Macrocyclic RIP2-kinase inhibitor

Abstract

The present invention relates to macrocyclic compounds and compositions containing such compounds that act as kinase inhibitors, particularly inhibitors of RIP2 kinase and / or its mutants, for use in the diagnosis, prevention, and / or treatment of RIP2 kinase-related diseases. Additionally, the present invention provides methods of using the compounds, for example, as pharmaceutical or diagnostic agents.

Description

Technical Field

[0001] The present invention relates to kinase inhibitors, particularly macrocyclic compounds that act as inhibitors of RIP2-kinase and / or their mutants, and compositions containing such compounds, which are used in the diagnosis, prevention and / or treatment of RIP2-kinase related diseases. Further, the present invention provides methods of using such compounds, for example, as medicaments or diagnostic agents.

Background Art

[0002] Protein kinases constitute a large family of structurally related enzymes that are responsible for controlling diverse signal transduction processes in cells. Protein kinases have been shown to be major regulators in almost all cellular functions, including proliferation, intracellular metabolism, cell survival, apoptosis, DNA damage repair, cell motility, and the like. Uncontrolled signal transduction due to imperfect control of protein phosphorylation has been implicated in numerous diseases, including, for example, cancer, inflammation, allergy, immune diseases, CNS disorders, angiogenesis, and the like.

[0003] Among the family of protein kinases, one specific example is the receptor-interacting serine / threonine kinase that includes RIP2. RIP2 (receptor-interacting protein 2) is also known as Card-containing Ice-related kinase (CARDIAK), CARD3 (C-terminal caspase recruitment domain 3), receptor-interacting protein kinase 2 (RIPK2), or Rip-like interacting Clarp kinase (RICK). The RIP2 kinase consists of an N-terminal kinase domain and a C-terminal caspase recruitment domain (CARD) bound via an intermediate (IM) region (Non-Patent Document 1). The CARD domain of the RIP2 kinase mediates the interaction with other CARD-containing proteins, such as the nucleotide oligomerization domain proteins NOD1 and NOD2 (Non-Patent Documents 2 and 3). NOD1 and NOD2 are cytoplasmic receptors that are activated by specific bacterial peptidoglycan motifs and play important roles in the innate immune surveillance mechanism. When the cell interior is exposed to bacteria, NOD1 or NOD2 binds to the protein kinase RIP2, linking the NF-κB (nuclear factor κB)-mediated cytokine response. Once associated with NOD1 / 2, RIP2 autophosphorylates at Tyr474 (Y474) and acts as a molecular scaffold together with other kinases (TAK1, IKKβ) involved in NF-κB and MAPK activation (Non-Patent Document 4).

[0004] Both NOD1 / 2 and RIP2 are NF-κB-regulated genes, and thus, their activation results in a positive feedback loop, where the activation of NOD1 / 2:RIP2 stimulates further activation and further inflammation. Furthermore, the expression of NOD1 / 2 and RIP2 is stimulated by various inflammatory mediators, including TNF (tumor necrosis factor) and IFN (interferon). In addition to the activation of the NF-κB pathway, the NOD1 / 2:RIP2 complex stimulates autophagy, bactericidal activity, the surface expression of MHC class II, and the activation of MAPK (mitogen-activated protein kinase). Overall, this pathway regulates the innate immune system and helps to coordinate the adaptive immune response to eradicate the causative pathogen.

[0005] Aberrant regulation of RIP2-dependent signaling is associated with autoinflammatory diseases. Patients with dysfunctional NOD2 alleles tend to develop Crohn's disease, an inflammatory disorder of the gastrointestinal tract (Non-Patent Documents 5 and 6). Several groups have shown that the NOD2 / RIPK2 pathway is involved in the pathogenesis of IBD (Non-Patent Documents 7, 8, 9, 10). Negroni first showed upregulation of both NOD2 and RIPK in colonic biopsies from CD patients (Non-Patent Document 7). Stronati confirmed this finding in a pediatric population with UC. Interestingly, this group also suggested that, in addition to upregulation of RIPK2 and NOD2 and subsequent cytokine increases, upregulation of HD5 and HD6 (two human defensins acting as major components of the epithelial innate immune system) may be due to NOD2 / RIPK2 (Non-Patent Document 8). Finally, Haile et al. showed that a selective RIPK2 inhibitor may block the secretion of spontaneous inflammation-inducing cytokines from biopsies of UC / CD patients. This result clearly shows that RIPK2 activation in the mucosa of UC / CD patients leads to the inflammatory-inducing state of these biopsies (Non-Patent Document 9). Also, the study by Chen et al. on the association between Fusobacterium nucleatum (F. nucleatum) and ulcerative colitis sheds new light on the role of RIK2 in epithelial injury. In this paper, the authors concluded that F. nucleatum targets CARD3 via NOD2 and activates the IL-17F / NF-κB pathway in vivo. Thus, F. nucleatum controls the UC process by directing a molecular network involving CARD3 and IL-17F (Non-Patent Document 10). Another cause of IBD is called IMC (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) carry a risk of immune-related adverse events. The incidence of IMC ranges from 0.3% to 7% and occurs 5 to 10 weeks after the second or third administration of ICI (Non-Patent Document 11).Current treatments are oral corticosteroids (in the mild to moderate stage) and systemic corticosteroids in the severe stage. However, approximately half of IMC patients have corticosteroid-resistant colitis. In such cases, treatment with anti-TNFα inhibitors is one option. RIPK2 inhibition may be an additional treatment option with a new mechanism of action.

[0006] Viera et al. (Non-Patent Document 12) initially described a different indication when pointing out the role of NOD2 / RIPK2 in the development of experimental arthritis.

[0007] These findings were confirmed in patients with rheumatoid arthritis (RA) by Franca et al. (Non-Patent Document 13). They showed that the NOD2 / RIPK2 pathway is upregulated in immune cells of RA patients, suggesting that RIPK2 inhibition may be beneficial in this population.

[0008] Gain-of-function NOD2 mutations are genetically associated with other inflammatory diseases such as Blau syndrome / early-onset sarcoidosis (EOS), a pediatric granulomatous disease characterized by uveitis, dermatitis, and arthritis (Non-Patent Documents 14 and 15). Extensive genotyping of young patients with allergic rhinitis and atopic dermatitis highlighted NOD2 polymorphisms common to Crohn's disease as a possible major cause of the observed excessive immune response to skin tissue.

[0009] Mutations in NOD1 are associated with asthma (Non-Patent Document 17) and early-onset inflammatory bowel disease and extra-intestinal inflammatory bowel disease (Non-Patent Document 18). Genetic and functional studies also suggested a role for RIP2-dependent signaling in various other granulomatous disorders such as sarcoidosis (Non-Patent Document 19) and Wegener's granulomatosis (Non-Patent Document 20).

[0010] Metabolic syndrome, a pathology closely related to obesity and overweight, is caused by chronic inflammation and is characterized by hypertension, hyperglycemia, and lipolysis dysfunction. Activation of the immune system via the NOD1 pathway has been observed in patients suffering from metabolic syndrome (Non-Patent Document 21). Recent functional studies addressing the impact of RIPK2 inhibitors on lipolysis have suggested a role for RIP2-dependent signaling in glucose regulation disorders and lipolysis (Non-Patent Document 22).

[0011] In cardiac hypertrophy, a complex and multifactorial pathology, inflammation has been shown to be an important feature of this disease, particularly through activation of NF-kB signaling (Non-Patent Document 23). Knockout studies of RIPK2 in a murine model of hypertrophic heart have suggested a role in the regulation of inflammation and subsequent tissue fibrosis and hypertrophy (Non-Patent Document 24).

[0012] In addition to immune-inflammatory diseases, regulation of RIPK2 has been reported in several cancers. In triple-negative breast cancer (TNBC), high expression of RIPK2 has been associated not only with worsening of the progression-free survival period (Non-Patent Document 25) but also with worsening of the overall survival period (Non-Patent Document 26). In an initial study, the authors showed that RIPK2 knockdown enhanced docetaxel sensitivity and reduced tumors and lung metastases. Another group studied a novel cancer gene cassette on chromosome 8 in breast cancer patients (Non-Patent Document 27). They discovered that RIPK2 is co-amplified with other tested cancer genes (such as MYC). In 2016, Mertins et al. studied TNBC biopsies to find druggable kinases other than HER2. RIPK2 was found to be hyperphosphorylated in biopsies of basal-like and luminal B breast cancers, suggesting that this pathway may be activated in these types of TNBC (Non-Patent Document 28).

[0013] Recently, it has been found that not only phospho-RIPK2 levels but also NF-κB activity are increased in biopsies of inflammatory breast cancer (Non-Patent Document 29). Wu et al. showed that knockdown of RIPK2 leads to cell death using 34 head and neck squamous cell carcinoma cell lines, indicating a central role of this protein in cell survival (Non-Patent Document 30). On the other hand, some have claimed that RIPK2 promotes glioma cell growth by regulating TRAF3 and activating the NF-κB pathway and p38 signaling (Non-Patent Document 31).

[0014] Collectively, these data strongly support the development of RIPK2 inhibitors in oncology. In 2017, Maloney et al. described a new role of RIPK2 in osteosarcoma invasion showing that gefitinib prevents the progression of lung metastasis via RIPK2 inhibition (Non-Patent Document 32). Furthermore, Liu et al. discovered that non-canonical NF-κB plays a central role in non-Hodgkin lymphoma (Non-Patent Document 33). Finally, Gambino et al. identified RIPK2 as a kinase involved in lymphatic remodeling, an important factor for cancer metastatic dissemination, using three-dimensional lymphatic endothelial cell tube formation (Non-Patent Document 34).

[0015] The fact that both loss-of-function polymorphisms and gain-of-function mutations cause inflammatory diseases may be due to the possibility that NOD2 functions as a potential function of NOD2, a rheostat, and helps maintain normal immune homeostasis. The lack of linkage between inflammatory signaling pathways affects the onset of inflammatory disorders, and the balance of NOD1 / 2:RIP2 activation is at the center of this linkage. Currently, the treatment of Crohn's disease and sarcoidosis relies on broad-spectrum non-specific immunosuppression (e.g., corticosteroids) or specific cytokine inhibition (e.g., anti-TNF therapy) with significant costs and side effects. However, not all agents are equally effective, the disease occurs over a long period, and not all agents remain effective in the same patients, so the treatment is not ideal. The event of autophosphorylation of RIP2 Y474 is required for efficient NOD2 signaling and has been shown not to occur in the presence of the most common loss-of-function Crohn's disease-related NOD2 alleles. This autophosphorylation is inhibited by gefitinib and erlotinib, which are kinase inhibitors with low selectivity, suggesting that the tyrosine kinase activity of RIP2 may be a specific target for the treatment of inflammatory diseases (Non-Patent Document 35). Some clinical cases have been reported regarding gefitinib or erlotinib treatment that is effective for the removal of psoriasis or the reduction of insulin resistance type 2 diabetes associated with arthritis symptoms or metabolic syndrome (Non-Patent Document 36). In an existing mouse model of chronic inflammatory bowel disease, inhibition of RIP2 activity by the small molecule SB203580 is effective in reducing induced colitis (Non-Patent Document 37). However, none of these small molecules primarily and selectively target RIP2. Therefore, an object of the present invention is to provide a potential, selective small molecule inhibitor of RIP2 kinase activity that can specifically block RIP2-dependent inflammatory promotion signaling, thereby providing a therapeutic effect in autoinflammatory diseases characterized by increased and / or unregulated RIP2 kinase activity.

[0016] Currently, the present inventors have found that the macrocyclic compounds and pharmaceutically acceptable compositions according to the present invention are useful for the treatment of inflammatory disorders, particularly Crohn's disease, intestinal diseases, 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, particularly Behçet's disease, immune-mediated colitis, multiple sclerosis, and diseases associated with RIP2 kinase activity (i.e., RIP2-kinase-related diseases). The macrocyclic compounds and pharmaceutically acceptable compositions of the present inventors according to the present invention are also useful for treating in oncology, particularly breast cancer (including inflammatory breast cancer), head and neck cancer, and glioma.

[0017] In a patent application of previously published Patent Document 1, a series of macrocyclic pyrazolopyrimidines with RIPK2 inhibition at nanomolar concentrations determined by biochemical assays were disclosed. Two representatives of that series are Example O4 and Example O11.

[0018]

Chemical formula

Prior art documents

Patent documents

[0019]

Patent Document 1

Non-patent documents

[0020]

Non-patent Document 1

Non-patent Document 2

Non-patent Document 3

Non-patent Document 16

Non-patent Document 17

Non-patent Document 18

Non-patent Document 19

Non-patent Document 20

Non-patent Document 21

Non-patent Document 22

Non-patent Document 23

Non-patent Document 24

Non-patent Document 25

Non-patent Document 26

Non-patent Document 27

[0021] The inventors have surprisingly found that certain combinations of specific structural modifications of the macrocyclic compounds described herein, for example, introducing substitutions in the pyrrolidine moiety and X1 = -NH-C1~6 Alkyl and X2 = O-C 1~6 Alkyl with X1 = O-C 1~6 Alkyl and X2 = -NH-C 1~6 Replacing alkyl (where X1 and X2 refer to Markush formula I described in the patent of Patent Document 1) has led to dramatic improvements in key development parameters and safety parameters such as human protein binding, metabolic stability in human microsomes, and inhibition of hERG channels. More specifically, as shown in the comparison table between some representative compounds of Patent Document 1 and the compounds of the present invention (see the end of the experimental section), the compounds described in the present invention have shown improvements in the human protein unbound fraction (Assay A), higher metabolic stability (Assay B), and a lower tendency to inhibit hERG (Assay C). Plasma protein binding, metabolic stability, and hERG liability have been recognized as key development parameters for optimization in addition to efficacy and specificity over the past 15 years (Towards Drugs of the Future, IOS Press, 2009, 9:53 - 74). For example, the relevance of hERG to cardiotoxicity has been recognized as a key development parameter to be addressed, as published by Danker et al (Danker et al, Front. Pharmacol. 2014, 5:203).

[0022] Accordingly, in a first aspect, the present invention provides a compound of formula I:

Chemical formula

[0023] Alternatively, in a first aspect, the present invention provides a compound of formula I:

Chemical formula

[0024] R1 is -halo, -O-C 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, and each of the above -C 1~6 alkyls is optionally substituted with one or more substituents selected from -D, -halo, -O-C 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 independently selected from -H and -C 1~6 alkyl, and where each of the above -C 1~6 alkyls may be optionally substituted with one or more -O-C 1~6 alkyls, when R3 and / or R 3’ is -C 1~6 alkyl, then R4 and R 4’ are each -H, when R4 and / or R 4’ is -C 1~6 alkyl, then R3 and R 3’ are each -H, R5 is -OH, -NR c R c’、 -NHC(O)R c , -halo, -O-C 1~6Alkyl, -O-C 3~5 -Cycloalkyl, -O-Het2, -C 1~6 alkyl, and -CN, where each of the above -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -OH, -C 1~6 alkyl, -C 3~5 -Cycloalkyl, -O-C 1~6 alkyl, and -Het2, R6 is -H, -halo, -C 1~6 alkyl, -O-C 1~6 alkyl, -O-Het4, and -Het3, where each of the above -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D and -O-C 1~6 alkyl, R9 is -H, -C 1~6 alkyl, -C(O)-C 1~6 alkyl, and -C(O)-O-C 1~6 alkyl, R a is -H and -C 1~6 alkyl, R b is -H, -C 1~6 alkyl, and -O-C 1~6 alkyl, R c and R c’ are each independently -H and -C 1~6 alkyl, Het1 and Het3 are each independently selected from 5- or 6-membered aromatic heterocycles having 1 to 3 heteroatoms selected from O and N, where each of the above Het1 and Het3 is optionally substituted with 1 to 3 -C 1~6 alkyl, Het2 is selected from 4- to 6-membered saturated heterocycles having 1 to 3 O atoms, Het4 is selected from 4- to 10-membered saturated heterocycles having 1 to 3 heteroatoms selected from O and N, where each of the above Het4 is optionally substituted with 1 to 3 -C 1~6Optionally substituted with alkyl, and the above -C 1~6 Each of the alkyls is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1~3 alkyl, and -OH, to provide a compound of formula I or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form, or solvate thereof.

[0025] In another specific embodiment, the present invention R1 is -halo, -O-C 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, and each of the above -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, -O-C 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 -OH, -halo, -O-C 1~6 alkyl, -O-C 3~5 -cycloalkyl, and -C 1~6 alkyl, where each of the above -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -OH, -C 1~6 alkyl, -C 3~5 -cycloalkyl, and -O-C 1~6 alkyl, R6 is -H, -halo, -C 1~6 alkyl, -O-C 1~6Selected from alkyl, -O-Het4, and -Het3, where said -C 1~6 Each of the alkyls is optionally substituted with one or more -O-C 1~6 alkyl, R9 is -H, -C 1~6 alkyl, -C(O)-C 1~6 alkyl, and -C(O)-O-C 1~6 alkyl, R a is selected from -H and -C 1~6 alkyl, R b is selected from -H, -C 1~6 alkyl, and -O-C 1~6 alkyl, where each of said -C 1~6 alkyl is optionally substituted with one or more substituents, Het1 and Het3 are each independently selected from 5- or 6-membered aromatic heterocycles having 1 to 3 heteroatoms selected from O and N, where each of said Het1 and Het3 is optionally substituted with 1 to 3 -C 1~6 alkyl, Het2 is selected from 4- to 6-membered saturated heterocycles having 1 to 3 O atoms, Het4 is selected from 4- to 10-membered saturated heterocycles having 1 to 3 heteroatoms selected from O and N, where each of said Het4 is optionally substituted with 1 to 3 -C 1~6 alkyl, and each of said -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1~3 alkyl, and -OH, to provide a compound of formula I or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form, or solvate thereof.

[0026] In yet another specific embodiment, the present invention R1 is -halo, -O-C 1~6 alkyl, -alkynyl, -C 1~6 alkyl, -C 3~6 -cycloalkyl, -C(O)-C1~6 -Alkyl, -C(O)-NR a R b , -Het1, and -CN, where each of the above -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, and -O-C 1~3 alkyl, R2 is selected from -H and -halo, R 10 is -H, R3, R 3’ , R4, R 4’ , R7, and R8 are each -H, R5 is -OH, -halo, -O-C 1~6 alkyl, -O-C 3~5 -cycloalkyl, and -C 1~6 alkyl, where each of the above -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -OH, -C 1~6 alkyl, -C 3~5 -cycloalkyl, and -O-C 1~6 alkyl, R6 is selected from -H, -halo, -C 1~6 alkyl, -O-C 1~6 alkyl, -O-Het4, and -Het3, where each of the above -C 1~6 alkyl is optionally substituted with one or more -O-C 1~6 alkyl, R9 is -H, R a is selected from -H and -C 1~6 alkyl, R b is selected from -H, -C 1~6 alkyl, and -O-C 1~6 alkyl, Het1 is a 5-membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from O and N, where the above Het1 is optionally substituted with 1 to 3 -C 1~6 alkyl, Het4 is selected from 4- to 10-membered saturated heterocycles having 1 to 3 heteroatoms selected from O and N, wherein each of said Het4 is optionally substituted with 1 to 3 -C 1~6 alkyl, and each of said -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1~3 alkyl, and -OH, to provide a compound of formula I or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form, or solvate thereof.

[0027] In a more specific embodiment, the present invention provides one selected from any of the tables disclosed herein.

[0028] In another specific embodiment, in the compounds of the present invention, the carbon atom bearing the R8 substituent may be in the S configuration.

[0029] In a further specific embodiment, in the compounds of the present invention, the carbon atom bearing the R5 substituent may be in the R configuration.

[0030] The present invention further provides a pharmaceutical composition comprising a compound according to the present invention.

[0031] In a further aspect, the present invention provides a compound or composition according to the present invention for use as a medicament.

[0032] In certain embodiments, the present invention provides a compound or composition according to the present invention for use in the diagnosis, prevention, and / or treatment of RIP2-kinase related diseases. The RIP2-kinase related diseases can be inflammatory disorders selected from the list including, but not limited to, Crohn's disease, bowel diseases, 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 diseases can be cancers more particularly selected from breast cancer (including inflammatory breast cancer), head and neck cancer, and glioma.

[0033] Furthermore, the present invention provides for the use of a compound or composition according to the present invention for inhibiting the activity of a kinase, particularly RIP2 kinase, or for use in the diagnosis, prevention and / or treatment of RIP2-kinase related diseases.

[0034] Finally, the present invention provides a method for preventing and / or treating RIP2-kinase related diseases, the method comprising administering a compound or composition according to the present invention to a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0035] DETAILED DESCRIPTION OF THE INVENTION The present invention will now be further described. In the following sections, various aspects of the present invention are defined in more detail. Each aspect so defined may be combined with any other aspect(s) (singular or plural), unless it is clearly indicated otherwise. In particular, any feature(s) indicated as being preferred or advantageous may be combined with any other feature(s) (singular or plural) indicated as being preferred or advantageous.

[0036] Unless otherwise indicated in the context, an asterisk is used herein to indicate the point at which the indicated monovalent or divalent radical is attached to the structure to which it is related and forms part of the radical.

[0037] As already described above, in the first aspect, the present invention relates to formula I:

Chemical formula

[0038] In any of the embodiments disclosed herein, R6 may alternatively be -H, -halo, -C 1~6 alkyl, -O-C 1~6 alkyl, and -Het3, and each of said -C 1~6 alkyl is optionally substituted with -D and -O-C 1~6Optionally substituted with one or more substituents selected from alkyl, and in this case, Het4 does not exist.

[0039] The term "alkyl" refers to a fully saturated hydrocarbon radical, either by itself or as part of another substituent. Generally, the alkyl groups of the present invention contain 1 to 6 carbon atoms. The alkyl group may be linear or branched and may be substituted as shown herein. When a subscript is used after a carbon atom in this specification, the subscript refers to the number of carbon atoms that the specified group may contain. Thus, for example, C 1~6 "Alkyl" means alkyl having 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g., n-butyl, i-butyl, and t-butyl), pentyl and its isomers, hexyl and its isomers. C 1~ C6 alkyl includes all linear or branched alkyl groups having 1 to 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g., n-butyl, i-butyl, and t-butyl), pentyl and its isomers, hexyl and its isomers.

[0040] The term "optionally substituted alkyl" refers to an alkyl group optionally substituted at any available bond with one or more substituents (e.g., 1 to 3 substituents, e.g., 1, 2 or 3 substituents or 1 or 2 substituents). Non-limiting examples of such substituents include -D, -halo, -OH, primary amides and secondary amides, -O-C 1~6 alkyl, heteroaryl, aryl, cycloalkyl, heterocyclyl, etc.

[0041] As used herein, the term "alkenyl" means a straight-chain, cyclic or branched hydrocarbon radical containing at least one carbon-carbon double bond, unless otherwise specified. Examples of alkenyl radicals include ethenyl, E-propenyl and Z-propenyl, isopropenyl, E-butenyl and Z-butenyl, E-isobutenyl and Z-isobutenyl, E-pentenyl and Z-pentenyl, E-hexenyl and Z-hexenyl, E,E-hexadienyl, E,Z-hexadienyl, Z,E-hexadienyl, Z,Z-hexadienyl, etc. Optionally substituted alkenyl refers to an alkenyl having one or more (e.g., one, two, three, or four) substituents arbitrarily selected from those defined above for substituted alkyl.

[0042] As used herein, the term "alkynyl" means a straight-chain or branched hydrocarbon radical containing at least one carbon-carbon triple bond, unless otherwise specified. Examples of alkynyl radicals include ethynyl, E-propynyl and Z-propynyl, isopropynyl, E-butynyl and Z-butynyl, E-isobutynyl and Z-isobutynyl, E-pentynyl and Z-pentynyl, E-hexynyl, Z-hexynyl, etc. Optionally substituted alkynyl refers to an alkynyl having one or more (e.g., one, two, three, or four) substituents arbitrarily selected from those defined above for substituted alkyl.

[0043] The term "cycloalkyl" is a cyclic alkyl group, i.e., a monovalent saturated or unsaturated hydrocarbyl group having a cyclic structure, either by itself or as part of another substituent. Cycloalkyl includes hydrocarbon groups that are fully saturated or partially saturated (containing one or two double bonds) having a cyclic structure. The cycloalkyl group may contain three or more carbon atoms in the ring and generally, according to the present invention, contains 3 to 6 atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane.

[0044] When the defined alkyl group is divalent, i.e., has two single bonds for attachment to two other groups, it is termed an "alkylene" group. Non-limiting examples of alkylene groups include methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1,2-dimethylethylene, pentamethylene, and hexamethylene.

[0045] Generally, the alkylene groups of the present invention preferably contain the same number of carbon atoms as their alkyl counterparts. When an alkylene or cycloalkylene biradical is present, the connectivity to the molecular structure in which it forms part can be via common or different carbon atoms. To illustrate this, applying the nomenclature by asterisks of the present invention, a C3 alkylene group can be, for example * -CH2CH2CH2- * , * -CH(-CH2CH3)- * , or * -CH2CH(-CH3)- * for example.

[0046] The term "heterocycle" as used herein refers to an aromatic, non-aromatic, fully saturated or partially unsaturated cyclic group (e.g., a 3- to 6-membered monocyclic ring system, or an 8- to 10-membered bicyclic ring) having at least one heteroatom in at least one carbon atom-containing ring, either by itself or as part of another group. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms. An optionally substituted heterocyclic refers to a heterocycle optionally having one or more substituents (e.g., 1 to 4 substituents, or for example 1, 2, 3, or 4 substituents) selected from those defined above for substituted alkyl.

[0047] Exemplary non-aromatic heterocyclic groups include piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H-indolyl, isoindolinyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyranyl, dihydro-2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, 3-dioxolanyl, 1,3-dioxanyl, 2,5-dioxoimidazolidinyl, 2,2,4-piperidonyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 6H-1,2,5-thiadiazinyl, 2H-1,5,2-dithiazinyl, 2H-oxocinyl, 1H-pyrrolidinyl, tetrahydro-1,1-dioxothienyl, N-formylpiperazinyl and morpholinyl; in particular, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, dioxolanyl, dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl and tetrahydrofuranyl are mentioned.

[0048] 7- to 10-membered heterocyclic groups are also intended to include spiro groups, and the spiro group is a bicyclic compound in which both rings are bonded via one atom, such as spiro[4.5]decane, which is a spiro compound composed of a cyclohexane ring and a cyclopentane ring. Another example includes oxaspiro[3.3]heptane, which is a spiro compound composed of a C4 cycloalkyl and an oxetane ring.

[0049] As used herein, the term "aryl" refers to a polyunsaturated aromatic hydrocarbyl group having 5 to 10 atoms. Aryl is also intended to include partially hydrogenated derivatives of the carbocyclic systems listed herein. Non-limiting examples of aryl include phenyl, biphenylyl, biphenylylenyl, 1-naphthyl or 2-naphthyl, 1-indenyl, 2-indenyl, or 3-indenyl, 1-acephenanthrylenyl, 2-acephenanthrylenyl, 3-acephenanthrylenyl, 4-acephenanthrylenyl, or 5-acephenanthrylenyl, 1-pentalenyl or 2-pentalenyl, 4-indanyl or 5-indanyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 7-tetrahydronaphthyl, or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, and 1-pyrenyl, 2-pyrenyl, 3-pyrenyl, 4-pyrenyl, or 5-pyrenyl, particularly including phenyl.

[0050] The aryl ring may be optionally substituted by one or more substituents. "Optionally substituted aryl" refers to aryl optionally having one or more substituents (e.g., 1 to 5 substituents, e.g., 1, 2, 3, or 4 substituents) at any available point of attachment selected from those defined above for substituted alkyl.

[0051] When a carbon atom of an aryl group is replaced by a heteroatom, the resulting ring is referred to herein as a heteroaryl ring. Such a ring structure is also called an aromatic heterocyclic ring.

[0052] As used herein, the term "heteroaryl" or "aromatic heterocycle" refers to an aromatic ring of 5 to 10 carbon atoms, which may be replaced by one or more oxygen, nitrogen, or sulfur atoms, either by itself or as part of another group, but is not limited thereto. Non-limiting examples of such heteroaryl include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, benzotriazolyl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl.

[0053] "Optionally substituted heteroaryl" refers to a heteroaryl optionally having one or more substituents (e.g., from 1 to 4 substituents, e.g., 1, 2, 3, or 4 substituents) selected from those defined above for substituted alkyl.

[0054] As used herein, the term "halo" or "halogen" is a general term for fluoro, chloro, bromo, or iodo, and any suitable isotopes thereof, as a group or part of a group.

[0055] As used herein, the term "oxo" refers to the =O group.

[0056] As used herein, the term "alkoxy" or "alkyloxy" refers to the formula -ORb (wherein R b is alkyl). Preferably, the alkoxy is C1-C 10 alkoxy, C1-C6 alkoxy, or C1-C4 alkoxy. Non-limiting examples of suitable alkoxys include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy. When the oxygen atom in the alkoxy group is replaced by sulfur, the resulting radical is referred to as thioalkoxy. "Haloalkoxy" is an alkoxy group in which one or more hydrogen atoms in the alkyl group are replaced by halogen.

[0057] As used in the present invention, the term "substituted" is always intended to mean that one or more hydrogens on the atom specified using the expression "substituted" in this expression are replaced by a group selected from the specified group, provided that the normal valence of the specified atom is not exceeded and that the substitution results in a chemically stable compound, i.e., a compound that can be isolated in useful purity from the reaction mixture and that is sufficiently robust to withstand formulation into a therapeutic and / or diagnostic agent.

[0058] When a group can be optionally substituted, such group can be substituted one or more times, preferably once, twice or three times. The substituents can be selected from those defined above for substituted alkyl.

[0059] As used herein, terms such as "alkyl, aryl, or cycloalkyl, each optionally substituted" or "alkyl, aryl, or cycloalkyl optionally substituted" refer to optionally substituted alkyl, optionally substituted aryl, and optionally substituted cycloalkyl.

[0060] More generally, from the above, it will be apparent to those skilled in the art that the compounds of the present invention can exist in various isomeric and / or tautomeric forms, including but not limited to geometric isomers, conformational isomers, E / Z isomers, stereochemical isomers (i.e., enantiomers and diastereoisomers), and isomers corresponding to the presence of the same substituents at different positions of the rings present in the compounds of the present invention. All such possible isomers, tautomers, and mixtures thereof are included within the scope of the present invention.

[0061] Furthermore, the present invention includes isotopically labeled compounds and salts that are identical to the compounds of formula (I), but in which one or more atoms are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into the compounds of formula (I) include 2 H (deuterium), 3 H, 11 C, 13 N, 14 C, 15 O and 18 isotopes of hydrogen, carbon, nitrogen, and fluorine such as F. Such isotopically labeled compounds of formula (I) are useful in tissue distribution assays of drugs and / or substrates. For example, 2 H (deuterium) is particularly useful for reducing metabolism when appropriately positioned in the chemical structure, thus improving the pharmacokinetic profiles of deuterated analogs in animals and humans (Uttamsingh et al., Phase 1 study results of CTP-656). For example, 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography). PET is useful as a diagnostic or therapeutic monitoring tool that can be applied in a conventional manner in preclinical and clinical settings. PET is also applied to PK determination of compounds including biodistribution. Isotopically labeled compounds of formula (I) can generally be prepared by carrying out the procedures disclosed below by substituting readily available unlabeled isotopes with labeled isotopes.

[0062] When used in the present invention, the term "compound of the present invention" or similar terms are always intended to include compounds of general formula I and any of its subgroups. This term also refers to the compounds shown in Table 1, their derivatives, N-oxides, salts, solvates, hydrates, stereoisomers, racemic mixtures, tautomers, optical isomers, analogs, and their quaternized nitrogen analogs. The N-oxide form of the above compounds is intended to include compounds in which one or several nitrogen atoms are oxidized to form so-called N-oxides.

[0063] As used in this specification and the appended claims, the singular forms "a", "an", and "the" specifying a quantity include plural referents unless the context clearly dictates otherwise. By way of example, "compound" means one compound or two or more compounds.

[0064] The above terms and other terms used in this specification are well understood by those skilled in the art.

[0065] In certain embodiments, the present invention applies one or more of the following: R1 is selected from -halo, -O-C 1~6 alkyl, -alkynyl, -C 1~6 alkyl, -C(O)-C 1~6 -alkyl, -C(O)-C 1~6 cycloalkyl, -C(O)-Het2, -C(O)-NR a R b and -Het1, and -CN, where each of the above -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1~3 alkyl, -C 3~6 -cycloalkyl, -Ph, -Het1, -Het2, and -OH, and each of the above -alkynyl is optionally substituted with one substituent selected from -C 1~6 alkyl and -CH2-O-C 1~6 alkyl, R2 and R 10are each independently selected from -H and -halo, R3, R 3’ , R4, R 4’ , R7, and R8 are each independently selected from -H and -C 1~6 alkyl, where each of the above -C 1~6 alkyl may optionally be substituted with one or more -O-C 1~6 alkyl, when R3 and / or R 3’ is -C 1~6 alkyl, R4 and R 4’ are each -H, when R4 and / or R 4’ is -C 1~6 alkyl, R3 and R 3’ are each -H, R5 is -OH, -NR c R c’、 -NHC(O)R c , -NC(O)R c R c’ , -NC(O)OR c , -NHS(O2)R c , -halo, -O-C 1~6 alkyl, -O-C 3~5 -cycloalkyl, -O-Het2, -C 1~6 alkyl, and -CN, where each of the above -C 1~6 alkyl may optionally be substituted with one or more substituents selected from -D, -OH, -C 1~6 alkyl, -C 3~5 -cycloalkyl, -O-C 1~6 alkyl, and -Het2, R6 is -H, -halo, -C 1~6 alkyl, -O-C 1~6 alkyl, -O-Het4, and -Het3, where each of the above -C 1~6 alkyl may optionally be substituted with one or more substituents selected from -D and -O-C 1~6 alkyl, R9 is -H, -C 1~6 alkyl, -C(O)-C 1~6Alkyl, and -C(O)-O-C 1~6 selected from alkyl, R a is -H and -C 1~6 selected from alkyl, wherein each of said -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D and -C 1~6 alkyl, R b is -H, -C 1~6 alkyl, and -O-C 1~6 selected from alkyl, wherein each of said -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -C 1~6 alkyl, and -C 3~5 optionally substituted with one or more substituents selected from -cycloalkyl, R c and R c’ are each independently selected from -H and -C 1~6 alkyl, wherein each of said -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D and -C 1~6 alkyl, Het1 and Het3 are each independently selected from 5- or 6-membered aromatic heterocycles having 1 to 3 heteroatoms selected from O, N, and S, wherein each of said Het1 or Het3 is optionally substituted with 1 to 3 -C 1~6 alkyl, and each of said -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1~3 alkyl, and -OH, Het2 is selected from 4- to 6-membered saturated heterocycles having 1 to 3 heteroatoms selected from O and N, wherein each of said Het2 is optionally substituted with 1 to 3 -C 1~6 alkyl, and each of said -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1~3 alkyl, and -OH, Het4 is selected from 4- to 10-membered saturated heterocycles having 1 to 3 heteroatoms selected from O and N, wherein each of said Het4 is optionally substituted with 1 to 3 -C 1~6 alkyl, and each of said -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1~3 alkyl, and -OH, There is provided a compound of formula I, or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form, or solvate thereof.

[0066] In a specific embodiment, the present invention R1 is selected from -halo, -O-C 1~6 alkyl, -alkynyl, -C 1~6 alkyl, -C(O)-C 1~6 -alkyl, -C(O)-C 1~6 cycloalkyl, -C(O)-Het2, -C(O)-NR a R b , -Het1, and -CN, and each of said -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, -O-C 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 independently selected from -H and -C 1~6 alkyl, where each of said -C 1~6 alkyl may optionally be substituted with one or more -O-C 1~6 alkyl, When R3 and / or R 3’ is -C 1~6 alkyl, R4 and R 4’ are each -H, When R4 and / or R 4’ is -C1~6 When it is alkyl, R3 and R 3’ are each -H, R5 is -OH, -NR c R c’、 -NHC(O)R c , -halo, -O-C 1~6 alkyl, -O-C 3~5 -cycloalkyl, -O-Het2, -C 1~6 alkyl, and -CN, where each of the above -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -OH, -C 1~6 alkyl, -C 3~5 -cycloalkyl, -O-C 1~6 alkyl, and -Het2, R6 is -H, -halo, -C 1~6 alkyl, -O-C 1~6 alkyl, -O-Het4, and -Het3, where each of the above -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D and -O-C 1~6 alkyl, R9 is -H, -C 1~6 alkyl, -C(O)-C 1~6 alkyl, and -C(O)-O-C 1~6 alkyl, R a is -H and -C 1~6 alkyl, R b is -H, -C 1~6 alkyl, and -O-C 1~6 alkyl, R c and R c’ are each independently selected from -H and -C 1~6 alkyl, Het1 and Het3 are each independently selected from 5- or 6-membered aromatic heterocycles having 1 to 3 heteroatoms selected from O and N, where each of the above Het1 and Het3 is optionally substituted with 1 to 3 -C 1~6 alkyl, Het2 is selected from 4- to 6-membered saturated heterocyclic rings having 1 to 3 O atoms, Het4 is selected from 4- to 10-membered saturated heterocyclic rings having 1 to 3 heteroatoms selected from O and N, wherein each of said Het4 is optionally substituted with 1 to 3 -C 1~6 alkyl, and each of said -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1~3 alkyl, and -OH, a compound of formula I, or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form, or solvate thereof is provided.

[0067] In another specific embodiment, the present invention R1 is selected from -halo, -O-C 1~6 alkyl, -alkynyl, -C 1~6 alkyl, -C(O)-C 1~6 -alkyl, -C(O)-C 1~6 cycloalkyl, -C(O)-Het2, -C(O)-NR a R b 、-Het1, and -CN, and each of said -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, -O-C 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, -O-C 1~6 alkyl, -O-C 3~5 -cycloalkyl, and -C 1~6 alkyl, wherein each of said -C 1~6 alkyl is selected from -D, -OH, -C 1~6 alkyl, -C 3~5-Cycloalkyl, and -O-C 1~6 Optionally substituted with one or more substituents selected from R6 is -H, -halo, -C 1~6 Alkyl, -O-C 1~6 Alkyl, -O-Het4, and -Het3, where each of the above -C 1~6 Alkyl is optionally substituted with one or more -O-C 1~6 Alkyl, R9 is -H, -C 1~6 Alkyl, -C(O)-C 1~6 Alkyl, and -C(O)-O-C 1~6 Alkyl, R a Is -H and -C 1~6 Alkyl, R b Is -H, -C 1~6 Alkyl, and -O-C 1~6 Alkyl, where each of the above -C 1~6 Alkyl is optionally substituted with one or more substituents, Het1 and Het3 are each independently selected from 5- or 6-membered aromatic heterocycles having 1 to 3 heteroatoms selected from O and N, where each of the above Het1 and Het3 is optionally substituted with 1 to 3 -C 1~6 Alkyl, Het2 is selected from 4- to 6-membered saturated heterocycles having 1 to 3 O atoms, Het4 is selected from 4- to 10-membered saturated heterocycles having 1 to 3 heteroatoms selected from O and N, where each of the above Het4 is optionally substituted with 1 to 3 -C 1~6 Alkyl, where each of the above -C 1~6 Alkyl is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1~3 Alkyl, and -OH, to provide a compound of formula I, or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form, or solvate thereof.

[0068] In a further specific embodiment, the present invention is R1 is selected from -halo, -O-C 1~6 alkyl, -alkynyl, -C 1~6 alkyl, -C(O)-C 1~6 -alkyl, -C(O)-NR a R b , -Het1, and -CN, and each of the above -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, and -O-C 1~3 alkyl; R2 is selected from -H and -halo; R 10 is -H; R3, R 3’ , R4, R 4’ , R7, and R8 are each -H; R5 is selected from -OH, -halo, -O-C 1~6 alkyl, -O-C 3~5 -cycloalkyl, and -C 1~6 alkyl, where each of the above -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -OH, -C 1~6 alkyl, -C 3~5 -cycloalkyl, and -O-C 1~6 alkyl; R6 is selected from -H, -halo, -C 1~6 alkyl, -O-C 1~6 alkyl, -O-Het4, and -Het3, where each of the above -C 1~6 alkyl is optionally substituted with one or more -O-C 1~6 alkyl; R9 is -H; R a is selected from -H and -C 1~6 alkyl; R b is selected from -H, -C 1~6 alkyl, and -O-C 1~6 alkyl; Het1 is a 5-membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from O and N, where said Het1 is optionally substituted with 1 to 3 -C 1~6 alkyl, Het4 is selected from 4- to 10-membered saturated heterocyclic rings having 1 to 3 heteroatoms selected from O and N, where each of said Het4 is optionally substituted with 1 to 3 -C 1~6 alkyl, and each of said -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1~3 alkyl, and -OH, to provide a compound of formula I, or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form, or solvate thereof.

[0069] In yet a further embodiment, the present invention applies one or more of the following: R1 is selected from -halo, -O-C 1~6 alkyl, -alkynyl, -C 1~6 alkyl-C(O)-C 1~6 -alkyl, -C(O)-NR a R b , -Het1, and -CN, where each of said -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, and -O-C 1~3 alkyl, R2 is selected from -H and -halo, R 10 is -H, R3, R 3’ , R4, R 4’ , R7, and R8 are each -H, R5 is selected from -OH, -halo, -O-C 1~6 alkyl, -O-C 3~5 -cycloalkyl, and -C 1~6 alkyl, where each of said -C 1~6 alkyl is -D, -OH, -C 1~6 alkyl, -C 3~5 -cycloalkyl, and -O-C1~6 Optionally substituted with one or more substituents selected from alkyl, R6 is -H, -halo, -C 1~6 alkyl, -O-C 1~6 alkyl, -O-Het4, and -Het3, wherein each of said -C 1~6 alkyl is optionally substituted with one or more -O-C 1~6 alkyl, R9 is -H, R a is selected from -H and -C 1~6 alkyl, R b is selected from -H, -C 1~6 alkyl, and -O-C 1~6 alkyl, Het1 is a 5-membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from O and N, wherein said Het1 is optionally substituted with 1 to 3 -C 1~6 alkyl, Het4 is selected from 4- to 10-membered saturated heterocyclic rings having 1 to 3 heteroatoms selected from O and N, wherein each of said Het4 is optionally substituted with 1 to 3 -C 1~6 alkyl, and each of said -C 1~6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1~3 alkyl, and -OH, or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form, or solvate thereof of the compound of formula I is provided.

[0070] In a more specific embodiment, the present invention provides a compound selected from any of the tables disclosed herein.

[0071] The compounds of the present invention can be prepared according to the reaction schemes shown in the following examples, but those skilled in the art will understand 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.

[0072] The present invention further provides a pharmaceutical composition comprising a compound according to the present invention.

[0073] In a further aspect, the present invention provides a compound or composition according to the present invention for use as a human or veterinary pharmaceutical.

[0074] In certain embodiments, the present invention provides a compound or composition according to the present invention for use in the diagnosis, prevention, and / or treatment of RIP2-kinase related diseases.

[0075] Said RIP2-kinase related diseases may in particular be inflammatory disorders, in particular Crohn's disease, bowel diseases, 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, Behçet's disease, immune-mediated colitis, and multiple sclerosis.

[0076] Alternatively, said RIP2-kinase related diseases may more particularly be cancers selected from breast cancer (including inflammatory breast cancer), head and neck cancer, and glioma.

[0077] Furthermore, the present invention provides the use of a compound or composition according to the present invention for inhibiting the activity of a kinase, in particular RIP2 kinase, or for the diagnosis, prevention and / or treatment of RIP2-kinase related diseases.

[0078] Finally, the present invention provides a method for preventing and / or treating an RIP2-kinase related disease, comprising administering a compound or composition according to the present invention to a subject in need thereof.

[0079] Treatment method A compound of formula (I) or (Ia), its stereoisomers, tautomers, racemates, metabolites, prodrugs or predrugs, salts, hydrates, N-oxide forms or solvates is an inhibitor of RIP2 kinase activity and thus is thought to be useful in the diagnosis, prevention and / or treatment of inflammatory disorders or cancer.

[0080] As used herein, the term "inflammatory disorder" or "inflammatory disease" can refer to a disorder or disease characterized by abnormal activation of the immune system that leads to or causes some acute and chronic conditions, such as Crohn's disease, bowel disease, 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 can include tissue damage, cell injury, antigens, infections and / or a state of response to some unknown causes. Symptoms of inflammation can include, but are not limited to, cell infiltration and tissue swelling.

[0081] As used herein, the term "cancer" can refer to a disorder or disease characterized by abnormal cell growth that can invade or spread to various parts of the body, such as breast cancer (including inflammatory breast cancer), head and neck cancer, and glioma.

[0082] In the present invention, in the following RIP2 inhibition assay, compounds of formula I or any subgroup thereof that inhibit kinase activity with an IC 50 value of less than 10 μM, preferably less than 1 μM, most preferably less than 100 nM are particularly preferred.

[0083] The above inhibition can be achieved in vitro and / or in vivo, and when achieved in vivo, it is preferably achieved selectively as defined above.

[0084] As used herein, the term "RIP2 kinase-mediated disorder" or "RIP2 kinase-mediated disease" means any disease or other adverse condition known to involve RIP2 kinase and / or its mutants. The term "RIP2 kinase-mediated disorder" or "RIP2 kinase-mediated disease" also means a disease or condition that is alleviated by treatment with an RIP2 kinase inhibitor. Accordingly, another embodiment of the invention relates to treating or reducing the severity of one or more diseases known to involve RIP2 kinase.

[0085] For pharmaceutical use, the compounds of the invention may be used in the form of the free acid or free base and / or in the form of pharmaceutically acceptable acid addition salts and / or base addition salts (e.g., obtained using non-toxic organic or inorganic acids or bases), hydrates, solvates, and / or complexes. As used herein, the term "solvate" includes, unless otherwise specified, any combination with a suitable inorganic solvent (e.g., hydrate) or an organic solvent such as alcohol, ketone, ester, etc. (not limited thereto) that can be formed by the compounds of the invention.

[0086] Pharmaceutically acceptable salts of the compounds according to the invention, i.e., in the form of water-soluble, fat-soluble, or dispersible products, include, for example, conventional non-toxic salts or quaternary ammonium salts formed from inorganic or organic acids or bases.

[0087] Generally, for pharmaceutical use, the compounds of the invention can be formulated as a pharmaceutical preparation or pharmaceutical composition comprising at least one compound of the invention, at least one pharmaceutically acceptable carrier, diluent, or additive, and / or adjuvant, and optionally one or more further pharmaceutically active compounds.

[0088] By way of non-limiting example, such formulations may be in a form suitable for oral administration, parenteral administration (e.g., intravenous injection, intramuscular injection or subcutaneous injection or intravenous infusion), inhalation, transdermal patch, implant, administration by suppository, etc. Such suitable dosage forms (which may be solid, semi-solid, or liquid depending on the mode of administration), as well as the methods used for their manufacture, and carriers, diluents, and additives will be apparent to those skilled in the art.

[0089] 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 gelatin capsules and hard gelatin capsules, suppositories, eye drops, sterile injection solutions, and sterile packaged powders for bolus administration and / or continuous administration (usually reconstituted before use), which may be formulated with carriers, additives, and diluents that are themselves suitable for such preparations. The formulations may optionally contain other pharmaceutical active substances (which may or may not have a synergistic effect with the compounds of the present invention) and other substances commonly used in pharmaceutical formulations. The composition can also be formulated to provide rapid release, sustained release, or delayed release of the active compound(s) contained therein.

[0090] In the case of topical administration, the compound can be advantageously used in the form of a spray, ointment, or transdermal patch, or in another form suitable for topical, transdermal, and / or intradermal administration.

[0091] Composition The compound of formula (1) or a pharmaceutically acceptable salt thereof can be formulated into a pharmaceutical composition before administration to a subject. According to one aspect, the present invention provides a pharmaceutical composition comprising the compound of formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive. According to another aspect, the present invention provides a method for preparing a pharmaceutical composition, comprising mixing the compound of formula (1) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable additive.

[0092] The pharmaceutical composition can be provided in unit dosage form containing a predetermined amount of the active ingredient per unit dosage. Such units can contain, for example, 0.1 mg, 0.5 mg, or 1 mg to 50 mg, 100 mg, 200 mg, 250 mg, 500 mg, 750 mg, or 1 g of the compound of the present invention, depending on the disease to be treated, the route of administration, and the age, weight, and condition of the subject, or the pharmaceutical composition can be provided in unit dosage form containing a predetermined amount of the active ingredient per unit dosage. In other embodiments, the unit dosage composition is a composition containing the daily dose or partial dose of the active ingredient described herein, or appropriate fractions thereof. Furthermore, such pharmaceutical compositions can be prepared by any of the methods well known to those skilled in the art.

[0093] The therapeutically effective amount of the compound of formula (1) will depend on a number of factors including, for example, the age and weight of the subject, the exact condition and its severity for which treatment is required, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the prescribing physician. However, the therapeutically effective amount of the compound of formula (1) for treating the diseases described in the present invention is generally in the range of 0.1 mg to 100 mg per kg of the subject's body weight per day, more typically in the range of 1 mg to 10 mg per kg of body weight per day. Thus, in the case of a 70 kg adult mammal, the actual amount per day will usually be 70 mg to 700 mg, and this amount can be given in a single administration per day, or in several divided administrations such as 2, 3, 4, 5, or 6 administrations per day. Alternatively, the administration can be intermittent, for example, once every 2 days, once a week, or once a month. The therapeutically effective amount of a pharmaceutically acceptable salt or solvate, etc., can be determined as a proportion of the therapeutically effective amount of the compound of formula (1) itself. Similar dosages are considered appropriate for the treatment of the other diseases described above.

[0094] The pharmaceutical composition of the present invention may contain one or more compounds of formula (1) or their pharmaceutically acceptable salts. In some embodiments, the pharmaceutical composition may contain two or more compounds of the present invention. For example, in some embodiments, the pharmaceutical composition may contain two or more compounds of formula (1) or their pharmaceutically acceptable salts. Further, the pharmaceutical composition may optionally further contain one or more additional active pharmaceutical ingredients (APIs).

[0095] As used herein, "pharmaceutically acceptable additive" means a pharmaceutically acceptable material, composition, or vehicle involved in imparting shape or consistency to a pharmaceutical composition. Each additive is compatible with the other components of the pharmaceutical composition when combined so as to avoid interactions that would substantially reduce the effectiveness of the compounds of the present invention when administered to a subject and interactions that would result in a pharmaceutically unacceptable pharmaceutical composition.

[0096] Herein, the present invention will be described by the following synthesis examples and biological examples, which do not limit the scope of the present invention in any way.

[0097] Abbreviations The following abbreviations are used herein: Ph = phenyl Ac = acetate Bn = benzyl t-Bu = tert-butyl n-Bu = n-butyl Me = methyl Et = ethyl Pr = propyl iPr = isopropyl Bu = butyl TMS = trimethylsilyl TBS = tert-butyldimethylsilyl THF = tetrahydrofuran DMF = dimethylformamide AA = acetic acid TFA = trifluoroacetic acid i-Pr2NEt or DIPEA = diisopropylethylamine TEA = triethylamine DMAP = 4-dimethylaminopyridine Pd / C = palladium on carbon KOH = potassium hydroxide NaOH = sodium hydroxide LiOH = lithium hydroxide Ar = argon N2 = nitrogen EDC = 3-ethyl-3'-(dimethylamino)propyl-carbodiimide hydrochloride (or 1-[(3-(dimethyl)amino)propyl])-3-ethylcarbodiimide hydrochloride) HOBT = 1-hydroxybenzotriazole hydrate DIC = 1,3-dipropylcarbodiimide BOP = (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate PyBOP = benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate LiHMDS = lithium bis(trimethylsilyl)amide LAH = lithium aluminum hydride Boc = tert-butoxycarbonyl Cbz = carboxybenzyl LDA = lithium diisopropylamide NBS = N-bromosuccinimide ACN = acetonitrile min = minute h or hr = hour L = liter mL = milliliter μL = microliter g = gram mg = milligram mol = mole mmol = millimole meq = milliequivalent rt = room temperature RT = retention time sat or sat'd = saturated aq. = aqueous TLC = thin layer chromatography HPLC = high performance liquid chromatography LC / MS = high performance liquid chromatography / mass spectrometry MS or Mass Spec = mass spectrometry NMR = nuclear magnetic resonance mp = melting point

Example

[0098] The compounds of the present invention can be synthesized by many methods available to those skilled in the art of organic chemistry (Maffrand, J.P. et al., Heterocycles, 16(1):35 - 37 (1981)). A general synthetic scheme for preparing the compounds of the present invention is described below. These schemes are illustrative and are not to be construed as limiting the possible techniques that can be used by those skilled in the art to prepare the compounds disclosed herein. Various methods for preparing the compounds of the present invention will be apparent to those skilled in the art. Further, the various steps in the synthesis can be carried out in alternative sequences to obtain the desired one or more compounds.

[0099] General scheme: As shown above herein, the present invention generally relates to a compound of formula I:

Chemical formula

[0100] Examples of the compounds of the present invention prepared by the methods described in the general scheme are shown in the Intermediates and Examples sections below. The preparation of homochiral examples can be carried out by techniques known to those skilled in the art. For example, homochiral compounds can be prepared by resolution of racemic products by chiral preparative HPLC or preparative SFC. Alternatively, the compounds of the Examples can be prepared by methods known to obtain enantiomerically enriched products. These methods include, but are not limited to, incorporating an asymmetric auxiliary functionality into a racemic intermediate that serves to control the diastereoselectivity of the transformation and obtaining an enantioconcentrated product upon cleavage of the asymmetric auxiliary agent.

[0101] The compounds of the present invention can be prepared by numerous methods known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereof understood by those skilled in the art. Preferred methods include, but are not limited to, the methods described below. The reactions are carried out in a solvent or solvent mixture appropriate for the reagents and materials used and suitable for the transformation being carried out. It will be understood by those skilled in the art of organic synthesis that the functional groups present on the molecule should be compatible with the proposed transformation. This may require a decision to modify the order of the synthetic steps or to select one particular method scheme from among them in order to obtain the desired compound of the present invention.

[0102] Another major consideration in planning any synthetic route in this field will also be recognized as the appropriate selection of protecting groups used to protect the reactive functional groups present in the compounds described in the present invention. An authoritative report listing many options for the skilled practitioner is Greene et al., Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience (2006).

[0103] The compounds of the present invention having the formula (I) can be prepared by the methods exemplified in the following schemes.

[0104] As shown in Scheme 1a, the commercially available compound P1a can be alkylated using either silver oxide or sodium hydride to obtain compound P1b. The expected compound P1c can be obtained by reducing the acid moiety or ester moiety in the presence of a reducing agent (such as LAH, sodium borohydride, or BH3·SMe2).

[0105] Scheme 1a

Chemical formula

[0106] As shown in Scheme 1b, the commercially available compound P1a can be silylated in the presence of a weak base (such as imidazole) to obtain compound P2a. The ether P2b can be obtained by reacting with an aldehyde or ketone in the presence of BiBr3 and triethylsilane. Sequential hydrogenation in the presence of Pd / C, Boc protection, and ester reduction in the presence of a borohydride reagent can be carried out to obtain the expected compound P2e.

[0107] Scheme 1b

Chemical formula

[0108] As shown in Scheme 1c, commercially available compound P1a can be reacted in the presence of TMSOTf to obtain enolate P3b. Cyclopropanation can be achieved in the presence of diethyl zinc to obtain P3c. After achieving two-step protecting group exchange by sequentially deprotecting Cbz in the presence of palladium on charcoal and then reacting with Boc2O, P3e can be obtained. Finally, reduction in the presence of a borohydride reagent can obtain the expected compound P3f.

[0109] Scheme 1c

Chemical formula

[0110] As shown in Scheme 1d, commercially available compound P1a can be subjected to a reduction reaction in the presence of a borane reagent (such as BH3·SMe2, etc.) to obtain compound P4a. After protecting the primary alcohol in the presence of TBDPSCl, Dess-Martin oxidation can be carried out to obtain ketone P4c. Following the Wittig reaction and then reducing the double bond by hydrogenation, enolate P4d can be obtained. For example, by deprotecting the silyl group in the presence of a fluorine-containing reagent, the expected compound P4f can be obtained.

[0111] Scheme 1d

Chemical formula

[0112] As shown in Scheme 1e, compound P1b can be alkylated in the presence of a strong base (such as LDA) to obtain compound P2a. The ester moiety can be reduced in the presence of sodium borohydride to obtain the expected compound P2b.

[0113] Scheme 1e

Chemical Structure

[0114] As shown in Scheme 1f, after oxidizing compound P1c under Swern conditions, pyrrolidine P4b can be obtained with a strong alkylating agent (such as alkylmagnesium bromide).

[0115] Scheme 1f

Chemical Structure

[0116] As shown in Scheme 2a, compound S1a can be cyclized in the presence of amino-pyrazole S1b. Intermediate S1c can be sequentially treated with phosphorus oxychloride followed by N-bromosuccinimide to obtain intermediate S1e. Aromatic nucleophilic substitution can be achieved in the presence of ammonia to obtain compound S1f. After diazotization in the presence of isopentyl nitrite and then elimination in a one-pot reaction, skeleton S1g can be obtained.

[0117] Scheme 2a

Chemical Structure

[0118] As shown in Scheme 2b, compound S1g can be brominated in the presence of N-bromosuccinimide to obtain compound S2a. The expected compound S2b can be obtained by alkylating the skeleton with sodium alcoholate.

[0119] Scheme 2b

Chemical Structure

[0120] As shown in Scheme 2c, compound S1g can be brominated in the presence of N-bromosuccinimide to obtain compound S3a. The expected compound S3b can be obtained by alkylating the skeleton with sodium alcoholate.

[0121] Scheme 2c

Chemical Structure

[0122] As shown in Scheme 2d, after esterifying compound S4a in the presence of MeOH and acetyl chloride, it can be reacted with ethyl formate in the presence of a strong base. Intermediate S4c was converted to enol ester S4d. Subsequently, a cyclization reaction can be achieved in the presence of amino-pyrazole S1b. Intermediate S4e can be sequentially treated with phosphorus oxychloride followed by N-bromosuccinimide to obtain the expected compound S4g.

[0123] Scheme 2d

Chemical Structure

[0124] As shown in Scheme 3a, compound A1a can be subjected to the Miyaura boronation reaction to obtain A1b.

[0125] Scheme 3a

Chem.

[0126] As shown in Scheme 3b, compound A1a can be alkylated in the presence of an alkyl halide to obtain intermediate A2a. The aniline A2b can be obtained by the Miyaura boronation reaction.

[0127] Scheme 3b

Chem.

[0128] As shown in Scheme 3c, compound A3a can be subjected to Boc protection followed by the Sonogashira reaction to obtain intermediate A3c. The bromide can be converted to the free aniline A3d using a strong acid (such as HCl), and this can be subjected to the Miyaura boronation reaction to obtain A3e.

[0129] Scheme 3c

Chem.

[0130] As shown in Scheme 3d, compound A4a can be subjected to Boc protection followed by Boc deprotection (purification process) to obtain intermediate A4c. The compound A4d can be obtained by the Miyaura boronation reaction.

[0131] Scheme 3d

Chem.

[0132] As shown in Scheme 3e, after subjecting compound A5a to a cross-coupling reaction with a copper catalyst, nitro reduction (e.g., using iron and ammonium chloride) can be carried out to obtain intermediate A5c. Compound A5d can be obtained by the Miyaura borylation reaction.

[0133] Scheme 3e

Chem.

[0134] As shown in Scheme 3f, after subjecting compound A6a to a cross-coupling reaction with a copper catalyst, the Miyaura borylation reaction can be carried out to obtain boronic acid ester A6c.

[0135] Scheme 3f

Chem.

[0136] As shown in Scheme 3g, after subjecting compound A5a to a cross-coupling reaction with a copper catalyst, Boc hydrolysis can be carried out to obtain boronic acid ester A6c. A hydrazine derivative can be converted to pyrazole A7c. After decarboxylation of the intermediate in the presence of a strong acid, nitro reduction using iron and ammonium chloride can be carried out to obtain A7e. Compound A7f can be obtained by the Miyaura borylation reaction.

[0137] Scheme 3g

Chem.

[0138] As shown in Scheme 3h, after esterifying compound A8a, the Miyaura borylation reaction can be carried out to obtain boronic acid ester A8c.

[0139] Scheme 3h

Chem.

[0140] As shown in Scheme 3i, after subjecting compound A3a to Suzuki coupling and then protecting it by silylation with TBDPS, intermediate A9c can be obtained. After converting this compound to free aniline using a strong acid (e.g., HCl), the Miyaura borylation reaction can be carried out to obtain boronic acid ester A9d.

[0141] Scheme 3i

Chem.

[0142] As shown in Scheme 3j, after subjecting compound A10a to the Curtius reaction and then Suzuki coupling, intermediate A10c can be obtained. After converting this compound to free aniline using a strong acid (e.g., HCl), the Miyaura borylation reaction can be carried out to obtain boronic acid ester A10e.

[0143] Scheme 3j

Chem.

[0144] As shown in Scheme 1, compound 1a constituting an intermediate such as P1c or P2b can be subjected to aromatic nucleophilic substitution by reaction with 1b. Boronic acid ester 1d prepared by boronation from the corresponding bromophenyl can be introduced by cross-coupling with a transition metal catalyst to obtain 1e. Aniline can be sequentially nosylated, alkylated, and the Boc group can be deprotected to obtain amine 1h. Macrocyclization can be carried out using Finkelstein conditions to obtain 1i, which can then be oxidized in the presence of iodine to obtain 1j. Final compound 1k can be obtained by nosyl deprotection.

[0145] Scheme 1:

Chemical Structure

[0146] As shown in Scheme 2, compound 1j containing R1 = OBn can be deprotected in the presence of TFA and anisole to obtain phenol 2a. Subsequently, sequential alkylation and nosyl deprotection are carried out to obtain final compound 2c.

[0147] Scheme 2

Chemical Structure

[0148] As shown in Scheme 3, phenol 2a can be converted to triflate 3a. An acyl moiety is introduced by cross-coupling with a transition metal catalyst to obtain 3b. Subsequently, nosyl is deprotected to obtain final compound 3c.

[0149] Scheme 3 [Chemical] Suzuki reaction Deprotection

[0150] As shown in Scheme 4, after sequentially deprotecting the nosyl group, the final compound 4b could be obtained from compound 1j by removing the silyl moiety in the presence of methanol and a base.

[0151] Scheme 4 [Chemical] Deprotection Deprotection

[0152] As shown in Scheme 5, deprotection of the benzyl moiety of compound 1j containing R6 = OBn can be carried out in the presence of TFA and anisole to obtain phenol 5a. After forming a triflate in the presence of triflic anhydride and pyridine, a saturated heterocycle was introduced by cross-coupling with a transition metal catalyst to obtain compound 5c. The nosyl group was removed in the presence of thiophenol to obtain the final compound 5d.

[0153] Scheme 5 [Chemical] Deprotection Suzuki reaction Deprotection

[0154] As shown in Scheme 6, compound 1j containing R1 = COOMe can be hydrolyzed to obtain compound 6a. After saponification of compound 6b in the presence of a base, peptide coupling can be carried out to obtain the final compound 6c.

[0155] Scheme 6 [Chemical] Deprotection Hydrolysis Peptide coupling

[0156] As shown in Scheme 7, compound 6b can be reduced in the presence of borane dimethyl sulfide to obtain the final compound 7a.

[0157] Scheme 7

Chem.

[0158] As shown in Scheme 8, compound 7a can be chlorinated in the presence of thionyl chloride to obtain compound 8a. The final compound 8b is obtained by alkylation of the alcoholate.

[0159] Scheme 8

Chem.

[0160] As shown in Scheme 9, compound 1k containing R5 = OCH2CH2OBn can be hydrogenated in the presence of palladium on charcoal to obtain the final compound 9a.

[0161] Scheme 9

Chem.

[0162] As shown in Scheme 10, compound 1k can be subjected to an acylation reaction to obtain the final compound 10a.

[0163] Scheme 10

Chem.

[0164] As shown in Scheme 11, compound 1k can be subjected to an acylation reaction to obtain the final compound 11a.

[0165] Scheme 11

Chem.

[0166] As shown in Scheme 12, compound 1j can be converted to compound 12a in the presence of hydroxylamine. The formation of a heterocyclic ring is achieved in the presence of triethyl orthoformate to give 12b. The nosyl group is deprotected to give the final compound 12c.

[0167] Scheme 12

Chem.

[0168] As shown in Scheme 13, compound 1a can be subjected to aromatic nucleophilic substitution by reaction with 1b to give 13a. The acetal moiety is sequentially deprotected, the amine is protected with a Boc group, and a Wittig reaction is carried out to give the alkene 13d. The boronic acid ester 1d is introduced by cross-coupling with a transition metal catalyst to give 13e. The aniline is sequentially nosyl-protected, alkylated, and the Boc group is deprotected to give the amine 13i. Macrocyclization is carried out using Finkelstein conditions to give 13j, which is then oxidized in the presence of iodine to give 13k. Deprotection of the nosyl group gives the final compound 13l.

[0169] Scheme 13

Chem.

[0170] As shown in Scheme 14, Compound 1i can be oxidized in the presence of iodine following the deprotection of the nosyl group, and finally the excess iodine present in the structure can be reduced to obtain the final compound 14c.

[0171] Scheme 14:

Chem.

[0172] As shown in Scheme 15, the excess iodine of Compound 1k (present in the structure as a result of oxidation in the presence of iodine) can be reduced in the presence of an iridium catalyst to obtain the final compound 15a.

[0173] Scheme 15

Chem.

[0174] As shown in Scheme 16, Compound 1k can be subjected to Suzuki coupling in the presence of a boronic acid ester to obtain the final compound 16a.

[0175] Scheme 16

Chem.

[0176] As shown in Scheme 17, after alkylating Compound 16b in the presence of an alkyl halide, nosyl deprotection can be carried out using a sulfur derivative (e.g., methylbenzenethiol) to obtain the final compound 17b.

[0177] Scheme 17

Chem.

[0178] As shown in Scheme 18, compound 5a can be alkylated in the presence of an alkyl halide and a mild base (e.g., cesium carbonate), and then the nosyl group can be deprotected using a sulfur derivative (e.g., methylbenzenethiol) to obtain the final compound 18b.

[0179] Scheme 18 [Chemical formula] Alkylation Deprotection

[0180] As shown in Scheme 19, compound 1k can be deprotected in the presence of TBAF, for example, the silyl TBDPS group can be removed to obtain the final compound 19a.

[0181] Scheme 19 [Chemical formula] Deprotection

[0182] As shown in Scheme 20, compound 2a can be deprotected using a sulfur derivative (e.g., methylbenzenethiol) to remove the nosyl group to obtain the final compound 20a.

[0183] Scheme 20 [Chemical formula] Deprotection

[0184] As shown in Scheme 21, compound 1k can be dehalogenated in the presence of an iridium-based catalyst to obtain the final compound 21a.

[0185] Scheme 21 [Chemical formula] Dehalogenation

[0186] As shown in Scheme 22, after hydrolyzing compound 1j in the presence of sodium hydroxide, imine formation is carried out using dimethoxy-N,N-dimethylmethanamine, and then cyclization is carried out in the presence of hydroxylamine immediately thereafter to obtain intermediate 22c. The final compound 22d can be obtained by using a sulfur derivative (e.g., 4-methylbenzenethiol) for nosyl deprotection.

[0187] Scheme 22

Chemical Structure

[0188] As shown in Scheme 23, after subjecting compound 3a to nosyl deprotection using a sulfur derivative (e.g., 4-methylbenzenethiol), cross-coupling (such as Stille coupling) is carried out using a transition metal catalyst to obtain the final compound 23b.

[0189] Scheme 23

Chemical Structure

[0190] As shown in Scheme 24, after subjecting compound 3a to silyl deprotection using a fluoride-containing reagent (e.g., TBAF), a click reaction is carried out using an alkyl halide and sodium azide to obtain intermediate 24b. The final compound 24c could be obtained by using a sulfur derivative (e.g., 4-methylbenzenethiol) for nosyl deprotection.

[0191] Scheme 24

Chemical Structure

[0192] As shown in Scheme 25, compound 16b can be subjected to ether formation by reaction with an alkyl halide and TBAB to obtain the final compound 25a.

[0193] Scheme 25

Chem.

[0194] As shown in Scheme 26, after subjecting compound 16b to cross-coupling (such as Sonogashira coupling) with a transition metal catalyst, deprotection of the alkyne is carried out in alcohol in the presence of a weak base (such as potassium carbonate) to obtain the final compound 26b.

[0195] Scheme 26

Chem.

[0196] As shown in Scheme 27, after subjecting compound 1c to amine deprotection using a strong acid (such as HCl), alkylation is carried out in the presence of an alkyl halide to obtain intermediate 27b. The ester moiety can be reduced to a primary alcohol 27c in the presence of a reducing agent (such as sodium borohydride / calcium chloride), and then a protecting group is introduced (such as TBDMS) to obtain intermediate 27d. Next, this compound is used in a Suzuki coupling, followed by introduction of a nosyl protecting group and (in the case of a silyl protecting group, using TBAF) alcohol deprotection to obtain 27g. After macrocyclization by the Mitsunobu reaction, oxidation is carried out in the presence of iodine, and nosyl deprotection is carried out using a sulfur derivative (such as 4-methylbenzenethiol) to obtain the final compound 27j.

[0197] Scheme 27

Chem.

[0198] As shown in Scheme 28, after alkylating compound 5a using an alkyl halide in the presence of a weak base (e.g., potassium carbonate), nosyl deprotection was carried out using a sulfur derivative (e.g., 4-methylbenzenethiol) to obtain intermediate 28b. The final compound 28c could be obtained by alcohol deprotection (e.g., p-toluenesulfonic acid in the case of the THP protecting group).

[0199] Scheme 28

Chemical Structure

[0200] A. Physicochemical properties of the compounds Purification of the intermediates and final products was carried out by either normal-phase chromatography or reverse-phase chromatography. Unless otherwise indicated, normal-phase chromatography was performed using a pre-packed SiO2 cartridge and eluting with a gradient of either hexane and EtOAc or DCM and MeOH. Reverse-phase preparative HPLC was performed using a Gilson semi-preparative HPLC system operated by Gilson UNIPOINT software.

[0201] Purification method PA: Purification was carried out on a Phenomenex Luna column (length 100 mm × inner diameter 21.2 mm; 5 μm particles) at room temperature at a constant flow rate of 20.0 mL / min. Gradient elution was performed from 32% (25 mM aqueous NH4HCO3) / 68% (acetonitrile - methanol 1:1) → 4% (25 mM aqueous NH4HCO3) / 96% (acetonitrile - methanol 1:1) over 20 minutes. The UV detector was set at 226 nm, which corresponds to the wavelength of the maximum absorbance observed for the compound.

[0202] Purification method PB: Purification was carried out on a Phenomenex Gemini C18 column (length 100 mm × inner diameter 30 mm, particle size 5 μm) at room temperature at a flow rate of 30 mL / min. Gradient elution was performed from 70% (water + 25 mM ammonium bicarbonate) / 5% (acetonitrile - methanol 50% mixture) → 27% (water + 25 mM ammonium bicarbonate) / 73% (acetonitrile - methanol 50% mixture) over 20 minutes, then gradient elution was performed from 27% (water + 25 mM ammonium bicarbonate) / 73% (acetonitrile - methanol 50% mixture) → 0% (water + 25 mM ammonium bicarbonate) / 100% (acetonitrile - methanol 50% mixture) over 2 minutes, the resulting composition was held for 5 minutes, and then from 0% (water + 25 mM ammonium bicarbonate) / 100% (acetonitrile - methanol 50% mixture) → 95% (water + 25 mM ammonium bicarbonate) / 5% (acetonitrile - methanol 50% mixture) over 2 minutes, and the resulting composition was held for 5 minutes. The standard injection volume was 8 mL. Acquisition was set at 254 nm for the UV detector.

[0203] Unless otherwise specified, the analysis of the final product was carried out by LCMS or HPLC for reverse - phase analysis.

[0204] LCMS method A (MA) For analytical HPLC, elution was performed on an X-Select CSH C18 XP column (2.5 μm 30×4.6 mm (inner diameter)) with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B) using the following elution gradient: 5%→100% B from 0 min to 3 min and 100% B from 3 min to 4 min at a flow rate of 1.8 mL / min at 40 °C. The mass spectrum (MS) was recorded on a Waters ZQ mass spectrometer (scan 200 uma~900 uma) in electrospray positive ionization [to obtain MH molecular ion by ES+] mode or electrospray negative ionization [to obtain (M-H)- molecular ion by ES-] mode using a cone voltage of 20 V. + The molecular ion was obtained] mode or electrospray negative ionization [to obtain (M-H)- molecular ion by ES-] mode using a cone voltage of 20 V was used for recording.

[0205] LCMS method B (MB) For analytical HPLC, elution was performed on an X-Select CSH C18 XP column (2.5 μm 30×4.6 mm (inner diameter)) with 0.1% ammonia in water (solvent A) and 0.1% ammonia in acetonitrile (solvent B) using the following elution gradient: 5%→100% B from 0 min to 3 min and 100% B from 3 min to 4 min at a flow rate of 1.8 mL / min at 40 °C. The mass spectrum (MS) was recorded on a Waters ZQ mass spectrometer (scan 200 uma~900 uma) in electrospray positive ionization [to obtain MH molecular ion by ES+] mode or electrospray negative ionization [to obtain (M-H)- molecular ion by ES-] mode using a cone voltage of 20 V. + The molecular ion was obtained] mode or electrospray negative ionization [to obtain (M-H)- molecular ion by ES-] mode using a cone voltage of 20 V was used for recording.

[0206] LCMS method C (MC) HPLC for analysis was performed on an X-Select CSH C18 XP column (2.5 μm 30×4.6 mm (inner diameter)) with elution using an aqueous (NH4)2CO3 solution (2 g / L) in water (solvent A) and acetonitrile (solvent B) at a flow rate of 1.8 mL / min at 40 °C with the following elution gradient, i.e., 5%→100% B from 0 min to 3 min and 100% B from 3 min to 4 min. The mass spectrum (MS) was recorded on a Waters ZQ mass spectrometer (scan 200 uma~900 uma) using electrospray positive ionization [to obtain the MH + molecular ion] mode or electrospray negative ionization [to obtain the (M-H)- molecular ion by ES-] mode with a cone voltage of 20 V.

[0207] LCMS method D (MD) In addition to the LCMS of the general procedure, analysis was performed on a YMC pack ODS-AQ C18 column (length 50 mm × inner diameter 4.6 mm, 3 μm particles) at 35 °C at a flow rate of 2.6 mL / min. Gradient elution was performed from 95% (water + 0.1% formic acid) / 5% acetonitrile → 5% (water + 0.1% formic acid) / 95% acetonitrile at 4.80 min, and then the composition of the final mobile phase was held for an additional 1.00 min. The standard injection volume was 2 μL. The acquisition range was set to 190 nm~400 nm for the UV-PDA detector and 100 m / z~1400 m / z for the MS detector.

[0208] LCMS method E (ME) In addition to the general procedure of LCMS, analysis was performed on a Phenomenex Kinetex C18 column (length 50 mm × inner diameter 2.1 mm, particle size 2.6 μm) at 35 °C with a flow rate of 0.7 mL / min. Gradient elution was carried out with 95% (50 mM ammonium acetate in water) / 5% acetonitrile → 5% (50 mM ammonium acetate in water) / 95% acetonitrile over 4.80 minutes, and then the composition of the final mobile phase was held for an additional 1.00 minute. The standard injection volume was 2 μL. The acquisition range was set at 190 nm - 400 nm for the UV-PDA detector and 100 m / z - 1400 m / z for the MS detector.

[0209] LCMS method F (MF) Analysis was performed on a Phenomenex GEMINI C18 column (length 100 mm × inner diameter 4.6 mm, particle size 5 μm) at 25 °C with a flow rate of 3.014 mL / min. Gradient elution was carried out as follows: 95% (65 mM ammonium acetate in water + acetonitrile (90:10)) / 5% acetonitrile at 0.30 minute, from the previous composition to 100% acetonitrile at 4.26 minutes, held at the previous composition for 0.60 minutes, then advanced to 95% (65 mM ammonium acetate in water + acetonitrile (90:10)) / 5% acetonitrile at 1.02 minutes, and the composition of the final mobile phase was held for an additional 0.57 minute. The standard injection volume was 3 μL. The acquisition range was set at 200 nm - 400 nm for the UV-PDA detector and 100 m / z - 1000 m / z for the MS detector.

[0210] LCMS method G (MG) In addition to the general procedure of LCMS, analysis was performed on a YMC pack ODS-AQ C18 column (length 50 mm, inner diameter 4.6 mm, particle size 3 μm) at 35 °C with a flow rate of 2.6 mL / min. Gradient elution was carried out using an Agilent 1260 from 95% (water + 0.1% formic acid) / 5% acetonitrile to 5% (water + 0.1% formic acid) / 95% acetonitrile in 4.8 minutes, and the resulting composition was held for 1.0 minute, and then from 5% (water + 0.1% formic acid) / 95% acetonitrile to 95% (water + 0.1% formic acid) / 5% acetonitrile in 0.2 minute. The standard injection volume was 2 μL. The acquisition range was set at 190 nm to 400 nm for the UV-PDA detector and 100 m / z to 1000 m / z for the TOF-MS detector.

[0211] LCMS method H (MH) In addition to the general procedure of LCMS, analysis was performed on a Phenomenex Kinetex C18 column (length 50 mm, inner diameter 2.1 mm, particle 1.7 μm) at 60 °C with a flow rate of 1.5 mL / min. Gradient elution was carried out from 90% (water + 0.1% formic acid) / 10% acetonitrile to 10% (water + 0.1% formic acid) / 90% acetonitrile in 1.50 minutes, and then the composition of the final mobile phase was held for an additional 0.40 minutes. The standard injection volume was 2 μL. The acquisition range was set at 254 nm for the UV-PDA detector and 80 m / z to 800 m / z for the MS detector.

[0212] LCMS method I (MI) Analysis was performed on a Thermo Scientific Accucore C18 column (50 mm in length × 2.1 mm in inner diameter, 2.6 μm) at 35 °C with a flow rate of 1.50 mL / min. Gradient elution was carried out from 95% (water + 0.1% formic acid) / 5% acetonitrile to 5% (water + 0.1% formic acid) / 95% acetonitrile over 1.30 minutes, and the resulting composition was held for 0.5 minutes. Then, the final mobile phase composition was maintained, and a gradient from 5% (water + 0.1% formic acid) / 95% acetonitrile to 90% (water + 0.1% formic acid) / 10% acetonitrile was carried out over 0.10 minutes. The injection volume was 1 μL. The acquisition ranges of the MS and UV detectors were set to 100 m / z to 1000 m / z and 190 nm to 400 nm, respectively.

[0213] LCMS method K (MK) Analytical HPLC was performed on a Kinetex EVO C18 column (30 × 2.1 mm, 5 μm) at 50 °C with a flow rate of 1.5 mL / min using 0.0375% TFA (v / v) in water (solvent A) and 0.01875% TFA (v / v) in acetonitrile (solvent B) with the following elution gradient: 5% to 95% B from 0 to 1.20 minutes and 95% to 5% B from 1.2 to 1.55 minutes. The mass spectrum (MS) was recorded using an ESI ionization source [obtaining MH+ molecular ions by ES+] mode with a Qarray DC voltage of 20 V.

[0214] Purification was carried out using a Gilson system consisting of a binary pump (models 333 and 334), an ASPEC autosampler, a column valve selector, and a UV detector. Data acquisition was performed using Trilution 3.0 software.

[0215] Skeleton S1: 3-Bromo-5-chloro-6-methylpyrazolo[1,5-a]pyrimidine

Chemical Structure

[0216] Project 1 To a solution of 1H-pyrazol-5-amine (173 g, 2.09 mol) was added EtONa (343 g, 5.04 mol, 2000 mL), followed by diethyl 2-methylpropanedioate (400 g, 2.30 mol, 392 mL). The mixture was stirred at 100 °C for 12 h. TLC (petroleum ether / ethyl acetate = 0 / 1, compound 4, Rf = 0.3) indicated the completion of the reaction. The reaction mixture was cooled to 25 °C and filtered to obtain a pale yellow solid. The crude product was stirred in EtOH (5 L) for 12 h and filtered to obtain a white solid. The sodium salt of 7-hydroxy-6-methyl-4H-pyrazolo[1,5-a]pyrimidin-5-one (540 g) was obtained as a white solid.

[0217] The crude material was used in the subsequent steps without further purification.

[0218] 1 H NMR (ppm, 400 MHz), MeOD: 7.56 (d, J = 1.8 Hz, 1H), 5.75 (d, J = 2.0 Hz, 1H), 1.95 (s, 3H)

[0219] Project 2 To a solution of POCl3 (3.15 kg, 20.5 mol, 1.91 L) was added the sodium salt of 7-hydroxy-6-methyl-4H-pyrazolo[1,5-a]pyrimidin-5-one (366 g, 2.22 mol). The mixture was stirred at 105 °C for 40 h. The mixture was concentrated to remove most of the POCl3, and the reaction mixture was diluted with ethyl acetate (5000 mL), poured into ice water (10000 mL), and adjusted to pH = 7 - 8 by the addition of saturated NaHCO3 solution. Next, the aqueous phase was extracted with ethyl acetate (2000 mL×3), 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.

[0220] The crude substance is used in the subsequent process without further purification.

[0221] 1 H NMR (ppm, 400 MHz), CDCl3: 8.15 (d, J = 2.3 Hz, 1H), 6.69 (d, J = 2.3 Hz, 1H), 2.54 (s, 3H)

[0222] Step 3 To a solution of 5,7-dichloro-6-methyl-pyrazolo[1,5-a]pyrimidine (290 g, 1.44 mol) in THF (1.5 L) were added Zn (210 g, 3.21 mol), a solution of ammonia (35%) (528 g, 5.27 mol, 580 mL, 3.67 equivalents), and saturated NaCl solution (1.5 L). The reaction mixture was stirred at 25 °C for 2 h. TLC (petroleum ether:ethyl acetate = 3:1) indicated that the reaction was complete. After filtering off Zn, the mixture was 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 5-chloro-6-methyl-pyrazolo[1,5-a]pyrimidine (420 g) of the title compound (obtained as a yellow solid). The crude substance is used in the subsequent process without further purification.

[0223] 1 H NMR (ppm, 400 MHz), CDCl3: 8.49 (s, 1H), 8.05 (d, J = 1.8 Hz, 1H), 6.63 - 6.52 (m, 1H), 2.38 (s, 3H)

[0224] Step 4 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 h. Formation of the expected compound was indicated by LCMS. The mixture was poured into water (2000 mL), and the solid formed 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 subsequent step without further purification.

[0225] LCMS (MK) RT = 0.837 min, m / z = 247.9 (M+H) + 。

[0226] Skeleton S2: 3-bromo-5-chloro-6-methoxypyrazolo[1,5-a]pyrimidine

Chemical formula

[0227] Step 1: 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).

[0228] The reaction mixture was heated at 120 °C for 16 h. When complete conversion was monitored by LCMS, the mixture was cooled to 0 °C. The resulting violet solid was filtered off, washed with EtOH at 0 °C, concentrated, co-evaporated with acetonitrile, and dried under high vacuum.

[0229] The solid was added portionwise to a stirred solution of HCl (1 N) at 4 °C to 5 °C. The precipitate was filtered and washed with a minimum amount of cold water. The beige solid was concentrated in vacuo and co-evaporated with toluene (×3). The beige solid was dried under high vacuum and used as such in the subsequent step.

[0230] LCMS (MD) RT = 0.405 min, m / z = 182.0 (M+H) + 。

[0231] Step 2: 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 mixture was heated at 120 °C for 4 h. After cooling, the excess phosphorus oxychloride was removed, the residue was diluted with EtOAc and washed with a saturated solution of NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography using heptane / EtOAc (100:0 → 80:20) as eluent to give the title compound as a yellow solid (44.8 g, 27% yield).

[0232] LCMS (MH) RT = 0.556 min, m / z = 218.1 / 220.0 (M+H) + 。

[0233] Step 3: The title compound from Step 2 (22.1 g, 101.36 mmol) was dissolved in acetonitrile (304 mL) and cooled to 0 °C. Next, N-bromosuccinimide (18.04 g, 101.36 mmol) was added portionwise, and the mixture was stirred at room temperature for an additional 30 minutes. Once complete conversion was monitored by LCMS, the mixture was diluted with EtOAc and extracted with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. The product was purified by flash chromatography using heptane / EtOAc (100:0 → 80:20) as the eluent to afford the title compound as a yellow solid (23.7 g, 78.8%).

[0234] LCMS (MH) RT = 0.769 min, m / z = 295.2 / 299.0 (M+H) + 。

[0235] Step 4: 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 while stirring continuously. Once complete conversion was monitored by LCMS, the mixture was quenched with water. EtOAc was added and extraction was performed. The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by flash chromatography on silica gel using DCM / MeOH (100:0 → 90:10) as the eluent to afford the expected compound as a pale yellow solid.

[0236] LCMS (MH) RT = 0.655 min, m / z = 260.2 / 262.2 (M+H) + 。

[0237] Skeleton S3: 3-Bromo-6-(bromomethyl)-5-chloro-pyrazolo[1,5-a]pyrimidine

Chemical formula

[0238] Step 1 To a solution of 2-(benzyloxy)acetic acid (166 g, 999 mmol, 143 mL, 1 equiv) in MeOH (800 mL) was added acetyl chloride (117 g, 1.50 mol, 107 mL, 1.5 equiv) dropwise at 10 °C. The mixture was stirred at 20 °C for 1 h. The mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 → 5 / 1) to give the title compound (170 g, 943 mmol, 94.4% yield) as a colorless oil.

[0239] 1 1H NMR: 400 MHz, CDCl3: 7.45 - 7.30 (m, 5H), 4.66 (s, 2H), 4.13 (s, 2H), 3.79 (s, 3H)

[0240] Step 2 To a solution of sodium hydride (33.0 g, 824 mmol, 60% purity, 1.1 equiv) in THF (675 mL) was added ethyl formate (83.3 g, 1.12 mol, 90.4 mL, 1.5 equiv). Next, the title compound from Step 1 (135 g, 749 mmol, 1 equiv) in THF (135 mL) was 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 equiv) 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 dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (185 g, crude) as a yellow oil, which was used in the subsequent step without purification based on a theoretical yield of 100%.

[0241] Step 3 To a solution of 3-aminopyrazole (41.0 g, 493 mmol, 1 equiv) and the title compound from Step 2 (175 g, 740 mmol, 1.5 equiv) in DMF (1000 mL) was added Cs2CO3 (241 g, 740 mmol, 1.5 equiv). The mixture was stirred at 110 °C for 10 h. When complete conversion was monitored by LCMS, the mixture was cooled to 20 °C, poured into ice water (3000 mL), and adjusted to pH = 5 - 6 with 2 M HCl (700 mL), during which a large amount of solid precipitated. 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 afford the title compound (65.0 g, 269 mmol, 54.6% yield) as a yellow solid.

[0242] 1 H NMR: DMSO-d6 400 MHz: 12.40 (s, 1H), 8.33 (s, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.53 - 7.33 (m, 5H), 5.80 (d, J = 1.7 Hz, 1H), 5.05 (s, 2H)

[0243] Step 4 To a solution of the title compound from Step 3 (80.0 g, 332 mmol, 1 equiv) in acetonitrile (600 mL) was added POCl3 (127 g, 829 mmol, 77.0 mL, 2.5 equiv) and N,N - diethylaniline (495 mg, 3.32 mmol, 530 μL, 0.01 equiv). Next, the mixture was stirred at 100 °C for 4 h. When completely converted as monitored by LCMS, the mixture was concentrated under vacuum to remove most of the CH3CN and POCl3. Next, the mixture was diluted with ethyl acetate (1000 mL), poured into ice water (2000 mL), adjusted to pH = 7 with potassium carbonate, and extracted with ethyl acetate (1000 mL × 2). The combined organic layers were washed with brine (1000 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 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.

[0244] 1 H NMR: CDCl3, 400 MHz, 8.27 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.58 - 7.39 (m, 5H), 6.61 (d, J = 2.4 Hz, 1H), 5.19 (s, 2H)

[0245] Step 5 To a solution of the title compound from Step 4 (69.0 g, 266 mmol, 1 equiv) in dichloromethane (650 mL) was slowly added NBS (47.3 g, 266 mmol, 1 equiv). The mixture was stirred at 25 °C for 2 h. When completely converted as 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 afford the expected compound (85.3 g, 252 mmol, 94.7% yield) as a pale yellow solid.

[0246] 11H NMR: DMSO-d6, 400 MHz, 9.23 (s, 1H), 8.31 (s, 1H), 7.59 - 7.17 (m, 5H), 5.27 (s, 2H)

[0247] 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

Chemical Structure

[0248] 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 sequentially added N - bromosuccinimide (36.10 g, 202.84 mmol) and 2,2'-azobis(2 - methylpropionitrile) (333 mg, 2.028 mmol). The reaction mixture was stirred at 100 °C for 16 h.

[0249] The mixture was filtered, and the residue was washed with dichloromethane. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate 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 give the title compound as a white solid (1.885 g, 28% yield).

[0250] LCMS (MH) RT = 0.797 min, m / z = 325.7 - 327.7 (M + H) + .

[0251] Skeleton S5: 3 - Bromo - 5 - chloro - 6 - (dibromomethyl)pyrazolo[1,5 - a]pyrimidine was obtained as a pale yellow solid (5.045 g, 61% yield).

[0252] LCMS (MH) RT = 0.966 min, m / z = 403.6 - 405.6 (M+H) + 。

[0253] Skeleton S6: 3 - Bromo - 5 - chloro - 6 - (methoxymethyl)pyrazolo[1,5 - a]pyrimidine

Chem.

[0254] A solution of Skeleton S4 (1.885 g, 5.793 mmol) in methanol (38 mL) was heated in a sealed tube at 100 °C for 6 h. After cooling, the solvent was removed under reduced pressure and the residue was diluted in ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate 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 give the title compound as a white solid (1.378 g, 86% yield).

[0255] LCMS (MH) RT = 0.724 min, m / z = 275.9 - 277.9 (M+H) + 。

[0256] Skeleton S7: 3 - Bromo - 5 - chloro - 6 - fluoro - pyrazolo[1,5 - a]pyrimidine

Chem.

[0257] Step 1 To a mixture of diethyl 2-fluoro-malonic acid ester (10 g, 56.129 mmol) in ethanol (170 mL) was added 1H-pyrazol-3-ylamine (4.664 g, 56.129 mmol) and sodium ethoxide solution (21 wt% in ethanol) (42 mL, 112.258 mmol). The reaction mixture was heated at 120 °C for 30 h. The reaction mixture was concentrated under reduced pressure and co-evaporated with toluene. 1 M 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 give the title compound as a light brown solid (6.85 g, 72% yield), which was used without further purification.

[0258] LCMS (MH) RT = 0.100 min, m / z = 170.1 (M + H) + 。

[0259] Step 2 To a mixture of the title compound from Step 1 (6.85 g, 40.504 mmol) and phosphorus oxychloride (V) (50 mL, 263.276 mmol) was slowly added diethyl-phenyl-amine (11 mL, 56.706 mmol) at 0 °C. After warming the reaction mixture to room temperature, it was 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 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 give the title compound as a white solid (5.107 g, 61% yield).

[0260] LCMS (MH) RT = 0.664 min, m / z = 206.0 - 207.9 (M + H) + 。

[0261] Step 3 To a mixture of the title compound from Step 2 (4.395 g, 21.334 mmol) in acetonitrile (64 mL) was added N-bromosuccinimide (3.797 g, 21.334 mmol) portionwise at 0 °C. The reaction mixture was stirred for 30 minutes. Saturated aqueous sodium bicarbonate 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 give the title compound as a yellow solid (5.796 g, 95% yield).

[0262] LCMS (MH) RT = 0.859 min, m / z = 283.9 - 285.9 (M+H) + 。

[0263] Step 4 The title compound from Step 3 (5.79 g, 20.344 mmol) in aqueous ammonia (100 mL) was stirred at room temperature for 16 hours. 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 layers were 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 give the title compound as a pale yellow solid (4.10 g, 76% yield).

[0264] LCMS (MH) RT = 0.615 min, m / z = 265 - 267 (M+H) + 。

[0265] Step 5 To a solution of the title compound from Step 4 (5.060 g, 19.061 mmol) in dioxane (50 mL) was added isopentyl nitrite (5.133 mL, 38.122 mmol). The reaction mixture was heated at 110 °C for 2 hours. 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 give the expected compound as a yellow solid (2.158 g, 45% yield).

[0266] LCMS (MH) RT = 0.707 min, m / z = 249.9 - 251.9 (M + H) + 。

[0267] Skeleton S8: 3 - Bromo - 5 - chloro - 6 - (dibromomethyl)pyrazolo[1,5 - a]pyrimidine

Chemical Structure

[0268] 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 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. 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 give the expected compound as an off - white solid (2.89 g, 76% yield).

[0269] LCMS (MH) RT = 0.703 min, m / z = 303.9 - 305.9 (M + H) + 。

[0270] Pyrrolidine P1: tert-Butyl (2S,4R)-2-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate

Chem.

[0271] Step 1 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 addition of iodomethane (11.2 ml, 179.4 mmol) cooled to 0 °C. The resulting suspension was slowly warmed to ambient temperature and stirred vigorously for 2 days. When completed as monitored 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 gradient of heptane / EtOAc (10:0 → 5:5) to give the title product (8.8 g, yield: 94%) as a colorless liquid.

[0272] LCMS (MH) RT = 0.691 min, m / z = 160.1 (M - 56) + .

[0273] Step 2 The title compound from Step 1 (8.8 g, 33.938 mmol) was dissolved in dry THF and cooled to 0 °C under a N2 atmosphere. Lithium aluminum hydride (2.58 g, 67.876 mmol) was added portionwise and stirred for 2 hours. When completed as monitored by LCMS, H2O was added to quench the reaction, and the reaction mixture was filtered through a pad of Celite and rinsed with EtOAc. The product was purified by flash chromatography (on silica gel) using DCM / MeOH (100: → 95:5) as the eluent to give the expected compound as a colorless oil (6.2 g, 78.99%).

[0274] LCMS (MH) RT = 0.518 min, m / z = 132.1 (M - 99)+ .

[0275] Similarly, the following intermediates were prepared.

[0276]

Table 1

[0277] Pyrrolidine P3: tert-butyl (2S,4R)-4-(cyclobutoxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

Chemical formula

[0278] Step 1 A suspension of O1-benzyl O2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (5.0 g, 17.90 mmol) in dichloromethane (50 mL) was treated with 1H-imidazole (2.438 g, 35.80 mmol) and tert-butyldimethylsilyl chloride (4.048 g, 26.85 mmol). The reaction mixture was stirred at room temperature for 8 h, 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 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 give O1-benzyl O2-methyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxypyrrolidine-1,2-dicarboxylate (6.372 g, 90% yield) as a colorless oil.

[0279] LCMS (MA) RT = 3.36 min, m / z = 394.1 (M+H) + 。

[0280] Step 2 A suspension of bismuth tribromide (1.423 g, 3.17 mmol) in acetonitrile (25 mL) at 0 °C under argon was treated with triethylsilane (2.54 mL, 15.85 mmol). The reaction mixture was stirred at 0 °C for 10 min, and a suspension of the title compound from step 1 (4.160 g, 10.57 mmol) and cyclobutanone (3.95 mL, 52.85 mmol) in acetonitrile (12 mL) 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 aqueous 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 afford the title compound as a pale yellow oil (2.03 g, 55% yield).

[0281] LCMS (MA) RT = 2.70 min, m / z = 334.1 (M+H) + 。

[0282] Step 3 To a suspension of the title compound from step 2 (2.030 g, 6.09 mmol) in methanol (35 mL) under argon was added 10% Pd / C (200 mg). The reaction mixture was stirred at room temperature for 6 h under a hydrogen atmosphere. The reaction mixture was filtered through a Celite pad and washed with methanol and ethyl acetate. The filtrate was evaporated under reduced pressure to afford the title compound as a colorless oil (1.205 g, 99% yield), which was used in the subsequent step without further purification.

[0283] 1 H NMR (400 MHz, CDCl3) 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).

[0284] Step 4 To a solution of the title compound (1.205 g, 6.05 mmol) from Step 3 in tetrahydrofuran (90 mL) were added triethylamine (2.53 mL, 18.15 mmol), DMAP (74 mg, 0.61 mmol), and Boc2O (3.961 g, 18.15 mmol). The reaction 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 afford the title compound as a pale yellow oil (1.460 g, 81% yield).

[0285] 1 H NMR (400 MHz, CDCl3) 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).

[0286] Step 5 To a suspension of the title compound (1.460 g, 4.88 mmol) from Step 4 in a mixture of EtOH / THF (1:1, 44 mL) cooled to 0 °C were added sodium borohydride (369 mg, 9.76 mmol) and calcium chloride (542 mg, 4.88 mmol). The solution was warmed to room temperature and stirred at room temperature for 2 h. The reaction mixture was quenched by adding water and HCl aqueous solution (1 M) to pH = 4. EtOAc was added. The layers were separated. The aqueous layer was extracted with EtOAc (3×40 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 as eluent with a gradient from 100:0 to 50:50.

[0287] The expected fraction was collected and evaporated under reduced pressure to afford the expected compound as a colorless oil (1.242 g, 4.58 mmol, 94%).

[0288] 1 1H NMR (400 MHz, CDCl3), 4.14 - 4.06 (1H, m), 4.00 - 3.90 (2H, m), 3.72 (1H, dd, J = 2.4, 11.5 Hz), 3.59 - 3.54 (2H, m), 3.38 (1H, dd, J = 4.6, 12.0 Hz), 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).

[0289] Similarly, the following intermediates were prepared.

[0290] [Table 2] Intermediate No. Structure Yield In 97% yield as a colorless oil In 95% yield as a colorless oil

[0291] Pyrrolidine P6: tert - butyl (2S,4R)-2-(hydroxymethyl)-4-(trideuteromethoxy)pyrrolidine - 1 - carboxylate [Chemical formula]

[0292] Step 1 A solution of 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (3.2 g, 13.046 mmol) dissolved in dry tetrahydrofuran (65 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil) (1.044 g, 26.092 mmol). The reaction mixture was stirred for 45 minutes. Iodomethane-d3 (1.624 g, 26.092 mmol) was added and the reaction mixture was stirred for 30 minutes. 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 give the title compound as a white solid (2.6 g, 39% yield).

[0293] LCMS (MH) RT = 0.736 min, m / z = 163.1 (M+H) + -Boc.

[0294] Step 2 To the title compound from Step 1 (2.6 g, 10.471 mmol) was added dropwise a solution of borane dimethyl sulfide complex (2.0 M / THF) (15 mL) at 0 °C. The mixture was stirred at room temperature for 16 hours. 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 give the expected compound as a colorless solid (2.2 g, 90% yield).

[0295] LCMS (MH) RT = 0.534 min, m / z = 135.1 (M+H) + -Boc.

[0296] Similarly, the following intermediates were prepared.

[0297]

Table 3

[0298] Pyrrolidine P9: tert-Butyl (2S,4R)-4-cyclopropoxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate [Chemical formula]

[0299] Step 1 To a suspension of benzyl chloroformate (23.4 mL, 166.8 mmol) in THF / water (100 mL / 50 mL), potassium carbonate (46.11 g, 333.6 mmol) was added, followed by careful addition of methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate hydrochloride (16.15 g, 111.2 mmol) with vigorous stirring. The reaction mixture was stirred at room temperature for 2 hours. When complete conversion was monitored by LCMS, the mixture was acidified to pH = 1 with aqueous HCl (1 M). The layers were separated. The aqueous layer was extracted with EtOAc (3 × 100 mL), 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 → 0:100) as the eluent to obtain the title compound as a yellow oily substance (20.58 g, 66% yield).

[0300] LCMS (MA) RT = 1.93 min, m / z = 280.1 (M + H) +

[0301] Step 2 Palladium(II) acetate (787 mg, 3.50 mmol) and 1,10-phenanthroline (695 mg, 3.85 mmol) were dissolved in dry dichloromethane (40 mL) under argon, and the resulting solution was stirred at room temperature for 10 minutes. Next, ethyl vinyl ether (140 mL) was added. The solution was degassed for 10 minutes by bubbling argon. The reaction mixture was stirred at room temperature under an argon atmosphere for 15 minutes, and a solution of the title compound from Step 1 (9.79 g, 35.05 mmol) in dry dichloromethane (110 mL) was added. The reaction mixture was stirred overnight under reflux. When complete conversion was monitored by TLC plate, the reaction mixture was cooled to room temperature and diluted with water (100 mL). The aqueous layer was extracted with DCM (3 × 60 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 → 50:50) as the eluent to afford the title compound as a pale yellow oil (6.796 g, 64%).

[0302] LCMS (MA) RT = 2.56 min, m / z = 306.1 (M+H) +

[0303] Step 3 A suspension of diethylzinc (1 M) (86.0 mL, 85.53 mmol) in hexane in DCM (300 mL) cooled to 0 °C under an argon atmosphere was added dropwise to diiodomethane (6.94 mL, 85.53 mmol) in DCM (60 mL). The reaction mixture was stirred at 0 °C for 30 minutes. Next, the title compound from Step 2 (8.70 g, 28.51 mmol) in DCM (100 mL) was added dropwise at 0 °C. The mixture was warmed to room temperature and stirred overnight at room temperature. Partial conversion was revealed by LCMS monitoring. The mixture was stirred at room temperature for an additional 10 hours. The reaction mixture was quenched by adding saturated aqueous ammonium chloride (150 mL). The layers were separated and the aqueous layer was extracted with DCM (3 × 100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the title compound as a colorless oil (6.69 g, 74% yield). The crude product was used directly in the subsequent step without further purification.

[0304] LCMS (MA) RT = 2.55 min, m / z = 320.1 (M+H) +

[0305] Step 4 To a suspension of the title compound from Step 3 (2.83 g, 8.88 mmol) in methanol (50 mL) under argon was added palladium on charcoal (10%) (275 mg). The reaction mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. When complete conversion was monitored by TLC plate, the mixture was filtered through Celite and washed with MeOH and EtOAc. The filtrate was evaporated under reduced pressure to give the title compound as a colorless oil (1.54 g, 94% yield). The crude product was used directly in the subsequent step without further purification.

[0306] 11H NMR (400 MHz, DMSO) δ 4.11 - 4.06 (1H, m), 3.75 (1H, t, J = 7.8 Hz), 3.62 (3H, s), 3.28 - 3.23 (1H, m), 2.95 (1H, dd, J = 4.7, 11.5 Hz), 2.84 (1H, qd, J = 1.3, 11.6 Hz), 2.67 (1H, s), 2.08 - 2.01 (1H, m), 1.90 - 1.83 (1H, m), 0.48 - 0.41 (4H, m);

[0307] Project 5 To a solution of the title compound (1.54 g, 8.31 mmol) from Step 4 in THF (125 mL) was added Et3N (3.48 mL, 24.94 mmol), DMAP (101 mg, 0.83 mmol), and then Boc2O (5.44 g, 24.94 mmol). The reaction mixture was stirred at 70 °C overnight. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography using cyclohexane / EtOAc (100:0 → 50:50) as the eluent to afford the title compound as a pale yellow oil (1.52 g, 64% yield).

[0308] 1 1H NMR (400 MHz, DMSO) δ 4.18 - 4.13 (2H, m), 3.67 (3H, s), 3.45 (2H, dd, J = 4.5, 7.5 Hz), 3.33 - 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);

[0309] Project 6 A suspension of the title compound from Step 5 (1.52 g, 5.34 mmol) in a mixture of EtOH / THF (1:1) (50 mL) cooled to 0 °C was treated with sodium borohydride (404 mg, 10.68 mmol) and calcium chloride (593 mg, 5.34 mmol). The solution was warmed to room temperature and stirred at room temperature for 1 h. The reaction mixture was quenched by adding water and aqueous HCl (1 M) to pH = 4. EtOAc was added. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 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 → 50:50) as eluent to afford the expected compound as a colorless oil (1.30 g, 95% yield).

[0310] 1 H NMR (400 MHz, DMSO) δ 4.71 (1H, t, J = 5.7 Hz), 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).

[0311] Pyrrolidine P10: tert - butyl (2S)-2-(hydroxymethyl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

Chem.

[0312] Step 1 (2S,4R)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (10 g, 43.243 mmol) was added to borane-methyl sulfide complex (30 mL) at 0 °C under a nitrogen atmosphere. The mixture started to heat spontaneously with effervescence. The mixture was continuously stirred at room temperature for 16 h. Methanol was slowly added dropwise at 0 °C until the effervescence stopped, and the mixture was concentrated under vacuum to obtain the title compound as a colorless oil (9.3 g, yield: 99%). The crude product was used as such in the subsequent step.

[0313] LCMS (MH) RT = 0.340 min, m / z = 162.1 (M - 56) / 118.2 (M - 100)

[0314] Step 2 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-butyldichlorophenylsilane (11.93 mL, 46.427 mmol) at 0 °C, and the mixture was stirred for 16 h. When complete conversion was monitored by LCMS, a saturated NaHCO3 solution (200 mL) was added, and the mixture was extracted with EtOAc (4 × 100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified on a silica gel column using heptane / EtOAc (100.0→40:60) as the eluent to obtain the expected compound as a pale yellow rubbery solid (3.75 g, yield: 19.5%).

[0315] LCMS (MH) RT = 1.396 min, m / z = 356.1 (M - 100)

[0316] Step 3 To a solution of the title compound (3.75 g, 8.23 mmol) from Step 2 in DCM (40 mL), Dess-Martin periodinane (6.981 g, 16.458 mmol) was added portionwise at room temperature and stirring was continued for 16 h. A solution of saturated aqueous NaHCO3 (100 mL) was added and the mixture was extracted with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The product was purified on a silica gel column using heptane / EtOAc (80:20) as eluent to afford the expected compound (3.6 g, yield: 96%) as a colorless rubbery solid.

[0317] LCMS (MH) RT = 1.478 min, m / z = 354.1 (M - 100) / 320.0 (M - 259)

[0318] Step 4 To (methoxymethyl)triphenylphosphonium chloride (5.78 g, 16.88 mmol) in dry THF (25 ml), a solution of potassium bis(trimethylsilyl)amide (1 M) in THF (17 ml, 16.884 mmol) was added portionwise at -78 °C and stirring was continued for 30 min. To the mixture was added the title compound (3.83 g, 8.442 mmol) from Step 3 in dry THF (15 ml). The resulting mixture was stirred at the same temperature for 1 h. When complete conversion was monitored by LCMS, a saturated aqueous solution of NaHCO3 (100 mL) was added and the mixture was extracted with EtOAc (4 × 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The product was purified on a silica gel column using heptane / EtOAc (93:7) as eluent to afford the expected compound as a viscous pale yellow oil (3.06 g, yield: 75%).

[0319] LCMS (MH) RT = 1.650 min, m / z = 382.1 (M - 100)

[0320] Step 5 To a solution of the title compound from step 4 (3.03 g, 6.298 mmol) in ethyl acetate (20 mL) was added palladium on activated carbon (wet 10%) (0.5 g), purged with hydrogen atmosphere (balloon), and stirred at room temperature for 16 hours. When completely converted as 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 product was dried under high vacuum to obtain the expected compound as a yellow rubbery solid (2.95 g, yield: 96.83%), which was used as such in the subsequent step.

[0321] LCMS (MH) RT = 1.645 min, m / z = 384.1 (M - 100)

[0322] Step 6 To the title compound from step 5 (2.95 g, 6.098 mmol) in THF (40 ml) was added tetrabutylammonium fluoride (1 M) in THF (18.3 mL) at room temperature, and the mixture was stirred for 16 hours. The mixture was diluted with EtOAc (100 mL) and washed twice with a saturated aqueous solution of NaHCO3 (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified on a silica gel column using heptane / EtOAc (80:20) as the eluent to obtain the expected product as a colorless oil (1.29 g, yield: 86%).

[0323] LCMS (MH) RT = 0.595 min, m / z = 190.1 (M - 56) / 146.1 (M - 100)

[0324] Pyrrolidine P15: tert - butyl (4R)-2-(hydroxymethyl)-4 - methoxy - 2 - methylpyrrolidine - 1 - carboxylate

Chemical Structure

[0325] Step 1 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 addition of iodomethane (11.2 ml, 179.4 mmol) cooled to 0 °C. The resulting suspension was slowly warmed to ambient temperature and stirred vigorously for 2 days. When completed as monitored 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 gradient of heptane / EtOAc (10:0 → 5:5) to afford the title product (8.8 g, yield: 94%) as a colorless liquid.

[0326] LCMS (MH) RT = 0.691 min, m / z = 160.1 (M - 56) + 。

[0327] Step 2 n-Butyllithium (2.5 M) in n-hexane (6.94 mL, 17.35 mmol) 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 minutes. Next, the mixture was cooled to -35 °C and combined with a solution of the title compound from Step 1 (3.00 g, 11.57 mmol) in THF (100 mL). The mixture was stirred at 0 °C for 1 hour and then cooled to -78 °C. Methyl iodide (1.080 mL, 17.35 mmol) was added dropwise and the mixture was stirred at -78 °C for 4 hours. Next, 10 mL of saturated ammonium chloride solution was added dropwise and the mixture was heated to room temperature. Then, this was 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 the eluent to afford the title compound as a yellow oil (1.548 g, 5.66 mmol, 49% yield).

[0328] Step 3 A suspension of the title compound from step 2 (1.55 g, 5.66 mmol) in a mixture of EtOH / THF (30 mL / 30 mL) cooled to 0 °C was treated with sodium borohydride (0.428 g, 11.33 mmol) and calcium chloride (0.629 g, 5.66 mmol). The solution was warmed to room temperature and stirred at room temperature for 1 h. The reaction mixture was quenched by adding water and aqueous HCl solution (1 M) to pH = 4. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc (3 × 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 → 60 / 40) as eluent to afford the expected product as a colorless oil (0.782 g, 3.19 mmol, 56% yield).

[0329] 1 H NMR (400 MHz, 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 = 3.8 Hz), 1.28 - 1.22 (3H, m).

[0330] Pyrrolidine P16: tert - butyl (4R)-2-(1 - hydroxyethyl)-4 - methoxypyrrolidine - 1 - carboxylate

Chemical Structure

[0331] Step 1 A stirred solution of 2 M oxalyl chloride in DCM (10 mL, 20 mmol) in dichloromethane (100 mL) at -78 °C was added dropwise via syringe with dimethyl sulfoxide (2.84 mL, 40 mmol). The mixture was stirred at -78 °C for 10 minutes, 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 that 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 afford the title compound (a mixture of diastereomers) as a colorless oil (2.44 g).

[0332] Dia1: 1 H NMR (400 MHz, CDCl3) 9.45 (1H, d, J = 3.8 Hz), 4.23 - 4.17 (1H, m), 3.98 - 3.93 (1H, m), 3.75 (1H, d, J = 12.0 Hz), 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).

[0333] Dia2: 1 H NMR (400 MHz, CDCl3) 9.57 (1H, d, J = 2.7 Hz), 4.32 (1H, t, J = 8.1 Hz), 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).

[0334] Step 2 A solution of the title compound from Step 1 (1.63 g, 7.10 mmol) in anhydrous diethyl ether (105 mL) cooled to 0 °C under a nitrogen atmosphere was added with methylmagnesium bromide (3 M in diethyl ether, 5.92 mL, 17.77 mmol) via syringe, and the resulting solution was stirred at 0 °C for 2 h. The reaction was quenched with a saturated solution of ammonium chloride and extracted with diethyl 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 → 50 / 50) to give the expected compound (a mixture of diastereomers) as a colorless oil (150 mg, 0.611 mmol).

[0335] Dia1: 1 H NMR (400 MHz, CDCl3), 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 = 6.6 Hz).

[0336] Dia2: 1 H NMR (400 MHz, CDCl3), 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 = 6.7 Hz).

[0337] Intermediate I1: 1-(3-Bromo-5-nitrophenyl)-5-methyl-1H-pyrazole

Chemical Structure

[0338] Step 1 In a sealed 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 copper(I) iodide (174 mg, 0.915 mmol) were added, and the reaction mixture was stirred at 50 °C for 4 hours. 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 give tert-butyl 1-(3-bromo-5-nitrophenyl)hydrazine-1-carboxylate (1.045 g, 34% yield) as a brown sticky solid.

[0339] LCMS (MH) RT = 1.044 min, m / z = 275.9 - 277.9 (M+H) + 。

[0340] Step 2 The title compound from Step 1 (1.040 g, 3.131 mmol) was dissolved in HCl (4 M / dioxane) (10 mL). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure to give crude (3-bromo-5-nitrophenyl)hydrazine dihydrochloride (950 mg, 100% yield) as a brown solid, which was used without further purification.

[0341] LCMS (MH) RT = 0.518 min, m / z = 231.9 - 233.9 (M+H) + 。

[0342] Step 3 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 hours. After cooling, saturated aqueous sodium bicarbonate 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 (elution solvent 80% / 20% heptane / ethyl acetate) to give ethyl 1-(3-bromo-5-nitrophenyl)-5-methyl-1H-pyrazole-4-carboxylate (780 mg, 75% yield) as an orange solid.

[0343] LCMS (MH) RT = 1.026 min, m / z = 353.9 - 356.0 (M+H) + 。

[0344] Step 4 In a pressure flask, to the title compound (780 mg, 2.202 mmol) from Step 3 was added acetic acid / HBr (3:1) (7 mL) and the mixture was heated at 150 °C for 5 days. After cooling, the solvent was removed under reduced pressure, the crude residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate 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 (elution solvent 90% / 10% heptane / ethyl acetate) to give the expected compound (300 mg, 48% yield) as a brown solid.

[0345] LCMS (MH) RT = 0.896 min, m / z = 281.9 - 283.9 (M+H) + 。

[0346] Intermediate I2: 1-bromo-3-nitro-5-(propan-2-yloxy)benzene

Chemical Structure

[0347] To a solution of 3-bromo-5-nitrophenol (5.0 g, 22.9 mmol) in acetone (100 mL) was added potassium carbonate (4.75 g, 34.4 mmol) portionwise. The reaction mixture was stirred at room temperature for 10 minutes. Next, 2-iodopropane (4.0 mL, 68.70 mmol) was added and the reaction mixture was heated at 70 °C for 5 hours. The reaction mixture was cooled to room temperature. The insoluble material was filtered off and washed with acetone. The filtrate was concentrated under reduced pressure to give the expected compound (6.0 g, 100% yield) as a yellow liquid.

[0348] LCMS (MA) RT = 3.12 min, m / z = 260.1 (M+H) + 。

[0349] Intermediate I3: 1-(benzyloxy)-3-bromo-5-nitrobenzene

Chemical formula

[0350] To a solution of 3-bromo-5-nitrophenol (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 minutes. Next, bromomethylbenzene (11.46 mL, 96.33 mmol) was added and the reaction mixture was heated at 70 °C for 2 hours. The reaction mixture was cooled to room temperature. The insoluble material was filtered off and washed with acetone. The filtrate was concentrated under reduced pressure to give the expected compound (28.3 g, 100% yield) as a cream-colored solid.

[0351] 1 H NMR (400 MHz, CDCl3) 8.01 - 7.99 (1H, m), 7.79 - 7.78 (1H, m), 7.48 - 7.44 (6H, m), 5.16 (2H, s).

[0352] Intermediate I4: Mixture of 1-(3-bromo-5-nitrophenyl)-1H-pyrazole and 1-(3-iodo-5-nitrophenyl)-1H-pyrazole

Chem.

[0353] 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) in DMF (45 mL). The reaction mixture was bubbled with a nitrogen stream for 5 minutes, and the mixture was stirred at 50 °C for 12 hours. The reaction mixture was filtered through a pad of Celite 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 obtain a mixture of the expected compound and 1-(3-iodo-5-nitrophenyl)-1H-pyrazole (3.3 g, 25% yield) as a brown solid.

[0354] LCMS (MH) RT = 0.902 min, m / z = 267.9 - 269.9 (M+H) + and RT = 0.942 min, m / z = 315.9 (M+H) + 。

[0355] Intermediate I5: tert-Butyl N-(3-bromo-5-iodophenyl)carbamate

Chem.

[0356] A solution of 3-bromo-5-iodobenzoic acid (30 g, 91.77 mmol) in dry tert-butanol (150 mL) and triethylamine (16.6 mL, 119.30 mmol) was stirred under argon and diphenylphosphoryl azide (21.7 mL, 100.95 mmol) was added. The reaction mixture was refluxed at 80 °C for 16 h under argon. 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 successively with 10% sodium hydroxide solution, water and brine. 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 give the expected compound (32.2 g, 88% yield) as a pale yellow amorphous solid.

[0357] 1 H NMR (400 MHz, 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).

[0358] Prepared similarly.

[0359]

Table 4

[0360] Intermediate I7: tert-Butyl N-{3-bromo-5-[2-(triethylsilyl)ethynyl]phenyl}carbamate

Chem.

[0361] To a solution of Intermediate I5 (32.2 g, 80.9 mmol) in dry tetrahydrofuran (250 mL) under argon was added (triethylsilyl)acetylene (21.74 mL, 121.35 mmol), bis(triphenylphosphine)palladium(II) dichloride (2.84 g, 4.045 mmol), copper(I) iodide (770 mg, 4.045 mmol), and triethylamine (33.83 mL, 242.7 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, 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 give the expected compound (27.1 g, 82% yield) as a brown oil.

[0362] 1 H NMR (400 MHz, CDCl3) 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).

[0363] Intermediate I8: 3 - Bromo - 5 - (propan - 2 - yloxy)aniline

Chemical formula

[0364] To a solution of Intermediate I2 (6.0 g, 22.9 mmol) in ethanol (140 mL) was added stannous chloride (II) dihydrate (20.7 g, 91.6 mmol) portionwise. The reaction mixture was heated under reflux for 2 h. The reaction mixture was poured into water. The aqueous phase was basified 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 give the expected compound (5.30 g, 100% yield) as a pale yellow liquid.

[0365] LCMS (MA) RT = 2.51 min, m / z = 232.1 (M+H) + 。

[0366] Intermediate I9: 3-(Benzyloxy)-5-bromoaniline

Chemical Structure

[0367] To a solution of Intermediate I3 (13 g, 42.19 mmol) in ethanol (250 mL) was added stannous chloride (II) dihydrate (38.08 g, 168.76 mmol) portionwise and the reaction mixture was heated under reflux for 1 h. The reaction mixture was poured into water. The aqueous phase was basified 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 give the expected compound (11.35 g, 96% yield) as a pale yellow oil.

[0368] LCMS (MA) RT = 2.93 min, m / z = 280.0 (M+H) + 。

[0369] Intermediate I10: 3-Bromo-5-[2-(triethylsilyl)ethynyl]aniline

Chem.

[0370] To a solution of Intermediate I7 (27.10 g, assumed 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 hours. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: 90% / 10% cyclohexane / ethyl acetate) to give the expected compound (18.90 g, 92% yield) as a brown solid.

[0371] LCMS (MA) RT = 3.65 min, m / z = 351 - 353 (M + H) + 。

[0372] Intermediate I11: 5-Bromo-2-fluoro-3-methoxyaniline

Chem.

[0373] 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 hours. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the expected compound (700 mg, 97% yield) as a brown solid.

[0374] LCMS (MA) RT = 2.27 min, m / z = 220 - 222 (M + H) + 。

[0375] Intermediate I12: 3-Bromo-5-(3,5-dimethyl-1H-pyrazol-1-yl)aniline

Chem.

[0376] 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 nitrogen flow for 1 minute, and the mixture was stirred at 150 °C for 16 hours. 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 obtain the expected compound (220 mg, 23% yield) as a brown solid.

[0377] LCMS (MH) RT = 0.744 min, m / z = 266 - 268 (M + H) + 。

[0378] Intermediate I13: A mixture of 3-bromo-5-(1H-pyrazol-1-yl)aniline and 3-iodo-5-(1H-pyrazol-1-yl)aniline

Chemical Structure

[0379] 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 Celite pad. The filtrate was washed with saturated aqueous sodium bicarbonate 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 give a mixture of the expected compound and 3-iodo-5-(1H-pyrazol-1-yl)aniline (1.8 g, 61% yield) as a brown sticky solid.

[0380] LCMS (MH) RT=0.647 min, m / z=237.9-239.9 (M+H) + and RT=0.688 min, m / z=286.0 (M+H) + .

[0381] Intermediate I14: 3-Bromo-5-(5-methyl-1H-pyrazol-1-yl)aniline [ka]

[0382] 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 through 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 give the expected compound (200 mg, 75% yield) as a brown solid.

[0383] LCMS (MH) RT = 0.669 min, m / z = 252.0 - 253.9 (M+H) + 。

[0384] Intermediate I15: Methyl 3-amino-5-bromobenzoate

Chem.

[0385] To a solution of 3-amino-5-bromobenzoic acid (5.00 g, 23.144 mmol) in methanol (93 mL) under a nitrogen atmosphere, thionyl chloride (25.184 mL, 347.16 mmol) was added dropwise at 0 °C. After warming the reaction mixture to room temperature, it was stirred at 70 °C for 4 hours. After evaporating the solvent under reduced pressure, it was co-evaporated with heptane. The residue was dried under reduced pressure to obtain methyl 3-amino-5-bromobenzoate (7.85 g, 100% yield) as an off-white solid, which was used without further purification.

[0386] LCMS (MH) RT = 0.692 min, m / z = 230 - 232 (M+H) + 。

[0387] Intermediate I16: 3-Bromo-5-(1-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}-1H-pyrazol-4-yl)aniline

Chem.

[0388] Step 1 To a suspension of Intermediate I5 (1.50 g, 3.77 mmol) in dioxane / water (48 mL / 12 mL) was added 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 potassium phosphate tribasic (2.40 g, 11.31 mmol). The reaction mixture was degassed by bubbling with argon for 10 minutes and stirred at 100 °C for 1 hour. 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→0:100) as the eluent. The expected fractions were combined and evaporated under reduced pressure to give the title compound as a yellow oil (1.63 g, quantitative).

[0389] LCMS (MA) RT = 2.46 min, m / z = 382.1 / 384.1 (M+H) + 。

[0390] Step 2 To a solution of the title compound from Step 1 (1.53 g, 4.00 mmol) in THF (15 mL) was added imidazole (544 mg, 8.00 mmol) and tert-butyldiphenylchlorosilane (1.56 mL, 6.00 mmol). The mixture was stirred at room temperature for 1 hour. When complete conversion was monitored by LCMS, water and EtOAc were added and the layers were separated. The aqueous layer was extracted with EtOAc (2×20 mL), and the combined organic layers were 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→50:50) as the eluent to give the title compound as a pale yellow foam (1.91 g, 77%).

[0391] LCMS (MA) RT = 3.83 min, m / z = 620.2 / 622.2 (M+H) + 。

[0392] Step 3 To a solution of the title compound (1.91 g, 3.07 mmol) from Step 2 in DCM (45 mL) was added HCl (4 M) in 1,4 - dioxane (2.30 mL, 9.22 mmol). The mixture was stirred at room temperature for 5 hours. Since partial conversion was indicated by LCMS monitoring, additional HCl (4 M) in 1,4 - dioxane (1.50 mL, 6.14 mmol, 2 eq) was added and the mixture was stirred at room temperature overnight. When complete conversion was monitored by LCMS, the mixture was carefully quenched with saturated NaHCO3 solution. The layers were separated. The aqueous layer was extracted with DCM (2×20 mL), and 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→60:40) as the eluent to afford the title compound as an orange oil (1.39 g, 88% yield).

[0393] LCMS (MA) RT = 3.44 min, m / z = 520.2 / 522.2 (M + H) + 。

[0394] Aniline A1: 3 - Fluoro - 5 - (tetramethyl - 1,3,2 - dioxaborolan - 2 - yl) aniline

Chemical Structure

[0395] 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, filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution gradient 0%→20% pentane / ethyl acetate). The residue was triturated in n-heptane, filtered, and dried to give the expected compound (11.73 g, 44% yield) as an off-white solid.

[0396] LCMS (MA) RT = 2.53 min, m / z = 238.2 (M+H) + 。

[0397] Prepared similarly.

[0398] Intermediate number Structure Name Starting intermediate Analytical data A2: 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline From 3-bromo-5-chloroaniline As an off-white solid in 79% yield A3: 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline From 3-bromo-5-methoxyaniline As a red oil in 90% yield A4: 3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline From 3-bromo-5-ethoxyaniline As a cream-colored crystal with a yield of 71% A5: 3-Isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline From Intermediate I8 As a red oil with a yield of 82% A6: 3-Amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile From 3-Amino-5-bromo-benzonitrile As a white solid with a yield of 84% A7: 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline From 3-Amino-5-bromobenzotrifluoride As a brown oil with a yield of 99% A8: 3-(Difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline From 3-Bromo-5-(difluoromethoxy)aniline As a pale orange oil with a yield of 64% A9: 3-Benzyloxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline From Intermediate I9 As a cream-colored solid with a yield of 71% A10: 3,4-Difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline From 3-Bromo-4,5-difluoro-aniline As a yellow oil with a yield of 69% A11: 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5(2-triethylsilylethynyl)aniline From Intermediate I10 As a brown oil with a yield of 67% A12: 3-Ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline From 3-bromo-5-ethyl-aniline As a yellow solid in 44% yield A13: 2-Fluoro-3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline From intermediate I11 As a white solid in 58% yield A14: 2,3-Difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline From 5-bromo-2,3-difluoro-aniline As a white solid in 40% yield A15: 3-Pyrazol-1-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline From intermediate I13 As a brown solid in 90% yield A16: 3-(3,5-Dimethylpyrazol-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline From intermediate I12 As a brown sticky solid in 34% yield A17: 3-(5-Methylpyrazol-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline From intermediate I14 As a black solid in 100% yield A18: Methyl 3-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate From intermediate I15 As an off-white solid in 92% yield A19: 3-[1-[2-[tert-Butyl(diphenyl)silyl]oxyethyl]pyrazol-4-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline From intermediate I16 As a brown oil in 76% yield

Table 5-1

Table 5-2

Table 5-3

[0399] Aniline A 20:3-Cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Chemical formula

[0400] Step 1 To a stirred solution of 3-bromo-5-iodobenzoic acid (20.0 g, 61.18 mmol) in dry tert-butanol (100 mL) and triethylamine (11.0 mL, 79.53 mmol) under argon was added diphenylphosphoryl azide (14.5 mL, 67.30 mmol). 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 (50 mL) and washed successively with 10% NaOH solution (30 mL), water (2 × 50 mL), and brine. 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 the eluent to afford the title compound as a yellow amorphous solid (16.2 g, 67% yield).

[0401] LCMS (MA) RT = 3.38 min, m / z = 341.8 / 343.8 (M+H) + 。

[0402] Step 2 To a suspension of the title compound from Step 1 (3.0 g, 7.54 mmol) in toluene / water (36 mL / 6 mL), cyclopropylboronic acid (842 mg, 9.80 mmol), palladium(II) acetate (85 mg, 0.38 mmol), tricyclohexylphosphine (211 mg, 0.75 mmol), and potassium tertiary phosphate (4.801 g, 22.62 mmol) were added. The reaction mixture was degassed by bubbling with argon for 10 minutes and stirred at 110 °C for 39 hours. When monitored by LCMS and 95% conversion was achieved, 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 → 85:15) as the eluent. A second purification on a silica gel column using cyclohexane / EtOAc (100:0 → 90:10) as the eluent was performed to obtain the title compound as an orange oil (1.26 g, 53% yield).

[0403] LCMS (MA) RT = 3.16 - 3.22 min, m / z = 312.2 / 314.1 (M+H) + 。

[0404] Step 3 To a solution of the title compound from Step 2 (1.26 g, 4.03 mmol) in DCM (60 mL), HCl (4 M) in 1,4 - dioxane (5.04 mL, 20.15 mmol) was added. The mixture was stirred at room temperature for 8 hours. When monitored by LCMS and complete conversion was achieved, the mixture was carefully quenched with a saturated solution of NaHCO3. The layers were separated and the aqueous layer was extracted with DCM (2 × 20 mL). 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 → 90:10) as the eluent to obtain the title compound as an orange oil (660 mg, 3.11 mmol, 77%).

[0405] LCMS (MA) RT = 2.45 min, m / z = 212.0 / 214.0 (M+H) + 。

[0406] Step 4 The title compound from Step 3 was further purified by column chromatography using cyclohexane / EtOAc (100:0 → 85:15) as the eluent to obtain 483 mg of an orange oil. Under an argon atmosphere, to a solution of 3-bromo-5-cyclopropyl-aniline (433 mg, 2.04 mmol) in dry 1,4-dioxane (12 mL) were added bis(pinacolato)diboron (544 mg, 2.14 mmol), KOAc (600 mg, 6.12 mmol), and DCM (42 mg, 0.05 mmol) together with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex. The reaction mixture was heated at 90 °C for 3 hours. 50% conversion was shown by LCMS monitoring. Additional bis(pinacolato)diboron (272 mg, 1.07 mmol), KOAc (300 mg, 3.06 mmol), and DCM (42 mg, 0.05 mmol) together with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex were added and the reaction was stirred at 90 °C for 5 hours. When complete conversion was shown by LCMS monitoring, the mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was diluted with a saturated solution of NaCl and EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 20 mL), 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 → 85:15) as the eluent to obtain the expected compound as a light brown foam (251 mg, 48% yield).

[0407] LCMS (MA) RT = 2.11 min, m / z = 260.2 (M+H) + .

[0408] Example 1: (12R,14S)-4-Fluoro-12,18-dimethoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23Penta - 1(23),2(25),3,5,17(24),18,21 - heptaen - 11 - one

Chem.

[0409] Step 1 To a solution of pyrrolidine P1 (2.7 g, 10.29 mmol) in dry DMF (50 mL) was added sodium hydride (60%) in mineral oil (0.823 g, 20.57 mmol) at 0 °C. After 30 minutes, scaffold S2 (2.617 g, 11.31 mmol) was added and the mixture was stirred at 4 °C - 5 °C for 15 minutes. Monitoring by LCMS indicated complete conversion. Water was carefully added dropwise at 4 °C - 5 °C and the mixture was extracted with EtOAc (4 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The product was purified on a silica gel column using cyclohexane / EtOAc (100 - 0 → 50 - 50) as the eluent to afford the expected compound (3.498 g, 7.65 mmol, 74%) as a light brown oil.

[0410] LCMS (MA) RT = 2.76 min, m / z = 459 (M + H) + 。

[0411] Step 2 A solution of K3PO4 (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 minutes. Pd(PPh3)4 (0.14 mmol, 162 mg) was added to the reaction mixture and the reaction was heated at 100 °C for 3 hours. Monitoring by LC / MS indicated that the reaction was complete. The reaction mixture was filtered through Celite and then the solvent was removed under reduced pressure. The compound was purified by flash chromatography eluting with cyclohexane / EtOAc (100 / 0 → 50 / 50) using a 120 g SiO2 column to give the expected compound (3.395 g, 6.96 mmol, 99%) as a brown oil.

[0412] LCMS (MA) RT = 2.61 min, m / z = 488.2 (M+H)+.

[0413] Step 3 To a solution of the title compound from step 2 (3.524 g, 7.23 mmol) in CH3CN (36 mL) was added pyridine (0.877 mL, 10.84 mmol) and 2-nitrobenzenesulfonyl chloride (2.083 g, 9.40 mmol). The reaction mixture was heated at 70 °C overnight. Monitoring of the reaction by LCMS indicated a complete reaction. The reaction mixture was poured into water. After extraction with EtOAc, the organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was triturated in diisopropyl ether to give the title compound (4.064 g, 6.04 mmol, 84%) as a brown oil.

[0414] LCMS (MA) RT = 2.95 min, m / z = 673.2 (M+H)+.

[0415] Step 4 To a solution of the title compound from step 3 (0.500 g, 0.74 mmol) 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. Monitoring of the reaction mixture by LCMS indicated completion of the reaction. The solvent was removed and the residue was taken up in EtOAc (50 mL), extracted with water (50 mL) and then with brine (2×40 mL), the organic layer was dried over anhydrous Na2SO4, filtered and dried under vacuum to afford the expected compound (0.598 g, 0.74 mmol assumed, quantitative yield) as a yellow / orange solid.

[0416] LCMS (MA) RT = 3.13 min, m / z = 780 (M+H)+.

[0417] Step 5 To a suspension of the title compound from step 4 (0.598 g, 0.77 mmol) in DCM (5 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M) (1.918 mL, 7.67 mmol). The reaction mixture was stirred continuously overnight. LCMS indicated a complete reaction. The solvent was removed under reduced pressure to afford the expected compound (0.622 g, 0.77 mmol assumed, quantitative yield) as a brown solid.

[0418] LCMS (MA) RT = 1.97 min, m / z = 679 (M+H)+.

[0419] Step 6 To a solution of the title compound from Step 5 (0.622 g, 0.87 mmol) in CH3CN (62 mL), sodium hydrogen carbonate (0.365 g, 4.34 mmol) was added, and after adding cesium carbonate (0.849 g, 2.61 mmol), potassium iodide (0.433 g, 2.61 mmol) was added. The resulting mixture was heated at 90 °C for 4 h. Monitoring by LC / MS indicated that the reaction was complete. After filtering the reaction mixture, the solid was purified on a silica gel column using DCM / MeOH (100 / 0 → 98 / 2) as the eluent to afford the expected compound (0.106 g, 0.18 mmol, 20% yield) as a white solid.

[0420] LCMS (MA) RT = 2.29 min, m / z = 599 (M+H)+.

[0421] Step 7 To a mixture of the title compound from Step 6 (0.106 g, 0.18 mmol) in THF / H2O (9 mL / 3.9 mL), sodium bicarbonate (0.298 g, 3.54 mmol) was added. After stirring the reaction mixture at room temperature for 10 min, iodine (0.674 g, 2.66 mmol) was added. The reaction mixture was stirred at 60 °C for 2 h. Monitoring by LC / MS indicated that the reaction was complete. After quenching the reaction mixture with saturated sodium thiosulfate solution, it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford the expected compound (0.118 g, assumed 0.18 mmol, quantitative yield) as a yellow solid.

[0422] LCMS (MA) RT = 2.49 min, m / z = 613 (M+H)+.

[0423] Step 8 The title compound from Step 7 (0.118 g, 0.19 mmol) and cesium carbonate (0.126 g, 0.39 mmol) were dissolved in DMF (2 mL). 4-Methylbenzenethiol (0.029 g, 0.23 mmol) was added and the mixture was stirred at room temperature overnight. Monitoring of the reaction mixture by LCMS indicated that the reaction was complete. The reaction mixture was filtered to remove cesium carbonate. The solvent was evaporated and the residue was purified by flash column chromatography using DCM / MeOH (100 / 0 → 95 / 5) as the eluent. The product fractions were collected and the solvent was evaporated. The residue was purified by flash column chromatography using cyclohexane / EtOAc (100 / 0 → 0 / 100) as the eluent to give the expected product (0.008 g, 10% yield) as a pale yellow powder.

[0424] LCMS (MA) RT = 2.15 min, m / z = 428 (M+H)+. LCMS (MB) RT = 2.22 min, m / z = 428 (M+H)+. 1 1H NMR (400 MHz, DMSO) δ 8.79 (1H, s), 8.40 (1H, s), 7.63 (1H, s), 6.73 (1H, dd, J = 1.2, 9.2 Hz), 6.33 (1H, t, J = 5.8 Hz), 6.22 - 6.17 (1H, m), 4.96 (1H, d, J = 10.4 Hz), 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).

[0425] Prepared in the same manner.

[0426] Example No. Structure / Name Starting Intermediate Analytical Data 2: (12R,14S)-12,18-dimethoxy-4-(trifluoromethyl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton S2 pyrrolidine P1 aniline A7 As a pale yellow solid, 27% yield 3: (12R,14S)-4-fluoro-12-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine pyrrolidine P1 aniline A1 As an off-white crystal, 58% yield 4: (12R,14S)-4-chloro-12-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine pyrrolidine P1 aniline A2 As a yellow solid, 17% yield 5: (12R,14S)-4,12-dimethoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine pyrrolidine P1 aniline A3 As a white solid, 38% yield 6: (12R,14S)-12-Ethoxy-4-methoxy-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine pyrrolidine P2 aniline A3 As a cream-colored solid in a 50% yield 7: (12R,14S)-4-Ethoxy-12-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine pyrrolidine P1 aniline A4 As a yellow solid in an 11% yield 8: (12R,14S)-12-Methoxy-4-(propan-2-yloxy)-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine pyrrolidine P1 aniline A5 As a white solid in a 21% yield 9: (12R,14S)-4-Fluoro-12-(propan-2-yloxy)-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine pyrrolidine P4 aniline A1 As a white solid in 52% yield 10:(12R,14S)-12-cyclobutoxy-4-fluoro-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P3 Aniline A1 As a white solid in 36% yield 11:(12R,14S)-12-(cyclopropylmethoxy)-4-fluoro-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P5 Aniline A1 As a yellow solid in 26% yield 12:(12R,14S)-12-methoxy-11-oxo-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-4-carbonitrile Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P1 Aniline A6 As an off-white solid in 22% yield 13: (12R,14S)-4-(Difluoromethoxy)-12-methoxy-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P1 Aniline A8 As a salmon-colored solid in 31% yield 14: (12R,14S)-4-(Benzyloxy)-12-methoxy-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P1 Aniline A9 As white crystals in 69% yield 15: (12R,14S)-3,4-Difluoro-12-methoxy-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P1 Aniline A14 As white solid in 17% yield 16: (12R,14S)-4-Methoxy-12-(propan-2-yloxy)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23Pentacosa-1(23),2,4,6(25),17(24),18,21-heptaen-11-one Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine pyrrolidine P4 Aniline A3 As a beige solid in 20% yield 17:(12R,14S)-12-ethoxy-4-fluoro-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P2 Aniline A1 As a beige solid in 10% yield 18:(12R,14S)-12-ethoxy-4-fluoro-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 Skeleton S1 Pyrrolidine P2 Aniline A1 As a white solid in 45% yield 19:(12R,14S)-4,12-dimethoxy-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(25),3,5,17(24),18,21-heptaen-11-one Skeleton S1 Pyrrolidine P1 Aniline A3 As a white solid in 3% yield (12R,14S)-4-chloro-12-ethoxy-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P2 Aniline A2 As a pale yellow solid in 48% yield (12R,14S)-4-ethyl-12-methoxy-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P1 Aniline A12 As a light yellow solid in 31% yield (12R,14S)-12-(cyclopropylmethoxy)-4-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P5 Aniline A3 As a yellow solid in 46% yield (12R,14S)-12-ethoxy-11-oxo-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23Penta - 1(23),2,4,6(25),17(24),18,21 - heptaen - 4 - carbonitrile Skeleton 3 - bromo - 5 - chloro - pyrazolo[1,5 - a]pyrimidine Pyrrolidine P2 Aniline A6 As a white solid in a 21% yield 24:(12R,14S) - 4 - chloro - 12 - methoxy - 18 - methyl - 16 - oxa - 7,10,20,21,24 - pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 Penta - 1(23),2(25),3,5,17(24),18,21 - heptaen - 11 - one Skeleton S1 Pyrrolidine P1 Aniline A2 As a white solid in a 47% yield 25:(12S,14S) - 4 - fluoro - 12 - methoxy - 16 - oxa - 7,10,20,21,24 - pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 Penta - 1(23),2(25),3,5,17(24),18,21 - heptaen - 11 - one Skeleton 3 - bromo - 5 - chloro - pyrazolo[1,5 - a]pyrimidine Pyrrolidine 215918 - 39 - 1 Aniline A1 As a yellow solid in a 21% yield 26:(12R,14S) - 4,12 - difluoro - 16 - oxa - 7,10,20,21,24 - pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 Penta - 1(23),2,4,6(25),17(24),18,21 - heptaen - 11 - one Skeleton 3 - bromo - 5 - chloro - pyrazolo[1,5 - a]pyrimidine Pyrrolidine 1138324 - 48 - 7 Aniline A1 As an off - white solid in a 40% yield 27: (12R,14S)-5-Fluoro-4,12-dimethoxy-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P1 Aniline A13 As a yellow solid in a 32% yield 28: (12R,14S)-4,12-diethoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P2 Aniline A4 As a yellow solid in a 39% yield 29: (12R,14S)-4,5-difluoro-12-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P1 Aniline A10 As a yellow solid in a 39% yield 30: (12R,14S)-4-fluoro-12-methoxy-18-methyl-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23Pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton S1 Pyrrolidine P1 Aniline A1 As a white solid in 89% yield 31: E1-(12R,14S)-4-Fluoro-12-(methoxymethyl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 Pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P10 Aniline A1 As a white solid in 71% yield 32: E2-(12S,14S)-4-Fluoro-12-(methoxymethyl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 Pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P10 Aniline A1 As a white solid in 68% yield 33: (12R,14S)-4-Fluoro-12-methoxy-18-(methoxymethyl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 Pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton S6 Pyrrolidine P1 Aniline A1 As a white solid in 66% yield 34: (12R,14S)-4,18-difluoro-12-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton S7 Pyrrolidine P1 Aniline A1 As a white solid in 13% yield 35: (12R,14S)-4-fluoro-12-(2-methoxyethoxy)-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine pyrrolidine P7 Aniline A1 As an off-white solid in 70% yield 36: (12R,14S)-4-fluoro-12-( 2 H3)methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine pyrrolidine P6 Aniline A1 As a white solid in 49% yield 37: (12R,14S)-12-( 2 H3)methoxy-4-methoxy-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P6 Aniline A3 As a beige solid in 12% yield 38: (12R,14S)-4-chloro-12-(propan-2-yloxy)-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P4 Aniline A2 As a beige solid in 40% yield 39: (2 3 Z,2 4 E,5 2 S,5 4 R)-5 4 -ethoxy-1 5 -methoxy-2 6 -methyl-3-oxa-8-aza-2(3,5)-pyrazolo[1,5-a]pyrimidine-5(2,1)-pyrrolidina-1(1,3)-benzenocyclooctafan-5 5 -one Skeleton S1 Pyrrolidine P2 Aniline A3 As a beige solid in 42% yield 40: (12R,14S)-12-ethoxy-4-methoxy-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine pyrrolidine P12 Aniline A1 As a white solid in 24% yield 41: (12R,14S)-12-Methoxy-4-(1H-pyrazol-1-yl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P1 Aniline A15 As a white solid, 35 mg, 88% yield 42: (12R,14S)-12-Methoxy-18-methyl-4-(1H-pyrazol-1-yl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton S1 Pyrrolidine P1 Aniline A15 As a white solid, 185 mg, 81% yield 43: (12R,14S)-12-Methoxy-4-(5-methyl-1H-pyrazol-1-yl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P1 Aniline A17 Over 3 steps, 29 mg, 9% 117: (12R,14S)-4-(4-Iodo-5-methyl-1H-pyrazol-1-yl)-12-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .010,14 .0 20,23 Penta - 1(23),2,4,6(25),17(24),18,21 - heptaen - 11 - one Skeleton 3 - bromo - 5 - chloro - pyrazolo[1,5 - a]pyrimidine Pyrrolidine P1 Aniline A17 180 mg over 3 steps, 43% 85:E1 - (12R,14S) - 4 - fluoro - 12 - methoxy - 14 - methyl - 16 - oxa - 7,10,20,21,24 - pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 Penta - 1(23),2(25),3,5,17(24),18,21 - heptaen - 11 - one Skeleton 3 - bromo - 5 - chloro - pyrazolo[1,5 - a]pyrimidine Pyrrolidine P15 Aniline A1 6 mg obtained as a white solid after SFC separation 86:E2 - (12R,14R) - 4 - fluoro - 12 - methoxy - 14 - methyl - 16 - oxa - 7,10,20,21,24 - pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 Penta - 1(23),2(25),3,5,17(24),18,21 - heptaen - 11 - one Skeleton 3 - bromo - 5 - chloro - pyrazolo[1,5 - a]pyrimidine Pyrrolidine P15 Aniline A1 6 mg obtained as a white solid after SFC separation 87:(12R,14R) - 12 - ethoxy - 4 - methoxy - 16 - oxa - 7,10,20,21,24 - pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 Penta - 1(23),2,4,6(25),17(24),18,21 - heptaen - 11 - one Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P11 Aniline A3 As a pale salmon-colored solid in 75% yield 129:(12R,14S)-4-(1-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}-1H-pyrazol-4-yl)-12-methoxy-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P1 Aniline A19 As an orange-colored foam in 99% yield 103:E1-(12R,14S,15R * )-4-fluoro-12-methoxy-15-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P16 Aniline A1 As a green solid in 37% yield 108:(12R,14S)-4-cyclopropyl-12-methoxy-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P1 Aniline A20 As a pale yellow solid in 27% yield 111: (12R,14S)-4-(Difluoromethoxy)-12-(2-methoxyethoxy)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P7 Aniline A8 Using DL-cysteine instead of 4-methylbenzenethiol as a pale yellow solid in 27% yield 114: (12R,14S)-12-(2-methoxyethoxy)-11-oxo-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-4-carbonitrile Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P7 Aniline A8 Using DL-cysteine instead of 4-methylbenzenethiol as an off-white solid in 48% yield 116: (12R,14S)-4-chloro-12-(2-methoxyethoxy)-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P7 Aniline A2 Using DL-cysteine instead of 4-methylbenzenethiol to obtain a beige solid in 48% yield 117: (12R,14S)-4,18-dimethoxy-12-(2-methoxyethoxy)-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 Skeleton S2 Pyrrolidine P7 Aniline A3 Using DL-cysteine instead of 4-methylbenzenethiol to obtain a yellowish solid in 31% yield 118: (12R,14S)-4-ethynyl-12-(2-methoxyethoxy)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P7 Aniline A11 Using DL-cysteine instead of 4-methylbenzenethiol to obtain a white solid in 22% yield 121: (12S,14S)-12-ethoxy-4-methoxy-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 Skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine Pyrrolidine P14 Aniline A3 Obtaining a salmon-colored solid in 27% yield 129: (12R,14S)-4-Fluoro-18-methoxy-12-(2-methoxyethoxy)-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 Skeleton S2 Pyrrolidine P7 Aniline A1 As a beige solid, 11 mg, 13% yield 145: (12R,14S)-18-Methoxy-12-(2-methoxyethoxy)-11-oxo-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-4-carbonitrile Skeleton S2 Pyrrolidine P7 Aniline A6 As a beige solid, 40 mg, 22% yield

Table 6-1

Table 6-2

Table 6-3

Table 6-4

Table 6-5

Table 6-6

Table 6-7

Table 6-8

Table 6-9

Table 6-10

Table 6-11

Table 6-12

Table 6-13

Table 6-14

Table 6-15

Table 6-16

Table 6-17

[0427] 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 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

Chem.

[0428] According to the general synthetic scheme 1 represented for the synthesis of Example 1, using the skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine, pyrrolidine P1, and aniline A9, (12R,14S)-4-(benzyloxy)-12-methoxy-7-(2-nitrobenzenesulfonyl)-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 was obtained as intermediate I18.

[0429] Step 1 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 h. LCMS indicated a complete reaction. The mixture was cooled to room temperature. The solvent was evaporated under reduced pressure. The gummy residue was triturated with DCM / iPr2O (1 / 1). The resulting precipitate was filtered, washed with diisopropyl ether and then with pentane, and dried to give the title compound (intermediate I19, (12R,14S)-4-hydroxy-12-methoxy-7-(2-nitrobenzenesulfonyl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2,4,6(25),17(24),18,21-heptaen-11-one) (0.81 g, 93.6% yield) as a cream solid.

[0430] LCMS (MA) RT = 2.20 min m / z = 581.1 (M+H) + .

[0431] Step 2 To a solution of the title compound (50 mg, 0.0861 mmol) from Step 1 under nitrogen in DMF (3 mL), 3-(bromomethyl)pyridine hydrobromide (65 mg, 0.258 mmol) and cesium carbonate (168 mg, 0.517 mmol) were added. The solution was stirred at 80 °C for 1 hour. Monitoring by LCMS indicated that the reaction was complete. The crude product was evaporated under vacuum. The residue was purified by chromatography on silica eluting with a gradient of 0%→50% of (3:1 EtOAc:EtOH) / cyclohexane to give the expected compound (75 mg, 65% yield) as a yellow glassy solid.

[0432] LCMS (MA) RT = 2.02 min m / z = 672.1 (M+H) + 。

[0433] Step 3 To a suspension of the title compound (75 mg, 0.112 mmol) from Step 2 in DMF (5 mL), cesium carbonate (73 mg, 0.224 mmol) and 4-methylbenzenethiol (17 mg, 0.134 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours and then stirred overnight. The mixture was partitioned between water and EtOAc, and the organic layer was dried over Na2SO4 and evaporated under vacuum. The residue was purified by chromatography on silica eluting with a gradient of 0%→50% of (3:1 EtOAc:EtOH) / cyclohexane. Appropriate fractions were evaporated under vacuum and the residue was treated with CH3CN whereupon a solid cream crystallized which was filtered, washed with water and dried under vacuum at 60 °C to give the expected product (26 mg, 48% yield) as a cream-colored solid.

[0434] LCMS (MA) RT = 1.67 min m / z = 487.1 (M+H) + 。 LCMS (MC) RT = 2.10 min m / z = 487.1 (M+H) + 。 11H NMR (400 MHz, DMSO) δ 8.97 (1H, d, J = 7.6 Hz), 8.69 (1H, d, J = 1.7 Hz), 8.56 - 8.51 (2H, m), 7.90 - 7.86 (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 (1H, d, J = 10.8 Hz), 4.49 - 4.46 (1H, m), 4.36 - 4.30, (1H, m), 3.94 (1H, t, J = 10.7Hz), 3.58 - 3.48 (1H, 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)

[0435] Prepared in the same manner.

[0436]

Table 7-1

Table 7-2

Table 7-3

Table 7-4

Table 7-5

Table 7-6

[0437] Example 54: (12R,14S)-4-acetyl-12-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23Penta - 1(23),2,4,6(25),17(24),18,21 - heptaen - 11 - one [Chemical formula]

[0438] Step 1 To a solution of triethylamine (0.13 mL, 0.956 mmol) and Intermediate I19 (370 mg, 0.637 mmol) in dichloromethane (30 mL), N - phenyl - bis(trifluoromethanesulfonimide) (250 mg, 0.701 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 5 hours. Water (30 mL) was added to the reaction, and the mixture was extracted with dichloromethane. The combined organic layers were 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 afford the title compound (430 mg, 95% yield) as a pale yellow solid.

[0439] LCMS (MA) RT = 2.91 min, m / z = 713.2 (M + H) + [Full stop]

[0440] Step 2 To a solution of the title compound from Step 1 (100 mg, 0.140 mmol) in DMF (3.5 mL), cesium carbonate (91 mg, 0.280 mmol) and 4 - methylbenzenethiol (21 mg, 0.168 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water (3 mL) and EtOAc (3 mL), and the two layers were separated. The aqueous layer was extracted with ethyl acetate three times (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate. The crude residue was purified by silica gel chromatography using cyclohexane / ethyl acetate (100:0→0:100) as the eluent to afford the title compound (65 mg, 88% yield) as a white amorphous solid.

[0441] LCMS (MA) RT = 2.62 min, m / z = 528.1 (M+H) + 。

[0442] Step 3 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 minutes. Tributyl(1-ethoxyvinyl)stannane (0.024 mL, 0.070 mmol) and Pd(PPh3)4 (7 mg, 0.006 mmol) were added, the vial containing the resulting clear solution was sealed, and heated at 100 °C for 1 hour. The reaction mixture was partitioned between 1 M solution of HCl (2 mL) and ethyl acetate (2 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate three times (3 × 2 mL). The combined organic layers were washed with brine (2 mL), dried over sodium sulfate, and concentrated in vacuo. The crude residue was purified by silica gel chromatography using cyclohexane / ethyl acetate (50:50 → 0:100) as the eluent to afford the expected product (13 mg, 52% yield) as a pale yellow amorphous solid.

[0443] LCMS (MA) RT = 2.00 min, m / z = 422.2 (M+H) + 。 LCMS (MC) RT = 2.02 min, m / z = 422.3 (M+H) + 。 11H NMR (400 MHz, DMSO) 9.00 (1H, d, J = 7.6 Hz), 8.63 (1H, s), 8.04 - 8.03 (1H, m), 7.50 (1H, s), 7.05 (1H, dd, J = 1.4, 2.4 Hz), 6.67 (1H, d, J = 7.4 Hz), 6.37 (1H, s), 4.93 (1H, d, J = 10.4 Hz), 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). The signal of water overlapped with one proton.

[0444] Prepared in the same manner.

[0445]

Table 8

[0446] Example 55: (12R,14S)-N,12-dimethoxy-N-methyl-11-oxo-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-heptaene-4-carboxamide

Chemical formula

[0447] According to the general synthetic scheme 1 represented for the synthesis of Example 1, using the skeleton 3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine, pyrrolidine P1, and aniline A18, methyl (12R,14S)-12-methoxy-11-oxo-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-heptaene-4-carboxylate was obtained as intermediate I20.

[0448] Step 1 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 1 N sodium hydroxide solution (3.6 mL, 3.657 mmol). The reaction mixture was stirred at 50 °C for 3 h. After cooling the reaction mixture to room temperature, it was acidified slightly with 1 N HCl solution (approx. pH = 4 - 5) and concentrated under reduced pressure. Water was added to the residue. The resulting precipitate was filtered, washed with water and then with pentane, and dried to give the title compound (280 mg, 90% yield) as an off - white solid.

[0449] L36119 - 1 LCMS (MA) RT = 1.89 min, m / z = 424.1 (M + H)+.

[0450] Step 2 To a solution of the title compound from Step 1 (50 mg, 0.118 mmol) in N,N - dimethylformamide (5 mL) were added HATU (67 mg, 0.177 mmol), N - methoxymethanamine 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 the mixture was extracted 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 (elution solvent 90%→10% dichloromethane / methanol). The gummy residue was triturated with dichloromethane / pentane (1:4). The resulting precipitate was filtered, washed with pentane, and dried under reduced pressure to give the expected product (35 mg, 63% yield) as a white solid.

[0451] LCMS (MA) RT = 1.90 min, m / z = 467.1 (M + H) + 。 LCMS (MC) RT = 1.89 min, m / z = 467.2 (M + H) + 。 11H NMR (400 MHz, DMSO): δ 8.99 (1H, d, J = 7.4 Hz), 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 = 10.6 Hz), 4.49 (1H, t, J = 8.1 Hz), 4.37 - 4.31 (1H, m), 3.95 (1H, t, J = 10.7 Hz), 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).

[0452] Prepared in the same manner.

[0453]

Table 9-1

Table 9-2

Table 9-3

Table 9-4

[0454] 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 10,14 .0 20,23 Penta - 1(23),2,4,6(25),17(24),18,21 - hepten - 11 - one

Chemical Structure

[0455] According to the general synthetic scheme 1 represented for the synthesis of Example 1, using skeleton S1, pyrrolidine P1, and aniline A18, methyl (12R,14S) - 12 - methoxy - 18 - methyl - 11 - oxo - 16 - oxa - 7,10,20,21,24 - pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23Penta - 1(23),2,4,6(25),17(24),18,21 - heptaene - 4 - carboxylate was obtained as Intermediate I21.

[0456] Step 1 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 hours. The mixture was concentrated under reduced pressure and co - evaporated with heptane. The crude residue was dried under vacuum to obtain the expected compound as a pink solid. The crude product was used in the subsequent step without further purification.

[0457] LCMS (MH) RT = 0.696 min, m / z = 438.1 (M + H) + 。

[0458] Step 2 Borane dimethyl sulfide complex (2 M / 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 hour. 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 obtain the expected product (40 mg, 45% yield) as a white solid.

[0459] LCMS (MD) RT = 2.374 min, m / z = 424.1 (M + H) + 。 LCMS (ME) RT = 2.977 min, m / z = 424.1 (M + H) + 。 11H NMR (400 MHz, DMSO) δ 8.88 (d, J = 1.2 Hz, 1H), 8.34 (s, 1H), 7.67 (s, 1H), 6.83 (s, 1H), 6.45 (s, 1H), 6.02 (t, J = 5.9 Hz, 1H), 5.04 (t, J = 5.7 Hz, 1H), 4.94 (d, J = 10.7 Hz, 1H), 4.46 (t, J = 8.5 Hz, 1H), 4.42 (d, J = 5.8 Hz, 2H), 4.36 (d, J = 8.0 Hz, 1H), 3.99 (t, J = 10.7 Hz, 1H), 3.60 - 3.48 (m, 1H), 3.45 (s, 3H), 3.38 (dd, J = 9.6, 3.6 Hz, 1H), 3.25 - 3.12 (m, 2H), 2.46 (dd, J = 12.0, 6.0 Hz, 1H), 2.18 (d, J = 1.0 Hz, 3H), 1.96 (dd, J = 21.4, 8.7 Hz, 1H).

[0460] Examples 65 and 66: (12R or 12S,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) [Chemical formula]

[0461] Step 1 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 hour. The solvent was removed under reduced pressure. The residue was diluted with toluene and evaporated to dryness to give the title compound (160 mg) as an off-white solid, which was used without further purification.

[0462] LCMS (MD) RT = 0.860 min, m / z = 444.1 (M+H) + 。

[0463] Step 2 To a solution of the title compound from Step 1 (160 mg, 0.362 mmol) in methanol (6 mL) was added a sodium methoxide solution (25 wt% in methanol) (1.6 mL). The reaction mixture was stirred at 80 °C for 3 hours. Saturated aqueous sodium bicarbonate 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.

[0464] Reverse-phase purification: 72% [25 mM NH4HCO3] - 28% [acetonitrile:methanol 1:1] 36% [25 mM NH4HCO3] - 64% [acetonitrile:methanol 1:1]

[0465] Example 65: Single unknown isomer 1 70 mg as a white solid, 44.3% yield

[0466] LCMS (MD) RT = 2857 min, m / z = 438.1 (M+H) + 。 LCMS (ME) RT = 3.349 min, m / z = 438.2 (M+H) + 。 11H NMR (400 MHz, DMSO) δ 8.88 (dd, J = 12.0, 6.0 Hz, 1H), 8.38 (s, 1H), 7.73 (s, 1H), 6.84 (s, 1H), 6.42 (s, 1H), 6.07 (t, J = 5.8 Hz, 1H), 4.95 (d, J = 10.6 Hz, 1H), 4.48 (t, J = 9.1 Hz, 1H), 4.36 (d, J = 8.0 Hz, 1H), 4.32 (s, 2H), 3.99 (t, J = 10.7 Hz, 1H), 3.60 - 3.48 (m, 1H), 3.45 (s, 3H), 3.43 - 3.35 (m, 1H), 3.29 (s, 3H), 3.27 - 3.16 (m, 2H), 2.48 - 2.42 (m, 1H), 2.18 (s, 3H), 1.96 (dt, J = 12.3, 8.3 Hz, 1H)

[0467] Example 66: Single unknown isomer 2 8.1 mg as a white solid, 5.1% yield

[0468] LCMS (MD) RT = 3.007 min, m / z = 438.2 (M + H) + . LCMS (ME) RT = 3.390 min, m / z =: 438.1 (M + H) + . 11H NMR (400 MHz, DMSO) δ 8.88 (d, J = 1.2 Hz, 1H), 8.38 (s, 1H), 7.73 (s, 1H), 6.84 (s, 1H), 6.42 (s, 1H), 6.07 (t, J = 5.8 Hz, 1H), 5.11 (d, J = 10.6 Hz, 1H), 4.50 - 4.40 (m, 1H), 4.33 (s, 2H), 3.93 (t, J = 10.5 Hz, 1H), 3.80 (d, J = 6.4 Hz, 1H), 3.67 - 3.53 (m, 1H), 3.45 (s, 3H), 3.30 (d, J = 3.8 Hz, 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 = 0.7 Hz, 3H), 1.98 (d, J = 14.1 Hz, 1H).

[0469] 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 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

Chemical Structure

[0470] According to the general synthetic scheme 1 described for the synthesis of Example 1, using skeleton S3, pyrrolidine P1, and aniline A1, (12R,14S)-18-(benzyloxy)-4-fluoro-12-methoxy-7-(2-nitrobenzenesulfonyl)-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 was obtained as intermediate I22.

[0471] Project 1 In a sealed tube, intermediate I22 (664 mg, 0.964 mmol), anisole (4.212 mL, 38.56 mmol), and trifluoroacetic acid (4.5 mL) were added. The reaction mixture was stirred at 130 °C for 16 hours. The solvent was removed under reduced pressure, and the product was crystallized from acetonitrile to give the title compound (intermediate I28, (12R,14S)-4-fluoro-18-hydroxy-12-methoxy-7-(2-nitrobenzenesulfonyl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2,4,6(25),17(24),18,21-heptaen-11-one) (432 mg, 75% yield) as a brown solid.

[0472] LCMS (MH) RT = 0.821 min, m / z = 599 (M+H) + 。

[0473] Project 2 Trifluoromethanesulfonic anhydride (0.061 mL, 0.367 mmol) was added to a stirred solution of the title compound from Project 1 (200 mg, 0.334 mmol) and pyridine (0.079 mL, 1.002 mmol) in dry dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added, and the mixture was 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 give the expected compound (220 mg, 90% yield) as a brown solid.

[0474] LCMS (MH) RT = 1.084 min, m / z = 730.9 (M+H) + 。

[0475] Project 3 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 nitrogen stream for 5 minutes. Next, tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.008 mmol) and Xphos (8 mg, 0.016 mmol) were added, and the mixture was stirred at 80 °C for 2 hours. Water was added, and the mixture was 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 obtain the expected compound (22 mg, 24% yield) as a brown solid.

[0476] LCMS (MD) RT = 3.423 min, m / z = 677.1 (M+H) + 。

[0477] Step 4 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. When complete conversion was monitored by LCMS, a saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with EtOAc (×3). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The product was purified by flash chromatography (on silica gel) using DCM / MeOH (100:0→97:3) as the eluent to obtain the expected product as a white solid (10 mg, 23.01%).

[0478] LCMS (MD) RT = 2.977 min, m / z = 478.1(M+H) + 。 LCMS (ME) RT = 3.551 min, m / z = 478.1 (M+H) + 。 1 H NMR (400 MHz, 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 = 9.4 Hz, 1H), 6.34 (t, J = 5.8 Hz, 1H), 6.21 (dt, J = 11.8, 2.1 Hz, 1H), 5.06 (d, J = 10.5 Hz, 1H), 4.53 (brs, 1H), 4.35 (t, J = 8.9 Hz, 1H), 4.08 (t, J = 10.7 Hz, 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, 8.2 Hz, 1H), 1.97 (dt, J = 11.9, 9.0 Hz, 1H).

[0479] Prepared in the same manner.

[0480]

Table 10

[0481] Example 70: (12R,14S)-4-Ethynyl-12-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

Chemical Structure

[0482] Step 1 To a solution of tert-butyl (2S,4R)-2-(hydroxymethyl)-4-methoxy-pyrrolidine-1-carboxylate (4.674 g, 20.21 mmol) in dry DMF (65 mL) was added sodium hydride (60%) in mineral oil (1.347 g, 33.68 mmol) at 0 °C. After 30 minutes, 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 hour. Monitoring by LCMS indicated a complete reaction. Water was carefully added dropwise at 0 °C and the mixture was extracted with EtOAc (4 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography using cyclohexane / EtOAc (100 / 0 → 60 / 40) as eluent to afford the title compound as a yellow oil (3.831 g, 53% yield).

[0483] LCMS (MA) RT = 2.73 min, m / z = 428 (M+H) + 。

[0484] Step 2 A mixture of 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 K3PO4 (0.487 g, 2.30 mmol) was dissolved in 1,4-dioxane / water (3 mL / 1 mL) and degassed with argon for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.018 g, 0.02 mmol) was added and the reaction mixture was stirred at 110 °C for 3 hours. Monitoring of the reaction mixture by LCMS indicated completion of the reaction. The reaction mixture was cooled, filtered through Celite and the solvent was evaporated. The residue was purified by column chromatography using cyclohexane / EtOAc (100 / 0 → 50 / 50) as eluent to afford the title compound as a yellow oil (0.272 g, 62% yield).

[0485] LCMS (MA) RT = 3.55 min, m / z = 578 (M+H) + 。

[0486] Step 3 To a solution of the title compound from Step 2 (0.272 g, 0.47 mmol) in acetonitrile (3.4 mL) were 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 overnight at room temperature. Monitoring of the reaction by LCMS indicated a complete reaction. 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 (3 × 40 mL), the organic layer was washed with brine (2 × 40 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give the title compound (0.485 g, quantitative yield) as an orange solid.

[0487] LCMS (MA) RT = 3.72 min, m / z = 763.3 (M+H) + 。

[0488] Step 4 To a solution of the title compound from Step 3 (0.485 g, 0.64 mmol) in acetonitrile (4 mL) were 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. Monitoring of the reaction mixture by LCMS indicated that the reaction was complete. The mixture was taken up in EtOAc (50 mL), extracted with water (50 mL) and then with brine (2 × 40 mL), the organic layer was dried over Na2SO4, filtered, and dried under vacuum. The residue was purified by column chromatography using cyclohexane / EtOAc (100 / 0 → 60 / 40) as the eluent to give the title compound (0.301 g, 54% yield) as a yellow oil.

[0489] LCMS (MA) RT = 3.82 min, m / z = 870 (M+H) + 。

[0490] Step 5 To a suspension of the title compound from Step 4 (0.301 g, 0.35 mmol) in DCM (3 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M) (0.865 mL, 3.46 mmol). The reaction mixture was stirred continuously overnight. LCMS indicated a complete reaction. The solvent was removed under reduced pressure to afford the title compound as a yellow oil (0.489 g, quantitative yield).

[0491] LCMS (MA) Rt = 2.60 min, m / z = 770 (M+H) + 。

[0492] Step 6 To a solution of the title compound from Step 5 (0.489 g, assumed 0.35 mmol) in acetonitrile (48 mL) was added sodium hydrogen carbonate (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. Monitoring by LC / MS indicated completion of the reaction. The mixture was taken up in EtOAc (50 mL) and washed with water (50 mL) and brine (2 × 40 mL). The organic layer was dried over Na2SO4, filtered, and dried under vacuum. The residue was purified by silica gel column chromatography using cyclohexane / EtOAc (100 / 0 → 50 / 50) as the eluent to afford the title compound as a white solid (0.067 g, 28% yield).

[0493] LCMS (MA) RT = 3.31 min m / z = 689 (M+H) + 。

[0494] Step 7 To a mixture of the title compound from Step 6 (0.067 g, 0.10 mmol) in THF / H2O (5 mL / 2 mL), sodium bicarbonate (0.163 g, 1.95 mmol) was added. After the reaction mixture was stirred at room temperature for 10 minutes, iodine (0.370 g, 1.46 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours. Monitoring by LC / MS indicated a complete reaction. 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 give 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[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2,4,6(25),17(24),18,21-heptaen-11-one, 0.150 g, quantitative yield).

[0495] LCMS (MA) RT = 3.44 min, m / z = 703 (M+H) + 。

[0496] Step 8 The title compound from Step 7 (150 mg, 0.10 mmol) and cesium carbonate (139 mg, 0.43 mmol) were dissolved in N,N-dimethylformamide (8 mL). 4-Methylbenzenethiol (32 mg, 0.26 mmol) was added and the mixture was stirred at room temperature for 2 hours. 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→98:2) as the eluent to give the title compound (28 mg, 25% yield) as a yellow solid.

[0497] LCMS (MA) RT = 3.34 min, m / z = 518 (M+H) + 。

[0498] Step 9 To a solution of the title compound from Step 8 (28 mg, 0.05 mmol) in methanol (2 mL) at room temperature was added potassium carbonate (37 mg, 0.27 mmol). 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 → 80:20) as the eluent to afford the expected product (17 mg, 0.04 mmol) as a beige powder.

[0499] LCMS (MA) RT = 2.25 min, m / z = 404 (M+H) + 。 LCMS (MC) RT = 2.25 min, m / z = 404 (M+H) + 。 1 1H NMR (400 MHz, 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 = 7.4 Hz), 6.57 - 6.55 (1H, m), 6.23 (1H, t, J = 6.0 Hz), 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 = 10.8 Hz), 3.58 - 3.52 (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).

[0500] Prepared similarly.

[0501]

Table 11

[0502] Example 73: Ethyl (12R,14S)-4-fluoro-12-methoxy-11-oxo-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-heptaene-7-carboxylate

Chem.

[0503] To a solution of Example 3 (50 mg, 0.13 mmol) in tetrahydrofuran (3 mL), triethylamine (53 μL, 0.38 mmol) and ethyl chloroformate (36 μL, 0.38 mmol) were added 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, [(NH4)2CO3 aqueous solution (2 g / L) / acetonitrile] 45% B→55% B for 7 min - hold time 19 mL per minute) to give the expected product (33 mg, 56% yield) as a pale yellow solid.

[0504] LCMS (MA) RT = 2.47 min, m / z = 470.2 (M+H) + 。 LCMS (MC) RT = 2.47 min, m / z = 470.3 (M+H) + 。 1 1H NMR (400 MHz, DMSO) 9.02 (1H, d, J = 7.4 Hz), 8.77 - 8.76 (1H, m), 8.54 (1H, s), 7.53 - 7.48 (1H, m), 7.37 - 7.31 (1H, m), 6.70 (1H, d, J = 7.4 Hz), 5.06 (1H, d, J = 11.2 Hz), 4.61 (1H, t, J = 8.6 Hz), 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 = 12.2 Hz), 2.46 - 2.39 (1H, m), 2.00 - 1.88 (1H, m), 1.30 (3H, t, J = 7.3 Hz).

[0505] 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 10,14 .0 20,23 pentacosa-1(23),2,4,6(25),17(24),18,21-heptaen-11-one

Chem.

[0506] To a solution of Example 3 (50 mg, 0.13 mmol) in tetrahydrofuran (3 mL) were 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 [(NH4)2CO3 aqueous solution (2 g / L) / acetonitrile] 35% B → 45% B for 7 min, retention time 19 mL per minute) to give the expected product (40 mg, 72% yield) as a white solid.

[0507] LCMS (MA) RT = 2.12 min, m / z = 440.2 (M+H) + 。 LCMS (MC) RT = 2.13 min, m / z = 440.3 (M+H) + 。 1 1H NMR (400 MHz, DMSO) 9.03 (1H, d, J = 7.6 Hz), 8.78 (1H, s), 8.62 (1H, s), 7.59 (1H, d, J = 10.2 Hz), 7.25 (1H, s), 6.71 (1H, d, J = 7.4 Hz), 5.06 (1H, d, J = 10.6 Hz), 4.68 - 4.63 (1H, m), 4.33 (2H, t, J = 8.9 Hz), 4.20 - 4.14 (1H, m), 3.98 (1H, t, J = 10.9 Hz), 3.44 (3H, s), 3.35 (2H, s), 2.39 (1H, dd, J = 8.1, 12.6 Hz), 2.20 (3H, s), 1.94 - 1.86 (1H, m).

[0508] 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 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

Chemical formula

[0509] To a solution of Example 3 (50 mg, 0.13 mmol) in N,N-dimethylformamide (5 mL) under an argon atmosphere, sodium hydride (60% dispersion in mineral oil) (10 mg, 0.25 mmol) was added at room temperature. After 30 minutes, iodomethane (0.117 mL, 1.89 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. Additional sodium hydride (60% dispersion in mineral oil) (10 mg, 0.25 mmol) and iodomethane (0.117 mL, 1.89 mmol) were successively added after 2 hours, 18 hours, 20 hours, 24 hours, 40 hours, and 44 hours until the starting material was completely converted. Water and ethyl acetate were added to the reaction mixture. After extraction with ethyl acetate (3×30 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 19×100 mm 5 μm [(NH4)2CO3 aqueous solution (2 g / L) / acetonitrile] 45% B→50% B for 7 minutes, retention time 19 mL per minute) to obtain the expected product (15 mg, 29% yield) as a white solid.

[0510] LCMS (MA) RT = 2.42 minutes, m / z = 412 (M+H) + . LCMS (MC) RT = 2.41 minutes, m / z = 412 (M+H) + . 1 1H NMR (400 MHz, DMSO) 9.00 (1H, d, J = 7.4 Hz), 8.56 (1H, s), 7.78 (1H, s), 6.83 (1H, d, J = 9.9 Hz), 6.67 (1H, d, J = 7.4 Hz), 6.33 (1H, d, J = 12.9 Hz), 4.95 (1H, d, J = 10.2 Hz), 4.49 - 4.46 (1H, m), 4.35 (1H, t, J = 8.7 Hz), 3.96 (1H, t, J = 10.5 Hz), 3.73 (2H, dd, J = 12.6, 21.2 Hz), 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)

[0511] 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 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

Chem.

[0512] According to the general synthetic scheme 1 described for the synthesis of Example 1, using the skeletal 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine, pyrrolidine P1, and aniline A6, (12R,14S)-12-methoxy-7-(2-nitrobenzenesulfonyl)-11-oxo-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaene-4-carbonitrile was obtained as intermediate I23.

[0513] LCMS (MA) RT = 2.38 min, m / z = 590.2 (M+H) + 。

[0514] Step 1 To a solution of Intermediate I23 (589 mg, 1 mmol) in ethanol / water mixture (10 mL / 4 mL) were added sodium carbonate (318 mg, 3 mmol) and hydroxylamine hydrochloride (271 mg, 3.9 mmol). The reaction mixture was stirred and heated at 65 °C for 2 h. When the reaction mixture was cooled, a precipitate appeared. The obtained precipitate was filtered, washed with cold diethyl ether and then dried under reduced pressure to give the title compound (520 mg, 83% yield) as a yellow solid.

[0515] LCMS (MA) RT = 1.75 min, m / z = 623.2 (M+H) + 。

[0516] Step 2 To a stirred solution of the title compound from Step 1 (520 mg, 0.83 mmol) in tetrahydrofuran (5 mL) was added triethyl orthoformate (0.415 mL, 2.5 mmol). The mixture was cooled to 0 °C. Next, boron trifluoride ethyl etherate (0.123 mL, 1 mmol) was 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, the precipitate was filtered off and dried under reduced pressure. The residue was triturated with diethyl ether and dried to give the title compound (454 mg, 87% yield) as a cream solid.

[0517] LCMS (MA) RT = 2.44 min, m / z = 633.1 (M+H) + 。

[0518] Step 3 To the title compound from Step 2 (0.454 g, 0.72 mmol) in DMF (3 mL) were added cesium carbonate (469 mg, 1.44 mmol) and 4-methylbenzenethiol (107 mg, 0.86 mmol), and the reaction mixture was stirred at room temperature for 1 hour. Monitoring of the reaction mixture by LCMS indicated that the reaction was complete. The reaction mixture was adsorbed onto silica and evaporated to dryness. The residue was purified by chromatography using DCM / MeOH (98 / 2 → 85 / 15) as the eluent. The expected fractions were combined and evaporated under reduced pressure. The residue was triturated in MeOH, filtered, and dried under vacuum to obtain the expected product (99 mg, 31%) as a cream-colored solid.

[0519] LCMS (MA) RT = 2.12 min, m / z = 448.1 (M+H) + 。 LCMS (MC) RT = 2.18 min, m / z = 448 (M+H) + 。 1 H NMR (400 MHz, DMSO) 9.69 - 9.68 (1H, m), 9.02 - 8.99 (1H, m), 8.61 - 8.59 (1H, m), 7.99 (1H, s), 7.54 (1H, s), 7.20 (1H, s), 6.68 (1H, d, J = 7.6 Hz), 6.49 (1H, t, J = 6.0Hz), 4.96 (1H, d, J = 11.2 Hz), 4.50 - 4.31 (2H, m), 3.96 (1H, t, J = 10.6 Hz), 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);

[0520] 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 10,14 .020,23 Pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

Chem.

[0521] Step 1 To pyrrolidine P1 (0.720 g, 3.113 mmol) in 16 mL of dry DMF (5 mL / mmol) was added sodium hydride (60%) in mineral oil (C, 0.373 g, 9.339 mmol) at 0 °C. After 30 minutes, skeleton S8 (1.043 g, 3.424 mmol) was added and the mixture was stirred at 4 °C to 5 °C for 15 minutes. When complete conversion was monitored by TLC, EtOAc was added and the mixture was carefully quenched at 0 °C by dropwise addition of water. Next, this was extracted with EtOAc (×3), the combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The product was purified by flash chromatography on silica gel using heptane / EtOAc (100:0 → 60:40) as the eluent to obtain the expected compound as a yellow oil (2.253 g, 54.9% yield).

[0522] LCMS (MI) RT = 0.884 min, m / z = 499 - 401 (M+H) + -Boc.

[0523] Step 2 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 hours. The solvent was evaporated under reduced pressure to obtain the title compound (2.804 g, 100% yield) as a dark orange oil, which was used without further purification.

[0524] LCMS (MI) RT = 0.303 min, m / z = 355 - 357 (M+H) + .

[0525] Step 3 To a solution of the title compound from Step 2 (2.804 g, 4.512 mmol) in dichloromethane (14 mL), di-tert-butyl dicarbonate (2.954 g, 13.536 mmol) was added followed by triethylamine (1.887 mL, 13.536 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (elution solvent 70%→30% heptane / ethyl acetate) to give the title compound (1.332 g, 65% yield) as a yellow solid.

[0526] LCMS (MH) RT = 0.987 min, m / z = 355 - 357 (M+H) + -Boc.

[0527] Step 4 To a solution of (methoxymethyl)triphenylphosphonium chloride (2.579 g, 7.524 mmol) in dry THF (14 ml), potassium bis(trimethylsilyl)amide solution (1 M / THF) (12.54 mL, 12.540 mmol) was added at once at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour. 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 hours. Methyl-tert-butyl-ether and saturated aqueous sodium bicarbonate were added and the reaction mixture was warmed to room temperature. The reaction mixture was heated to 60 °C and stirred for 16 hours. 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 give the title compound (314 mg, 26% yield) as a yellow sticky solid.

[0528] LCMS (MH) RT = 1.216 min, m / z = 483 - 485 (M+H) + .

[0529] Step 5 The title compound from Step 4 (0.300 g, 0.621 mmol), aniline A1 (0.191 g, 0.807 mmol), tripotassium phosphate (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 minutes. Next, tetrakis(triphenylphosphine)palladium(0) (C, 0.036 g, 0.031 mmol) was added, and the mixture was stirred at 90 °C for 16 hours in a pressure flask. Water was added, and the mixture was extracted with EtOAc (×2). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to obtain a crude product, which was purified by flash chromatography on silica gel using heptane / EtOAc (100:0→40:60) as the eluent to obtain the title compound (0.168 g, 52.68% yield) as a yellow solid.

[0530] LCMS (MH) RT = 1.107 min, m / z = 514.2 (M+H)+.

[0531] Step 6 To a solution of the title compound from Step 5 (168 mg, 0.327 mmol) in ethyl acetate (33 mL) under a nitrogen atmosphere, Pd / C (10%) (67 mg) was added. The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. Additional palladium / C (10%) (67 mg) was added, and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction was filtered through a Celite pad and washed with a dichloromethane / methanol (4:1) mixture. The filtrate was concentrated under reduced pressure to obtain the title compound (143 mg, 85% yield) as an orange sticky solid, which was used in the subsequent step without further purification.

[0532] LCMS (MH) RT = 1.029 min, m / z = 516.2 (M+H) + 。

[0533] Step 7 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. Next, 2-nitrobenzenesulfonyl chloride (0.068 g, 0.305 mmol) was added portionwise and the mixture was stirred at room temperature for 16 h. A solution of NaHCO3 (10%) was added and the mixture was extracted with DCM (×2). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel using heptane / EtOAc (100:0 → 20:80) as eluent to afford the title compound (0.136 g, 70.1% yield) as a yellow solid.

[0534] LCMS (MH) RT = 1.173 min, m / z = 701.1 (M+H) + 。

[0535] Step 8 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 of DMA (8.5 mL / mmol). The mixture was stirred at 50 °C for 16 h. Water was added and the mixture was extracted with EtOAc (×2). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a crude which was purified by flash chromatography on silica gel using heptane / EtOAc (100:0 → 50:50) as eluent to afford the title compound (0.100 g, 63.8% yield) as a colorless sticky solid.

[0536] LCMS (MH) RT = 1.281 min, m / z = 707.0 - 708.9 (M+H)+ - Boc.

[0537] Step 9 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 h. The mixture was concentrated under vacuum and co-evaporated with heptane to afford the title compound (0.090 g) as an orange sticky solid. The crude product was used in the subsequent step without purification.

[0538] LCMS (MH) RT = 0.959 min, m / z = 707 - 709 (M+H) + 。

[0539] Step 10 The title compound from Step 9 (0.087 g, 0.117 mmol), sodium hydrogen carbonate (0.098 g, 1.170 mmol), and potassium iodide (0.058 g, 0.351 mmol) in 12 mL of acetonitrile were added, and the mixture was stirred at 90 °C for 16 h. Further sodium hydrogen carbonate (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 h. EtOAc and water were added, and the product was extracted with EtOAc (×3). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to afford the title compound (0.069 g) as a cream-colored solid. The crude product was used in the subsequent step without purification.

[0540] LCMS (MI) RT = 0.803 min, m / z = 627.2 (M+H) + 。

[0541] Step 11 To a mixture of the title compound from Step 10 (0.066 g, 0.105 mmol) in THF:H2O (2.5:1) (1.00 mL), sodium bicarbonate (0.176 g, 2.100 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes. Next, iodine (0.400 g, 1.575 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc and washed with an aqueous solution of sodium thiosulfate (10%). The aqueous phase was extracted with EtOAc (×3), and the combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. Finally, the product was purified by silica gel column chromatography using DCM / EtOAc (100:0→40:60) as the eluent to obtain the title compound (0.025 g, 37.2% yield) as a white solid.

[0542] LCMS (MH) RT = 1.041 min, m / z = 641.0 (M+H) + 。

[0543] Step 12 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 of 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 (×2). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to obtain a crude product, which was purified by flash chromatography on silica gel using heptane / EtOAc (100:0→40:60) as the eluent to obtain the expected product (0.004 g, 22.52% yield) as an off-white solid.

[0544] LCMS (MD) RT = 3.081 min, m / z = 456.2 (M+H) + 。 LCMS (MF) RT = 4.575 min, m / z = 456.2 (M+H) + 。 11H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 8.48 (s, 1H), 7.65 (s, 1H), 6.74 (d, J=9.4 Hz, 1H), 6.32 (t, J=5.8 Hz, 1H), 6.20 (dt, J=11.8, 2.0 Hz, 1H), 4.98 (d, J=10.5 Hz, 1H), 4.49 (t, J=9.9 Hz, 1H), 4.36 (t, J=8.9 Hz, 1H), 4.00 (t, J=10.7 Hz, 1H), 3.60 (t, J=6.5 Hz, 2H), 3.55 (dd, J=11.9, 7.2 Hz, 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=6.5 Hz, 2H), 2.48 - 2.42 (m, 1H), 1.96 (dt, J=11.7, 8.8 Hz, 1H).

[0545] Prepared in the same manner.

[0546]

Table 12

[0547] Example 79: (12R,14S)-4-Fluoro-12-(2-hydroxyethoxy)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

Chemical formula

[0548] According to the general synthetic scheme 1 described for the synthesis of Example 1, using the skeletal 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine, pyrrolidine P8, and aniline A1, (12R,14S)-12-[2-(benzyloxy)ethoxy]-4-fluoro-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 was obtained as intermediate I24.

[0549] Step 1 To a solution of intermediate I24 (100 mg, 0.193 mmol) in ethyl acetate (2 mL) under a nitrogen atmosphere, 10% palladium / C (20 mg) was added. The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. Additional palladium / C (10%) (67 mg) was added, and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The crude product was filtered through 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 obtain the expected product (40 mg, 48.49% yield) as a white solid.

[0550] LCMS (MG) RT = 2.813 minutes, m / z = 428.1 (M+H) + . LCMS (MF) RT = 4.652 min, m / z = 428.1 (M+H) + 。 1H NMR (400 MHz, DMSO) δ 8.98 (d, J = 7.5 Hz, 1H), 8.53 (s, 1H), 7.67 (s, 1H), 6.79 - 6.70 (m, 1H), 6.66 (d, J = 7.5 Hz, 1H), 6.33 (t, J = 5.8 Hz, 1H), 6.21 (dt, J = 11.8, 2.1 Hz, 1H), 4.93 (d, J = 10.9 Hz, 1H), 4.71 (t, J = 5.5 Hz, 1H), 4.56 - 4.36 (m, 2H), 3.95 (t, J = 10.8 Hz, 1H), 3.82 (dt, J = 9.6, 4.7 Hz, 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, 8.2 Hz, 1H), 2.05 - 1.90 (m, 1H).

[0551] Example 80: (12R,14S)-12-Cyclopropoxy-4-fluoro-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

Chem.

[0552] Step 1 To a solution of pyrrolidine P9 (0.500 g, 1.943 mmol) in dry DMF (10 mL) was added sodium hydride (60%) in mineral oil (0.233 g, 5.829 mmol) at 0 °C. After stirring for 30 minutes, 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (0.903 g, 3.886 mmol) was added and the mixture was stirred at 4 °C - 5 °C for 30 minutes. Water was carefully added dropwise at 4 °C - 5 °C and the mixture was extracted with EtOAc (×4). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The product was purified on a silica gel column using heptane / EtOAc (100:0 → 85:15) as the eluent to give the title compound (0.471 g, yield: 53.47%) as a pale yellow rubbery solid.

[0553] LCMS (MH) RT = 1.142 min, m / z = 353.0 (M - 100)

[0554] Step 2 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 K3PO4 (0.632 g, 2.979 mmol) were mixed in dioxane / H2O (4:1) (6 mL) and the reaction mixture was bubbled with a nitrogen stream for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.070 g, 0.060 mmol) and Xphos (0.057 g, 0.119 mmol) were added and the mixture was stirred at 80 °C for 16 hours. When complete conversion was monitored by LCMS, water was added and the mixture was extracted with EtOAc (×3). The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (on silica gel) using DCM / MeOH (100:0 → 97:3) as the eluent to give the title compound (0.291 g, 61% yield) as a brown solid.

[0555] LCMS (MH) RT = 1.082 min, m / z = 484.1 (M + H) + 。

[0556] Step 3 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. Aqueous NaHCO3 solution (10%) was added, and the mixture was extracted with DCM (×3). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (on silica gel) using DCM / MeOH (100:0 → 96:4) as the eluent to obtain the title compound (0.370 g, 91.3% yield) as a brown rubbery substance.

[0557] LCMS (MH) RT = 1.215 min, m / z = 569.0 (M + H) + 。

[0558] Step 4 The title compound from Step 3 (0.360 g, 0.538 mmol) was dissolved in DMA (18 mL, 33 mL / mmol). Next, cesium carbonate (0.876 g, 2.69 mmol) and 1,2-dibromoethane (0.464 mL, 5.380 mmol) were added, and the mixture was stirred at 50 °C for 16 h. When completely converted as monitored by LCMS, water was added, and the mixture was extracted with EtOAc (×3). The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using DCM / MeOH (100:0 → 98:2) as the eluent to obtain the title compound (0.380 g, 91.06% yield) as a brown solid.

[0559] LCMS (MH) RT = 1.342 min, m / z = 675.0 / 677.0 (M - 100).

[0560] Step 5 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 the mixture was stirred from 0 °C to room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give the title compound as a crude brown sticky solid (0.320 g), which was used as such in the subsequent step without further purification.

[0561] LCMS (MH) RT = 0.901 min, m / z = 675.0 / 677.0 (M+H) + 。

[0562] Step 6 To a solution of the title compound from Step 5 (crude, 0.36 g, 0.46 mmol) in acetonitrile (138 mL) were added sodium hydrogen carbonate (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 the mixture was extracted with EtOAc (×3). The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (on silica gel) using DCM / MeOH (100:0 → 98:2) as the eluent to give the title compound (0.202 g, 73.8% yield) as a yellow solid.

[0563] LCMS (MH) RT = 1.047 min, m / z = 595.0 (M+H) + 。

[0564] Step 7 To a mixture of the title compound from step 6 (0.125 g, 0.210 mmol) in DMF (5 mL) was added cesium carbonate (0.205 g, 0.630 mmol). After cooling the mixture in an ice-water bath, 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 (×4). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel using DCM / MeOH (100:0→97.5:2.5) as the eluent to give the title compound (0.068 g, 79.08% yield) as a pale yellow solid.

[0565] LCMS (MH) RT = 0.710 min, m / z = 410.1 (M+H) + 。

[0566] Step 8 To a solution of the title compound from step 7 (0.058 g, 0.142 mmol) in THF:H2O (9:1) (8.5 mL) was added sodium bicarbonate (0.179 g, 2.130 mmol). The reaction mixture was stirred at room temperature for 10 minutes. Next, iodine (0.252 g, 0.994 mmol) was added and the mixture was stirred at room temperature. LCMS indicated partial conversion. The mixture was heated at 50 °C and stirred for 6 hours. The mixture was diluted with EtOAc, water was added, and the mixture was extracted with EtOAc (×4). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel using DCM / MeOH (100:0→90:10) as the eluent to give the title compound (0.019 g) contaminated with the diiodo derivative as a pale yellow solid.

[0567] LCMS (MH) RT = 0.710 min, m / z = 410.1 (M+H) + 。

[0568] Step 9 Into a vial equipped with a magnetic stir bar, 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) were added. Acetonitrile (0.2 mL) was added to the vial, followed by DIPEA (0.006 g, 0.036 mmol), and then tris(trimethylsilyl)silane (0.006 g, 0.018 mmol) was added. The mixture was stirred with the vial open and then irradiated for 45 minutes using a 42 W blue LED strip. The temperature near the surface of the vial was 40 °C. When completion was monitored by LCMS, the solvent was removed under reduced pressure, and the crude product was purified on a silica gel column using DCM / MeOH (98:2) as the eluent to obtain the expected product (4.2 mg, 55%) as a white solid.

[0569] LCMS (MD) RT = 3.250 min, m / z = 424.1 (M+H) + 。 1H NMR (400 MHz, CDCl3): 8.51 (d, J = 7.5 Hz, 1H), 8.26 (s, 1H), 7.69 (s, 1H), 6.69 (d, J = 9.6 Hz, 1H), 6.41 (d, J = 7.5 Hz, 1H), 6.24 (d, J = 10.8 Hz, 1H), 5.06 (d, J = 11.0 Hz, 1H), 3.91 - 3.83 (m, 1H), 3.81 (dd, J = 6.1, 3.0 Hz, 1H), 3.76 (t, J = 10.8 Hz, 1H), 3.63 - 3.50 (m, 3H), 3.26 (t, J = 11.5 Hz, 1H), 2.61 (dd, J = 13.1, 8.1 Hz, 1H), 2.14 (dd, J = 21.9, 9.0 Hz, 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).

[0570] Prepared in the same manner.

[0571]

Table 13

[0572] 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 10,14 .0 20,23 Pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

Chem.

[0573] According to the general synthetic scheme 1 represented for the synthesis of Example 1, using the skeleton 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine, pyrrolidine P1, and aniline A16, (12R,14S)-4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)-12-methoxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2,4,6(25),17(24),18,21-heptaen-11-one was obtained as Intermediate I25.

[0574] Step 1 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 the addition of tris(trimethylsilyl)silane (0.385 mL, 1.240 mmol) and (Ir[dF(CF3)ppy]2(dtbpy))PF6 (18 mg, 0.016 mmol). After stirring the reaction mixture with the vial open, it was irradiated for 2 hours using a 42 W blue LED strip. 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 obtain the expected product (55 mg, 75% yield) as a beige solid.

[0575] LCMS (MD) RT = 2.881 min, m / z = 474.2 (M+H) + . LCMS (ME) RT = 3.361 min, m / z = 474.2 (M+H) + . 11H NMR (400 MHz, DMSO) δ 8.91 (d, J=7.5 Hz, 1H), 8.50 (s, 1H), 7.75 (s, 1H), 6.89 (s, 1H), 6.58 (d, J=7.5 Hz, 1H), 6.46 (t, J=2.0 Hz, 1H), 6.22 (t, J=5.8 Hz, 1H), 5.95 (s, 1H), 4.88 (d, J=10.9 Hz, 1H), 4.26 (t, J=8.9 Hz, 1H), 3.88 (t, J=10.7 Hz, 1H), 3.48 (dt, J=12.7, 8.9 Hz, 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, 8.2 Hz, 1H), 2.23 (s, 3H), 2.09 (s, 3H), 1.89 (dt, J=12.1, 8.9 Hz, 1H).

[0576] 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 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

Chemical Structure

[0577] Step 1 Intermediate I17 (60 mg, 0.102 mmol), methylboronic acid (18 mg, 0.306 mmol), and 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 minutes, 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 hours 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 NH4HCO3] - 30% [acetonitrile:MeOH 1:1] 27% [25 mM NH4HCO3] - 73% [acetonitrile:MeOH 1:1]) to afford the expected product (26 mg, 53% yield) as a white solid.

[0578] LCMS (MD) RT = 3.093 min, m / z = 474.2 (M+H) + 。 LCMS (ME) RT = 3.450 min, m / z = 474.2 (M+H) + 。 11H NMR (400 MHz, DMSO) δ 9.00 (d, J=7.5 Hz, 1H), 8.58 (s, 1H), 7.85 (s, 1H), 7.40 (s, 1H), 6.98 (s, 1H), 6.68 (d, J=7.5 Hz, 1H), 6.53 (t, J=1.9 Hz, 1H), 6.34 (t, J=5.9 Hz, 1H), 4.97 (d, J=10.8 Hz, 1H), 4.52 (t, J=8.5 Hz, 1H), 4.35 (t, J=8.9 Hz, 1H), 3.57 (dd, J=16.4, 5.9 Hz, 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, 9.0 Hz, 1H)

[0579] 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 10,14 .0 20,23 pentacosa-1(23),2,4,6(25),17(24),18,21-heptaen-11-one

Chemical Structure

[0580] Step 1 In a microwave vial (5 mL), Example 20 (205 mg, 0.5 mmol) was suspended in acetonitrile (5 mL). At room temperature, Xphos (50 mg, 0.1 mmol) and cesium carbonate (490 mg, 1.5 mmol) were added. After the resulting mixture was degassed by bubbling with argon for 10 minutes, bis(acetonitrile)dichloropalladium(II) (15 mg, 0.05 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes. Next, trimethyl(prop-2-yn-1-yl)silane (0.375 mL, 2.5 mmol) was added. The reaction vessel was sealed and heated at 120 °C for 5 hours under microwave irradiation using a Biotage initiator. Monitoring by LCMS indicated that the reaction was complete. The reaction mixture was adsorbed onto silica and purified by silica gel column chromatography using DCM / MeOH (100 / 0 → 9 / 1) as the eluent. The expected fractions were combined and evaporated under reduced pressure. The residue was recrystallized twice from EtOH. The expected product was obtained as a cream-colored solid (35 mg, 0.08 mmol, 17%).

[0581] LCMS (MA) RT = 2.28 min, m / z = 418.4 (M+H) + 。 LCMS (MC) RT = 2.28 min, m / z = 418.4 (M+H) + 。 1 H NMR (400 MHz, 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 = 10.3 Hz), 4.46 (1H, s), 4.33 (1H, t, J = 8.7 Hz), 3.94 (1H, t, J = 10.6 Hz), 3.54 (1H, d, J = 18.3 Hz), 3.35 - 3.32 (6H, m), 2.46 - 2.40 (1H, m), 2.05 - 2.01 (4H, m)

[0582] Example 89: (12R,14S)-4,12-dimethoxy-8-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

Chemical Structure

[0583] Step 1 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 minutes, 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 minutes and then at room temperature for 4 hours. The mixture was carefully diluted with water and EtOAc (250 ml) was added. The layers were separated. The aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the title compound as a yellow solid (17 g, 39.79 mmol, 99%).

[0584] LCMS (MA) RT = 2.84 min, m / z = 429.1 (M+H) + .

[0585] Step 2 To a suspension of the title compound from Step 1 (3.33 g, 7.79 mmol) in acetonitrile (10 mL) was added HCl (4 M) in 1,4-dioxane (9.75 mL, 38.9 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure to give the title compound as a yellow foam (2.83 g) which was used directly in the subsequent step without further purification.

[0586] LCMS (MA) RT = 1.29 min, m / z = 329.1 (M+H) + 。

[0587] Step 3 To a solution of the title compound (363 mg, 1 mmol) from Step 2 in DCM (20 mL) was added triethylamine (0.418 mL, 3 mmol). The resulting mixture was stirred at room temperature for 15 minutes, after which 2-(tert-butyldimethylsilyloxy)propanal was added (375 mg, 1.2 mmol). After stirring for an additional 15 minutes, sodium triacetoxyborohydride (318 mg, 1.5 mmol) was added. The reaction mixture was continuously stirred at room temperature for 3 hours. Monitoring of the reaction mixture by LCMS indicated that the reaction was complete. The reaction mixture was diluted in DCM (50 ml) and water was added. The aqueous 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 product was purified by flash chromatography using cyclohexane / EtOAc (100 / 0 → 6 / 4) as the eluent to obtain the title compound as a colorless oil (0.39 g, 79%).

[0588] LCMS (MA) RT = 2.20 min, m / z = 421.1 (M+H) + 。

[0589] Step 4 To a solution of the title compound from Step 3 (3.06 g, 6.12 mmol) in dioxane / water (30 mL / 7 mL), aniline A3 (1.98 g, 7.96 mmol), tetrakis(triphenylphosphine)palladium(0) (139 mg, 0.12 mmol), Xphos (114 mg, 0.24 mmol), and potassium phosphate tribasic (3.9 g, 18.36 mmol) were added. The reaction mixture was degassed by bubbling with argon for 15 minutes and stirred at 90 °C for 4 hours. When 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 layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using cyclohexane / EtOAc - EtOH (3:1) (100:0→6:4) as the eluent to afford the title compound as a yellow oil (3.21 g, 97%).

[0590] LCMS (MA) RT = 2.04 min, m / z = 542.4 (M + H) + 。

[0591] Step 5 To a solution of the title compound from Step 4 (3.21 g, 5.9 mmol) in acetonitrile (45 mL), pyridine (0.62 mL, 7.7 mmol) and 2-nitrobenzenesulfonyl chloride (1.44 g, 6.5 mmol) were added portionwise. The reaction mixture was stirred at room temperature for 2 hours. When complete conversion was monitored by LCMS, the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography using cyclohexane / EtOAc - EtOH (3:1) (100:0→6:4) as the eluent to afford the title compound as a yellow foam (3.8 g, 88%).

[0592] LCMS (MA) RT = 2.49 min, m / z = 727.3 (M + H) + 。

[0593] Step 6 To a solution of the title compound from Step 5 (3.8 g, 5.23 mmol) in THF (100 mL) was added a solution of TBAF (5.75 mL, 5.75 mmol). The reaction mixture was stirred at room temperature for 72 h. Once complete conversion was monitored by LCMS, the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography using DCM / MeOH (100 / 0 → 9 / 1) as the eluent to afford the title compound as a yellow foam (3.62 g, 100%).

[0594] LCMS (MA) RT = 1.78 min, m / z = 613.3 (M+H) + 。

[0595] Step 7 Solutions of the title compound from Step 6 (3.31 g, 5.4 mmol) in THF (30 mL) and DIAD (3.18 mL, 16.2 mmol) in toluene (30 mL) were added dropwise simultaneously (over 1 h) to a solution of triphenylphosphine (4.25 g, 16.2 mmol) in toluene (300 mL) heated to 90 °C. The reaction mixture was heated at 90 °C for 1 h. Once 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 → 9 / 1) as the eluent. Purification was repeated using cyclohexane / EtOAc - EtOH (3:1) (100 / 0 → 3 / 7) as the eluent to afford the title compound as a cream-colored foam (700 mg, 22% yield).

[0596] LCMS (MA) RT = 2.05 min, m / z = 595.2 (M+H) + 。

[0597] Step 8 To a solution of the title compound from Step 7 (700 mg, 1.17 mmol) in acetonitrile / water (60 mL / 20 mL) was added sodium bicarbonate (0.98 g, 11.7 mmol). After the reaction mixture was stirred at 45 °C for 30 minutes, iodine (1.9 g, 8.77 mmol) was added. The reaction mixture was stirred at 45 °C for 3 hours. When complete conversion was monitored by LCMS, the reaction mixture was quenched with saturated sodium thiosulfate solution (100 mL). DCM (200 mL) was added to the mixture, and this 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→9 / 1) as the eluent to give the title compound as a cream-colored solid (0.5 g, 70% yield).

[0598] LCMS (MA) RT = 2.50 min, m / z = 609.2 (M+H) + 。

[0599] Step 9 To a suspension of the title compound from Step 8 (0.5 g, 0.82 mmol) in THF / acetonitrile (40 mL / 4 mL) were added cesium carbonate (0.53 g, 1.64 mmol) and 4-methylbenzenethiol (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→90:10) as the eluent. The expected fractions were combined and evaporated under reduced pressure. The residue was triturated in diethyl ether / acetonitrile (98 / 2) to give the expected product as a cream-colored solid (0.18 g, 52% yield).

[0600] LCMS (MA) RT = 2.09 min, m / z = 424.4 (M+H) + 。 LCMS (MC) RT = 2.90 min, m / z = 424.4 (M+H) + 。 1 1H NMR (400 MHz, DMSO) δ 8.99 - 8.95 (1H, m), 8.60 - 8.60 (1H, m), 7.98 (1H, s), 6.65 (1H, d, J = 7.7 Hz), 6.61 - 6.59 (1H, m), 6.14 - 6.10 (1H, m), 6.03 (1H, t, J = 2.1 Hz), 5.30 - 5.25 (1H, m), 4.39 - 4.33 (1H, m), 4.23 - 4.19 (1H, m), 4.08 (1H, t, J = 11.4 Hz), 3.75 (1H, d, J = 12.6 Hz), 3.63 - 3.55 (1H, m), 3.45 - 3.44 (6H, m), 2.47 - 2.41 (1H, m), 2.02 - 1.94 (1H, m), 1.28 (3H, d, J = 6.8 Hz), 1.15 - 1.12 (1H, m)

[0601] Example 90: (12R,14S)-12-Hydroxy-4-methoxy-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 [Chemical formula]

[0602] According to the general synthetic scheme 1 described for the synthesis of Example 1, using the skeleton 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine, pyrrolidine P13, and aniline A3, (12R,14S)-4-methoxy-7-(2-nitrobenzenesulfonyl)-12-(prop-2-en-1-yloxy)-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-heptaene was obtained as intermediate I26.

[0603] LCMS (MA) RT = 2.29 min, m / z = 607.2 (M+H) + 。

[0604] Project 1 Under argon, to a suspension of Intermediate I26 (315 mg, 0.52 mmol) in EtOH / TFA (4.5 mL / 0.4 mL) was added tetrakis(triphenylphosphine)palladium(0) (120 mg, 0.10 mmol). The reaction mixture was stirred at 80 °C for 14 h. When complete conversion was monitored by LCMS, the reaction mixture was cooled to room temperature and carefully quenched with saturated NaHCO3 solution. If an emulsion was observed, the mixture was filtered and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 15 mL), and 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 / EtOH 3:1) (100:0 → 50:50) as the eluent to afford the title compound as an orange foam (184 mg, 62% yield).

[0605] LCMS (MA) RT = 1.80 min, m / z = 567.1 (M+H) + 。

[0606] Project 2 A suspension of the title compound (1.38 g, 2.44 mmol) from Step 1 in THF / H2O (80 mL / 16 mL) was treated with sodium bicarbonate (4.100 g, 48.80 mmol). After the reaction mixture was stirred at room temperature for 10 minutes, iodine (9.29 g, 36.60 mmol) was added. The reaction mixture was stirred at 60 °C for 1 hour. When complete conversion was monitored by LCMS, the reaction mixture was cooled to room temperature, quenched with a saturated solution of sodium thiosulfate, and diluted with ethyl acetate. The layers were separated. The aqueous layer was extracted with EtOAc (2 × 25 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the title compound (Intermediate I27, (12R,14S)-12-hydroxy-4-methoxy-7-(2-nitrobenzenesulfonyl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2,4,6(25),17(24),18,21-heptaene-11-one) as an off-white solid (1.679 g). The compound was used directly in the subsequent step without further purification.

[0607] LCMS (MA) RT = 2.27 min, m / z = 581.1 (M+H) + 。

[0608] Step 3 To a suspension of the title compound (100 mg, 0.17 mmol) from Step 2 in DMF (1.5 mL), cesium carbonate (110 mg, 0.34 mmol) and 4-methylbenzenethiol (25 mg, 0.20 mmol) were added. The reaction mixture was stirred at room temperature for 30 minutes. Once complete conversion was monitored by LCMS, the mixture was diluted with water and ethyl acetate. The layers were separated. The aqueous layer was extracted with EtOAc (2 × 15 mL), and 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 DCM / MeOH (100:0 → 95:5) as the eluent. The compound was triturated in acetonitrile, filtered, and dried under reduced pressure to afford the expected product as a pale beige solid (26 mg, 38% yield).

[0609] LCMS (MA) RT = 1.79 min, m / z = 396.4 (M+H) + 。 LCMS (MC) RT = 1.78 min, m / z = 396.4 (M+H) + 。 1 H NMR (400 MHz, DMSO) 8.96 (1H, d, J = 7.6 Hz), 8.51 (1H, s), 7.48 (1H, s), 6.64 (1H, d, J = 7.4 Hz), 6.55 - 6.54 (1H, m), 6.05 - 6.02 (2H, m), 5.59 (1H, d, J = 5.7 Hz), 4.92 - 4.89 (1H, m), 4.50 - 4.42 (2H, m), 3.96 (1H, t, J = 10.8 Hz), 3.73 (3H, s), 3.57 - 3.49 (1H, 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)

[0610] Prepared similarly.

[0611]

Table 14

[0612] Example 91: (12R,14S)-4-Fluoro-12-(oxetan-3-ylmethoxy)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

Chem.

[0613] Step 1 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. When complete conversion was monitored by LCMS, water was carefully added dropwise at 0 °C. The resulting mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound as a yellow oil (0.030 g, 27% yield).

[0614] LCMS (MA) RT = 2.51 min, m / z = 639.1 (M+H) + 。

[0615] Step 2 The title compound from Step 1 (0.03 g, 0.05 mmol) and cesium carbonate (0.031 g, 0.09 mmol) were dissolved in DMF (1.1 mL). 4-Methylbenzenethiol (0.007 g, 0.06 mmol) was added, and the mixture was stirred at room temperature overnight. When complete conversion was monitored by LCMS, the reaction mixture was filtered. The solvent was evaporated, and the residue was purified by flash column chromatography using cyclohexane / EtOAc (100 / 0 → 0 / 100) as eluent to afford the expected product as a white solid (0.011 g, 52% yield).

[0616] LCMS (MA) RT = 2.12 min, m / z = 454.2 (M+H) + 。 LCMS (MC) RT = 2.11 min, m / z = 454.2 (M+H) + 。 11H NMR (400 MHz, CDCl3) δ 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 = 6.9 Hz), 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, 12.9 Hz), 2.07 - 2.07 (1H, m), 1.30 - 1.26 (2H, m);

[0617] Prepared in the same manner.

[0618]

Table 15 - 1

Table 15 - 2

Table 15 - 3

[0619] Example 92:(12R,14S) - 4 - fluoro - 18 - ( 2 H3)methoxy - 12 - methoxy - 16 - oxa - 7,10,20,21,24 - pentaazapentacyclo[15.5.2.1 2,6 .010,14 .0 20,23 Penta-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

Chem.

[0620] Step 1 To a suspension of Intermediate I28 (0.064 g, 0.11 mmol) in DMF (3.3 mL), cesium carbonate (0.105 g, 0.32 mmol) and iodide( 2 H3)methane (0.046 g, 0.32 mmol) were added. The reaction mixture was stirred at 70 °C for 2 h. When complete conversion was monitored by LCMS, the reaction mixture was cooled to room temperature. After the solution was concentrated under reduced pressure, it was diluted with water and EtOAc. The layers were separated. The aqueous layer was extracted with EtOAc (3 × 20 mL), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the title compound as a yellow solid (0.202 g).

[0621] LCMS (MA) RT = 2.55 min, m / z = 616.2 (M+H) + .

[0622] Step 2 The title compound from Step 1 (0.066 g, 0.11 mmol) and cesium carbonate (0.070 g, 0.21 mmol) were dissolved in DMF (2.4 mL). 4-Methylbenzenethiol (0.016 g, 0.13 mmol) was added and the mixture was stirred at room temperature overnight. When complete conversion was monitored by LCMS, the reaction mixture was filtered and the solvent was evaporated to dryness. The residue was purified by flash column chromatography using cyclohexane / EtOAc (100 / 0 → 20 / 80) as the eluent to obtain the expected product as a white solid (25 mg, 54% yield).

[0623] LCMS (MA) RT = 2.23 min, m / z = 431.2 (M+H) + . LCMS (MC) RT = 2.14 min, m / z = 431.3 (M+H) + 。 1 H NMR (400 MHz, DMSO) δ 8.79 - 8.78 (1H, m), 8.40 - 8.39 (1H, m), 7.63 - 7.62 (1H, m), 6.72 (1H, d, J = 9.9 Hz), 6.40 - 6.25 (1H, m), 6.22 - 6.17 (1H, m), 4.95 (1H, d, J = 10.1 Hz), 4.48 (1H, s), 4.33 (1H, t, J = 8.9 Hz), 4.03 (1H, t, J = 10.7 Hz), 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);

[0624] Prepared in the same manner.

[0625]

Table 16 - 1

Table 16 - 2

Table 16 - 3

Table 16 - 4

Table 16 - 5

[0626] 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 10,14 .0 20,23 pentacosa-1(23),2,4,6(25),17(24),18,21-heptaen-11-one

Chemical Structure

[0627] Step 1 To a suspension of Intermediate I29 (170 mg, 0.23 mmol) in THF (1.2 mL) was added TBAF (1 M) in THF (0.25 mL, 0.25 mmol). The reaction mixture was stirred at room temperature for 1 h. When 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→90:10) as the eluent. The expected fractions were combined and evaporated under reduced pressure. The resulting solid was triturated in acetonitrile, filtered and dried under vacuum to afford the expected product as a pale pink solid (80 mg, 98%).

[0628] LCMS (MA) RT = 1.75 min, m / z = 490.4 (M+H) + 。 LCMS (MC) RT = 1.76 min, m / z = 490.4 (M+H) + 。 1 H NMR (400 MHz, DMSO) δ 8.98 (1H, d, J = 7.4 Hz), 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 = 7.6 Hz), 6.64 - 6.63 (1H, m), 6.03 (1H, t, J = 5.9 Hz), 4.97 - 4.93 (1H, m), 4.95 (1H, t, J = 5.3 Hz), 4.51 - 4.50 (1H, m), 4.34 (1H, t, J = 9.0 Hz), 4.17 (2H, t, J = 5.6 Hz), 3.95 (1H, t, J = 10.9 Hz), 3.78 (2H, q, J = 5.5 Hz), 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).

[0629] Example 96: (12R,14S)-12-Ethoxy-4-hydroxy-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

Chemical formula

[0630] According to the general synthetic scheme 1 represented for the synthesis of Example 1, using the skeletal 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine, pyrrolidine P2, and aniline A9, (12R,14S)-4-(benzyloxy)-12-ethoxy-7-(2-nitrobenzenesulfonyl)-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 was obtained as Intermediate I30.

[0631] LCMS (MA) RT = 2.87 min, m / z = 685.3 (M+H) + .

[0632] Step 1 Anisole (15.19 mL, 138.9 mmol) was added to a solution of Intermediate I30 (2.38 g, 3.47 mmol) in TFA (43 mL). The reaction mixture was stirred at 130 °C for 2 hours. When completely converted as monitored by LCMS, the mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using cyclohexane / EtOAc (100 / 0 → 0 / 100) as the eluent to obtain the title compound as a brown solid (1.96 g, 95% yield).

[0633] Step 2 The title compound from Project 1 (0.20 g, 0.34 mmol) and cesium carbonate (0.219 g, 0.67 mmol) were dissolved in DMF (7.4 mL). 4-Methylbenzenethiol (0.050 g, 0.40 mmol) was added and the mixture was stirred at room temperature overnight. When complete conversion was monitored by LCMS, the reaction mixture was filtered and the mother liquor was concentrated to dryness. The residue was purified by flash column chromatography using cyclohexane / EtOAc (100 / 0 → 20 / 80) as the eluent to obtain the expected product as a green solid (33 mg, 24% yield).

[0634] LCMS (MA) RT = 1.81 min, m / z = 410.4 (M+H) + 。 LCMS (MC) RT = 1.80 min, m / z = 410.4 (M+H) + 。 1 H NMR (400 MHz, 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 = 2.0 Hz), 4.94 - 4.89 (1H, m), 4.44 - 4.38 (2H, m), 3.98 - 3.82 (2H, m), 3.48 (4H, d, J = 10.4 Hz), 3.20 - 3.14 (1H, m), 2.01 - 1.91 (1H, m), 1.17 - 1.04 (4H, m);

[0635] Prepared similarly.

[0636]

Table 17

[0637] Example 100: (12R,14S)-12-(2-methoxyethoxy)-4-(3-methoxyprop-1-yn-1-yl)-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one

Chem.

[0638] According to the general synthetic scheme 1 represented for the synthesis of Example 1, using the skeleton 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine, pyrrolidine P7, and aniline A9, (12R,14S)-4-(benzyloxy)-12-(2-methoxyethoxy)-7-(2-nitrobenzenesulfonyl)-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 was obtained as Intermediate I31.

[0639] LCMS (MA) RT = 2.75 min, m / z = 715.4 (M+H) + 。

[0640] Step 1 Anisole (1.78 mL, 16.4 mmol) was added to a suspension of Intermediate I31 (296 mg, 0.41 mmol) in TFA (6 mL). The reaction mixture was stirred at 130 °C overnight. When completely converted as monitored by LCMS, the reaction mixture was cooled to room temperature. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using DCM / MeOH (100:0 → 95:5) as the eluent to obtain the title compound as an off-white solid (250 mg, 97% yield).

[0641] LCMS (MA) RT = 2.15 min, m / z = 625.3 (M+H) + 。

[0642] Step 2 To a suspension of the title compound (250 mg, 0.4 mmol) from Step 1 in DCM (20 mL) was added triethylamine (0.085 mL, 0.6 mmol). N-Phenyl-bis(trifluoromethanesulfonimide) (157 mg, 0.44 mmol) was added portionwise to the slurry. The reaction mixture was stirred overnight at room temperature. When complete conversion was monitored by LCMS, the reaction mixture was diluted with water and the layers were separated. The aqueous layer was extracted with DCM (2×15 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the title compound as a beige-colored foam (450 mg). The crude product was used directly in the subsequent step without further purification.

[0643] LCMS (MA) RT = 2.73 min, m / z = 757.3 (M+H) + 。

[0644] Step 3 To a suspension of the title compound (303 mg, 0.4 mmol) from Step 2 in DMF (3.5 mL) was added cesium carbonate (260 mg, 0.8 mmol), followed by 4-methylbenzenethiol (60 mg, 0.48 mmol). The reaction was stirred overnight at room temperature. When complete conversion was monitored by LCMS, the reaction mixture was adsorbed onto silica and evaporated to dryness. The residue was purified by silica gel column chromatography using DCM / MeOH (100 / 0 → 9 / 1) as the eluent to give the title compound as a white solid (Intermediate I33, (12R,14S)-12-(2-methoxyethoxy)-11-oxo-16-oxa-7,10,20,21,24-pentaazapentacyclo[15.5.2.1 2,6 .0 10,14 .0 20,23 pentacosa-1(23),2,4,6(25),17(24),18,21-heptaene-4-yl trifluoromethanesulfonate, 150 mg, 66% yield).

[0645] LCMS (MA) RT = 2.54 min, m / z = 572.2 (M+H) + 。

[0646] Step 4 In a sealed tube, lithium chloride (0.011 g, 0.26 mmol) was added to a suspension of the title compound from Step 3 (0.050 g, 0.09 mmol) in dry 1,4-dioxane (1.5 mL). The mixture was degassed by bubbling with argon for 10 minutes. Tributyl(vinyl)stannane (0.038 g, 0.10 mmol) and Pd(PPh3)4 (0.010 g, 0.01 mmol) were added, and the reaction was stirred at 100 °C for 2 hours in a sand bath. When complete conversion was monitored by LCMS, the reaction mixture was cooled, filtered through Celite, and then the solvent was evaporated. The residue was purified by column chromatography using cyclohexane / EtOAc (100 / 0 → 0 / 100) as the eluent to give the expected product as a white solid (17 mg, 40% yield).

[0647] LCMS (MA) RT = 2.22 min, m / z = 492.4 (M+H) + 。 LCMS (MC) RT = 2.21 min, m / z = 492.4 (M+H) + 。 11H NMR (400 MHz, DMSO) 9.00 - 8.98 (1H, m), 8.57 (1H, s), 7.85 (1H, s), 7.03 (1H, d, J = 1.3 Hz), 6.66 (1H, d, J = 7.4 Hz), 6.54 (1H, dd, J = 1.5, 2.3 Hz), 6.26 - 6.22 (1H, m), 4.93 (1H, d, J = 11.0 Hz), 4.45 (2H, dd, J = 8.3, 9.4 Hz), 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 = 4.7 Hz), 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 = 1.0 Hz), 0.88 (1H, t, J = 7.3 Hz);

[0648] Example 101: (12R,14S)-4-Cyclopropanecarbonyl-12-(2-methoxyethoxy)-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

Chemical Structure

[0649] Step 1 In a sealed tube, to a suspension of intermediate I33 (64 mg, 0.11 mmol) in dry toluene (0.22 mL) under argon were added cyclopropane - methanol (10 μL, 0.13 mmol), acetone (40 μL, 0.55 mmol), and TMP (37 μL, 0.22 mmol). The mixture was degassed by bubbling argon for 10 minutes, then Triphos (8 mg, 0.01 mmol) and Ni(OTf)2 (4 mg, 0.01 mmol) were added. The tube was sealed and heated at 140 °C using a sand bath preheated to 140 °C. The reaction mixture was stirred at 140 °C for 48 hours. When the starting material was completely converted as monitored by LCMS, the layers were separated. The aqueous layer was extracted with EtOAc (2 × 10 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The reaction was restarted on the crude product under the same conditions. The mixture was warmed to 140 °C overnight. When completion was monitored by LCMS, the reaction was cooled to room temperature and the mixture was diluted with water and ethyl acetate. The layers were separated. The aqueous layer was extracted with EtOAc (2 × 10 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 Waters XSELECT C18 19×100 mm, 5 μm, A: aqueous (NH4)2CO3 solution (2 g / L), B: ACN, 19 ml / min, room temperature, 40% B → 45% B for 7 minutes). The residue (about 15 mg) was purified once again by preparative TLC (0.5 mm) using cyclohexane / (EtOAc / EtOH 3:1)(1:1) as the eluent to give the expected product as a pale yellow solid (11 mg, 16%).

[0650] LCMS (MA) RT = 2.15 min, m / z = 492.4 (M + H) + 。 LCMS (MC) RT = 2.15 min, m / z = 492.4 (M + H) + 。 11H NMR (400 MHz, CDCl3) δ 8.54 (1H, d, J = 7.4 Hz), 8.42 (1H, s), 8.10 (1H, ls), 7.62 - 7.60 (1H, m), 7.16 - 7.14 (1H, m), 6.45 (1H, d, J = 7.4 Hz), 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)

[0651] Example 102: (12R,14S)-4-ethenyl-12-ethoxy-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

Chemical Structure

[0652] Step 1 Anisole (15.168 mL, 138.86 mmol) was added to a solution of Intermediate I30 (2.38 g, 3.47 mmol) in TFA (43 mL). The reaction mixture was stirred at 130 °C for 2 h. When complete conversion was monitored by LCMS, the mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using cyclohexane / EtOAc (100 / 0 → 0 / 100) as the eluent to afford the title compound as a brown solid (1.96 g, 95% yield).

[0653] LCMS (MA) RT = 2.35 min, m / z = 595.2 (M + H)+ .

[0654] Step 2 To a suspension of the title compound (250 mg, 0.42 mmol) from Step 1 in DCM (20 mL), after triethylamine (0.09 mL, 0.63 mmol), N-phenylbis(trifluoromethanesulfonimide) (165 mg, 0.46 mmol) was added portionwise. When complete conversion was monitored by LCMS, the reaction mixture was diluted with water. The layers were separated. The aqueous layer was extracted with DCM (2 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the title compound as a gray foamy solid (430 mg), which was used directly in the subsequent step without further purification.

[0655] LCMS (MA) RT = 2.86 min, m / z = 727.1 (M+H) + .

[0656] Step 3 To a suspension of the title compound (305 mg, 0.42 mmol) from Step 2 in DMF (3.4 ...

Claims

1. Formula I: 【Chemical 1】 wherein R 1 is selected from -halo, -O-C 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, wherein each of said -C 1～6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1～3 alkyl, -C 3～6 -cycloalkyl, -Ph, -Het 1 , -Het 2 , and -OH, and each of said -alkynyl is optionally substituted with one substituent selected from -C 1～6 alkyl and -CH 2 -O-C 1～6 alkyl, R 2 and R 10 are each independently selected from -H and -halo, R 3 、R 3’ 、R 4 、R 4’ 、R 7 、and R 8 are each independently selected from -H and -C 1～6 alkyl, where each of said -C 1～6 alkyl may optionally be substituted with one or more -O-C 1～6 alkyl. R 3 and / or R 3’ is -C 1～6 when it is alkyl, R 4 and R 4’ are each -H, R 4 and / or R 4’ is -C 1～6 When it is alkyl, R 3 and R 3’ are each -H, R 5 is selected from -OH, -NR c R c’、 -NHC(O)R c , -NHS(O 2 )R c , -halo, -O-C 1～6 alkyl, -O-cycloalkyl, -O-Het 3～5 , -C 2 alkyl, and -CN, wherein each of said -C 1～6 alkyl is optionally substituted with one or more substituents selected from -D, -OH, -C 1～6 alkyl, -C 1～6 -cycloalkyl, -O-C 3～5 alkyl, and -Het 1～6 , and 2 is optionally substituted with one or more substituents selected from; R 6 is selected from -H, -halo, -C 1～6 alkyl, -O-C 1～6 alkyl, -O-Het 4 , and -Het 3 and is selected from, where each of said -C 1～6 alkyl is optionally substituted with one or more substituents selected from -D and -O-C 1～6 alkyl. R 9 is selected from -H, -C 1～6 alkyl, -C(O)-C 1～6 alkyl, and -C(O)-O-C 1～6 alkyl, and is selected from R a is selected from -H and -C 1～6 alkyl, wherein each of said -C 1～6 alkyl is optionally substituted with one or more substituents selected from -D and -C 1～6 alkyl, R b is selected from -H, -C 1～6 alkyl, and -O-C 1～6 alkyl, wherein each of said -C 1～6 alkyl is optionally substituted with one or more substituents selected from -D, -C 1～6 alkyl, and -C 3～5 -cycloalkyl; R c and R c’ are each independently, -H and -C 1～6 alkyl, wherein each of said -C 1～6 alkyl is optionally substituted with one or more substituents selected from -D and -C 1～6 alkyl, Het 1 and Het 3 each independently is selected from 5- or 6-membered aromatic heterocycles having 1 to 3 heteroatoms selected from O, N, and S, wherein said Het 1 or Het 3 each is optionally substituted with 1 to 3 -C 1～6 alkyl, and each of said -C 1～6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1～3 alkyl, and -OH, Het 2 is selected from 4- to 6-membered saturated heterocycles having 1 to 3 heteroatoms selected from O and N, wherein each of said Het 2 is optionally substituted with 1 to 3 -C 1～6 alkyls, and each of said -C 1～6 alkyls is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1～3 alkyl, and -OH. Het 4 is selected from 4- to 10-membered saturated heterocycles having 1 to 3 heteroatoms selected from O and N, wherein each of said Het 4 is optionally substituted with 1 to 3 -C 1～6 alkyls, and each of said -C 1～6 alkyls is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1～3 alkyl, and -OH), or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form, or solvate thereof.

2. R 1 is selected from -halo, -O-C 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, and each of said -C 1～6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1～3 alkyl, -C 3～6 -cycloalkyl, -Ph, -Het 1 , -Het 2 , and -OH, R 2 and R 10 are each independently selected from -H and -halo, R 3 、R 3’ 、R 4 、R 4’ 、R 7 、and R 8 are each independently selected from -H and -C 1～6 alkyl, where each of said -C 1～6 alkyl may optionally be substituted with one or more -O-C 1～6 alkyl. R 3 and / or R 3’ is -C 1～6 When it is alkyl, R 4 and R 4’ are each -H, R 4 and / or R 4’ is -C 1～6 when it is alkyl, R 3 and R 3’ are each -H, R 5 is selected from -OH, -NR c R c’、 -NHC(O)R c , -halo, -O-C 1～6 alkyl, -O-C 3～5 -cycloalkyl, -O-Het 2 , -C 1～6 alkyl, and -CN, wherein each of said -C 1～6 alkyl is optionally substituted with one or more substituents selected from -D, -OH, -C 1～6 alkyl, -C 3～5 -cycloalkyl, -O-C 1～6 alkyl, and -Het 2 ; and R 6 is selected from -H, -halo, -C 1～6 alkyl, -O-C 1～6 alkyl, -O-Het 4 , and -Het 3 wherein each of said -C 1～6 alkyl is optionally substituted with one or more substituents selected from -D and -O-C 1～6 alkyl, R 9 is selected from -H, -C 1～6 alkyl, -C(O)-C 1～6 alkyl, and -C(O)-O-C 1～6 alkyl, and is selected from R a is selected from -H and -C 1～6 alkyl, R b is -H, -C 1～6 alkyl, and -O-C 1～6 selected from alkyl, and R c and R c’ are each independently -H and -C 1～6 selected from alkyl, Het 1 and Het 3 is independently selected from 5- or 6-membered aromatic heterocycles having 1 to 3 heteroatoms selected from O and N, wherein said Het 1 and Het 3 each is optionally substituted with 1 to 3 -C 1～6 alkyl, Het 2 is selected from 4- to 6-membered saturated heterocycles having 1 to 3 O atoms, Het 4 is selected from 4- to 10-membered saturated heterocycles having 1 to 3 heteroatoms selected from O and N, wherein each of said Het 4 is optionally substituted with 1 to 3 -C 1～6 alkyls, and each of said -C 1～6 alkyls is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1～3 alkyl, and -OH, the compound according to claim 1.

3. R 1 is selected from - halo, -O - C 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, and each of said -C 1～6 alkyl is optionally substituted with one or more substituents selected from -D, - halo, -O - C 1～3 alkyl, -C 3～6 - cycloalkyl, -Ph, -Het 1 , -Het 2 , and -OH, R 2 and R 10 each independently is selected from -H and -halo, R 3 、R 3’ 、R 4 、R 4’ 、R 7 、and R 8 are each -H, R 5 is selected from -OH, -halo, -O-C 1～6 alkyl, -O-C 3～5 -cycloalkyl, and -C 1～6 alkyl, wherein each of said -C 1～6 alkyl is optionally substituted with one or more substituents selected from -D, -OH, -C 1～6 alkyl, -C 3～5 -cycloalkyl, and -O-C 1～6 alkyl, and is optionally substituted with one or more substituents selected from -D, -OH, -C R 6 is selected from -H, -halo, -C 1～6 alkyl, -O-C 1～6 alkyl, -O-Het 4 , and -Het 3 wherein each of said -C 1～6 alkyl is optionally substituted with one or more -O-C 1～6 alkyl, R 9 is selected from -H, -C 1～6 alkyl, -C(O)-C 1～6 alkyl, and -C(O)-O-C 1～6 alkyl, and is selected from R a is selected from -H and -C 1～6 alkyl, R b is selected from -H, -C 1～6 alkyl, and -O-C 1～6 alkyl, wherein each of said -C 1～6 alkyl is optionally substituted with one or more Het 1 and Het 3 is each independently selected from 5- or 6-membered aromatic heterocycles having 1 to 3 heteroatoms selected from O and N, wherein said Het 1 and Het 3 each of which is optionally substituted with 1 to 3 -C 1～6 alkyl, Het 2 is selected from 4- to 6-membered saturated heterocycles having 1 to 3 O atoms, Het 4 is selected from 4- to 10-membered saturated heterocycles having 1 to 3 heteroatoms selected from O and N, wherein each of said Het 4 is optionally substituted with 1 to 3 -C 1～6 alkyls, and each of said -C 1～6 alkyls is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1～3 alkyl, and -OH, the compound according to claim 1.

4. R 1 is selected from -halo, -O-C 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, and each of said -C 1～6 alkyl is optionally substituted with one or more substituents selected from -D, -halo, and -O-C 1～3 alkyl, R 2 is selected from -H and -halo, R 10 is -H, R 3 、R 3’ 、R 4 、R 4’ 、R 7 、and R 8 are each -H, R 5 is selected from -OH, -halo, -O-C 1～6 alkyl, -O-C 3～5 -cycloalkyl, and -C 1～6 alkyl, wherein each of said -C 1～6 alkyl is optionally substituted with one or more substituents selected from -D, -OH, -C 1～6 alkyl, -C 3～5 -cycloalkyl, and -O-C 1～6 alkyl, and R 6 is selected from -H, -halo, -C 1～6 alkyl, -O-C 1～6 alkyl, -O-Het 4 , and -Het 3 wherein each of said -C 1～6 alkyl is optionally substituted with one or more -O-C 1～6 alkyl, R 9 is -H, R a is selected from -H and -C 1～6 alkyl, R b is -H, -C 1～6 alkyl, and -O-C 1～6 selected from alkyl, Het 1 is a 5-membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from O and N, wherein said Het 1 is optionally substituted with 1 to 3 -C 1～6 alkyl, Het 4 is selected from 4- to 10-membered saturated heterocycles having 1 to 3 heteroatoms selected from O and N, wherein each of said Het 4 is optionally substituted with 1 to 3 -C 1～6 alkyls, and each of said -C 1～6 alkyls is optionally substituted with one or more substituents selected from -D, -halo, -O-C 1～3 alkyl, and -OH, the compound according to any one of claims 1 to 3.

5. 【Fig. 2-1】 【Chemical formula 2-2】 【Chemical 2-3】 【Chemical Formula 2-4】 [Chemical Formula 2-5] [[Chemical Formula 2-6]] [[Chemical Formula 2-7]] ​ 【Chemical Formula 2-9】 The compound according to claim 1, selected from the list comprising

6. Said R 8 The compound according to any one of claims 1 to 4, wherein the carbon atom having the substituent has an S configuration.

7. The aforementioned R 5 The compound according to any one of claims 1 to 4, wherein the carbon atom to which the substituent is attached has an R configuration.

8. A pharmaceutical composition comprising the compound defined in any one of claims 1 to 7.

9. The compound defined in any one of claims 1 to 7, for use as a human or veterinary pharmaceutical.

10. The pharmaceutical composition according to claim 8, for use as a human or veterinary pharmaceutical.

11. The compound defined in any one of claims 1 to 7, for use in the diagnosis, prevention and / or treatment of RIP2-kinase related diseases.

12. The pharmaceutical composition according to claim 8, for use in the diagnosis, prevention and / or treatment of RIP2-kinase related diseases.

13. For use in the diagnosis, prevention, and / or treatment of RIP2-kinase related diseases, wherein the RIP2-kinase related disease is an inflammatory disorder selected from the list comprising Crohn's disease, intestinal disease, 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, Behçet's disease, immune-mediated colitis, and multiple sclerosis, the compound defined in any one of claims 1 to 7.

14. For use in the diagnosis, prevention, and / or treatment of RIP2-kinase related diseases, wherein the RIP2-kinase related disease is an inflammatory disorder selected from the list comprising Crohn's disease, intestinal disease, 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, Behçet's disease, immune-mediated colitis, and multiple sclerosis, the pharmaceutical composition according to claim 8.

15. For use in the diagnosis, prevention, and / or treatment of RIP2-kinase related diseases, wherein the RIP2-kinase related disease is a cancer selected from breast cancer (including inflammatory breast cancer), head and neck cancer, and glioma, the compound defined in any one of claims 1 to 7.

16. The pharmaceutical composition according to claim 8, which is used in the diagnosis, prevention, and / or treatment of RIP2-kinase-related diseases, wherein the RIP2-kinase-related diseases are cancers selected from breast cancer (including inflammatory breast cancer), head and neck cancer, and glioma.

17. Use of a compound defined in any one of claims 1 to 7 or a pharmaceutical composition defined in claim 8 for the manufacture of an agent for inhibiting the activity of a kinase or RIP2 kinase.

18. Use of a compound defined in any one of claims 1 to 7 or a pharmaceutical composition defined in claim 8 for the manufacture of an agent for the diagnosis, prevention, and / or treatment of RIP2-kinase-related diseases.

19. A medicament comprising a compound defined in any one of claims 1 to 7 or a composition defined in claim 8 for administration to a subject.

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