TW202245760A - Macrocycles and their use - Google Patents

Abstract

The present disclosure relates to macrocyclic compounds, pharmaceutical compositions containing macrocyclic compounds, and methods of using macrocyclic compounds to treat disease, such as cancer.

Description

Macrocycles and their uses

The present invention relates to macrocycles, pharmaceutical compositions containing the macrocycles and methods of using the macrocycles to treat diseases such as cancer.

Protein kinases are tightly regulated signaling proteins that coordinate the activation of signaling cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli. The human genome encodes approximately 518 protein kinases (Manning G et al. The protein kinase complement of the human genome. Science. 2002, 298:1912-34). Dysregulation of kinase activity is associated with many diseases, including cancer and cardiovascular, degenerative, immune, infectious, inflammatory and metabolic diseases (Levitzki, A. Protein kinase inhibitors as a therapeutic modality. Acc. Chem. Res. 2003, 36: 462-469). The molecular basis for various diseases includes kinase gain-of-function and loss-of-function mutations, gene amplification and deletion, splicing changes and translocations (Wilson LJ et al. New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome. Cancer Res. 2018, 78:15-29). The central role of kinases in cancer and other diseases makes them attractive targets for drug discovery, with 52 small-molecule kinase inhibitors approved and 46 of them used in targeted cancer therapies (Roskoski R Jr, Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2020 Update. Pharmacol Res 2020, 152:104609). Despite the great success of kinase inhibitors in targeted cancer therapy, the development of therapeutic resistance remains a challenge for small molecule kinase inhibitors. Acquired secondary mutations in the kinase domain during therapy often lead to therapeutic resistance to kinase inhibitors (Pottier C et al Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy. Cancers (Basel), 2020, 12:731 ). Therefore, there is a need to develop kinase inhibitors that not only target the oncogenic drivers of kinases, but also overcome the most common resistance mutations for better efficacy and longer-term disease control.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide (World Health Organization. Cancer Fact Sheet 2017). Activating EGFR mutations have been reported in approximately 10% to 15% of Caucasian patients and 50% of Asian patients with adenocarcinoma (Chan BA, Hughes BG. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future . Transl Lung Cancer Res 2015; 4:36-54). The two most common EGFR alterations found in NSCLC tumors are a short in-frame deletion (del19) in exon 19 of the EGFR gene and a single missense mutation L858R in exon 21 (Konduri K. et al. EGFR Fusions as Novel Therapeutic Targets in Lung Cancer. Cancer Discovery 2016, 6:601-11). Except for exon 19 deletions and L858R mutations, 4-10% of EGFR mutations in NSCLC are of 10 = -7 amino acids in exon 20 spanning a span of approximately 15 amino acids (D761 to C775) Insertion in heterogeneous frame (Vyse S and Huang PH, Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Sig Transduct Target Ther 4 , 5 (2019)). First-generation reversible EGFR inhibitors erlotinib and gefitinib are superior to chemotherapy in patients with advanced EGFR mutation-positive (Del19 or L858R) NSCLC and have been used as first-line standard of care in this setting . However, over time on treatment, most patients will develop resistance to gefitinib or erlotinib, with 50% to 70% of tumors harboring EGFR T790M gatekeeper mutations (Sequist LV et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011; 3:75ra26). The second-generation EGFR inhibitors, afatinib and dacomitinib, are covalent, irreversible EGFR inhibitors that also inhibit HER2 and ERB4 of the ERB family (Li D et al. BIBW2992, an irreversible EGFR/ HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008; 27: 4702-11; Ou SH, Soo RA. Dacomitinib in lung cancer: a 「lost generation」 EGFR tyrosine-kinase inhibitor from a bygone era? Drug Des Devel Ther 2015 ; 9:5641-53). Although compared with gefitinib and erlotinib, afatinib and dacomitinib are more effective EGFR inhibitors, approved as first-line therapy for advanced EGFR mutation-positive (Del19 or L858R) NSCLC, with more Long progression-free survival (PFS), but already developed EGFR T790M when treated with afatinib (Tanaka K et al. Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor-naive patients with non-small cell lung cancer harboring EGFR mutations. Onco-target 2017; 8:68123-30). Egfr T790M confers resistance to dacomitinib in in vitro studies (Kobayashi Y et al EGFR T790M and C797S mutations as mechanisms of acquired resistance to dacomitinib. J Thorac Oncol 2018; 13: 727-31). The third-generation EGFR inhibitor Osimertinib is also an irreversible inhibitor, targeting both EGFR activating mutations (Del19 and L858R) and T790M resistance double mutations, with selectivity over wild-type EGFR (Finlay MR et al. Human Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem 2014; 57:8249-67). Osimertinib was first approved for patients with metastatic EGFR T790M mutation-positive NSCLC after failure of first-line EGFR inhibitors, and was subsequently approved for use in the phase III FLAURA trial compared with erlotinib or gefitinib First-line therapy in patients with EGFR mutation-positive NSCLC following a head-to-head trial (Soria JC et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018; 378:113-25). Mutation C797S has been detected in osimertinib-resistant patients at the EGFR covalently binding residue to the irreversible EGFR inhibitor osimertinib (Ramalingam SS et al. Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. Presented at the ESMO 2018). Therefore, it is necessary to develop drug resistance mutations, L858R/T790M/C979S, Del19/T790M/C979S, L858R/C979S and Del19/C979S and other drug-resistant A new generation of reversible EGFR inhibitors with effective drug compound mutations and good selectivity over wild-type EGFR. To date, clinically approved EGFR inhibitors have failed to effectively treat NSCLC driven by EGFR exon 20 insertion mutations. There is an urgent need to develop a new generation of EGFR inhibitors that are effective against EGFR exon 20 insertion mutations.

Amplification of HER2 (ERBB2) has been identified as an oncogenic driver in breast cancer, allowing the monoclonal antibodies trastuzumab and pertuzumab, the antibody-drug conjugate trastuzumab Trastuzumab emantasine and trastuzumab deruxtecan are approved for advanced breast cancer. Three small-molecule tyrosine kinase inhibitors targeting HER2, lapatinib, neratinib, and tucatinib, have also been approved for the treatment of HER2+ breast cancer (Conlon NT et al. Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors, British Journal of Cancer 2021, 124:1249-1259). Activating mutations of the HER2 gene have been reported in various solid cancers and may serve as viable targets for therapeutic inventions (Cocco E et al. Prevalence and role of HER2 mutations in cancer. Pharmacol Ther. 2019, 199:188-196). However, efforts to target HER2 mutations have not been successful in clinical studies. Additionally, the success of HER2-targeting agents in HER2+ breast cancer has been overshadowed by the development of treatment resistance. HER2 and HER3 heterodimers can act as oncogenic drivers and also contribute to the development of drug resistance in HER2-targeted therapies. Inhibition of HER2 kinase stimulates the HER2/HER3 heterodimeric complex either through growth factors such as neuregulin-1 (NRG1 ) or by increasing the concentration of HER2 and HER3 at the membrane. The approved HER2 small molecule kinase inhibitors lapatinib, neratinib and tucatinib are type II kinase inhibitors targeting the inactive form of HER2. HER2/HER3 heterodimers stabilize HER2 in the active conformation, resulting in attenuated activity of approved HER2 TKIs (Novotny CJ et al. Overcoming resistance to HER2 inhibitors through state-specific kinase binding. Nat Chem Biol. 2016, 12:923 -930). In addition, NRG1-related gene fusions have been reported as oncogene drivers in solid tumors. NRG1 fusions cause activation of ErbB-mediated pathways and appear to be logical candidates for targeted therapy (Laskin J et al. NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Ann Oncol . 2020, 31:1693-1703).

Overall, there is an urgent need to develop next-generation kinase inhibitors that can target primary mutations and clinically emerging secondary mutations to achieve better efficacy and longer treatment duration as first-line therapy or to overcome drug resistance in refractory patients mutation. For example, there is a need to develop a new generation of reversible EGFR inhibitors that are effective against oncogenic driver EGFR mutations such as L858R, Del19, exon 20 insertions, L858R/ T790M, Del19/T790M, L858R/T790M/C979S, Del19/T790M/C979S, L858R/C979S and Del19/C979S and other emerging and confirmed drug resistance mutations. Furthermore, there is an urgent need to develop next-generation HER2 inhibitors targeting the active form of HER2 to effectively treat patients with resistance to HER2-targeted therapies or cancers with HER2 or NRG1 mutations.

In one aspect, the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof,

in

X is -X ¹ - or -X ¹ -(ring A)-;

X ¹ is -O-, -S-, -NR ¹ -;

each Y is independently ring B or -C(O)NR ² -;

Ring A is C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl, and wherein each hydrogen atom in C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently optionally Deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C (O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to Each hydrogen atom in the 10-membered heteroaryl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC (O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O )R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , - C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution;

Each ring B is a C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl, wherein each hydrogen atom in the C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently selected by Deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C (O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to Each hydrogen atom in the 10-membered heteroaryl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC (O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O )R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , - C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution;

Each L is independently -C(R ³ )(R ⁴ )-, -C(O)-, -O-, -N(R ⁵ )-, -S-, -S(O)- or -S( O) ₂ -, with the proviso that (L) _n does not contain -OO-, -OS-, -SS- or -ON(R ⁵ )- bonds;

Z ¹ is N or C (R ⁶ );

Z ² is N or C (R ⁷ );

Z ³ is N or C (R ⁸ );

Z ⁴ is N or C (R ⁹ );

Z ⁵ is N or C (R ¹⁰ );

Z ⁶ is N or C (R ¹¹ );

The restriction is that at least one of Z ¹ to Z ⁶ is N;

Each of R ¹ , R ² and R ⁵ is independently H, deuterium, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ ring Alkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ Each hydrogen atom in alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently optionally replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS( O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S (O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C( O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e' , -CN or -NO ₂ replaced;

Each R ³ and R ⁴ is independently H, deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, -OR ^c , -OC(O)R ^c , -OC(O)NR ^c R ^d , -OC(=N )NR ^c R ^d , -OS(O)R ^c , -OS(O) ₂ R ^c , -OS(O)NR ^c R ^d , -OS(O) ₂ NR ^c R ^d , -SR ^c , -S (O)R ^c , -S(O) ₂ R ^c , -S(O)NR ^c R ^d , -S(O) ₂ NR ^c R ^d , -NR ^c R ^d , -NR ^c C(O)R ^d , -N(C(O)R ^c )(C(O)R ^d ), -NR ^c C(O)OR ^d , -NR ^c C(O)NR ^c R ^d , -NR ^c C(=N )NR ^c R ^d , -NR ^c S(O)R ^d , -NR ^c S(O) ₂ R ^d , -NR ^c S(O)NR ^c R ^d , -NR ^c S(O) ₂ NR ^c R ^d , -C(O)R ^c , -C(O)OR ^c , -C(O)NR ^c R ^d , -C(=N)NR ^c R ^d , -PR ^c R ^d , -P(O) R ^c R ^d , -P(O) ₂ R ^c R ^d , -P(O)NR ^c R ^d , -P(O) ₂ NR ^c R ^d , -P(O)OR ^c , -P(O) ₂ OR ^c , -CN, -NO ₂ , or both R ³ and R ⁴ form a C ₃ -C ₆ cycloalkyl or 4 to 6 membered heterocycloalkyl together with one or more carbons to which they are attached, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 Each hydrogen atom in the 10- to 10-membered heteroaryl group or the 4- to 6-membered heterocycloalkyl group is independently optionally replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C (O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution;

Each of R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ is independently H, deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ - C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , - S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , - P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ ; or R ⁶ and R ⁷ , R ⁷ and R ⁸ or R ¹⁰ and R ¹¹ form C ₄ together with the carbon to which they are attached -C ₆ cycloalkyl, 4 to 7 membered heterocycloalkyl, 5 to 10 membered heteroaryl or C ₆ -C ₁₀ aryl, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl or Each hydrogen atom in the 4 to 7-membered heterocycloalkyl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , - SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , - NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O) R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P (O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution;

Each R ^a , R ^b , R ^c , R ^d , ^Re and R ^f are independently selected from the group consisting of H, deuterium, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ - C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkylene-C ₆ -C ₁₀ aryl and 5 to 10 membered heteroaryl, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C Each hydrogen atom in ₆ -C ₁₀ aryl, C ₁ -C ₆ alkylene-C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently optionally replaced by deuterium, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ haloalkyl, -OH, -OC ₁ -C ₆ alkyl, -OC(O)-(H or C ₁ -C ₆ alkyl), -OC(O)N(H or C ₁ -C ₆ alkyl) ₂ , -OC(O)N(C ₂ -C ₆ alkylene), -OS(O)-(H or C ₁ -C ₆ alkyl), -OS(O ) ₂ -(H or C ₁ -C ₆ alkyl), -OS(O)N(H or C ₁ -C ₆ alkyl) ₂ , -OS(O)N(C ₂ -C ₆ alkylene) , -OS(O) ₂ N(H or C ₁ -C ₆ alkyl) ₂ , -OS(O) ₂ N(C ₂ -C ₆ alkylene), -S(H or C ₁ -C ₆ alkyl group), -S(O) (H or C ₁ -C ₆ alkyl), -S(O) ₂ (H or C ₁ -C ₆ alkyl), -S(O)N(H or C ₁ - C ₆ alkyl) ₂ , -S(O)N(C ₂ -C ₆ alkylene), -S(O) ₂ N(H or C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ N(C ₂ -C ₆ alkylene), -N(H or C ₁ -C ₆ alkylene) ₂ , -N(C ₂ -C ₆ alkylene), -N(H or C ₁ -C ₆ Alkyl)C(O)-(H or C ₁ -C ₆ alkyl), -N(H or C ₁ -C ₆ alkyl)C(O)O(H or C ₁ -C ₆ alkyl), -N(H or C ₁ -C ₆ alkyl)C(O)N(H or C ₁ -C ₆ alkyl) ₂ , -N(H or C ₁ -C ₆ alkyl)C(O)N( C ₂ -C ₆ alkylene), -N(H or C ₁ -C ₆ alkyl)S(O)-(H or C ₁ -C ₆ alkyl), -N(H or C ₁ -C ₆ Alkyl)S(O) ₂ (H or C ₁ -C ₆ alkyl), -N(H or C ₁ -C ₆ alkyl)S(O)N(H or C ₁ -C ₆ alkyl) ₂ , -N(H or C ₁ -C ₆ alkyl)S(O)N(C ₂ -C ₆ alkylene), -N(H or C ₁ -C ₆ alkyl)S(O) ₂ N(H or C ₁ -C ₆ alkyl) ₂ , -N(H or C ₁ -C ₆ alkyl)S(O) ₂ N(C ₂ -C ₆ alkylene), -C(O)-(H or C ₁ -C ₆ alkyl), -C(O)O(H or C ₁ -C ₆ alkyl), -C (O)N(C ₂ -C ₆ alkylene), -P(H or C ₁ -C ₆ alkylene) ₂ , -P(C ₂ -C ₆ alkylene), -P(O)(H or C ₁ -C ₆ alkyl) ₂ , -P(O)(C ₂ -C ₆ alkylene), -P(O) ₂ (H or C ₁ -C ₆ alkyl) ₂ , -P(O ) ₂ (C ₂ -C ₆ alkylene), -P(O)N(H or C ₁ -C ₆ alkylene) ₂ , -P(O)N(C ₂ -C ₆ alkylene), - P(O) ₂ N(H or C ₁ -C ₆ alkyl) ₂ , -P(O) ₂ N(C ₂ -C ₆ alkylene), -P(O)O(H or C ₁ -C ₆ alkyl), -P(O) ₂ O (H or C ₁ -C ₆ alkyl), -CN or -NO ₂ substitution;

m is 0, 1 or 2; and

n is 3, 4, 5, 6, 7, 8 or 9.

In another aspect, the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof,

in

X is -X ¹ - or -X ¹ -(ring A)-;

X ¹ is -O-, -S-, -NR ¹ -;

each Y is independently ring B or -C(O)NR ² -;

Ring A is C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl, and wherein each hydrogen atom in C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently optionally Deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C (O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to Each hydrogen atom in the 10-membered heteroaryl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC (O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O )R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , - C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution;

Each ring B is a C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl, wherein each hydrogen atom in the C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently selected by Deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C (O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to Each hydrogen atom in the 10-membered heteroaryl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC (O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O )R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , - C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution;

Each L is independently -C(R ³ )(R ⁴ )-, -C(O)-, -O-, -N(R ⁵ )-, -S-, -S(O)- or -S( O) ₂ -, with the proviso that (L) _n does not contain -OO-, -OS-, -SS- or -ON(R ⁵ )- bonds;

Z ¹ is N or C (R ⁶ );

Z ² is N or C (R ⁷ );

Z ³ is N or C (R ⁸ );

Z ⁴ is N or C (R ⁹ );

Z ⁵ is N or C (R ¹⁰ );

Z ⁶ is N or C (R ¹¹ );

The restriction is that at least one of Z ¹ to Z ⁶ is N;

Each of R ¹ , R ² and R ⁵ is independently H, deuterium, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ ring Alkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ Each hydrogen atom in alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently optionally replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS( O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S (O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C( O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e' , -CN or -NO ₂ replaced;

Each R ³ and R ⁴ is independently H, deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, -OR ^c , -OC(O)R ^c , -OC(O)NR ^c R ^d , -OC(=N )NR ^c R ^d , -OS(O)R ^c , -OS(O) ₂ R ^c , -OS(O)NR ^c R ^d , -OS(O) ₂ NR ^c R ^d , -SR ^c , -S (O)R ^c , -S(O) ₂ R ^c , -S(O)NR ^c R ^d , -S(O) ₂ NR ^c R ^d , -NR ^c R ^d , -NR ^c C(O)R ^d , -N(C(O)R ^c )(C(O)R ^d ), -NR ^c C(O)OR ^d , -NR ^c C(O)NR ^c R ^d , -NR ^c C(=N )NR ^c R ^d , -NR ^c S(O)R ^d , -NR ^c S(O) ₂ R ^d , -NR ^c S(O)NR ^c R ^d , -NR ^c S(O) ₂ NR ^c R ^d , -C(O)R ^c , -C(O)OR ^c , -C(O)NR ^c R ^d , -C(=N)NR ^c R ^d , -PR ^c R ^d , -P(O) R ^c R ^d , -P(O) ₂ R ^c R ^d , -P(O)NR ^c R ^d , -P(O) ₂ NR ^c R ^d , -P(O)OR ^c , -P(O) ₂ OR ^c , -CN, -NO ₂ , or both R ³ and R ⁴ form a C ₃ -C ₆ cycloalkyl or 4 to 6 membered heterocycloalkyl together with one or more carbons to which they are attached, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 Each hydrogen atom in the 10- to 10-membered heteroaryl group or the 4- to 6-membered heterocycloalkyl group is independently optionally replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C (O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution;

Each of R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ is independently H, deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ - C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , - S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , - P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ ; or R ⁶ and R ⁷ , R ⁷ and R ⁸ or R ¹⁰ and R ¹¹ form C ₄ together with the carbon to which they are attached -C ₆ cycloalkyl, 4 to 7 membered heterocycloalkyl, 5 to 10 membered heteroaryl or C ₆ -C ₁₀ aryl, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl or Each hydrogen atom in the 4 to 7-membered heterocycloalkyl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , - SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , - NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O) R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P (O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution;

Each R ^a , R ^b , R ^c , R ^d , ^Re and R ^f are independently selected from the group consisting of H, deuterium, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ - C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkyl-C ₆ -C ₁₀ aryl and 5 to 10 member heteroaryl;

m is 1 or 2; and

n is 3, 4, 5, 6, 7 or 8.

In some embodiments of the above aspects, the present invention provides a compound of formula II or a pharmaceutically acceptable salt thereof,

wherein R ² , A, L, X ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments of the above aspects, the present invention provides a compound of formula III or a pharmaceutically acceptable salt thereof,

wherein A, B, L, X ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

其中R ²、A、B、L、X ¹、Z ¹、Z ²、Z ³、Z ⁴、Z ⁵、Z ⁶及n如本文所描述。 In some embodiments of the above aspects, the present invention provides a compound of formula IV or a pharmaceutically acceptable salt thereof,

wherein R ² , A, B, L, X ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments of the above aspects, the present invention provides a compound of formula V or a pharmaceutically acceptable salt thereof,

wherein R ² , L, X ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments of the above aspects, the present invention provides a compound of formula VI or a pharmaceutically acceptable salt thereof,

wherein B, L, X ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

其中R ²、A、L、X ¹、Z ¹、Z ²、Z ³、Z ⁴、Z ⁵、Z ⁶及n如本文所描述。 In some embodiments of the above aspects, the present invention provides a compound of formula VII or a pharmaceutically acceptable salt thereof,

wherein R ² , A, L, X ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments of the above aspects, the present invention provides a compound of formula VIII or a pharmaceutically acceptable salt thereof,

wherein R ¹ , R ² , L, Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments of the above aspects, the present invention provides a compound of formula IX or a pharmaceutically acceptable salt thereof,

wherein R ¹ , B, L, Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

其中R ¹、R ²、B、L、Z ¹、Z ²、Z ³、Z ⁴、Z ⁵、Z ⁶及n如本文所描述。 In some embodiments of the above aspects, the present invention provides a compound of formula X or a pharmaceutically acceptable salt thereof,

wherein R ¹ , R ² , B, L, Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments of the above aspects, the present invention provides a compound of formula XI or a pharmaceutically acceptable salt thereof,

wherein R ² , L, X, Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments of the above aspects, the present invention provides a compound of formula XII or a pharmaceutically acceptable salt thereof,

wherein B, L, X, Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments of the above aspects, the present invention provides a compound of formula XIII or a pharmaceutically acceptable salt thereof,

wherein R ² , B, L, X, Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments of the above aspects, the present invention provides a compound of formula XIV or a pharmaceutically acceptable salt thereof,

wherein L, X, Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In certain embodiments of the above aspects and embodiments, the compounds of formulas (I) to (XIV) are compounds selected from those described or exemplified in the embodiments below.

In other aspects, the present invention is directed to a pharmaceutical composition comprising at least one compound of formulas (I) to (XIV) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to the present invention may further comprise pharmaceutically acceptable excipients.

In other aspects, the invention relates to compounds of formulas (I) to (XIV) or pharmaceutically acceptable salts thereof for use as a medicament.

In other aspects, the invention is directed to a method of treating a disease, such as cancer, comprising administering to an individual in need of such treatment an effective amount of at least one compound of formulas (I) to (XIV) or a pharmaceutically acceptable The salt of acceptance.

In other aspects, the present invention relates to the use of compounds of formulas (I) to (XIV) or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of diseases such as cancer, and the use of such compounds and salts for the treatment of such diseases.

In other aspects, the invention relates to a method of inhibiting tyrosine kinases, such as EGFR, comprising administering to a cell comprising one or more kinases an effective amount of at least one compound of formulas (I) to (XIV) or a medicament thereof The pharmaceutically acceptable salt is contacted and/or contacted with at least one pharmaceutical composition of the present invention, wherein the contacting is in vitro, ex vivo or in vivo.

Additional embodiments, features, and advantages of the invention will become apparent from the following description and through practice of the invention. Compounds of the present invention may be described as embodiments in any one of the terms listed below. It should be understood that any of the embodiments described herein may be used in combination with any other embodiment described herein to the extent the embodiments do not conflict with each other.

1. A compound of formula I or a pharmaceutically acceptable salt thereof,

in

X is -X ¹ - or -X ¹ -(ring A)-;

X ¹ is -O-, -S-, -NR ¹ -;

each Y is independently ring B or -C(O)NR ² -;

Ring A is C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl, and wherein each hydrogen atom in C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently optionally Deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C (O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to Each hydrogen atom in the 10-membered heteroaryl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC (O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O )R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , - C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution;

Each ring B is a C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl, wherein each hydrogen atom in the C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently selected by Deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C (O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to Each hydrogen atom in the 10-membered heteroaryl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC (O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O )R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , - C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution;

Each L is independently -C(R ³ )(R ⁴ )-, -C(O)-, -O-, -N(R ⁵ )-, -S-, -S(O)- or -S( O) ₂ -, with the proviso that (L) _n does not contain -OO-, -OS-, -SS- or -ON(R ⁵ )- bonds;

Z ¹ is N or C (R ⁶ );

Z ² is N or C (R ⁷ );

Z ³ is N or C (R ⁸ );

Z ⁴ is N or C (R ⁹ );

Z ⁵ is N or C (R ¹⁰ );

Z ⁶ is N or C (R ¹¹ );

The restriction is that at least one of Z ¹ to Z ⁶ is N;

Each of R ¹ , R ² and R ⁵ is independently H, deuterium, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ ring Alkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ Each hydrogen atom in alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently optionally replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS( O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S (O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C( O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e' , -CN or -NO ₂ replaced;

Each R ³ and R ⁴ is independently H, deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, -OR ^c , -OC(O)R ^c , -OC(O)NR ^c R ^d , -OC(=N )NR ^c R ^d , -OS(O)R ^c , -OS(O) ₂ R ^c , -OS(O)NR ^c R ^d , -OS(O) ₂ NR ^c R ^d , -SR ^c , -S (O)R ^c , -S(O) ₂ R ^c , -S(O)NR ^c R ^d , -S(O) ₂ NR ^c R ^d , -NR ^c R ^d , -NR ^c C(O)R ^d , -N(C(O)R ^c )(C(O)R ^d ), -NR ^c C(O)OR ^d , -NR ^c C(O)NR ^c R ^d , -NR ^c C(=N )NR ^c R ^d , -NR ^c S(O)R ^d , -NR ^c S(O) ₂ R ^d , -NR ^c S(O)NR ^c R ^d , -NR ^c S(O) ₂ NR ^c R ^d , -C(O)R ^c , -C(O)OR ^c , -C(O)NR ^c R ^d , -C(=N)NR ^c R ^d , -PR ^c R ^d , -P(O) R ^c R ^d , -P(O) ₂ R ^c R ^d , -P(O)NR ^c R ^d , -P(O) ₂ NR ^c R ^d , -P(O)OR ^c , -P(O) ₂ OR ^c , -CN, -NO ₂ , or both R ³ and R ⁴ form a C ₃ -C ₆ cycloalkyl or 4 to 6 membered heterocycloalkyl together with one or more carbons to which they are attached, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 Each hydrogen atom in the 10- to 10-membered heteroaryl group or the 4- to 6-membered heterocycloalkyl group is independently optionally replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C (O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution;

Each of R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ is independently H, deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ - C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , - S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , - P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ ; or R ⁶ and R ⁷ , R ⁷ and R ⁸ or R ¹⁰ and R ¹¹ form C ₄ together with the carbon to which they are attached -C ₆ cycloalkyl, 4 to 7 membered heterocycloalkyl, 5 to 10 membered heteroaryl or C ₆ -C ₁₀ aryl, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl or Each hydrogen atom in the 4 to 7-membered heterocycloalkyl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , - SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , - NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O) R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P (O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution;

Each R ^a , R ^b , R ^c , R ^d , ^Re and R ^f are independently selected from the group consisting of H, deuterium, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ - C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkyl-C ₆ -C ₁₀ aryl and 5 to 10 membered heteroaryl, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ Each hydrogen atom in -C ₁₀ aryl, C ₁ -C ₆ alkylene -C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently optionally replaced by deuterium, halogen, C ₁ -C ₆ alkane group, C ₁ -C ₆ haloalkyl, -OH, -OC ₁ -C ₆ alkyl, -OC(O)-(H or C ₁ -C ₆ alkyl), -OC(O)N(H or C ₁ -C ₆ alkyl) ₂ , -OC(O)N(C ₂ -C ₆ alkylene), -OS(O)-(H or C ₁ -C ₆ alkyl), -OS(O) ₂ -(H or C ₁ -C ₆ alkyl), -OS(O)N(H or C ₁ -C ₆ alkyl) ₂ , -OS(O)N(C ₂ -C ₆ alkylene), -OS(O) ₂ N(H or C ₁ -C ₆ alkyl) ₂ , -OS(O) ₂ N(C ₂ -C ₆ alkylene), -S(H or C ₁ -C ₆ alkyl ), -S(O) (H or C ₁ -C ₆ alkyl), -S(O) ₂ (H or C ₁ -C ₆ alkyl), -S(O)N (H or C ₁ -C ₆ alkyl) ₂ , -S(O)N(C ₂ -C ₆ alkylene), -S(O) ₂ N(H or C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ N (C ₂ -C ₆ alkylene), -N(H or C ₁ -C ₆ alkylene) ₂ , -N(C ₂ -C ₆ alkylene), -N(H or C ₁ -C ₆ alkylene group)C(O)-(H or C ₁ -C ₆ alkyl), -N(H or C ₁ -C ₆ alkyl)C(O)O(H or C ₁ -C ₆ alkyl), - N(H or C ₁ -C ₆ alkyl)C(O)N(H or C ₁ -C ₆ alkyl) ₂ , -N(H or C ₁ -C ₆ alkyl)C(O)N(C ₂ -C ₆ alkylene), -N(H or C ₁ -C ₆ alkyl)S(O)-(H or C ₁ -C ₆ alkyl), -N(H or C ₁ -C ₆ alkane radical)S(O) ₂ (H or C ₁ -C ₆ alkyl), -N(H or C ₁ -C ₆ alkyl)S(O)N(H or C ₁ -C ₆ alkyl) ₂ , -N(H or C ₁ -C ₆ alkyl)S(O)N(C ₂ -C ₆ alkylene), - N(H or C ₁ -C ₆ alkyl)S(O) ₂ N(H or C ₁ -C ₆ alkyl) ₂ , -N(H or C ₁ -C ₆ alkyl)S(O) ₂ N (C ₂ -C ₆ alkylene), -C(O)-(H or C ₁ -C ₆ alkyl), -C(O)O(H or C ₁ -C ₆ alkyl), -C( O)N(C ₂ -C ₆ alkylene), -P(H or C ₁ -C ₆ alkylene) ₂ , -P(C ₂ -C ₆ alkylene), -P(O)(H or C ₁ -C ₆ alkyl) ₂ , -P(O)(C ₂ -C ₆ alkylene), -P(O) ₂ (H or C ₁ -C ₆ alkyl) ₂ , -P(O) ₂ (C ₂ -C ₆ alkylene), -P(O)N(H or C ₁ -C ₆ alkylene) ₂ , -P(O)N(C ₂ -C ₆ alkylene), -P (O) ₂ N(H or C ₁ -C ₆ alkyl) ₂ , -P(O) ₂ N(C ₂ -C ₆ alkylene), -P(O)O(H or C ₁ -C ₆ Alkyl), -P(O) ₂ O(H or C ₁ -C ₆ alkyl), -CN or -NO ₂ substitution;

m is 0, 1 or 2; and

n is 3, 4, 5, 6, 7, 8 or 9.

2. A compound as in item 1, which has formula II

or a pharmaceutically acceptable salt thereof.

3. A compound as in item 1, which has formula III

or a pharmaceutically acceptable salt thereof.

4. A compound as in item 1, which has formula IV

or a pharmaceutically acceptable salt thereof.

5. A compound as in item 1, which has formula V

or a pharmaceutically acceptable salt thereof.

6. A compound as in item 1, which has formula VI

or a pharmaceutically acceptable salt thereof.

7. A compound as in item 1, which has formula VII

or a pharmaceutically acceptable salt thereof.

8. A compound as in item 1, which has formula VIII

or a pharmaceutically acceptable salt thereof.

9. A compound as in item 1, which has formula IX

or a pharmaceutically acceptable salt thereof.

10. The compound according to item 1, which has the formula X

or a pharmaceutically acceptable salt thereof.

11. A compound as in item 1, which has formula XI

or a pharmaceutically acceptable salt thereof.

12. A compound as in item 1, which has formula XII

or a pharmaceutically acceptable salt thereof.

13. The compound according to item 1, which has the formula XIII

or a pharmaceutically acceptable salt thereof.

14. The compound according to item 1, which has the formula XIV

or a pharmaceutically acceptable salt thereof.

15. The compound according to any one of items 1 to 14, or a pharmaceutically acceptable salt thereof, wherein ring A (if present) is phenylene, furyl, thienyl, pyrrolyl, oxene Azolyl, extended isoxazolyl, extended thiazolyl, extended isothiazolyl, extended pyrazolyl, extended imidazolyl, extended diazolyl, extended thiadiazolyl, extended triazolyl, extended pyridyl, extended pyridyl phenylene, furyl, thienyl, pyrrolyl, azolyl, isoxazolyl, thiazolyl, isothiazole Among the group, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrimidinyl, diazolyl or triazolyl Each hydrogen atom is independently optionally deuterium, fluorine, chlorine, bromine, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O )R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substitution; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkane Each hydrogen atom in radical, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently optionally deuterium, fluorine, chlorine, bromine, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkane base, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , - S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C( O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O) R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution.

16. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein ring A (if present) is phenylene or pyridyl, wherein each hydrogen in phenylene or pyridyl is Atoms are independently optionally substituted with deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl.

， 17. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein ring A (if present) is a phenylene or pyridylene group having the formula

,

wherein each hydrogen atom is independently optionally substituted by deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl.

。 18. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein Ring A (if present) is

.

19. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein X ¹ is -NR ¹ -.

20. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein R ¹ (if present) is hydrogen, C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, or 5 to 10-membered heteroaryl, wherein each hydrogen atom in C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl or 5 to 10-membered heteroaryl is independently optionally replaced by deuterium, halogen, C ₁ -C ₆ alkane group, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C( O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e' , -CN or -NO ₂ substitution.

21. The compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R ¹ , if present, is hydrogen.

22. The compound according to any one of clauses 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R ¹ (if present) is phenyl or pyridyl, wherein each hydrogen atom in phenyl or pyridyl is independently Optionally via deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS( O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S( O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O) OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e' , -CN or -NO ₂ substituted.

23. The compound according to any one of clauses 1 to 20 or 22, or a pharmaceutically acceptable salt thereof, wherein R ¹ (if present) is phenyl or pyridyl, wherein each hydrogen in phenyl or pyridyl is Atoms are independently optionally substituted with deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl.

。 24. The compound according to any one of clauses 1 to 20, 22 or 23, or a pharmaceutically acceptable salt thereof, wherein R ¹ (if present) has the formula

.

25. The compound according to any one of clauses 1 to 18, or a pharmaceutically acceptable salt thereof, wherein X ¹ is -O-.

26. The compound according to any one of clauses 1 to 18, or a pharmaceutically acceptable salt thereof, wherein X ¹ is -S-.

27. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein Ring B (if present) is a 5 to 10 membered heteroaryl, wherein one of the 5 to 10 membered heteroaryls is Each hydrogen atom is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered hetero Cycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P (O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substitution; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ Each hydrogen atom in -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC (O)R ^e , -OC(O)NR ^e R ^f , -OS(O)Re , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O _{) 2} ^{NR e} R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ N R ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P( O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or - NO ₂ replaced.

28. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein ring B (if present) is phenylene, furyl, thienyl, pyrrolyl, oxazolyl , Extended isoxazolyl, extended thiazolyl, extended isothiazolyl, extended pyrazolyl, extended imidazolyl, extended diazolyl, extended thiadiazolyl, extended triazolyl, extended pyridyl, extended pyridyl, pyrimidinyl, pyrimidinyl or trisulphinyl, of which phenylene, furyl, thienyl, pyrrolyl, azolyl, isoxazolyl, thiazolyl, isothiazolyl, Each hydrogen in pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrimidinyl, diazolyl or triazolyl The atoms are independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR e R f , -OC(O)NR ^e R ^f , - OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , - S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C( O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O) R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution.

。 29. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein Ring B (if present) is

.

30. The compound according to any one of the preceding clauses, wherein Z ¹ is N, or a pharmaceutically acceptable salt thereof.

31. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein Z ² is C(R ⁷ ), Z ³ is C(R ⁸ ), Z ⁴ is N, and Z ⁵ is C (R ¹⁰ ), and Z ⁶ is C(R ¹¹ ).

32. The compound according to any one of items 1 to 30, or a pharmaceutically acceptable salt thereof, wherein Z ² is C(R ⁷ ), Z ³ is C(R ⁸ ), Z ⁴ is C(R ⁹ ), Z ⁵ is C(R ¹⁰ ), and Z ⁶ is C(R ¹¹ ).

33. The compound according to any one of items 1 to 30, or a pharmaceutically acceptable salt thereof, wherein Z ² is C(R ⁷ ), Z ³ is N, Z ⁴ is N, Z ⁵ is C(R ¹⁰ ), and Z ⁶ is C(R ¹¹ ).

34. The compound according to any one of items 1 to 30, or a pharmaceutically acceptable salt thereof, wherein Z ² is C(R ⁷ ), Z ³ is N, Z ⁴ is C(R ⁹ ), Z ⁵ is C(R ¹⁰ ), and Z ⁶ is C(R ¹¹ ).

35. The compound according to any one of the preceding clauses, wherein R ⁶ (if present) is H, or a pharmaceutically acceptable salt thereof.

36. The compound according to any one of the preceding clauses, wherein R ⁷ (if present) is H, or a pharmaceutically acceptable salt thereof.

37. The compound according to any one of the preceding clauses, wherein R ⁸ (if present) is H, or a pharmaceutically acceptable salt thereof.

38. The compound according to any one of the preceding clauses, wherein R ⁹ (if present) is H, or a pharmaceutically acceptable salt thereof.

39. The compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ (if present) is H or —OCH ₃ .

40. The compound according to any one of the preceding clauses, wherein R ¹¹ (if present) is H, or a pharmaceutically acceptable salt thereof.

41. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein each L is independently selected from -C(R ³ )(R ⁴ )-, -C(O)-, -O Groups consisting of - or -N(R ⁵ )-, with the proviso that (L) _n does not contain an -OO- or -ON(R ⁵ )- bond.

42. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein -(L) _n - is (CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₄ -, (CR ³ R ⁴ ) ₅ -, (CR ³ R ⁴ ) ₆ , (CR ³ R ⁴ ) ₇ -, (CR ³ R ⁴ ) ₈ -, C(O)N(R ⁵ )-(CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ -C(O)N(R ⁵ )-(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ C(O)N(R ⁵ )-( CR ³ R ⁴ ) ₃ O-, N(R ⁵ )C(O)CR ³ R ⁴ O(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ N(R ⁵ )C(O)(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ N(R ⁵ )C(O)(CR ³ R ⁴ ) ₃ O-, CR ³ R ⁴ O(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ O(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₂ O-CR ³ R ⁴ -, (CR ³ R ⁴ ) ₃ O-CR ³ R ⁴ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₃ O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₅ O(CR ³ R ⁴ ) ₃ -, OCR ³ R ⁴ -O(CR ³ R ⁴ ) ₃ -, CR ³ R ⁴ -O(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ -O( CR ³ R ⁴ ) ₃ O-, O(CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₃ O-, O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ O-, -O-(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₃ O-, O(CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ -N(R ⁵ )(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ N (R ⁵ )(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₃ O(CR ³ R ⁴ )C(O)N(R ⁵ )(CR ³ R ⁴ )-, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ )C(O)N (R ⁵ )-(CR ³ R ⁴ )-, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ C(O)N(R ⁵ )-(CR ³ R ⁴ )-, (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₃ -, O(CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ N(R ⁵ )(CR ³ R ⁴ ) ₂ O-, (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₂ O- or (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₃ O -.

43. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein each R ³ and R ⁴ are independently selected from the group consisting of H, deuterium, C ₁ -C ₆ alkyl, -NR ^c C(O)R ^d and -CN, wherein each hydrogen atom in C ₁ -C ₆ alkyl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkane base, OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)Re , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S ⁽ O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O) OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substituted.

44. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein -(L) _n - comprises (CH ₂ ) ₃ -, (CH ₂ ) ₄ -, (CH ₂ ) ₅ - , (CH ₂ ) ₆ -, (CH ₂ ) ₇ -, (CH ₂ ) ₈ -, C(O)NH(CH ₂ ) ₂ O(CH ₂ ) ₂ -, C(O)N(CH ₃ )- (CH ₂ ) ₂ O(CH ₂ ) ₂ -, NHC(O)CH ₂ O(CH ₂ ) ₂ -, N(CH ₃ )C(O)CH ₂ O(CH ₂ ) ₂ -, CH ₂ O( CH ₂ ) ₂ -, CH ₂ O(CH ₂ ) ₃ -, CH ₂ O(CH ₂ ) ₂ CH(CH ₃ )-, CH ₂ OCH ₂ CH(CH ₃ )-CH ₂ -, CH ₂ OCH(CH ₃ )-(CH ₂ ) ₂ -, CH(CN)O(CH ₂ ) ₃ -, CH(CH ₃ )O(CH ₂ ) ₃ -, CH ₂ O(CH ₂ ) ₂ -O-, (CH ₂ ) ₂ O(CH ₂ ) ₂ -, CH ₂ -C(CH ₃ ) ₂ -O(CH ₂ ) ₂ -, CH ₂ C(CH ₃ ) ₂ -O(CH ₂ ) ₃ -, (CH ₂ ) ₂ OCH ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₂ -, (CH ₂ ) ₃ O(CH ₂ ) ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₃ -, (CH ₂ ) ₂ OCH( CH ₃ )-(CH ₂ ) ₂ -, (CH ₂ ) ₂ OC(CH ₃ ) ₂ -(CH ₂ ) ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₂ -CH(CH ₃ )-, ( CH ₂ ) ₂ O(CH ₂ ) ₂ -C(CH ₃ ) ₂ -CH ₂ CH(CH ₃ )-O-(CH ₂ ) ₃ -, CH ₂ CH(CH ₃ )O(CH ₂ ) ₂ -, CH(CH ₃ )CH ₂ O(CH ₂ ) ₂ -, O(CH ₂ ) ₂ -, -O-(CH ₂ ) ₃ -, OCH ₂ CH(OH)CH ₂ -, O(CH ₂ ) ₂ O (CH ₂ ) ₂ -, OCH ₂ CH(CH ₃ )-O(CH ₂ ) ₂ -, OCH(CH ₃ )CH ₂ O(CH ₂ ) ₂ -, (CH ₂ ) ₂ OCH ₂ CH(NHC(O )CH=CH ₂ )CH ₂ O-, (CH ₂ ) ₂ OCH ₂ CH(N(CH ₃ )-C (O)-CH=CH ₂ )CH ₂ O-, (CH ₂ ) ₂ OCH ₂ CH(NH-C(O)-CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ OCH ₂ CH(N (CH ₃ )-C(O)-CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ NH-CH ₂ CH(NH-C(O)-CH=CH ₂ )CH ₂ O-, (CH ₂ ) ₂ NHCH ₂ CH(N(CH ₃ )C(O)CH=CH ₂ )CH ₂ O-, (CH ₂ ) ₂ NHCH ₂ CH(NHC(O)CH ₂ CH ₂ )CH ₂ O-, ( CH ₂ ) ₂ N(CH ₃ )CH ₂ CH(N(CH ₃ )C(O)CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ N(CH ₃ )CH ₂ CH(N(CH ₃ )C(O)CH=CH ₂ )CH ₂ O-, (CH ₂ ) ₂ N(CH ₃ )CH ₂ CH(NHC(O)CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ N( CH ₃ )CH ₂ CH(N(CH ₃ )C(O)CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₃ O(CH ₂ )C(O)N(CH ₃ )CH ₂ -, ( CH ₂ ) ₃ O(CH ₂ )C(O)N(H)CH ₂ -, (CH ₂ ) ₂ O(CH ₂ )C(O)N(CH ₃ )CH ₂ -, (CH ₂ ) ₂ O (CH ₂ )C(O)N(H)CH ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₂ C(O)N(CH ₃ )CH ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₂ C(O)N(H)CH ₂ -, O(CH ₂ ) ₂ NH(CH ₂ ) ₂ -, OCH ₂ CH(CH ₃ )-NH-(CH ₂ ) ₂ -, OCH(CH ₃ )CH ₂ NH-(CH ₂ ) ₂ -, CH ₂ NH(CH ₂ ) ₂ -, (CH ₂ ) ₂ NH(CH ₂ ) ₂ -, (CH ₂ ) ₂ NH(CH ₂ ) ₃ -, (CH ₂ ) ₂ N(CH ₃ )(CH ₂ ) ₂ -, (CH ₂ ) ₂ N(CH ₃ )(CH ₂ ) ₃ -, CH ₂ CH(CH ₃ )NH(CH ₂ ) ₂ -, CH(CH ₃ ) CH ₂ NH-(CH ₂ ) ₂ -, O(CH ₂ ) ₂ N(CH ₃ )(CH ₂ ) ₂ -, OCH ₂ CH(CH ₃ )-N(CH ₃ )-(CH ₂ ) ₂ -, OCH(CH ₃ )CH ₂ N(CH ₃ )(CH ₂ ) ₂ -, CH ₂ N(CH ₃ )(CH ₂ ) ₂ -, (CH ₂ ) ₂ N(CH ₃ )(CH ₂ ) ₂ -, CH ₂ C(O)N(H)(CH ₂ ) ₃ O-, CH ₂ C(O)N(CH ₃ )( CH ₂ ) ₃ O—, CH ₂ CH(CH ₃ )—N(CH ₃ )—(CH ₂ ) ₂ — or OCH(CH ₃ )CH ₂ N(CH ₃ )—(CH ₂ ) ₂ —.

45. The compound of item 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 1-(3-chloro-4-fluorophenyl)-17-methoxy-2,3 ,5,6,7,8-hexahydro-10,12-vinylidene pyrido[4,3- e ][1,4,7,10]oxatriazacyclotridecene-9( 1 H )-ketone;

1-(3-Chloro-2-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-vinylidenepyrido[4,3- e ][1,4 ,7,10] oxatriazacyclotridecen-9( 1H )-one;

(3 R )-1-(3-chloro-4-fluorophenyl)-3-methyl-2,3,5,6,7,8-hexahydro-10,12-vinylidene pyrido[ 4,3- e ][1,4,7,10]oxatriazacyclotridecen-9(1 H )-one;

(3S)-1-(3-Chloro-4-fluorophenyl)-3-methyl-2,3,5,6,7,8-hexahydro-10,12-vinylidene pyrido[4 ,3- e ][1,4,7,10]oxatriazacyclotridecen-9(1 H )-one;

1-(3-Chloro-4-fluorophenyl)-3,3-dimethyl-2,3,5,6,7,8-hexahydro-10,12-vinylidenepyrido[4, 3- e ][1,4,7,10]oxatriazacyclotridecen-9(1 H )-one;

(5 S )-1-(3-Chloro-4-fluorophenyl)-5-methyl-2,3,5,6,7,8-hexahydro-10,12-vinylidene pyrido[ 4,3- e ][1,4,7,10]oxatriazacyclotridecen-9(1 H )-one;

(7 R )-1-(3-chloro-4-fluorophenyl)-7-methyl-2,3,5,6,7,8-hexahydro-10,12-vinylidene pyrido[ 4,3- e ][1,4,7,10]oxatriazacyclotridecen-9(1 H )-one;

12-(3-Chloro-4-fluorophenyl)-1-methyl-4,13,14,16-tetrahydro-1 H -6,8-vinylidenepyrazolo[4,3- k ]pyrido[4,3- e ][1,4,7,10] oxatriazacyclotridecen -5(12H)-one;

14-(3-Chloro-4-fluorophenyl)-5-methyl-5,9,10,12,13,14-hexahydro-2,18-vinylidene-3,6-( Methenyl)pyrido[3,4- l ][1,4,7,8,11,14]oxapentaazacyclohexadecen-7( 8H )-one; and

1-(3-Chloro-4-fluorophenyl)-10-methyl-1,2,3,6,7,10-hexahydro-12,9-(oxazoenyl)-13,15-bridge Vinylidenepyrido[3,4- l ][1,4,7,14]oxatriazacyclohexadecen-8( 5H )-one.

46. The compound of item 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 7-chloro-6-fluoro-15-methyl-5,12,13,15-tetrahydro -10 H -1,18-vinylidenepyrazolo[4,3- f ]pyrido[4,3- b ][8,11,1,4]benzodioxadiazecyclodeca tetraene;

7-Chloro-6-fluoro-15-methyl-5,12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- f ]pyrido[4, 3- b ][8,11,1]benzodioxazacyclotetradecene;

7-Chloro-15-methyl-5,12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- f ]pyrido[4,3- b ] [8,11,1]benzodioxazacyclotetradecene;

15-methyl-5,12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- f ]pyrimido[4,5- b ][8,11 ,1,4]benzodioxadiazacyclotetradecene;

7-Chloro-15-methyl-5,12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- f ]pyrimido[4,5- b ] [8,11,1]benzodioxazacyclotetradecene;

7,15-Dimethyl-5,12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- m ]pyrido[3,4- f ]pyrimidine And[4,5- i ][1,4,8]dioxazacyclotetradecene;

7-Chloro-6-fluoro-5,10,12,13-tetrahydro-1,19-vinylidenedipyrido[4,3- b :2',3'- f ][8,11, 1] Benzodioxazacyclotetradecene;

7-Chloro-6,17-difluoro-5,10,12,13-tetrahydro-1,19-vinylidene dibenzo[ e , l ]pyrido[3,4- i ][1, 4,8,11] dioxadiazacyclotetradecene;

7-Chloro-6-fluoro-14-methyl-5,13,14,17-tetrahydro-10 H -19,16-(azazoenyl)-1,20-vinylidenepyrido[4 ,3- b ][14,1,8,11]benzotriazacycloheptadecen-15(12 H )-one;

7-Chloro-6-fluoro-14,17-dimethyl-5,13,14,17-tetrahydro-10 H -19,16-(azazenyl)-1,20-vinylidenepyridine And[4,3- b ][14,1,8,11]benzotriazacycloheptadecen-15(12 H )-one;

7-Chloro-6-fluoro-14,17-dimethyl-5,13,14,17-tetrahydro-10 H -1,20-vinylidene-19,16-(methenylene) Pyrido[4,3- b ][14,1,4,7,8,11]benzozacyclohexadecen-15(12 H )-one;

7-Chloro-6-fluoro-14-methyl-13,14-dihydro-10 H ,17 H -19,16-(azazoenyl)-1,20-vinylidene pyrido[4, 3- b ][1,14,8,11]benzodioxadiazacyclohexadecen-15(12 H )-one;

[ _ _ 1,14,8,11] benzodioxadiazacyclohexadecen-15(12 H )-one;

[ _ _ 1,14,8,11] benzodioxadiazacyclohexadecen-15(12 H )-one;

7-Chloro-6-fluoro-14,17-dimethyl-13,14-dihydro-10 H ,17 H -19,16-(azazenyl)-1,20-vinylidene pyrido [4,3- b ][1,14,8,11]benzodioxadiazacyclohexadecen-15(12 H )-one;

16-Chloro-17-fluoro-8-methyl- 8,9,10,11,13,18 -hexahydro-7H-4,6-vinylidenepyrido[4,3- b ][11 ,1,4,7]benzotriazacyclotetradecen-7-one;

16-Chloro-17-fluoro-8,9,10,11,13,18-hexahydro-7H-4,6-vinylidenepyrido[4,3- b ][ 11,1,4 , 7] Benzotriazacyclotetradecen-7-one;

(13 R )-16-Chloro-17-fluoro-13-methyl-8,9,10,11,13,18-hexahydro-7 H -4,6-vinylidenepyrido[4,3 - b ][11,1,4,7]benzotriazacyclotetradecen-7-one;

(13 S )-16-Chloro-17-fluoro-7-oxo- 8,9,10,11,13,18 -hexahydro-7H-4,6-vinylidenepyrido[4, 3- b ][11,1,4,7]benzotriazacyclotetradecene-13-carbonitrile;

(9 R )-16-chloro-17-fluoro-9-methyl-8,9,10,11,13,18-hexahydro-7 H -4,6-vinylidenepyrido[4,3 - b ][11,1,4,7]benzotriazacyclotetradecen-7-one;

16-Chloro-17-fluoro-8-methyl-8,9,10,11-tetrahydro-7 H ,13 H -4,6-vinylidenepyrido[4,3- b ][1, 11,7] benzodioxazacyclotetradecen-7-one; and

16-Chloro-17-fluoro-8-methyl-8,9,10,11-tetrahydro-7 H ,13 H -4,6-vinylidenepyrido[4,3- b ][11, 1,7]Benzotriazacyclotetradecen-7-one.

47. The compound of item 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 1-(3-chloro-4-fluorophenyl)-2,3,5,6,7 ,8-hexahydro-10,12-vinylidene pyrido[4,3- e ][1,4,7,10]oxatriazacyclotridecen-9(1 H )-one;

1-(3-Chloro-4-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-vinylidenepyrido[4,3- e ][1,4 ,10] oxadiazacyclotridecen-9( 1H )-one;

15-(3-Chloro-4-fluorophenyl)-8,9,10,11,14,15-hexahydro-4,6-vinylidenepyrimido[4,5-e][1,4 ,10] Oxadiazacyclotridecen-7(13H)-one;

1-(3-Chloro-4-fluorophenyl)-11-methyl-1,2,3,5,6,7,8,11-octahydro-9H-14,16-vinylidene-13 , 10-(endomethylene)pyrido[4,3-e][1,4,10,11,14]oxa tetraazacycloheptadecen-9-one;

1-(3-Chloro-4-fluorophenyl)-8,11-dimethyl-1,2,3,5,6,7,8,11-octahydro-9H-14,16-vinylidene Base-13,10-(methenylene)pyrido[4,3-e][1,4,10,11,14]oxa tetraazacycloheptadecen-9-one;

1-(3-Chloro-4-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-vinylidene-13,10 -(methenylene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecen-9(2H)-one;

1-(3-Chloro-4-fluorophenyl)-7,10-dimethyl-1,2,3,6,7,10-hexahydro-13,15-vinylidene-12,9- (Methylene)pyrido[3,4-l][1,4,7,8,14]oxatetraazacyclohexadecen-8(5H)-one;

1-(3-Chloro-4-fluorophenyl)-8,11-dimethyl-1,3,4,8,9,11-hexahydro-2H-14,16-vinylidene-13, 10-(methenylene)pyrido[3,4-l][1,4,7,8,14]oxatetraazacyclohexadecen-7(6H)-one;

N-cyclopropyl-3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-vinylidene-13, 10-(methenylidene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecen-1(11H)-yl]benzamide;

3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-vinylidene-13,10-(methano Enyl)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecen-1(11H)-yl]-N-(prop-2-yl)benzyl Amide;

N-methyl-3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-vinylidene-13,10 -(methenylene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecen-1(11H)-yl]benzamide;

1-(3,4-Dichloro-2-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-vinylidene- 13,10-(methenylene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecen-9(2H)-one;

1-(3-Chloro-2-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-vinylidene-13,10 -(methenylene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecen-9(2H)-one;

2-[1-(3-Chloro-4-fluorophenyl)-11-methyl-9-oxo-1,2,3,4,5,6,7,11-octahydro-14,16 -Ethylene-13,10-(methenylene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecene-8(9H)- Base]-N-methylacetamide;

15-(3-Chloro-4-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene-3,6 -(methenylene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one;

N-[1-(3-Chloro-4-fluorophenyl)-2,3,6,7-tetrahydro-1H,5H-9,11-vinylidenepyrido[4,3-e][ 1,9,4]dioxazacyclododecen-6-yl]prop-2-enamide;

N-[1-(3-Chloro-4-fluorophenyl)-2,3,6,7-tetrahydro-1H,5H-9,11-vinylidenepyrido[4,3-e][ 1,9,4]dioxazacyclododecen-6-yl]acrylamide;

N-[1-(3-chloro-4-fluorophenyl)-4-methyl-2,3,4,5,6,7-hexahydro-1H-9,11-vinylidene pyrido[ 4,3-i][1,5,8]oxadiazacyclododecen-6-yl]prop-2-enamide;

15-(3-Chloro-4-fluorophenyl)-5,12-dimethyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene- 3,6-(methenylene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one;

15-(4-Chloro-3-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene-3,6 -(methenylene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one;

15-(3,4-Dichlorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene-3,6- (Ethomylenyl)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one;

15-(3-Chloro-4-fluorophenyl)-5,8-dimethyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene- 3,6-(methenylene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one;

10-(3-Chloro-4-fluorophenyl)-4,5,6,7,9,10-hexahydro-8H-2,14-vinylidenepyrido[3,4-d][1 ,3,6,9] oxatriazacyclododecen-8-one;

1-(3-Chloro-4-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-9,11-vinylidenepyrido[4,3-i][1 ,5,8] oxadiazacyclododecen-3-one;

15-(3,4-Dichloro-2-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene- 3,6-(methenylidene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one; and

7-Chloro-8-fluoro-17-methyl-5,13,14,17-tetrahydro-10H-1,20-vinylidene-19,16-(methenylidene)pyrido[4 ,3-b][14,1,4,7,8,11]Benzopentaazacyclohexadecen-15(12H)-one.

48. A pharmaceutical composition comprising at least one compound according to any one of items 1 to 47, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients .

49. A method of treating a disease such as cancer comprising administering to an individual in need of such treatment an effective amount of a compound according to any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof according to clause 48. The pharmaceutical composition.

50. The compound according to any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to clause 48, for use in a method of treating cancer in a subject.

51. A compound according to any one of items 1 to 47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 48, for use in the treatment of cancer in a subject.

52. Use of a compound according to any one of items 1 to 47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 48, for the manufacture of a medicament for treating cancer in an individual.

Cross References to Related Applications

Pursuant to 35 U.S.C. § 119(e), this application claims priority over U.S. Provisional Application No. 63/153,686, filed February 25, 2021, and U.S. Provisional Application No. 63/309,910, filed February 14, 2022 All disclosures of these two applications are hereby incorporated by reference.

Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

For brevity, the disclosures of publications (including patents) cited in this specification are incorporated herein by reference. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications, and other publications mentioned herein are incorporated by reference in their entirety. To the extent that definitions set forth in this section are contrary to or otherwise inconsistent with definitions set forth in patents, applications, or other publications that are incorporated by reference herein, they are not incorporated by reference The definition of , the definition explained in this section shall prevail.

As used herein and in the appended claims, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise. It should be further noted that claims may be drafted to exclude any optional elements. Accordingly, this statement is intended to serve as a precondition for the use of such exclusive terminology as "solely," "only" and similar terms or the use of "negative" limitations in conjunction with the recitation of claimed elements.

As used herein, the terms "comprises," "comprising," and "comprising" are used in their open, non-limiting sense.

To provide a more concise description, some quantitative expressions given herein are not qualified by the term "about". It is to be understood that, whether or not the term "about" is explicitly used, each quantity given herein is intended to mean the actual given value, and that it is also intended to mean an approximation of that given value based on what one of ordinary skill in the art would reasonably infer, Equivalents and approximations obtained as a result of the experimental and/or measurement conditions under which the value is given are included. Whenever yields are given as a percentage, such yields refer to the mass of the same entity relative to the maximum amount of the entity obtainable under the specified stoichiometric conditions for which the yield is given. Concentrations given in percentages refer to mass ratios unless indicated differently.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

The methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this disclosure unless otherwise indicated. See e.g. Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.

Chemical names for compounds described herein were generally obtained using commercially available ACD/Name 2014 (ACD/Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).

」表示其中展示標識符之化學基團或化學結構與相鄰化學基團或化學結構之共價連接點。舉例而言，在假想的化學結構A-B中，其中A及B藉由共價鍵接合，在一些實施例中，由基團或化學結構A定義的A-B之部分可由「

」表示，其中「

」表示連至A之鍵及與B之共價鍵連接點。替代地，在一些實施例中，由基團或化學結構B定義的A-B之部分可由「

」表示，其中「

」表示連至B之鍵及與A之共價鍵連接點。 As used herein and in conjunction with the chemical structures depicting the various embodiments described herein, "

" denotes the point of covalent attachment of the chemical group or chemical structure in which the identifier is displayed to an adjacent chemical group or chemical structure. For example, in the hypothetical chemical structure AB, where A and B are joined by a covalent bond, in some embodiments, the portion of AB defined by the group or chemical structure A can be represented by "

” means that “

"Denotes the bond to A and the point of covalent bond to B. Alternatively, in some embodiments, the portion of AB defined by the group or chemical structure B can be represented by "

” means that “

"Denotes the bond to B and the point of covalent bond attachment to A.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of different embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of examples with respect to chemical groups represented by variables are specifically encompassed by the invention and disclosed herein to the extent such combinations encompass compounds that are stable compounds (ie, compounds that can be isolated, characterized and tested for biological activity) , as if each combination and each combination were individually and expressly disclosed. In addition, all subcombinations of chemical groups listed in the examples describing such variables are also expressly encompassed by the invention and disclosed herein, as if each such subcombination of chemical groups and each such subcombination individually and are explicitly disclosed herein. chemical definition

The term "alkyl" refers to a straight or branched chain monovalent hydrocarbon group. The term "alkylene" refers to a straight or branched divalent hydrocarbon group. In some embodiments, it may be advantageous to limit the number of atoms in an "alkyl" or "alkylene" to a specific atomic range, such as C ₁ -C ₂₀ alkyl or C ₁ -C ₂₀ alkylene, C ₁ -C ₁₂ alkyl or C ₁ -C ₁₂ alkylene or C ₁ -C ₆ alkyl or C ₁ -C ₆ alkylene. Examples of alkyl groups include: methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl (tBu), pentyl, isobutyl Pentyl, tertiary pentyl, hexyl, isohexyl, and groups would be considered equivalent to any of the preceding examples given the ordinary skill in the art and the teachings provided herein. Examples of alkylene groups include methylene (-CH ₂ -), ethylidene ((-CH ₂ -) ₂ ), n-propylidene ((-CH ₂ -) ₃ ), isopropylidene ((-C (H)(CH ₃ )CH ₂ -)), n-butyl ((-CH ₂ -) ₄ ) and the like. It is understood that an alkyl or alkylene group may be combined with another group or an atom such as N, O or S as described herein. For example, O can be combined with an alkyl group to provide a monovalent -O-alkyl group with an open valence on only one end for attachment to another structure, such as -OCi _{- C6alkyl} group. Alternatively, O can be combined with an alkylene group to provide a divalent -O-alkylene group with open valences at both ends of the group for covalent attachment to two different structures, such as -OC ₁ -C ₆ alkylene group- , -O-(C ₁ -C ₆ alkylene)- or -O(C ₁ -C ₆ alkylene)-. It is understood that an alkyl or alkylene group can be unsubstituted or substituted as described herein. An alkyl or alkylene group may be substituted with any of the various embodiments described herein, including one or more of such substituents.

The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical having one or more double bonds. The term "alkenylene" refers to a straight or branched divalent hydrocarbon radical having one or more double bonds. In some embodiments, it may be advantageous to limit the number of atoms in an "alkenyl" or "alkenyl" to a specific atomic range, such as C ₂ -C ₂₀ alkenyl or C ₂ -C ₂₀ alkenyl, C ₂ -C ₁₂ alkenyl or C ₂ -C ₁₂ alkenyl or C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkenyl. Examples of alkenyl include ethenyl/vinyl, allyl and but-3-en-1-yl. Examples of alkenylene groups include ethenylene/vinylene (-CH=CH-), n-propenyl (-CH=CHCH ₂ -), isopropenyl (-CH=CH(CH ₃ )-) and its similar groups. Included within this term are cis and trans isomers and mixtures thereof. It is understood that an alkenyl or alkenyl group may be combined with another group or an atom such as N, O or S as described herein. For example, O can be combined with an alkyl group to provide a monovalent -O-alkenyl group with an open valency on only one end for attachment to another structure, such as -OC ₁ -C ₆ alkenyl. Alternatively, O can be combined with an alkenyl group to provide a divalent -O-alkenyl group with open valences at both ends of the group for covalent attachment to two different structures, such as -OC ₁ -C ₆ alkenyl group- , -O-(C ₁ -C ₆ alkenyl)- or -O(C ₁ -C ₆ alkenyl)-. It is understood that an alkenyl or alkenylene group can be unsubstituted or substituted as described herein. An alkenyl or alkenylene group can be substituted with any of the various embodiments described herein, including one or more of such substituents.

The term "alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical having one or more triple bonds. The term "alkynyl" refers to a straight or branched divalent hydrocarbon radical having one or more triple bonds. In some embodiments, it may be advantageous to limit the number of atoms in an "alkynyl" or "alkynyl" group to a specific atomic range, such as C ₂ -C ₂₀ alkynyl or C ₂ -C ₂₀ alkynyl, C ₂ -C ₁₂ alkynyl or C ₂ -C ₁₂ alkynyl or C ₂ -C ₆ alkynyl or C ₂ -C ₆ alkynyl. Examples of alkynyl groups include ethynyl (-C≡CH) and propargyl (-CH ₂ C≡CH), but-3-yn-1,4-diyl (-C≡C-CH ₂ CH ₂ -) and similar groups. It is understood that an alkynyl or alkynyl group may be combined with another group or an atom such as N, O or S as described herein. For example, O can be combined with an alkyl group to provide a monovalent -O-alkynyl group with an open valence on only one terminus for attachment to another structure, such as -OCi _{- C6alkynyl} . Alternatively, O can be combined with an alkynyl group to provide a divalent -O-alkynylene- group with open valences at both ends of the group for covalent attachment to two different structures, such as -OC ₁ -C ₆ alkynylene -, -O-(C ₁ -C ₆ alkynyl)- or -O(C ₁ -C ₆ alkynyl)-. It is understood that an alkynyl or alkynyl group can be unsubstituted or substituted as described herein. An alkynyl or alkynylene group may be substituted with any of the various embodiments described herein, including one or more of such substituents.

。 特定言之，環丙基部分可由結構式

描繪。特定言之，伸環丙基部分可由結構式

描繪。應瞭解，環烷基或伸環烷基可未經取代或如本文所描述經取代。環烷基或伸環烷基可經本文所描述之各種實施例中之任一取代基取代，包括此類取代基中之一或多者。 The term "cycloalkyl" refers to a saturated or partially saturated monocyclic or polycyclic monovalent carbocyclic ring. The term "cycloalkylene" refers to a saturated or partially saturated monocyclic or polycyclic divalent carbocyclic ring. In some embodiments, it may be desirable to limit the number of atoms in a "cycloalkyl" or "cycloalkylene" to a specific atomic range, such as having 3 to 12 ring atoms. Polycyclic carbocycles include fused, bridged and spiro polycyclic ring systems. Illustrative examples of cycloalkyl groups include monovalent groups of the following entities, while cycloalkylene groups include divalent groups of the following entities, in the form of suitable linking moieties:

. In particular, the cyclopropyl moiety can be given by the formula

depict. Specifically, the cyclopropylene moiety can be given by the formula

depict. It is understood that a cycloalkyl or cycloalkylene group can be unsubstituted or substituted as described herein. A cycloalkyl or cycloalkylene group can be substituted with any of the various embodiments described herein, including one or more of such substituents.

The term "halogen" or "halo" means chlorine, fluorine, bromine or iodine.

The term "haloalkyl" refers to an alkyl group having one or more halo substituents. Examples _of haloalkyl groups include _-CF3 , _- ( _CH2 )F, _-CHF2 , _-CH2Br , _-CH2CF3 , and _-CH2CH2F . The term "haloalkylene" refers to an alkyl group having one or more halo substituents. Examples of haloalkyl include -CF2-, _-C (H)(F)-, _-C (H)(Br)-, _-CH2CF2- , and _-CH2C (H)(F)-.

The term "aryl" refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a fully conjugated π-electron system. The term "arylylene" refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a fully conjugated π-electron system. In some embodiments, it may be desirable to limit the number of atoms in an "aryl" or "aryl" group to a specific atomic range, such as a monovalent all-carbon monocyclic or fused-ring polycyclic ring having 6 to 14 carbon atoms Group (C ₆ -C ₁₄ aryl), monovalent all-carbon monocyclic or condensed ring polycyclic group (C ₆ -C ₁₀ aryl) with 6 to 10 carbon atoms, 6 to 14 carbon atoms Divalent full-carbon monocyclic or fused-ring polycyclic groups (C ₆ -C ₁₄ aryl groups) and divalent full-carbon monocyclic or condensed-ring polycyclic groups (C ₆ -C ₁₀ aryl). Examples of aryl groups are, but are not limited to, phenyl, naphthyl and anthracenyl. Examples of aryl groups are, but are not limited to, phenylene, naphthylene and anthracenyl. It is understood that an aryl or arylenyl group may be combined with another group or an atom such as N, O or S as described herein. For example, O can be combined with an alkyl group to provide a monovalent -O-aryl group with an open valence on only one end for attachment to another structure, such as -OC ₆ -C ₁₀ aryl. Alternatively, O can be combined with an arylyl to provide a divalent -O-arylylene- with open valences at both ends of the group for covalent attachment to two different structures, such as -OC6 _{- C10arylylene} -, -O-(C ₆ -C ₁₀ arylylene)- or -O(C ₆ -C ₁₀ arylylene)-. It is understood that an aryl or arylenyl group can be unsubstituted or substituted as described herein. An aryl or arylenyl group may be substituted with any of the various embodiments described herein, including one or more of such substituents.

。 The term "heterocycloalkyl" refers to a saturated or partially saturated monovalent monocyclic or polycyclic ring structure having one or more non-carbon ring atoms. The term "heterocycloalkylene" refers to a saturated or partially saturated monovalent monocyclic or polycyclic ring structure having one or more non-carbon ring atoms. In some embodiments, it may be advantageous to limit the number of atoms in a "heterocycloalkyl" or "heterocycloalkylene" to a specific range of ring atoms, such as 3 to 12 ring atoms (3 to 12 members), Or 3 to 7 ring atoms (3 to 7 members), or 3 to 6 ring atoms (3 to 6 members), or 4 to 6 ring atoms (4 to 6 members), or 5 to 7 ring atoms ( 5 to 7 members). In some embodiments, it may be advantageous to limit the number and type of ring heteroatoms in a "heterocycloalkyl" or "heterocycloalkylene" to a specific range or type of heteroatoms, such as 1 to 5 selected from Ring heteroatoms of nitrogen, oxygen and sulfur. Polycyclic systems include fused, bridged and spiro systems. The ring structure can optionally contain pendant oxy groups on carbocyclic members or up to two pendant oxy groups on a sulfur ring member. Illustrative examples of heterocycloalkyl groups include monovalent groups of the following entities, while heterocycloalkylene groups include divalent groups of the following entities, in the form of suitable linking moieties:

.

It will be appreciated that nitrogen-containing heterocycloalkyl groups may be represented by the formula -N(alkylene), where the alkylene system is described by parentheses in which no open valence is specified, in which case the alkylene group is understood to occupy the nitrogen atom of the two valences to provide a heterocycloalkyl structure. For example, the group -N(C2 _{- C6alkylene} ) falls within the term 3 to 7 membered heterocycloalkyl, wherein the 3 to 7 membered heterocycloalkyl has one point of attachment in the ring representing of nitrogen atoms. In particular, -N(C ₂ -C ₆ alkylene) includes each of the following heterocycloalkyl structures.

It is understood that a heterocycloalkyl or heterocycloalkylene may be combined with another group or an atom such as N, O or S as described herein. For example, O can be combined with an alkyl group to provide a monovalent -O-heterocycloalkyl group with an open valency on only one end for attachment to another structure, such as -O-(3 to 7 membered heterocycloalkyl) . Alternatively, O can be combined with a heterocycloalkylene to provide a divalent -O-heterocycloalkylene with open valences at both ends of the group for covalent attachment to two different structures, such as -O-3 to 7 Heterocycloalkyl-, -O-(3 to 7-membered heterocycloalkyl)- or -O(3 to 7-membered heterocycloalkyl)-. It is understood that a heterocycloalkyl or heterocycloalkylene can be unsubstituted or substituted as described herein. A heterocycloalkyl or heterocycloalkylene group can be substituted with any of the various embodiments described herein, including one or more of such substituents.

。 在一些實施例中，「單環」雜芳基可為芳族五員或六員雜環。五員雜芳基或伸雜芳基可含有至多四個雜原子環原子，其中(a)至少一個環原子為氧及硫，且零個、一個、兩個或三個環原子為氮，或(b)零個環原子為氧或硫且至多四個環原子為氮。五員雜芳基之非限制性實例包括呋喃、噻吩、吡咯、㗁唑、異㗁唑、噻唑、異噻唑、吡唑、咪唑、㗁二唑、噻二唑、三唑或四唑之單價基團。五員伸雜芳基之非限制性實例包括呋喃、噻吩、吡咯、㗁唑、異㗁唑、噻唑、異噻唑、吡唑、咪唑、㗁二唑、噻二唑、三唑或四唑之二價基團。六員雜芳基或伸雜芳基可含有至多四個雜原子環原子，其中(a)至少一個環原子為氧及硫，且零個、一個、兩個或三個環原子為氮，或(b)零個環原子為氧或硫且至多四個環原子為氮。六員雜芳基之非限制性實例包括吡啶、吡𠯤、嘧啶、嗒𠯤或三𠯤之單價基團。六員伸雜芳基之非限制性實例包括吡啶、吡𠯤、嘧啶、嗒𠯤或三𠯤之二價基團。「雙環雜芳基」或「雙環伸雜芳基」為包含一個與苯基或另一雜芳基環稠合之雜芳基環的稠合雙環系統。 特定言之，吡唑基部分可由結構式

描繪。特定言之，伸吡唑基部分之實例可由結構式

描繪。 The term "heteroaryl" means a monovalent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (with carbon atoms selected from the group consisting of up to four ring structure of ring atoms or members of heteroatoms selected from nitrogen, oxygen and sulfur). The term "heteroaryl" refers to a divalent monocyclic, fused bicyclic or fused polycyclic aromatic heterocycle (with carbon atoms selected from and up to four selected from Ring structures of ring atoms or members of heteroatoms of nitrogen, oxygen and sulfur). In some embodiments, it may be desirable to limit the number of ring atoms in a "heteroaryl" or "heteroaryl" to a specific range of atomic members, such as 5 to 10 membered heteroaryl or 5 to 10 membered heteroaryl Aryl. In some cases, the 5- to 10-membered heteroaryl can be a monocyclic or fused bicyclic ring having 5 to 10 ring atoms, at least one of which is a heteroatom, such as N, O, or S. In some cases, the 5 to 10 membered heteroaryl group can be a monocyclic or fused bicyclic ring having 5 to 10 ring atoms, at least one of which is a heteroatom, such as N, O, or S. Illustrative examples of 5 to 10 membered heteroaryl groups include monovalent groups of the following entities, while examples of 5 to 10 membered heteroaryl groups include divalent groups of the following entities, in the form of appropriate linking moieties:

. In some embodiments, a "monocyclic" heteroaryl can be an aromatic five or six membered heterocycle. A five-membered heteroaryl or heteroarylylene group may contain up to four heteroatom ring atoms, wherein (a) at least one ring atom is oxygen and sulfur, and zero, one, two or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heteroaryl groups include monovalent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole group. Non-limiting examples of five-membered heteroaryl groups include furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. Valence group. A six-membered heteroaryl or heteroaryl may contain up to four heteroatom ring atoms, wherein (a) at least one ring atom is oxygen and sulfur, and zero, one, two or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heteroaryl groups include monovalent groups of pyridine, pyridine, pyrimidine, pyridine, or tricarbamide. Non-limiting examples of six-membered heteroaryl groups include divalent groups of pyridine, pyridine, pyrimidine, pyridine, or trivalent. A "bicyclic heteroaryl" or "bicyclic heteroarylylene" is a fused bicyclic ring system comprising one heteroaryl ring fused to a phenyl or another heteroaryl ring. Specifically, the pyrazolyl moiety can be represented by the formula

depict. In particular, an example of a pyrazolyl moiety can be given by the formula

depict.

It is understood that a heteroaryl or heteroaryl group may be combined with another group or an atom such as N, O or S as described herein. For example, O can be combined with an alkyl group to provide a monovalent -O-heteroaryl with an open valence on only one end for attachment to another structure, such as -O-5 to 10 membered heteroaryl. Alternatively, O can be combined with a heteroaryl group to provide a divalent -O-heteroaryl group with open valences at both ends of the group for covalent attachment to two different structures, such as -O-5 to 10-membered Heteroaryl-, -O-(5 to 10 membered heteroaryl)- or -O(5 to 10 membered heteroaryl)-. It is understood that a heteroaryl or heteroaryl group can be unsubstituted or substituted as described herein. A heteroaryl or heteroaryl group can be substituted with any of the various embodiments described herein, including one or more of such substituents.

The term "side oxy" means carbonyl oxygen. For example, a pendant oxy-substituted cyclopentyl group is cyclopentanone.

The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. Where the term "substituted" is used to describe a structural system, substitution means occurrence on the system at any position permitted by the valence. In some embodiments, "substituted" means that the specified group or moiety bears one, two or three substituents. In other embodiments, "substituted" means that the specified group or moiety bears one or two substituents. In yet other embodiments, "substituted" means that the specified group or moiety bears a substituent.

Any formula depicted herein is intended to represent compounds of that formula as well as certain variations or forms. For example, the formulas given herein are intended to include the racemic form or one or more enantiomeric, diastereomeric or geometric isomers or mixtures thereof. Additionally, any formula given herein is intended to also refer to hydrates, solvates or polymorphs of such compounds, or mixtures thereof.

Any formula given herein is also intended to represent unlabeled as well as isotopically labeled forms of the compound. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by atoms of a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of the present invention also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl and ¹²⁵ I. Such isotopically labeled compounds are useful in metabolic studies (preferably using ¹⁴ C); reaction kinetics studies (using eg ² H or ³ H); detection or imaging techniques [such as positron emission tomography (PET) or single photon emission computed tomography (SPECT)], including drug or substrate tissue distribution analysis; or radiation therapy for patients. Furthermore, substitution with heavier isotopes such as deuterium (ie,2H ⁾ may yield certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically-labeled compounds of the invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the Examples and Preparations described below by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent. Reagents are prepared.

The term "(ATOM) _ij " for j > i, when applied herein to a class of substituents, is intended to refer to the embodiment of the invention in which each of the number of atomic members i to j (inclusive) is realized independently one. As examples, the term C _1-3 independently refers to an embodiment having one carbon member (C ₁ ), an embodiment having two carbon members (C ₂ ), and an embodiment having three carbon members (C ₃ ).

Where more than one possibility of attachment is permitted, any disubstituent mentioned herein is intended to embrace each such possibility. For example, a reference to a disubstituent -AB- (where A≠B) refers herein to such disubstituent having A attached to the first substituted member and B attached to the second substituted member , and it also refers to such disubstituents having A attached to the second substituted member and B attached to the first substituted member. For example, in certain embodiments, where applicable, a compound moiety -(L) _n having the formula -CH(CH ₃ )-CH ₂ NH-(CH ₂ ) ₂ - linking two groups A and B - will be understood as -CH(CH ₃ )-CH ₂ NH-(CH ₂ ) ₂ -may include examples A-CH(CH ₃ )-CH ₂ NH-(CH ₂ ) ₂ -B and B-CH(CH ₃ )-CH ₂ NH-(CH ₂ ) ₂ -A both. More specifically, in the context of the present invention, the compound moiety -(L) of the formula -CH(CH ₃ )-CH ₂ NH-(CH ₂ ) ₂ - having the linking groups -Z- and -NR ² - Compounds of formulas (I) to (XIV) for _n- are understood to include the examples -Z-CH(CH ₃ )-CH ₂ NH-(CH ₂ ) ₂ -NR ² - and -NR ² -CH(CH ₃ ) -CH ₂ NH-(CH ₂ ) ₂ -A both.

The present invention also includes pharmaceutically acceptable salts of the compounds represented by formulas (I) to (XIV), preferably the compounds described above and the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts and methods of using such salts.

"Pharmaceutically acceptable salt" is intended to mean a salt of the free acid or base of a compound represented herein that is non-toxic, biotolerable or otherwise biologically suitable for administration to a subject. See generally S.M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for use in contact with the tissues of an individual without undue toxicity, irritation or allergic response. The compounds described herein may have sufficiently acidic groups, sufficiently basic groups, two types of functional groups, or more than one of each type, and thus react with a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutical acceptable salt.

Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate , chloride, bromide, iodide, acetate, propionate, caprate, caprylate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate salt, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne -1,6-diacid salt, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, ortho Phthalate, sulfonate, methanesulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, benzene Acetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Ed., Mack Publishing Company, Easton, Pa., 1985.

For compounds of formula (I) to (XIV) containing a basic nitrogen, pharmaceutically acceptable salts may be prepared by any suitable method available in the art, such as treatment of the free base with the following acid: Inorganic acid , such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid and similar acids; or organic acids such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, butene Diacid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid , lauric acid, pyranonic acid (such as glucuronic acid or galacturonic acid), alpha-hydroxy acid (such as mandelic acid, citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid) , aromatic acids (such as benzoic acid, 2-acetyloxybenzoic acid, naphthoic acid, or cinnamic acid), sulfonic acids (such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid); or acids and any other acids and mixtures thereof that are considered equivalents or acceptable substitutes in view of the ordinary skill in the art.

The present invention also relates to pharmaceutically acceptable prodrugs of compounds of formulas (I) to (XIV), and methods of treatment utilizing such pharmaceutically acceptable prodrugs. The term "prodrug" means a precursor of a given compound that produces the compound in vivo via chemical or physiological processes (such as solvolysis or enzymatic cleavage) or under physiological conditions after administration to an individual (e.g., the prodrug is Conversion to compounds of formulas (I) to (XIV) upon introduction of physiological pH). A "pharmaceutically acceptable prodrug" is a prodrug that is non-toxic, biotolerable and otherwise biologically suitable for administration to a subject. Illustrative procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

The invention also relates to pharmaceutically active metabolites of the compounds of formulas (I) to (XIV), and the use of such metabolites in the methods of the invention. "Pharmaceutically active metabolite" means a pharmacologically active product of the compounds of formulas (I) to (XIV) or their salts metabolized in vivo. Prodrugs and active metabolites of a compound can be determined using routine techniques known or available in the art. See eg Bertolini et al., J. Med. Chem. 1997, 40 , 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7) , 765-767; Bagshawe, Drug Dev. Res. 1995, 34 , 220-230; Bodor, Adv. Drug Res. 1984, 13 , 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., Harwood Academic Publishers, 1991). representative example

In some embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof,

wherein L, X, Y, Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ , m and n are as described herein.

In some embodiments, the present invention provides a compound of formula II or a pharmaceutically acceptable salt thereof,

wherein R ² , A, L, X ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments, the present invention provides a compound of formula III or a pharmaceutically acceptable salt thereof,

wherein A, B, L, X ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments, the present invention provides a compound of formula IV or a pharmaceutically acceptable salt thereof,

wherein R ² , A, B, L, X ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments, the present invention provides a compound of formula V or a pharmaceutically acceptable salt thereof,

wherein R ² , L, X ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments, the present invention provides a compound of formula VI or a pharmaceutically acceptable salt thereof,

wherein B, L, X ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

其中R ²、B、L、X ¹、Z ¹、Z ²、Z ³、Z ⁴、Z ⁵、Z ⁶及n如本文所描述。 In some embodiments, the present invention provides a compound of formula VII or a pharmaceutically acceptable salt thereof,

wherein R ² , B, L, X ¹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments, the present invention provides a compound of formula VIII or a pharmaceutically acceptable salt thereof,

wherein R ¹ , R ² , L, Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments, the present invention provides a compound of formula IX or a pharmaceutically acceptable salt thereof,

wherein R ¹ , B, L, Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments, the present invention provides a compound of formula X or a pharmaceutically acceptable salt thereof,

wherein R ¹ , R ² , B, L, Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments, the present invention provides a compound of formula XI or a pharmaceutically acceptable salt thereof,

wherein R ² , L, X, Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments, the present invention provides a compound of formula XII or a pharmaceutically acceptable salt thereof,

wherein B, L, X, Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments, the present invention provides a compound of formula XIII or a pharmaceutically acceptable salt thereof,

wherein R ² , B, L, X, Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and n are as described herein.

In some embodiments, X is -X ¹ -. In some embodiments, X is -X ¹ -(Ring A)-.

In some embodiments, Ring A is a 5 to 10 membered heteroaryl, wherein each hydrogen atom in the 5 to 10 membered heteroaryl is independently optionally deuterium, fluorine, chlorine, bromine, C ₁ -C ₆ Alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heterocycloalkyl Aryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O )R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O) R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C( O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; and wherein C ₁ -C ₆ alkyl, C ₂ Each of -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl The hydrogen atoms are independently optionally deuterium, fluorine, chlorine, bromine, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O )R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O) NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C( O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution.

In some embodiments, Ring A is a 5 to 10 membered heteroaryl, wherein each hydrogen atom in the 5 to 10 membered heteroaryl is independently optionally deuterium, fluorine, chlorine, bromine, C ₁ -C ₆ Alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heterocycloalkyl Aryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O )R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O) R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C( O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted. In some embodiments, Ring A is a 5 to 10 membered heteroaryl, wherein each hydrogen atom in the 5 to 10 membered heteroaryl is independently optionally deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ Alkyl substitution. In some embodiments, Ring A is a 5- to 10-membered heteroaryl, wherein one hydrogen atom in the 5- to 10-membered heteroaryl is substituted with deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl. In some embodiments, ring A is a 5 to 10 membered heteroaryl group, wherein two hydrogen atoms in the 5 to 10 membered heteroaryl group are independently replaced by deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ Alkyl substitution. In some embodiments, Ring A is a 5 to 10 membered heteroaryl, wherein three hydrogen atoms in the 5 to 10 membered heteroaryl are independently replaced by deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ Alkyl substitution. In some embodiments, Ring A is a 5 to 10 membered heteroaryl.

In some embodiments, Ring A is a C ₆ -C ₁₀ aryl, wherein each hydrogen atom in the C ₆ -C ₁₀ aryl is independently optionally deuterium, fluorine, chlorine, bromine, C ₁ -C ₆ Alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heterocycloalkyl Aryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O )R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O) R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C( O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; and wherein C ₁ -C ₆ alkyl, C ₂ Each of -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl The hydrogen atoms are independently optionally deuterium, fluorine, chlorine, bromine, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O )R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O) NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P( Substituted by O) ^NReRf , -P(O) ^2NReRf , -P(O ₎ ^{ORe ,} -P(O ₎ ^{2ORe ,} -CN or _-NO2 .

In some embodiments, Ring A is a C ₆ -C ₁₀ aryl, wherein each hydrogen atom in the C ₆ -C ₁₀ aryl is independently optionally deuterium, fluorine, chlorine, bromine, C ₁ -C ₆ Alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heterocycloalkyl Aryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O )R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O) R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C( O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted. In some embodiments, ring A is a C ₆ -C ₁₀ aryl, wherein each hydrogen atom in the C ₆ -C ₁₀ aryl is independently optionally deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ Alkyl substitution. In some embodiments, ring A is a C ₆ -C ₁₀ aryl, wherein one hydrogen atom in the C ₆ -C ₁₀ aryl is substituted by deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl. In some embodiments, ring A is a C ₆ -C ₁₀ aryl, wherein two hydrogen atoms in the C ₆ -C ₁₀ aryl are each independently replaced by deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ Alkyl substitution. In some embodiments, ring A is a C ₆ -C ₁₀ aryl, wherein three hydrogen atoms in the C ₆ -C ₁₀ aryl are independently replaced by deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ Alkyl substitution. In some embodiments, Ring A is a C ₆ -C ₁₀ arylylene group.

In some embodiments, Ring A is phenylene, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, Imidazolyl, diazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl, pyrimidinyl, diazolyl or triazolyl, among which phenylene, furyl , thienyl, pyrrolyl, zozolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, diazolyl, thiadiazolyl, Each hydrogen atom in triazolyl, pyridyl, pyridyl, pyrimidinyl, pyridyl or triazolyl is independently deuterium, fluorine, chlorine, bromine, C ₁ -C ₆ alkyl , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl , -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O) OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; where C ₁ -C ₆ alkyl, C ₂ -C ₆ Each hydrogen atom in alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independent Optionally deuterium, fluorine, chlorine, bromine, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O ) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S( O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , - C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR Substituted by ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ .

In some embodiments, Ring A is phenylene, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, Imidazolyl, diazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl, pyrimidinyl, diazolyl or triazolyl, among which phenylene, furyl , thienyl, pyrrolyl, zozolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, diazolyl, thiadiazolyl, Triazolyl, pyridyl, pyridyl, pyrimidinyl, pyridyl or triazolyl through deuterium, fluorine, chlorine, bromine, C ₁ -C ₆ alkyl, C ₂ - C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S (O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , - NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , - C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O ) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C Each hydrogen atom in ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently optionally selected Deuterium, fluorine, chlorine, bromine, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS( O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S( O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ N R ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O) R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C( O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution.

In some embodiments, Ring A is phenylene, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, Imidazolyl, diazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrimidinyl, diazolyl or triazolyl, among which phenylene, furyl , thienyl, pyrrolyl, zozolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, diazolyl, thiadiazolyl, The two hydrogen atoms in triazolyl, pyridyl, pyridyl, pyrimidinyl, pyridyl or triazolyl are independently deuterium, fluorine, chlorine, bromine, C ₁ -C ₆ alkyl , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl , -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O) OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; where C ₁ -C ₆ alkyl, C ₂ -C ₆ Each hydrogen atom in alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independent Optionally deuterium, fluorine, chlorine, bromine, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O ) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S( O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , - C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR Substituted by ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ .

In some embodiments, Ring A is phenylene, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, Imidazolyl, diazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrimidinyl, diazolyl or triazolyl, among which phenylene, furyl , thienyl, pyrrolyl, zozolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, diazolyl, thiadiazolyl, The three hydrogen atoms in triazolyl, pyridyl, pyridyl, pyrimidinyl, pyridyl or triazolyl are independently deuterium, fluorine, chlorine, bromine, C ₁ -C ₆ alkyl , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl , -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O) OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; where C ₁ -C ₆ alkyl, C ₂ -C ₆ Each hydrogen atom in alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independent Optionally deuterium, fluorine, chlorine, bromine, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O ) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S( O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , - C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR Substituted by ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ .

In some embodiments, Ring A is phenylene, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, Imidazolyl, diazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl, pyrimidinyl, diazolyl or triazolyl, among which phenylene, furyl , thienyl, pyrrolyl, zozolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, diazolyl, thiadiazolyl, Each hydrogen atom in triazolyl, pyridyl, pyridyl, pyrimidinyl, pyridyl or triazolyl is independently optionally deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl replace.

In some embodiments, Ring A is phenylene, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, Imidazolyl, diazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl, pyrimidinyl, diazolyl or triazolyl, among which phenylene, furyl , thienyl, pyrrolyl, zozolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, diazolyl, thiadiazolyl, One of the hydrogen atoms in triazolyl, pyridyl, pyridyl, pyrimidinyl, pyridyl or triazolyl is substituted by deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl.

In some embodiments, Ring A is phenylene, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, Imidazolyl, diazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrimidinyl, diazolyl or triazolyl, among which phenylene, furyl , thienyl, pyrrolyl, zozolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, diazolyl, thiadiazolyl, Two hydrogen atoms in triazolyl, pyridyl, pyridyl, pyrimidinyl, pyridyl or triazolyl are independently deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl replace.

In some embodiments, Ring A is phenylene, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, Imidazolyl, diazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl, pyrimidinyl, diazolyl or triazolyl, among which phenylene, furyl , thienyl, pyrrolyl, zozolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, diazolyl, thiadiazolyl, Three hydrogen atoms in triazolyl, pyridyl, pyridyl, pyrimidinyl, pyridyl or triazolyl are independently deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl replace.

In some embodiments, ring A is phenylene or pyridylene, wherein each hydrogen atom in phenylene or pyridylene is independently optionally deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl replace. In some embodiments, ring A is phenylene or pyridylene, wherein one hydrogen atom in phenylene or pyridylene is substituted with deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl. In some embodiments, ring A is phenylene or pyridylene, wherein two hydrogen atoms in phenylene or pyridylene are independently replaced by deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl replace. In some embodiments, ring A is phenylene or pyridylene, wherein three hydrogen atoms in phenylene or pyridylene are independently replaced by deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl replace.

， In some embodiments, Ring A is phenylene or pyridylene of the formula

,

wherein each hydrogen atom is independently optionally substituted by deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl.

， In some embodiments, Ring A is phenylene or pyridylene of the formula

,

One of the hydrogen atoms is independently substituted by deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl.

， In some embodiments, Ring A is phenylene or pyridylene of the formula

,

wherein two hydrogen atoms are independently substituted by deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl.

， In some embodiments, Ring A is phenylene or pyridylene of the formula

,

wherein three hydrogen atoms are independently optionally substituted by deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl.

。 In some embodiments, Ring A is

.

In some embodiments, -X ¹ - is -O-. In some embodiments, -X ¹ - is -S-. In some embodiments, -X ¹ - is -NR ¹ -.

In some embodiments, R ¹ is hydrogen, C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, or 5 to 10 membered heteroaryl, wherein C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl Each hydrogen atom in the radical or 5 to 10 membered heteroaryl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , - SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f 、-PR ^e R ^f 、-P(O)R ^e R ^f 、-P(O) ₂ R ^e R ^f 、-P(O)NR ^e R ^f 、-P(O) ₂ NR ^e R ^f 、- Substituted by P(O)OR ^e , -P(O) ₂ OR ^e' , -CN or -NO ₂ . ^In some embodiments, R is phenyl or pyridyl, wherein each hydrogen atom in phenyl or pyridyl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkane base, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f 、-OS(O) ₂ NR ^e R ^f 、-SR ^e 、-S(O)R ^e 、-S(O) ₂ R ^e 、-S(O)NR ^e R ^f 、-S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O )OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e' , -CN or -NO ₂ substitution.

。 In some embodiments, R ¹ is phenyl or pyridyl, wherein each hydrogen atom in phenyl or pyridyl is independently optionally substituted with deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl. In some embodiments, R ¹ has the formula

.

In some embodiments, R ¹ is H.

In some embodiments, Ring B is a C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl, wherein each hydrogen atom in the C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl , C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS( O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS (O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C( O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ Substitution; wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ Each hydrogen atom in aryl or 5 to 10 membered heteroaryl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O) R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , - NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f 、-NR ^e S(O)NR ^e R ^f 、-NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ replace.

In some embodiments, Ring B is a C ₆ -C ₁₀ aryl, wherein each hydrogen atom in the C ₆ -C ₁₀ aryl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, - OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , - NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P (O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; and wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkene Each hydrogen atom in radical, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently Optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O )R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O ) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C( O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution.

In some embodiments, ring B is a C ₆ -C ₁₀ aryl, wherein one hydrogen atom in the C ₆ -C ₁₀ aryl is replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , - OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O ) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S( O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C( O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; and wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ Each hydrogen atom in -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently optionally deuterized , halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e 、-C(O)NR ^e R ^f 、-PR ^e R ^f 、-P(O)R ^e R ^f 、-P(O) ₂ R ^e R ^f 、-P(O)NR ^e R ^f 、- Substituted by P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ . In some embodiments, ring B is a C ₆ -C ₁₀ aryl, wherein one hydrogen atom in the C ₆ -C ₁₀ aryl is replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , - OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O ) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S( O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C( O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substitution.

In some embodiments, ring B is a C ₆ -C ₁₀ aryl, wherein two hydrogen atoms in the C ₆ -C ₁₀ aryl are each independently replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, - OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , - NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P (O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; and wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkene Each hydrogen atom in radical, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently Optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O )R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O ) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C( O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution. In some embodiments, ring B is a C ₆ -C ₁₀ aryl, wherein two hydrogen atoms in the C ₆ -C ₁₀ aryl are each independently replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, - OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , - NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P Substituted by (O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ .

In some embodiments, Ring B is a C ₆ -C ₁₀ aryl, wherein three hydrogen atoms in the C ₆ -C ₁₀ aryl are independently replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, - OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , - NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P (O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; and wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkene Each hydrogen atom in radical, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently Optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O )R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O ) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C( O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution. In some embodiments, Ring B is a C ₆ -C ₁₀ aryl, wherein three hydrogen atoms in the C ₆ -C ₁₀ aryl are independently replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, - OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , - NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P Substituted by (O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ .

In some embodiments, ring B is a 5 to 10 membered heteroaryl, wherein each hydrogen atom in the 5 to 10 membered heteroaryl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, - OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , - NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P (O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl in each hydrogen atom independently In case of deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O) R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f 、-NR ^e C(O)NR ^e R ^f 、-NR ^e S(O)R ^f 、-NR ^e S(O) ₂ R ^f 、-NR ^e S(O)NR ^e R ^f 、-NR ^e S (O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P (O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substituted. In some embodiments, ring B is a 5 to 10 membered heteroaryl, wherein each hydrogen atom in the 5 to 10 membered heteroaryl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, - OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , - NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P Substituted by (O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ .

In some embodiments, Ring B is a 5 to 10 membered heteroaryl group, wherein one hydrogen atom in the 5 to 10 membered heteroaryl group is replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , - OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O ) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S( O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C( O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ - Each hydrogen atom in C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently optionally replaced by deuterium, Halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , - OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O )NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution. In some embodiments, Ring B is a 5 to 10 membered heteroaryl group, wherein one hydrogen atom in the 5 to 10 membered heteroaryl group is replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , - OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O ) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S( O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C( O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substitution.

In some embodiments, Ring B is a 5 to 10 membered heteroaryl, wherein two hydrogen atoms in the 5 to 10 membered heteroaryl are each independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, - OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , - NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P (O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl in each hydrogen atom independently In case of deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O) R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f 、-NR ^e C(O)NR ^e R ^f 、-NR ^e S(O)R ^f 、-NR ^e S(O) ₂ R ^f 、-NR ^e S(O)NR ^e R ^f 、-NR ^e S (O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P (O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substituted. In some embodiments, Ring B is a 5 to 10 membered heteroaryl, wherein two hydrogen atoms in the 5 to 10 membered heteroaryl are each independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, - OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , - NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P Substituted by (O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ .

In some embodiments, ring B is a 5 to 10 membered heteroaryl group, wherein three hydrogen atoms in the 5 to 10 membered heteroaryl group are independently replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, - OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , - NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P (O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl in each hydrogen atom independently In case of deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S( O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P( O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substituted. In some embodiments, ring B is a 5 to 10 membered heteroaryl group, wherein three hydrogen atoms in the 5 to 10 membered heteroaryl group are independently replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, - OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , - NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P Substituted by (O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ .

In some embodiments, Ring B is phenylene, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, Imidazolyl, diazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrimidinyl, diazolyl or triazolyl, among which phenylene, furyl , thienyl, pyrrolyl, zozolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, diazolyl, thiadiazolyl, