Macrocyclic RIP2-kinase inhibitors

Abstract

The present invention relates to macrocyclic compounds used as kinase inhibitors, in particular as inhibitors of RIP2-kinase and / or its mutants, and compositions containing the compounds, which are used for diagnosing, preventing and / or treating RIP2-kinase related diseases. In addition, the present invention provides methods of using the compounds, for example as drugs or diagnostic agents.

Description

Field of the Invention

[0001] The present invention relates to macrocyclic compounds useful as kinase inhibitors, in particular as inhibitors of RIP2-kinase and / or its mutants, and compositions containing said compounds, which are useful for diagnosing, preventing and / or treating RIP2-kinase-related diseases. In addition, the present invention provides methods of using said compounds, for example as medicaments or diagnostic agents. Background of the Invention

[0003] Protein kinases constitute a large family of structurally related enzymes that are responsible for controlling numerous signal transduction processes in cells. They have been shown to be key regulators in most cellular functions, including proliferation, cell metabolism, cell survival, apoptosis, DNA damage repair, cell motility, etc. Uncontrolled signaling due to defective control of protein phosphorylation has been implicated in a variety of diseases, including, for example, cancer, inflammation, allergies, immune diseases, CNS disorders, angiogenesis, etc.

[0004] In the protein kinase family, a specific example is the receptor-interacting serine / threonine kinase including RIP2. RIP2 (receptor interacting protein 2) is also known as Card-containing Ice-related kinase (CARDIAK), CARD3 (C-terminal caspase-recruiting domain 3), receptor interacting protein kinase 2 (RIPK2) or Rip-like interacting Clarp kinase (RICK). RIP2 kinase consists of an N-terminal kinase domain and a C-terminal caspase-recruiting domain (CARD) connected by an intermediate (IM) region (Chin et al., Curr. Med. Chem. 2005 4 1: 35-42). The CARD domain of RIP2 kinase mediates interactions with other CARD-containing proteins such as nucleotide oligomerization domain proteins NOD1 and NOD2 (Inohara et al., J. Biol. Chem. 2000 36: 27823-31 and Girardin et al., EMBO Rep. 2001 2: 736-742). NOD1 and NOD2 are cytoplasmic receptors activated by specific bacterial peptidoglycan motifs and play a key role in innate immune surveillance. After intracellular bacterial exposure, NOD1 or NOD2 binds to protein kinase RIP2 to coordinate NF-κB (nuclear factor κB)-mediated cytokine responses. Once bound to NOD1 / 2, RIP2 undergoes autophosphorylation on Tyr 474 (Y474) and functions as a molecular scaffold linking together other kinases (TAK1, 1KKβ) involved in NF-κB and MAPK activation (Strober et al., Nat. Rev. Immunol. 2006 1:9-20).

[0005] Both NOD1 / 2 and RIP2 are genes that regulate NF-κB, and therefore their activation causes a positive feedback loop in which activation of NOD1 / 2:RIP2 stimulates further activation and further inflammation. In addition, a variety of inflammatory mediators, including TNF (tumor necrosis factor) and IFN (interferon), stimulate NOD1 / 2 and RIP2 expression. In addition to NF-κB pathway activation, the NOD1 / 2:RIP2 complex stimulates autophagy, bactericidal activity, MHC class II presentation, and MAPK (mitogen-activated protein kinase) activation. In short, this pathway regulates the innate immune system to help adjust the adaptive immune response to eradicate invading pathogens.

[0006] Abnormal regulation of RIP2-dependent signaling has been associated with autoinflammatory diseases. Patients with NOD2 allele functional loss are prone to Crohn's disease, an inflammatory disorder of the gastrointestinal tract (Lesage et al., Am. J. Hum. Genet. 2002 70: 845-857 and Yamamoto et al., Microbes & Infections 2009 12: 912-918). Several research groups have confirmed that the NOD2 / RIPK2 pathway is involved in the pathogenesis of IBD (Negroni et al., Inflamm. Bowel. Dis. 2009 8: 1145-1154; Stronati et al., Digestive and Liver Disease 2010 12: 848-853; Haile et al., J. Med. Chem. 2019 14: 6482-6494; Chen et al., J. Pathol. 2020250 2: 170-182). Negroni first demonstrated upregulation of NOD2 and RIPK in colon biopsies from CD patients (Negroni et al., Inflamm. Bowel Dis. 2009 8: 1145-1154). Stronati confirmed this finding in a UC pediatric population. Interestingly, in addition to upregulation of RIPK2 and NOD2 and subsequent cytokine increases, the research group also suggested that upregulation of HD5 and HD6 (two human defensins, which serve as major components of the epithelial innate immune system) can be attributed to NOD2 / RIPK2 (Stronati et al., Digestive and Liver Disease 2010 12: 848-853). Finally, Haile et al. demonstrated that selective RIPK2 inhibitors can block spontaneous proinflammatory cytokine secretion from biopsies of UC / CD patients. The results emphasize that RIPK2 activation in the mucosa of UC / CD patients leads to the pro-inflammatory state of these biopsies (Haile et al., J.Med.Chem.2019 14:6482-6494). In addition, Chen et al.'s study on the association between Fusobacterium nucleatum (F.nucleatum) and ulcerative colitis provides new clues to the role of RIK2 in epithelial damage. In this paper, the authors concluded that Fusobacterium nucleatum targets CARD3 through NOD2 to activate the IL-17F / NF-κB pathway in vivo. Therefore, Fusobacterium nucleatum coordinates a molecular network involving CARD3 and IL-17F to control the UC process (Chen et al., J.Pathol.2020 250 2:170-182).Another cause of IBD is called IMC (for immune-mediated colitis). IMC is a side effect of immune checkpoint inhibition (ICI). All immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1 and anti-PD-L1) have the risk of immune-related adverse events. The incidence of IMC ranges from 0.3% to 7%, and occurs between 5 and 10 weeks after the 2nd or 3rd dose of ICI (Som et al., World J.Clin.Cases 2019 4: 405-418). Current treatment is oral corticosteroids (mild to moderate stage) and systemic corticosteroids (for severe stage). However, about half of IMC patients have colitis refractory to corticosteroids. Then, anti-TNFα inhibitor treatment is an option. RIPK2 inhibition can be another treatment option with a new mechanism of action.

[0007] Another indication has been described for the first time by Viera et al. (Vieira et al., J. Immunol. 2012 10:5116-5122) when they indicated a role for NOD2 / RIPK2 in the development of experimental arthritis.

[0008] Franca et al. (Franca et al., Scand. J. Rheumatol. 2016 45: 8-12) confirmed these findings in patients with rheumatoid arthritis (RA). They demonstrated that the NOD2 / RIPK2 pathway is upregulated in immune cells of RA patients, suggesting that RIPK2 inhibition may be beneficial in this population.

[0009] Gain-of-function NOD2 mutations have been genetically associated with other inflammatory diseases such as Blau syndrome / early-onset sarcoidosis (EOS), pediatric granulomatous disease (characterized by uveitis, dermatitis, and arthritis) (Miceli-Richard et al., Nature Genetics 2001 29:19-20 and Becker et al., Curr. Rheum. Reports 2005 7:427-433). Extensive genotyping of young patients with allergic rhinitis and atopic dermatitis highlighted a common NOD2 polymorphism in Crohn's disease (Kabesh et al., J. Allergy Clin. Immunol. 2003 4:813-7), which may be the main cause of the observed excessive immune response to skin tissue.

[0010] Mutations in NOD1 have been associated with asthma (Hysi et al., Hum. Mol. Genet. 2005 14:935-941) and early-onset and extraintestinal inflammatory bowel disease (McGovern et al., Hum. Mol. Genet. 2005 14:1245-1250). Genetic and functional studies have also suggested a role for RIP2-dependent signaling in a variety of other granulomatous disorders such as sarcoidosis (Wiken et al., J. Clin. Immunol. 2009 29:78-89) and Wegener's granulomatosis (Uehara et al., Diag. Path. 2009 4:23).

[0011] Metabolic syndrome is a pathology closely related to obesity and overweight, which is caused by chronic inflammation and is characterized by hypertension, hyperglycemia and lipolysis dysfunction. Activation of the immune system by the NOD1 pathway has been observed in patients with metabolic syndrome (Zhou et al., Obesity 2015 7: 1394-1400). A recent functional study emphasized the effect of RIPK2 inhibitors on lipolysis, suggesting the role of RIP2-dependent signaling in glucose metabolism disorders and lipolysis (Duggan et al., Scientific reports 2017 7: 1578).

[0012] In the complex and multifactorial pathological process of cardiac hypertrophy, inflammation has been shown to be an important hallmark of the disease, especially through the activation of NF-kB signaling (Yang et al., PLoS One 2012 8:e40196). Studies on RIPK2 knockout in a hypertrophic heart mouse model suggest a role in the regulation of inflammation and subsequent tissue fibrosis and hypertrophy (Zhao et al., Biochem. Biophys. Res. Commun. 2017 2:1151-1158).

[0013] In addition to immune inflammatory diseases, RIPK2 regulation has also been described in several cancers. In triple negative breast cancer (TNBC), RIPK2 high expression has been associated with worse progression-free survival (Singel et al., Breast Cancer Res. 2014 16: R28) and worse overall survival (Jaafar et al., Biochem. Biophys. Res. Commun. 20181: 115-121). In the first study, the authors showed that RIPK2 knockdown would increase docetaxel sensitivity and reduce tumor and lung metastasis. Another group studied the new oncogene box (Inaki et al., Genome Research 2014 24: 1559) on chromosome 8 of breast cancer patients. They found that RIPK2 was co-amplified with other tested oncogenes (such as MYC). In 2016, Mertins et al. studied TNBC biopsies to find druggable kinases other than HER2. RIPK2 was demonstrated to be hyperphosphorylated in basal-like and luminal B breast cancer biopsies, suggesting that this pathway may be activated in these types of TNBC (Mertins et al., Nature 2016 7605:55-62).

[0014] Recently, phosphorylated RIPK2 levels and NF-kB activity were confirmed to be elevated in biopsies of inflammatory breast cancer (Zare et al., Cancers 2018 10: 184). Using 34 head and neck squamous cell carcinoma cell lines, Wu et al. confirmed that RIPK2 knockdown resulted in cell death, indicating the central role of the protein for cell survival (Wu et al., Mol. Cell. Proteomics 2011 10: 1-14). At the same time, others claim that RIPK2 promotes glioma cell growth by regulating TRAF3 and activating NF-kB pathways and p38 signaling (Cai et al., Oncology Reports 2018 39: 2915-2923).

[0015] In summary, these data strongly support the development of RIPK2 inhibitors in oncology. In 2017, Maloney et al. described the new role of RIPK2 in osteosarcoma invasion, indicating that gefitinib inhibits the progression of lung metastasis by RIPK2 inhibition (Maloney et al., J.Am.Col.Surg.2017 4 (S1): S150). In addition, Liu et al. found that non-classical NF-κB plays a key role in non-Hodgkin lymphoma (Liu et al., Cell.Biochem.Biophys.2015 72 3: 681-5). Finally, using three-dimensional lymphatic endothelial cell tube formation, Gambino et al. identified RIPK2 as a kinase involved in lymphatic vessel remodeling, i.e., a key factor of metastatic spread of cancer (Gambino et al., Assay Drug.Dev.Technol.2017 15 1: 30-43).

[0016] The fact that both loss-of-function polymorphism and gain-of-function mutations can lead to inflammatory diseases may be due to the fact that NOD2 plays the possible role of NOD2 as a rheostat to help maintain normal immunological homeostasis. The lack of coordination between inflammatory signaling pathways can affect the development of inflammatory disorders, and NOD1 / 2:RIP2 activation balance is the core of this coordination. The treatment of Crohn's disease and sarcoidosis currently relies on extensive nonspecific immunosuppression (e.g., corticosteroids) or specific cytokine inhibition (e.g., anti-TNF therapy) with significant cost and side effects. However, treatment is not ideal because not all agents are equally effective, the disease can occur over a long period of time, and not all agents are effective for the same patient. RIP2 Y474 autophosphorylation events have been shown to be necessary for effective NOD2 signaling, and do not occur in the presence of the most common loss-of-function Crohn's disease-related NOD2 alleles. This autophosphorylation is inhibited by the non-highly selective kinase inhibitors gefitinib and erlotinib, suggesting that the tyrosine kinase activity of RIP2 can be specifically targeted in the treatment of inflammatory diseases (Tigno-Aranjuez et al., Genes Dev 2010 1:2666-77). Several clinical cases have been reported for treatment with gefitinib or erlotinib, which effectively clear psoriasis or alleviate arthritis symptoms or insulin-resistant type 2 diabetes associated with metabolic syndrome (Brooks, The Oncologist 2013 1:e3-e5). In a mouse model of chronic inflammatory bowel disease, inhibition of RIP2 activity by the small molecule SB203580 effectively alleviated induced colitis (Hollenbach et al., JBC, 2005, 280:14981-8). However, none of these small molecules primarily and selectively target RIP2. It is therefore an object of the present invention to provide potent, selective, small molecule inhibitors of RIP2 kinase activity that can specifically block RIP2-dependent proinflammatory signaling and thereby provide therapeutic benefit in autoinflammatory diseases characterized by increased and / or dysregulated RIP2 kinase activity.

[0017] We have now found that the macrocyclic compounds and pharmaceutically acceptable compositions according to the present invention are useful for treating inflammatory disorders, in particular Crohn's disease, enteropathy, sarcoidosis, psoriasis, atopic dermatitis, allergic rhinitis, rheumatoid arthritis, asthma, insulin-resistant type 2 diabetes, obesity metabolic syndrome, cardiac hypertrophy, ulcerative colitis, lupus, uveitis, Blau syndrome, granulomatous inflammation, in particular Behcet's disease, immune-mediated colitis, multiple sclerosis and diseases associated with RIP2 kinase activity (i.e. RIP2-kinase-associated diseases). Our macrocyclic compounds and pharmaceutically acceptable compositions according to the present invention may also be used in oncology, in particular for the treatment of breast cancer (including inflammatory breast cancer), head and neck cancer and gliomas.

[0018] In previously published patent application WO2016 / 042087, a series of macrocyclic pyrazolopyrimidines were disclosed that had nanomolar RIPK2 inhibition as determined by biochemical assays. Representatives of this series are two examples, O4 and O11.

[0019] SUMMARY OF THE INVENTION

[0021] We have surprisingly found that certain combinations of several structural modifications of the macrocyclic compounds described herein, such as the introduction of substitutions on the pyrrolidine moiety and X1=OC 1-6 Alkyl and X2=-NH-C 1-6 Alkyl pair X1 = -NH-C 1-6 Alkyl and X2=OC 1-6Alkyl substitution (X1 and X2 represent the Markush formula I described in patent WO2016 / 042087), which leads to significant improvement of key developability and safety parameters such as human protein binding, human microsomal metabolic stability and hERG channel inhibition. In more detail, as described in the comparison table (see the end of the experimental section) between some representative compounds of WO2016 / 042087 and the compound of the present invention, the compound described in the present invention shows improved human protein binding free fraction (free fraction) (measurement A), higher metabolic stability (measurement B) and lower hERG inhibition tendency (measurement C). Plasma protein binding, metabolic stability and hERG tendency have been recognized as key developability parameters (Towards Drugs of the Future, IOS Press, 2009, 9: 53-74) to be optimized in addition to efficacy and specificity in the past 15 years. For example, the association of hERG with cardiotoxicity is recognized as a key developability parameter to achieve, as disclosed by Danker et al. (Danker et al., Front. Pharmacol. 2014, 5:203).

[0022] Thus, in a first aspect, the present invention provides a compound of formula I or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form or solvate thereof,

[0023]

[0024] in

[0025] R 1 Selected from -halogenated, -OC 1-6 Alkyl, -alkynyl, -C 1-6 Alkyl, -C 3-6 -cycloalkyl, -C(O)-C 1-6 -alkyl, -C(O)-C 1-6 Cycloalkyl, -C(O)-Het 2 、-C(O)-NR a R b 、-Het 1 and -CN; said -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl, -C 3-6 -cycloalkyl, -Ph, -Het 1 、-Het 2 and -OH; each of the -alkynyl groups is optionally substituted with a substituent selected from -C 1-6 Alkyl and -CH 2-OC 1-6 alkyl;

[0026] R 2 and R 10 are each independently selected from -H and -halo;

[0027] R 3 , R 3’ , R 4 , R 4’ , R 7 and R 8 are each independently selected from -H and -C 1-6 Alkyl; wherein the -C 1-6 Each of the alkyl groups may be optionally replaced by one or more -OC 1-6 Alkyl substitution;

[0028] When R 3 and / or R 3’ Yes-C 1-6 When it is an alkyl group, then R 4 and R 4’ Each is -H;

[0029] When R 4 and / or R 4’ Yes-C 1-6 When it is an alkyl group, then R 3 and R 3’ Each is -H;

[0030] R 5 Selected from -OH, -NR c R c’ 、-NHC(O)R c 、-NC(O)R c R c’ 、-NC(O)OR c 、-NHS(O 2 )R c 、-halogenated、-OC 1-6 Alkyl, -OC 3-5 -cycloalkyl, -O-Het 2 , -C 1-6 Alkyl and -CN; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -OH, -C 1-6 Alkyl, -C 3-5 -cycloalkyl, -OC 1-6 Alkyl and -Het 2 ;

[0031] R 6 Selected from -H, -halo, -C 1-6Alkyl, -OC 1-6 Alkyl and -Het 3 ; said-C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D and -OC 1-6 alkyl;

[0032] R 9 Selected from -H, -C 1-6 Alkyl, -C(O)-C 1-6 Alkyl and -C(O)-OC 1-6 alkyl;

[0033] R a Selected from -H and -C 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D and -C 1-6 alkyl;

[0034] R b Selected from -H, -C 1-6 Alkyl and -OC 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -C 1-6 Alkyl and -C 3-5 - cycloalkyl;

[0035] R c and R c’ are each independently selected from -H and -C 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D and -C 1-6 alkyl;

[0036] Het 1 and Het 3 are each independently selected from a 5- or 6-membered aromatic heterocycle having 1 to 3 heteroatoms selected from O, N and S, wherein the Het 1 or Het 3 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substituted; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl and -OH;

[0037] Het 2 is selected from a 4-6 membered saturated heterocyclic ring having 1-3 heteroatoms selected from O and N; wherein said Het 2Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substituted; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl and -OH.

[0038] Alternatively, in a first aspect, the present invention provides a compound of formula I or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form or solvate thereof,

[0039]

[0040] in

[0041] R 1 Selected from -halogenated, -OC 1-6 Alkyl, -alkynyl, -C 1-6 Alkyl, -C 3-6 -cycloalkyl, -C(O)-C 1-6 -alkyl, -C(O)-C 1-6 Cycloalkyl, -C(O)-Het 2 、-C(O)-NR a R b 、-Het 1 and -CN; said -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl, -C 3-6 -cycloalkyl, -Ph, -Het 1 、-Het 2 and -OH; each of the -alkynyl groups is optionally substituted with a substituent selected from -C 1-6 Alkyl and -CH 2 -OC 1-6 alkyl;

[0042] R 2 and R 10 are each independently selected from -H and -halo;

[0043] R 3 , R 3’ , R 4 , R 4’ , R 7 and R 8 are each independently selected from -H and -C 1-6 Alkyl; wherein the -C 1-6 Each of the alkyl groups may be optionally replaced by one or more -OC 1-6 Alkyl substitution;

[0044] When R 3 and / or R 3’ Yes-C 1-6 When it is an alkyl group, then R 4 and R 4’ Each is -H;

[0045] When R 4 and / or R 4’ Yes-C 1-6 When it is an alkyl group, then R 3 and R 3’ Each is -H;

[0046] R 5 Selected from -OH, -NR c R c’ 、-NHC(O)R c 、-NC(O)R c R c’ 、-NC(O)OR c 、-NHS(O 2 )R c 、-halogenated、-OC 1-6 Alkyl, -OC 3-5 -cycloalkyl, -O-Het 2 , -C 1-6 Alkyl and -CN; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -OH, -C 1-6 Alkyl, -C 3-5 -cycloalkyl, -OC 1-6 Alkyl and -Het 2 ;

[0047] R 6 Selected from -H, -halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -O-Het 4 Het 3 ; said-C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D and -OC 1-6 alkyl;

[0048] R 9 Selected from -H, -C 1-6 Alkyl, -C(O)-C 1-6 Alkyl and -C(O)-OC 1-6 alkyl;

[0049] R a Selected from -H and -C1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D and -C 1-6 alkyl;

[0050] R b Selected from -H, -C 1-6 Alkyl and -OC 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -C 1-6 Alkyl and -C 3-5 - cycloalkyl;

[0051] R c and R c’ are each independently selected from -H and -C 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D and -C 1-6 alkyl;

[0052] Het 1 and Het 3 are each independently selected from a 5- or 6-membered aromatic heterocycle having 1 to 3 heteroatoms selected from O, N and S, wherein the Het 1 or Het 3 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substituted; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl and -OH;

[0053] Het 2 is selected from a 4-6 membered saturated heterocyclic ring having 1-3 heteroatoms selected from O and N; wherein said Het 2 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substituted; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl and -OH

[0054] Het 4 is selected from a 4-10 membered saturated heterocyclic ring having 1-3 heteroatoms selected from O and N; wherein said Het 4 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substituted; the -C 1-6Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl and -OH.

[0055] In one embodiment, the present invention provides a compound of formula I or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form or solvate thereof, wherein

[0056] R 1 Selected from -halogenated, -OC 1-6 Alkyl, -alkynyl, -C 1-6 Alkyl, -C 3-6 -cycloalkyl, -C(O)-C 1-6 -alkyl, -C(O)-C 1-6 Cycloalkyl, -C(O)-Het 2 、-C(O)-NR a R b 、-Het 1 and -CN; said -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl, -C 3-6 -cycloalkyl, -Ph, -Het 1 、-Het 2 and -OH;

[0057] R 2 and R 10 are each independently selected from -H and -halo;

[0058] R 3 , R 3’ , R 4 , R 4’ , R 7 and R 8 are each independently selected from -H and -C 1-6 Alkyl; wherein the -C 1-6 Each of the alkyl groups may be optionally replaced by one or more -OC 1-6 Alkyl substitution;

[0059] When R 3 and / or R 3’ Yes-C 1-6 When it is an alkyl group, then R 4 and R 4’ Each is -H;

[0060] When R 4 and / or R 4’ Yes-C 1-6 When it is an alkyl group, then R3 and R 3’ Each is -H;

[0061] R 5 Selected from -OH, -NR c R c’ 、-NHC(O)R c 、-halogenated、-OC 1-6 Alkyl, -OC 3-5 -cycloalkyl, -O-Het 2 , -C 1-6 Alkyl and -CN; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -OH, -C 1-6 Alkyl, -C 3-5 -cycloalkyl, -OC 1-6 Alkyl and -Het 2 ;

[0062] R 6 Selected from -H, -halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -O-Het 4 Het 3 ; said-C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D and -OC 1-6 alkyl;

[0063] R 9 Selected from -H, -C 1-6 Alkyl, -C(O)-C 1-6 Alkyl and -C(O)-OC 1-6 alkyl;

[0064] R a Selected from -H and -C 1-6 alkyl;

[0065] R b Selected from -H, -C 1-6 Alkyl and -OC 1-6 alkyl;

[0066] R c and R c’ are each independently selected from -H and -C 1-6 alkyl;

[0067] Het 1 and Het 3 are each independently selected from a 5- or 6-membered aromatic heterocycle having 1-3 heteroatoms selected from O and N, wherein the Het 1 and Het3 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substitution;

[0068] Het 2 is selected from a 4-6 membered saturated heterocyclic ring having 1-3 O atoms;

[0069] Het 4 is selected from a 4-10 membered saturated heterocyclic ring having 1-3 heteroatoms selected from O and N; wherein said Het 4 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substituted; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl and -OH.

[0070] In another specific embodiment, the present invention provides a compound of formula I or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form or solvate thereof, wherein

[0071] R 1 Selected from -halogenated, -OC 1-6 Alkyl, -alkynyl, -C 1-6 Alkyl, -C 3-6 -cycloalkyl, -C(O)-C 1-6 -alkyl, -C(O)-C 1-6 Cycloalkyl, -C(O)-Het 2 、-C(O)-NR a R b 、-Het 1 and -CN; said -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl, -C 3-6 -cycloalkyl, -Ph, -Het 1 、-Het 2 and -OH;

[0072] R 2 and R 10 are each independently selected from -H and -halo;

[0073] R 3 , R 3’ , R 4 , R 4’ , R 7 and R 8 Each is -H;

[0074] R 5Selected from -OH, -halo, -OC 1-6 Alkyl, -OC 3-5 -cycloalkyl and -C 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -OH, -C 1-6 Alkyl, -C 3-5 -cycloalkyl and -OC 1-6 alkyl;

[0075] R 6 Selected from -H, -halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -O-Het 4 Het 3 ; said-C 1-6 Each of the alkyl groups is optionally substituted with one or more -OC 1-6 Alkyl substitution;

[0076] R 9 Selected from -H, -C 1-6 Alkyl, -C(O)-C 1-6 Alkyl and -C(O)-OC 1-6 alkyl;

[0077] R a Selected from -H and -C 1-6 alkyl;

[0078] R b Selected from -H, -C 1-6 Alkyl and -OC 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more;

[0079] Het 1 and Het 3 are each independently selected from a 5- or 6-membered aromatic heterocycle having 1-3 heteroatoms selected from O and N, wherein the Het 1 and Het 3 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substitution;

[0080] Het 2 Selected from 4-6 membered saturated heterocyclic rings with 1-3 O atoms

[0081] Het 4 is selected from a 4-10 membered saturated heterocyclic ring having 1-3 heteroatoms selected from O and N; wherein said Het 4 Each of these is optionally replaced by 1-3 -C 1-6Alkyl substituted; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl and -OH.

[0082] In another specific embodiment, the present invention provides a compound of formula I or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form or solvate thereof, wherein

[0083] R 1 Selected from -halogenated, -OC 1-6 Alkyl, -alkynyl, -C 1-6 Alkyl, -C 3-6 -cycloalkyl, -C(O)-C 1-6 -alkyl, -C(O)-NR a R b 、-Het 1 and -CN; said -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from the group consisting of -D, -halo, and -OC 1-3 alkyl;

[0084] R 2 is selected from -H and -halo;

[0085] R 10 Yes - H;

[0086] R 3 , R 3’ , R 4 , R 4’ , R 7 and R 8 Each is -H

[0087] R 5 Selected from -OH, -halo, -OC 1-6 Alkyl, -OC 3-5 -cycloalkyl and -C 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -OH, -C 1-6 Alkyl, -C 3-5 -cycloalkyl and -OC 1-6 alkyl;

[0088] R 6 Selected from -H, -halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -O-Het 4 Het 3 ; said-C1-6 Each of the alkyl groups is optionally substituted with one or more -OC 1-6 Alkyl substitution;

[0089] R 9 Yes - H;

[0090] R a Selected from -H and -C 1-6 alkyl;

[0091] R b Selected from -H, -C 1-6 Alkyl and -OC 1-6 alkyl;

[0092] Het 1 is a 5-membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from O and N, wherein Het 1 Optionally 1-3 -C 1-6 Alkyl Substitution

[0093] Het 4 is selected from a 4-10 membered saturated heterocyclic ring having 1-3 heteroatoms selected from O and N; wherein said Het 4 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substituted; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl and -OH.

[0094] In a more specific embodiment, the present invention provides a compound selected from any one of the tables disclosed herein.

[0095] In another specific embodiment, in the compounds of the present invention, the compound having R 8 The carbon atoms of the substituents may be in the S-configuration.

[0096] In another specific embodiment, in the compounds of the present invention, the compound having R 5 The carbon atoms of the substituents may be in the R-configuration.

[0097] The invention further provides pharmaceutical compositions comprising a compound according to the invention.

[0098] In another aspect, the invention provides a compound or composition according to the invention for use as a medicament.

[0099] In a particular embodiment, the present invention provides compounds or compositions according to the present invention for use in diagnosing, preventing and / or treating RIP2-kinase-related diseases. The RIP2-kinase-related disease may specifically be an inflammatory disorder, particularly selected from a list comprising the following diseases: Crohn's disease, enteropathy, sarcoidosis, psoriasis, atopic dermatitis, allergic rhinitis, rheumatoid arthritis, asthma, insulin-resistant type 2 diabetes, obesity metabolic syndrome, cardiac hypertrophy, ulcerative colitis, lupus, uveitis, Blau syndrome, granulomatous inflammation, Behcet's disease, immune-mediated colitis and multiple sclerosis. Alternatively, the RIP2-kinase-related disease may be cancer, more particularly selected from breast cancer (including inflammatory breast cancer), head and neck cancer and glioma.

[0100] Furthermore, the present invention provides the use of the compounds or compositions according to the present invention, which are suitable for inhibiting the activity of kinases, in particular RIP2 kinase; or for diagnosing, preventing and / or treating RIP2-kinase related diseases.

[0101] Finally, the present invention provides a method for preventing and / or treating a RIP2-kinase-related disease; the method comprises administering a compound or composition according to the present invention to a subject in need thereof. DETAILED DESCRIPTION OF THE INVENTION

[0103] The present invention will now be further described. In the following paragraphs, different aspects of the present invention are defined in more detail. Unless clearly indicated to the contrary, each aspect defined may also be combined with one or more other aspects as desired. Specifically, any characteristic that is expressed as preferred or advantageous may also be combined with one or more other features that are expressed as preferred or advantageous.

[0104] Unless the context dictates otherwise, asterisks used herein indicate the point at which a described monovalent or divalent group is attached to its associated structure and the structure of which the group forms a part.

[0105] As already mentioned above, in a first aspect, the present invention provides a compound of formula I or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form or solvate thereof,

[0106]

[0107] in

[0108] R 1 Selected from -halogenated, -OC 1-6 Alkyl, -alkynyl, -C 1-6 Alkyl, -C(O)-C 1-6 -alkyl, -C(O)-C 1-6Cycloalkyl, -C(O)-Het 2 、-C(O)-NR a R b 、-Het 1 and -CN; said -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl, -C 3-6 -cycloalkyl, -Ph, -Het 1 、-Het 2 and -OH; each of the -alkynyl groups is optionally substituted with a substituent selected from -C 1-6 Alkyl and -CH 2 -OC 1-6 alkyl;

[0109] R 2 and R 10 are each independently selected from -H and -halo;

[0110] R 3 , R 3’ , R 4 , R 4’ , R 7 and R 8 are each independently selected from -H and -C 1-6 Alkyl; wherein the -C 1-6 Each of the alkyl groups may be optionally replaced by one or more -OC 1-6 Alkyl substitution;

[0111] When R 3 and / or R 3’ Yes-C 1-6 When it is an alkyl group, then R 4 and R 4’ Each is -H;

[0112] When R 4 and / or R 4’ Yes-C 1-6 When it is an alkyl group, then R 3 and R 3’ Each is -H;

[0113] R 5 Selected from -OH, -NR c R c’ 、-NHC(O)R c 、-NC(O)R c R c’ 、-NC(O)OR c 、-NHS(O 2 )R c、-halogenated、-OC 1-6 Alkyl, -OC 3-5 -cycloalkyl, -O-Het 2 , -C 1-6 Alkyl and -CN; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -OH, -C 1-6 Alkyl, -C 3-5 -cycloalkyl, -OC 1-6 Alkyl and -Het 2 ;

[0114] R 6 Selected from -H, -halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -O-Het 4 Het 3 ; said-C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D and -OC 1-6 alkyl;

[0115] R 9 Selected from -H, -C 1-6 Alkyl, -C(O)-C 1-6 Alkyl and -C(O)-OC 1-6 alkyl;

[0116] R a Selected from -H and -C 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D and -C 1-6 alkyl;

[0117] R b Selected from -H, -C 1-6 Alkyl and -OC 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -C 1-6 Alkyl and -C 3-5 - cycloalkyl;

[0118] R c and R c’ are each independently selected from -H and -C 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D and -C 1-6 alkyl;

[0119] Het 1 and Het 3 are each independently selected from a 5- or 6-membered aromatic heterocycle having 1 to 3 heteroatoms selected from O, N and S, wherein the Het 1 or Het 3 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substituted; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl and -OH;

[0120] Het 2 is selected from a 4-6 membered saturated heterocyclic ring having 1-3 heteroatoms selected from O and N; wherein said Het 2 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substituted; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl and -OH;

[0121] Het 4 is selected from a 4-10 membered saturated heterocyclic ring having 1-3 heteroatoms selected from O and N; wherein said Het 4 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substituted; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl and -OH.

[0122] In any of the embodiments disclosed herein, R 6 may alternatively be selected from -H, -halo, -C 1-6 Alkyl, -OC 1-6 Alkyl and -Het 3 ; said-C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D and -OC 1-6 Alkyl; in this case, Het 4 Does not exist.

[0123] The term "alkyl" by itself or as part of another substituent refers to a fully saturated hydrocarbon radical. Typically, the alkyl groups of the present invention contain 1-6 carbon atoms. Alkyl groups can be straight or branched and can be substituted as indicated herein. When a subscript is used after a carbon atom herein, the subscript indicates the number of carbon atoms that the named group may contain. Thus, for example, C 1-6Alkyl refers to an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, butyl and isomers thereof (e.g., n-butyl, isobutyl and tert-butyl); pentyl and isomers thereof, hexyl and isomers thereof. 1 -C 6 Alkyl includes all straight-chain or branched alkyl groups having 1 to 6 carbon atoms and thus includes methyl, ethyl, n-propyl, isopropyl, butyl and isomers thereof (eg n-butyl, isobutyl and tert-butyl); pentyl and isomers thereof, hexyl and isomers thereof.

[0124] The term "optionally substituted alkyl" means an alkyl group optionally substituted with one or more substituents (e.g., 1-3 substituents, e.g., 1, 2 or 3 substituents or 1-2 substituents) at any available point of attachment. Non-limiting examples of such substituents include -D, -halo, -OH, primary and secondary amides, -OC 1-6 Alkyl, heteroaryl, aryl, cycloalkyl, heterocyclyl, etc.

[0125] Unless otherwise indicated, the term "alkenyl" as used herein refers to a straight chain, cyclic or branched hydrocarbon group containing at least one carbon-carbon double bond. Examples of alkenyl radicals include vinyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl, E- and Z-hexenyl, E, E-, E, Z-, Z, E-, Z, Z-hexadienyl, etc. Optionally substituted alkenyl represents an alkenyl group optionally having one or more substituents (e.g., 1, 2, 3 or 4), the substituents being selected from those defined above for substituted alkyl.

[0126] Unless otherwise indicated, the term "alkynyl" as used herein refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond. Examples of alkynyl radicals include ethynyl, E- and Z-propynyl, isopropynyl, E- and Z-butynyl, E- and Z-isobutynyl, E- and Z-pentynyl, E, Z-hexynyl, etc. Optionally substituted alkynyl means an alkynyl group optionally having one or more substituents (e.g., 1, 2, 3 or 4) selected from those defined above for substituted alkyl.

[0127] The term "cycloalkyl" by itself or as part of another substituent is a cycloalkyl group, i.e., a monovalent, saturated or unsaturated hydrocarbon group having a cyclic structure. Cycloalkyl includes all saturated or partially saturated (containing 1 or 2 double bonds) hydrocarbon groups having a cyclic structure. Cycloalkyl groups may contain 3 or more carbon atoms in the ring, and typically, according to the present invention, contain 3-6 atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane.

[0128] If the defined alkyl groups are divalent, i.e., have two single bonds connecting two other groups, they are referred to as "alkylene" groups. Non-limiting examples of alkylene groups include methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1,2-dimethylethylene, pentamethylene, and hexamethylene.

[0129] In general, the alkylene groups of the present invention preferably contain the same number of carbon atoms as their alkyl counterparts. In the case of an alkylene or cycloalkylene diradical, it may be connected to the molecular structure of which it forms a part through a common carbon atom or different carbon atoms. To explain this, the asterisk nomenclature of the present invention is applied, C 3 An alkylene group may be, for example, *-CH 2 CH 2 CH 2 -*、*-CH(-CH 2 CH 3 )-* or *-CH 2 CH(-CH 3 )-*.

[0130] As used herein, the term "heterocycle" by itself or as part of another group refers to an aromatic, non-aromatic, fully saturated or partially unsaturated cyclic group (e.g., a 3-6-membered monocyclic ring system or an 8-10-membered bicyclic ring) having at least one heteroatom in at least one carbon-containing ring. Each ring of the heterocyclic group containing heteroatoms may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms. An optionally substituted heterocycle refers to a heterocycle optionally having one or more substituents (e.g., 1-4 substituents, or, for example, 1, 2, 3 or 4) selected from those defined above for substituted alkyl.

[0131] Exemplary non-aromatic heterocyclic groups include piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, isoindolyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, , 2-pyrazolyl, 3-pyrazolyl, pyranyl, dihydro-2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, 3-dioxolanyl, 1,3-dioxanyl, 2,5-dioximidazolidinyl, 2,2,4-piperidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl yl), 2-oxoazepinene, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane, 1,4-oxathiacyclohexane, 1,4-dithiacyclohexane, 1,3,5-trioxane, 6H-1,2,5-thiadiazinyl, 2H-1,5,2-dithiazinyl, oxazolidinyl, 2H-oxacinyl, 1H-pyrrolizinyl, tetrahydro-1,1-dioxothienyl, N-formylpiperazinyl and morpholinyl; in particular pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, dioxolanyl, dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, tetrahydrofuranyl,

[0132] The 7-10 membered heterocyclic group is also intended to include a spiro-group, which is a bicyclic compound with two rings connected by a single atom, such as spiro[4.5]decane, which is a spirocyclic compound composed of a cyclohexane ring and a cyclopentane ring. Other examples include oxaspiro[3.3]heptane, which is a bicyclic compound composed of C 4 A spirocyclic compound composed of a cycloalkyl and an oxetane ring.

[0133] The term "aryl" as used herein means a polyunsaturated aromatic hydrocarbon group having 5-10 atoms. Aryl is also intended to include partially hydrogenated derivatives of the carbocyclic ring systems listed herein. Non-limiting examples of aryl include phenyl, biphenyl, biphenylene, 1- or 2-naphthyl, 1-, 2- or 3-indenyl, 1-, 2-, 3-, 4- or 5-acenaphthyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and 1-, 2-, 3-, 4- or 5-pyrenyl; particularly phenyl.

[0134] The aryl ring may be optionally substituted with one or more substituents. "Optionally substituted aryl" means an aryl group optionally having one or more substituents (e.g., 1-5 substituents, e.g., 1, 2, 3, or 4) at any available point of attachment, the substituents being selected from those defined above for substituted alkyl.

[0135] In cases where a carbon atom in an aryl group is replaced with a heteroatom, the resulting ring is referred to herein as a heteroaryl ring, alternatively, such ring structures are also referred to as aromatic heterocycles.

[0136] As used herein, the term "heteroaryl" or "aromatic heterocycle" by itself or as part of another group refers to, but is not limited to, an aromatic ring of 5-10 carbon atoms, in which one or more of the carbon atoms may be replaced by oxygen, nitrogen or sulfur atoms. Non-limiting examples of such heteroaryl groups include: pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[2,3-d]imidazolyl, tetrazolyl[1,5-a]pyridinyl, indole ... indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, benzotriazolyl, 1,3-benzodioxolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl.

[0137] "Optionally substituted heteroaryl" means a heteroaryl group optionally having one or more substituents (eg 1 to 4 substituents, such as 1, 2, 3 or 4) selected from those defined above for substituted alkyl.

[0138] The term "halo" or "halogen" as a group or part of a group is a generic name for fluorine, chlorine, bromine or iodine, and any suitable isotopes thereof.

[0139] As used herein, the term "oxo" refers to the group =0.

[0140] As used herein, the term "alkoxy" or "alkyloxy" refers to a radical having the formula -OR b The free radical, R b Preferably, the alkoxy group is C1 -C 10 Alkoxy, C 1 -C 6 Alkoxy or C 1 -C 4 Alkoxy. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy. In the case where the oxygen atom in the alkoxy group is replaced by sulfur, the resulting free radical is referred to as a thioalkoxy. "Haloalkoxy" is an alkoxy group in which one or more hydrogen atoms in the alkyl group are replaced by halogen.

[0141] Whenever the term "substituted" is used in the present invention, it is intended to indicate that one or more hydrogens on the atom indicated in the expression using "substituted" are replaced with a group selected from the specified group, provided that the normal valency of the designated atom is not exceeded and that the substitution results in a chemically stable compound, i.e., a compound that is sufficiently stable to survive isolation to a useful grade of purity from a reaction mixture, and formulation into a therapeutic and / or diagnostic agent.

[0142] Where groups may be optionally substituted, such groups may be substituted one or more times, and preferably one, two or three times. The substituents may be selected from those defined above for substituted alkyl groups.

[0143] As used herein, terms such as "alkyl, aryl or cycloalkyl, each optionally substituted with" or "alkyl, aryl or cycloalkyl optionally substituted with" refer to optionally substituted alkyl, optionally substituted aryl and optionally substituted cycloalkyl.

[0144] More generally, from the above, it will be clear to the skilled person that the compounds of the present invention may exist in the form of different isomers and / or tautomers, including, but not limited to, geometric isomers, conformational isomers, E / Z-isomers, stereochemical isomers (i.e., enantiomers and diastereomers) and isomers corresponding to the presence of the same substituents at different positions of the ring in the compounds of the present invention. All such possible isomers, tautomers and mixtures thereof are included within the scope of the present invention.

[0145] In addition, the present invention includes isotopically labeled compounds and salts, which are identical to the compounds of formula (I), but in fact one or more atoms are replaced by specific atoms, the atomic mass or mass number of which is different from the most common atomic mass or mass number found in nature. Examples of isotopes that can be incorporated into the compounds of formula (I) are isotopes of hydrogen, carbon, nitrogen, fluorine, such as 2 H (deuterium), 3 H. 11C. 13 N. 14 C. 15 O and 18 F. Such isotopically labeled compounds of formula (I) are useful in drug and / or substrate tissue distribution assays. For example, when appropriately distributed in the chemical structure to reduce metabolism and thereby improve the pharmacokinetic properties of deuterated analogs in animals and humans, 2 H (deuterium) is particularly useful (Uttamsingh et al., CTP-656 Phase 1 study results). For example, 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography). PET can be used as a diagnostic or therapeutic follow-up tool, which can be applied in a translational manner in preclinical and clinical settings. It is also used to determine the PK of compounds, including biodistribution. Isotopically labeled compounds of formula (I) can be prepared generally by performing the procedures disclosed below, by substituting isotopically labeled reagents for readily available non-isotopically labeled reagents.

[0146] Whenever used in the present invention, the term "compounds of the present invention" or similar terms is intended to include compounds of Formula I and any subgroups thereof. The term also refers to the compounds depicted in Table 1, their derivatives, N-oxides, salts, solvates, hydrates, stereoisomeric forms, racemic mixtures, tautomeric forms, optical isomers, analogs, and quaternized nitrogen analogs thereof. The N-oxide forms of the compounds are intended to encompass compounds in which one or several nitrogen atoms are oxidized to form the so-called N-oxides.

[0147] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. By way of example, "a compound" means one compound or more than one compound.

[0148] The terms described above and other terms used in the specification are well known to those skilled in the art.

[0149] In a specific embodiment, the present invention provides a compound of formula I or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form or solvate thereof; wherein one or more of the following apply:

[0150] R 1 Selected from -halogenated, -OC 1-6 Alkyl, -alkynyl, -C 1-6 Alkyl, -C(O)-C 1-6 -alkyl, -C(O)-C 1-6 Cycloalkyl, -C(O)-Het 2、-C(O)-NR a R b 、-Het 1 and -CN; said -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl, -C 3-6 -cycloalkyl, -Ph, -Het 1 、-Het 2 and -OH; each of the -alkynyl groups is optionally substituted with a substituent selected from -C 1-6 Alkyl and -CH 2 -OC 1-6 alkyl;

[0151] R 2 and R 10 are each independently selected from -H and -halo;

[0152] R 3 , R 3’ , R 4 , R 4’ , R 7 and R 8 are each independently selected from -H and -C 1-6 Alkyl; wherein the -C 1-6 Each of the alkyl groups may be optionally replaced by one or more -OC 1-6 Alkyl substitution;

[0153] When R 3 and / or R 3’ Yes-C 1-6 When it is an alkyl group, then R 4 and R 4’ Each is -H;

[0154] When R 4 and / or R 4’ Yes-C 1-6 When it is an alkyl group, then R 3 and R 3’ Each is -H;

[0155] R 5 Selected from -OH, -NR c R c’ 、-NHC(O)R c 、-NC(O)R c R c’ 、-NC(O)OR c 、-NHS(O 2 )R c 、-halogenated、-OC 1-6Alkyl, -OC 3-5 -cycloalkyl, -O-Het 2 , -C 1-6 Alkyl and -CN; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -OH, -C 1-6 Alkyl, -C 3-5 -cycloalkyl, -OC 1-6 Alkyl and -Het 2 ;

[0156] R 6 Selected from -H, -halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -O-Het 4 Het 3 ; said-C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D and -OC 1-6 alkyl;

[0157] R 9 Selected from -H, -C 1-6 Alkyl, -C(O)-C 1-6 Alkyl and -C(O)-OC 1-6 alkyl;

[0158] R a Selected from -H and -C 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D and -C 1-6 alkyl;

[0159] R b Selected from -H, -C 1-6 Alkyl and -OC 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -C 1-6 Alkyl and -C 3-5 - cycloalkyl;

[0160] R c and R c’ are each independently selected from -H and -C 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D and -C 1-6 alkyl;

[0161] Het 1 and Het3 are each independently selected from a 5- or 6-membered aromatic heterocycle having 1 to 3 heteroatoms selected from O, N and S, wherein the Het 1 or Het 3 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substituted; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl and -OH;

[0162] Het 2 is selected from a 4-6 membered saturated heterocyclic ring having 1-3 heteroatoms selected from O and N; wherein said Het 2 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substituted; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl and -OH

[0163] Het 4 is selected from a 4-10 membered saturated heterocyclic ring having 1-3 heteroatoms selected from O and N; wherein said Het 4 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substituted; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl and -OH.

[0164] In one embodiment, the present invention provides a compound of formula I or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form or solvate thereof, wherein

[0165] R 1 Selected from -halogenated, -OC 1-6 Alkyl, -alkynyl, -C 1-6 Alkyl, -C(O)-C 1-6 -alkyl, -C(O)-C 1-6 Cycloalkyl, -C(O)-Het 2 、-C(O)-NR a R b 、-Het 1 and -CN; said -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl, -C 3-6 -cycloalkyl, -Ph, -Het1 、-Het 2 and -OH;

[0166] R 2 and R 10 are each independently selected from -H and -halo;

[0167] R 3 , R 3’ , R 4 , R 4’ , R 7 and R 8 are each independently selected from -H and -C 1-6 Alkyl; wherein the -C 1-6 Each of the alkyl groups may be optionally replaced by one or more -OC 1-6 Alkyl substitution;

[0168] When R 3 and / or R 3’ Yes-C 1-6 When it is an alkyl group, then R 4 and R 4’ Each is -H;

[0169] When R 4 and / or R 4’ Yes-C 1-6 When it is an alkyl group, then R 3 and R 3’ Each is -H;

[0170] R 5 Selected from -OH, -NR c R c’ 、-NHC(O)R c 、-halogenated、-OC 1-6 Alkyl, -OC 3-5 -cycloalkyl, -O-Het 2 , -C 1-6 Alkyl and -CN; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -OH, -C 1-6 Alkyl, -C 3-5 -cycloalkyl, -OC 1-6 Alkyl and -Het 2 ;

[0171] R 6 Selected from -H, -halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -O-Het 4 Het 3 ; said-C 1-6Each of the alkyl groups is optionally substituted with one or more substituents selected from -D and -OC 1-6 alkyl;

[0172] R 9 Selected from -H, -C 1-6 Alkyl, -C(O)-C 1-6 Alkyl and -C(O)-OC 1-6 alkyl;

[0173] R a Selected from -H and -C 1-6 alkyl;

[0174] R b Selected from -H, -C 1-6 Alkyl and -OC 1-6 alkyl;

[0175] R c and R c’ are each independently selected from -H and -C 1-6 alkyl;

[0176] Het 1 and Het 3 are each independently selected from a 5- or 6-membered aromatic heterocycle having 1-3 heteroatoms selected from O and N, wherein the Het 1 and Het 3 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substitution;

[0177] Het 2 Selected from 4-6 membered saturated heterocyclic rings with 1-3 O atoms

[0178] Het 4 is selected from a 4-10 membered saturated heterocyclic ring having 1-3 heteroatoms selected from O and N; wherein said Het 4 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substituted; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl and -OH.

[0179] In another specific embodiment, the present invention provides a compound of formula I or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form or solvate thereof, wherein

[0180] R 1 Selected from -halogenated, -OC 1-6 Alkyl, -alkynyl, -C 1-6 Alkyl, -C(O)-C1-6 -alkyl, -C(O)-C 1-6 Cycloalkyl, -C(O)-Het 2 、-C(O)-NR a R b 、-Het 1 and -CN; said -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl, -C 3-6 -cycloalkyl, -Ph, -Het 1 、-Het 2 and -OH;

[0181] R 2 and R 10 are each independently selected from -H and -halo;

[0182] R 3 , R 3’ , R 4 , R 4’ , R 7 and R 8 Each is -H;

[0183] R 5 Selected from -OH, -halo, -OC 1-6 Alkyl, -OC 3-5 -cycloalkyl and -C 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -OH, -C 1-6 Alkyl, -C 3-5 -cycloalkyl and -OC 1-6 alkyl;

[0184] R 6 Selected from -H, -halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -O-Het 4 Het 3 ; said-C 1-6 Each of the alkyl groups is optionally substituted with one or more -OC 1-6 Alkyl substitution;

[0185] R 9 Selected from -H, -C 1-6 Alkyl, -C(O)-C 1-6 Alkyl and -C(O)-OC 1-6 alkyl;

[0186] R aSelected from -H and -C 1-6 alkyl;

[0187] R b Selected from -H, -C 1-6 Alkyl and -OC 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more;

[0188] Het 1 and Het 3 are each independently selected from a 5- or 6-membered aromatic heterocycle having 1-3 heteroatoms selected from O and N, wherein the Het 1 and Het 3 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substitution;

[0189] Het 2 is selected from a 4-6 membered saturated heterocyclic ring having 1-3 O atoms;

[0190] Het 4 is selected from a 4-10 membered saturated heterocyclic ring having 1-3 heteroatoms selected from O and N; wherein said Het 4 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substituted; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl and -OH.

[0191] In another specific embodiment, the present invention provides a compound of formula I or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form or solvate thereof, wherein

[0192] R 1 Selected from -halogenated, -OC 1-6 Alkyl, -alkynyl, -C 1-6 Alkyl, -C(O)-C 1-6 -alkyl, -C(O)-NR a R b 、-Het 1 and -CN; said -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from the group consisting of -D, -halo, and -OC 1-3 alkyl;

[0193] R 2 is selected from -H and -halo;

[0194] R 10 Yes - H;

[0195] R 3 , R 3’ , R 4 , R 4’ , R 7 and R 8 Each is -H

[0196] R 5 Selected from -OH, -halo, -OC 1-6 Alkyl, -OC 3-5 -cycloalkyl and -C 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -OH, -C 1-6 Alkyl, -C 3-5 -cycloalkyl and -OC 1-6 alkyl;

[0197] R 6 Selected from -H, -halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -O-Het 4 Het 3 ; said-C 1-6 Each of the alkyl groups is optionally substituted with one or more -OC 1-6 Alkyl substitution;

[0198] R 9 Yes - H;

[0199] R a Selected from -H and -C 1-6 alkyl;

[0200] R b Selected from -H, -C 1-6 Alkyl and -OC 1-6 alkyl;

[0201] Het 1 is a 5-membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from O and N, wherein Het 1 Optionally 1-3 -C 1-6 Alkyl Substitution

[0202] Het 4 is selected from a 4-10 membered saturated heterocyclic ring having 1-3 heteroatoms selected from O and N; wherein said Het 4 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substituted; the -C 1-6Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl and -OH.

[0203] In another embodiment, the present invention provides a compound of formula I or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form or solvate thereof, wherein one or more of the following apply:

[0204] R 1 Selected from -halogenated, -OC 1-6 Alkyl, -alkynyl, -C 1-6 Alkyl, -C(O)-C 1-6 -alkyl, -C(O)-NR a R b 、-Het 1 and -CN; said -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from the group consisting of -D, -halo, and -OC 1-3 alkyl;

[0205] R 2 is selected from -H and -halo;

[0206] R 10 Yes - H;

[0207] R 3 , R 3’ , R 4 , R 4’ , R 7 and R 8 Each is -H

[0208] R 5 Selected from -OH, -halo, -OC 1-6 Alkyl, -OC 3-5 -cycloalkyl and -C 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -OH, -C 1-6 Alkyl, -C 3-5 -cycloalkyl and -OC 1-6 alkyl;

[0209] R 6 Selected from -H, -halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -O-Het 4 Het 3 ; said-C 1-6 Each of the alkyl groups is optionally substituted with one or more -OC1-6 Alkyl substitution;

[0210] R 9 Yes - H;

[0211] R a Selected from -H and -C 1-6 alkyl;

[0212] R b Selected from -H, -C 1-6 Alkyl and -OC 1-6 alkyl;

[0213] Het 1 is a 5-membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from O and N, wherein Het 1 Optionally 1-3 -C 1-6 Alkyl Substitution

[0214] Het 4 is selected from a 4-10 membered saturated heterocyclic ring having 1-3 heteroatoms selected from O and N; wherein said Het 4 Each of these is optionally replaced by 1-3 -C 1-6 Alkyl substituted; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl and -OH.

[0215] In a more specific embodiment, the present invention provides a compound selected from any one of the tables disclosed herein.

[0216] The compounds of the present invention can be prepared according to the reaction schemes provided in the examples below, but those skilled in the art will appreciate that these are merely illustrative of the present invention and that the compounds of the present invention can be prepared by any of several standard synthetic methods commonly used by those skilled in the art of organic chemistry.

[0217] The invention further provides pharmaceutical compositions comprising a compound according to the invention.

[0218] In another aspect, the invention provides a compound or composition according to the invention for use as a human or veterinary medicine.

[0219] In a specific embodiment, the present invention provides a compound or composition according to the present invention for use in the diagnosis, prevention and / or treatment of a RIP2-kinase related disease.

[0220] The RIP2-kinase-associated disease may specifically be an inflammatory disorder, in particular Crohn's disease, enteropathy, sarcoidosis, psoriasis, atopic dermatitis, allergic rhinitis, rheumatoid arthritis, asthma, insulin-resistant type 2 diabetes, obesity metabolic syndrome, cardiac hypertrophy, ulcerative colitis, lupus, uveitis, Blau syndrome, granulomatous inflammation, Behcet's disease, immune-mediated colitis and multiple sclerosis.

[0221] Alternatively, the RIP2-kinase associated disease may be cancer, more particularly selected from breast cancer (including inflammatory breast cancer), head and neck cancer and glioma.

[0222] Furthermore, the present invention provides the use of a compound or composition according to the invention, which is suitable for inhibiting the activity of a kinase, in particular a RIP2 kinase, or for diagnosing, preventing and / or treating a RIP2-kinase-related disease.

[0223] Finally, the present invention provides a method for preventing and / or treating a RIP2-kinase-related disease; the method comprises administering a compound or composition according to the present invention to a subject in need thereof.

[0224] Treatment

[0225] The compounds of formula (I) or (Ia), their stereoisomers, tautomers, racemates, metabolites, prodrugs or prodrugs (pro-or pre-drugs), salts, hydrates, N-oxide forms or solvates are inhibitors of RIP2 kinase activity and are therefore considered to have potential applications in the diagnosis, prevention and / or treatment of inflammatory disorders or cancer.

[0226] As used herein, the term "inflammatory disorder" or "inflammatory disease" may refer to a disorder or disease characterized by abnormal activation of the immune system that causes or contributes to the pathogenesis of several acute and chronic conditions, including, for example, Crohn's disease, enteropathy, sarcoidosis, psoriasis, rheumatoid arthritis, asthma, ulcerative colitis, lupus, uveitis, Blau syndrome, granulomatous inflammation, particularly Behcet's disease, multiple sclerosis, and insulin-resistant type 2 diabetes. Inflammatory diseases may include states in which there is a response to tissue damage, cell damage, antigens, infectious diseases, and / or some unknown cause. Symptoms of inflammation may include, but are not limited to, cellular infiltration and tissue swelling.

[0227] As used herein, the term "cancer" may refer to a disorder or disease characterized by abnormal cell growth that has the potential to invade or spread to different parts of the body; for example, breast cancer (including inflammatory breast cancer), head and neck cancer, and glioma.

[0228] In the present invention, it is particularly preferred that the inhibitory activity of the inhibitory agent be less than 10 μM, preferably less than 1 μM, and most preferably less than 100 nM in the RIP2 inhibition assay described below. 50 The invention further comprises compounds of formula I or any subgroup thereof that inhibit kinase activity.

[0229] Said inhibition may be achieved in vitro and / or in vivo and, when achieved in vivo, is preferably achieved in a selective manner as defined above.

[0230] As used herein, the term "RIP2 kinase-mediated condition" or "disease" refers to any disease or other deleterious condition in which RIP2 kinase and / or its mutants are known to play a role. The term "RIP2 kinase-mediated condition" or "disease" also refers to those diseases or conditions that are alleviated by treatment with a RIP2 kinase inhibitor. Thus, another embodiment of the present invention relates to treating or lessening the severity of a disease in which one or more RIP2 kinases are known to play a role.

[0231] For pharmaceutical use, the compounds of the present invention can be used as free acids or bases, and / or in the form of pharmaceutically acceptable acid addition salts and / or base addition salts (e.g., obtained with non-toxic organic or inorganic acids or bases), in the form of hydrates, solvates and / or complexes. As used herein and unless otherwise indicated, the term "solvate" includes any combination that can be formed by a compound of the present invention and a suitable inorganic solvent (e.g., hydrate) or organic solvent (such as, but not limited to, alcohols, ketones, esters, etc.).

[0232] Pharmaceutically acceptable salts of the compounds according to the present invention, ie in the form of water-soluble, oil-soluble or dispersible products, include conventional non-toxic salts or quaternary ammonium salts formed, for example, from inorganic or organic acids or bases.

[0233] Generally, for pharmaceutical use, the compounds of the present invention can be formulated into a pharmaceutical preparation or pharmaceutical composition comprising at least one compound of the present invention and at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and optionally one or more other pharmaceutically active compounds.

[0234] By way of non-limiting example, such formulations may be in a form suitable for oral administration, parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), administration by inhalation, by skin patch, by implant, by suppository, etc. Such suitable administration forms (which may be solid, semi-solid or liquid, depending on the mode of administration) as well as methods for their preparation and carriers, diluents and excipients for their preparation will all be known to the skilled person.

[0235] Some preferred but non-limiting examples of such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, eye drops, sterile injectable solutions for bolus administration and / or for continuous administration, and sterile packaged powders (which are usually reconstituted prior to use), which can be formulated with carriers, excipients and diluents suitable for such preparations. The preparations may optionally contain other pharmaceutically active substances (which may or may not produce a synergistic effect with the compounds of the invention) and other substances commonly used in pharmaceutical preparations. The compositions may also be formulated to provide rapid, sustained or delayed release of the active compound contained therein.

[0236] For topical administration, the compounds may advantageously be used as a spray, ointment or a transdermal patch or another appropriate form for topical, transdermal and / or intradermal administration.

[0237] Composition

[0238] Before administration to a subject, the compound of formula (1) or a pharmaceutically acceptable salt thereof can be formulated into a pharmaceutical composition. According to one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. According to another aspect, the present invention provides a method for preparing a pharmaceutical composition comprising mixing a compound of formula (1) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient.

[0239] Pharmaceutical composition can be presented as the unit dosage form that each unit dose contains the active component of predetermined amount.Such unit can contain, for example, 0.1mg, 0.5mg or 1mg to 50mg, 100mg, 200mg, 250mg, 500mg, 750mg or 1g compound of the present invention, depending on the disease treated, route of administration and age, body weight and condition of the subject, or pharmaceutical composition can be presented as the unit dosage form that each unit dose contains the active component of predetermined amount.In other embodiments, unit dose composition is those containing daily dose or subdose or its appropriate part of active component as described herein.In addition, by any one of the methods well known to those skilled in the art, such pharmaceutical composition can be prepared.

[0240] The therapeutically effective amount of the compound of formula (1) will depend on many factors, including, for example, the age and weight of the intended recipient, the exact illness to be treated and its severity, the nature of the preparation and the route of administration, and will ultimately be determined by the physician who prescribes the drug. However, the therapeutically effective amount of the compound of formula (1) for treating the disease described in the present invention is generally within the range of 0.1-100 mg / kg recipient body weight per day, and more generally within the range of 1-10 mg / kg body weight per day. Thus, for a 70 kg adult mammal, the actual amount per day is generally 70-700 mg, and the amount can be administered in a single dose per day or in many sub-doses per day, such as 2, 3, 4, 5 or 6 doses per day. Alternatively, the administration can be completed intermittently, such as once every other day, once a week or once a month. The therapeutically effective amount of a pharmaceutically acceptable salt or solvate, etc. can be determined as the ratio of the therapeutically effective amount of the compound of formula (1) itself. It is anticipated that similar dosages will be appropriate for the treatment of other diseases mentioned above.

[0241] The pharmaceutical composition of the present invention may contain one or more compounds of formula (1) or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition may contain more than one compound of the present invention. For example, in certain embodiments, the pharmaceutical composition may contain two or more compounds of formula (1) or pharmaceutically acceptable salts thereof. In addition, the pharmaceutical composition may optionally further comprise one or more additional active pharmaceutical ingredients (API).

[0242] As used herein, "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable substance, composition or vehicle involved in providing form or consistency to the pharmaceutical composition. Each excipient can be compatible with the other ingredients of the pharmaceutical composition when mixed, thereby avoiding interactions that would substantially reduce the efficacy of the compounds of the invention when administered to a subject and interactions that would result in a pharmaceutically unacceptable pharmaceutical composition.

[0243] The present invention will now be explained by the following synthetic and biological examples, which however do not limit the scope of the present invention in any way.

[0244] abbreviation

[0245] This article uses the following abbreviations:

[0246] Ph = Phenyl

[0247] Ac = Acetate

[0248] Bn=Benzyl

[0249] t-Bu=tert-butyl

[0250] n-Bu=linear butyl

[0251] Me = methyl

[0252] Et=ethyl

[0253] Pr=propyl

[0254] iPr=isopropyl

[0255] Bu=Butyl

[0256] TMS = trimethylsilyl

[0257] TBS = tert-butyldimethylsilyl

[0258] THF = Tetrahydrofuran

[0259] DMF = dimethylformamide

[0260] AA = Acetic acid

[0261] TFA = trifluoroacetic acid

[0262] i-Pr 2 NEt or DIPEA = diisopropylethylamine

[0263] TEA = triethylamine

[0264] DMAP = 4-dimethylaminopyridine

[0265] Pd / C = Palladium on Carbon

[0266] KOH = Potassium Hydroxide

[0267] NaOH = Sodium Hydroxide

[0268] LiOH = lithium hydroxide

[0269] Ar=Argon

[0270] N 2 = Nitrogen

[0271] EDC = 3-ethyl-3'-(dimethylamino)propyl-carbodiimide hydrochloride (or 1-[(3-(dimethyl)amino)propyl])-3-ethylcarbodiimide hydrochloride)

[0272] HOBT = 1-Hydroxybenzotriazole hydrate

[0273] DIC = 1,3-dipropylcarbodiimide

[0274] BOP = (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate

[0275] PyBOP = benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate

[0276] HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0277] LiHMDS = Lithium Bis(trimethylsilyl)amide

[0278] LAH = Lithium Aluminum Hydride

[0279] Boc=tert-butyloxycarbonyl

[0280] Cbz = carboxybenzyl

[0281] LDA = lithium diisopropylamide

[0282] NBS = N-bromosuccinimide

[0283] ACN = acetonitrile

[0284] min = minutes

[0285] h or hr = hours

[0286] L = liters

[0287] mL = milliliters

[0288] μL = microliter

[0289] g = grams

[0290] mg = milligrams

[0291] mol = mole

[0292] mmol = millimole

[0293] meq = milliequivalent

[0294] rt = room temperature

[0295] RT = retention time

[0296] sat or sat'd = saturated

[0297] aq.=water-based

[0298] TLC = Thin Layer Chromatography

[0299] HPLC = High Performance Liquid Chromatography

[0300] LC / MS = High Performance Liquid Chromatography / Mass Spectrometry

[0301] MS or Mass Spec = mass spectrometry

[0302] NMR = Nuclear Magnetic Resonance

[0303] mp = melting point Example

[0304] The compounds of the present invention can be synthesized by many methods available to those skilled in the art of organic chemistry (Maffrand, JP et al., Heterocycles, 16(1):35-37(1981)). General synthetic schemes for preparing the compounds of the present invention are described below. These schemes are exemplary and are not intended to limit the possible techniques that can be used by those skilled in the art to prepare the compounds disclosed herein. The different methods for preparing the compounds of the present invention will be understood by those skilled in the art. In addition, the various steps in the synthesis can be performed in an alternating order in order to produce the desired compound or compounds.

[0305] General scheme:

[0306] As indicated above, the present invention generally provides compounds according to formula I,

[0307]

[0308] Examples of compounds of the invention prepared by the methods described in the general schemes are given in the intermediates and examples section set forth below. The preparation of homochiral embodiments can be achieved by techniques known to those skilled in the art. For example, homochiral compounds can be prepared by separating racemic products using chiral phase preparative HPLC or preparative SFC. Alternatively, example compounds can be prepared by methods known to produce enantiomerically enriched products. These include, but are not limited to, the incorporation of chiral auxiliary functional groups into racemic intermediates, which are used to control the diastereoselectivity of the conversion, thereby providing enantiomerically enriched products after cleavage of the chiral auxiliary group.

[0309] The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. Using the methods described below and synthetic methods known in the field of synthetic organic chemistry, or by variations thereon as understood by those skilled in the art, the compounds of the present invention can be synthesized. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture suitable for the reagents and materials used and suitable for the transformation to be performed. Those skilled in the art of organic synthesis will understand that the functional groups present on the molecule should be consistent with the proposed transformation. This will sometimes require judgment to modify the order of the synthesis steps or select a specific process scheme instead of another to obtain the desired compound of the present invention.

[0310] It should also be recognized that another important consideration when planning any synthetic route in this field is the judicious choice of protecting groups used to protect reactive functional groups present in the compounds described herein. An authoritative document describing many alternatives for the trained practitioner is Greene et al. (Protective Groups in Organic Synthesis, 4th edition, Wiley-Interscience (2006)).

[0311] The compounds of the present invention having formula (I) can be prepared by the methods illustrated in the following schemes.

[0312] As shown in Scheme 1a, compound P1a (commercially available) can undergo an alkylation reaction using silver oxide or sodium hydride to provide compound P1b. 3 .SMe 2 ) in the presence of , the acid or ester portion can be reduced to afford the desired compound P1c.

[0313] Option 1a

[0314]

[0315] As shown in Scheme 1b, compound P1a (commercially available) can undergo a silylation reaction in the presence of a weak base such as imidazole to provide compound P2a. 3 Reaction with aldehydes or ketones in the presence of triethylsilane can afford ether P2b. Sequential hydrogenation in the presence of Pd / C, Boc protection, and ester reduction in the presence of a borohydride reagent can provide the desired compound P2e.

[0316] Option 1b

[0317]

[0318] As shown in Scheme 1c, compound P1a (commercially available) can undergo reaction in the presence of TMSOTf to provide enolate P3b. Cyclopropanation can be achieved in the presence of diethylzinc to provide P3c. By sequentially deprotecting Cbz in the presence of palladium on carbon, followed by Boc 2 O reaction can achieve a two-step transprotection to give P3e. The final reduction in the presence of a borohydride reagent can provide the desired compound P3f.

[0319] Solution 1c

[0320]

[0321] As shown in Scheme 1d, compound P1a (commercially available) is reacted with a borane reagent such as BH 3 .SMe 2 ) can undergo a reduction reaction to provide compound P4a. The primary alcohol can be protected in the presence of TBDPSCl, followed by Dess-Martin oxidation to provide ketone P4c. Enolate P4d can be obtained by Wittig reaction, followed by reduction of the double bond by hydrogenation. Deprotection of the silyl group, for example in the presence of a fluorinated reagent, can provide the desired compound P4f.

[0322] Scheme 1d

[0323]

[0324] As shown in Scheme 1e, compound P1b can undergo an alkylation reaction in the presence of a strong base such as LDA to provide compound P2a. Reduction of the ester moiety in the presence of sodium borohydride can provide the desired compound P2b.

[0325] Option 1e

[0326]

[0327] As shown in Scheme 1f, compound P1c can undergo oxidation under Swern conditions followed by treatment with a strong alkylating agent such as an alkylmagnesium bromide to provide pyrrolidine P4b.

[0328] Scheme 1f

[0329]

[0330] As shown in Scheme 2a, compound S1a can undergo a cyclization reaction in the presence of amino-pyrazole S1b. Intermediate S1c can be treated sequentially with phosphorus oxychloride followed by N-bromosuccinimide to produce intermediate S1e. Aromatic nucleophilic substitution can be achieved in the presence of ammonia to provide compound S1f. The skeleton S1g is obtained by diazotization in the presence of isoamyl nitrite followed by elimination in a one-pot reaction.

[0331] Option 2a

[0332]

[0333] As shown in Scheme 2b, compound S1g can undergo bromination in the presence of N-bromosuccinimide to provide compound S2a. Alkylation of the backbone with sodium alcoholate can afford the desired compound S2b.

[0334] Option 2b

[0335]

[0336] As shown in Scheme 2c, compound S1g can undergo bromination in the presence of N-bromosuccinimide to provide compound S3a. Alkylation of the backbone by sodium alcoholate can afford the desired compound S3b.

[0337] Solution 2c

[0338]

[0339] As shown in Scheme 2d, compound S4a can undergo esterification in the presence of MeOH and acetyl chloride, followed by reaction with ethyl formate in the presence of a strong base. Intermediate S4c is converted to enol ester S4d. Subsequent cyclization can be achieved in the presence of amino-pyrazole S1b. Intermediate S4e can be treated sequentially with phosphorus oxychloride followed by N-bromosuccinimide to provide the desired compound S4g.

[0340] Scheme 2d

[0341]

[0342] As shown in Scheme 3a, compound A1a can undergo a Miyaura borylation reaction to provide A1b.

[0343] Option 3a

[0344]

[0345] As shown in Scheme 3b, compound A1a can undergo alkylation in the presence of an alkyl halide to provide intermediate A2a. Aniline A2b can be obtained via Miyaura borylation.

[0346] Option 3b

[0347]

[0348] As shown in Scheme 3c, compound A3a can undergo Bocylation followed by Sonogashira to give intermediate A3c. The bromide can be converted to the free aniline A3d using a strong acid such as HCl, which can undergo Miyaura borylation to provide A3e.

[0349] Solution 3c

[0350]

[0351] As shown in Scheme 3d, compound A4a can undergo Boc ylation followed by Boc deprotection (purification process) to provide intermediate A4c. Compound A4d can be obtained by Miyaura borylation reaction.

[0352] Scheme 3d

[0353]

[0354] As shown in Scheme 3e, compound A5a can undergo a copper-catalyzed cross-coupling reaction followed by nitro reduction (eg, using iron and ammonium chloride) to provide intermediate A5c. Compound A5d can be obtained by Miyaura borylation.

[0355] Option 3e

[0356]

[0357] As shown in Scheme 3f, compound A6a can undergo a copper-catalyzed cross-coupling reaction followed by a Miyaura borylation reaction to provide the boronate ester A6c.

[0358] Option 3f

[0359]

[0360] As shown in Scheme 3g, compound A5a can undergo a copper-catalyzed cross-coupling reaction followed by Boc hydrolysis to provide boronate ester A6c. The hydrazine derivative can be converted to the pyrazole A7c. The intermediate can be decarboxylated in the presence of a strong acid followed by nitro reduction using iron and ammonium chloride to provide A7e. Boronate ester A7f can be obtained by Miyaura borylation.

[0361] Solution 3g

[0362]

[0363] As shown in Scheme 3h, compound A8a can undergo esterification followed by Miyaura borylation to provide boronate ester A8c.

[0364] Solution 3h

[0365]

[0366] As shown in Scheme 3i, compound A3a can undergo Suzuki coupling followed by silylation protection by TBDPS to give intermediate A9c. The compound can be converted to the free aniline using a strong acid such as HCl followed by Miyaura borylation to provide the boronate ester A9d.

[0367] Solution 3i

[0368]

[0369] As shown in Scheme 3j, compound A10a can undergo Curtius reaction followed by Suzuki coupling to give intermediate A10c. The compound can be converted to the free aniline using a strong acid such as HCl followed by Miyaura borylation to provide the boronate ester A10e.

[0370] Solution 3j

[0371]

[0372] As shown in Scheme 1, compound 1a (accounting for intermediates such as P1c or P2b) can undergo aromatic nucleophilic substitution by reaction with 1b. Boronate 1d (prepared from its corresponding bromophenyl group by borylation) can be introduced by transition metal-catalyzed cross-coupling to provide 1e. Sequential p-nitrobenzenesulfonyl (Nosyl) protection of the aniline, its alkylation, and deprotection of the Boc group can produce the amine 1h. Macrocyclic cyclization can be carried out using Finkelstein conditions to produce 1i, which can be subsequently oxidized in the presence of iodine to provide 1j. P-nitrobenzenesulfonyl deprotection can provide the final compound 1k.

[0373] Scenario 1:

[0374]

[0375] As shown in Scheme 2, compound 1j (containing R 1 =OBn) to provide phenol 2a. Subsequent and sequential alkylation and deprotection of the p-nitrobenzenesulfonyl group provided the final compound 2c.

[0376] Solution 2

[0377]

[0378] Phenol 2a can be converted to triflate 3a as shown in Scheme 3. The acyl moiety is introduced by transition metal catalyzed cross coupling to provide 3b. Subsequent deprotection of the p-nitrobenzenesulfonyl group provides the final compound 3c.

[0379] Solution 3

[0380]

[0381] As shown in Scheme 4, the final compound 4b can be obtained by sequentially deprotecting the p-nitrobenzenesulfonyl group and then removing the silyl moiety from compound 1j in the presence of methanol and a base.

[0382] Solution 4

[0383]

[0384] As shown in Scheme 5, compound 1j (containing R 6 =OBn) can undergo deprotection of the benzyl moiety in the presence of TFA and anisole to provide phenol 5a. After the formation of the triflate in the presence of trifluoromethanesulfonic anhydride and pyridine, the saturated heterocycle is introduced by transition metal catalyzed cross coupling to provide compound 5c. The p-nitrobenzenesulfonyl group is removed in the presence of thiophenol to provide the final compound 5d.

[0385] Solution 5

[0386]

[0387] As shown in Scheme 6, compound 1j (containing R 1 =COOMe) can undergo hydrolysis to compound 6a. After saponification to compound 6b in the presence of base, peptide coupling can provide the final compound 6c.

[0388] Solution 6

[0389]

[0390] As shown in Scheme 7, compound 6b can undergo reduction in the presence of borane dimethyl sulfide to provide the final compound 7a.

[0391] Solution 7

[0392]

[0393] As shown in Scheme 8, compound 7a can undergo chlorination in the presence of thionyl chloride to produce compound 8a. Alkylation of the alcoholate affords the final compound 8b.

[0394] Solution 8

[0395]

[0396] As shown in Scheme 9, compound 1k (containing R 5 =OCH 2 CH 2 OBn) can be subjected to hydrogenation in the presence of palladium on carbon to provide the final compound 9a.

[0397] Solution 9

[0398]

[0399] As shown in Scheme 10, compound 1k can undergo an acylation reaction to provide the final compound 10a.

[0400] Solution 10

[0401]

[0402] As shown in Scheme 11, compound 1k can undergo an alkylation reaction to provide the final compound 11a.

[0403] Solution 11

[0404]

[0405] Compound 1j can be converted to compound 12a in the presence of hydroxylamine as shown in Scheme 12. Heterocycle formation is achieved in the presence of triethyl orthoformate to produce 12b. Deprotection of the p-nitrobenzenesulfonyl group affords the final compound 12c.

[0406] Solution 12

[0407]

[0408] As shown in Scheme 13, compound 1a can undergo aromatic nucleophilic substitution by reaction with 1b to provide 13a. By sequentially carrying out deprotection of the acetal moiety, protection of the amine with a Boc group, and Wittig reaction, olefin 13d can be obtained. Boronate 1d can be introduced by transition metal catalyzed cross coupling to provide 13e. Sequentially carrying out p-nitrobenzenesulfonyl protection of the aniline, its alkylation, and deprotection of the Boc group affords amine 13i. Macrocyclic cyclization using Finkelstein conditions produces 13j, which is subsequently oxidized in the presence of iodine to provide 13k. p-nitrobenzenesulfonyl deprotection provides the final compound 13l.

[0409] Solution 13

[0410]

[0411]

[0412] As shown in Scheme 14, compound 1i can undergo deprotection of the p-nitrobenzenesulfonyl group, followed by oxidation in the presence of iodine, and finally reduction of the additional iodine present in the structure to provide the final compound 14c.

[0413] Solution 14:

[0414]

[0415] As shown in Scheme 15, compound 1k can undergo reduction of additional iodine (present in the structure due to oxidation in the presence of iodine) in the presence of an iridium catalyst to provide the final compound 15a.

[0416] Solution 15

[0417]

[0418] As shown in Scheme 16, compound 1k can undergo Suzuki coupling in the presence of a boronate ester to provide the final compound 16a.

[0419] Scheme 16

[0420]

[0421] As shown in Scheme 17, compound 16b can undergo alkylation in the presence of an alkyl halide followed by p-nitrobenzenesulfonyl deprotection using a sulfur derivative such as methylthiophenol to provide the final compound 17b.

[0422] Solution 17

[0423]

[0424] As shown in Scheme 18, compound 5a can undergo alkylation in the presence of an alkyl halide and a weak base (eg, cesium carbonate), followed by p-nitrobenzenesulfonyl deprotection using a sulfur derivative (eg, methylthiophenol) to provide the final compound 18b.

[0425] Scheme 18

[0426]

[0427] As shown in Scheme 19, compound 1k can undergo deprotection, such as silyl TBDPS removal, in the presence of TBAF to provide the final compound 19a.

[0428] Solution 19

[0429]

[0430] As shown in Scheme 20, compound 2a can undergo p-nitrobenzenesulfonyl deprotection using a sulfur derivative such as methylthiophenol to provide the final compound 20a.

[0431] Solution 20

[0432]

[0433] As shown in Scheme 21, compound 1k can undergo dehalogenation in the presence of an iridium-based catalyst to provide the final compound 21a.

[0434] Solution 21

[0435]

[0436] As shown in Scheme 22, compound 1j can undergo hydrolysis in the presence of sodium hydroxide, followed by imine formation using dimethoxy-N,N-dimethylmethanamine, followed by direct cyclization in the presence of hydroxylamine to provide intermediate 22c. Deprotection of the p-nitrobenzenesulfonyl group using a sulfur derivative (e.g., 4-methylthiophenol) can provide the final compound 22d.

[0437] Solution 22

[0438]

[0439] As shown in Scheme 23, compound 3a can undergo p-nitrobenzenesulfonyl deprotection using a sulfur derivative (eg, 4-methylthiophenol) followed by a transition metal-catalyzed cross-coupling (such as Stille coupling) to provide the final compound 23b.

[0440] Solution 23

[0441]

[0442] As shown in Scheme 24, compound 3a can undergo silyl deprotection using a fluoride-containing reagent (e.g., TBAF), followed by a click reaction using an alkyl halide and sodium azide to provide intermediate 24b. The final compound 24c can be obtained by p-nitrobenzenesulfonyl deprotection using a sulfur derivative (e.g., 4-methylthiophenol).

[0443] Solution 24

[0444]

[0445] As shown in Scheme 25, compound 16b can undergo ether formation by reaction with an alkyl halide and TBAB to provide the final compound 25a.

[0446] Solution 25

[0447]

[0448] As shown in Scheme 26, compound 16b can undergo transition metal catalyzed cross coupling such as Sonogashira coupling followed by alkyne deprotection in the presence of a weak base such as potassium carbonate in alcohol to provide the final compound 26b.

[0449] Scheme 26

[0450]

[0451] As shown in Scheme 27, compound 1c can undergo amine deprotection using a strong acid such as HCl, followed by alkylation in the presence of an alkyl halide to give intermediate 27b. The ester moiety can be reduced to the primary alcohol 27c in the presence of a reducing agent such as sodium borohydride / calcium chloride, followed by introduction of a protecting group such as TBDMS to give intermediate 27d. The compound is then subjected to Suzuki coupling, followed by introduction of a p-nitrobenzenesulfonyl protecting group and alcohol deprotection (using TBAF in the case of a silyl protecting group) to give 27g. Macrocyclic cyclization can be performed by Mitsunobu reaction, followed by oxidation in the presence of iodine and p-nitrobenzenesulfonyl deprotection using a sulfur derivative such as 4-methylthiophenol to provide the final compound 27j.

[0452] Scheme 27

[0453]

[0454] As shown in Scheme 28, compound 5a can undergo alkylation using an alkyl halide in the presence of a weak base (e.g., potassium carbonate), followed by p-nitrobenzenesulfonyl deprotection using a sulfur derivative (e.g., 4-methylthiophenol) to provide intermediate 28b. Deprotection by an alcohol (e.g., p-toluenesulfonic acid in the case of the THP protecting group) can afford the final compound 28c.

[0455] Scheme 28

[0456]

[0457] A. Physical and chemical properties of compounds

[0458] Purification of intermediates and final products was performed by normal or reverse phase chromatography. Normal phase chromatography was performed using pre-filled SiO2 cartridges, with gradient elution of hexanes and EtOAc or DCM and MeOH, unless otherwise noted. Reverse phase preparative HPLC was performed using a Gilson semi-preparative HPLC system operated by Gilson UNIPOINT software.

[0459] Purification Method PA Purification was performed on a Phenomenex Luna column (100 mm length x 21.2 mm inner diameter; 5 μm particles) at room temperature with a constant flow rate of 20.0 mL / min. 4 HCO 3 aqueous solution) / 68% (acetonitrile-methanol 1:1) to 4% (25 mM NH 4 HCO 3The gradient elution was performed with 1% (1:1) / 96% (1:1) (aqueous solution) / 96% (acetonitrile-methanol). The UV detector was set to 226 nm, which corresponds to the wavelength of maximum absorbance observed for the compound.

[0460] Purification method PB: Purification was performed on a Phenomenex Gemini C18 column (100 mm length x 30 mm inner diameter; 5 μm particle size) at room temperature with a flow rate of 30 mL / min. Gradient elution was performed from 70% (water + 25 mM ammonium bicarbonate) / 5% (acetonitrile-methanol 50% mixture) to 27% (water + 25 mM ammonium bicarbonate) / 73% (acetonitrile-methanol 50% mixture) in 20 minutes; thereafter, gradient elution was performed from 27% (water + 25 mM ammonium bicarbonate) / 73% (acetonitrile-methanol 50% mixture) to 0% (water + 25 mM ammonium bicarbonate) / 100% (acetonitrile-methanol 50% mixture) in 2 minutes; the resulting composition was maintained for 5 minutes; from 0% (water + 25 mM ammonium bicarbonate) / 100% (acetonitrile-methanol 50% mixture) to 95% (water + 25 mM ammonium bicarbonate) / 5% (acetonitrile-methanol 50% mixture) in 2 minutes, and the resulting composition was maintained for 5 minutes. The standard injection volume was 8 mL. For the UV detector, the acquisition was set to 254 nm.

[0461] Unless otherwise stated, analysis of final products was performed by LCMS or reverse phase analytical HPLC.

[0462] LCMS Method A (MA)

[0463] Analytical HPLC was performed on an X-Select CSH C18 XP column (2.5 μm 30 x 4.6 mm inner diameter) using the following elution gradient with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B): 0-3 min: 5% to 100% B, 3-4 min 100% B, flow rate 1.8 mL / min at 40° C. Electrospray positive ionization [ES+ to generate MH + Mass spectra (MS) were recorded on a Waters ZQ mass spectrometer (scanning 200-900 μA) in either electrospray negative ionization [ES- to produce (MH)-molecular ions] mode.

[0464] LCMS Method B (MB)

[0465] Analytical HPLC was performed on an X-Select CSH C18 XP column (2.5 μm 30 x 4.6 mm id) using the following elution gradient with 0.1% ammonia in water (solvent A) and 0.1% ammonia in acetonitrile (solvent B): 0-3 min: 5% to 100% B, 3-4 min 100% B, flow rate 1.8 mL / min at 40° C. Electrospray positive ionization [ES+ to generate MH] was used at 20 V cone voltage. + Mass spectra (MS) were recorded on a Waters ZQ mass spectrometer (scanning 200-900 μA) in either electrospray negative ionization [ES- to produce (MH)-molecular ions] mode.

[0466] LCMS Method C(MC)

[0467] Analytical HPLC was performed on an X-Select CSH C18 XP column (2.5 μm 30 x 4.6 mm inner diameter) using the following elution gradient with (NH 4 ) 2 CO 3 2 g / L solution in water (solvent A) and acetonitrile (solvent B) eluted: 0-3 min: 5% to 100% B, 3-4 min 100% B, flow rate 1.8 mL / min, at 40° C. Electrospray positive ionization [ES+ to generate MH + Mass spectra (MS) were recorded on a Waters ZQ mass spectrometer (scanning 200-900 μA) in either electrospray negative ionization [ES- to produce (MH)-molecular ions] mode.

[0468] LCMS Method D(MD)

[0469] In addition to the general procedures LCMS: Analyses were performed on a YMC pack ODS-AQ C18 column (50 mm length x 4.6 mm inner diameter; 3 μm particles) at 35°C with a flow rate of 2.6 mL / min. Gradient elution was performed from 95% (water + 0.1% formic acid) / 5% acetonitrile to 5% (water + 0.1% formic acid) / 95% acetonitrile in 4.80 minutes, and the final mobile phase composition was then held for an additional 1.00 min. The standard injection volume was 2 μL. The acquisition range was set to 190-400 nm (for UV-PDA detector) and 100-1400 m / z (for MS detector).

[0470] LCMS Method E(ME)

[0471] In addition to the general procedures LCMS: Analyses were performed on a Phenomenex Kinetex C18 column (50 mm length x 2.1 mm inner diameter; 2.6 μm particles) at 35°C with a flow rate of 0.7 mL / min. Gradient elution was performed from 95% (50 mM ammonium acetate in water) / 5% acetonitrile to 5% (50 mM ammonium acetate in water) / 95% acetonitrile in 4.80 minutes, and the final mobile phase composition was then held for an additional 1.00 min. The standard injection volume was 2 μL. The acquisition range was set to 190-400 nm (for UV-PDA detector) and 100-1400 m / z (for MS detector).

[0472] LCMS Method F(MF)

[0473] The analysis was performed on a Phenomenex GEMINI C18 column (100 mm length x 4.6 mm inner diameter; 5 μm particles) at 25°C with a flow rate of 3.014 mL / min. Gradient elution was performed as follows: 95% (65 mM ammonium acetate in water + acetonitrile (90:10)) / 5% acetonitrile for 0.30 min; from the previous composition to 100% acetonitrile in 4.26 min; the previous composition was maintained for 0.60 min, and then reached 95% (65 mM ammonium acetate in water + acetonitrile (90:10)) / 5% acetonitrile in 1.02 min; the final mobile phase composition was maintained for another 0.57 min. The standard injection volume was 3 μL. The acquisition range was set to 200-400 nm (for UV-PDA detector) and 100-1000 m / z (for MS detector).

[0474] LCMS Method G(MG)

[0475] In addition to the general procedures LCMS: Analysis was performed on a YMC pack ODS-AQ C18 column (50 mm length x 4.6 mm inner diameter; 3 μm particle size) at 35°C with a flow rate of 2.6 mL / min. Gradient elution was performed using an Agilent 1260 as follows: from 95% (water + 0.1% formic acid) / 5% acetonitrile to 5% (water + 0.1% formic acid) / 95% acetonitrile in 4.8 min; the resulting composition was held for 1.0 min; from 5% (water + 0.1% formic acid) / 95% acetonitrile to 95% (water + 0.1% formic acid) / 5% acetonitrile in 0.2 min. The standard injection volume was 2 μL. The acquisition range was set to 190-400 nm (for UV-PDA detector) and 100-1000 m / z (for TOF-MS detector).

[0476] LCMS Method H(MH)

[0477] In addition to the general procedures LCMS: Analyses were performed on a Phenomenex Kinetex C18 column (50 mm length x 2.1 mm inner diameter; 1.7 μm particles) at 60°C with a flow rate of 1.5 mL / min. Gradient elution was performed from 90% (water + 0.1% formic acid) / 10% acetonitrile to 10% (water + 0.1% formic acid) / 90% acetonitrile in 1.50 minutes, and the final mobile phase composition was then held for an additional 0.40 min. The standard injection volume was 2 μL. The acquisition range was set to 254 nm (for the UV-PDA detector) and 80-800 m / z (for the MS detector).

[0478] LCMS Method I (MI)

[0479] The analysis was performed on a Thermo Scientific Accucore C18 (50 mm length x 2.1 mm inner diameter, 2.6 μm) at 35°C with a flow rate of 1.50 mL / min. Gradient elution was performed from 95% (water + 0.1% formic acid) / 5% acetonitrile to 5% (water + 0.1% formic acid) / 95% acetonitrile in 1.30 minutes; the resulting composition was held for 0.5 minutes; followed by the final mobile phase composition; from 5% (water + 0.1% formic acid) / 95% acetonitrile to 90% (water + 0.1% formic acid) / 10% acetonitrile in 0.10 minutes. The injection volume was 1 μL. The MS acquisition range and UV detector were set to 100-1000 m / z and 190-400 nm, respectively.

[0480] LCMS Method K(MK)

[0481] Analytical HPLC was performed on a Kinetex EVO C18 30*2.1 mm, 5 um using the following elution gradient with 0.0375% TFA in water (v / v) (solvent A) and 0.01875% TFA in acetonitrile (v / v) (solvent B): 0-1.20 min: 5% to 95% B, 1.2-1.55 min 95% to 5% B, flow rate of 1.5 mL / min, at 50° C. Mass spectra (MS) were recorded in ESI ionization source [ES+ to generate MH+ molecular ions] mode with 20 VQarray DC voltage.

[0482] Purification was performed using a Gilson system consisting of a binary pump (333 Model and 334 Model), an ASPEC autosampler, a column valve selector, and a UV detector. Data acquisition was performed using Trilution 3.0 software.

[0483] Skeleton S1: 3-bromo-5-chloro-6-methylpyrazolo[1,5-a]pyrimidine

[0484]

[0485] Step 1

[0486] To a solution of 1H-pyrazole-5-amine (173 g, 2.09 mol) was added EtONa (343 g, 5.04 mol, 2000 mL), followed by diethyl 2-methylpropanediolate (400 g, 2.30 mol, 392 mL). The mixture was stirred at 100 ° C for 12 hours. TLC (petroleum ether / ethyl acetate = 0 / 1, compound 4, Rf = 0.3) indicated that the reaction was complete. The reaction mixture was cooled to 25 ° C and filtered to obtain a light yellow solid. The crude was stirred in EtOH (5 L) for 12 hours and filtered to obtain a white solid. 7-hydroxy-6-methyl-4H-pyrazolo[1,5-a]pyrimidin-5-one, sodium salt (540 g) was obtained as a white solid.

[0487] The crude material was used in the next step without further purification.

[0488] 1 H NMR (ppm, 400MHz), MeOD: 7.56 (d, J = 1.8Hz, 1H), 5.75 (d, J = 2.0Hz, 1H), 1.95 (s, 3H)

[0489] Step 2

[0490] POCl 3 7-Hydroxy-6-methyl-4H-pyrazolo[1,5-a]pyrimidin-5-one, sodium salt (366 g, 2.22 mol) was added to a solution of 1.91 L (3.15 kg, 20.5 mol, 1.91 L). The mixture was stirred at 105 °C for 40 hours. The mixture was concentrated to remove most of the POCl 3 The reaction mixture was diluted with ethyl acetate (5000 mL), poured into ice water (10000 mL) and heated to 40 ℃ by adding saturated NaHCO 3 The solution was adjusted to pH = 7-8. The aqueous phase was then extracted with ethyl acetate (2000 mL*3), and the combined organic layers were washed with brine (1000 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The title compound, 5,7-dichloro-6-methyl-pyrazolo[1,5-a]pyrimidine, (590 g, 2.92 mol, 43.9% yield) was obtained as a black oil.

[0491] The crude material was used in the next step without further purification.

[0492] 1 H NMR (ppm, 400MHz), CDCl 3:8.15(d,J=2.3Hz,1H),6.69(d,J=2.3Hz,1H),2.54(s,3H)

[0493] Step 3

[0494] To a solution of 5,7-dichloro-6-methyl-pyrazolo[1,5-a]pyrimidine (290 g, 1.44 mol) in THF (1.5 L) was added Zn (210 g, 3.21 mol), ammonia solution (35%) (528 g, 5.27 mol, 580 mL, 3.67 equiv) and saturated NaCl solution (1.5 L). The reaction mixture was stirred at 25 °C for 2 hours. TLC (petroleum ether: ethyl acetate = 3: 1) indicated that the reaction was complete. The mixture was filtered to remove Zn and then extracted with ethyl acetate (1000 mL*3). The combined organic layers were washed with brine (1000 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound, 5-chloro-6-methyl-pyrazolo[1,5-a]pyrimidine (420 g) as a yellow solid. The crude material was used in the next step without further purification.

[0495] 1 H NMR (ppm, 400MHz), CDCl 3 :8.49(s,1H),8.05(d,J=1.8Hz,1H),6.63-6.52(m,1H),2.38(s,3H)

[0496] Step 4

[0497] To a solution of 5-chloro-6-methyl-pyrazolo[1,5-a]pyrimidine (400 g, 2.39 mol) in acetonitrile (2 L) was added N-bromosuccinimide (480 g, 2.70 mol). The reaction mixture was stirred at 20 ° C for 0.5 hours. LCMS showed the formation of the expected compound. The mixture was poured into water (2000 mL) and the formed solid was collected by filtration. The title compound, 3-bromo-5-chloro-6-methyl-pyrazolo[1,5-a]pyrimidine (500 g, 2.03 mol, 85% yield) was obtained as a yellow solid. The crude material was used in the next step without further purification.

[0498] LCMS(MK)RT=0.837min,m / z=247.9(M+H) + .

[0499] Skeleton S2: 3-bromo-5-chloro-6-methoxypyrazolo[1,5-a]pyrimidine

[0500]

[0501] Step 1:

[0502] Dimethyl 2-methoxymalonate (100 g, 616.7 mmol) was diluted in ethanol (200 mL) and added to a mixture of 3-aminopyrazole (51.25 g, 616.7 mmol) and sodium ethoxide (370 mL) in ethanol (1.65 L).

[0503] The reaction mixture was heated at 120° C. for 16 h. After complete conversion monitored by LCMS, the mixture was cooled at 0° C. The resulting purple solid was filtered off and washed with EtOH at 0° C., concentrated, co-evaporated with acetonitrile and dried under high vacuum.

[0504] The solid was added portionwise to a stirred solution of 1 N HCl at 4-5°C. The precipitate was filtered and washed with minimal cold water. The beige solid was concentrated in vacuo and co-evaporated with toluene (x3). The beige solid was dried under high vacuum and used as is in the next step.

[0505] LCMS(MD)RT=0.405min,m / z=182.0(M+H) + .

[0506] Step 2:

[0507] To a solution of the title compound from step 1 (135.8 g, 7449.6 mmol) and phosphorus oxychloride (449.8 g, 2248.9 mmol) was slowly added N,N-diethylaniline (101.71 mL, 1049.5 mmol) at 0°C. The reaction was heated at 120°C for 4 hours. After cooling, the excess phosphorus oxychloride was removed and the residue was diluted with EtOAc and washed with saturated NaHCO 3 The organic layer was washed with MgSO 4 Dry, filter and concentrate under vacuum.The product was purified by flash chromatography using heptane / EtOAc (100:0 to 80:20) as eluent to afford the title compound (44.8 g, 27% yield) as a yellow solid.

[0508] LCMS(MH)RT=0.556min,m / z=218.1 / 220.0(M+H) + .

[0509] Step 3:

[0510] The title compound from step 2 (22.1 g, 101.36 mmol) was dissolved in acetonitrile (304 mL) and cooled to 0°C. Then, N-bromosuccinimide (18.04 g, 101.36 mmol) was added portionwise, and the mixture was stirred at room temperature for 30 min. After complete conversion monitored by LCMS, the mixture was diluted with EtOAc and washed with saturated NaHCO 3 The organic layer was extracted with MgSO 4 Dried, filtered and concentrated.The product was purified by flash chromatography using heptane / EtOAc (100:0 to 80:20) as eluent to afford the title compound (23.7 g, 78.8%) as a yellow solid.

[0511] LCMS(MH)RT=0.769min,m / z=295.2 / 299.0(M+H) + .

[0512] Step 4:

[0513] The title compound from step 3 (20.0 g, 67.35 mmol) was suspended in EtOH (303 mL). Sodium borohydride (3.06 g, 80.8 mmol) was added portionwise at 0 °C. The reaction mixture was maintained at 0 °C with continuous stirring. After complete conversion monitored by LCMS, the mixture was quenched with water. EtOAc was added and extracted. The organic layer was purified by MgSO 4 Dried, filtered and concentrated to dryness.The crude was purified by flash chromatography on silica gel using DCM / MeOH (100:0 to 90:10) as eluent to afford the desired compound as a yellowish solid.

[0514] LCMS(MH)RT=0.655min,m / z=260.2 / 262.2(M+H) + .

[0515] Skeleton S3: 3-bromo-6-(bromomethyl)-5-chloro-pyrazolo[1,5-a]pyrimidine

[0516]

[0517] Step 1

[0518] To a solution of 2-(benzyloxy)acetic acid (166 g, 999 mmol, 143 mL, 1 eq) in MeOH (800 mL) was added acetyl chloride (117 g, 1.50 mol, 107 mL, 1.5 eq) dropwise at 10 °C. The mixture was stirred at 20 °C for 1 hour. The mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate = 10 / 1-5 / 1) to afford the title compound (170 g, 943 mmol, 94.4% yield) as a colorless oil.

[0519] 1 H NMR:400MHz,CDCl 3 :7.45-7.30(m,5H),4.66(s,2H),4.13(s,2H),3.79(s,3H)

[0520] Step 2

[0521] To a solution of sodium hydride (33.0 g, 824 mmol, 60% purity, 1.1 eq.) in THF (675 mL) was added ethyl formate (83.3 g, 1.12 mol, 90.4 mL, 1.5 eq.). A solution of the title compound from step 1 (135 g, 749 mmol, 1 eq.) in THF (135 mL) was then added dropwise to the mixture at 0°C. The mixture was stirred at 25°C for 3 h. DMF (400 mL) and ethyl iodide (117 g, 749 mmol, 59.9 mL, 1 eq.) were added dropwise to the mixture. The resulting mixture was stirred at 35°C for 1 h. The mixture was poured into ice water (1500 mL) and extracted with ethyl acetate (1000 mL*3). The combined organic layers were purified by Na 2 SO 4 Drying, filtration and concentration under reduced pressure afforded the title compound as a yellow oil (185 g, crude), which was used in the next step without purification based on theoretical 100% yield.

[0522] Step 3

[0523] To a solution of 3-aminopyrazole (41.0 g, 493 mmol, 1 eq.), the title compound from step 2 (175 g, 740 mmol, 1.5 eq.) in DMF (1000 mL) was added Cs 2 CO 3 (241 g, 740 mmol, 1.5 eq.). The mixture was stirred at 110 °C for 10 hours. After complete conversion monitored by LCMS, the mixture was cooled to 20 °C and poured into ice water (3000 mL), pH = 5-6 was adjusted with 2M HCl (700 mL), and many solids precipitated out at this stage. The mixture was filtered and the filter cake was washed with water (600 mL). The filter cake was triturated with tert-butyl methyl ether (500 mL) to provide the title compound (65.0 g, 269 mmol, 54.6% yield) as a yellow solid.

[0524] 1 H NMR:DMSO-d6 400MHz:12.40(s,1H),8.33(s,1H),7.66(d,J=2.1Hz,1H),7.53-7.33(m,5H),5.80(d,J=1.7Hz,1H),5.05(s,2H)

[0525] Step 4

[0526] To a solution of the title compound from step 3 (80.0 g, 332 mmol, 1 eq) in acetonitrile (600 mL) was added POCl 3 (127 g, 829 mmol, 77.0 mL, 2.5 eq) and N,N-diethylaniline (495 mg, 3.32 mmol, 530 uL, 0.01 eq). The mixture was then stirred at 100 °C for 4 hours. After complete conversion as monitored by LCMS, the mixture was concentrated under vacuum to remove most of the CH 3 CN and POCl 3 The mixture was then diluted with ethyl acetate (1000 mL) and poured into ice water (2000 mL), the pH was adjusted to 7 with potassium carbonate, and extracted with ethyl acetate (1000 mL*2). The combined organic layers were washed with brine (1000 mL), filtered through Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue is purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1-5 / 1) to afford the title compound (66.0 g, 254 mmol, 76.6% yield) as a pale yellow solid.

[0527] 1 H NMR:CDCl 3 ,400MHz,8.27(s,1H),8.02(d,J=2.4Hz,1H),7.58-7.39(m,5H),6.61(d,J=2.4Hz,1H),5.19(s,2H)

[0528] Step 5

[0529] To a solution of the title compound from step 4 (69.0 g, 266 mmol, 1 eq.) in dichloromethane (650 mL) was slowly added NBS (47.3 g, 266 mmol, 1 eq.). The mixture was stirred at 25 °C for 2 hours. After complete conversion was monitored by LCMS, the mixture was concentrated under reduced pressure. The residue was triturated with a solution of DCM:PE=1:1 (300 mL) and filtered. The filter cake was washed with water (1000 mL) to provide the desired compound (85.3 g, 252 mmol, 94.7% yield) as a light yellow solid.

[0530] 1 H NMR:DMSO-d 6, 400MHz,9.23(s,1H),8.31(s,1H),7.59-7.17(m,5H),5.27(s,2H)

[0531] Skeleton S4: 3-bromo-6-(bromomethyl)-5-chloro-pyrazolo[1,5-a]pyrimidine and Skeleton S5: 3-bromo-5-chloro-6-(dibromomethyl)pyrazolo[1,5-a]pyrimidine

[0532]

[0533] To a solution of 3-bromo-5-chloro-6-methyl-pyrazolo[1,5-a]pyrimidine (5.00 g, 20.28 mmol) in carbon tetrachloride (100 mL) were added N-bromosuccinimide (36.10 g, 202.84 mmol) and 2,2'-azobis(2-methylpropionitrile) (333 mg, 2.028 mmol) in sequence. The reaction mixture was stirred at 100° C. for 16 h.

[0534] The mixture was filtered and the remaining crude material was rinsed with dichloromethane. The mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate aqueous solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-5% heptane / dichloromethane (9: 1) / ethyl acetate) to provide the title compound (1.885 g, 28% yield) as a white solid.

[0535] LCMS(MH)RT=0.797min,m / z=325.7-327.7(M+H) + .

[0536] Skeleton S5: 3-Bromo-5-chloro-6-(dibromomethyl)pyrazolo[1,5-a]pyrimidine was obtained as a slightly yellow solid (5.045 g, 61% yield).

[0537] LCMS(MH)RT=0.966min,m / z=403.6-405.6(M+H) + .

[0538] Skeleton S6: 3-bromo-5-chloro-6-(methoxymethyl)pyrazolo[1,5-a]pyrimidine

[0539]

[0540] A solution of framework S4 (1.885 g, 5.793 mmol) in methanol (38 mL) was heated at 100 ° C for 6 h in a sealed test tube. After cooling, the solvent was removed under reduced pressure and the residue was diluted in ethyl acetate. The mixture was washed with saturated sodium bicarbonate aqueous solution and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-20% heptane / ethyl acetate) to provide the title compound (1.378 g, 86% yield) as a white solid.

[0541] LCMS(MH)RT=0.724min,m / z=275.9-277.9(M+H) + .

[0542] Skeleton S7: 3-bromo-5-chloro-6-fluoro-pyrazolo[1,5-a]pyrimidine

[0543]

[0544] Step 1

[0545] 1H-pyrazol-3-ylamine (4.664 g, 56.129 mmol) and sodium ethoxide solution (21% by weight in ethanol) (42 mL, 112.258 mmol) were added to a mixture of 2-fluoro-malonic acid diethyl ester (10 g, 56.129 mmol) in ethanol (170 mL). The reaction mixture was heated at 120 ° C for 30 h. The reaction mixture was concentrated under reduced pressure and co-evaporated with toluene. 1M HCl solution (100 mL) was added to the residue. Water was added to the reaction mixture and the precipitate was filtered. The precipitate was suspended in acetonitrile and evaporated to dryness. The residue was suspended in toluene and evaporated to dryness under reduced pressure to provide the title compound (6.85 g, 72% yield) as a light brown solid, which was used without further purification.

[0546] LCMS(MH)RT=0.100min,m / z=170.1(M+H) + .

[0547] Step 2

[0548] To a mixture of the title compound from step 1 (6.85 g, 40.504 mmol) and phosphorus (V) oxychloride (50 mL, 263.276 mmol) was slowly added diethyl-phenyl-amine (11 mL, 56.706 mmol) at 0°C. The reaction mixture was warmed to room temperature and then heated at 120°C for 3 h. After cooling, the reaction mixture was co-evaporated with toluene under reduced pressure. The crude residue was diluted with ethyl acetate and cooled to 0°C. Saturated aqueous sodium bicarbonate solution was slowly added. The reaction mixture was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 5-20% heptane / ethyl acetate) to provide the title compound (5.107 g, 61% yield) as a white solid.

[0549] LCMS(MH)RT=0.664min,m / z=206.0-207.9(M+H) + .

[0550] Step 3

[0551] N-bromosuccinimide (3.797 g, 21.334 mmol) was added portionwise to a mixture of the title compound (4.395 g, 21.334 mmol) from step 2 in acetonitrile (64 mL) at 0 ° C. The reaction mixture was stirred for 30 min. A saturated aqueous sodium bicarbonate solution was added, and the reaction mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 5-20% heptane / ethyl acetate) to provide the title compound (5.796 g, 95% yield) as a yellow solid.

[0552] LCMS(MH)RT=0.859min,m / z=283.9-285.9(M+H) + .

[0553] Step 4

[0554] The title compound (5.79 g, 20.344 mmol) from step 3 in ammonia (100 mL) was stirred at room temperature for 16 h. The reaction mixture was evaporated under reduced pressure. The residue was diluted with ethyl acetate and aqueous sodium carbonate. After separation, the aqueous phase was extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 10-50% heptane / ethyl acetate) to provide the title compound (4.10 g, 76% yield) as a slightly yellow solid.

[0555] LCMS(MH)RT=0.615min,m / z=265-267(M+H) + .

[0556] Step 5

[0557] Isoamyl nitrite (5.133 mL, 38.122 mmol) was added to a solution of the title compound (5.060 g, 19.061 mmol) from step 4 in dioxane (50 mL). The reaction mixture was heated at 110 ° C for 2 h. After cooling, the reaction mixture was concentrated under reduced pressure and the crude material was washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product was purified by silica gel chromatography (elution gradient 10-20% heptane / ethyl acetate) to provide the expected compound (2.158 g, 45% yield) as a yellow solid.

[0558] LCMS(MH)RT=0.707min,m / z=249.9-251.9(M+H) + .

[0559] Skeleton S8: 3-bromo-5-chloro-6-(dibromomethyl)pyrazolo[1,5-a]pyrimidine

[0560]

[0561] To a solution of skeleton S5 (5.00 g, 12.479 mmol) in N,N-dimethylformamide (38 mL) was added ethylene glycol (15.5 mL, 249.580 mmol) at room temperature. The reaction mixture was stirred at 70 ° C for 20 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-20% heptane / ethyl acetate) to provide the expected compound (2.89 g, 76% yield) as a beige solid.

[0562] LCMS(MH)RT=0.703min,m / z=303.9-305.9(M+H) + .

[0563] Pyrrolidine P1: (2S,4R)-2-(Hydroxymethyl)-4-methoxypyrrolidine-1-carboxylic acid tert-butyl ester

[0564]

[0565] Step 1

[0566] To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (8.3 g, 35.892 mmol) in anhydrous acetonitrile (500 ml) was added silver (I) oxide (24.9 g, 107.67 mmol) followed by iodomethane (11.2 ml, 179.4 mmol) (cooled at 0 °C). The resulting suspension was slowly warmed to ambient temperature and stirred vigorously for 2 days. After monitoring by LCMS, the solid material was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography eluting with a heptane / EtOAc gradient (from 10:0 to 5:5) to provide the title product (8.8 g, yield: 94%) as a colorless liquid.

[0567] LCMS(MH)RT=0.691min,m / z=160.1(M-56) + .

[0568] Step 2

[0569] The title compound from step 1 (8.8 g, 33.938 mmol) was dissolved in dry THF and stirred at N 2 The mixture was cooled to 0°C under a vacuum atmosphere. Lithium aluminum hydride (2.58 g, 67.876 mmol) was added portionwise and stirred for 2 hours. After the LCMS monitoring, H 2 The reaction was quenched with 0 and filtered through a pad of celite, rinsing with EtOAc. The product was purified by flash chromatography (on silica gel) using DCM / MeOH (100: to 95:5) as eluent to afford the desired compound (6.2 g, 78.99%) as a colorless oil.

[0570] LCMS(MH)RT=0.518min,m / z=132.1(M-99) + .

[0571] Similarly, the following intermediates were prepared:

[0572]

[0573]

[0574] Pyrrolidine P3: (2S,4R)-4-(cyclobutyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0575]

[0576] Step 1

[0577] 1H-imidazole (2.438 g, 35.80 mmol) and tert-butyldimethylsilyl chloride (4.048 g, 26.85 mmol) were added to a suspension of (2S, 4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid O1-benzyl O2-methyl ester (5.0 g, 17.90 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 8 h and 1H-imidazole (2.438 g, 35.80 mmol) and tert-butyldimethylsilyl chloride (4.048 g, 26.85 mmol) were added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-20% cyclohexane / ethyl acetate) to afford (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxypyrrolidine-1,2-dicarboxylic acid 01-benzyl 02-methyl ester (6.372 g, 90% yield) as a colorless oil.

[0578] LCMS(MA)RT=3.36min,m / z=394.1(M+H) + .

[0579] Step 2

[0580] Triethylsilane (2.54 mL, 15.85 mmol) was added to a suspension of bismuth tribromide (1.423 g, 3.17 mmol) in acetonitrile (25 mL) at 0 ° C under argon. The reaction mixture was stirred at 0 ° C for 10 min, and a suspension of the title compound (4.160 g, 10.57 mmol) and cyclobutanone (3.95 mL, 52.85 mmol) in acetonitrile (12 mL) from step 1 was added. The reaction mixture was stirred at 0 ° C for 1 h and then at room temperature for 1 h. The mixture was filtered and washed with ethyl acetate. The filtrate was diluted with water and ethyl acetate. The layers were separated and the water layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-20% cyclohexane / ethyl acetate) to provide the title compound (2.03 g, 55% yield) as a light yellow oil.

