weight, diet, and administration time, will cause the need to adjust the dosage to an appropriate therapeutic concentration.Therefore, the dosages above are examples of average cases.Of course, there may be individual cases in which higher or lower dosage ranges are effective, and such cases are within the scope of the present invention.

[0608] Pharmaceutically acceptable salts Pharmaceutically acceptable acid / anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estrus, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, The acid salts include, but are not limited to, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucoate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theoclate, tosylate, and triethiodide.The organic or inorganic acid includes, but is not limited to, hydroiodic acid, perchloric acid, sulfuric acid, phosphoric acid, propionic acid, glycolic acid, methanesulfonic acid, hydroxyethanesulfonic acid, oxalic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, saccharic acid, or trifluoroacetic acid.

[0609] Pharmaceutically acceptable base / cation salts include aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (also known as tris(hydroxymethyl)aminomethane, tromethane, or "TRIS"), ammonia, benzathine, t-butylamine, calcium, calcium gluconate, calcium hydroxide, chloroprocaine, choline, choline bicarbonate, choline chloride, cyclohexylamine, diethanolamine, ethylenediamine, lithium, LiOMe, L-lysine, magnesium, meglumine, NH 3 , N.H. 4These include, but are not limited to, OH, 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.

[0610] Pharmaceutical Compositions The compound of formula I or its pharmaceutically acceptable salt can be formulated in a pharmaceutical composition that includes any known pharmaceutically acceptable carrier.Similarly, the compound of formula I' or its pharmaceutically acceptable salt can be formulated in a pharmaceutical composition that includes any known pharmaceutically acceptable carrier.Representative carriers include, but are not limited to, any suitable solvent, dispersion medium, coating, antibacterial and antifungal agent, and isotonicity agent.Representative excipients that can also be a component of the formulation include fillers, binders, disintegrants, and lubricants.

[0611] The pharmaceutically acceptable salts of the compounds of formula I include conventional non-toxic salts or quaternary ammonium salts formed from inorganic or organic acids or bases. Similarly, the pharmaceutically acceptable salts of the compounds of formula I' also include conventional non-toxic salts or quaternary ammonium salts formed from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, benzoate, benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride, hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate and tartrate. The basic salts include ammonium salts, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts with organic bases such as dicyclohexylamino salts, and salts with amino acids such as arginine. In addition, basic nitrogen-containing groups may be quaternized, for example, by alkyl halides.

[0612] The pharmaceutical composition of the present invention can be administered by any means that achieves its intended purpose. Examples include parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal, or ocular administration. Alternatively, or in conjunction, it may be administered by oral route. Suitable formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form, such as water-soluble salts, acidic solutions, alkaline solutions, aqueous dextrose solutions, isotonic carbohydrate solutions, and cyclodextrin inclusion complexes.

[0613] Also disclosed herein is a method of making a pharmaceutical composition comprising mixing a pharma- ceutically acceptable carrier with any of the compounds of formula I or its pharma- ceutically acceptable salts. Further disclosed herein is a method of making a pharmaceutical composition comprising mixing a pharma- ceutically acceptable carrier with any of the compounds of formula I' or its pharma- ceutically acceptable salts. Additionally, the present application includes a pharmaceutical composition made by mixing a pharma- ceutically acceptable carrier with any of the compounds of the present invention. EXAMPLES

[0614] Abbreviation The following abbreviations may be used throughout this specification and application:

[0615] [Table 24-1]

[0616] [Table 24-2]

[0617] In some embodiments, provided herein are processes and intermediates disclosed herein that are useful for preparing the disclosed compounds, or pharma- ceutically acceptable salts thereof.

[0618] General scheme:

[0619] [ka]

[0620] In the present invention, certain compounds of formula I-aa can be prepared, for example, according to Scheme 1. 2 (dba) 3 Cyanation of AI using a reagent such as zinc cyanide in the presence of a catalyst such as HCl affords the nitrile A-II. Removal of the Boc group under acidic conditions such as aqueous HCl affords the amine, which is then coupled to a carboxylic acid through the use of 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 afford the 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 to a carboxylic acid in a manner similar to the conversion of A-II to A-III to afford compounds of general structure I-aa as shown in Scheme 1.

[0621] [ka]

[0622] [ka]

[0623] In the present invention, certain compounds of general structure I-aa-1 and I-aa can also be prepared according to schemes 2a and 2b, respectively. Removal of the Boc group of compounds of type A-Ia or A-Ib under acidic conditions, such as aqueous hydrochloric acid or TFA, gives 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 A-VII can be carried out by the addition of Pd(dtbpf)Cl 2 This was accomplished using a mixture of reagents capable of transferring a vinyl group, such as potassium trifluoro(vinyl)borate, in the presence of a catalyst such as potassium osmate. Compounds of general structure A-VII could be converted to compounds of structure A-VIII through oxidative cleavage of the vinyl substituent using a reagent such as sodium periodate in the presence of a catalyst such as potassium osmate in a solvent such as aqueous 1,4-dioxane. Subsequent condensation of compounds of general structure A-VIII with (S)-(-)-2-methyl-2-propanesulfinamide affords the corresponding sulfinimide, which upon addition of a nucleophilic carbon-containing reagent such as an alkylmagnesium halide affords the sulfinamide of general structure A-IX. Conversion of compounds of structure A-IX to AX could be accomplished under acidic conditions, such as aqueous hydrochloric acid, and could then be converted to compounds of general structure 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 were subjected to additional purification techniques such as HPLC or SFC using columns with chiral stationary phases to give the single isomeric products I-aa-1 and I-aa.

[0624] [ka]

[0625] Compound I-aa-2 can be prepared by the reaction shown in Scheme 2c: Treatment of N-oxide IA with trimethylphosphite in toluene produces compound I-aa-2.

[0626] [ka]

[0627] Compound I-aa-3 can be prepared as shown in Scheme 2d. Co(acac) in THF under an oxygenated atmosphere. 2 , (cobalt(II) acetylacetonate), and PhSiH 3 Hydration of the olefin within IAI using a reagent such as (phenylsilane) provides compounds I-aa-3.

[0628] [ka]

[0629] In the present invention, compounds of formula I-aa can also be prepared according to scheme 3, in which the relative order of transformations is reversed compared to scheme 2b. Aldehydes of formula A-XI can be formed from AI (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 sulfinamide functionality from compounds of general structure A-XII under acidic conditions, such as aqueous hydrochloric acid in EtOAc, gives amines of general structure A-XIII. Acylation of A-XIII, followed by removal of the Boc group and amide formation to give compounds of general structure I-aa can be carried out as described in the previous scheme, but in some cases by (i) using an acid chloride in a solvent such as DCM, or (ii) using Al(CH) in a solvent such as toluene. 3 ) 3or (iii) by conversion of the N-hydroxysuccinic acid ester in the presence of DIPEA in a solvent such as acetonitrile.

[0630] [ka]

[0631] Compounds of general structure A-XXXI can be prepared as shown in Scheme 3a. Chlorides A-1a can be converted to the corresponding aldehydes A-XIa in a two-step sequence by the following sequence similar to that shown in Scheme 3. Condensation of compounds A-XIa with either (R)- or (S)-2-methyl-2-propanesulfinamide gives the corresponding sulfinimides A-XXX. R 2 Addition of a Grignard reagent such as MgX (X=halide) to A-XXX (method a) gives compounds of general formula A-XXXI. Addition of A-XXX to TMSCF in the presence of a reagent such as TBAF in a solvent such as THF gives compounds of general formula A-XXXI. 3 Addition of a nucleophilic carbon-containing reagent such as (Method b) provides compounds of general formula A-XXXI. Alternatively, addition of a nucleophilic carbon-containing reagent such as TMSCHF in the presence of a reagent such as potassium tert-butoxide in a solvent such as THF provides compounds of general formula A-XXXI. 2 Addition of a nucleophilic carbon-containing reagent such as (Method c) provides compounds of general formula A-XXXI. Trimethylsilylacetenonitrile may be metallated (Method d) using a reagent such as tetrabutylammonium phenolate in a solvent such as THF to provide sulfinamides of general structure A-XXXI. Cycloalkylnitriles are deprotonated (Method e) using a base such as LiHMDS in a solvent such as THF to provide compounds A-XXXI upon addition to A-XXX. Addition of an indium reagent such as allylindium, formed in situ by treatment of allyl bromide and indium in THF (Method f) to A-XXX provides compounds A-XXXI.

[0632] [ka]

[0633] Compounds of formula A-XXXIV can be prepared according to scheme 3b. Ketones of formula A-XXXIII can be formed from A-Ia by oxidative cleavage of the vinyl substituent using a vinyl transfer agent such as 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (J-III) in the presence of a catalyst such as RuPhos Pd G3, followed by a reagent such as sodium periodate in the presence of a catalyst such as potassium osmate in a solvent such as aqueous 1,4-dioxane. Reductive amination using a reagent such as ammonium formate in the presence of a reducing agent such as sodium cyanoborohydride with an additive such as acetic acid in a solvent such as methanol gives amines of general structure A-XXXIV.

[0634] [ka]

[0635] 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 with XtalFluor-E® in the presence of reagents such as triethylamine trihydrofluoride and DAST in a solvent such as DCM then gives the corresponding geminal difluorinated product A-XVIIa. These can then be converted to analogs 1-aa using the sequence shown in Scheme 3.

[0636] [ka]

[0637] Compounds of general formula A-Xaa can be prepared using the sequence shown in scheme 3d. Protection of the amine in A-XIIIa using FmocCl in the presence of DIPEA in a solvent such as DCM then gives the carbamate A-XVIIIa. Deprotection of the Boc group using an acid such as HCl in a solvent such as EtOAc then gives the corresponding amine hydrochloride A-XIXa. Sequential amide bond formation using the conditions described above and Fmoc deprotection using a reagent such as piperidine in a solvent such as DCM then gives the amine A-Xaa.

[0638] [ka]

[0639] 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, gives amides A-XX. NaNO in the presence of HCl in a solvent such as acetonitrile. 2 Treatment of A-XX with hydroxylamine in THF then gives the oxime A-XXI. Subsequent treatment of A-XXI with hydroxylamine in THF then gives the oxadiazole A-XXII. 2 WO 4 2H 2 Oxidation of the amine in A-XXII using O affords the nitro compound A-XXIII. Replacement of the nitro group in A-XXIII with a hydroxyl group to give the oxadiazole A-XXIV can be carried out using THF / H 2 This can be achieved using sodium hydroxide in a solvent such as HO, water and CH 3 In the presence of LiCl in a solvent such as CN, NaNO 2 Treatment of amine A-XXII with an aliphatic alcohol, R in the presence of a base such as sodium hydride in a solvent such as THF, affords chloride A-XXIVa. 4ccTreatment of chloride A-XXIVa with OH gives compound I-aa-4, R 4cc But, C (1~3) Alkyl or C (0~2) Alkyl-C (3~4) cycloalkyl, R 4cc is unsubstituted or 1 to 6 R 4d is substituted with a group.

[0640] [ka]

[0641] Additional oxadiazole-containing analogs can be prepared by the route shown in Scheme 3f. Treatment of amine A-XIIIa with lactone I-XI in a solvent such as DCM or in the presence of triazabicyclodecene in a solvent such as THF gives amide A-XXV. If A-XXV contains a primary alcohol, the corresponding aldehyde A-XXVI can be generated by oxidation using DMP. Treatment of A-XXVI with DAST in a solvent such as DCM then gives compound I-aa-5.

[0642] [ka]

[0643] Amides of general formula A-XXVII can be prepared by the method shown in Scheme 3g. 3 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 CN provides the homologated amide A-XXVII.

[0644] [ka]

[0645] Compounds of formula AI can be prepared according to the route of Scheme 4. Under halide interconversion conditions such as sodium iodide in acetone, chloromethyl ketone BI is converted to the corresponding iodomethyl ketone B-II. Cyclocondensation with 5-chloropyridazin-3-amine then gives the imidazopyridazine AI.

[0646] [ka]

[0647] Compounds of formula A-Ia can be prepared according to the route of Scheme 4a. Ylides of general structure CX undergo cyclocondensation with 5-chloropyridazin-3-amine in the presence of a catalyst such as chlorocyclopentadienylbis(triphenylphosphine)ruthenium(II) in the presence of an additive such as sodium triflate and 4 Å molecular sieves in a solvent such as toluene to give imidazopyridazines A-Ia.

[0648] [ka]

[0649] Compounds of general structure A-XVII can be prepared as shown in scheme 4b. Cyclocondensation of aminopyridazine GI with iodoketone B-Ic in the presence of 4 Å molecular sieves in a solvent such as DMA gives compound A-XVII. Alternatively, chlorinated compound G-Ia can be subjected to cyclocondensation with iodoketone B-Ic under similar conditions to give chlorinated aminopyridazine A-XVIIb. Hydrogenation using palladium catalyst in the presence of hydrogen gas and ammonium formate in ethanol or in the presence of hydrogen gas and acetic acid in a solvent such as THF then gives compound A-XVII.

[0650] [ka]

[0651] Alternatively, AI (e.g., A-Ib) may be prepared as shown in Scheme 5. Treatment of 4,4-difluorocyclohexyl ketone with methyl 2-((tert-butoxycarbonyl)amino)-2-(dimethoxyphosphoryl)acetate and a base such as DBU gives 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 gives racemic B-IV. Deprotonation of trimethylsulfoxonium iodide with a base such as sodium tert-butoxide gives the (dimethyl(oxo)-lambda)-olefin B-III. 6 Treatment of B-IV with 5-chloropyridazin-3-amine in the presence of a catalyst such as di-μ-chlorobis[(1,2,5,6-η)-1,5-cyclooctadiene]diiridium gives the ylide BV, followed by resolution of the enantiomers to give compound A-Ib.

[0652] [ka]

[0653] Chloromethyl ketone B-Ia can also be prepared by the route outlined in Scheme 6. Treatment of (S)-methyl 2-amino-2-cyclohexylacetate with di-tert-butyl dicarbonate with or without a base such as TEA in a solvent such as DCM gives B-VI, which can then be converted to chloromethyl ketone B-Ia upon treatment with chloroiodomethane treated with LDA in an aprotic solvent such as THF.

[0654] [ka]

[0655] 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 esterification of the acid under acidic conditions such as thionyl chloride in dry methanol, followed by treatment with di-tert-butyl dicarbonate in the presence of a mild base such as potassium carbonate in a solvent mixture such as water and 1,4-dioxane. Reduction of the phenyl ring of CI using a hydrogen source such as hydrogen gas in a solvent such as HOAc and a catalyst such as platinum(IV) oxide gives C-II. Oxidation of the alcohol of C-II with an oxidizing agent such as DMP gives the ketone C-III. Conversion of C-III to the geminal difluoride B-IV can be achieved by treatment with a deoxygenating fluorination reagent such as BAST (bis(2-methoxyethyl)aminosulfur trifluoride) in a solvent such as DCM. Saponification of the ester using a base such as lithium hydroxide provides the corresponding acid C-IV, which upon conversion to the mixed anhydride by treatment with a reagent such as isobutyl chloroformate followed by addition of diazomethane gives the corresponding diazoketone CV, which can be converted to B-Ib by treatment with aqueous hydrochloric acid.

[0656] [ka]

[0657] Compounds of general formula B-Ic and C-IX can be prepared as shown in scheme 7b. Condensation of aldehyde H-II with (S)-(-)-2-methyl-2-propanesulfinamide gives the corresponding sulfinimide C-VI. Cyanation using TMSCN in the presence of scandium triflate then gives the nitrile C-VII. Subsequent treatment with HCl in methanol then gives the ester C-VIII. Simultaneous ester saponification and Boc protection of the amine then gives C-IX. Activation of the carboxylic acid in C-IX using a reagent such as CDI or isobutyl chloroformate in the presence of a base such as potassium tert-butoxide in a solvent such as THF then gives structure CX. Treatment of ylide CX with methanesulfonic acid in the presence of lithium chloride in a solvent such as THF then gives chloromethyl ketone B-Ib, which can be converted to the corresponding iodide by treatment with sodium iodide in acetone to give compound B-Ic. Alternatively, acid C-IX may be prepared from nitrile C-VII by treatment with aqueous HCl and subsequent treatment of the resulting amino acid C-XI with sodium hydroxide and Boc anhydride to give the protected amino acid C-IX.

[0658] [ka]

[0659] 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 gives the 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 2-epimerization of D-III under basic conditions such as sodium methoxide in methanol, followed by treatment with di-tert-butyl dicarbonate using a base such as aqueous sodium bicarbonate, and then converting the ester to the corresponding acid under alkaline conditions such as aqueous LiOH in a solvent such as THF.

[0660] [ka]

[0661] Substituted 1,2,3-triazole-5-carboxylic acids E-II can be prepared as shown in Scheme 9. Methyl or ethyl 1H-1,2,3-triazole-5-carboxylates can be alkylated by treating the ester with a base such as potassium carbonate or sodium hydride and an alkylating agent such as an alkyl bromide, alkyl brosylate, or alkyl tosylate in a solvent such as DMF to give a mixture of 1,2,3-triazole-5-carboxylates EI alkylated at the N1, N2, or N3 positions, which can be separated by silica gel chromatography. Alternatively, alkylation can be achieved by treatment of methyl or ethyl 1H-1,2,3-triazole-5-carboxylates with an alcohol using Mitsunobu conditions such as DIAD and triphenylphosphine in a solvent such as THF to provide EI. Hydrolysis of the ester with an aqueous base such as sodium or potassium hydroxide in a solvent such as THF or EtOH provides the carboxylic acid E-II.

[0662] [ka]

[0663] Scheme 10 shows a method for the synthesis of methyl 1,2,4-triazole-5-carboxylate using PCy 3 It is shown that substituted 1,2,4-triazole-5-carboxylic acids E-IV can be prepared in a similar sequence to that described in Scheme 9, where E-IV is tricyclohexylphosphine.

[0664] [ka]

[0665] 5-Substituted isoxazole-4-carbonyl chlorides EV can be prepared as described in Scheme 11. 5-Substituted isoxazole-4-carboxylic acids are treated with excess thionyl chloride and upon concentration give the corresponding acid chlorides EV.

[0666] [ka]

[0667] Scheme 12 illustrates that substituted 1,2-pyrazole-4-carboxylic acids E-VII can be prepared in a similar sequence to that described in Scheme 9.

[0668] [ka]

[0669] 3-Substituted isoxazole 4-carboxylic acids EX can be prepared as shown in Scheme 13. Condensation of 4,4,4-trifluorobutanal with hydroxylamine hydrochloride in a solvent such as ethanol gives the corresponding oxime E-VIII. Subsequent treatment with NCS and cycloaddition with ethyl-3-(diethylamino)acrylate in a solvent such as chloroform gives the ester E-IX. Saponification of the ester is achieved with a reagent such as sodium hydroxide in aqueous ethanol to provide the isoxazole 4-carboxylic acid EX.

[0670] [ka]

[0671] 3-Substituted isoxazole 4-carboxylic acid esters E-IXa can be prepared as shown in Scheme 13a. Condensation of the aldehyde with hydroxylamine hydrochloride in a solvent such as ethanol gives the corresponding oxime E-VIIIa. Subsequent treatment with NCS and cycloaddition with ethyl-3-(diethylamino)acrylate in a solvent such as THF gives the ester E-IXa.

[0672] [ka]

[0673] Isoxazoles E-Xa can be prepared by the process outlined in Scheme 13b. 3 Treatment of a suitable nitroalkane with phenylisocyanate in the presence of N followed by treatment with 3-pyrrolidin-1-yl-acrylic acid ethyl ester in the presence of triethylamine in a solvent such as benzene gives the corresponding ester E-IXa. Subsequent saponification using a reagent such as LiOH or NaOH in aqueous ethanol gives the corresponding acid E-Xa.

[0674] [ka]

[0675] The isoxazole esters E-XIII and E-XV can be prepared by the route shown in Scheme 13c. Desilylation of the ester E-XI using TBAF gives the alcohol E-XII. CH 3 Additives such as CuI in a solvent such as CN and Et 3 Difluoromethylation using 2,2-difluoro-2-(fluorosulfonyl)acetic acid in the presence of a base such as N gives the ester E-XIII. Ethyl 3-hydroxyisoxazole-4-carboxylate E-XIV can be alkylated with an iodoalkane in the presence of sodium hydride in a solvent such as DMF to give the ether E-XV. Alternatively, treatment of ethyl 3-hydroxyisoxazole-4-carboxylate E-XIV with an aliphatic alcohol and a reagent such as triphenylphosphine and DIAD in a solvent such as THF provides the ether E-XV.

[0676] [ka]

[0677] Isoxazole acids E-XVI can be prepared by the route shown in Scheme 13d. Alkylation of ethyl 4-hydroxyisoxazole-3-carboxylate using an alkyl iodide in the presence of a base such as cesium carbonate in a solvent such as DMF gives the corresponding ester. Subsequent saponification using a reagent such as LiOH in a solvent mixture such as THF and water gives the isoxazole acids E-XVI.

[0678] [ka]

[0679] 4-Substituted isoxazole-3-carboxylic acids of general formula E-XVIII can be prepared as shown in scheme 13e. Condensation of a suitable aldehyde with ethyl 2-chloro-2-(hydroxyimino)acetate in the presence of pyrrolidine in a solvent such as DCM and a base such as triethylamine gives compound E-XVII. Oxidation of the pyrrolidine in E-XVII using a reagent such as mCPBA in a solvent such as DCM then gives the corresponding isoxazole-3-carboxylic ester (structure not shown), which upon saponification using a reagent such as aqueous LiOH in a solvent such as THF gives compound of formula E-XVIII.

[0680] [ka]

[0681] R 5 Compounds I-ab having =F can be prepared as shown in Scheme 14. Compound A-XIV (prepared from A-VIII shown in Scheme 3) is treated with a fluorination reagent such as 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) in a solvent such as acetonitrile to give R 5 Compounds containing structures A-XV with =F can then be obtained. Subsequent amide bond formation as described above then provides compounds I-ab.

[0682] [ka]

[0683] 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 gives the aminated product (not shown). Subsequent dechlorinative reduction using a palladium catalyst and Boc protection of the amine gives the tetrazine FI.

[0684] [ka]

[0685] Aminopyridazines of general structure GI can be prepared by the route shown in Scheme 16. Conversion of a Boc-protected amino acid to the corresponding aldehyde by 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 gives the aldehyde G-II. Treatment of the aldehyde G-II with dimethyl (1-diazo-2-oxopropyl)phosphonate in a solvent such as methanol in the presence of a base such as potassium carbonate then gives the alkyne G-III. Deprotection of the Boc group using hydrochloric acid in methanol then provides the 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 gives the amide GV. Condensation of GV with tetrazine FI under thermal conditions (60-115° C.) produces compound G-VI. Deprotection of the Boc with HCl in methanol gives G-VII, followed by subsequent deprotection of the 4-methoxybenzyl group with TFA gives the aminopyridazine GI.

[0686] [ka]

[0687] Aminopyridazines of general structure G-Ia can be prepared by the route shown in Scheme 17. Treatment of 6-chloropyridazin-3-amine with pivaloyl chloride in the presence of pyridine in DCM then gives amide G-VIII. Metallation of amide G-VIII using a reagent such as TMPMgCl·LiCl in a solvent such as THF, followed by treatment with sulfinimine HI then gives sulfinamine G-IX. Removal of the sulfinimine and pivaloyl groups by acidic hydrolysis using a reagent such as aqueous hydrochloric acid then gives diamine GX. Subsequent amide bond formation gives aminopyridazine G-Ia.

[0688] [ka]

[0689] Sulfinimides HI are prepared as shown in Scheme 18. Condensation of an aldehyde with a sulfinamide, such as (S)-2-methylpropane-2-sulfinamide, in the presence of a reagent such as copper sulfate and PPTS in a solvent such as DCM, THF, and / or toluene gives the sulfinimine HI.

[0690] [ka]

[0691] Aldehydes of general structure H-II are prepared as shown in Scheme 19. Optionally, carboxylic acid ester H-III may be reduced using a reagent such as DIBAL-H in a solvent such as DCM to give aldehyde H-II. Carboxylic acid H-IV can be converted to the corresponding amide HV by treatment with N,O-dimethylhydroxylamine in the presence of a reagent such as HATU or CDI in a solvent such as DCM and in the presence of an additive such as DIPEA. Reduction of amide HV using a reducing agent such as DIBAL-H or lithium aluminum hydride in a solvent such as DCM or ethyl ether gives the corresponding aldehyde H-II. The terminal olefin H-VI can be cleaved to give H-II under oxidative conditions by treatment with a reagent such as ozone in DCM followed by treatment with dimethyl sulfide. Alternatively, treatment of H-VI with a reagent such as potassium osmate dihydrate and sodium periodate in a solvent such as THF and water gives the aldehyde H-II.

[0692] [ka]

[0693] 5-Substituted oxadiazole-4-carbonyl chlorides (I-II) and N-hydroxysuccinic acid esters (I-III) can be prepared as described in Scheme 20. Treatment of acid II with an excess of a chlorinating agent such as thionyl chloride, which upon concentration, gives the corresponding acid chloride I-II. Subsequent reaction with N-hydroxysuccinimide gives the corresponding ester I-III.

[0694] [ka]

[0695] Oxadiazole acids IV can be prepared as shown in Scheme 21. Treatment of an α,β-unsaturated aldehyde with sodium nitrite in a solvent such as acetic acid gives the corresponding oxadiazole formyl-1,2,5-oxadiazole 2-oxide I-IV. Oxidation of I-IV with a reagent such as Jones' reagent in a solvent such as acetone gives the carboxylic acid IV.

[0696] [ka]

[0697] Oxadioxolic acids of general formula II can be prepared as shown in Scheme 22. Treatment of acid IV with aniline gives amide I-VI. Reduction with trimethylphosphite in a solvent such as toluene then gives compound I-VII. Subsequent treatment of I-VII with di-tert-butyl dicarbonate in the presence of DMAP in a solvent such as DCM gives I-VIII. Treatment of I-VIII with LiOH in THF / water then gives acid II.

[0698] [ka]

[0699] Amides I-IX can be prepared by the route shown in Scheme 23. Lactones I-XI can be prepared using the procedure outlined 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]triazole and 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 affords amide I-IX.

[0700] [ka]

[0701] 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. 3 Activation of the hydroxyl in I-IXa using methanesulfonyl chloride in the presence of N gives I-XIII. Treatment of I-XIII with the presence of 3-DIPEA in a solvent such as DCM gives I-XIV.

[0702] [ka]

[0703] Oxadiazole amides I-IXb and I-IXc can be prepared as shown in Scheme 25. Treatment of chloro-N-phenyl-1,2,5-oxadiazole-3-carboxamide with certain amines in the presence of DIPEA in 1,4-dioxane, or sodium hydride in THF or neat sodium hydride gives amides I-IXb. Similarly, treatment of chloro-N-phenyl-1,2,5-oxadiazole-3-carboxamide with certain amines in the presence of sodium hydride in THF or neat sodium hydride gives amides I-IXb. 4cc =Me Treatment of chloro N-phenyl-1,2,5-oxadiazole-3-carboxamide with certain alcohols in the presence of sodium methoxide in methanol gives amides I-IXc.

[0704] [ka]

[0705] Diazoketone JI can be prepared as shown in Scheme 26. Treatment of 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid with oxalyl chloride in the presence of DMF in a solvent such as DCM gives the corresponding acid chloride J-II. Subsequent treatment of J-II with (trimethylsilyl)diazomethane in THF and acetonitrile then gives diazoketone JI.

[0706] Intermediates Intermediate 1 3-(Trifluoromethyl)picolinic acid methyl ester

[0707] [ka]

[0708] Methanol (600 mL) was cooled to 0° C. in an ice bath and then AcCl (95 g, 1.2 mol) was added dropwise at a rate that maintained the internal temperature below 10° C. After the addition was complete, the resulting solution was allowed to warm to room temperature. Neat 3-(trifluoromethyl)pyridine-2-carboxylic acid (30 g, 160 mmol) was then added and the resulting solution was heated at reflux for 16 h. After this time, the reaction mixture was allowed to cool to room temperature and then concentrated. The residue was dissolved in EtOAc and saturated NaHCO 3 The solution was diluted with aqueous solution, the layers were mixed and then separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined and washed with anhydrous MgSO 4 and concentrated to give the title compound as a yellow oil.

[0709] Intermediate 2 (cis-2,3)-3-(trifluoromethyl)piperidine-2-carboxylate methyl ester

[0710] [ka]

[0711] Methyl 3-(trifluoromethyl)picolinate (20 g, 97 mmol, intermediate 1), HCO 2 NH 4 (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) under a nitrogen gas atmosphere, and the resulting mixture was stirred at room temperature for 3 h. After this time, 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 provide the title compound as a yellow oil.

[0712] Intermediate 3 (trans-2,3)-1-(tert-butoxycarbonyl)-3-(trifluoromethyl)piperidine-2-carboxylic acid

[0713] [ka]

[0714] To a solution of methyl (cis-2,3)-3-(trifluoromethyl)piperidine-2-carboxylate (10 g, 47 mmol, intermediate 2) in dry MeOH (100 mL) was added sodium methoxide (2.6 g, 47 mmol) and the resulting solution was maintained at room temperature for 1 h. The solution was then warmed to 45° C. and maintained at that temperature overnight. The solution was then cooled to room temperature and maintained at that temperature for an additional 24 h. After this time, aqueous HCl (80 mL, 1.0 M, 80 mmol) was added and the mixture was partially concentrated to remove most of the MeOH. The resulting concentrated aqueous solution was diluted with water (220 mL) and then Boc 2 O (46g, 0.21mol) and NaHCO 3 (18 g, 0.21 mol) was added. The resulting mixture was stirred at room temperature for 20 h. After this time, the pH of the reaction mixture was adjusted to pH 6-7 using 1N aqueous HCl. The mixture was 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. After this time, 1N aqueous HCl 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.

[0715] Intermediate 4 (S)-2-(((tert-butoxycarbonyl)amino)-2-cyclohexylacetate methyl

[0716] [ka]

[0717] Di-tert-butyl dicarbonate (200 mL, 870 mmol) was added to a mixture of (S)-methyl 2-amino-2-cyclohexylacetate hydrochloride (120 g, 578 mmol) and TEA (240 mL, 1.73 mol) in DCM (1.5 L) and the resulting mixture was stirred at room temperature for 16 h. After this time, the pH of the mixture was adjusted to pH 5 by adding saturated aqueous citric acid. The mixture was then poured into water (1 L) and extracted three times with DCM. The organic extracts were combined and washed with anhydrous Na 2 SO 4 The residue was triturated with petroleum ether (350 mL) and then isolated by filtration to give the title compound as a colorless solid.

[0718] Intermediate 5 tert-Butyl (S)-(3-chloro-1-cyclohexyl-2-oxopropyl)carbamate

[0719] [ka]

[0720] A solution of LDA was prepared by adding n-BuLi (194 mL, 2.5 M in hexanes, 485 mmol) dropwise to a −70° C. solution of diisopropylamine (62.0 mL, 441 mmol) in THF (80 mL), and then the resulting solution was warmed to 0° C. (ice bath) over 30 min. This solution was then added dropwise to a −70° C. solution of (S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylmethylacetate (20 g, 74 mmol, Intermediate 4) and chloroiodomethane (21.6 mL, 295 mmol) in THF (120 mL). The resulting mixture was stirred at −70° C. for 3 h, then washed with saturated NH 4 The mixture was quenched with aqueous Cl (200 mL) and warmed to room temperature. The resulting mixture was extracted three times with EtOAc. The organic extracts were combined and washed with anhydrous Na 2 SO 4The residue was purified by silica gel chromatography (20:1 to 5:1 petroleum ether / EtOAc) to give the title compound as a black oil.

[0721] Intermediate 6 tert-Butyl (S)-(1-cyclohexyl-3-iodo-2-oxopropyl)carbamate

[0722] [ka]

[0723] Sodium iodide (11.0 g, 73.4 mmol) was added to a solution of tert-butyl (S)-(3-chloro-1-cyclohexyl-2-oxopropyl)carbamate (35.0 g, 121 mmol, Intermediate 5) in acetone (150 mL) and the resulting mixture was stirred at room temperature for 48 h. The mixture was then concentrated and the residue was diluted with EtOAc (150 mL). The resulting suspension was filtered and the filter cake was washed with EtOAc. The filtrate and washings were combined and concentrated to give the title compound, which was used directly in the next step without further purification.

[0724] Intermediate 7 (S)-2-Amino-2-(4-hydroxyphenyl)acetic acid methyl ester hydrochloride

[0725] [ka]

[0726] 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. After this time, the mixture was cooled to room temperature and then concentrated to provide the title compound as a yellow solid.

[0727] Intermediate 8 (S)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate methyl

[0728] [ka]

[0729] K in water (2.0L) 2 CO 3 A solution of (508 g, 3.68 mol) was added to a suspension of (S)-methyl 2-amino-2-(4-hydroxyphenyl)acetate hydrochloride (400 g, 1.84 mol, Intermediate 7) in 1,4-dioxane (1.0 L) and the mixture was cooled to 0° C. Then di-tert-butyl dicarbonate (421 g, 1.93 mol) was added and the mixture was warmed to 18° C. and stirred for 12 h. After this time the mixture was diluted with EtOAc and the layers were mixed and then separated. The organic layer was washed with brine and anhydrous Na 2 SO 4 Drying at rt, filtration and concentration afforded the title compound as a colorless solid.

[0730] Intermediate 9 (S)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxycyclohexyl)acetate methyl

[0731] [ka]

[0732] Platinum dioxide (7.50 g, 33.1 mmol) was added to a solution of (S)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)methyl acetate (100 g, 355 mmol, Intermediate 8) in acetic acid (1.0 L) and the resulting mixture was heated at 30° C. in H 2 (48 psi) for 96 hours. After this time, the reaction mixture was filtered and the filtrate was concentrated to give a yellow oil. This oil was purified by gel silica chromatography (10:1 to 1:1 petroleum ether / EtOAc) to give the title compound as a colorless oil.

[0733] Intermediate 10 (S)-2-((tert-butoxycarbonyl)amino)-2-(4-oxocyclohexyl)acetate methyl

[0734] [ka]

[0735] Dess-Martin periodinane (442 g, 1.04 mol) was added to a 0° C. solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxycyclohexyl)acetate (200 g, 696 mmol, Intermediate 9) in DCM (2.0 L) and the resulting mixture was stirred at 10° C. for 12 h. After this time, a solution of Na in water (5 L) was added. 2 SO 3 A solution of (400 g, 3.2 mol) was added. The layers were mixed and then separated. The organic layer was diluted with saturated NaHCO 3 aqueous solution, then brine, and anhydrous Na 2 SO 4 The mixture was dried at rt, filtered and concentrated to give the title compound as a yellow oil.

[0736] Intermediate 11 (S)-2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetate methyl

[0737] [ka]

[0738] Bis(2-methoxyethyl)aminosulfur trifluoride (85.6 g, 387 mmol) was added dropwise to a 0° C. solution of methyl (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. After this time, cold saturated NaHCO 3Aqueous solution was added with stirring until the pH of the aqueous layer was maintained at pH 7. The layers were then separated and the organic layer was washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give a yellow oil which was purified by gel silica chromatography (10:1 petroleum ether / EtOAc) to give the title compound as a yellow solid.

[0739] Intermediate 12 (S)-2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid

[0740] [ka]

[0741] LiOH H in water (250 mL) 2 A solution of 21.8 g, 520 mmol) was added to a solution of (S)-2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)methyl 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 time, 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 1 M aqueous HCl and the resulting mixture was extracted three times with DCM. The organic extracts were combined and washed with anhydrous Na 2 SO 4 Dry at 40° C., filter and concentrate to give the title compound as a yellow solid.

[0742] Intermediate 13 tert-Butyl (S)-(3-diazo-1-(4,4-difluorocyclohexyl)-2-oxopropyl)carbamate

[0743] [ka]

[0744] Isobutyl chloroformate (25.6 g, 187 mmol) was added dropwise to a −20° C. 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), and the resulting mixture was then stirred at −20° C. for 30 min. After this time, the mixture was filtered. Et 2 O * A freshly prepared solution of diazomethane in (1.8 L, approximately 3 equiv.) was added to the filtrate at 0° C. and the resulting solution was maintained at 0° C. for 12 h. After this time, the solution was partially concentrated to remove excess diazomethane, washed with water, and rinsed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give a yellow solid which was purified by gel silica chromatography (20:1 petroleum ether / EtOAc) to give the title compound as a light yellow solid.

[0745] * Prepared according to de Boer, Th. J; Backer, H. J. Org. Synth. 1956, 36, 16.

[0746] Intermediate 14 tert-Butyl (S)-(3-chloro-1-(4,4-difluorocyclohexyl)-2-oxopropyl)carbamate

[0747] [ka]

[0748] 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-diazolo-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 NaHCO 3 Wash with aqueous solution of anhydrous Na2 SO 4 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 under vacuum to give the title compound as a colorless solid.

[0749] Intermediate 15 tert-Butyl (S)-(1-(4,4-difluorocyclohexyl)-3-iodo-2-oxopropyl)carbamate

[0750] [ka]

[0751] The title compound was prepared as described for the synthesis of Intermediate 6, using tert-butyl (S)-(3-chloro-1-(4,4-difluorocyclohexyl)-2-oxopropyl)carbamate (Intermediate 14) instead of tert-butyl (S)-(3-chloro-1-cyclohexyl-2-oxopropyl)carbamate.

[0752] Intermediate 16 N-(5-chloropyridazin-3-yl)-1,1-diphenylmethanimine

[0753] [ka]

[0754] Cs in DME (1.4L) 2 CO 3 (875g, 2.68mol), dppf (59.5g, 107mmol) and Pd 2 (dba) 3A stirred mixture of (49.2 g, 53.7 mmol) 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 an internal temperature of 40-45° C. Upon complete addition, the resulting mixture was stirred at 85° C. for 16 h. After this time, 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 give the title compound as a brown solid.

[0755] Intermediate 17 5-Chloropyridazin-3-amine

[0756] [ka]

[0757] N-(5-chloropyridazin-3-yl)-1,1-diphenylmethanimine (297 g, 84% w / w, 0.85 mol, Intermediate 16) was diluted with EtOAc (1.0 L) and water (700 mL). Aqueous HCl (300 mL, 5.0 N, 1.5 mol) was then added dropwise at 20° C. and the resulting mixture was stirred at 20° C. for 30 min. After this time, the mixture was filtered and the filter pad was washed with 1N aqueous HCl (100 mL). The layers of the combined filtrate and washings were separated and the aqueous layer was washed three times with EtOAc. The aqueous layers were combined and the pH was adjusted to pH 8-9 using 5N aqueous NaOH. After stirring at 10-20° C. for 1 h, the precipitate was collected by filtration and washed with water to give the crude title compound as a brown solid (134 g, 71% w / w). This material was combined with another batch obtained in a similar manner (36.2 g, 56% w / w). The combined batches were 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). SiliaMetS® thiol (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. Two additional treatments with SiliaMetS® thiol as above were carried out. The final pH of the filtrate was adjusted to pH 9-10 using 5N aqueous NaOH and the resulting mixture was stirred at 10-20° C. for 1 h. The precipitate was isolated by filtration and then dried under vacuum to give the title compound as an off-white solid.

[0758] Intermediate 18 2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexylidene)acetic acid methyl ester

[0759] [ka]

[0760] A solution of 4,4-difluorocyclohexan-1-one (250 g, 1.86 mol) in DCM (500 mL) was added dropwise to a stirred solution of methyl 2-tert-butoxycarbonyl)amino)-2-(dimethoxyphosphoryl)acetate (582 g, 1.96 mol) and DBU (289 g, 1.90 mol) in DCM (2.0 L) at 0° C. (ice bath) at a rate that maintained the internal temperature below 10° C. The reaction was then warmed to 20° C. and maintained at this temperature for 16 h. After this time, water (800 mL) was added and the mixture was stirred for 30 min. The layers were separated and the organic layer was washed three times with water and then concentrated. The residue was diluted with n-heptane (1 L) and the resulting slurry was stirred and then filtered. The filter cake was dried under vacuum at 50° C. to give the title compound as an off-white solid.

[0761] Intermediate 19 2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetate methyl

[0762] [ka]

[0763] Methyl-2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexylidene)acetate (750.0 g, 2.46 mol, Intermediate 18) and Pd / C (75.0 g, 10% w / w, 71 mmol) were added to a reactor containing THF (6.0 L) under a nitrogen gas atmosphere. The resulting mixture was stirred at room temperature for 18 h under H 2 The mixture was hydrogenated using a balloon. After this time, the reaction mixture was filtered and the filter cake was rinsed with THF (1.5 L). The filtrate and rinse were combined and concentrated. The residue was diluted with n-heptane (3.75 L) and the resulting slurry was stirred and then filtered. The filter cake was dried under vacuum at 50° C. to give the title compound as an off-white solid.

[0764] Intermediate 20 tert-Butyl(1-(4,4-difluorocyclohexyl)-3-(dimethyl(oxo)-lambda 6 -Sulfanilidene)-2-oxopropyl)carbamate

[0765] [ka]

[0766] A suspension of trimethylsulfoxonium chloride (552 g, 4.29 mol) and potassium tert-butoxide (386 g, 3.44 mol) in THF (2.64 L) was stirred for 2 h at 10-20 °C. After this time, a solution of methyl 2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetate (660 g, 2.15 mol, Intermediate 19) in THF (2.64 L) was added dropwise at a rate to maintain the internal temperature below 20 °C. After addition was complete, the resulting mixture was stirred at 10-20 °C for 48 h. After this time, saturated NH 4 Aqueous Cl (1.32 L) was added dropwise. The resulting mixture was diluted with water (1.32 L) and stirred for 30 min. The mixture was then partially concentrated to remove THF and the precipitate was isolated by filtration. The filter cake was suspended in water (1 L) and stirred for 2 h. The mixture was filtered and the filter cake was dried under vacuum at 50° C. to give the title compound as an off-white solid.

[0767] Intermediate 21 tert-Butyl N-[(S)-(7-chloroimidazo[1,2-b]pyridazin-2-yl)-(4,4-difluorocyclohexyl)methyl]carbamate

[0768] [ka]

[0769] 5-Chloropyridazin-3-amine (15.0 g, 116 mmol, Intermediate 17), tert-butyl(1-(4,4-difluorocyclohexyl)-3-(dimethyl(oxo)-λ) in toluene (500 mL)6 -sulfaneylidene)-2-oxopropyl)carbamate (46.8 g, 127 mmol, intermediate 20), K 3 PO 4 A mixture of (1.23 g, 5.80 mmol) and 4 Å molecular sieves (3.0 g) was stirred at room temperature for 30 min. Then, [Ir(cod)Cl] 2 (1.56 g, 2.32 mmol) was added under a nitrogen atmosphere and the resulting mixture was heated to 95° C. and stirred at this temperature for 16 h. After this time, 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 then concentrated. The residue was purified by silica gel chromatography (5:1 petroleum ether / EtOAc) to give a bright yellow solid. This solid was purified by chromatography on a chiral stationary phase (Daicel CHIRALPAK® AS-H, 2 mM NH in 60:40 MeOH solution). 3 / CO 2 ) to give the S enantiomer as the second eluting isomer. The desired fractions were concentrated, diluted with n-heptane (2.5 vol) and stirred at room temperature for 1 h. The product was isolated by filtration and then dried under vacuum to give the title compound as a colorless solid.

[0770] Alternative synthesis of intermediate 21 tert-Butyl (S)-(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 3 (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. After that time, the reaction was cooled to room temperature and 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 silics gel chromatography (10-100% petroleum ether:ethyl acetate) to give the title compound as a white solid.

[0771] Intermediate 22 tert-Butyl (S)-((7-chloroimidazo[1,2-b]pyridazin-2-yl)(cyclohexyl)methyl)carbamate

[0772] [ka]

[0773] 5-Chloropyridazin-3-amine (1.5 g, 12 mmol, Intermediate 17) was dissolved in tert-butyl (S)-(1-cyclohexyl-3-iodo-2-oxopropyl)carbamate (13.2 g, 34.6 mmol, Intermediate 6) and NaHCO in t-BuOH (30 mL). 3 (3.89 g, 46.3 mmol). The mixture was then stirred at 130° C. for 48 h. After this time, the mixture was cooled to room temperature and then filtered through a pad of Celite®. 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 and diluted with anhydrous Na 2 SO 4 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.

[0774] Intermediate 23 tert-Butyl (S)-((7-cyanoimidazo[1,2-b]pyridazin-2-yl)(cyclohexyl)methyl)carbamate

[0775] [ka]

[0776] tert-Butyl (S)-((7-chloroimidazo[1,2-b]pyridazin-2-yl)(cyclohexyl)methyl)carbamate (800 mg, 2.19 mmol, Intermediate 22), Zn(CN) in DMA (8.0 mL) 2 A mixture of Pd (644 mg, 5.48 mmol) and zinc powder (29 mg, 0.44 mmol) was sparged with argon for 5 min and then 2 (dba) 3 (405 mg, 0.442 mmol) and XPhos (420 mg, 0.881 mmol) were added. The mixture was sparged with argon for an additional 5 min. The mixture was then stirred under microwave irradiation at 120° C. for 2 h. After this time, the mixture was cooled to room temperature and then filtered through a pad of Celite®. 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 and washed with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (2:1 petroleum ether / EtOAc) to give the title compound as a brown oil.

[0777] Intermediate 24 (S)-2-(Amino(cyclohexyl)methyl)imidazo[1,2-b]pyridazine-7-carbonitrile hydrochloride

[0778] [ka]

[0779] A solution of HCl (5.5 mL, 4.0 M in EtOAc, 22 mmol) was added to a 0° C. solution of tert-butyl (S)-((7-cyanoimidazo[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.

[0780] Intermediate 25 (S)-N-((7-cyanoimidazo[1,2-b]pyridazin-2-yl)(cyclohexyl)methyl)benzamide

[0781] [ka]

[0782] Neat 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, and washed with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (1:0 to 3:1 DCM / EtOAc) to give the title compound as a yellow oil.

[0783] Intermediate 26 (S)-N-((7-(aminomethyl)imidazo[1,2-b]pyridazin-2-yl)(cyclohexyl)methyl)benzamide

[0784] [ka]

[0785] Raney®-nickel (193 mg, slurry in water) was reacted with (S)—N-((7-cyanoimidazo[1,2-b]pyridazin-2-yl)(cyclohexyl)methyl)benzamide (191 mg, 0.531 mmol, Intermediate 25) and NH in EtOH (10 mL). 4 The reaction mixture was added to a mixture of aqueous OH (1.0 mL, 28% w / w ammonia, 15 mmol). 2The mixture was stirred at room temperature (15 psi) for 2 h. After this time, the mixture was filtered through a pad of Celite® and the pad was washed with EtOH. The filtrate and washings were combined and then concentrated to give the title compound as a brown oil.

[0786] Intermediate 27 tert-Butyl (trans-2,3)-2-(((2-((S)-enzamido(cyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)carbamoyl)-3-(trifluoromethyl)piperidine-1-carboxylate

[0787] [ka]

[0788] Neat HATU (399 mg, 1.05 mmol) was added to a 0° C. 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) and the resulting mixture was stirred at 0° C. for 2 h. The mixture was poured into water (30 mL) and then extracted three times with DCM. The organic extracts were combined, washed with brine and washed with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (1:0 to 1:2 petroleum ether / EtOAc) to give the title compounds as a diastereomeric mixture as a yellow solid.

[0789] Intermediate 28 tert-Butyl (trans-2R * ,3R *)-2-(((2-((S)-benzamido(cyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)carbamoyl)-3-(trifluoromethyl)piperidine-1-carboxylate

[0790] [ka]

[0791] Intermediate 29 tert-Butyl (trans-2S * ,3S * )-2-(((2-((S)-benzamido(cyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)methyl)carbamoyl)-3-(trifluoromethyl)piperidine-1-carboxylate

[0792] [ka]

[0793] 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 dissolved in 1000 mL of 1000 sulphuric acid in a 50:1 column of 1000 sulphuric acid buffer (1000 mL) on a chiral stationary phase (Daicel CHIRALPAK® IC, 45:55 (0.1% (v / v) of 25% NH 3 EtOH / CO (containing aqueous solution) 2 ) to give a pair of diastereomers. The first eluting isomer was intermediate 28 and the second eluting isomer was intermediate 29.

[0794] Intermediate 30 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

[0795] [ka]

[0796] 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 afford the title compound as a brown solid.

[0797] Intermediate 31 tert-Butyl (trans-2R*,3R*)-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

[0798] [ka]

[0799] 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 dissolved in 100 mL of 1000 s ... 3 (containing aqueous solution) i-PrOH / CO 2 ) to give the title compound as the first eluting isomer.

[0800] Intermediate 32 (S)-(7-Chloroimidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methanamine

[0801] [ka]

[0802] Trifluoroacetic acid (8.0 mL, 100 mmol) was added to tert-butyl N-[(S)-(7-chloroimidazo[1,2-b]pyridazin-2-yl)-(4,4-difluorocyclohexyl)methyl]carbamate (2.00 g, 4.99 mmol, Intermediate 21) and the mixture was stirred at room temperature for 10 min. After this time, the resulting solution was concentrated and then washed with saturated NaHCO 3 The aqueous solution was diluted with EtOAc and the layers were mixed and then separated, and the aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine and diluted with anhydrous MgSO 4 Dry at rt, filter and concentrate to give the title compound as an off-white solid.

[0803] Intermediate 33 (S)-N-((7-chloroimidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0804] [ka]

[0805] Hunig's base (0.52 mL, 3.0 mmol) was added to a mixture of (S)-(7-chloroimidazo[1,2-b]pyridazin-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. After this time, 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, which became heterogeneous as water was introduced, was combined with the filter cake and refiltered. The new cake was washed with water and then dried by suction. The 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.

[0806] Intermediate 34 (S)-N-((4,4-difluorocyclohexyl)(7-vinylimidazo[1,2-b]pyridazin-2-yl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0807] [ka]

[0808] (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)Cl 2 (180 mg, 0.27 mmol), and K 3 PO 4(870 mg, 4.1 mmol) were combined in a reactor, and the reactor 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 sparged with argon for 15 minutes. The mixture was then stirred at 100° C. for 2.5 hours. After this time, the reaction mixture was cooled to room temperature and then diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine, and diluted with anhydrous MgSO 4 The mixture was dried at 40° C., filtered, and concentrated to give a brown residue which was purified by silica gel chromatography (50% to 100% EtOAc / Hexanes, then 50% to 100% acetone / Hexanes) to give the title compound as a colorless solid.

[0809] Intermediate 35 (S)-N-((4,4-difluorocyclohexyl)(7-formylimidazo[1,2-b]pyridazin-2-yl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0810] [ka]

[0811] NaIO in water (25 mL) 4 A solution of (1.1 g, 5.2 mmol) 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 K 2 OsO 4 2H 2 O (76 mg, 0.21 mmol) was added and the resulting mixture was stirred at room temperature for 1.5 h. After this time, the resulting thick suspension was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with brine and diluted with anhydrous MgSO 4The mixture was dried at 40° C., filtered, and concentrated to give a brown residue, which was purified by silica gel chromatography (30% to 100% acetone / hexanes) to give the title compound as a colorless solid.

[0812] Intermediate 36 N-((S)-(7-((E)-(((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

[0813] [ka]

[0814] Copper(II) sulfate (311 mg, 1.95 mmol) was added followed by PPTS (15 mg, 0.061 mmol) 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-propanesulfinamide (77 mg, 0.64 mmol) in THF (2 mL) and the mixture was stirred at room temperature for 18 h. After this time, CuSO 4 An additional portion of (311 mg, 1.95 mmol) was added and the mixture was stirred at 55° C. for 8 h, then at 45° C. for a further 16 h. After this time, Celite® was added and the mixture was filtered. The pad was washed with DCM and the filtrate and washings were combined and then concentrated to give the title compound as a brown solid.

[0815] Intermediate 37 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

[0816] [ka]

[0817] A solution of cyclopropylmagnesium bromide (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 allowed to warm slowly to 0° C. over 1 h. After this time, saturated NH 4 Aqueous Cl 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 and anhydrous MgSO 4 The mixture was dried at rt, filtered, and concentrated to give a brown foam, which was purified by silica gel chromatography (50% to 100% acetone / hexanes) to give the title compound as a colorless film. 1 1 H NMR analysis showed a 4:1 mixture of diastereomers.

[0818] Intermediate 38 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

[0819] [ka]

[0820] A solution of HCl (0.32 mL, 4.0 M in dioxane, 1.3 mmol) was added 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) and the mixture was stirred for 1.5 h. After this time the resulting solution was concentrated. The residue was diluted with EtOAc and water. The layers were mixed then separated and the aqueous layer was washed with EtOAc. The organic layers were combined and extracted with water then discarded. The aqueous layers were combined, made basic with 15% aqueous NaOH, and extracted three times with EtOAc. The organic extracts were combined and washed with anhydrous MgSO 4 The mixture was dried at rt, filtered and concentrated to give the title compound as a diastereomeric mixture as an off-white solid.

[0821] Intermediate 39 N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0822] [ka]

[0823] 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). Hunig'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 and anhydrous MgSO 4 The residue was purified by silica gel chromatography (40% to 100% acetone / hexanes) to give the title compounds as a diastereomeric mixture as a colorless film.

[0824] Intermediate 40 N-((1S)-(7-(cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0825] [ka]

[0826] 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, a mixture of diastereomers.

[0827] Intermediate 41 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

[0828] [ka]

[0829] 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 afford the title compound as a colorless solid, a mixture of diastereomers.

[0830] Intermediate 42 N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)benzamide

[0831] [ka]

[0832] 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 afford the title compound as a colorless solid, a mixture of diastereomers.

[0833] Intermediate 43 N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0834] [ka]

[0835] 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 afford the title compound as a colorless solid, a mixture of diastereomers.

[0836] Intermediate 44 N-((1S)-(7-(cyclopropyl(4,4,4-trifluoro-3-(trifluoromethyl)butanamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)benzamide

[0837] [ka]

[0838] 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 afford the title compound, a diastereomeric mixture, as a colorless solid.

[0839] Intermediate 45 tert-Butyl (S)-((4,4-difluorocyclohexyl)(7-vinylimidazo[1,2-b]pyridazin-2-yl)methyl)carbamate

[0840] [ka]

[0841] 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 K 3 PO 4 (14.3 g, 67.4 mmol) was added to a reactor containing 1,4-dioxane and water (250 mL, 5:1 v / v, sparged with argon before use) under positive nitrogen gas pressure. The mixture was heated to reflux temperature (88 °C) and then a solution of RuPhos Pd G3 (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. After this time, 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 and anhydrous MgSO 4 Dry at 40° C., filter and concentrate to give the title compound as a brown foam.

[0842] Intermediate 46 tert-Butyl (S)-((4,4-difluorocyclohexyl)(7-formylimidazo[1,2-b]pyridazin-2-yl)methyl)carbamate

[0843] [ka]

[0844] NaIO in water (540 mL) 4A solution of (24.0 g, 112 mmol) 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 K 2 OsO 4 2H 2 2H 3 O (827 mg, 2.25 mmol) was added. The reaction began to warm immediately so the reactor was placed in an ice bath for 15 min to maintain the temperature near 30° C. After this time the reaction mixture was stirred at room temperature for 1.75 h. After this time the resulting thick suspension was filtered through Celite® and the filter cake was washed with EtOAc. The filtrate and washings were combined, the layers mixed then separated and the aqueous layer was extracted twice with EtOAc. The organic layers were combined and washed with concentrated Na 2 O. 2 S 2 O 3 aqueous solution, then washed with brine and anhydrous MgSO 4 The mixture was dried at 40° C., filtered, and concentrated to give a tan foam which was purified by silica gel chromatography (20% to 50% acetone / hexanes) to give the title compound as a pale yellow foam.

[0845] Intermediate 47 tert-Butyl ((S)-(7-((((S)-tert-butylsulfinyl)imino)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0846] [ka]

[0847] tert-Butyl (S)-((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-propanesulfinamide (2.47 g, 20.4 mmol), CuSO 4A mixture of (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. After this time the mixture was diluted with DCM, Celite® was added and 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.

[0848] Intermediate 48 tert-Butyl ((S)-(7-((R)-(((S)-tert-butylsulfinyl)amino)(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0849] [ka]

[0850] 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. Then a solution of cyclopropylmagnesium bromide in 2-MeTHF (51 mL, 0.88 M, 45 mmol) was added at a rate to maintain the internal temperature below −60° C. Upon complete addition, the resulting solution was transferred to an ice bath and allowed to warm slowly to 0° C. over 1 h. After this time, saturated NH 4 Aqueous Cl was added. Sufficient water was then added to dissolve NH 4 The precipitate formed upon addition of the Cl solution was dissolved, and the layers were mixed and then separated. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine and diluted with anhydrous MgSO 4 The mixture was dried at 40° C., filtered, and concentrated to give a brown foam. The residue was purified twice by silica gel chromatography (30% to 70% acetone / hexanes) to give the title compound as a colorless foam.

[0851] Intermediate 49 tert-Butyl ((S)-(7-((R)-amino(cyclopropyl)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0852] [ka]

[0853] 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 mixed and then separated. The organic layer was extracted twice with water (2×10 mL) and all the aqueous layers were combined and then extracted with Et 2 The mixture was washed with EtO (25 mL). 2 The O 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 and washed with anhydrous MgSO 4 The mixture was dried at 40° C., filtered and concentrated to give the title compound as a tan foam.

[0854] Intermediate 50 tert-Butyl ((S)-(7-((R)-cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)carbamate

[0855] [ka]

[0856] A flask was charged with a stir bar, 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 Hunig's base (0.29 mL, 1.67 mmol) and the solution was stirred until homogeneous (approximately 5 min). To the solution was added EDCI (224 mg, 1.17 mmol) 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 (3x10 mL). The combined organics were washed with brine and anhydrous MgSO 4 Dry at 40° C., filter and concentrate to give the title compound as a white solid.

[0857] Intermediate 51 N-((R)-(2-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[1,2-b]pyridazin-7-yl)(cyclopropyl)methyl)-4,4,4-trifluorobutanamide

[0858] [ka]

[0859] The vial was charged with a stir bar, 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 then stirred for 5 min. The reaction was condensed to a yellow oil and diluted with saturated NaHCO 3The mixture was quenched by careful addition of aqueous solution of ethyl acetate (2×15 mL). The basic aqueous phase was extracted with ethyl acetate (2×15 mL). The combined organics were washed with brine and anhydrous MgSO 4 It was dried at 40° C., filtered and concentrated to give the title compound as an off-white foam.

[0860] Intermediate 52 (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

[0861] [ka]

[0862] A flask was charged with a stir bar, (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 Hunig's base (1.02 mL, 0.75 g / mL, 5.93 mmol). The reaction was stirred for 5 minutes 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 (3x3 mL). The combined organics were washed with brine and anhydrous MgSO 4 It was dried at 40° C., filtered and concentrated to give the title compound as an off-white foam.

[0863] Intermediate 53 (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

[0864] [ka]

[0865] Insert a microwave vial containing a stir bar, (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 3 PO 4 (596 mg, 2.81 mmol) and 1,4-dioxane and water (10 mL, 5:1 v / v). The reaction mixture was sparged with argon for 5 min and then Pd(dtbpf)Cl 2 (122 mg, 0.187 mmol) was added and the mixture was further sparged with argon for 5 min. The vial was sealed and heated to 100 °C under microwave irradiation and stirred for 2 h. After this time 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 and anhydrous MgSO 4 The crude material was purified by silica gel chromatography (0-100% ethyl acetate / hexanes) to give the title compound as a tan solid.

[0866] Intermediate 54 (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

[0867] [ka]

[0868] A flask was charged with a stir bar, (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 K 2 OsO 4 2H 2 The solution was charged with NaIO (53.3 mg, 0.145 mmol). 4 (0.774 g, 3.62 mmol) was added 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 and anhydrous MgSO 4 The crude material was purified by silica gel chromatography (10-100% ethyl acetate / hexanes) to give the title compound as an off-white solid.

[0869] Intermediate 55 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

[0870] [ka]

[0871] A vial was charged with a stir bar, 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, Celite® was added, and the mixture was filtered with a DCM wash. The filtrate and combined washings were concentrated to give the title compound as a glassy yellow solid.

[0872] Intermediate 56 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

[0873] [ka]

[0874] 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 diluted with saturated NH4 Poured into aqueous Cl 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 and anhydrous MgSO 4 It was dried at 40° C., filtered and concentrated to give the title compound as an off-white foam. 1 1 H NMR analysis showed a 3:1 mixture of diastereomers.

[0875] Intermediate 57 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

[0876] [ka]

[0877] A flask was charged with a stir bar, 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, 4M in dioxane). The reaction was stirred for 10 min and then condensed to an off-white residue. The crude was taken up in water and washed with hexanes (2×5 mL). The aqueous layer was made basic by the addition of 1N aqueous NaOH and then extracted with ethyl acetate (3×5 mL). The combined organics were washed with brine and anhydrous MgSO 4 The mixture was dried at rt, filtered and concentrated to give the title compound as a diastereomeric mixture as an off-white foam.

[0878] Intermediate 58 N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide

[0879] [ka]

[0880] A vial was charged with a stir bar, 4,4,4-trifluorobutyric acid (40 mg, 0.27 mmol), HATU (105 mg, 0.27 mmol), and DMF (1 mL) and then stirred for 5 min. To the stirred homogenous 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 Hunig's base (0.072 mL, 0.42 mmol). The reaction was stirred for an additional 10 min and then poured into water and diluted with ethyl acetate. The layers were separated and the aqueous phase was further extracted with ethyl acetate (2×5 mL). The combined organics were washed with 10% aqueous lithium chloride, then with brine and anhydrous MgSO 4 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.

[0881] Intermediate 59 N-((1S)-(7-(cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxamide

[0882] [ka]

[0883] 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-trifluorobutanoic acid to afford the title compound as a glassy solid, a mixture of diastereomers.

[0884] Intermediate 60 N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboxamide

[0885] [ka]

[0886] The title compound was prepared as described for the synthesis of intermediate 59, using 4,4,4-trifluorobutanoic acid instead of 2-(3,3-difluorocyclobutyl)acetic acid to afford the title compound as a glassy solid, a mixture of diastereomers.

[0887] Intermediate 61 N-((1S)-(7-(cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxamide

[0888] [ka]

[0889] 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-trifluorobutanoic acid to afford the title compound as a glassy solid, a mixture of diastereomers.

[0890] Intermediate 62 N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-methyl-1H-pyrazole-5-carboxamide

[0891] [ka]

[0892] 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 afford the title compound as a glassy solid, a mixture of diastereomers.

[0893] Intermediate 63 N-((1S)-(7-(cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-1-methyl-1H-pyrazole-5-carboxamide

[0894] [ka]

[0895] 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-trifluorobutanoic acid to afford the title compound as a glassy solid, a mixture of diastereomers.

[0896] Intermediate 64 N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxamide

[0897] [ka]

[0898] 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 afford the title compound as a glassy solid, a mixture of diastereomers.

[0899] Intermediate 65 N-((1S)-(7-(cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxamide

[0900] [ka]

[0901] 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-trifluorobutanoic acid to afford the title compound as a glassy solid, a mixture of diastereomers.

[0902] Intermediate 66 N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(2,2,2-trifluoroethyl)-2H-1,2,3-triazole-4-carboxamide

[0903] [ka]

[0904] 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 afford the title compound as a glassy solid, a mixture of diastereomers.

[0905] Intermediate 67 N-((1S)-(7-(cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(2,2,2-trifluoroethyl)-2H-1,2,3-triazole-4-carboxamide

[0906] [ka]

[0907] 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-trifluorobutanoic acid to afford the title compound as a glassy solid, a mixture of diastereomers.

[0908] Intermediate 68 N-((1S)-(7-(cyclopropyl((R)-2-hydroxy-3,3-dimethylbutanamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(cyclopropylmethyl)-2H-1,2,3-triazole-4-carboxamide

[0909] [ka]

[0910] The title compound was prepared as described for the synthesis of Intermediate 64, using (R)-2-hydroxy-3,3-dimethylbutanoic acid instead of 4,4,4-trifluorobutanoic acid to afford the title compound as a glassy solid, a mixture of diastereomers.

[0911] Intermediate 69 N-((1S)-(7-(cyclopropyl(4-4,4-trifluoro-2-hydroxybutanamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-2-(2,2,2-trifluoroethyl)-2H-1,2,3-triazole-4-carboxamide

[0912] [ka]

[0913] The title compound was prepared as described for the synthesis of Intermediate 66, using 4,4,4-trifluoro-2-hydroxybutanoic acid instead of 4,4,4-trifluorobutanoic acid to afford the title compound as a glassy solid, a mixture of diastereomers.

[0914] Intermediate 70 (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

[0915] [ka]

[0916] A microwave vial was charged with a stir bar, (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), XPhosPd G1 (122 mg, 0.155 mmol), and NMP (15 mL). The vial was purged with argon for 5 min, sealed, and warmed 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 and diluted with anhydrous MgSO 4 The crude residue was purified by silica gel chromatography (0-100% (10% methanol in ethyl acetate) / hexanes) to give the title compound as an off-white solid.

[0917] Intermediate 71 (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

[0918] [ka]

[0919] A flask was charged with a stir bar, (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 (400 mg, 0.83 mmol, Intermediate 70), Raney® Nickel (340 mg, 2.9 mmol), NH 3 (8 mL, 28% in water), 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 filtered through a pad of Celite® washing with MeOH. The combined filtrate and organic washings were condensed to a glassy brown solid. The material was purified by acidic HPLC (SunFire® Prep C18 OBD™ 5 μm, 30×250 mm column, 0-100% acetonitrile (0.05% TFA) / water (0.05% TFA)) to give the title compound as an off-white solid.

[0920] Intermediate 72 (4,4,4-trifluorobutanoyl)-D-leucine methyl ester

[0921] [ka]

[0922] A flask was charged with a stir bar, methyl D-leucinate (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 Hunig's base (1.2 mL, 6.88 mmol). The reaction was stirred for 10 min and 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 x 15 mL). The combined organic extracts were washed with brine and anhydrous MgSO 4 The mixture was dried at rt and condensed to a clear oil which was purified by silica gel chromatography (0-100% ethyl acetate / hexanes, ELSD detection, CAM stain for TLC visualization) to give the title compound as a clear oil.

[0923] Intermediate 73 (4,4,4-Trifluorobutanoyl)-D-Leucine

[0924] [ka]

[0925] A flask was charged with a stir bar, methyl (4,4,4-trifluorobutanoyl)-D-leucinate (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 concentrated to remove the ethanol and further diluted with water. The reaction was made acidic (pH 5) by the addition of acetic acid. The aqueous phase was extracted with ethyl acetate (3×5 mL). The combined organic extracts were washed with brine and anhydrous MgSO 4 It was dried at 40° C., filtered and concentrated to give the title compound as a white solid.

[0926] Intermediate 74 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylate methyl

[0927] [ka]

[0928] 1H-1,2,3-Triazole-4-carboxylate methyl (5 g, 38.2 mmol), K 2 CO 3 To a mixture of 3-bromo-1,1,1-trifluoropropane (4.07 mL, 38.2 mmol) (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. After that time, the mixture was filtered through a pad of Celite®, rinsed with EtOAc, and the filtrate was concentrated under vacuum. The residue was partitioned between EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous was further extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine (50 mL) and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (0-75% EtOAc / Hexanes, second eluting isomer) to provide the title compound as a white solid.

[0929] Intermediate 75 1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxylate methyl

[0930] [ka]

[0931] The title compound was prepared as described for the synthesis of intermediate 74 and the first eluting isomer was isolated as a clear, colorless oil.

[0932] Intermediate 76 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-carboxylic acid

[0933] [ka]

[0934] 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 aqueous NaOH (58 mL, 115 mmol) and stirred at room temperature for 15 h. After that time, the mixture was concentrated to remove THF and then washed with EtOAc (2×50 mL). The aqueous layer was then acidified to pH 3 by addition of 1N aqueous HCl and extracted with 2-MeTHF (3×50 mL). The organic layers were combined, washed with brine (50 mL) and concentrated with anhydrous Na 2 SO 4 The mixture was dried at rt, filtered and concentrated to dryness to provide the title compound as a white solid.

[0935] Intermediate 77 1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-carboxylic acid

[0936] [ka]

[0937] The title compound was prepared as described for the synthesis of Intermediate 76 using 1-(3,3,3-trifluoropropyl)-1H-1,2,3-triazole-5-methyl carboxylate (Intermediate 75) instead of 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-methyl carboxylate to provide the title compound as a white solid.

[0938] Intermediate 78 1-(3,3-difluoropropyl)-1H-1,2,4-triazole-5-carboxylate methyl

[0939] [ka]

[0940] In a microwave vial, add methyl-1H-1,2,4-triazole-3-carboxylate (1.25 g, 9.64 mmol), 3,3-difluoropropan-1-ol (1.39 g, 14.5 mmol), PPh 3 (2.76 g, 10.5 mmol) and THF (16 mL) were added. Then DIAD (2 mL, 10.5 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness and the residue was purified by silica gel chromatography (0-100% EtOAc / Hexanes) to provide the title compound as a light yellow oil.

[0941] Intermediate 79 1-(3-fluoropropyl)-1H-1,2,4-triazole-5-carboxylate methyl

[0942] [ka]

[0943] 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, the mixture was cooled to 0° C., and then DIAD was added to provide the title compound as a clear, colorless oil.

[0944] Intermediate 80 1-(3-fluoropropyl)-1H-1,2,4-triazole-5-carboxylic acid

[0945] [ka]

[0946] Methyl 1-(3-fluoropropyl)-1H-1,2,4-triazole-5-carboxylate (300 mg, 1.6 mmol, intermediate 79) in THF (1.6 mL) was cooled to 0° C., then 1M aqueous LiOH (1.76 mL, 1.76 mmol) was added slowly. The resulting mixture was stirred at 0° C. for 1 h. After that time, 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 addition of 1N aqueous HCl, forming a precipitate. The formed precipitate was collected by filtration, washed with water, and dried under vacuum to provide the title compound as a white solid.

[0947] Intermediate 81 1-(Cyclopropylmethyl)-1H-1,2,3-triazole-5-carboxylate methyl

[0948] [ka]

[0949] 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.

[0950] Intermediate 82 1-(Cyclopropylmethyl)-1H-1,2,3-triazole-5-carboxylic acid

[0951] [ka]

[0952] The title compound was prepared as described for the synthesis of Intermediate 76 using 1-(cyclopropylmethyl)-1H-1,2,3-triazole-5-methyl carboxylate (Intermediate 81) instead of 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-methyl carboxylate to provide the title compound as a white solid.

[0953] Intermediate 83 1-(3,3-difluoropropyl)-1H-1,2,3-triazole-5-carboxylate ethyl

[0954] [ka]

[0955] 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 the mixture was cooled to 0° C., followed by addition of DIAD and stirring at room temperature for 2.5 hours instead of 1 hour to provide the title compound as a yellow oil.

[0956] Intermediate 84 1-(3,3-difluoropropyl)-1H-1,2,3-triazole-5-carboxylic acid

[0957] [ka]

[0958] 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 stirred at room temperature for 5 days instead of 15 hours to provide the title compound as a white solid.

[0959] Intermediate 85 (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

[0960] [ka]

[0961] 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. EDCI (50 mg, 0.26 mmol) was then added and the resulting mixture was stirred at room temperature for 3.5 h. After this time, 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), and concentrated with anhydrous NaCl. 2 SO 4 The mixture was dried at rt, filtered and concentrated to dryness to provide the title compound as a light brown solid.

[0962] Intermediate 86 (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

[0963] [ka]

[0964] In a microwave vial, add (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), K 3 PO 4(1.24 g, 5.85 mmol), and 1,4-dioxane / water (5 / 1, 17 mL total) were added and the mixture was sparged with nitrogen for 10 min. Then, Pd(dtbpf)Cl 2 (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. After that time, the mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3 x 25 mL). The organic layers were combined, washed with brine (30 mL) and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (0-100% EtOAc / Hexanes) to provide the title compound as an amber oil.

[0965] Intermediate 87 (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

[0966] [ka]

[0967] (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 K in 1,4-dioxane / water (1:1, 30 mL). 2 OsO 4 2H 2 To a mixture of 2H2O (86 mg, 0.23 mmol), NaIO 4 (1.25 g, 5.84 mmol) was added and the resulting mixture was stirred at room temperature for 1.5 h. After that time, K 2 OsO 4 2H 2Another portion of O (86 mg, 0.23 mmol) was added and the mixture was stirred at 37° C. for 30 min. After that time, 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) and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (0-100% EtOAc / Hexanes) to provide the title compound as a yellow foam.

[0968] Intermediate 88 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

[0969] [ka]

[0970] 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-methylbenzenesulfonic acid pyridine (56 mg, 0.22 mmol), copper(II) sulfate (1.39 g, 8.72 mmol), (S)-(−)-2-methyl-2-propanesulfinamide (206 mg, 1.7 mmol), and THF (10.5 mL). The tube was capped and stirred at 80° C. for 16 h. After that time, the mixture was cooled to room temperature and filtered through a pad of Celite®, rinsing with DCM. The filtrate was concentrated to dryness and the resulting residue was purified by silica gel chromatography (0-100% EtOAc / hexanes) to provide the title compound as a yellow oil.

[0971] Intermediate 89 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

[0972] [ka]

[0973] A solution of cyclopropylmagnesium bromide (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 allowed to warm slowly to 0 °C over 1 h. The solution was then allowed to warm to room temperature over 1.5 h. After this time, saturated NH 4 Cl aqueous 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) and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (0-100% (10% 2M NH 3 / MeOH) / DCM) to provide the title compound as a light yellow oil.

[0974] Intermediate 90 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

[0975] [ka]

[0976] A solution of HCl (0.21 mL, 4.0 M in dioxane, 0.84 mmol) was added 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 mL, 0.42 mmol, intermediate 89) in EtOAc (4.5 mL) 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 (2×25 mL). The organic layers were combined, washed with brine (25 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to dryness to provide the title compound as a diastereomeric mixture as a yellow oil.

[0977] Intermediate 91 N-((1S)-(7-(cyclopropyl(2-(3,3-difluorocyclobutyl)acetamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0978] [ka]

[0979] 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. After this time, water was added and the mixture was extracted with EtOAc (2×20 mL). The organic layers were combined, washed with brine (25 mL), and concentrated with anhydrous NaCl. 2 SO 4 The residue was purified by silica gel chromatography (0-100% (10% 2M NH in MeOH) 3 Purification by distillation with ethyl acetate (100% aqueous solution) gave the title compound as a diastereomeric mixture as a cream solid.

[0980] Intermediate 92 N-((1S)-(7-(cyclopropyl(4,4,4-trifluorobutanamido)methyl)imidazo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)-5-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

[0981] [ka]

[0982] 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 the mixture was heated to 40° C. for 1.5 hours and then stirred at room temperature to give the title compound, a diastereomeric mixture, as a cream-colored solid.

[0983] Intermediate 93 1-(Cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylate methyl

[0984] [ka]

[0985] The title compound was prepared as described for the synthesis of intermediate 74, using 1H-1,2,4-methyl triazole-3-carboxylate instead of 1H-1,2,3-methyl triazole-4-carboxylate and (bromomethyl)cyclopropane instead of 3-bromo-1,1,1-trifluoropropane to provide the title compound as a light yellow oil.

[0986] Intermediate 94 1-(Cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylic acid

[0987] [ka]

[0988] To a mixture of methyl 1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylate (500 mg, 2.76 mmol, Intermediate 93) in THF (2.76 mL) was added 2 M aqueous NaOH (2.76 mL, 5.52 mmol) and the mixture was stirred at room temperature for 2 h. After that time, the mixture was concentrated to remove THF and then washed with EtOAc (2×15 mL). The aqueous layer was then acidified to pH 1-2 by addition of 1 N aqueous HCl, forming a precipitate. The mixture was filtered and the filter cake was rinsed with water and dried under vacuum to provide the title compound as a white solid.

[0989] Intermediate 95 1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazole-5-carboxylate methyl

[0990] [ka]

[0991] 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 stirred under microwave at 120° C. instead of room temperature for 2 hours to provide the title compound as a clear, colorless oil.

[0992] Intermediate 96 1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazole-5-carboxylic acid

[0993] [ka]

[0994] The title compound was prepared as described for the synthesis of Intermediate 94 using 1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazole-5-methyl carboxylate (Intermediate 95) instead of 1-(cyclopropylmethyl)-1H-1,2,4-triazole-5-carboxylate to provide the title compound as a white solid.

[0995] Intermediate 97 1-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxylate

[0996] [ka]

[0997] Ethyl 1H-pyrazole-4-carboxylate (650 mg, 4.64 mmol), K 2 CO 3To a mixture of 1-bromo-2-(trifluoromethoxy)ethane (0.56 mL, 4.64 mmol) (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. After that time, 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 and washed with water (30 mL) followed by brine (30 mL) and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (0-75% EtOAc / Hexanes) to provide the title compound as a white solid.

[0998] Intermediate 98 1-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxylic acid

[0999] [ka]

[1000] The title compound was prepared as described for the synthesis of Intermediate 76 using 1-(2-trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxylate (Intermediate 97) instead of 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-methyl carboxylate and stirred at 90° C. for 2 hours, then at room temperature for 19 hours to provide the title compound as a white solid.

[1001] Intermediate 99 1-(2-(difluoromethoxy)ethyl)-1H-pyrazole-4-carboxylate

[1002] [ka]

[1003] 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.

[1004] Intermediate 100 1-(2-(difluoromethoxy)ethyl)-1H-pyrazole-4-carboxylic acid

[1005] [ka]

[1006] The title compound was prepared as described for the synthesis of Intermediate 76 using 1-(2-difluoromethoxy)ethyl)-1H-pyrazole-4-carboxylate (Intermediate 99) instead of 2-(3,3,3-trifluoropropyl)-2H-1,2,3-triazole-4-methyl carboxylate and stirred at 90° C. for 3 hours, then at room temperature for 19 hours to provide the title compound as a white solid.

[1007] Intermediate 101 2-(3,3-difluoropropyl)-2H-1,2,3-triazole-4-carboxylate ethyl

[1008] [ka]

[1009] 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 the mixture was cooled to 0° C., after which DIAD was added and stirred at room temperature for 2.5 hours instead of 1 hour to provide the title compound as a clear colorless oil.

[1010] Intermediate 102 2-(3,3-difluoropropyl)-2H-1,2,3-triazole-4-carboxylic acid

[1011] [ka]

[1012] 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 stirred at room temperature for 2 hours instead of 15 hours to provide the title compound as a white solid.

[1013] Intermediate 103 2-(2,2,2-trifluoroethyl)-2H-1,2,3-triazole-4-carboxylate ethyl

[1014] [ka]

[1015] 1H-1,2,3-triazole-4-carboxylate ethyl (1g, 6.73mmol), Cs 2 CO 3 To a mixture of 2-iodo-1,1,1-trifluoroethane (0.67 mL, 6.73 mmol) (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. After that time, 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 days. After that time, the mixture was stirred at 80° C. for 3 days. After that time, th...

Claims

1. A compound of formula I', 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof, wherein: R １ But, -C （１～６） Alkyl, -C （０～２） Alkyl C （３～６） Cycloalkyl, -C （０～２） Alkyl-cyclopropyl-C （１～３） perfluoroalkyl, or a 5- to 6-membered heterocyclyl having 1 to 2 nitrogen atoms; Said-C （１～６） Alkyl is unsubstituted or has 1 to 6 R １ａ is substituted with a group, Said-C （０～２） Alkyl C （３～６） Cycloalkyl is unsubstituted or has 1 to 6 R １ｂ is substituted with a group, The 5- to 6-membered heterocyclyl is unsubstituted or has 1 to 3 R １ｃ is substituted with a group, R ２ But H, -C （３～５） Cycloalkyl, -C （１～４） alkyl, or a 6-membered heterocycle having 1 to 2 oxygen atoms, （１～４） Alkyl is unsubstituted or has 1 to 6 R ２ａ group, （３～５） cycloalkyl is unsubstituted or substituted with -CN; R １ａ , R １ｂ , and R ２ａ each independently represents fluorine, —C （３～５） Cycloalkyl, -CN, -OH, -OC （１～３） Alkyl, or -OC （３～４） cycloalkyl, and the —OC （１～３） Alkyl and -OC （３～４） the cycloalkyl group is unsubstituted or substituted with 1 to 3 fluorine atoms; Each R １ｃ is independently -OCH ３ , -OCF ３ , -OCHF ２ or -C unsubstituted or substituted with 1 to 6 fluorine atoms （１～４） is alkyl, R ３ But, -C （０～１） Alkyl C （３～６） Cycloalkyl, -C （３～６） Alkyl, or -C （１～２） Alkyl-O-C （１～３） alkyl, （０～１） Alkyl C （３～６） Cycloalkyl, -C （３～６） Alkyl, and -C （１～２） Alkyl-O-C （１～３） Alkyl is unsubstituted or substituted with fluorine, —CH ３ -CHF ２ , -CF ３ 1 to 5 R independently selected from , OH, and ═O; ３ａ is substituted with a group, R ４ But, -C （３～６） cycloalkyl, phenyl, or 5-6 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S; Said C （３～６） Cycloalkyl is unsubstituted or is selected from halogen, —OC （１～３） Alkyl, and -C （１～４） 1 to 3 R independently selected from alkyl ４ａ group, （１～３） Alkyl and -C （１～４） Alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms; Alternatively, two R's attached to the same ring atom ４ａ The groups, in combination with the atoms to which they are attached, are C （３～６） may form a cycloalkyl, The phenyl is unsubstituted or is selected from the group consisting of 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） 1 to 3 R independently selected from alkyl, and 3- to 6-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; ４ｂ group, （１～３） Alkyl, -C （０～２） Alkyl-C （３～４） Cycloalkyl, and -C （１～４） the alkyl is unsubstituted or substituted with 1 to 3 fluorine atoms, and the heterocyclyl is unsubstituted or substituted with one oxo; The 5- to 6-membered heteroaryl is unsubstituted or has one or two R ４ｃ is substituted with a group, 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 heterocyclyl having 1 to 2 heteroatoms selected from N and O, （０～２） Alkyl C （３～６） Cycloalkyl, -C （１～４） Alkyl, -OC （１～３） Alkyl and heterocyclyl groups are unsubstituted or have 1 to 6 R ４ｄ is substituted with a group, Alternatively, two R's attached to adjacent ring atoms ４ｃ The groups combine to form C （４～６） may form a cycloalkyl, 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 3-6 membered heterocyclyl having 1 to 2 heteroatoms selected from N and O, （１～３） Alkyl, -OC （１～３） Alkyl, -OC （３～４） cycloalkyl and heterocyclyl groups are unsubstituted or substituted with 1 to 3 fluorine atoms; R ４ｃ１ , R ４ｃ２ , R ４ｄ１ , and R ４ｄ２ each independently represents H or -C （１～３） alkyl, （１～３） alkyl is unsubstituted or substituted with 1 to 6 groups selected from fluorine and chlorine; Or, R ４ｄ１ and R ４ｄ２ may combine with the atom to which they are attached to form a 3-6 membered heterocyclyl having 1-3 heteroatoms selected from N, O and S, said heterocyclyl being unsubstituted or substituted with 1-4 fluorine atoms; R ５ is hydrogen or halogen; R ４ When is 1,2,4-triazolyl, R ４ but, 【Chemistry 4】 and R ４ or a pharma- ceutically acceptable salt thereof, wherein when is a substituted 6-membered heteroaryl, said substituted heteroaryl is unsubstituted at the para position;

2. R １ But, -C （３～５） Alkyl, 【Chemistry 28】 and Said-C （３～５） Alkyl is 1 to 6 R １ａ is substituted with a group, The above 【Chemical 29】 is unsubstituted or substituted with 1 to 2 fluorine atoms, The above 【Chemistry 30】 is unsubstituted or substituted with 1 to 4 fluorine atoms; The above 【Chemistry 31】 is substituted with two fluorine atoms, The above 【Chemistry 32】 But -CF ３ is replaced by each １ａ is independently —OH or fluorine; R ２ is H, methyl, isopropyl, cyclopropyl, or cyclobutyl, said cyclopropyl and cyclobutyl being unsubstituted or substituted with -CN; R ３ is cyclohexyl, or 【Chemical 33】 and R ４ is cyclopropyl, spiropentanyl, spirohexanyl, phenyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, triazolyl, tetrazolyl, imidazolyl, 1,2,3-thiadiazolyl, or 1,2,5-thiadiazolyl; The cyclopropyl is selected from fluorine and unsubstituted or substituted with three fluorine atoms. （１） substituted with 1 to 2 groups selected from alkyl; The phenyl is unsubstituted or is -chlorine or -C （１～２） is substituted with alkyl, The 1,2,3-thiadiazolyl and 1,2,5-thiadiazolyl are C （２～３） is substituted with alkyl, The pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, triazolyl, tetrazolyl, and imidazolyl are each independently selected from the group consisting of one or two R ４ｃ is substituted with a group, Each R ４ｃ But independently, -C （０～１） Alkyl C （３～４） Cycloalkyl, or -C （１～３） alkyl, （０～１） Alkyl C （３～４） Cycloalkyl and -C （１～３） The alkyl group is unsubstituted or has 1 to 4 R ４ｄ is substituted with a group, Each R ４ｄ is independently -OCH ３ , -OCF ３ , -OCHF ２ or fluorine, R ５ is hydrogen, R ４ When is 1,2,4-triazolyl, R ４ but, 【Chemical 34】 2. The compound of claim 1, wherein:

3. R １ but, 【Chemical 36】 【Chemical 37】 3. The compound of claim 2, wherein:

4. R １ but, 【Chemical 38】 3. The compound of claim 2, wherein:

5. R ２ or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 1 to 4, wherein: is cyclopropyl substituted with -CN; or a pharma- ceutically acceptable salt thereof.

6. R ２ but, 【Chemistry 42】 6. The compound of claim 5, wherein:

7. R ２ or a pharma- ceutically acceptable salt thereof, according to claim 5, wherein is cyclobutyl substituted with -CN.

8. R ２ but, 【Chemistry 43】 8. The compound of claim 7, which is: or a pharma- ceutically acceptable salt thereof.

9. R ３ but, 【Chemistry 45】 9. The compound according to any one of claims 1 to 8, wherein:

10. R ４ but, 【Chemistry 52】 10. The compound according to any one of claims 1 to 9, wherein:

11. R ４ but, 【Chemistry 55】 10. The compound according to any one of claims 1 to 9, wherein:

12. Each R ４ｃ are independently fluorine, -CN, -NH ２ , N(CH ３ ) ２ , methyl, ethyl, isopropyl, -CD ３ , -CD ２ CDs ３ , -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ , -OC(CH ３ ) ３ , CH(CH ３ )OH, -CHF ２ , -CF ３ , -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CF ３ , -CF ２ CH ３ , -CH ２ CH ２ CH ２ F, -CH ２ CH ２ CHF ２ , -CH ２ CH ２ CF ３ , -CH(CH ３ ) CHF ２ , -CH(CH ３ ) CF ３ , -CH(CH ２ F) ２ , -CH ２ CF ２ CH ３ , -CH ２ CH ２ CF ２ CH ３ , -CH ２ OCH ３ , -CH ２ CH ２ OCH ３ , -CH ２ CH ２ O.C.F. ２ , -CH ２ CH ２ O.C.F. ３ , -CH ２ O.C.F. ２ , -OCHF ２ , -OCH ２ CHF ２ , -OCH ２ CH ２ F, -OCH ２ CF ３ , cyclopropyl, cyclobutyl, cyclopentyl, -CH ２ -cyclopropyl, -O-cyclopropyl, -O-cyclobutyl, 【Chemical Formula 59】 or Alternatively, two R's attached to adjacent ring atoms ４ｃ The groups may combine to form the following groups: 【Chemistry 60】 The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, which may form:

13. R ４ But one or two R ４ｃ pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, or thiadiazolyl substituted by a group; R ４ When is 1,2,4-triazolyl, R ４ but, 【Chemistry 62】 10. The compound according to any one of claims 1 to 9, wherein:

14. R ４ but, Each independently is methyl, ethyl, isopropyl, -CF ３ , -CH ２ CH ２ F, -CH ２ CH ２ CF ３ , -CH ２ OCH ３ , cyclopropyl, cyclopentyl, or 【Chemistry 66】 One or two R ４ｃ isoxazolyl substituted with a group; oxazolyl substituted with one isopropyl; or One methyl, one ethyl, one -OCH ２ CHF ２ 10. The compound according to any one of claims 1 to 9, which is oxadiazolyl substituted with cyclopropyl, or a pharma- ceutically acceptable salt thereof.

15. R ４ but, 【Chemical Formula 72】 10. The compound according to any one of claims 1 to 9, wherein:

16. The compound according to any one of claims 1 to 14, which is a compound of formula I'f, or a pharma- ceutically acceptable salt thereof: 【Chemical 73】

17. 2. The compound of claim 1, which is a compound of formula I'g, or a pharma- ceutically acceptable salt thereof: 【Chemical 74】

18. 2. The compound of claim 1, which is a compound of formula I'h, or a pharma- ceutically acceptable salt thereof: 【Chemistry 75】

19. R ４ but, Each independently is cyclopropyl, methyl, ethyl, isopropyl, -CD ３ , -CD ２ CDs ３ , fluorine, -CHF ２ , -CF ３ , -CH ２ CHF ２ , -CH ２ CF ３ , -CH(CH ３ ) CF ３ , -CH(CH ２ F) ２ , -CH ２ CH ２ O.C.F. ２ , or -CH ２ CH ２ O.C.F. ３ One or two R ４ｃ pyrazolyl substituted with a group, or 10. The compound according to any one of claims 1 to 9, which is imidazolyl substituted with one methyl or isopropyl, or a pharma- ceutically acceptable salt thereof.

20. R ４ is unsubstituted or has one or two R ４ｃ is a triazolyl substituted with a group; Each R ４ｃ are independently methyl, ethyl, isopropyl, -CH ２ CH ２ OCH ３ , -CHF ２ , -CF ３ , -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CF ３ , -CH ２ CH ２ CH ２ F, -CH ２ CH ２ CHF ２ , -CH ２ CH ２ CF ３ , -CH ２ CH ２ O.C.F. ２ , -CH ２ CH ２ O.C.F. ３ , cyclopropyl, -CH ２ -cyclopropyl, 【Chemistry 82】 and R ４ When is 1,2,4-triazolyl, R ４ but, 【Chemistry 83】 10. The compound according to any one of claims 1 to 9, wherein:

21. R ４ 10. The compound according to any one of claims 1 to 9, wherein is thienyl, thiazolyl, isothiazolyl, or thiadiazolyl, each of which is substituted with methyl, isopropyl, or cyclopropyl, or a pharma- ceutically acceptable salt thereof.

22. 【Catalogue 109】 【Chemistry 110】 2. The compound of claim 1, selected from the group consisting of:

23. 【Chemical 111】 2. The compound of claim 1, wherein:

24. 【Chemical 112】 2. The compound of claim 1, wherein:

25. 【Chemical 113】 2. The compound of claim 1, wherein:

26. 【Catalogue 114】 2. The compound of claim 1, wherein:

27. 【Chemical 115】 2. The compound of claim 1, wherein:

28. 【Catalogue 116】 2. The compound of claim 1, wherein:

29. 【Catalogue 117】 2. The compound of claim 1, wherein:

30. 【Catalog 118】 2. The compound of claim 1, wherein:

31. 【Catalogue 119】 2. The compound of claim 1, wherein:

32. 【Catalog 120】 2. The compound of claim 1, wherein:

33. 【Chemical 121】 2. The compound of claim 1, wherein:

34. 【Catalogue 122】 2. The compound of claim 1, wherein: 【Request 35】 【Chemical 123】 2. The compound of claim 1, wherein:

36. 36. A pharmaceutical composition comprising a compound according to any one of claims 1 to 35, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

37. 37. The pharmaceutical composition of claim 36, which is administered orally.

38. 38. The pharmaceutical composition of claim 37, administered as a tablet or capsule.

39. 36. A pharmaceutical composition comprising a compound according to any one of claims 1 to 35, or a pharma- ceutically acceptable salt thereof, for use in a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A.

40. The pharmaceutical composition of claim 39, for use in a method for treating and / or ameliorating an inflammatory syndrome, disorder, or disease mediated by IL-17A, wherein the inflammatory syndrome, disorder, or disease mediated by IL-17A is selected from the group consisting of psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, hidradenitis suppurativa, bullous pemphigoid, atopic dermatitis, vitiligo, multiple sclerosis, asthma, uveitis, chronic obstructive pulmonary disorder, multiple myeloma, and systemic lupus erythematosus.

Images