[0581] LCMS(MA)RT=2.70min,m / z=334.1(M+H) + .

[0582] Step 3

[0583] To a suspension of the title compound (2.030 g, 6.09 mmol) from step 2 in methanol (35 mL) was added 10% Pd / C (200 mg) under argon. The reaction mixture was stirred at room temperature for 6 h under a hydrogen atmosphere. The reaction mixture was filtered on a celite pad and washed with methanol and ethyl acetate. The filtrate was evaporated under reduced pressure to provide the title compound (1.205 g, 99% yield) as a colorless oil, which was used in the next step without further purification.

[0584] 1 H NMR (400 MHz, CDCl 3 )4.07-3.91(3H,m),3.75-3.75(3H,s),3.15-3.10(1H,m),3.03-2.98(1H,m),2.59( 1H,s),2.26-2.17(3H,m),2.05-1.85(3H,m),1.74-1.65(1H,m),1.57-1.46(1H,m).

[0585] Step 4

[0586] To a solution of the title compound from step 3 (1.205 g, 6.05 mmol) in tetrahydrofuran (90 mL) were added triethylamine (2.53 mL, 18.15 mmol), DMAP (74 mg, 0.61 mmol) and Boc 2 The mixture was stirred at 70 °C for 16 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-20% cyclohexane / ethyl acetate) to provide the title compound (1.460 g, 81%) as a light yellow oil.

[0587] 1 H NMR (400 MHz, CDCl 3 )4.44-4.32(1H,m),4.11-4.05(1H,m),4.00-3.91(1H,m),3.75(3H,m),3.63-3.41(2H,m),2. 32-2.18(3H,m),2.09-1.92(3H,m),1.74-1.66(1H,m),1.56-1.51(1H,m),1.48-1.41(9H,m).

[0588] Step 5

[0589] Sodium borohydride (369 mg, 9.76 mmol) and calcium chloride (542 mg, 4.88 mmol) were added to a suspension of the title compound (1.460 g, 4.88 mmol) from step 4 in a mixture (44 mL) of EtOH / THF 1:1 cooled at 0 ° C. The solution was warmed to room temperature and stirred at room temperature for 2 h. The reaction mixture was quenched by adding water and 1M HCl aqueous solution until pH = 4. EtOAc was added. The layers were separated. The aqueous layer was extracted with EtOAc (3x40 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using cyclohexane / EtOAc 100:0 to 50:50 as eluent.

[0590] The desired fractions were collected and evaporated under reduced pressure to afford the desired compound (1.242 g, 4.58 mmol, 94%) as a colorless oil.

[0591] 1 H NMR (400 MHz, CDCl 3 ),4.14-4.06(1H,m),4.00-3.90(2H,m),3.72(1H,dd,J=2.4,11.5Hz),3.59-3.54(2H,m),3.38(1H,dd,J =4.6,12.0Hz),2.27-2.19(2H,m),2.13-1.89(3H,m),1.75-1.64(2H,m),1.55-1.51(1H,m),1.49(9H,m).

[0592] Similarly, the following intermediates were prepared:

[0593]

[0594]

[0595] Pyrrolidine P6: tert-butyl (2S,4R)-2-(hydroxymethyl)-4-(trideuteromethoxy)pyrrolidine-1-carboxylate

[0596]

[0597] Step 1

[0598] To a solution of (2S, 4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (3.2 g, 13.046 mmol) dissolved in dry tetrahydrofuran (65 mL) was added sodium hydride (60% dispersion in mineral oil) (1.044 g, 26.092 mmol) at 0°C. The reaction mixture was stirred for 45 min. Iodomethane-d3 (1.624 g, 26.092 mmol) was added and the reaction mixture was stirred for 30 min. The reaction mixture was quenched with water at 0°C and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-50% heptane / ethyl acetate) to provide the title compound (2.6 g, 39% yield) as a white solid.

[0599] LCMS(MH)RT=0.736min,m / z=163.1(M+H) + -Boc.

[0600] Step 2

[0601] Borane dimethyl sulfide complex solution (2.0M / THF) (15mL) was added dropwise to the title compound (2.6g, 10.471mmol) from step 1 at 0°C. The mixture was stirred at room temperature for 16h. The reaction mixture was carefully quenched with methanol at 0°C. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-40% heptane / ethyl acetate) to provide the expected compound (2.2g, 90% yield) as a colorless oil.

[0602] LCMS(MH)RT=0.534min,m / z=135.1(M+H) + -Boc.

[0603] Similarly, the following intermediates were prepared:

[0604]

[0605] Pyrrolidine P9: (2S,4R)-4-cyclopropyloxy-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0606]

[0607] Step 1

[0608] To a suspension of benzyl chloroformate (23.4 mL, 166.8 mmol) in THF / water (100 mL / 50 mL) was added potassium carbonate (46.11 g, 333.6 mmol) carefully under vigorous stirring, followed by the addition of (2S, 4R)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride (16.15 g, 111.2 mmol). The reaction mixture was stirred at room temperature for 2 h. After complete conversion was monitored by LCMS, the mixture was acidified with 1 M aqueous HCl until pH = 1. The layers were separated. The aqueous layer was extracted with EtOAc (3x100 mL) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column using cyclohexane / EtOAc (100:0 to 0:100) as eluent to provide the title compound (20.58 g, 66% yield) as a yellow oil.

[0609] LCMS(MA)RT=1.93min,m / z=280.1(M+H) +

[0610] Step 2

[0611] Under argon, palladium acetate (II) (787mg, 3.50mmol) and 1,10-phenanthroline (695mg, 3.85mmol) are dissolved in dry dichloromethane (40mL), and the resulting solution is stirred at room temperature for 10min. Ethyl vinyl ether (140mL) is then added. The solution is degassed by bubbling with argon for 10min. The reaction mixture is stirred at room temperature for 15min, and the argon atmosphere solution of the title compound (9.79g, 35.05mmol) from step 1 in dry dichloromethane (110mL) is added. The reaction mixture is refluxed and stirred overnight. After being completely converted by TLC plate monitoring, the reaction mixture is cooled to room temperature and diluted with water (100mL). The water layer is extracted with DCM (3x60mL). The combined organic layer is dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using cyclohexane / EtOAc (100:0 to 50:50) as eluent to afford the title compound as a light yellow oil (6.796 g, 64%).

[0612] LCMS(MA)RT=2.56min,m / z=306.1(M+H) +

[0613] Step 3

[0614] Under an argon atmosphere, diiodomethane (6.94 mL, 85.53 mmol) in DCM (60 mL) was added dropwise to a suspension of a 1M diethylzinc solution (86.0 mL, 85.53 mmol) in DCM (300 mL) cooled at 0 ° C. The reaction mixture was stirred at 0 ° C for 30 min. The title compound (8.70 g, 28.51 mmol) from step 2 in DCM (100 mL) was then added dropwise at 0 ° C. The mixture was warmed to room temperature and stirred at room temperature overnight. LCMS monitoring showed partial conversion, and the mixture was further stirred at room temperature for 10 h. The reaction mixture was quenched by adding saturated aqueous ammonium chloride solution (150 mL). The layers were separated and the water layer was extracted with DCM (3x100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide the title compound (6.69 g, 74% yield) as a colorless oil. The crude product was used directly in the next step without further purification.

[0615] LCMS(MA)RT=2.55min,m / z=320.1(M+H) +

[0616] Step 4

[0617] Under argon, 10% palladium on carbon (275 mg) was added to a suspension of the title compound (2.83 g, 8.88 mmol) from step 3 in methanol (50 mL). The reaction mixture was stirred at room temperature for 4 h under a hydrogen atmosphere. After complete conversion was monitored by TLC plates, the mixture was filtered on diatomaceous earth and washed with MeOH and EtOAc. The filtrate was evaporated under reduced pressure to provide the title compound (1.54 g, 94% yield) as a colorless oil. The crude product was used directly in the next step without further purification.

[0618] 1 H NMR (400MHz, DMSO) δ4.11-4.06(1H,m),3.75(1H,t,J=7.8Hz),3.62(3H,s),3.28-3.23(1H,m),2.95(1H,dd,J=4. 7,11.5Hz),2.84(1H,qd,J=1.3,11.6Hz),2.67(1H,s),2.08-2.01(1H,m),1.90-1.83(1H,m),0.48-0.41(4H,m);

[0619] Step 5

[0620] To a solution of the title compound from step 4 (1.54 g, 8.31 mmol) in THF (125 mL) was added Et3N (3.48 mL, 24.94 mmol), DMAP (101 mg, 0.83 mmol), and then Boc 2 The product was purified by silica gel chromatography using cyclohexane / EtOAc (100:0 to 50:50) as eluent to provide the title compound (1.52 g, 64% yield) as a light yellow oil.

[0621] 1 H NMR(400MHz,DMSO)δ4.18-4.13(2H,m),3.67(3H,s),3.45(2H,dd,J=4.5,7.5Hz),3.3 3-3.29(1H,m),2.39-2.28(1H,m),2.03-1.92(1H,m),1.34(9H,s),0.50-0.43(4H,m);

[0622] Step 6

[0623] Sodium borohydride (404 mg, 10.68 mmol) and calcium chloride (593 mg, 5.34 mmol) were added to a suspension of the title compound (1.52 g, 5.34 mmol) from step 5 in a mixture (50 mL) of EtOH / THF 1:1 cooled at 0 ° C. The solution was warmed to room temperature and stirred at room temperature for 1 h. The reaction mixture was quenched by adding water and 1M HCl aqueous solution until pH=4. EtOAc was added. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using cyclohexane / EtOAc (100:0 to 50:50) as eluent to provide the expected compound (1.30 g, 95% yield) as a colorless oil.

[0624] 1 H NMR (400MHz, DMSO) δ4.71 (1H, t, J = 5.7Hz), 4.15-4.10 (1H, m), 3.73 (1H, s), 3.47-3 .43(3H,m),3.28-3.23(2H,m),2.08-1.92(2H,m),1.40(9H,s),0.48-0.42(4H,m).

[0625] Pyrrolidine P10: (2S)-2-(Hydroxymethyl)-4-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0626]

[0627] Step 1

[0628] Borane-methyl sulfide complex (30 mL) was added to (2S, 4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (10 g, 43.243 mmol) at 0°C under a nitrogen atmosphere. The mixture spontaneously began to generate heat with effervescence. The mixture was kept stirring at room temperature for 16 h. Methanol was added slowly and dropwise at 0°C until bubbling stopped, and the mixture was concentrated under vacuum to provide the title compound (9.3 g, yield: 99%) as a colorless oil. The crude material was used as is in the next step. LCMS (MH) RT = 0.340 min, m / z = 162.1 (M-56) / 118.2 (M-100)

[0629] Step 2

[0630] To a solution of the title compound from step 1 (9.17 g, 42.206 mmol) in DMF (130 mL) was added imidazole (5.75 g, 84.41 mmol) followed by tert-butylchlorodiphenylsilane (11.93 mL, 46.427 mmol) at 0°C and stirred for 16 h. After complete conversion as monitored by LCMS, saturated NaHCO 3 solution (200 mL), and the mixture was extracted with EtOAc (4 x 100 mL). The combined organic layers were purified by MgSO 4 Dried, filtered and concentrated under vacuum.The crude was purified on silica gel column using heptane / EtOAc (from 100.0 to 40:60) as eluent to afford the desired compound (3.75 g, yield: 19.5%) as yellowish gum.

[0631] LCMS(MH)RT=1.396min,m / z=356.1(M-100)

[0632] Step 3

[0633] To a solution of the title compound from step 2 (3.75 g, 8.23 ​​mmol) in DCM (40 mL) was added portionwise Dess-Martin periodinane (6.981 g, 16.458 mmol) at room temperature and stirring was maintained for 16 h.

[0634] Add saturated NaHCO 3Aqueous solution (100 mL) was added and the mixture was extracted with DCM. The combined organic layers were purified by MgSO 4 Dried, filtered and concentrated under vacuum.The product was purified on silica gel column using heptane / EtOAc (80:20) as eluent to afford the desired compound (3.6 g, yield: 96%) as colorless gum.

[0635] LCMS(MH)RT=1.478min, m / z=354.1(M-100) / 320.0(M-259)

[0636] Step 4

[0637] To triphenylphosphonium chloride (5.78 g, 16.88 mmol) in dry THF (25 ml) was added portionwise a 1 M solution of potassium bis(trimethylsilyl)amide in THF (17 ml, 16.884 mmol) at -78 °C and stirred for 30 min. To the mixture was added the title compound from step 3 (3.83 g, 8.442 mmol) in dry THF (15 ml). The resulting mixture was stirred at the same temperature for 1 h. After complete conversion as monitored by LCMS, saturated NaHCO 3 The solution was added into a water solution (100 mL) and extracted with EtOAc (4 x 50 mL). The combined organic layers were washed with MgSO 4 Dried, filtered and concentrated under vacuum.The product was purified on silica gel column using heptane / EtOAc (93:7) as eluent to afford the desired compound (3.06 g, yield: 75%) as yellowish viscous oil.

[0638] LCMS(MH)RT=1.650min,m / z=382.1(M-100)

[0639] Step 5

[0640] To a solution of the title compound from step 4 (3.03 g 6.298 mmol) in ethyl acetate (20 mL) was added 10% wet activated carbon palladium (0.5 g) and purged with a hydrogen atmosphere (balloon) and stirred at room temperature for 16 h. After complete conversion monitored by LCMS, the mixture was filtered through a pad of celite and rinsed with EtOAc. The solvent was removed on a rotary evaporator. The crude was dried under high vacuum to provide the desired compound (2.95 g, yield: 96.83%) as a yellow gum, which was used as is in the next step.

[0641] LCMS(MH)RT=1.645min,m / z=384.1(M-100)

[0642] Step 6

[0643] To the title compound from step 5 (2.95 g, 6.098 mmol) in THF (40 ml) was added 1 M tetrabutylammonium fluoride in THF (18.3 mL) at room temperature and stirred for 16 h. The mixture was diluted with EtOAc (100 mL) and washed with saturated NaHCO 3 The organic layer was washed with MgSO 4 Dried, filtered and concentrated under vacuum.The crude was purified on silica gel column using heptane / EtOAc (80:20) as eluent to afford the desired product (1.29 g, yield: 86%) as colorless oil.

[0644] LCMS(MH)RT=0.595min,m / z=190.1(M-56) / 146.1(M-100)

[0645] Pyrrolidine P15: (4R)-2-(Hydroxymethyl)-4-methoxy-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0646]

[0647] Step 1

[0648] To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (8.3 g, 35.892 mmol) in anhydrous acetonitrile (500 ml) was added silver (I) oxide (24.9 g, 107.67 mmol) followed by iodomethane (11.2 ml, 179.4 mmol) (cooled at 0 °C). The resulting suspension was slowly warmed to ambient temperature and stirred vigorously for 2 days. After monitoring by LCMS, the solid material was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography eluting with a heptane / EtOAc gradient (from 10:0 to 5:5) to provide the title product (8.8 g, yield: 94%) as a colorless liquid.

[0649] LCMS(MH)RT=0.691min,m / z=160.1(M-56) + .

[0650] Step 2

[0651] 2.5M n-butyl lithium (6.94 mL, 17.35 mmol) in n-hexane was added dropwise to a solution of diisopropylamine (2.44 mL, 17.35 mmol) in THF (100 mL) at 5 ° C and stirred for 10 min. The mixture was then cooled to -35 ° C and combined with a solution of the title compound (3.00 g, 11.57 mmol) from step 1 in THF (100 mL). The mixture was stirred at 0 ° C for 1 h and then cooled to -78 ° C. Iodomethane (1.080 mL, 17.35 mmol) was added dropwise, and the mixture was stirred at -78 ° C for 4 h. 10 mL of saturated ammonium chloride solution was then added dropwise, and the mixture was heated to room temperature. It was then mixed with water and extracted 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated under vacuum. The residue was purified by column chromatography using cyclohexane / EtOAc (80 / 20) as eluent to afford the title compound (1.548 g, 5.66 mmol, 49% yield) as a yellow oil.

[0652] Step 3

[0653] Sodium borohydride (0.428 g, 11.33 mmol) and calcium chloride (0.629 g, 5.66 mmol) were added to a suspension of the title compound (1.55 g, 5.66 mmol) from step 2 in a mixture of EtOH / THF (30 mL / 30 mL) cooled at 0 ° C. The solution was warmed to room temperature and stirred at room temperature for 1 h. The reaction mixture was quenched by adding water and 1M aqueous HCl until pH = 4. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 60 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using cyclohexane / EtOAc (100 / 0 to 60 / 40) as eluent to provide the expected product (0.782 g, 3.19 mmol, 56% yield) as a colorless oil.

[0654] 1 H NMR(400MHz,DMSO)4.77-4.68(1H,m),3.85-3.79(1H,m),3.72-3.36(3H,m),3.31-3.23(1H,m),3 .22-3.20(3H,m),2.33-2.13(1H,m),1.77-1.65(1H,m),1.39(9H,d,J=3.8Hz),1.28-1.22(3H,m).

[0655] Pyrrolidine P16: (4R)-2-(1-hydroxyethyl)-4-methoxypyrrolidine-1-carboxylic acid tert-butyl ester

[0656]

[0657] Step 1

[0658] Dimethyl sulfoxide (2.84 mL, 40 mmol) was added dropwise via a syringe to a stirred solution of 2M oxalyl chloride solution (10 mL, 20 mmol) in dichloromethane (100 mL) in DCM at -78 ° C. The mixture was stirred at -78 ° C for 10 min and a solution of pyrrolidine P1 (2.31 g, 10 mmol) in dichloromethane (25 mL) was added. The mixture was stirred at -78 ° C for 15 minutes, and triethylamine (4.30 mL, 40 mmol) was added. After 15 minutes, the reaction mixture was warmed to 0 ° C and stirred at this temperature for 30 minutes. The mixture was washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using cyclohexane / EtOAc (0-50%) to provide the title compound (diastereoisomer mixture) (2.44 g) as a colorless oil.

[0659] Dia1: 1 H NMR (400 MHz, CDCl 3 )9.45(1H,d,J=3.8Hz),4.23-4.17(1H,m),3.98-3.93(1H,m),3.75(1H,d,J=12.0Hz) ,3.57-3.49(1H,m),3.35(3H,s),2.29-2.19(1H,m),2.00-1.89(1H,m),1.45(9H,s).

[0660] Dia2: 1 H NMR (400 MHz, CDCl 3 )9.57(1H,d,J=2.7Hz),4.32(1H,t,J=8.1Hz),3.98-3.93(1H,m),3.57-3. 49(2H,m),3.35(3H,s),2.29-2.19(1H,m),2.00-1.89(1H,m),1.49(9H,s).

[0661] Step 2

[0662] To a solution of the title compound from step 1 (1.63 g, 7.10 mmol) in anhydrous ether (105 mL) cooled to 0 ° C was added methylmagnesium bromide (3M in ether; 5.92 mL, 17.77 mmol) via a syringe under a nitrogen atmosphere, and the resulting solution was stirred at 0 ° C for 2 hours. The reactant was quenched with a saturated ammonium chloride solution and extracted with ether. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane / EtOAc (100 / 0 to 50 / 50) to provide the expected compound (diastereoisomer mixture) (150 mg, 0.611 mmol) as a colorless oil.

[0663] Dia1: 1 H NMR (400 MHz, CDCl 3 ),4.06-3.68(4H,m),3.32-3.31(4H,m),2.17-2.09(1H,m),1.82-1.68(1H,m),1.50(9H,s),1.15(3H,d,J=6.6Hz).

[0664] Dia2: 1 H NMR (400 MHz, CDCl 3 ),4.06-3.68(4H,m),3.32-3.31(4H,m),2.17-2.09(1H,m),1.82-1.68(1H,m),1.50(9H,s),1.09(3H,d,J=6.7Hz).

[0665] Intermediate I1: 1-(3-bromo-5-nitrophenyl)-5-methyl-1H-pyrazole

[0666]

[0667] Step 1

[0668] In a sealed test tube, 1-bromo-3-iodo-5-nitrobenzene (3.0 g, 9.149 mmol) was dissolved in DMSO (9 mL). Tert-butyl carbazate (1.451 g, 10.979 mmol), cesium carbonate (4.471 g, 13.723 mmol) and cuprous (I) iodide (174 mg, 0.915 mmol) were added, and the reaction mixture was stirred at 50 ° C for 4 h. Water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-15% heptane / ethyl acetate) to provide tert-butyl 1-(3-bromo-5-nitrophenyl) hydrazine-1-carboxylate (1.045 g, 34% yield) as a brown sticky solid.

[0669] LCMS(MH)RT=1.044min,m / z=275.9-277.9(M+H) + .

[0670] Step 2

[0671] The title compound from step 1 (1.040 g, 3.131 mmol) was dissolved in HCl (4M / dioxane) (10 mL). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure to provide crude (3-bromo-5-nitrophenyl)hydrazine dihydrochloride (950 mg, 100% yield) as a brown solid, which was used without further purification.

[0672] LCMS(MH)RT=0.518min,m / z=231.9-233.9(M+H) + .

[0673] Step 3

[0674] To a solution of the title compound (950 mg, 3.131 mmol) from step 2 in ethanol (12 mL) was added triethylamine (1.306 mL, 9.39 mmol) followed by ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (696 mg, 3.757 mmol) at room temperature. The reaction mixture was heated at 100 ° C for 2 h. After cooling, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluting solvent 80 / 20% heptane / ethyl acetate) to provide ethyl 1-(3-bromo-5-nitrophenyl)-5-methyl-1H-pyrazole-4-carboxylate (780 mg, 75% yield) as an orange solid.

[0675] LCMS(MH)RT=1.026min,m / z=353.9-356.0(M+H) + .

[0676] Step 4

[0677] In a pressure flask, acetic acid / HBr (3: 1) (7 mL) was added to the title compound from step 3 (780 mg, 2.202 mmol), and the mixture was heated at 150 ° C for 5 days. After cooling, the solvent was removed under reduced pressure and the crude residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent 90 / 10% heptane / ethyl acetate) to provide the expected compound (300 mg, 48% yield) as a brown solid.

[0678] LCMS(MH)RT=0.896min,m / z=281.9-283.9(M+H) + .

[0679] Intermediate I2: 1-Bromo-3-nitro-5-(propan-2-yloxy)benzene

[0680]

[0681] To a solution of 3-bromo-5-nitro-phenol (5.0 g, 22.9 mmol) in acetone (100 mL) potassium carbonate (4.75 g, 34.4 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 10 min. 2-iodopropane (4.0 mL, 68.70 mmol) was then added, and the reaction mixture was heated at 70 ° C for 5 h. The reaction mixture was cooled to room temperature. Insoluble matter was filtered out and washed with acetone. The filtrate was concentrated under reduced pressure to provide the expected compound (6.0 g, 100% yield) as a yellow liquid.

[0682] LCMS(MA)RT=3.12min,m / z=260.1(M+H) + .

[0683] Intermediate I3: 1-(Benzyloxy)-3-bromo-5-nitrobenzene

[0684]

[0685] To a solution of 3-bromo-5-nitro-phenol (20 g, 91.74 mmol) in acetone (200 mL) was added potassium carbonate (19.02 g, 137.61 mmol) portionwise. The reaction mixture was stirred at room temperature for 10 min. Bromomethylbenzene (11.46 mL, 96.33 mmol) was then added, and the reaction mixture was heated at 70 ° C for 2 h. The reaction mixture was cooled to room temperature. The insoluble matter was filtered out and washed with acetone. The filtrate was concentrated under reduced pressure to provide the desired compound (28.3 g, 100% yield) as a cream solid.

[0686] 1 H NMR (400 MHz, CDCl 3 )8.01-7.99(1H,m),7.79-7.78(1H,m),7.48-7.44(6H,m),5.16(2H,s).

[0687] Intermediate I4: a mixture of 1-(3-bromo-5-nitrophenyl)-1H-pyrazole and 1-(3-iodo-5-nitrophenyl)-1H-pyrazole

[0688]

[0689] In a pressure flask, 3-bromo-5-iodonitrobenzene (7.2 g, 21.958 mmol), pyrazole (1.495 g, 21.958 mmol), copper (I) iodide (836 mg, 4.392 mmol), trans-N, N'-dimethylcyclohexane-1,2-diamine (1.249 mL, 21.958 mmol) and cesium carbonate (21.67 g, 65.67 mmol) were placed in DMF (45 mL). The reaction mixture was bubbled with a stream of nitrogen for 5 min, and the mixture was stirred at 50 ° C for 12 h. The reaction mixture was filtered on a celite pad and rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-20% heptane / ethyl acetate) to provide a mixture of the expected compound and 1-(3-iodo-5-nitrophenyl)-1H-pyrazole as a brown solid (3.3 g, 25% yield).

[0690] LCMS(MH)RT=0.902min,m / z=267.9-269.9(M+H) + and RT = 0.942 min, m / z = 315.9 (M+H) + .

[0691] Intermediate I5: tert-butyl N-(3-bromo-5-iodophenyl)carbamate

[0692]

[0693] Diphenylphosphoryl azide (21.7 mL, 100.95 mmol) was added to a stirred solution of 3-bromo-5-iodo-benzoic acid (30 g, 91.77 mmol) in dry tert-butyl alcohol (150 mL) and triethylamine (16.6 mL, 119.30 mmol) under argon. The reaction mixture was refluxed at 80 ° C under argon for 16 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 10% sodium hydroxide solution, water and brine in succession. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent 90 / 10% cyclohexane / ethyl acetate) to provide the expected compound (32.2 g, 88% yield) as a slightly yellow amorphous solid.

[0694] 1 H NMR (400MHz, DMSO) 9.66 (1H, s), 7.86 (1H, t, J = 1.6 Hz), 7.70 (1H, t, J = 1.8 Hz), 7.50 (1H, t, J = 1.6 Hz), 1.48-1.47 (9H, m).

[0695] Prepare similarly:

[0696]

[0697]

[0698] Intermediate I7: tert-butyl N-{3-bromo-5-[2-(triethylsilyl)ethynyl]phenyl}carbamate

[0699]

[0700] To a solution of intermediate I5 (32.2 g, 80.9 mmol) in dry tetrahydrofuran (250 mL) was added (triethylsilyl)acetylene (21.74 mL, 121.35 mmol), bis(triphenylphosphine)palladium(II) dichloride (2.84 g, 4.045 mmol), cuprous iodide (770 mg, 4.045 mmol) and triethylamine (33.83 mL, 242.7 mmol) under argon. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent 90 / 10% cyclohexane / ethyl acetate) to afford the desired compound (27.1 g, 82% yield) as a brown oil.

[0701] 1 H NMR (400 MHz, CDCl 3)7.63(1H,m),7.45-7.37(1H,m),7.30-7.27(1H,m),6.47-6.43(1H,m),1.54-1.53(9H,m),1.08-1.03(9H,m),0.71-0.65(6H,m).

[0702] Intermediate I8: 3-bromo-5-(propan-2-yloxy)aniline

[0703]

[0704] Tin (II) chloride dihydrate (20.7 g, 91.6 mmol) was added portionwise to a solution of intermediate I2 (6.0 g, 22.9 mmol) in ethanol (140 mL). The reaction mixture was heated under reflux for 2 h. The reaction mixture was poured into water. The aqueous phase was alkalized with 33% NaOH solution and stirred at room temperature for 10 min. After extraction with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 10-40% cyclohexane / ethyl acetate) to provide the desired compound (5.30 g, 100% yield) as a slightly yellow liquid.

[0705] LCMS(MA)RT=2.51min,m / z=232.1(M+H) + .

[0706] Intermediate I9:3-(Benzyloxy)-5-bromoaniline

[0707]

[0708] Tin (II) chloride dihydrate (38.08 g, 168.76 mmol) was added portionwise to a solution of intermediate I3 (13 g, 42.19 mmol) in ethanol (250 mL), and the reaction mixture was heated under reflux for 1 h. The reaction mixture was poured into water. The aqueous phase was alkalized with 33% NaOH solution and stirred at room temperature for 10 min. After extraction with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 10-40% cyclohexane / ethyl acetate) to provide the expected compound (11.35 g, 96% yield) as a light yellow oil.

[0709] LCMS(MA)RT=2.93min,m / z=280.0(M+H) + .

[0710] Intermediate I10: 3-bromo-5-[2-(triethylsilyl)ethynyl]aniline

[0711]

[0712] To a solution of intermediate I7 ​​(27.10 g, assuming 66.03 mmol) in dichloromethane (300 mL) was added trifluoroacetic acid (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluting solvent 90 / 10% cyclohexane / ethyl acetate) to provide the desired compound (18.90 g, 92% yield) as a brown solid.

[0713] LCMS(MA)RT=3.65min,m / z=351-353(M+H) + .

[0714] Intermediate I11: 5-bromo-2-fluoro-3-methoxyaniline

[0715]

[0716] To a solution of intermediate I6 (1.05 g, 3.27 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL, 26.11 mmol), and the reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to provide the desired compound (700 mg, 97% yield) as a brown solid.

[0717] LCMS(MA)RT=2.27min,m / z=220-222(M+H) + .

[0718] Intermediate I12: 3-Bromo-5-(3,5-dimethyl-1H-pyrazol-1-yl)aniline

[0719]

[0720] In a pressure flask, 3-bromo-5-iodoaniline hydrochloride (1.2 g, 3.589 mmol), 3,5-dimethylpyrazole (345 mg, 3.589 mmol), copper (I) iodide (410 mg, 2.153 mmol), DL-proline (165 mg, 1.436 mmol) and cesium carbonate (3.508 g, 10.767 mmol) in DMSO (12 mL) were bubbled with a stream of nitrogen for 1 min, and the mixture was stirred at 150 °C for 16 h. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-1.5% dichloromethane / methanol) to provide the desired compound (220 mg. 23% yield) as a brown solid.

[0721] LCMS(MH)RT=0.744min,m / z=266-268(M+H) + .

[0722] Intermediate I13: a mixture of 3-bromo-5-(1H-pyrazol-1-yl)aniline and 3-iodo-5-(1H-pyrazol-1-yl)aniline

[0723]

[0724] A mixture of intermediate I4 (3.3 g, 5.659 mmol) and ammonium chloride (1.311 g, 24.5 mmol) was dissolved in ethanol / water (4: 1) (30 mL). Iron powder (3.4 g, 28.295 mmol) was added, and the reaction mixture was stirred at 50 ° C for 88 h. The reaction mixture was diluted with ethyl acetate and filtered through a diatomaceous earth pad. The filtrate was washed with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-50% heptane / ethyl acetate) to provide a mixture of the expected compound and 3-iodo-5-(1H-pyrazole-1-yl)aniline as a brown sticky solid (1.8 g, 61% yield).

[0725] LCMS(MH)RT=0.647min,m / z=237.9-239.9(M+H) + and RT = 0.688 min, m / z = 286.0 (M+H) + .

[0726] Intermediate I14: 3-bromo-5-(5-methyl-1H-pyrazol-1-yl)aniline

[0727]

[0728] To a stirred solution of intermediate I1 (300 mg, 1.063 mmol) in ethanol / water (5: 1) (11 mL) was added ammonium chloride (398 mg, 7.441 mmol) and iron powder (297 mg, 5.315 mmol). The reaction mixture was stirred at 50 ° C for 4 h. The reaction mixture was filtered on a celite pad and rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-25% heptane / ethyl acetate) to provide the desired compound (200 mg, 75% yield) as a brown solid.

[0729] LCMS(MH)RT=0.669min,m / z=252.0-253.9(M+H) + .

[0730] Intermediate I15: 3-amino-5-bromobenzoic acid methyl ester

[0731]

[0732] To a solution of 3-amino-5-bromobenzoic acid (5.00 g, 23.144 mmol) in methanol (93 mL) was added thionyl chloride (25.184 mL, 347.16 mmol) dropwise at 0 °C under a nitrogen atmosphere. The reaction mixture was warmed to room temperature and then stirred at 70 °C for 4 h. The solvent was evaporated under reduced pressure and then co-evaporated with heptane. The residue was dried under reduced pressure to provide methyl 3-amino-5-bromobenzoate (7.85 g, 100% yield) as a beige solid, which was used without further purification.

[0733] LCMS(MH)RT=0.692min,m / z=230-232(M+H) + .

[0734] Intermediate I16: 3-bromo-5-(1-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}-1H-pyrazol-4-yl)aniline

[0735]

[0736] Step 1

[0737] 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethanol (1.08 g, 4.52 mmol), tetrakis(triphenylphosphine)palladium(0) (87 mg, 0.07 mmol), Xphos (72 mg, 0.15 mmol) and tripotassium phosphate (2.40 g, 11.31 mmol) were added to a suspension of intermediate I5 (1.50 g, 3.77 mmol) in dioxane / water (48 / 12 mL). The reaction mixture was degassed by bubbling under argon for 10 min and stirred at 100 ° C for 1 h. The resulting mixture was cooled to room temperature. The solvent was evaporated under reduced pressure. The residue was purified by flash chromatography using cyclohexane / EtOAc (100:0 to 0:100) as eluent. The desired fractions were combined and evaporated under reduced pressure to afford the title compound as a yellow oil (1.63 g, quant.).

[0738] LCMS(MA)RT=2.46min,m / z=382.1 / 384.1(M+H) + .

[0739] Step 2

[0740] Imidazole (544mg, 8.00mmol) and tert-butyldiphenylchlorosilane (1.56mL, 6.00mmol) are added to a solution of the title compound (1.53g, 4.00mmol) from step 1 in THF (15mL). The mixture is stirred at room temperature for 1h. After complete conversion is monitored by LCMS, water and EtOAc are added and the layers are separated. The aqueous layer is extracted with EtOAc (2x 20mL) and the combined organic layer is dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue is purified by silica gel column chromatography using cyclohexane / EtOAc (100:0 to 50:50) as eluent to provide the title compound (1.91g, 77%) as a light yellow foam.

[0741] LCMS(MA)RT=3.83min,m / z=620.2 / 622.2(M+H) + .

[0742] Step 3

[0743] To a solution of the title compound from step 2 (1.91 g, 3.07 mmol) in DCM (45 mL) was added 4 M HCl in 1,4-dioxane (2.30 mL, 9.22 mmol). The mixture was stirred at room temperature for 5 h. LCMS monitoring indicated partial conversion, so additional 4 M HCl in 1,4-dioxane (1.50 mL, 6.14 mmol, 2 eq) was added and the mixture was stirred at room temperature overnight. After complete conversion as monitored by LCMS, the mixture was washed with saturated NaHCO 3 The solution was quenched carefully. Separate the layers. The aqueous layer was extracted with DCM (2x20mL) and the combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column using cyclohexane / EtOAc (100:0 to 60:40) as eluent to provide the title compound (1.39 g, 88% yield) as an orange oil.

[0744] LCMS(MA)RT=3.44min,m / z=520.2 / 522.2(M+H) + .

[0745] Aniline A1:3-Fluoro-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0746]

[0747] A mixture of 3-bromo-5-fluoroaniline (21.2 g, 111.61 mmol), bis(pinacolato)diboron (28.34 g, 111.61 mmol), potassium acetate (32.86 g, 334.83 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.45 g, 3.90 mmol) in 1,4-dioxane (120 mL) was purged with argon and then heated at 90° C. for 16 h. The hot reaction mixture was filtered through Whatmann filter paper. The filtrate was diluted in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, then filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-20% pentane / ethyl acetate). The residue was ground in n-heptane, then filtered and dried to provide the desired compound (11.73 g, 44% yield) as a beige solid.

[0748] LCMS(MA)RT=2.53min,m / z=238.2(M+H) + .

[0749] Prepare similarly:

[0750]

[0751]

[0752]

[0753] Aniline A20: 3-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0754]

[0755] Step 1

[0756] Diphenylphosphoryl-azide (14.5mL, 67.30mmol) was added to a stirred solution of 3-bromo-5-iodo-benzoic acid (20.0g, 61.18mmol) in dry tert-butyl alcohol (100mL) and triethylamine (11.0mL, 79.53mmol) under argon. The reaction mixture was refluxed (80°C) overnight under argon. The reaction mixture was cooled to room temperature and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (50mL) and washed with 10% NaOH solution (30mL), water (2x50mL) and brine in succession. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo. The crude residue was purified by silica gel chromatography using cyclohexane / EtOAc (90:10) as eluent to provide the title compound (16.2g, 67% yield) as a yellow amorphous solid.

[0757] LCMS(MA)RT=3.38min,m / z=341.8 / 343.8(M+H) + .

[0758] Step 2

[0759] Cyclopropylboronic acid (842mg, 9.80mmol), palladium (II) acetate (85mg, 0.38mmol), tricyclohexylphosphine (211mg, 0.75mmol) and tripotassium phosphate (4.801g, 22.62mmol) were added to a suspension of the title compound (3.0g, 7.54mmol) from step 1 in toluene / water (36 / 6mL). The reaction mixture was degassed by bubbling under argon for 10min and stirred at 110°C for 39h. After 95% conversion was monitored by LCMS, the mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified on a silica gel column using cyclohexane / EtOAc (100:0 to 85:15) as eluent. A second purification on a silica gel column was performed using cyclohexane / EtOAc (100:0 to 90:10) as eluent to provide the title compound (1.26g, 53% yield) as an orange oil.

[0760] LCMS(MA)RT=3.16-3.22min,m / z=312.2 / 314.1(M+H) + .

[0761] Step 3

[0762] To a solution of the title compound from step 2 (1.26 g, 4.03 mmol) in DCM (60 mL) was added 4 M HCl in 1,4-dioxane (5.04 mL, 20.15 mmol). The mixture was stirred at room temperature for 8 h. After complete conversion monitored by LCMS, the mixture was washed with saturated NaHCO 3 The solution was quenched carefully. The layers were separated and the aqueous layer was extracted with DCM (2x20mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on a silica gel column using cyclohexane / EtOAc (100:0 to 90:10) as eluent to provide the title compound (660mg, 3.11mmol, 77%) as an orange oil.

[0763] LCMS(MA)RT=2.45min,m / z=212.0 / 214.0(M+H) + .

[0764] Step 4

[0765] The title compound from step 3 was further purified by column chromatography using cyclohexane / EtOAc (100:0 to 85:15) as eluent to provide 483 mg of an orange oil.

[0766] To a solution of 3-bromo-5-cyclopropyl-aniline (433 mg, 2.04 mmol) in dry 1,4-dioxane (12 mL) was added bis(pinacol)diboron (544 mg, 2.14 mmol), KOAc (600 mg, 6.12 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (42 mg, 0.05 mmol) under argon atmosphere. The reaction mixture was heated at 90°C for 3 h. LCMS monitoring indicated 50% conversion. Additional bis(pinacol)diboron (272 mg, 1.07 mmol), KOAc (300 mg, 3.06 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (42 mg, 0.05 mmol) were added and the reaction was stirred at 90°C for 5 h. The mixture was stirred for 2 hours at 4 ℃ for 10 minutes at 4 ℃ for 30 minutes.After being completely converted by LCMS monitoring, the mixture was cooled to room temperature and the solvent was evaporated under reduced pressure.Residue was diluted with saturated NaCl and EtOAc solution and separated each layer.Water layer was extracted with EtOAc (2x 20mL) and the organic layer combined was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure.Residue was purified on silica gel column using cyclohexane / EtOAc (100:0 to 85:15) as eluent, to provide the expected compound (251mg, 48% yield) as light brown foam.

[0767] LCMS(MA)RT=2.11min,m / z=260.2(M+H) + .

[0768] Example 1: (12R, 14S)-4-fluoro-12,18-dimethoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

[0769]

[0770] Step 1

[0771] To a solution of pyrrolidine P1 (2.7 g, 10.29 mmol) in dry DMF (50 mL) was added 60% sodium hydride (0.823 g, 20.57 mmol) in mineral oil at 0°C. After 30 min, framework S2 (2.617 g, 11.31 mmol) was added and the mixture was stirred at 4-5°C for 15 min. LCMS monitoring indicated complete conversion. Water was carefully added dropwise at 4-5°C and the mixture was extracted with EtOAc (4x20 mL). The combined organic layers were washed with brine and then purified by Na 2 SO 4 Dry, filter and concentrate under vacuum.The product was purified on silica gel column using cyclohexane / EtOAc (100-0-50-50) as eluent to afford the desired compound (3.498 g, 7.65 mmol, 74%) as light brown oil.

[0772] LCMS(MA)RT=2.76min,m / z=459(M+H) + .

[0773] Step 2

[0774] K 3 PO 4 A solution of (21.01 mmol, 4.46 g) in water (9 mL) was added to a solution of the title compound from step 1 (7 mmol, 3.203 g), aniline A1 (9.11 mmol, 2.159 g) and Xphos (0.28 mmol, 229 mg) in dioxane (26 mL). The reaction mixture was degassed with argon for 15 min. Pd(PPh 3 ) 4 To the mixture of 4-nitropropene (0.14mmol, 162mg), and the reactant was heated at 100°C for 3h. LC / MS monitoring showed that the reaction was complete. The reaction mixture was filtered on diatomaceous earth, and the solvent was then removed under reduced pressure. The compound was purified by flash chromatography using 120g SiO2 columns, eluted with cyclohexane / EtOAc 100 / 0 to 50 / 50, to provide the expected compound (3.395g, 6.96mmol, 99%) as a brown oil.

[0775] LCMS(MA)RT=2.61min, m / z=488.2(M+H)+.

[0776] Step 3

[0777] The title compound from step 2 (3.524 g, 7.23 mmol) was reacted in CH 3Pyridine (0.877 mL, 10.84 mmol) and 2-nitrobenzenesulfonyl chloride (2.083 g, 9.40 mmol) were added to the solution in CN (36 mL). The reaction mixture was heated at 70 °C overnight. The reaction was monitored by LCMS, indicating that the reaction was complete. The reaction mixture was poured into water. After extraction with EtOAc, the organic phase was dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude was triturated in diisopropyl ether to give the title compound (4.064 g, 6.04 mmol, 84%) as a brown oil.

[0778] LCMS(MA)RT=2.95min, m / z=673.2(M+H)+.

[0779] Step 4

[0780] To a solution of the title compound (0.500 g, 0.74 mmol) from step 3 in acetonitrile (5 mL) was added cesium carbonate (0.727 g, 2.23 mmol) and 1,2-dibromoethane (0.961 mL, 11.15 mmol). The reaction mixture was heated to reflux for 4 h. The reaction mixture was monitored by LCMS, indicating that the reaction was complete. The solvent was removed, the residue was dissolved in EtOAc (50 mL), extracted with water (50 mL), then extracted with brine (2 x 40 mL), and the organic layer was purified by anhydrous Na 2 SO 4 Dry, filter and dry under vacuum to afford the desired compound as a yellow / orange solid (0.598 g, 0.74 mmol postulated, quantitative yield).

[0781] LCMS(MA)RT=3.13min, m / z=780(M+H)+.

[0782] Step 5

[0783] To a suspension of the title compound from step 4 (0.598 g, 0.77 mmol) in DCM (5 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (1.918 mL, 7.67 mmol). The reaction mixture was stirred overnight. LCMS indicated that the reaction was complete. The solvent was removed under reduced pressure to provide the desired compound (0.622 g, assuming 0.77 mmol, quantitative yield) as a brown solid.

[0784] LCMS(MA)RT=1.97min, m / z=679(M+H)+.

[0785] Step 6

[0786] The title compound from step 5 (0.622 g, 0.87 mmol) was reacted in CH 3 To a solution in CN (62 mL) was added sodium bicarbonate (0.365 g, 4.34 mmol), cesium carbonate (0.849 g, 2.61 mmol), followed by potassium iodide (0.433 g, 2.61 mmol). The resulting mixture was heated at 90 °C for 4 h. LC / MS monitoring indicated that the reaction was complete. The reaction mixture was filtered and the solid was then purified on a silica gel column using DCM / MeOH 100 / 0 to 98 / 2 as eluent to provide the desired compound (0.106 g, 0.18 mmol, 20% yield) as a white solid.

[0787] LCMS(MA)RT=2.29min, m / z=599(M+H)+.

[0788] Step 7

[0789] The title compound from step 6 (0.106 g, 0.18 mmol) was dissolved in THF / H 2 O (9mL / 3.9mL) was added with sodium bicarbonate (0.298g, 3.54mmol). The reaction mixture was stirred at room temperature for 10min, and then iodine (0.674g, 2.66mmol) was added. The reaction mixture was stirred at 60°C for 2h. LC / MS monitoring showed that the reaction was complete. The reaction mixture was quenched with saturated sodium thiosulfate solution and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to provide the expected compound (0.118g, assuming 0.18mmol, quantitative yield) as a yellow solid.

[0790] LCMS(MA)RT=2.49min, m / z=613(M+H)+.

[0791] Step 8

[0792] The title compound (0.118g, 0.19mmol) and cesium carbonate (0.126g, 0.39mmol) from step 7 are dissolved in DMF (2mL). 4-Methylthiophenol (0.029g, 0.23mmol) is added, and the mixture is stirred at room temperature overnight. The reaction mixture is monitored by LCMS, indicating that the reaction is terminated. The reaction mixture is filtered to remove cesium carbonate. The solvent is evaporated, and the residue is purified by flash column chromatography using (DCM / MeOH 100 / 0 to 95 / 5) as eluent. The product fractions are collected and the solvent is evaporated. The residue is purified by flash column chromatography using cyclohexane / EtOAc (100 / 0 to 0 / 100) as eluent, to provide the expected product (0.008g, 10% yield) as a light yellow powder.

[0793] LCMS(MA)RT=2.15min, m / z=428(M+H)+.

[0794] LCMS (MB) RT=2.22min, m / z=428(M+H)+.

[0795] 1 H NMR(400MHz,DMSO)8.79(1H,s),8.40(1H,s),7.63(1H,s),6.73(1H,dd,J=1.2,9.2H z),6.33(1H,t,J=5.8Hz),6.22-6.17(1H,m),4.96(1H,d,J=10.4Hz),4.49-4.46(1H, m),4.36-4.31(1H,m),4.07-4.00(1H,m),3.90-3.89(3H,m),3.62-3.51(1H,m),3.42 -3.35(1H,m),3.33(3H,s),3.25-3.19(2H,m),2.50-2.40(1H,m),2.00-1.91(1H,m).

[0796] Prepare similarly:

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825] Example 44: (12R, 14S)-12-methoxy-4-(pyridin-3-ylmethoxy)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° ,23 ]pentacosane-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

[0826]

[0827] Following General Synthetic Scheme 1, as depicted for the synthesis of Example 1, the backbone 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine, pyrrolidine P1 and aniline A9 were used to obtain (12R,14S)-4-(benzyloxy)-12-methoxy-7-(2-nitrobenzenesulfonyl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.12,6.010,14.020,23]pentacosane-1(23),2,4,6(25),17(24),18,21-hepten-11-one as intermediate I18.

[0828] Step 1

[0829] A solution of intermediate I18 (1 g, 1.491 mmol) in TFA (5 mL) and anisole (15 mL) was heated at 130 °C for 4 hours. LCMS indicated that the reaction was complete. The mixture was cooled to room temperature. The solvent was evaporated under reduced pressure. The gummy residue was mixed with DCM / iPr 2 The resulting precipitate was filtered, washed with diisopropyl ether, then pentane, and dried to provide the title compound (Intermediate I19, (12R, 14S)-4-hydroxy-12-methoxy-7-(2-nitrobenzenesulfonyl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.12,6.010,14.020,23]pentacosane-1(23),2,4,6(25),17(24),18,21-hepten-11-one) as a cream solid (0.81 g, 93.6% yield).

[0830] LCMS(MA)RT=2.20min m / z=581.1(M+H) + .

[0831] Step 2

[0832] To a solution of the title compound (50 mg, 0.0861 mmol) from step 1 in DMF (3 mL) was added 3-(bromomethyl)pyridine, hydrobromide (65 mg, 0.258 mmol) and cesium carbonate (168 mg, 0.517 mmol) under nitrogen. The solution was stirred to 80 ° C for 1 h. Monitoring by LCMS indicated that the reaction was complete. The crude was evaporated under vacuum and the residue was purified by chromatography on silica gel, eluting with a gradient of (3: 1 EtOAc: EtOH) / cyclohexane from 0% to 50%, to provide the desired compound (75 mg, 65% yield) as a yellow glassy solid.

[0833] LCMS(MA)RT=2.02min m / z=672.1(M+H) + .

[0834] Step 3

[0835] To a suspension of the title compound from step 2 (75 mg, 0.112 mmol) in DMF (5 mL) was added cesium carbonate (73 mg, 0.224 mmol) and 4-methylthiophenol (17 mg, 0.134 mmol). The reaction mixture was stirred at room temperature for 2 h and then overnight. The mixture was partitioned between water and EtOAc, and the organic layer was purified by Na 2 SO 4 The residue was purified by chromatography on silica gel, eluting with a gradient of 0% to 50% (3:1 EtOAc:EtOH) / cyclohexane. The appropriate fractions were evaporated under vacuum and the residue was washed with CH 3 CN treatment, solid cream-colored crystals, which were filtered, washed with water and dried under vacuum at 60°C to afford the desired product (26 mg, 48% yield) as a cream-colored solid.

[0836] LCMS(MA)RT=1.67min m / z=487.1(M+H) + .

[0837] LCMS(MC)RT=2.10min m / z=487.1(M+H) + .

[0838] 1H NMR(400MHz, DMSO)8.97(1H,d,J=7.6Hz),8.69(1H,d,J=1.7Hz),8.56-8.51(2H,m),7.90-7.8 6(1H,m),7.52-7.42(2H,m),6.67-6.63(2H,m),6.13-6.05(2H,m),5.14-5.13(2H,m),4.92(1 H,d,J=10.8Hz),4.49-4.46(1H,m),4.36-4.30,(1H,m),3.94(1H,t,J=10.7Hz),3.58-3.48(1 H,m),3.44-3.36(1H,m),3.33(3H,s),3.25-3.16(2H,m),2.46-2.40(1H,m),2.01-1.92(1H,m)

[0839] Prepare similarly:

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850] Example 54: (12R, 14S)-4-acetyl-12-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2,4,6(25),17(24),18,21-heptaen-11-one

[0851]

[0852] Step 1

[0853] To a solution of triethylamine (0.13mL, 0.956mmol) and intermediate I19 (370mg, 0.637mmol) in dichloromethane (30mL) was added portionwise N-phenyl-bis(trifluoromethanesulfonimide) (250mg, 0.701mmol). The reaction mixture was stirred at room temperature for 5h. Water (30mL) was added to the reactant and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-50% cyclohexane / ethyl acetate) to provide the title compound (430mg, 95% yield) as a slightly yellow solid.

[0854] LCMS(MA)RT=2.91min,m / z=713.2(M+H) + .

[0855] Step 2

[0856] To the solution of the title compound (100mg, 0.140mmol) from step 1 in DMF (3.5mL), cesium carbonate (91mg, 0.280mmol) and 4-methylthiophenol (21mg, 0.168mmol) are added. The reaction mixture is stirred at room temperature for 30min. The mixture is diluted with water (3mL) and EtOAc (3mL) and the two layers are separated. The water layer is extracted 3 times (3x5mL) with ethyl acetate. The organic layers are merged, washed with brine (5mL) and dried over sodium sulfate. The crude residue is purified by silica gel chromatography using cyclohexane / ethyl acetate 100:0 to 0:100 as eluent, to provide the title compound (65mg, 88% yield) as a white amorphous solid.

[0857] LCMS(MA)RT=2.62min,m / z=528.1(M+H) + .

[0858] Step 3

[0859] In a microwave vial, the title compound from step 2 (31 mg, 0.059 mmol) and LiCl (8 mg, 0.177 mmol) were dissolved in dioxane (1 mL) and the mixture was degassed with Ar for 10 min. Tributyl(1-ethoxyvinyl)stannane (0.024 mL, 0.070 mmol) and Pd(PPh 3 ) 4To the mixture of 4-nitropropene (2-nitropropene)-2-nitropropene (2-nitropropene)-2-nitropropene (7mg, 0.006mmol), and the bottle containing the obtained clear solution is sealed, and heated to 100 ° C for 1h. The reaction mixture is distributed between 1M HCl solution (2mL) and ethyl acetate (2mL). The two layers are separated, and the aqueous layer is extracted 3 times with ethyl acetate (3x2mL). The combined organic layer is washed with brine (2mL), dried over sodium sulfate and concentrated in vacuo. The crude residue is purified by silica gel chromatography using cyclohexane / ethyl acetate 50:50 to 0:100 as eluent, to provide the expected product (13mg, 52% yield) as a slightly yellow amorphous solid.

[0860] LCMS(MA)RT=2.00min,m / z=422.2(M+H) + .

[0861] LCMS(MC)RT=2.02min,m / z=422.3(M+H) + .

[0862] 1 H NMR(400MHz,DMSO)9.00(1H,d,J=7.6Hz),8.63(1H,s),8.04-8.03(1H,m),7.50(1H,s) ,7.05(1H,dd,J=1.4,2.4Hz),6.67(1H,d,J=7.4Hz),6.37(1H,s),4.93(1H,d,J=10.4H z), 4.52-4.47 (1H, m), 4.37-4.31 (1H, m), 3.95 (1H, t, J = 10.8 Hz), 3.46-3.45 (4H, m), 3.28-3.24 (2H, m), 2.58-2.57 (3H, m), 2.44 (1H, dd, J = 8.6, 15.4 Hz), 2.05-1.92 (1H, m). One proton was overlapped by the water signal.

[0863] Prepare similarly:

[0864]

[0865]

[0866] Example 55: (12R, 14S)-N, 12-dimethoxy-N-methyl-11-oxo-16-oxa-7, 10, 20, 21, 24-pentaazapentacyclo[15.5.2.12, 6.01°, 14.02°, 23]pentacosane-1(23), 2, 4, 6(25), 17(24), 18, 21-heptaene-4-carboxamide

[0867]

[0868] Following general synthetic scheme 1, as depicted for the synthesis of Example 1, the backbone 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine, pyrrolidine P1 and aniline A18 were used to obtain (12R,14S)-12-methoxy-11-oxo-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.12,6.010,14.020,23]pentacosane-1(23),2,4,6(25),17(24),18,21-heptaene-4-carboxylic acid methyl ester as intermediate I20.

[0869] Step 1

[0870] To a solution of intermediate I20 (0.32 g, 0.731 mmol) in methanol (15 mL), tetrahydrofuran (15 mL) and water (15 mL) was added 1N sodium hydroxide solution (3.6 mL, 3.657 mmol). The reaction mixture was stirred at 50 ° C for 3 h. The reaction mixture was cooled to room temperature, then slightly acidified with 1N HCl solution (about pH = 4-5) and concentrated under reduced pressure. Water was added to the residue. The resulting precipitate was filtered, washed with water, then washed with pentane, and dried to provide the title compound (280 mg, 90% yield) as an off-white solid.

[0871] L36119-1 LCMS(MA)RT=1.89min, m / z=424.1(M+H)+.

[0872] Step 2

[0873] To a solution of the title compound (50 mg, 0.118 mmol) from step 1 in N, N-dimethylformamide (5 mL) was added HATU (67 mg, 0.177 mmol), N-methoxymethylamine hydrochloride (35 mg, 0.354 mmol) and triethylamine (0.08 mL, 0.59 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. Water was added to the residue and after extraction with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (eluting solvent 90-10% dichloromethane / methanol). The gelatinous residue was ground with dichloromethane / pentane (1:4). The resulting precipitate was filtered, washed with pentane and dried under reduced pressure to provide the expected product (35 mg, 63% yield) as a white solid.

[0874] LCMS(MA)RT=1.90min,m / z=467.1(M+H) + .

[0875] LCMS(MC)RT=1.89min,m / z=467.2(M+H) + .

[0876] 1 H NMR(400MHz,DMSO):8.99(1H,d,J=7.4Hz),8.55(1H,s),7.93-7.89(1H,m),7.06(1H,s) ,6.67-6.62(2H,m),6.31-6.26(1H,m),4.95(1H,d,J=10.6Hz),4.49(1H,t,J=8.1Hz),4. 37-4.31(1H,m),3.95(1H,t,J=10.7Hz),3.61(3H,s),3.58-3.51(1H,m),3.46(3H,s),3 .44-3.36(1H,m),3.26(3H,s),3.26-3.17(2H,m),2.47-2.42(1H,m),2.02-1.93(1H,m).

[0877] Prepare similarly:

[0878]

[0879]

[0880]

[0881]

[0882]

[0883]

[0884] Example 64: (12R, 14S)-4-(Hydroxymethyl)-12-methoxy-18-methyl-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2,4,6(25),17(24),18,21-heptaen-11-one

[0885]

[0886] Following general synthetic scheme 1, as depicted for the synthesis of Example 1, skeleton S1, pyrrolidine P1 and aniline A18 were used to obtain (12R,14S)-12-methoxy-18-methyl-11-oxo-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.12,6.010,14.020,23]pentacosane-1(23),2,4,6(25),17(24),18,21-heptaene-4-carboxylic acid methyl ester as intermediate I21.

[0887] Step 1

[0888] Intermediate I21 (50 mg, 0.11 mmol) was suspended in water (2 mL) and 37% hydrochloric acid solution (2 mL) was added. The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and co-evaporated with heptane. The crude residue was dried under vacuum to provide the expected compound as a pink solid. The crude was used in the next step without further purification.

[0889] LCMS(MH)RT=0.696min,m / z=438.1(M+H) + .

[0890] Step 2

[0891] Borane dimethyl sulfide complex (2M / THF) (1.14 mL, 2.11 mmol) was added to a stirred solution of the title compound from step 1 (100 mg, 0.211 mmol) in dry THF (3 mL) at 0 ° C under a nitrogen atmosphere. The reaction mixture was warmed to ambient temperature and stirred for 1 h. The reaction mixture was cooled to 0 ° C and quenched with a few drops of methanol. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-2.5% dichloromethane / methanol) to provide the expected product (40 mg.45% yield) as a white solid.

[0892] LCMS(MD)RT=2.374min,m / z=424.1(M+H) + .

[0893] LCMS(ME)RT=2.977min,m / z=424.1(M+H) + .

[0894] 1H NMR(400MHz,DMSO)d 8.88(d,J=1.2Hz,1H),8.34(s,1H),7.67(s,1H),6.83(s,1H),6.45(s,1H),6.02(t,J=5.9Hz,1H),5 .04(t,J=5.7Hz,1H),4.94(d,J=10.7Hz,1H),4.46(t,J=8.5Hz,1H),4.42(d,J=5.8Hz,2H),4.36(d,J =8.0Hz,1H),3.99(t,J=10.7Hz,1H),3.60-3.48(m,1H),3.45(s,3H),3.38(dd,J=9.6,3.6Hz,1H),3 .25-3.12(m,2H),2.46(dd,J=12.0,6.0Hz,1H),2.18(d,J=1.0Hz,3H),1.96(dd,J=21.4,8.7Hz,1H).

[0895] Examples 65 and 66: (12R or S, 14S)-12-methoxy-4-(methoxymethyl)-18-methyl-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 ]Pentacosa-1(23),2,4,6(25),17(24),18,21-heptaen-11-one (single unknown isomer 1, single unknown isomer 2)

[0896]

[0897] Step 1

[0898] To a stirred solution of Example 64 (150 mg, 0.354 mmol) in dichloromethane (4.5 mL) was added thionyl chloride (0.129 mL, 1.170 mmol). The reaction was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The residue was diluted with toluene and evaporated to dryness to provide the title compound (160 mg) as a beige solid, which was used without further purification.

[0899] LCMS(MD)RT=0.860min,m / z=444.1(M+H) + .

[0900] Step 2

[0901] To a solution of the title compound from step 1 (160 mg, 0.362 mmol) in methanol (6 mL) was added sodium methoxide solution (25 wt % in methanol) (1.6 mL). The reaction mixture was stirred at 80 °C for 3 h. Saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.

[0902] Reverse Phase Purification:

[0903] 72% [25 mM NH 4 HCO 3 ]-28% [acetonitrile: methanol 1:1] 36% [25 mM NH 4 HCO 3 ]-64% [acetonitrile:methanol 1:1]

[0904] Example 65: Single unknown isomer 1

[0905] 70 mg, 44.3% yield, as a white solid

[0906] LCMS(MD)RT=2857min,m / z=438.1(M+H) + .

[0907] LCMS(ME)RT=3.349min,m / z=438.2(M+H) + .

[0908] 1 H NMR(400MHz,DMSO)d 8.88(dd,J=12.0,6.0Hz,1H),8.38(s,1H),7.73(s,1H),6.84(s,1H),6.42(s,1H),6.07( t,J=5.8Hz,1H),4.95(d,J=10.6Hz,1H),4.48(t,J=9.1Hz,1H),4.36(d,J=8.0Hz,1H),4.3 2(s,2H),3.99(t,J=10.7Hz,1H),3.60-3.48(m,1H),3.45(s,3H),3.43-3.35(m,1H),3.2 9(s,3H),3.27-3.16(m,2H),2.48-2.42(m,1H),2.18(s,3H),1.96(dt,J=12.3,8.3Hz,1H)

[0909] Example 66: Single unknown isomer 2

[0910] 8.1 mg, 5.1% yield, as a white solid.

[0911] LCMS(MD)RT=3.007min,m / z=438.2(M+H) + .

[0912] LCMS(ME)RT=3.390min,m / z=:438.1(M+H) + .

[0913] 1 H NMR(400MHz,DMSO)d 8.88(d,J=1.2Hz,1H),8.38(s,1H),7.73(s,1H),6.84(s,1H),6.42(s,1H),6.07(t,J=5.8Hz ,1H),5.11(d,J=10.6Hz,1H),4.50-4.40(m,1H),4.33(s,2H),3.93(t,J=10.5Hz,1H),3.80(d ,J=6.4Hz,1H),3.67-3.53(m,1H),3.45(s,3H),3.30(d,J=3.8Hz,4H),3.24(dd,J=11.0,6.1 Hz, 1H), 3.19-3.06 (m, 1H), 2.41-2.30 (m, 1H), 2.18 (d, J = 0.7Hz, 3H), 1.98 (d, J = 14.1Hz, 1H).

[0914] Example 67: (12R, 14S)-4-fluoro-12-methoxy-18-(1-methyl-1H-pyrazol-4-yl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

[0915]

[0916] Following General Synthetic Scheme 1, as depicted for the synthesis of Example 1, skeleton S3, pyrrolidine P1 and aniline A1 were used to obtain (12R,14S)-18-(benzyloxy)-4-fluoro-12-methoxy-7-(2-nitrobenzenesulfonyl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.12,6.010,14.020,23]pentacosane-1(23),2,4,6(25),17(24),18,21-hepten-11-one as intermediate I22.

[0917] Step 1

[0918] Intermediate I22 (664 mg, 0.964 mmol), anisole (4.212 mL, 38.56 mmol) and trifluoroacetic acid (4.5 mL) were added to a sealed test tube. The reaction mixture was stirred at 130 °C for 16 h. The solvent was removed under reduced pressure and the product was crystallized in acetonitrile to provide the title compound (Intermediate I28, (12R, 14S) -4-fluoro-18-hydroxy-12-methoxy-7-(2-nitrobenzenesulfonyl) -16-oxa-7, 10, 20, 21, 24-pentaazapentacyclo [15.5.2.12, 6.010, 14.020, 23] pentacosane-1 (23), 2, 4, 6 (25), 17 (24), 18, 21-hepten-11-one) as a brown solid (432 mg, 75% yield).

[0919] LCMS(MH)RT=0.821min,m / z=599(M+H) + .

[0920] Step 2

[0921] Trifluoromethanesulfonic anhydride (0.061mL, 0.367mmol) is added to a stirred solution of the title compound (200mg, 0.334mmol) from step 1 and pyridine (0.079mL, 1.002mmol) in dry dichloromethane (2mL). The reaction mixture is stirred at room temperature for 1h. A saturated aqueous solution of sodium bicarbonate is added and extracted with ethyl acetate. The combined organic phases are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (elution gradient 0-2% dichloromethane / methanol) to provide the expected compound (220mg, 90% yield) as a brown solid.

[0922] LCMS(MH)RT=1.084min,m / z=730.9(M+H) + .

[0923] Step 3

[0924] In a pressure flask, the title compound from step 2 (100 mg, 0.137 mmol), 1,5-dimethyl-1H-pyrazole-4-boronic acid, pinacol ester (36 mg, 0.164 mmol) and tripotassium phosphate (87 mg, 0.411 mmol) were mixed in dioxane / water (4: 1) (2 mL). The reaction mixture was bubbled with a stream of nitrogen for 5 min. Tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.008 mmol) and Xphos (8 mg, 0.016 mmol) were then added, and the mixture was stirred at 80 ° C for 2 h. Water was added and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-2% dichloromethane / methanol) to provide the expected compound (22 mg, 24% yield) as a brown solid.

[0925] LCMS(MD)RT=3.423min,m / z=677.1(M+H) + .

[0926] Step 4

[0927] Thiophenol (0.028 mL, 0.273 mmol) was added to a stirred solution of the title compound from step 3 (0.060 g, 0.091 mmol) and cesium carbonate (0.089 g, 0.273 mmol) in DMF (2.0 mL) at 0°C. The mixture was stirred at room temperature for 1 hour. After complete conversion as monitored by LCMS, saturated NaHCO 3 The aqueous solution was added and the mixture was extracted with EtOAc (x3). The combined organic layers were purified by MgSO 4 Dried, filtered and concentrated under vacuum.The product was purified by flash chromatography (on silica gel) using DCM / MeOH as eluent (100:0 to 97:3) to afford the desired product (10 mg, 23.01%) as a white solid.

[0928] LCMS(MD)RT=2.977min,m / z=478.1(M+H) + .

[0929] LCMS(ME)RT=3.551min,m / z=478.1(M+H) + .

[0930] 1H NMR (400MHz, DMSO)9.38(s,1H),8.52(s,1H),8.29(s,1H),8.11(s,1H),7.68(s,1H),6.76(d,J=9 .4Hz,1H),6.34(t,J=5.8Hz,1H),6.21(dt,J=11.8,2.1Hz,1H),5.06(d,J=10.5Hz,1H),4.53(brs, 1H),4.35(t,J=8.9Hz,1H),4.08(t,J=10.7Hz,1H),3.93(s,3H),3.63-3.52(m,1H),3.48(s,3H), 3.44-3.36(m,1H),3.28-3.19(m,2H),2.64(dd,J=12.7,8.2Hz,1H),1.97(dt,J=11.9,9.0Hz,1H).

[0931] Prepare similarly:

[0932]

[0933]

[0934] Example 70: (12R, 14S)-4-ethynyl-12-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

[0935]

[0936] Step 1

[0937] To a solution of (2S,4R)-2-(hydroxymethyl)-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (4.674 g, 20.21 mmol) in dry DMF (65 mL) was added 60% sodium hydride in mineral oil (1.347 g, 33.68 mmol) at 0°C. After 30 min, 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (3.915 g, 16.84 mmol) was added and the mixture was stirred at 0°C for 1 h. LCMS monitoring indicated that the reaction was complete. Water was carefully added dropwise at 0°C and the mixture was extracted with EtOAc (4 x 50 mL). The combined organic layers were washed with brine and then purified by Na 2 SO 4Dry, filter and concentrate under vacuum.The residue was purified by flash column chromatography using cyclohexane / EtOAc (100 / 0 to 60 / 40) as eluent to afford the title compound (3.831 g, 53% yield) as a yellow oil.

[0938] LCMS(MA)RT=2.73min,m / z=428(M+H) + .

[0939] Step 2

[0940] The title compound from step 1 (0.327 g, 0.77 mmol), aniline A11 (0.356 g, 0.99 mmol), Xphos (0.015 g, 0.03 mmol) and K 3 PO 4 A mixture of (0.487g, 2.30mmol) was dissolved in 1,4-dioxane / water (3mL / 1mL) and degassed with argon for 15min. Tetrakis(triphenylphosphine)palladium(0) (0.018g, 0.02mmol) was added, and the reaction mixture was stirred at 110 °C for 3h. The reaction mixture was monitored by LCMS, indicating that the reaction was terminated. The reaction mixture was cooled and filtered on diatomaceous earth, and the solvent was then evaporated. The residue was purified by column chromatography using cyclohexane / EtOAc (100 / 0 to 50 / 50) as eluent to provide the title compound (0.272g, 62% yield) as a yellow oil.

[0941] LCMS(MA)RT=3.55min,m / z=578(M+H) + .

[0942] Step 3

[0943] To a solution of the title compound from step 2 (0.272 g, 0.47 mmol) in acetonitrile (3.4 mL) was added pyridine (0.057 mL, 0.71 mmol) and 2-nitrobenzene-1-sulfonyl chloride (0.136 g, 0.61 mmol). The reaction mixture was stirred at room temperature overnight. Monitoring the reaction by LCMS indicated that the reaction was complete. The solvent was removed under reduced pressure and the residue was poured into water (40 mL) and EtOAc (80 mL). The aqueous layer was extracted with EtOAc (3x40 mL) and the organic layer was washed with brine (2x40 mL), dried (Na2O3) and purified by HPLC. 2 SO 4 ), filtered and concentrated under reduced pressure to afford the title compound (0.485 g, quantitative yield) as an orange solid.

[0944] LCMS(MA)RT=3.72min,m / z=763.3(M+H)+ .

[0945] Step 4

[0946] To a solution of the title compound (0.485 g, 0.64 mmol) from step 3 in acetonitrile (4 mL) was added cesium carbonate (0.621 g, 1.91 mmol) and 1,2-dibromoethane (0.822 mL, 9.54 mmol). The reaction mixture was heated to reflux for 4 h. The reaction mixture was monitored by LCMS, indicating that the reaction was complete. The mixture was dissolved in EtOAc (50 mL), extracted with water (50 mL), then with brine (2 x 40 mL), and the organic layer was purified by anhydrous Na 2 SO 4 Dried, filtered and concentrated under vacuum.The residue was purified by column chromatography using cyclohexane / EtOAc (100 / 0 to 60 / 40) as eluent to afford the title compound as a yellow oil (0.301 g, 54% yield).

[0947] LCMS(MA)RT=3.82min,m / z=870(M+H) + .

[0948] Step 5

[0949] To a suspension of the title compound (0.301 g, 0.35 mmol) from step 4 in DCM (3 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (0.865 mL, 3.46 mmol). The reaction mixture was stirred overnight. LCMS indicated that the reaction was complete. The solvent was removed under reduced pressure to provide the title compound (0.489 g, quantitative yield) as a yellow oil.

[0950] LCMS(MA)Rt=2.60min,m / z=770(M+H) + .

[0951] Step 6

[0952] To a solution of the title compound from step 5 (0.489 g, assumed 0.35 mmol) in acetonitrile (48 mL) was added sodium bicarbonate (0.255 g, 3.03 mmol), cesium carbonate (0.593 g, 1.82 mmol), and then potassium iodide (0.302 g, 1.82 mmol). The resulting mixture was heated at 90 ° C for 6 h. LC / MS monitoring indicated that the reaction was complete. The mixture was dissolved in EtOAc (50 mL) and washed with water (50 mL) and brine (2x40 mL). The organic layer was purified by anhydrous Na 2 SO 4Dried, filtered and concentrated under vacuum.The residue was purified on silica gel column chromatography using cyclohexane / EtOAc (100 / 0 to 50 / 50) as eluent to afford the title compound (0.067 g, 28% yield) as a white solid.

[0953] LCMS(MA)RT=3.31min m / z=689(M+H) + .

[0954] Step 7

[0955] The title compound from step 6 (0.067 g, 0.10 mmol) was dissolved in THF / H 2 To the mixture in 4% 4-nitropropene (5mL / 2mL) was added sodium bicarbonate (0.163 g, 1.95 mmol). The reaction mixture was stirred at room temperature for 10 min, and then iodine (0.370 g, 1.46 mmol) was added. The reaction mixture was stirred at 60 ° C for 2 h. LC / MS monitoring showed that the reaction was complete. The reaction mixture was quenched with saturated sodium thiosulfate solution and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford the title compound as a purple solid (Intermediate I32, (12R, 14S)-12-methoxy-7-(2-nitrobenzenesulfonyl)-4-[2-(triethylsilyl)ethynyl]-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.12,6.010,14.020,23]pentacosane-1(23),2,4,6(25),17(24),18,21-hepten-11-one, 0.150 g, quantitative yield).

[0956] LCMS(MA)RT=3.44min,m / z=703(M+H) + .

[0957] Step 8

[0958] The title compound (150 mg, 0.10 mmol) and cesium carbonate (139 mg, 0.43 mmol) from step 7 were dissolved in N, N-dimethylformamide (8 mL). 4-Methylthiophenol (32 mg, 0.26 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography using dichloromethane / methanol (100: 0 to 98: 2) as eluent to provide the title compound (28 mg, 25% yield) as a yellow solid.

[0959] LCMS(MA)RT=3.34min,m / z=518(M+H) + .

[0960] Step 9

[0961] To a solution of the title compound (28 mg, 0.05 mmol) from step 8 in methanol (2 mL) was added potassium carbonate (37 mg, 0.27 mmol) at room temperature. The reaction mixture was heated at 50 ° C for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography using cyclohexane / EtOAc (100: 0 to 80: 20) as eluent to provide the desired product (17 mg, 0.04 mmol) as a beige powder.

[0962] LCMS(MA)RT=2.25min,m / z=404(M+H) + .

[0963] LCMS(MC)RT=2.25min,m / z=404(M+H) + .

[0964] 1 H NMR(400MHz,DMSO)9.00-8.97(1H,m),8.56-8.56(1H,m),7.87-7.86(1H,m),7.04(1H, s),6.66(1H,d,J=7.4Hz),6.57-6.55(1H,m),6.23(1H,t,J=6.0Hz),4.96-4.92(1H,m) ,4.50-4.45(1H,m),4.36-4.31(1H,m),4.03(1H,s),3.95(1H,t,J=10.8Hz),3.58-3.5 2(1H,m),3.41-3.33(1H,m),3.32-3.31(5H,m),2.48-2.41(1H,m),2.00-1.94(1H,m).

[0965] Prepare similarly:

[0966]

[0967]

[0968] Example 73: (12R, 14S)-4-fluoro-12-methoxy-11-oxo-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23]pentacosane-1(23),2,4,6(25),17(24),18,21-heptadecene-7-carboxylic acid ethyl ester

[0969]

[0970] To a solution of Example 3 (50 mg, 0.13 mmol) in tetrahydrofuran (3 mL) was added triethylamine (53 μL, 0.38 mmol) and ethyl chloroformate (36 μL, 0.38 mmol) dropwise. The solution was stirred at room temperature for 36 h. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (column XSELECT C18 19*100 mm 5 μm, [(NH 4 ) 2 CO 3 Aqueous solution 2 g / L / acetonitrile] 45% B to 55% B-19 mL / min RT) was purified to afford the desired product (33 mg, 56% yield) as a light yellow solid.

[0971] LCMS(MA)RT=2.47min,m / z=470.2(M+H) + .

[0972] LCMS(MC)RT=2.47min,m / z=470.3(M+H) + .

[0973] 1 H NMR(400MHz,DMSO)9.02(1H,d,J=7.4Hz),8.77-8.76(1H,m),8.54(1H,s),7.53-7.4 8(1H,m),7.37-7.31(1H,m),6.70(1H,d,J=7.4Hz),5.06(1H,d,J=11.2Hz),4.61(1H, t,J=8.6Hz),4.37-4.17(4H,m),4.09-3.94(2H,m),3.63-3.52(1H,m),3.46(3H,s), 3.41(1H,d,J=12.2Hz), 2.46-2.39(1H,m), 2.00-1.88(1H,m), 1.30(3H,t,J=7.3Hz).

[0974] Example 74: (12R, 14S)-7-acetyl-4-fluoro-12-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23]pentacosane-1(23),2,4,6(25),17(24),18,21-heptaen-11-one

[0975]

[0976] To a solution of Example 3 (50 mg, 0.13 mmol) in tetrahydrofuran (3 mL) was added triethylamine (70 μL, 0.50 mmol) and acetyl chloride (20 μL, 0.28 mmol) dropwise. The reaction mixture was stirred at room temperature for 48 h. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (column XSELECT PHENYL-HEXYL 19*100 mm 5 μm, [(NH 4 ) 2 CO 3 Aqueous solution 2 g / L / acetonitrile] 35% B to 45% B, 19 mL / min RT) was purified to afford the desired product (40 mg, 72% yield) as a white solid.

[0977] LCMS(MA)RT=2.12min,m / z=440.2(M+H) + .

[0978] LCMS(MC)RT=2.13min,m / z=440.3(M+H) + .

[0979] 1 H NMR(400MHz,DMSO)9.03(1H,d,J=7.6Hz),8.78(1H,s),8.62(1H,s),7.59(1H,d,J =10.2Hz),7.25(1H,s),6.71(1H,d,J=7.4Hz),5.06(1H,d,J=10.6Hz),4.68-4.63 (1H,m),4.33(2H,t,J=8.9Hz),4.20-4.14(1H,m),3.98(1H,t,J=10.9Hz),3.44(3 H,s),3.35(2H,s),2.39(1H,dd,J=8.1,12.6Hz),2.20(3H,s),1.94-1.86(1H,m).

[0980] Example 75: (12R, 14S)-4-fluoro-12-methoxy-7-methyl-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23]pentacosane-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

[0981]

[0982] To a solution of Example 3 (50 mg, 0.13 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% dispersion in mineral oil) (10 mg, 0.25 mmol) at room temperature under argon atmosphere. After 30 min, iodomethane (0.117 mL, 1.89 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. Additional sodium hydride (60% dispersion in mineral oil) (10 mg, 0.25 mmol) and iodomethane (0.117 mL, 1.89 mmol) were added successively after 2 h, 18 h, 20 h, 24 h, 40 h, 44 h until complete conversion of the starting material. Water and ethyl acetate were added to the reaction mixture. After extraction with ethyl acetate (3x30 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Water and ethyl acetate were added to the reaction mixture. After extraction with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column XSELECT C18 19*100mm 5μm, [(NH 4 ) 2 CO 3 Aqueous solution 2 g / L / acetonitrile] 45% B to 50% B, 19 mL / min RT) was purified to afford the desired product (15 mg, 29% yield) as a white solid.

[0983] LCMS(MA)RT=2.42min,m / z=412(M+H) + .

[0984] LCMS(MC)RT=2.41min,m / z=412(M+H) + .

[0985] 1H NMR(400MHz,DMSO)9.00(1H,d,J=7.4Hz),8.56(1H,s),7.78(1H,s),6.83(1H,d,J=9.9 Hz),6.67(1H,d,J=7.4Hz),6.33(1H,d,J=12.9Hz),4.95(1H,d,J=10.2Hz),4.49-4.46( 1H,m),4.35(1H,t,J=8.7Hz),3.96(1H,t,J=10.5Hz),3.73(2H,dd,J=12.6,21.2Hz),3 .46(3H,s),3.03-3.01(3H,m),2.00-1.91(1H,m),1.25-1.23(2H,m),0.87-0.83(1H,m)

[0986] Example 76: (12R, 14S)-12-methoxy-4-(1,2,4-oxadiazol-3-yl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

[0987]

[0988] Following General Synthetic Scheme 1, as depicted for the synthesis of Example 1, the backbone 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine, pyrrolidine P1 and aniline A6 were used to obtain (12R,14S)-12-methoxy-7-(2-nitrobenzenesulfonyl)-11-oxo-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.12,6.010,14.020,23]pentacosane-1(23),2(25),3,5,17(24),18,21-heptaene-4-carbonitrile as intermediate I23.

[0989] LCMS(MA)RT=2.38min,m / z=590.2(M+H) + .

[0990] Step 1

[0991] To a solution of intermediate I23 (589 mg, 1 mmol) in an ethanol / water mixture (10 mL / 4 mL) was added sodium carbonate (318 mg, 3 mmol) and hydroxylamine hydrochloride (271 mg, 3.9 mmol). The reaction mixture was stirred and heated to 65 °C for 2 h. The reaction mixture was cooled and a precipitate appeared. The resulting precipitate was filtered and rinsed with cold ether and then dried under reduced pressure to provide the title compound (520 mg, 83% yield) as a yellow solid.

[0992] LCMS(MA)RT=1.75min,m / z=623.2(M+H) + .

[0993] Step 2

[0994] To a stirred solution of the title compound (520 mg, 0.83 mmol) from step 1 in tetrahydrofuran (5 mL) was added triethyl orthoformate (0.415 mL, 2.5 mmol). The mixture was cooled to 0 ° C. Boron trifluoride ethyl ether complex (0.123 mL, 1 mmol) was then added dropwise, and the reaction mixture was stirred at ambient temperature for 16 h. Additional ethanol (5 mL) and triethyl orthoformate (0.415 mL, 2.5 mmol) were added, and the mixture was heated to reflux for 24 h. The reaction mixture was cooled and the precipitate was filtered out and dried under reduced pressure. The residue was ground together with ether and dried to provide the title compound (454 mg, 87% yield) as a cream solid.

[0995] LCMS(MA)RT=2.44min,m / z=633.1(M+H) + .

[0996] Step 3

[0997] To the title compound from step 2 (0.454 g, 0.72 mmol) in DMF (3 mL) was added cesium carbonate (469 mg, 1.44 mmol) and 4-methylthiophenol (107 mg, 0.86 mmol), the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was monitored by LCMS, indicating that the reaction was complete. The reaction mixture was adsorbed on silica gel and evaporated to dryness. The residue was purified by chromatography using DCM / MeOH (98 / 2-85 / 15) as eluent. The expected fractions were combined and evaporated under reduced pressure. The residue was ground in MeOH, filtered and dried under vacuum to provide the expected product (99 mg, 31%) as a cream solid.

[0998] LCMS(MA)RT=2.12min,m / z=448.1(M+H) + .

[0999] LCMS(MC)RT=2.18min,m / z=448(M+H) + .

[1000] 1 H NMR(400MHz,DMSO)9.69-9.68(1H,m),9.02-8.99(1H,m),8.61-8.59(1H,m),7.99(1 H,s),7.54(1H,s),7.20(1H,s),6.68(1H,d,J=7.6Hz),6.49(1H,t,J=6.0Hz),4.96(1 H,d,J=11.2Hz),4.50-4.31(2H,m),3.96(1H,t,J=10.6Hz),3.61-3.52(1H,m),3.46 (3H,s),3.43-3.36(1H,m),3.32-3.25(2H,m),2.48-2.41(1H,m),2.02-1.94(1H,m);

[1001] Example 77: (12R, 14S)-4-fluoro-12-methoxy-18-(2-methoxyethyl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

[1002]

[1003] Step 1

[1004] Pyrrolidine P1 (0.720 g, 3.113 mmol) in 16 mL of dry DMF (5 mL / mmol) was added to 60% sodium hydride (C, 0.373 g, 9.339 mmol) in mineral oil at 0°C, and after 30 min, framework S8 (1.043 g, 3.424 mmol) was added, and the mixture was stirred at 4-5°C for 15 min. After complete conversion monitored by TLC, EtOAc was added and the mixture was carefully quenched by dropwise addition of water at 0°C. Then, it was extracted with EtOAc (x3) and the combined organic layers were purified by MgSO 4Dry, filter and concentrate under vacuum.The product was purified by flash chromatography on silica gel using heptane / EtOAc (100:0 to 60:40) as eluent to afford the desired compound (2.253 g, 54.9% yield) as a yellow oil.

[1005] LCMS(MI)RT=0.884min,m / z=499-401(M+H) + -Boc.

[1006] Step 2

[1007] To a solution of the title compound from step 1 (2.253 g, 4.512 mmol) in dichloromethane (7 mL) was added trifluoroacetic acid (7 mL). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure to give the title compound as a dark orange oil (2.804 g, 100% yield), which was used without further purification.

[1008] LCMS(MI)RT=0.303min,m / z=355-357(M+H) + .

[1009] Step 3

[1010] To a solution of the title compound (2.804 g, 4.512 mmol) from step 2 in dichloromethane (14 mL) was added di-tert-butyl dicarbonate (2.954 g, 13.536 mmol) at 0 ° C, followed by triethylamine (1.887 mL, 13.536 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (eluting solvent 70-30% heptane / ethyl acetate) to provide the title compound (1.332 g, 65% yield) as a yellow solid.

[1011] LCMS(MH)RT=0.987min,m / z=355-357(M+H) + -Boc.

[1012] Step 4

[1013] To a solution of methoxymethyl)triphenylphosphonium chloride (2.579 g, 7.524 mmol) in dry THF (14 mL) was added a solution of potassium bis(trimethylsilyl)amide (1M / THF) (12.54 mL, 12.540 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 1 h. The title compound from step 3 (1.142 g, 2.508 mmol) in dry THF (9 mL) was added dropwise, and the reaction mixture was stirred at -78 °C for 2 h. Methyl-tert-butyl-ether and saturated aqueous sodium bicarbonate solution were added, and the reaction mixture was warmed to room temperature. The reaction mixture was heated to 60 °C and stirred for 16 h. The phases were separated, and the aqueous phase was extracted with MTBE. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-30% heptane / ethyl acetate) to provide the title compound (314 mg, 26% yield) as a yellow sticky solid.

[1014] LCMS(MH)RT=1.216min,m / z=483-485(M+H) + .

[1015] Step 5

[1016] The title compound from step 4 (0.300 g, 0.621 mmol), aniline A1 (0.191 g, 0.807 mmol), potassium phosphate tripotassium (0.264 g, 1.242 mmol) and Xphos (0.030 g, 0.062 mmol) were mixed in dioxane / water (4:1) (7 mL / mmol) (4.30 mL), and the mixture was bubbled with nitrogen for 5 min. Then, tetrakis(triphenylphosphine)palladium(0) (C, 0.036 g, 0.031 mmol) was added, and the mixture was stirred at 90 ° C in a pressure flask for 16 hours. Water was added and the mixture was extracted with EtOAc (x2). The combined organic layers were purified by MgSO 4 Drying, filtering and concentration under vacuum gave the crude material which was purified by flash chromatography on silica gel using heptane / EtOAc (100:0 to 40:60) as eluent to afford the title compound (0.168 g, 52.68% yield) as a yellow solid.

[1017] LCMS(MH)RT=1.107min, m / z=514.2(M+H)+.

[1018] Step 6

[1019] Pd / C 10% (67 mg) was added to a solution of the title compound (168 mg, 0.327 mmol) from step 5 in ethyl acetate (33 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h under a hydrogen atmosphere. Additional palladium / C 10% (67 mg) was added and the reaction mixture was stirred at room temperature for 16 h under a hydrogen atmosphere. The reactant was filtered on a celite pad and washed with a mixture of dichloromethane / methanol (4: 1). The filtrate was concentrated under reduced pressure to provide the title compound (143 mg, 85% yield) as an orange sticky solid, which was used in the next step without further purification.

[1020] LCMS(MH)RT=1.029min,m / z=516.2(M+H) + .

[1021] Step 7

[1022] A solution of the title compound from step 6 (0.143 g, 0.277 mmol) and pyridine (0.066 mL, 0.831 mmol) in DCM (1.4 mL, 5 mL / mmol) was cooled to 0°C. Then, 2-nitrobenzenesulfonyl chloride (0.068 g, 0.305 mmol) was added portionwise, and the mixture was stirred at room temperature for 16 h. 10% NaHCO 3 The solution was added and the mixture was extracted with DCM (x2). The combined organic layers were purified by MgSO 4 Dry, filter and concentrate under vacuum.The product was purified by flash chromatography on silica gel using heptane / EtOAc (100:0 to 20:80) as eluent to afford the title compound (0.136 g, 70.1% yield) as a yellow solid.

[1023] LCMS(MH)RT=1.173min,m / z=701.1(M+H) + .

[1024] Step 8

[1025] 1,2-Dibromoethane (0.364 mL, 1.940 mmol) was added to a stirred solution of the title compound from step 7 (0.136 g, 0.194 mmol) and cesium carbonate (0.316 g, 0.970 mmol) in 1.65 mL DMA (8.5 mL / mmol). The mixture was stirred at 50 °C for 16 hours. Water was added and the mixture was extracted with EtOAc (x2). The combined organic layers were purified by MgSO 4Drying, filtering and concentration under vacuum afforded the crude material, which was purified by flash chromatography on silica gel using heptane / EtOAc (100:0 to 50:50) as eluent to afford the title compound (0.100 g, 63.8% yield) as a colorless sticky solid.

[1026] LCMS(MH)RT=1.281min, m / z=707.0-708.9(M+H)+-Boc.

[1027] Step 9

[1028] The title compound from step 8 (0.100 g, 0.124 mmol) was dissolved in hydrochloric acid [4 M] in dioxane (2 mL), and the resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum and co-evaporated with heptane to provide the title compound (0.090 g) as an orange sticky solid. The crude was used in the next step without purification.

[1029] LCMS(MH)RT=0.959min,m / z=707-709(M+H) + .

[1030] Step 10

[1031] To the title compound from step 9 (0.087 g, 0.117 mmol) in 12 mL of acetonitrile, sodium bicarbonate (0.098 g, 1.170 mmol) and potassium iodide (0.058 g, 0.351 mmol) were added and the mixture was stirred at 90 °C for 16 hours. Additional sodium bicarbonate (0.098 g, 1.170 mmol) and potassium iodide (0.058 g, 0.351 mmol) were added and the mixture was stirred at 90 °C for 16 hours. EtOAc and water were added and the product was extracted with EtOAc (x3). The combined organic layers were purified by MgSO 4 Drying, filtering and concentration in vacuo provided the title compound as a cream solid (0.069 g).The crude was used in the next step without purification.

[1032] LCMS(MI)RT=0.803min,m / z=627.2(M+H) + .

[1033] Step 11

[1034] The title compound from step 10 (0.066 g, 0.105 mmol) was dissolved in THF:H 2Sodium bicarbonate (0.176 g, 2.100 mmol) was added to the mixture in 4% 4-nitropropene (2.5:1) (1.00 mL). The reaction mixture was stirred at room temperature for 10 min. Then, iodine (0.400 g, 1.575 mmol) was added and stirred at room temperature for 1 h. The mixture was diluted with EtOAc and washed with 10% aqueous sodium thiosulfate solution. The aqueous phase was extracted with EtOAc (x3) and the combined organic layers were purified by MgSO 4 Dry, filter and concentrate under vacuum.Finally, the product was purified on silica gel column chromatography using DCM / EtOAc (100:0 to 40:60) as eluent to afford the title compound (0.025 g, 37.2% yield) as a white solid.

[1035] LCMS(MH)RT=1.041min,m / z=641.0(M+H) + .

[1036] Step 12

[1037] Thiophenol (0.013 mL, 0.117 mmol) was added to a suspension of the title compound from step 11 (0.025 g, 0.039 mmol) and cesium carbonate (0.038 g, 0.117 mmol) in 0.50 mL DMF at 0°C. The mixture was stirred at room temperature for 1 hour. EtOAc and water were added, and the mixture was extracted with EtOAc (x2). The combined organic layers were purified by MgSO 4 Drying, filtering and concentration under vacuum gave the crude material which was purified by flash chromatography on silica gel using heptane / EtOAc (100:0 to 40:60) as eluent to afford the desired product (0.004 g, 22.52% yield) as a beige solid.

[1038] LCMS(MD)RT=3.081min,m / z=456.2(M+H) + .

[1039] LCMS(MF)RT=4.575min,m / z=456.2(M+H) + .

[1040] 1H NMR(400MHz,DMSO)d 8.88(s,1H),8.48(s,1H),7.65(s,1H),6.74(d,J=9.4Hz,1H),6.32(t,J=5.8Hz,1H),6.20(dt,J=11 .8,2.0Hz,1H),4.98(d,J=10.5Hz,1H),4.49(t,J=9.9Hz,1H),4.36(t,J=8.9Hz,1H),4.00(t,J=10. 7Hz,1H),3.60(t,J=6.5Hz,2H),3.55(dd,J=11.9,7.2Hz,1H),3.45(s,3H),3.42-3.34(m,1H),3.28 (s,3H),3.26-3.16(m,2H),2.83(t,J=6.5Hz,2H),2.48-2.42(m,1H),1.96(dt,J=11.7,8.8Hz,1H).

[1041] Prepare similarly:

[1042]

[1043]

[1044] Example 79: (12R, 14S)-4-fluoro-12-(2-hydroxyethoxy)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

[1045]

[1046] Following General Synthetic Scheme 1, as depicted for the synthesis of Example 1, the backbone 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine, pyrrolidine P8 and aniline A1 were used to obtain (12R,14S)-12-[2-(benzyloxy)ethoxy]-4-fluoro-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.12,6.010,14.020,23]pentacosane-1(23),2,4,6(25),17(24),18,21-hepten-11-one as intermediate I24.

[1047] Step 1

[1048] To a solution of intermediate I24 (100 mg, 0.193 mmol) in ethyl acetate (2 mL) was added 10% palladium / C (20 mg) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h under a hydrogen atmosphere. Additional palladium / C 10% (67 mg) was added, and the reaction mixture was stirred at room temperature for 16 h under a hydrogen atmosphere. The crude product was filtered out on a celite pad, rinsed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-2% dichloromethane / methanol) to provide the expected product (40 mg, 48.49% yield) as a white solid.

[1049] LCMS(MG)RT=2.813min,m / z=428.1(M+H) + .

[1050] LCMS(MF)RT=4.652min,m / z=428.1(M+H) + .

[1051] 1H NMR(400MHz,DMSO)d 8.98(d,J=7.5Hz,1H),8.53(s,1H),7.67(s,1H),6.79-6.70(m,1H),6.66(d,J=7.5Hz,1H),6 .33(t,J=5.8Hz,1H),6.21(dt,J=11.8,2.1Hz,1H),4.93(d,J=10.9Hz,1H),4.71(t,J=5.5Hz ,1H),4.56-4.36(m,2H),3.95(t,J=10.8Hz,1H),3.82(dt,J=9.6,4.7Hz,1H),3.62-3.47(m, 4H),3.45-3.34(m,1H),3.27-3.12(m,2H),2.44(dd,J=12.7,8.2Hz,1H),2.05-1.90(m,1H).

[1052] Example 80: (12R, 14S)-12-cyclopropyloxy-4-fluoro-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

[1053]

[1054] Step 1

[1055] To a solution of pyrrolidine P9 (0.500 g, 1.943 mmol) in dry DMF (10 mL) was added 60% sodium hydride in mineral oil (0.233 g, 5.829 mmol) at 0°C. After stirring for 30 min, 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (0.903 g, 3.886 mmol) was added and the mixture was stirred at 4-5°C for 30 min. Water was carefully added dropwise at 4-5°C and the mixture was extracted with EtOAc (x4). The combined organic layers were purified by MgSO 4 Dry, filter and concentrate under vacuum.The product was purified on silica gel column using heptane / EtOAc (from 100:0 to 85:15) as eluent to afford the title compound (0.471 g, yield: 53.47%) as yellowish gum.

[1056] LCMS(MH)RT=1.142min,m / z=353.0(M-100)

[1057] Step 2

[1058] In a pressure flask, the title compound from step 1 (0.450 g, 0.993 mmol), aniline A1 (0.283 g, 1.192 mmol) and K 3 PO 4 (0.632 g, 2.979 mmol) in dioxane / H 2 O (4: 1) (6mL), and the reaction mixture was bubbled with nitrogen for 5min. Tetrakis (triphenylphosphine) palladium (0) (0.070g, 0.060mmol) and Xphos (0.057g, 0.119mmol) were added, and the mixture was stirred at 80 ° C for 16 hours. After complete conversion monitored by LCMS, water was added and extracted with EtOAc (x3). The combined organic phase was filtered through MgSO 4 Dry, filter and concentrate under reduced pressure.The crude was purified by flash chromatography (on silica gel) using DCM / MeOH (100:0 to 97:3) as eluent to afford the title compound (0.291 g, 61% yield) as a brown solid.

[1059] LCMS(MH)RT=1.082min,m / z=484.1(M+H) + .

[1060] Step 3

[1061] A solution of the title compound from step 2 (0.293 g, 0.606 mmol) and pyridine (0.13 mL, 1.82 mmol) in DCM (3 mL) was cooled to 0 °C, then 2-nitrobenzenesulfonyl chloride (0.15 g, 0.67 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 h. NaHCO was added 3 Aqueous solution (10%) was added and the mixture was extracted with DCM (x3). The combined organic layers were washed with MgSO 4 Dried, filtered and concentrated under reduced pressure.The crude was purified by flash chromatography (on silica gel) using DCM / MeOH (100:0 to 96:4) as eluent to afford the title compound (0.370 g, 91.3% yield) as a brown gum.

[1062] LCMS(MH)RT=1.215min,m / z=569.0(M+H) + .

[1063] Step 4

[1064] The title compound from step 3 (0.360 g, 0.538 mmol) was dissolved in DMA (18 mL, 33 mL / mmol). Then cesium carbonate (0.876 g, 2.69 mmol) and 1,2-dibromoethane (0.464 mL, 5.380 mmol) were added and stirred at 50 °C for 16 hours. After complete conversion monitored by LCMS, water was added and extracted with EtOAc (x3). The combined organic phases were purified by MgSO 4 Dry, filter and concentrate under reduced pressure.The crude was purified by flash chromatography using DCM / MeOH (100:0 to 98:2) as eluent to afford the title compound (0.380 g, 91.06% yield) as a brown solid.

[1065] LCMS (MH) RT=1.342min, m / z=675.0 / 677.0 (M-100).

[1066] Step 5

[1067] The title compound from step 4 (0.357 g, 0.460 mmol) was cooled to 0° C. DCM / TFA 1:1 (4 mL) was added and stirred from 0° C. to room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound (0.320 g) as a crude brown sticky solid, which was used as is in the next step without further purification.

[1068] LCMS(MH)RT=0.901min,m / z=675.0 / 677.0(M+H) + .

[1069] Step 6

[1070] To a solution of the title compound from step 5 (crude, 0.36 g, 0.46 mmol) in acetonitrile (138 mL) was added sodium bicarbonate (0.386 g, 4.600 mmol) and potassium iodide (0.076 g, 0.460 mmol), and the mixture was stirred at 90 °C for 16 hours. Water was added and extracted with EtOAc (x3). The combined organic phases were purified by MgSO 4 Dry, filter and concentrate under reduced pressure.The crude was purified by flash chromatography (on silica gel) using DCM / MeOH (100:0 to 98:2) as eluent to afford the title compound (0.202 g, 73.8% yield) as a yellow solid.

[1071] LCMS(MH)RT=1.047min,m / z=595.0(M+H) + .

[1072] Step 7

[1073] To a mixture of the title compound (0.125 g, 0.210 mmol) from step 6 in DMF (5 mL) was added cesium carbonate (0.205 g, 0.630 mmol). The mixture was cooled in an ice / water bath and then thiophenol (0.065 mL, 0.630 mmol) was added. The mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, water was added and the mixture was extracted with EtOAc (x4). The combined organic layers were purified by MgSO 4 Dry, filter and concentrate under vacuum.The crude was purified by flash chromatography on silica gel using DCM / MeOH (from 100:0 to 97.5:2.5) as eluent to afford the title compound (0.068 g, 79.08% yield) as a yellowish solid.

[1074] LCMS(MH)RT=0.710min,m / z=410.1(M+H) + .

[1075] Step 8

[1076] The title compound from step 7 (0.058 g, 0.142 mmol) was dissolved in THF:H 2Sodium bicarbonate (0.179 g, 2.130 mmol) was added to the solution in O (9:1) (8.5 mL). The reaction mixture was stirred at room temperature for 10 min. Then, iodine (0.252 g, 0.994 mmol) was added and stirred at room temperature. LCMS showed partial conversion. The mixture was heated at 50 ° C and stirred for 6 h. The mixture was diluted with EtOAc, water was added and the mixture was extracted with EtOAc (x4). The combined organic layers were purified by MgSO 4 Dry, filter and concentrate under vacuum.The crude was purified by flash chromatography on silica gel using DCM / MeOH (from 100:0 to 90:10) as eluent to afford the title compound (0.019 g) as a yellowish solid contaminated with the diiodo derivative.

[1077] LCMS(MH)RT=0.710min,m / z=410.1(M+H) + .

[1078] Step 9

[1079] A vial equipped with a magnetic stir bar was charged with the title compound from step 8 (0.005 g, 0.009 mmol) and (Ir[dF(CF3)ppy]2(dtbpy))PF6 (0.001 g, 0.0009 mmol). Acetonitrile (0.2 mL) was added to the vial followed by DIPEA (0.006 g, 0.036 mmol) followed by tris(trimethylsilyl)silane (0.006 g, 0.018 mmol). The mixture was stirred while keeping the vial open to the air and then irradiated with a 42 W blue LED bar for 45 min. The temperature close to the vial surface was 40°C. After completion of monitoring by LCMS, the solvent was removed under reduced pressure and the crude was purified on a silica gel column using DCM / MeOH (98:2) as eluent to afford the desired product (4.2 mg, 55%) as a white solid.

[1080] LCMS(MD)RT=3.250min,m / z=424.1(M+H) + .

[1081] 1H NMR (400MHz, CDCl 3):8.51(d,J=7.5Hz,1H),8.26(s,1H),7.69(s,1H),6.69(d,J=9.6Hz,1H),6.41(d,J=7.5Hz,1H),6 .24(d,J=10.8Hz,1H),5.06(d,J=11.0Hz,1H),3.91-3.83(m,1H),3.81(dd,J=6.1,3.0Hz,1H),3.76 (t,J=10.8Hz,1H),3.63-3.50(m,3H),3.26(t,J=11.5Hz,1H),2.61(dd,J=13.1,8.1Hz,1H),2.14(d d,J=21.9,9.0Hz,2H),0.90-0.81(m,1H),0.80-0.73(m,1H),0.70-0.63(m,1H),0.60-0.48(m,2H).

[1082] Prepare similarly:

[1083]

[1084]

[1085]

[1086] Example 83: (12R, 14S)-4-(3,5-dimethyl-1H-pyrazol-1-yl)-12-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

[1087]

[1088] Following General Synthetic Scheme 1, as depicted for the synthesis of Example 1, the backbone 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine, pyrrolidine P1 and aniline A16 were used to obtain (12R,14S)-4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)-12-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.12,6.010,14.020,23]pentacosane-1(23),2,4,6(25),17(24),18,21-hepten-11-one as intermediate I25.

[1089] Step 1

[1090] To a solution of intermediate I25 (93 mg, 0.155 mmol) in acetonitrile (4 mL) was added N,N-diisopropylethylamine (0.379 mL, 2.17 mmol), followed by tris(trimethylsilyl)silane (0.385 mL, 1.240 mmol) and (Ir[dF(CF 3 )ppy] 2 (dtbpy))PF 6 The reaction mixture was stirred while keeping the bottle open to the air and then irradiated with a 42W blue LED strip for 2 h. The mixture was diluted with ethyl acetate, water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0-2% dichloromethane / methanol) to provide the desired product (55 mg. 75% yield) as a beige solid.

[1091] LCMS(MD)RT=2.881min,m / z=474.2(M+H) + .

[1092] LCMS(ME)RT=3.361min,m / z=474.2(M+H) + .

[1093] 1 H NMR(400MHz,DMSO)d 8.91(d,J=7.5Hz,1H),8.50(s,1H),7.75(s,1H),6.89(s,1H),6.58(d,J=7.5Hz,1H),6.46(t,J=2. 0Hz,1H),6.22(t,J=5.8Hz,1H),5.95(s,1H),4.88(d,J=10.9Hz,1H),4.26(t,J=8.9Hz,1H),3.88(t ,J=10.7Hz,1H),3.48(dt,J=12.7,8.9Hz,1H),3.35-3.29(m,1H),3.24(s,3H),3.21(s,1H),3.20- 3.11(m,2H),2.36(dd,J=12.6,8.2Hz,1H),2.23(s,3H),2.09(s,3H),1.89(dt,J=12.1,8.9Hz,1H).

[1094] Example 84: (12R, 14S)-4-(4,5-dimethyl-1H-pyrazol-1-yl)-12-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

[1095]

[1096] Step 1

[1097] Intermediate I17 (60 mg, 0.102 mmol), methylboric acid (18 mg, 0.306 mmol), tripotassium phosphate (65 mg, 0.306 mmol) were mixed in dioxane / water (4:1) (1.8 mL). The reaction mixture was bubbled with nitrogen for 5 min and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5 mg, 0.006 mmol) was added. The reaction mixture was stirred at 80° C. for 6 h in a pressure flask. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Purification Method PB) 70% [25 mM NH 4 HCO 3 ]-30% [acetonitrile: MeOH 1:1] 27% [25 mM NH 4 HCO 3 ]-73% [acetonitrile:MeOH 1:1] purification to afford the desired product (26 mg, 53% yield) as a white solid.

[1098] LCMS(MD)RT=3.093min,m / z=474.2(M+H) + .

[1099] LCMS(ME)RT=3.450min,m / z=474.2(M+H) + .

[1100] 1H NMR(400MHz,DMSO)d 9.00(d,J=7.5Hz,1H),8.58(s,1H),7.85(s,1H),7.40(s,1H),6.98(s,1H),6.68(d,J=7.5Hz ,1H),6.53(t,J=1.9Hz,1H),6.34(t,J=5.9Hz,1H),4.97(d,J=10.8Hz,1H),4.52(t,J=8.5Hz ,1H),4.35(t,J=8.9Hz,1H),3.57(dd,J=16.4,5.9Hz,1H),3.46(s,3H),3.44-3.38(m,1H),3 .30-3.16(m,2H),2.47-2.39(m,2H),2.26(s,3H),2.02(s,3H),1.97(dd,J=12.5,9.0Hz,1H)

[1101] Example 88: (12R, 14S)-12-methoxy-4-(prop-1-yn-1-yl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2,4,6(25),17(24),18,21-heptaen-11-one

[1102]

[1103] Step 1

[1104] In a microwave bottle (5mL), Example 20 (205mg, 0.5mmol) was suspended in acetonitrile (5mL). At room temperature, Xphos (50mg, 0.1mmol) and cesium carbonate (490mg, 1.5mmol) were added. The resulting mixture was degassed by bubbling with argon for 10min, and then bis (acetonitrile) palladium dichloride (II) (15mg, 0.05mmol) was added. The reaction mixture was stirred at room temperature for 10min. Then, trimethyl (propargyl) silane (0.375mL, 2.5mmol) was added. The reaction vessel was sealed and heated at 120°C for 5 hours under microwave radiation using Biotage Initiator. LCMS monitoring showed that the reaction was terminated. The reaction mixture was adsorbed on silica gel, and DCM / MeOH (100 / 0 to 9 / 1) was used as eluent by silica gel column chromatography. The expected fractions were combined and evaporated under reduced pressure. The residue was recrystallized 2 times in EtOH. The expected product was obtained as a cream-colored solid (35 mg, 0.08 mmol, 17%).

[1105] LCMS(MA)RT=2.28min,m / z=418.4(M+H) + .

[1106] LCMS(MC)RT=2.28min,m / z=418.4(M+H) + .

[1107] 1 H NMR(400MHz,DMSO)9.00-8.96(1H,m),8.55-8.53(1H,m),7.79-7.76(1H,m),6 .96(1H,s),6.67-6.63(1H,m),6.49-6.47(1H,m),6.18-6.17(1H,m),4.94(1H ,t,J=10.3Hz),4.46(1H,s),4.33(1H,t,J=8.7Hz),3.94(1H,t,J=10.6Hz),3. 54(1H,d,J=18.3Hz),3.35-3.32(6H,m),2.46-2.40(1H,m),2.05-2.01(4H,m)

[1108] Example 89: (12R, 14S)-4,12-dimethoxy-8-methyl-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23]pentacosane-1(23),2,4,6(25),17(24),18,21-heptaen-11-one

[1109]

[1110] Step 1

[1111] To a suspension of sodium hydride (60% in oil) (3.2 g, 80.0 mmol) in dry THF (25 mL) was added a solution of pyrrolidine P1 (9.25 g, 40.0 mmol) in THF (25 mL) at 0 ° C. After 30 min, 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine (9.3 g, 40.01 mmol) was added, and the mixture was stirred at 0 ° C for 15 min, and then stirred at room temperature for 4 h. The mixture was carefully diluted with water and EtOAc (250 ml) was added. The layers were separated. The aqueous layer was extracted with EtOAc (2x100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to provide the title compound (17 g, 39.79 mmol, 99%) as yellow.

[1112] LCMS(MA)RT=2.84min,m / z=429.1(M+H) + .

[1113] Step 2

[1114] To a suspension of the title compound from step 1 (3.33 g, 7.79 mmol) in acetonitrile (10 mL) was added 4 M HCl (9.75 mL, 38.9 mmol) in 1,4-dioxane. The mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure to provide the title compound (2.83 g) as a yellow foam, which was used directly in the next step without further purification.

[1115] LCMS(MA)RT=1.29min,m / z=329.1(M+H) + .

[1116] Step 3

[1117] To a solution of the title compound (363mg, 1mmol) from step 2 in DCM (20mL) was added triethylamine (0.418mL, 3mmol). The resulting mixture was stirred at room temperature for 15min, and then 2-(tert-butyldimethylsilyloxy)propanal (375mg, 1.2mmol) was added. After further stirring for 15min, sodium triacetoxyborohydride (318mg, 1.5mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was monitored by LCMS, indicating that the reaction was terminated. The reaction mixture was diluted in DCM (50ml) and water was added. The water layer was extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by flash chromatography using cyclohexane / EtOAc (100 / 0 to 6 / 4) as eluent to provide the title compound (0.39g, 79%) as a colorless oil.

[1118] LCMS(MA)RT=2.20min,m / z=421.1(M+H) + .

[1119] Step 4

[1120] To the solution of the title compound (3.06 g, 6.12 mmol) from step 3 in dioxane / water (30 / 7 mL) was added aniline A3 (1.98 g, 7.96 mmol), tetrakis (triphenylphosphine) palladium (0) (139 mg, 0.12 mmol), Xphos (114 mg, 0.24 mmol) and tripotassium phosphate (3.9 g, 18.36 mmol). The reaction mixture was degassed by bubbling under argon for 15 min and stirred at 90 ° C for 4 h. After complete conversion was monitored by LCMS, the mixture was cooled to room temperature and diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography using cyclohexane / EtOAc-EtOH (3:1) (100:0 to 6:4) as eluent to afford the title compound as a yellow oil (3.21 g, 97%).

[1121] LCMS(MA)RT=2.04min,m / z=542.4(M+H) + .

[1122] Step 5

[1123] To a solution of the title compound (3.21 g, 5.9 mmol) from step 4 in acetonitrile (45 mL) was added pyridine (0.62 mL, 7.7 mmol) and 2-nitrobenzenesulfonyl chloride (1.44 g, 6.5 mmol) portionwise. The reaction mixture was stirred at room temperature for 2 h. After complete conversion was monitored by LCMS, the solvent was evaporated under reduced pressure. The crude was purified by flash chromatography using cyclohexane / EtOAc-EtOH (3: 1) (100: 0 to 6: 4) as eluent to provide the title compound (3.8 g, 88%) as a yellow foam.

[1124] LCMS(MA)RT=2.49min,m / z=727.3(M+H) + .

[1125] Step 6

[1126] To the solution of the title compound (3.8g, 5.23mmol) from step 5 in THF (100mL) was added a solution of TBAF (5.75mL, 5.75mmol). The reaction mixture was stirred at room temperature for 72h. After complete conversion was monitored by LCMS, the solvent was evaporated under reduced pressure. The crude material was purified by flash chromatography using DCM / MeOH (100 / 0 to 9 / 1) as eluent to provide the title compound (3.62g, 100%) as a yellow foam.

[1127] LCMS(MA)RT=1.78min,m / z=613.3(M+H) + .

[1128] Step 7

[1129] The title compound (3.31g, 5.4mmol) from step 6 in THF (30mL) and DIAD (3.18mL, 16.2mmol) in toluene (30mL) solution dropwise (lasting 1 hour) and added simultaneously to a solution of triphenylphosphine (4.25g, 16.2mmol) in toluene (300mL) heated at 90°C. The reaction mixture was heated at 90°C for 1h. After complete conversion was monitored by LCMS, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography using DCM / MeOH (100 / 0 to 9 / 1) as eluent. Cyclohexane / EtOAc-EtOH (3: 1) (100 / 0 to 3 / 7) was used as eluent to repeat purification, to provide the title compound (700mg, 22% yield) as a creamy foam.

[1130] LCMS(MA)RT=2.05min,m / z=595.2(M+H) + .

[1131] Step 8

[1132] Sodium bicarbonate (0.98 g, 11.7 mmol) was added to a solution of the title compound (700 mg, 1.17 mmol) from step 7 in acetonitrile / water (60 mL / 20 mL). The reaction mixture was stirred at 45 ° C for 30 min, and then iodine (1.9 g, 8.77 mmol) was added. The reaction mixture was stirred at 45 ° C for 3 h. After complete conversion was monitored by LCMS, the reaction mixture was quenched with a saturated sodium thiosulfate solution (100 mL). DCM (200 mL) was added to the mixture, which was extracted with water (100 mL) and brine (100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography using DCM / MeOH (100 / 0 to 9 / 1) as eluent to provide the title compound (0.5 g, 70% yield) as a cream solid.

[1133] LCMS(MA)RT=2.50min,m / z=609.2(M+H) + .

[1134] Step 9

[1135] To a suspension of the title compound (0.5 g, 0.82 mmol) from step 8 in THF / acetonitrile (40 mL / 4 mL) was added cesium carbonate (0.53 g, 1.64 mmol) and 4-methylthiophenol (0.12 g, 0.98 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography using DCM / MeOH (100: 0 to 90: 10) as eluent. The expected fractions were combined and evaporated under reduced pressure. The residue was ground in ether / acetonitrile (98 / 2) to provide the expected product (0.18 g, 52% yield) as a cream solid.

[1136] LCMS(MA)RT=2.09min,m / z=424.4(M+H) + .

[1137] LCMS(MC)RT=2.90min,m / z=424.4(M+H) + .

[1138] 1H NMR (400MHz, DMSO)8.99-8.95(1H,m),8.60-8.60(1H,m),7.98(1H,s),6.65(1H,d,J=7.7Hz), 6.61-6.59(1H,m),6.14-6.10(1H,m),6.03(1H,t,J=2.1Hz),5.30-5.25(1H,m),4.39-4.33(1H ,m),4.23-4.19(1H,m),4.08(1H,t,J=11.4Hz),3.75(1H,d,J=12.6Hz),3.63-3.55(1H,m),3.4 5-3.44(6H,m),2.47-2.41(1H,m),2.02-1.94(1H,m),1.28(3H,d,J=6.8Hz),1.15-1.12(1H,m)

[1139] Example 90: (12R, 14S)-12-Hydroxy-4-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2,4,6(25),17(24),18,21-heptaen-11-one

[1140]

[1141] Following General Synthetic Scheme 1, as depicted for the synthesis of Example 1, the backbone 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine, pyrrolidine P13 and aniline A3 were used to obtain (12R,14S)-4-methoxy-7-(2-nitrobenzenesulfonyl)-12-(prop-2-en-1-yloxy)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.12,6.010,14.020,23]pentacosane-1(23),2,4,6(25),17(24),18,21-heptaene as intermediate I26.

[1142] LCMS(MA)RT=2.29min,m / z=607.2(M+H) + .

[1143] Step 1

[1144] To a suspension of intermediate I26 (315 mg, 0.52 mmol) in EtOH / TFA (4.5 / 0.4 mL) under argon was added tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.10 mmol). The reaction mixture was stirred at 80 °C for 14 h. After complete conversion monitored by LCMS, the reaction mixture was cooled to room temperature and washed with saturated NaHCO 3 The solution is quenched carefully. Emulsion is observed, so the mixture is filtered and each layer is separated. The aqueous layer is extracted with EtOAc (2x15mL) and the combined organic layer is dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue is purified on a silica gel column using cyclohexane / (EtOAc / EtOH 3:1) (100:0 to 50:50) as eluent, to provide the title compound (184mg, 62% yield) as orange foam.

[1145] LCMS(MA)RT=1.80min,m / z=567.1(M+H) + .

[1146] Step 2

[1147] The title compound from step 1 (1.38 g, 2.44 mmol) was dissolved in THF / H 2 Sodium bicarbonate (4.100 g, 48.80 mmol) was added to the suspension in 0 (80 / 16 mL). The reaction mixture was stirred at room temperature for 10 min, and then iodine (9.29 g, 36.60 mmol) was added. The reaction mixture was stirred at 60 ° C for 1 h. After complete conversion was monitored by LCMS, the reaction mixture was cooled to room temperature, quenched with saturated sodium thiosulfate solution and diluted with ethyl acetate. Separate the layers. The aqueous layer was extracted with EtOAc (2 x 25 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford the title compound (Intermediate I27, (12R, 14S) -12-hydroxy-4-methoxy-7-(2-nitrobenzenesulfonyl) -16-oxa-7, 10, 20, 21, 24-pentaazapentacyclo [15.5.2.12, 6.010, 14.020, 23] pentacosane-1 (23), 2, 4, 6 (25), 17 (24), 18, 21-hepten-11-one) as a beige solid (1.679 g). The compound was used directly in the next step without further purification.

[1148] LCMS(MA)RT=2.27min,m / z=581.1(M+H) + .

[1149] Step 3

[1150] Cesium carbonate (110mg, 0.34mmol) and 4-methylthiophenol (25mg, 0.20mmol) are added to the suspension of the title compound (100mg, 0.17mmol) from step 2 in DMF (1.5mL). The reactant is stirred at room temperature for 30min. After being completely converted by monitoring by LCMS, the mixture is diluted with water and ethyl acetate. Separate the layers. The aqueous layer is extracted with EtOAc (2x15mL) and the combined organic layer is dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue is purified on a silica gel column using DCM / MeOH (100:0 to 95:5) as eluent. The compound is ground in acetonitrile, filtered and dried under reduced pressure to provide the expected product (26mg, 38% yield) as a light beige solid.

[1151] LCMS(MA)RT=1.79min,m / z=396.4(M+H) + .

[1152] LCMS(MC)RT=1.78min,m / z=396.4(M+H) + .

[1153] 1 H NMR(400MHz,DMSO)8.96(1H,d,J=7.6Hz),8.51(1H,s),7.48(1H,s),6.64(1H,d, J=7.4Hz),6.55-6.54(1H,m),6.05-6.02(2H,m),5.59(1H,d,J=5.7Hz),4.92-4. 89(1H,m),4.50-4.42(2H,m),3.96(1H,t,J=10.8Hz),3.73(3H,s),3.57-3.49(1 H,m),3.44-3.37(1H,m),3.26-3.16(2H,m),2.40-2.33(1H,m),1.96-1.88(1H,m)

[1154] Prepare similarly:

[1155]

[1156]

[1157] Example 91: (12R, 14S)-4-fluoro-12-(oxetane-3-ylmethoxy)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° ,23 ]pentacosane-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

[1158]

[1159] Step 1

[1160] To a solution of intermediate I27 (0.10 g, 0.18 mmol) and 3-bromomethyloxetane (0.032 g, 0.21 mmol) in dry DMF (2 mL) was added potassium tert-butoxide (0.024 g, 0.21 mmol) at 0°C, and the mixture was stirred at 0°C for 2 h. After complete conversion was monitored by LCMS, water was carefully added dropwise at 0°C. The resulting mixture was extracted with EtOAc (2x10 mL). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate in vacuo to afford the title compound as a yellow oil (0.030 g, 27% yield).

[1161] LCMS(MA)RT=2.51min,m / z=639.1(M+H) + .

[1162] Step 2

[1163] The title compound (0.03g, 0.05mmol) and cesium carbonate (0.031g, 0.09mmol) from step 1 are dissolved in DMF (1.1mL). 4-Methylthiophenol (0.007g, 0.06mmol) is added, and the mixture is stirred at room temperature overnight. After complete conversion is monitored by LCMS, the reaction mixture is filtered. The solvent is evaporated, and the residue is purified by flash column chromatography using cyclohexane / EtOAc (100 / 0 to 0 / 100) as eluent, to provide the expected product (0.011g, 52% yield) as a white solid.

[1164] LCMS(MA)RT=2.12min,m / z=454.2(M+H) + .

[1165] LCMS(MC)RT=2.11min,m / z=454.2(M+H) + .

[1166] 1 H NMR (400 MHz, CDCl 3)8.55-8.52(1H,m),8.31-8.30(1H,m),7.72-7.71(1H,m),6.74-6.69(1H,m ),6.46-6.43(1H,m),6.26-6.21(1H,m),5.11(1H,t,J=6.9Hz),4.87-4.82( 1H,m),4.53-4.49(3H,m),4.34-4.29(2H,m),3.93-3.57(6H,m),3.36-3.25 (1H,m),2.64(1H,dd,J=8.0,12.9Hz),2.07-2.07(1H,m),1.30-1.26(2H,m);

[1167] Prepare similarly:

[1168]

[1169]

[1170]

[1171]

[1172]

[1173] Example 92: (12R, 14S)-4-fluoro-18-( 2 H3) methoxy-12-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclic [15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

[1174]

[1175] Step 1

[1176] To a suspension of intermediate I28 (0.064 g, 0.11 mmol) in DMF (3.3 mL) were added cesium carbonate (0.105 g, 0.32 mmol) and iodine ( 2 H 3)methane (0.046g, 0.32mmol). The reaction mixture was stirred at 70 ° C for 2h. After complete conversion was monitored by LCMS, the reaction mixture was cooled to room temperature. The solution was concentrated under reduced pressure and then diluted with water and EtOAc. The layers were separated. The aqueous layer was extracted with EtOAc (3x20mL) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to provide the title compound (0.202g) as a yellow solid.

[1177] LCMS(MA)RT=2.55min,m / z=616.2(M+H) + .

[1178] Step 2

[1179] The title compound (0.066g, 0.11mmol) and cesium carbonate (0.070g, 0.21mmol) from step 1 are dissolved in DMF (2.4mL). 4-Methylthiophenol (0.016g, 0.13mmol) is added, and the mixture is stirred at room temperature overnight. After complete conversion is monitored by LCMS, the reaction mixture is filtered and the solvent is evaporated to dryness. The residue is purified by flash column chromatography using cyclohexane / EtOAc (100 / 0 to 20 / 80) as eluent to provide the expected product (25mg, 54% yield) as a white solid.

[1180] LCMS(MA)RT=2.23min,m / z=431.2(M+H) + .

[1181] LCMS(MC)RT=2.14min,m / z=431.3(M+H) + .

[1182] 1 H NMR(400MHz,DMSO)8.79-8.78(1H,m),8.40-8.39(1H,m),7.63-7.62(1H,m),6.7 2(1H,d,J=9.9Hz),6.40-6.25(1H,m),6.22-6.17(1H,m),4.95(1H,d,J=10.1Hz), 4.48(1H,s),4.33(1H,t,J=8.9Hz),4.03(1H,t,J=10.7Hz),3.59-3.51(1H,m),3. 41-3.36(1H,m),3.33(3H,s),3.31(1H,s),3.23-3.16(2H,m),1.99-1.91(1H,m);

[1183] Prepare similarly:

[1184]

[1185]

[1186]

[1187]

[1188]

[1189]

[1190]

[1191]

[1192] Example 93: (12R, 14S)-4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-12-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2,4,6(25),17(24),18,21-heptaen-11-one

[1193]

[1194] Step 1

[1195] To a suspension of intermediate I29 (170 mg, 0.23 mmol) in THF (1.2 mL) was added a 1 M solution of TBAF in THF (0.25 mL, 0.25 mmol). The reactant was stirred at room temperature for 1 h. After complete conversion was monitored by LCMS, the solvent was evaporated under reduced pressure. The residue was purified on silica gel column chromatography using DCM / MeOH (100:0 to 90:10) as eluent. The expected fractions were combined and evaporated under reduced pressure. The resulting solid was ground in acetonitrile, filtered and dried under vacuum to provide the expected product (80 mg, 98%) as a pale pink solid.

[1196] LCMS(MA)RT=1.75min,m / z=490.4(M+H) + .

[1197] LCMS(MC)RT=1.76min,m / z=490.4(M+H) + .

[1198] 1 H NMR (400MHz, DMSO)8.98(1H,d,J=7.4Hz),8.59(1H,s),8.07(1H,s),7.82(1H,s),7.70(1H,ls),7.19-7.18(1H ,m),6.65(1H,d,J=7.6Hz),6.64-6.63(1H,m),6.03(1H,t,J=5.9Hz),4.97-4.93(1H,m),4.95(1H,t,J=5.3Hz) ,4.51-4.50(1H,m),4.34(1H,t,J=9.0Hz),4.17(2H,t,J=5.6Hz),3.95(1H,t,J=10.9Hz),3.78(2H,q,J=5.5Hz ),3.59-3.51(1H,m),3.45(3H,s),3.44-3.39(1H,m),3.27-3.20(2H,m),2.47-2.41(1H,m),2.02-1.94(1H,m).

[1199] Example 96: (12R, 14S)-12-ethoxy-4-hydroxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

[1200]

[1201] Following General Synthetic Scheme 1, as depicted for the synthesis of Example 1, the backbone 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine, pyrrolidine P2 and aniline A9 were used to obtain (12R,14S)-4-(benzyloxy)-12-ethoxy-7-(2-nitrobenzenesulfonyl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.12,6.010,14.020,23]pentacosane-1(23),2,4,6(25),17(24),18,21-hepten-11-one as intermediate I30.

[1202] LCMS(MA)RT=2.87min,m / z=685.3(M+H) + .

[1203] Step 1

[1204] To a solution of intermediate I30 (2.38 g, 3.47 mmol) in TFA (43 mL) was added anisole (15.19 mL, 138.9 mmol). The reaction mixture was stirred at 130 ° C for 2 h. After complete conversion was monitored by LCMS, the mixture was cooled at room temperature and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using cyclohexane / EtOAc (100 / 0 to 0 / 100) as eluent to provide the title compound (1.96 g, 95% yield) as a brown solid.

[1205] Step 2

[1206] The title compound (0.20g, 0.34mmol) and cesium carbonate (0.219g, 0.67mmol) from step 1 are dissolved in DMF (7.4mL). 4-methylthiophenol (0.050g, 0.40mmol) is added, and the mixture is stirred at room temperature overnight. After complete conversion is monitored by LCMS, the reaction mixture is filtered and the mother liquor is concentrated to dryness. The residue is purified by flash column chromatography using cyclohexane / EtOAc (100 / 0 to 20 / 80) as eluent, to provide the expected product (33mg, 24% yield) as a green solid.

[1207] LCMS(MA)RT=1.81min,m / z=410.4(M+H) + .

[1208] LCMS(MC)RT=1.80min,m / z=410.4(M+H) + .

[1209] 1 H NMR (400MHz, DMSO)8.97-8.94(2H,m),8.39-8.38(1H,m),7.97-7.95(1H,m),7.35-7.32(1H,m),6.64-6.61(1H,m),6.35(1H,s),5.93(1H,t,J=2. 0Hz),4.94-4.89(1H,m),4.44-4.38(2H,m),3.98-3.82(2H,m),3.48(4H ,d,J=10.4Hz),3.20-3.14(1H,m),2.01-1.91(1H,m),1.17-1.04(4H,m);

[1210] Prepare similarly:

[1211]

[1212]

[1213] Example 100: (12R, 14S)-12-(2-methoxyethoxy)-4-(3-methoxyprop-1-yn-1-yl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosane-1(23),2(25),3,5,17(24),18,21-hepten-11-one

[1214]

[1215] Following General Synthetic Scheme 1, as depicted for the synthesis of Example 1, the backbone 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine, pyrrolidine P7 and aniline A9 were used to obtain (12R,14S)-4-(benzyloxy)-12-(2-methoxyethoxy)-7-(2-nitrobenzenesulfonyl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.12,6.010,14.020,23]pentacosane-1(23),2,4,6(25),17(24),18,21-hepten-11-one as intermediate I31.

[1216] LCMS(MA)RT=2.75min,m / z=715.4(M+H) + .

[1217] Step 1

[1218] To a suspension of intermediate I31 (296 mg, 0.41 mmol) in TFA (6 mL) was added anisole (1.78 mL, 16.4 mmol). The reaction mixture was stirred at 130 ° C overnight. After complete conversion was monitored by LCMS, the reaction mixture was cooled to room temperature. The solvent was evaporated under reduced pressure. The residue was purified on silica gel column chromatography using DCM / MeOH (100: 0 to 95: 5) as eluent to provide the title compound (250 mg, 97% yield) as a beige solid.

[1219] LCMS(MA)RT=2.15min,m / z=625.3(M+H) + .

[1220] Step 2

[1221] To the suspension of the title compound (250mg, 0.4mmol) from step 1 in DCM (20mL), triethylamine (0.085mL, 0.6mmol) is added. N-phenyl-bis(trifluoromethanesulfonimide) (157mg, 0.44mmol) is added to the slurry portion by portion. The reaction mixture is stirred at room temperature overnight. After being completely converted by LCMS monitoring, the reaction mixture is diluted with water and each layer is separated. The water layer is extracted with DCM (2x15mL), and the combined organic layer is dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to provide the title compound (450mg) as beige foam. The crude product is directly used in the next step without further purification.

[1222] LCMS(MA)RT=2.73min,m / z=757.3(M+H) + .

[1223] Step 3

[1224] To a suspension of the title compound from step 2 (303 mg, 0.4 mmol) in DMF (3.5 mL) was added cesium carbonate (260 mg, 0.8 mmol), and then 4-methylthiophenol (60 mg, 0.48 mmol). The reactants were stirred at room temperature overnight. After complete conversion was monitored by LCMS, the reaction mixture was adsorbed on silica gel and evaporated to dryness. The residue was purified by silica gel column chromatography using DCM / MeOH (100 / 0 to 9 / 1) as eluent to afford the title compound as a white solid (Intermediate I33, (12R,14S)-12-(2-methoxyethoxy)-11-oxo-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.12,6.010,14.020,23]pentacosane-1(23),2,4,6(25),17(24),18,21-hepten-4-yl trifluoromethanesulfonate, 150 mg, 66% yield).

[1225] LCMS(MA)RT=2.54min,m / z=572.2(M+H) + .

[1226] Step 4

[1227] To a suspension of the title compound from step 3 (0.050 g, 0.09 mmol) in dry 1,4-dioxane (1.5 mL) was added lithium chloride (0.011 g, 0.26 mmol) in a sealed tube. The mixture was degassed by bubbling with argon for 10 min. Tributyl(vinyl)stannane (0.038 g, 0.10 mmol) and Pd(PPh 3 )4 The mixture was stirred at 100 °C for 2 h with 4% paraformaldehyde (0.010 g, 0.01 mmol). ... After complete conversion was monitored by LCMS, the reaction mixture was cooled and filtered on diatomaceous earth, and the solvent was evaporated. The residue was purified by column chromatography using cyclohexane / EtOAc (100 / 0 to 0 / 100) as eluent to provide the expected product (17 mg, 40% yield) as a white solid.

[1228] LCMS(MA)RT=2.22min,m / z=492.4(M+H) + .

[1229] LCMS(MC)RT=2.21min,m / z=492.4(M+H) + .

[1230] 1 H NMR(400MHz, DMSO)9.00-8.98(1H,m),8.57(1H,s),7.85(1H,s),7.03(1H,d,J=1.3Hz),6.66(1H,d,J=7.4H z),6.54(1H,dd,J=1.5,2.3Hz),6.26-6.22(1H,m),4.93(1H,d,J=11.0Hz),4.45(2H,dd,J=8.3,9.4Hz),4. 32(2H,s),4.00-3.92(2H,m),3.68-3.62(1H,m),3.55-3.50(1H,m),3.48(2H,t,J=4.7Hz),3.45-3.35(3H, m),3.26-3.26(4H,m),2.50-2.40(1H,m),2.02-1.96(1H,m),1.15(1H,t,J=1.0Hz),0.88(1H,t,J=7.3Hz);

[1231] Example 101: (12R, 14S)-4-cyclopropanecarbonyl-12-(2-methoxyethoxy)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2,4,6(25),17(24),18,21-heptaen-11-one

[1232]

[1233] Step 1

[1234] In a sealed test tube, cyclopropane-methanol (10 μL, 0.13 mmol), acetone (40 μL, 0.55 mmol) and TMP (37 μL, 0.22 mmol) were added to a suspension of intermediate I33 (64 mg, 0.11 mmol) in dry toluene (0.22 mL) under argon. The mixture was degassed by bubbling with argon for 10 min, and then Triphos (8 mg, 0.01 mmol) and Ni(OTf) were added. 2 (4mg, 0.01mmol). The test tube was sealed and heated at 140°C with a sand bath preheated at 140°C. The reactants were stirred at 140°C for 48h. After complete conversion of the starting material was monitored by LCMS, the layers were separated. The aqueous layer was extracted with EtOAc (2x10mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was restarted under the same conditions. The mixture was warmed to 140°C overnight. After completion of the monitoring by LCMS, the reactants were cooled at room temperature and the mixture was diluted with water and ethyl acetate. The layers were separated. The aqueous layer was extracted with EtOAc (2x10mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC: column Waters XSELECT C18 19*100mm, 5μm, A: (NH 4 ) 2 CO 3 Aqueous solution 2 g / L, B: ACN, 19 ml / min, room temperature, 40% B to 45% B in 7 min. The residue (ca. 15 mg) was purified a second time by preparative TLC 0.5 mm using cyclohexane / (EtOAc / EtOH 3:1) 1:1 as eluent to afford the desired product (11 mg, 16%) as a light yellow solid.

[1235] LCMS(MA)RT=2.15min,m / z=492.4(M+H) + .

[1236] LCMS(MC)RT=2.15min,m / z=492.4(M+H) + .

[1237] 1 H NMR (400 MHz, CDCl 3)8.54(1H,d,J=7.4Hz),8.42(1H,s),8.10(1H,ls),7.62-7.60(1H,m),7.16-7.14(1 H,m),6.45(1H,d,J=7.4Hz),5.13-5.07(1H,m),4.54-4.47(1H,m),4.40-4.34(1H,m ),4.35-4.31(1H,m),4.27-4.21(1H,m),3.90-3.56(6H,m),3.43(3H,s),3.33-3.27 (1H,m),2.74-2.62(2H,m),2.28-2.21(1H,m),1.30-1.25(2H,m),1.10-1.05(2H,m)

[1238] Example 102: (12R, 14S)-4-vinyl-12-ethoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2,4,6(25),17(24),18,21-heptaen-11-one

[1239]

[1240] Step 1

[1241] To a solution of intermediate I30 (2.38 g, 3.47 mmol) in TFA (43 mL) was added anisole (15.168 mL, 138.86 mmol). The reaction mixture was stirred at 130 ° C for 2 h. After complete conversion was monitored by LCMS, the mixture was cooled at room temperature and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using cyclohexane / EtOAc (100 / 0 to 0 / 100) as eluent to provide the title compound (1.96 g, 95% yield) as a brown solid.

[1242] LCMS(MA)RT=2.35min,m / z=595.2(M+H) + .

[1243] Step 2

[1244] To the suspension of the title compound (250mg, 0.42mmol) from step 1 in DCM (20mL), triethylamine (0.09mL, 0.63mmol) is added, then N-phenylbis(trifluoromethanesulfonimide) (165mg, 0.46mmol) is added portion by portion. After being completely converted by LCMS monitoring, the reaction mixture is diluted with water. Each layer is separated. The water layer is extracted with DCM (2x15mL). The organic layer combined is dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to provide the title compound (430mg) as gray foam, which is directly used in the next step without further purification.

[1245] LCMS(MA)RT=2.86min,m / z=727.1(M+H) + .

[1246] Step 3

[1247] To the suspension of the title compound (305mg, 0.42mmol) from step 2 in DMF (3.4mL), cesium carbonate (274mg, 0.84mmol) is added, and then 4-methylthiophenol (62mg, 0.50mmol) is added. The reactant is stirred at room temperature for 45min. After complete conversion is monitored by LCMS, the mixture is diluted with water and ethyl acetate. Each layer is separated. The water layer is extracted with EtOAc (2x15mL). The combined organic layer is dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue is purified on a silica gel column using DCM / MeOH (100:0 to 95:5) as eluent to provide the title compound (169mg, 74% yield) as a white solid.

[1248] LCMS(MA)RT=2.69min,m / z=542.1(M+H) + .

[1249] Step 4

[1250] To a suspension of the title compound from step 3 (100 mg, 0.18 mmol) in dry 1,4-dioxane (3 mL) in a sealed tube was added lithium chloride (23 mg, 0.55 mmol) and the mixture was degassed by bubbling with argon for 10 min. Tributyl(vinyl)stannane (65 μL, 0.22 mmol) and Pd(PPh 3 ) 4(21 mg, 0.02 mmol), and the reactant was stirred at 100 ° C for 3 h with a sand bath. After complete conversion was monitored by LCMS, the mixture was cooled to room temperature. The mixture was diluted with water and ethyl acetate and the layers were separated. The aqueous layer was extracted with EtOAc (2x15 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC: column WatersXSelect C18 19*100mm, 5μm, [(NH 4 ) 2 CO 3 Aqueous solution 2 g / L / ACN], 19 ml / min, room temperature, 40% B to 60% B in 7 min to afford the desired product (71 mg, 55% yield) as a beige solid.

[1251] LCMS(MA)RT=2.36min,m / z=420.2(M+H) + .

[1252] LCMS(MC)RT=2.35min,m / z=420.2(M+H) + .

[1253] 1 H NMR (400MHz, DMSO)8.98(1H,d,J=7.6Hz),8.56(1H,s),7.76(1H,ls),7.08-7.07(1H,m),6.68-6.61(2H,m ),6.53-6.52(1H,m),6.09(1H,t,J=5.9Hz),5.79(1H,dd,J=1.1,17.7Hz),5.22(1H,dd,J=1.1,10.8Hz),4. 93(1H,d,J=10.6Hz),4.48-4.39(2H,m),3.95(1H,t,J=10.9Hz),3.91-3.83(1H,m),3.61-3.49(2H,m),3.4 3-3.36(1H,m),3.26-3.18(2H,m),2.44(1H,dd,J=8.1,12.4Hz),2.01-1.93(1H,m),1.15(3H,t,J=7.0Hz).

[1254] Examples 105 and 106: E1-(8R*,12R,14S)-4,12-dimethoxy-8-methyl-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° ,23 ]pentacosane-1(23),2,4,6(25),17(24),18,21-hepten-11-one / E2-(8R*,12R,14S)-4,12-dimethoxy-8-methyl-16-oxa-7,10,20,21,24-pentazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2,4,6(25),17(24),18,21-heptaen-11-one

[1255]

[1256] Step 1

[1257] To a suspension of sodium hydride (60% in oil) (3.2 g, 80.0 mmol) in dry THF (25 mL) at 0°C was added a solution of pyrrolidine P1 (9.25 g, 40.0 mmol) in THF (25 mL). After 30 min, 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine (9.3 g, 40.01 mmol) was added and the mixture was stirred at 0°C for 15 min and then at room temperature for 4 h. The mixture was carefully diluted with water and EtOAc (250 ml) was added. The layers were separated. The aqueous layer was extracted with EtOAc (2x100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to provide the title compound (17 g, 99% yield) as a yellow oil.

[1258] LCMS(MA)RT=2.84min,m / z=429.1(M+H) + .

[1259] Step 2

[1260] To a suspension of the title compound (3.33 g, 7.79 mmol) from step 1 in acetonitrile (10 mL) was added 4 M HCl (9.75 mL, 38.9 mmol) in 1,4-dioxane. The mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure to provide the title compound (2.83 g, quantitative) as a yellow foam. The crude product was used in the next step without further purification.

[1261] LCMS(MA)RT=1.29min,m / z=329.1(M+H) + .

[1262] Step 3

[1263] To the solution of the title compound (2.46g, 6.76mmol) from step 2 in DCM (60ml) was added triethylamine (2.83mL, 20.28mmol), which was stirred for 5min, and then 2-(tert-butyldimethylsilyloxy) propanal (2.54g, 8.11mmol) was added. After 15min, sodium triacetoxyborohydride (2.15g, 10.14mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After complete conversion was monitored by LCMS, the reaction mixture was diluted in DCM (60mL), and the aqueous solution was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane / EtOAc (100 / 0 to 6 / 4) as eluent to provide the title compound (2.66g, 78% yield) as a colorless oil.

[1264] LCMS(MA)RT=2.37min,m / z=501.2(M+H) + .

[1265] Step 4

[1266] Aniline A3 (1.98 g, 7.96 mmol), tetrakis(triphenylphosphine)palladium(0) (139 mg, 0.12 mmol), Xphos (114 mg, 0.24 mmol) and tripotassium phosphate (3.9 g, 18.36 mmol) were added to a solution of the title compound (3.06 g, 6.12 mmol) from step 3 in dioxane / water (30 / 7 mL). The reaction mixture was degassed by bubbling under argon for 15 min and stirred at 90 ° C for 4 h. After complete conversion was monitored by LCMS, the mixture was cooled to room temperature and diluted with water and EtOAc. The layers were separated. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane / EtOAc-EtOH (3: 1) (100: 0 to 6: 4) as eluent to provide the title compound (3.21 g, 97% yield) as a yellow oil.

[1267] LCMS(MA)RT=2.04min,m / z=542.4(M+H) + .

[1268] Step 5

[1269] Pyridine (0.62 mL, 7.7 mmol) was added to a solution of the title compound (3.21 g, 5.9 mmol) from step 4 in acetonitrile (45 mL), followed by portionwise addition of 2-nitrobenzenesulfonyl chloride (1.44 g, 6.5 mmol). The reaction mixture was stirred at room temperature for 2 h. After complete conversion was monitored by LCMS, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane / EtOAc-EtOH (3: 1) (100: 0 to 6: 4) as eluent to provide the title compound (3.8 g, 88% yield) as a yellow foam.

[1270] LCMS(MA)RT=2.49min,m / z=727.3(M+H) + .

[1271] Step 6

[1272] To the solution of the title compound (3.8g, 5.23mmol) from step 5 in THF (100mL), a solution of TBAF (5.75mL, 5.75mmol) was added. The reaction mixture was stirred at room temperature for 72h. After complete conversion was monitored by LCMS, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using DCM / MeOH (100 / 0 to 9 / 1) as eluent, to provide the title compound (3.62g, containing traces of TBAF) as yellow foam.

[1273] LCMS(MA)RT=1.78min,m / z=613.3(M+H) + .

[1274] Step 7

[1275] The title compound (3.31g, 5.4mmol) from step 6 in THF (30ml) and DIAD (3.18mL, 16.2mmol) in toluene (30mL) were slowly added dropwise (over 1 hour) and triphenylphosphine (4.25g, 16.2mmol) heated at 90 ° C was added in toluene (300mL) at the same time. The reaction mixture was heated at 90 ° C for 1h. After complete conversion was monitored by LCMS, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using DCM / MeOH (100 / 0 to 9 / 1) as eluent. Cyclohexane / EtOAc-EtOH (3: 1) (100 / 0 to 3 / 7) was used as eluent for the second flash chromatography to provide the title compound (700mg, 1.17mmol, 22% yield) as a cream foam.

[1276] LCMS(MA)RT=2.05min,m / z=595.2(M+H) + .

[1277] Step 8

[1278] To the solution of the title compound (700mg, 1.17mmol) from step 7 in acetonitrile / water (60mL / 20mL) was added sodium bicarbonate (0.983g, 11.7mmol). The reaction mixture was stirred at 45 ° C for 30min, and then iodine (1.9g, 8.77mmol) was added. The reaction mixture was stirred at 45 ° C for 3h. After complete conversion was monitored by LCMS, the reaction mixture was quenched with saturated sodium thiosulfate solution (100mL). The mixture was mixed with DCM (200mL) and extracted with water (100mL) and brine (100mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using DCM / MeOH (100 / 0 to 9 / 1) as eluent to provide the title compound (0.5g, 0.82mmol, 70%) as a cream solid.

[1279] LCMS(MA)RT=2.50 / 2.58min,m / z=609.2(M+H) + .

[1280] Step 9

[1281] To a suspension of the title compound (0.5 g, 0.82 mmol) from step 8 in THF / acetonitrile (40 mL / 4 mL) was added cesium carbonate (0.534 g, 1.64 mmol) and 4-methylthiophenol (0.122 g, 0.98 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using DCM / MeOH (100:0 to 90:10) as eluent to provide the title compound (0.18 g, 52% yield) as a cream solid.

[1282] LCMS(MA)RT=2.90min,m / z=424.4(M+H) + .

[1283] Step 10

[1284] The mixture of 2 diastereomers obtained in step 9 was separated by chiral preparative HPLC using the following conditions: Column Daicel IA 19×250 mm, 5 um (C7 / IPA) (75 / 25) + 0.1% DEA 19 ml / min, RT 30 min

[1285] Example 105 As E1-(8R*,12R,14S)-4,12-dimethoxy-8-methyl-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ] Pentacosane-1(23),2,4,6(25),17(24),18,21-heptaen-11-one (10 mg, 5.8% yield) as a white solid

[1286] LCMS(MA)RT=2.10min,m / z=424.3(M+H) + .

[1287] LCMS(MC)RT=2.11min,m / z=424.3(M+H) + .

[1288] Chiral HPLC method RT = 11.838min, ee 99.5%

[1289] 1 H NMR (400 MHz, CDCl 3 )8.53-8.50(1H,m),8.33-8.31(1H,m),7.57(1H,s),6.62-6.61(1H,m),6 .43-6.39(1H,m),6.12-6.11(1H,m),5.12(1H,d,J=11.0Hz),4.52(1H,d,J =9.9Hz),4.25(1H,dd,J=8.3,9.8Hz),3.85-3.84(6H,m),3.66-3.60(5H,m ), 2.68 (1H, dd, J = 7.7, 12.8 Hz), 2.13-2.06 (1H, m), 1.37 (3H, d, J = 5.7 Hz).

[1290] Example 106 As E2-(8R*,12R,14S)-4,12-dimethoxy-8-methyl-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2,4,6(25),17(24),18,21-heptaen-11-one (25 mg, 14.7% yield) as a white solid

[1291] LCMS(MA)RT=2.17min,m / z=424.2(M+H) + .

[1292] LCMS(MC)RT=2.11min,m / z=424.2(M+H) + .

[1293] Chiral HPLC method RT = 15.825min, ee 99.5%

[1294] 1 H NMR (400 MHz, CDCl 3 )8.53-8.50(1H,m),8.37(1H,s),8.10(1H,s),6.65(1H,s),6.44-6.41 (1H,m),6.16-6.14(1H,m),5.46-5.43(1H,m),4.43-4.38(1H,m),4.24 (1H,dd,J=7.3,10.2Hz),3.93-3.80(6H,m),3.72-3.62(5H,m),2.65(1H,dd,J=7.4,12.3Hz),2.20-2.12(1H,m),1.48-1.45(3H,d,J=6.8Hz).

[1295] Example 109: (12R, 14S)-12-methoxy-4-(1,2,4-oxadiazol-5-yl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

[1296]

[1297] Step 1

[1298] To a solution of intermediate I23 (1.10 g, 1.87 mmol) in methanol (17.6 mL) was added 1 M sodium hydroxide solution (2.052 mL, 2.05 mmol) and 30% hydrogen peroxide solution (0.212 mL, 2.05 mmol). The reaction mixture was stirred at 40 ° C for 1 h. After complete conversion was monitored by LCMS, the solvent was removed under reduced pressure. The crude was diluted with water (20 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (2x10 mL), and the combined organic layer was washed with brine (2x20 mL) and purified by Na2 SO 4 Dry, filter and concentrate under reduced pressure.The residue was purified by flash column chromatography using DCM / MeOH (100 / 0 to 95 / 5) as eluent to afford the title compound (0.19 g, 17% yield) as a yellow solid.

[1299] LCMS(MA)RT=2.02min,m / z=608.1(M+H) + .

[1300] Step 2

[1301] To a stirred solution of the title compound (0.19 g, 0.32 mmol) from step 1 in 1,4-dioxane (1.3 mL) was added dimethoxy-N,N-dimethylmethylamine (0.05 mL, 0.38 mmol). The reaction mixture was stirred at 50 ° C for 2 h. After complete conversion was monitored by LCMS, the reaction mixture was concentrated under vacuum to provide the title compound (0.168 g, 80% yield) as a yellow solid. The crude product was used directly in the next step without further purification.

[1302] LCMS(MA)RT=2.10min,m / z=663.2(M+H) + .

[1303] Step 3

[1304] To a stirred solution of the title compound (0.168 g, 0.25 mmol) from step 2 in ethanol (5 mL) was added hydroxylamine hydrochloride (0.021 g, 0.30 mmol). The reaction mixture was stirred at 90 ° C for 4 days, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using cyclohexane / EtOAc (100 / 0 to 0 / 100) as eluent to provide the title compound (0.105 g, 65% yield) as a white solid.

[1305] LCMS(MA)RT=2.43min,m / z=633.2(M+H) + .

[1306] Step 4

[1307] The title compound (0.105g, 0.17mmol) and cesium carbonate (0.108g, 0.33mmol) from step 3 are dissolved in DMF (3.7mL). 4-methylthiophenol (0.025g, 0.20mmol) is added, and the mixture is stirred at room temperature overnight. After being completely converted by LCMS monitoring, the reaction mixture is filtered and the solvent is evaporated under vacuum. The residue is purified by flash column chromatography using cyclohexane / EtOAc (100 / 0 to 0 / 100) as eluent, to provide the expected product (36mg, 48% yield) as a white solid.

[1308] LCMS(MA)RT=2.87min,m / z=448.4(M+H) + .

[1309] LCMS(MC)RT=2.05min,m / z=448.4(M+H) + .

[1310] 1 H NMR(400MHz,DMSO)9.09(1H,s),9.04-9.01(1H,m),8.68(1H,s),8.10(1H,s) ,7.63(1H,s),7.26(1H,s),6.70(1H,d,J=7.6Hz),6.65-6.55(1H,m),4.97(1 H,d,J=10.8Hz),4.51-4.49(1H,m),4.35(1H,t,J=8.7Hz),4.05-3.94(1H,m) ,3.59-3.53(1H,m),3.40-3.37(1H,m),3.33-3.29(6H,m),2.01-1.93(1H,m);

[1311] Example 119: (12R, 14S)-12-methoxy-4-(1-methyl-1H-1,2,3-triazol-4-yl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2,4,6(25),17(24),18,21-heptaen-11-one

[1312]

[1313] Step 1

[1314] 1M tetrabutylammonium fluoride (0.780mL, 0.78mmol) in THF was added dropwise to a solution of intermediate I32 (0.50g, 0.71mmol) in THF (3.5mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. After complete conversion was monitored by LCMS, the reaction mixture was poured into ice water and stirred for 20min. The aqueous phase was extracted with EtOAc (2x15mL), and the combined organic phase was washed with saturated brine (15mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on a silica gel column using cyclohexane / EtOAc (30 / 70) as eluent, to provide the title compound (0.151g, 36% yield) as a light brown solid.

[1315] LCMS(MA)RT=2.46min,m / z=404.4(M+H) + .

[1316] Step 2

[1317] To a solution of the title compound from step 1 (0.05 g, 0.08 mmol) in water (0.18 mL) and tert-butanol (0.05 mL) was added iodomethane (6 uL, 0.10 mmol), sodium azide (6 mg, 0.09 mmol), CuI (3 mg, 0.02 mmol) and sodium L-ascorbate (3 mg, 0.02 mmol). The reaction mixture was stirred and heated to 75 ° C overnight. LCMS showed that the reaction was incomplete, so additional iodomethane (6 uL, 0.10 mmol), sodium azide (6 mg, 0.09 mmol), CuI (3 mg, 0.02 mmol) and sodium L-ascorbate (3 mg, 0.02 mmol) in water (0.18 mL) and tert-butanol (0.05 mL) were added. The reaction mixture was stirred and heated at 75 ° C for 24 h. After 75% conversion was monitored by LCMS, the mixture was then diluted with dichloromethane and filtered out. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under vacuum to afford the title compound as a solid (36 mg, 66% yield). The crude was used directly in the next step without further purification.

[1318] LCMS(MA)RT=2.16min,m / z=646.4(M+H) + .

[1319] Step 3

[1320] The title compound from step 2 (36 mg, 0.06 mmol) and cesium carbonate (0.04 g, 0.11 mmol) were suspended in N,N-dimethylformamide (1 mL). 4-Methylthiophenol (0.01 g, 0.07 mmol) was added and the mixture was stirred at room temperature for 2 hours. After complete conversion monitored by LCMS, the reaction mixture was poured into water and then diluted with ethyl acetate. The suspension was filtered off and the organic layer was washed with brine and purified by Na 2 SO 4 Dry, filter and remove the solvent under reduced pressure.The residue was purified by flash column chromatography on silica gel column using DCM / MeOH (95 / 5) as eluent to afford the desired product (20 mg, 78% yield) as off-white solid.

[1321] LCMS(MA)RT=1.80min,m / z=461.4(M+H) + .

[1322] LCMS(MC)RT=1.80min,m / z=461.4(M+H) + .

[1323] 1 H NMR (400 MHz, CDCl 3 )8.54-8.51(1H,m),8.42(1H,s),7.90(1H,s),7.79(1H,s),7.46(1H,s) ,7.02(1H,s),6.44-6.41(1H,m),5.11(1H,d,J=10.8Hz),4.54(1H,t,J=8 .3Hz),4.19-4.18(4H,m),3.91-3.72(2H,m),3.65(4H,s),3.37-3.29(1H ,m),2.66(1H,dd,J=8.3,13.2Hz),2.19-2.11(1H,m),1.29-1.27(1H,m);

[1324] Example 120: (12R, 14S)-4-methoxy-12-(oxetane-2-ylmethoxy)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2,4,6(25),17(24),18,21-heptaen-11-one

[1325]

[1326] Step 1

[1327] In a sealed test tube, to a suspension of intermediate I27 (400 mg, 0.69 mmol) in dry THF (0.8 mL) was added n-tetrabutylammonium bromide (78 mg, 0.24 mmol) and 32% w aqueous sodium hydroxide solution (1.30 mL, 10.35 mmol). The mixture was stirred for 30 min and 2-(bromomethyl)oxetane (520 mg, 3.45 mmol) was added. The reactants were stirred at 80 ° C for 2 h. After complete conversion was monitored by LCMS, the reaction was stopped and cooled to room temperature. The mixture was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with EtOAc (2x15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC: column Waters XSELECT C18 19*100mm, 5μm, A: (NH 4 ) 2 CO 3 Aqueous solution 2g / L, B: CA N 19ml / min, room temperature, 30% B to 45% B in 7min. The expected fractions were collected and evaporated under reduced pressure. A second purification was performed by preparative TLC 0.25mm using DCM / MeOH (9: 1) as eluent. The compound was stripped and the silica gel was dissolved with DCM / MeOH 8: 2. The suspension was filtered and the solvent was evaporated under reduced pressure to provide the expected product as a beige solid (7mg, 0.02mmol, 2%).

[1328] LCMS(MA)RT=1.99min,m / z=466.4(M+H) + .

[1329] LCMS(MC)RT=1.99min,m / z=466.4(M+H) + .

[1330] 1 H NMR (400 MHz, CDCl 3)8.51(1H,d,J=7.4Hz),8.32(1H,s),7.55(1H,ls),6.61-6.59(1H,m),6.41(1H,d,J=7.6Hz),6.11-6.09(1H ,m),5.12-5.07(1H,m),5.07-5.00(1H,m),4.74-4.68(1H,m),4.65-4.59(1H,m),4.52-4.44(2H,m),4.20(1H ,dd,J=3.2,11.2Hz),3.93(1H,dd,J=6.6,11.3Hz),3.89-3.81(1H,m),3.84(3H,s),3.77-3.71(1H,m),3.67- 3.60(1H,m),3.60-3.52(1H,m),3.32-3.24(1H,m),2.76-2.63(2H,m),2.58-2.50(1H,m),2.24-2.17(1H,m);

[1331] Example 139: (12R, 14S)-18-(2-hydroxyethoxy)-4-methoxy-12-(2-methoxyethoxy)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2,4,6(25),17(24),18,21-heptaen-11-one

[1332]

[1333] Following general synthetic scheme 1, as depicted for the synthesis of Example 1, skeleton S3, pyrrolidine P7 and aniline A3 were used to obtain (12R,14S)-18-(benzyloxy)-4-methoxy-12-(2-methoxyethoxy)-7-(2-nitrobenzenesulfonyl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.12,6.010,14.020,23]pentacosane-1(23),2(25),3,5,17(24),18,21-hepten-11-one as intermediate I34.

[1334] Step 1

[1335] To a solution of intermediate I34 (5.46 g, 7.34 mmol) in TFA (92 mL) was added anisole (32.06 mL, 7.34 mmol). The reaction mixture was stirred overnight at 110 ° C. After complete conversion was monitored by LCMS, the mixture was cooled at room temperature and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using DCM / MeOH (100 / 0 to 95 / 5) as eluent to provide the title compound (4.66 g, 97% yield) as a brown solid.

[1336] LCMS(MA)RT=2.30min,m / z=655.2(M+H) + .

[1337] Step 2

[1338] To a suspension of the title compound from step 1 in DMF (2 mL) was added potassium carbonate (63 mg, 0.46 mmol) and 2-(2-bromoethoxy)oxane (0.028 mL, 0.18 mmol). The reaction mixture was stirred at 80 ° C for 60 min. The reaction mixture was filtered and concentrated under reduced pressure to provide the title compound as a light brown solid (120 mg, 100% yield). The crude was used directly in the next step without further purification.

[1339] LCMS(MA)RT=2.66min,m / z=783.3(M+H) + .

[1340] Step 3

[1341] The title compound (0.12g, 0.15mmol) and cesium carbonate (0.10g, 0.31mmol) from step 2 are suspended in N, N-dimethylformamide (1mL). 4-Methylthiophenol (0.023g, 0.18mmol) is added, and the mixture is stirred at room temperature for 2 hours. After complete conversion is monitored by LCMS, the reaction mixture is poured into water and then diluted with ethyl acetate. The suspension is filtered. The organic layer is washed with brine, dried over sodium sulfate, filtered and the solvent is removed under reduced pressure. The residue is purified by flash chromatography using DCM / MeOH (95 / 5) as eluent to provide the title compound (70mg, 76% yield) as a beige solid.

[1342] LCMS(MA)RT=1.99min,m / z=466.4(M+H) + .

[1343] Step 4

[1344] To the solution of the title compound (0.067g, 0.11mmol) from step 3 in MeOH (1.3mL) and water (0.2mL) was added p-toluenesulfonic acid monohydrate (0.107g, 0.56mmol), and the reaction mixture was stirred at 65 ° C for 16h. After complete conversion was monitored by LCMS, the reaction mixture was dissolved in ethyl acetate and then saturated sodium bicarbonate aqueous solution was added. After separation, the water layer was extracted with ethyl acetate (2x). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to provide the expected product (31mg, 54% yield) as a light yellow solid.

[1345] LCMS(MA)RT=1.81min,m / z=514.4(M+H) + .

[1346] LCMS(MC)RT=1.80min,m / z=514.3(M+H) + .

[1347] 1 H NMR (400MHz, DMSO)8.77(1H,s),8.36-8.35(1H,m),7.43-7.43(1H,m),6.52(1H,d,J= 0.8Hz),6.07-6.01(2H,m),4.99-4.92(2H,m),4.46(2H,t,J=8.8Hz),4.13-3.90(4H,m ),3.77(2H,s),3.72(2H,s),3.65(1H,s),3.58-3.51(1H,m),3.48(2H,t,J=4.8Hz),3 .43-3.36(1H,m),3.27-3.26(6H,m),2.46(1H,dd,J=7.5,12.9Hz),2.00-1.96(1H,m);

[1348] Example 142: (12R, 14S)-4,12-dimethoxy-9-methyl-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

[1349]

[1350] Step 1

[1351] To a solution of pyrrolidine P1 (5.97 g, 25.81 mmol) in dry DMF (83 mL) was added 60% sodium hydride in mineral oil (1.72 g, 43.02 mmol) at 0°C. After 30 min, 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (5.00 g, 21.51 mmol) was added and the mixture was stirred at room temperature for 1 h. After complete conversion monitored by LCMS, water was carefully added dropwise at 0°C and the mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under vacuum.The residue was purified by flash chromatography using cyclohexane / EtOAc (100 / 0 to 60 / 40) as eluent to afford the title compound as an orange oil (5.55 g, 60% yield).

[1352] LCMS(MA)RT=2.72min,m / z=427.1 / 429.1(M+H) + .

[1353] Step 2

[1354] To the suspension of the title compound (5.55g, 12.99mmol) from step 1 in acetonitrile (130mL) is added 4M hydrogen chloride solution (16.24mL, 64.97mmol) in 1,4-dioxane. The reaction mixture is stirred overnight. After complete conversion by LCMS monitoring, the solvent is removed under reduced pressure to provide the title compound (4.84g, quantitative yield) as a yellow solid. The crude product is directly used in the next step without further purification.

[1355] LCMS(MA)RT=1.17min,m / z=327.2 / 329.2(M+H) + .

[1356] Step 3

[1357] Potassium carbonate (5.99g, 43.32mmol) and ethyl 2-bromopropionate (5.23g, 28.88mmol) were added to a solution of the title compound (4.72g, 14.44mmol) from step 2 in acetonitrile (114mL). The reaction mixture was stirred overnight at 50 °C. After complete conversion was monitored by LCMS, a 1N NaOH aqueous solution was added and the reaction mixture was stirred for 10 minutes. Water and ethyl acetate were added to the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography using cyclohexane / EtOAc (100 / 0 to 70 / 30) as eluent to provide the title compound (4.729g, 77% yield) as a yellow oil.

[1358] LCMS(MA)RT=1.72 / 1.83min,m / z=427.1 / 429.1(M+H) + .

[1359] Step 4

[1360] Sodium borohydride (1.26 g, 33.20 mmol) and calcium chloride (1.84 g, 16.60 mmol) were added to a suspension of the title compound (4.73 g, 11.07 mmol) from step 3 in a mixture of EtOH / THF (60 mL / 60 mL) cooled at 0 ° C. The solution was allowed to reach room temperature and stirred at room temperature for 4 h. The reaction mixture was quenched by adding water and 1M aqueous HCl until pH = 4. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography using cyclohexane / AE (100 / 0 to 0 / 100) as eluent to provide the title compound (1.23 g, 29% yield) as a yellow oil.

[1361] LCMS(MA)RT=1.21 / 1.24min,m / z=385.3 / 385.3(M+H) + .

[1362] Step 5

[1363] To a solution of the title compound from step 4 (1.23 g, 3.20 mmol) in DMF (18 mL) was added imidazole (0.653 g, 9.59 mmol) and tert-butyldimethylsilyl chloride (1.44 g, 9.59 mmol). The reaction mixture was stirred at room temperature overnight. After complete conversion as monitored by LCMS, saturated NaHCO 3The aqueous solution was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using cyclohexane / EtOAc (100 / 0 to 70 / 30) as eluent to provide the title compound (1.279 g, 80% yield) as a yellow oil.

[1364] LCMS(MA)RT=2.20 / 2.25min,m / z=499.2 / 501.2(M+H) + .

[1365] Step 6

[1366] The title compound from step 5 (1.18 g, 2.36 mmol), aniline A3 (0.76 g, 3.07 mmol), Xphos (0.045 g, 0.09 mmol) and K 3 PO 4 The mixture of (1.50g, 7.08mmol) was dissolved in 1,4-dioxane / water (15mL / 5mL) and degassed with argon for 15min. Tetrakis (triphenylphosphine) palladium (0) (0.055g, 0.05mmol) was added, and the reaction mixture was stirred at 110 ° C for 1h. After being completely converted by LCMS monitoring, the reaction mixture was cooled and filtered on diatomaceous earth, and then the solvent was evaporated. The residue was purified by column chromatography using cyclohexane / EtOAc (100 / 0 to 40 / 60) as eluent, to provide the title compound (1.33g, quantitative yield) as a yellow oil.

[1367] LCMS(MA)RT=2.00 / 2.04min,m / z=542.5(M+H) + .

[1368] Step 7

[1369] Pyridine (0.29 mL, 3.54 mmol) and 2-nitrobenzene-1-sulfonyl chloride (0.68 g, 3.07 mmol) were added to a solution of the title compound (1.28 g, 2.36 mmol) from step 6 in acetonitrile (33 mL). The reaction mixture was stirred at room temperature overnight. After complete conversion was monitored by LCMS, the solvent was removed under reduced pressure and the residue was poured into water (40 mL) and EtOAc (80 mL). The aqueous layer was extracted with EtOAc (3x40 mL), and the organic layer was washed with brine (2x40 mL) and purified by Na 2 O 4 '-trifluoroacetic acid (THF). 2 SO 4 Dry, filter and concentrate under reduced pressure to afford the title compound as a red solid (1.88 g, quantitative yield).The crude was used directly in the next step without further purification.

[1370] LCMS(MA)RT=2.38min,m / z=727.5(M+H) + .

[1371] Step 8

[1372] 1M tetrabutylammonium fluoride (4.749mL, 4.75mmol) in THF is added to the solution of the title compound (1.73g, 2.37mmol) from step 7 in THF (21mL) at room temperature. The resulting reaction mixture is stirred at room temperature for 2h. After complete conversion by LCMS monitoring, the reaction mixture is diluted with saturated ammonium chloride solution and extracted with ethyl acetate 2 times. The combined organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography using DCM / MeOH (100 / 0 to 95 / 5) as eluent, to provide the title compound (1.653g, quantitative yield) as a brown solid.

[1373] LCMS(MA)RT=1.80min,m / z=613.3(M+H) + .

[1374] Step 9

[1375] At 90 ℃, the title compound (1.45g, 2.37mmol) from step 8 in Me-THF (71ml) and DIAD (1.399ml, 7.12mmol) in toluene (71ml) are added dropwise to a solution of triphenylphosphine (1.87g, 7.12mmol) in toluene (237ml) for 1.5h. After complete conversion by LCMS monitoring, the solvent is removed under reduced pressure. Residue is purified by column chromatography using cyclohexane / EtOAc (100 / 0 to 50 / 50). Desired fractions are collected and evaporated. Residue is ground in ether to provide the title compound (1.52g, 37% yield) as a yellow oil.

[1376] LCMS(MA)RT=2.76min,m / z=595.4(M+H) + .

[1377] Step 10

[1378] The title compound from step 9 (1.41 g, 2.37 mmol) was dissolved in THF / H 2Sodium bicarbonate (3.99 g, 47.49 mmol) and iodine (9.04 g, 35.62 mmol) were added to the mixture in O (185 mL / 49 mL). The reaction mixture was stirred at 60 ° C for 1 h. After complete conversion was monitored by LCMS, the reaction mixture was quenched with a saturated sodium thiosulfate solution and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography using cyclohexane / EtOAc (100 / 0 to 30 / 70) as eluent to provide the title compound (0.539 g, 37% yield) as a yellow solid.

[1379] LCMS(MA)RT=2.62min,m / z=609.3(M+H) + .

[1380] Step 11

[1381] To a solution of the title compound from step 10 (0.54 g, 0.89 mmol) in DMF (20 mL) were added lithium hydroxide (0.127 g, 5.31 mmol) and DL-cysteine ​​(0.13 g, 1.06 mmol), and the mixture was stirred at room temperature overnight. After complete conversion monitored by LCMS, water was added and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated brine, and the mixture was stirred overnight at room temperature. 2 SO 4 Dried, filtered and concentrated to dryness.The crude was triturated in acetonitrile to afford the desired product (0.201 g, 54% yield) as a white solid.

[1382] LCMS(MA)RT=2.10min,m / z=424.4(M+H) + .

[1383] LCMS(MC)RT=2.10min,m / z=424.4(M+H) + .

[1384] 1H NMR(400MHz,DMSO)8.97(1H,dd,J=7.6,9.7Hz),8.60(0.63H,s),8.47(0.37H,s),7.99(0.63H,s),7.22(0.37H,s),6.67-6.60(1.6 3H,m),6.48(0.37H,dd,J=1.0,2.2Hz),6.21(0.37H,t,J=5.8Hz),6.14-6.02(1.63H,m),5.28(0.63H,d,J=11.6Hz),4.87-4.83(0. 37H,m),4.52-4.47(0.37H,m),4.36(0.63H,dd,J=7.3,10.2Hz),4.21(1H,t,J=8.6Hz),4.12-3.98(1.37H,m),3.73-3.72(4H,m),3 .64-3.55(0.63H,m),3.45-3.41(4H,m),2.47-2.30(1H,m),2.03-1.95(1H,m),1.45(1.11H,d,J=6.8Hz),1.28(1.89H,d,J=6.8Hz);

[1385] Example 146: (12R, 14S)-4-ethynyl-18-methoxy-12-(2-methoxyethoxy)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2 ,6.0 1° , 1 4.0 2° , 23 ]pentacosane-1(23),2,4,6(25),17(24),18,21-heptaen-11-one

[1386]

[1387] Following General Synthetic Scheme 1, as depicted for the synthesis of Example 1, skeleton S2, pyrrolidine P7 and aniline A9 were used to obtain (12R,14S)-4-(benzyloxy)-18-methoxy-12-(2-methoxyethoxy)-7-(2-nitrobenzenesulfonyl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.12,6.010,14.020,23]pentacosane-1(23),2(25),3,5,17(24),18,21-hepten-11-one as intermediate I35.

[1388] LCMS(MA)RT=2.77min,m / z=745.3(M+H) + .

[1389] Step 1

[1390] To a solution of intermediate I35 (80 mg, 0.107 mmol) in TFA (1 mL) was added anisole (0.5 mL, 4.30 mmol). The reaction mixture was stirred at 130 ° C for 40 min. After complete conversion was monitored by LCMS, the mixture was cooled at room temperature and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using DCM / methanol (100 / 0 to 98 / 2) as eluent to provide the title compound (65 mg, 93% yield) as a light brown solid.

[1391] LCMS(MA)RT=2.20min,m / z=655.2(M+H) + .

[1392] Step 2

[1393] To triethylamine (0.02mL, 0.148mmol) and the title compound (65mg, 0.099mmol) from step 1 in a solution in dichloromethane (5mL), N-phenyl-bis (trifluoromethanesulfonimide) (39mg, 0.109mmol) is added portionwise, and the reaction mixture is stirred at room temperature for 5h. After being completely converted by LCMS monitoring, water (5mL) is added to the reaction solution. After this, the reaction solution is extracted with dichloromethane (3x5mL), the organic layer combined is washed with salt water (10mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide the title compound (80mg, assumed, quantitative) as a slightly yellow amorphous solid. The crude product is directly used further in the next step without purification.

[1394] LCMS(MA)RT=2.77min,m / z=787.2(M+H) + .

[1395] Step 3

[1396] To the solution of the title compound (80mg, assuming 0.099mmol) from step 2 in DMF (1mL), cesium carbonate (64mg, 0.148mmol) is added, and then 4-methylthiophenol (15mg, 0.119mmol) is added. The reactant is stirred at room temperature for 45min. After being completely converted by LCMS monitoring, the mixture is diluted with water (3mL) and ethyl acetate (3mL). Separate each layer. The water layer is extracted with EtOAc (2x3mL), and the combined organic layer is dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue is purified on silica gel column chromatography using DCM / MeOH (100:0 to 97.5:2.5) as eluent, to provide the title compound (40mg, 67% yield over 2 steps) as a slightly yellow amorphous solid.

[1397] LCMS(MA)RT=2.54min,m / z=602.3(M+H) + .

[1398] Step 4

[1399] In a microwave reactor, the title compound (15mg, 0.025mmol) from step 3 was degassed in a solution of dry acetonitrile / DMF (1.4:0.15mL) by bubbling with argon for 10min. Then, cesium carbonate (24mg, 0.075mmol), bis(acetonitrile)palladium dichloride (II) (0.6mg, 0.0025mmol), Xphos (2.4mg, 0.005mmol) and triethylsilyl acetylene (0.022mL, 0.125mmol) were added. The reaction mixture was stirred at 100°C for 1h under microwave irradiation. LCMS showed complete conversion and mainly formed the expected compound.

[1400] The reaction was repeated using similar conditions with the title compound (15 mg, 0.025 mmol) from step 3, but microwave radiation was maintained for 3 h. Two batches of reaction mixtures were merged, filtered on diatomaceous earth and concentrated in vacuo to provide the title compound (34 mg, quantitative, assumed) as a dark brown amorphous solid. The crude product was used directly in the next step without further purification.

[1401] LCMS(MA)RT=3.29min,m / z=592.4(M+H) + .

[1402] Step 5

[1403] Potassium carbonate (34 mg, 0.250 mmol) was added to a solution of the title compound (34 mg, assuming 0.050 mmol) from step 4 in methanol (1 mL). The reaction mixture was stirred at 50 ° C for 3 h. After complete conversion was monitored by LCMS, the reaction mixture was cooled to room temperature, then quenched with water (2 mL) and diluted with ethyl acetate (2 mL). The two layers were separated, and the aqueous layer was extracted 3 times with ethyl acetate (3x3 mL). The combined organic layer was washed with brine (3 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by preparative TLC using ethyl acetate / methanol (95: 5). The expected fraction was stripped, extracted with dichloromethane / methanol 9: 1, filtered out and concentrated in vacuo to provide the expected product (4 mg, 17% over 2 steps) as a light brown amorphous solid.

[1404] LCMS(MA)RT=2.26min,m / z=478.2(M+H) + .

[1405] LCMS(MC)RT=2.16min,m / z=478.3(M+H) + .

[1406] 1 H NMR (400 MHz, CDCl 3 )8.24-8.17(2H,m),7.86-7.86(1H,m),7.15-7.13(1H,m),6.67(1H,s),5. 12(1H,d,J=10.6Hz),4.53-4.48(1H,m),4.36(1H,t,J=8.7Hz),4.21-4.13 (1H,m),3.96(3H,s),3.93-3.79(3H,m),3.69-3.55(5H,m),3.43-3.41(3H ,m),3.29-3.23(1H,m),3.06(1H,s),2.76-2.70(1H,m),2.26-2.18(1H,m).

[1407] RIPK2 Assay (Amplified Luminescence Proximity Homogeneous Assay)

[1408] A non-specific kinase inhibitor (CZC-8004 Cayman #916603-07-1) bound to acceptor beads (#6772001 PerkinElmer) was mixed with recombinant hRIPK2 protein (kinase domain amino acids 1-299 - His-tagged - LifeTechnologies PR7829A) and Ni2+-labeled donor beads (#AS101D PerkinElmer). In the presence of inhibitor, signal loss occurred after displacement of compound beads from hRIPK2. (PerkinElmer, 6008280) added:

[1409] 2 μL RIPK2 inhibitor (in DMSO 0.8%).

[1410] 2 μL human recombinant RIPK2 (10 nM, diluted in AlphaLISA buffer 1X).

[1411] 4 μL of a mixture of donor compound-beads 1 / 1000 and acceptor Ni2+-beads 1 / 1000 in AlphaLISA buffer 1X.

[1412] Homogenize using a microtiter plate shaker and incubate at 23°C for 2 h.

[1413] Use according to manufacturer's instructions -Alpha reader (PerkinElmer).

[1414] + Indicates IC between 100nM and 1uM 50 , ++ indicates IC between 10nM and 100nM 50 , and +++ indicates IC 50 <10 nM; ND = not determined

[1415]

[1416]

[1417] Comparative table between the properties of representative compounds from WO2016 / 042087 and representative compounds from this patent application

[1418]

[1419]

[1420] Human protein bound free fraction data legend: + indicates F% below 0.1%, ++ indicates F% between 0.1-1%, and +++ indicates F% above 1%; ND = not determined

[1421] Human Clint data legend: + indicates hCl above 18 ug / min / mg protein, ++ indicates hCl between 6-18 ug / min / mg protein, and +++ indicates hCl equal to or below 5 ug / min / mg protein; ND = not determined

[1422] hERG q-patch inhibition data legend: + indicates IC50 below 1 uM, ++ indicates IC50 between 1-10 uM, and +++ indicates IC50 above 10 uM; ND = not determined

[1423] Human Clint protocol: Pooled liver microsomes (Sekisui Xenotech) were diluted at 0.5 mg / mL in 50 mM phosphate buffer (pH 7.4) and then pre-incubated at 37°C with 0.5 μM OD945 for 7 min. The reaction was started by adding pre-warmed cofactor (0.44 mM NADPH). Aliquots of the samples were taken at 0, 5, 10, 20 and 45 min and the reaction was stopped by adding cold acetonitrile containing the internal standard. The samples were centrifuged at 3000 g for 10 min at 4°C and then the amount of the parent compound remaining in the supernatant was analyzed by LC / MS / MS.

[1424] Human protein binding protocol: Compounds were added to plasma or brain homogenates and incubated at 2 μM in PBS buffer at 37°C in RED plates (Thermo n°96009, cutoff 8000 Da). After 4 h, aliquots of the plasma and buffer sides were transferred to wells containing acetonitrile and internal standards. After protein precipitation, samples were centrifuged and supernatants were injected in LC / MS / MS. Standards were prepared in the same matrix and processed as samples.

[1425] The unbound fraction (fu) was determined for each plasma sample as follows 血浆 ):

[1426]

[1427] hERG q-Patch Assay Protocol: Using Charles River hERG-HEK stably transfected cell lines were used to determine the potential of test compounds to inhibit hERG potassium channels on the Sophion Qube automated electrophysiology platform. The assay was performed at room temperature and hERG tail currents were recorded from the cell population using multi-well Qchips.

[1428] References

[1429] Becker et al., Curr. Rheum. Reports 2005 7:427-433

[1430] Brooks,The Oncologist 2013 1:e3-e5

[1431] Cai et al., Oncology Reports 2018 39:2915-2923

[1432] Chen et al., J. Pathol. 2020 250 2:170-182

[1433] Chin et al., Curr. Med. Chem. 2005 4 1:35-42

[1434] Duggan et al., Scientific reports 2017 7:1578

[1435] Franca et al., Scand. J. Rheumatol. 2016 45:8-12

[1436] Gambino et al., Assay Drug. Dev. Technol. 2017 15 1: 30-43

[1437] Girardin et al., EMBO Rep. 2001 2:736-742

[1438] Haile et al., J. Med. Chem. 2019 14:6482-6494

[1439] Hollenbach et al., JBC, 2005, 280: 14981-8

[1440] Hysi et al., Hum. Mol. Genet. 2005 14:935-941

[1441] Inaki et al., Genome Research 2014 24:1559

[1442] Inohara et al., J Biol Chem 2000 36:27823-31

[1443] Jaafar et al., Biochem. Biophys. Res. Commun. 2018 1: 115-121

[1444] Kabesh et al., J. Allergy Clin. Immunol. 2003 4:813-7

[1445] Lesage et al., Am. J. Hum. Genet. 2002 70:845-857

[1446] Liu et al., Cell. Biochem. Biophys. 2015 72 3:681-5

[1447] Maloney et al., JACS 2017 4(S1):S150

[1448] McGovern et al., Hum. Mol. Genet. 2005 14:1245-1250

[1449] Mertins et al., Nature 2016 7605:55-62

[1450] Miceli-Richard et al., Nature Genetics 2001 29:19-20

[1451] Negroni et al., Inflamm. Bowel Dis. 2009 8:1145-1154

[1452] Singel et al., Breast Cancer Res. 2014 16: R28

[1453] Som et al., World J. Clin. Cases 2019 4:405-418

[1454] Strober et al., Nat. Rev. Immunol. 2006 1:9-20

[1455] Stronati et al., Digestive and Liver Disease 2010 12:848-853

[1456] Tigno-Aranjuez et al., Genes Dev. 2010 1:2666-77

[1457] Uehara et al., Diag. Path. 2009 4:23

[1458] Vieira et al., J. Immunol. 2012 10:5116-5122

[1459] Wiken et al., J. Clin. Immunol. 2009 29:78-89

[1460] Wu et al., Mol. Cell. Proteomics 2011 10:1-14

[1461] Yamamoto et al., Microbes & Infections 2009 12:912-918

[1462] Yang et al., PLoS One 2012 8:e40196

[1463] Zare et al., Cancers 2018 10:184

[1464] Zhao et al., Biochem. Biophys. Res. Commun. 2017 2: 1151-1158

[1465] Zhou et al., Obesity 2015 7:1394-1400

Claims

1. A compound of formula I or a salt thereof, in R1 is selected from -halo, -OC 1-6 Alkyl, -alkynyl, -C 1-6 Alkyl, -C 3-6 -cycloalkyl, -C(O)-C 1-6 -alkyl, -C(O)-C 1-6 Cycloalkyl, -C(O)-Het2, -C(O)-NR a R b , -Het1 and -CN; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -halo, -OC 1-3 Alkyl, -C 3-6 -cycloalkyl, -Ph, -Het1, -Het2 and -OH; R2 and R 10 are each independently selected from -H and -halo; R3, R 3’ , R4, R 4’ , R7 and R8 are each -H; R5 is selected from -OH, -halo, -OC 1-6 Alkyl, -OC 3-5 -cycloalkyl and -C 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -OH, -C 1-6 Alkyl, -C 3-5 -cycloalkyl and -OC 1-6 alkyl; R6 is selected from -H, -halo, -C 1-6 Alkyl, -OC 1-6 Alkyl, and -Het3; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more -OC 1-6 Alkyl substitution; R9 is selected from -H, -C 1-6 Alkyl, -C(O)-C 1-6 Alkyl and -C(O)-OC 1-6 alkyl; R a Selected from -H and -C 1-6 alkyl; R b Selected from -H, -C 1-6 Alkyl and -OC 1-6 alkyl; Het1 and Het3 are each independently selected from a 5- or 6-membered aromatic heterocyclic ring having 1-3 heteroatoms selected from O and N, wherein each of said Het1 and Het3 is optionally substituted by 1-3 -C 1-6 Alkyl substitution; Het2 is selected from a 4-6 membered saturated heterocyclic ring having 1-3 O atoms.

2. The compound according to claim 1, wherein: R1 is selected from -halo, -OC 1-6 Alkyl, -alkynyl, -C 1-6 Alkyl, -C 3-6 -cycloalkyl, -C(O)-C 1-6 -alkyl, -C(O)-NR a R b , -Het1 and -CN; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from the group consisting of -D, -halo, and -OC 1-3 alkyl; R2 is selected from -H and -halo; R 10 Yes - H; R3, R 3’ , R4, R 4’ , R7 and R8 are each -H; R5 is selected from -OH, -halo, -OC 1-6 Alkyl, -OC 3-5 -cycloalkyl and -C 1-6 Alkyl; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more substituents selected from -D, -OH, -C 1-6 Alkyl, -C 3-5 -cycloalkyl and -OC 1-6 alkyl; R6 is selected from -H, -halo, -C 1-6 Alkyl, -OC 1-6 Alkyl and -Het3; the -C 1-6 Each of the alkyl groups is optionally substituted with one or more -OC 1-6 Alkyl substitution; R9 is -H; R a Selected from -H and -C 1-6 alkyl; R b Selected from -H, -C 1-6 Alkyl and -OC 1-6 alkyl; Het1 is a 5-membered aromatic heterocyclic ring having 1-3 heteroatoms selected from O and N, wherein said Het1 is optionally substituted by 1-3 -C 1-6 Alkyl substitution.

3. A compound selected from the group consisting of:

4. A compound according to any one of claims 1-2; wherein the carbon atom bearing the R8 substituent is in the S-configuration.

5. A compound according to any one of claims 1-2; wherein the carbon atom bearing the R5 substituent is in the R-configuration.

6. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 5.

7. Use of a compound as defined in any one of claims 1 to 5 or a composition according to claim 6 for the preparation of a human or veterinary medicine.

8. Use of a compound as defined in any one of claims 1 to 5 or a composition according to claim 6 for the preparation of a medicament for the diagnosis, prevention and / or treatment of a RIP2-kinase related disease.

9. Use of a compound as defined in any one of claims 1 to 5 or a composition according to claim 6 for the preparation of a medicament for the diagnosis, prevention and / or treatment of a RIP2-kinase related disease which is an inflammatory disorder.

10. Use of a compound as defined in any one of claims 1 to 5 or a composition according to claim 6 for the preparation of a medicament for the diagnosis, prevention and / or treatment of a RIP2-kinase-related disease selected from the group consisting of Crohn's disease, enteropathy, sarcoidosis, psoriasis, atopic dermatitis, allergic rhinitis, rheumatoid arthritis, asthma, insulin-resistant type 2 diabetes, obesity metabolic syndrome, cardiac hypertrophy, lupus, uveitis, Blau syndrome, granulomatous inflammation, Behcet's disease and multiple sclerosis.

11. Use of a compound as defined in any one of claims 1 to 5 or a composition according to claim 6 for the preparation of a medicament for the diagnosis, prevention and / or treatment of a RIP2-kinase related disease selected from ulcerative colitis and immune-mediated colitis.

12. Use of a compound as defined in any one of claims 1 to 5 or a composition according to claim 6 for the preparation of a medicament for the diagnosis, prevention and / or treatment of a RIP2-kinase related disease which is cancer.

13. Use of a compound as defined in any one of claims 1 to 5 or a composition according to claim 6 for the preparation of a medicament for the diagnosis, prevention and / or treatment of a RIP2-kinase related disease selected from breast cancer, head and neck cancer and glioma. The use according to claim 13 , wherein the breast cancer is inflammatory breast cancer.

Images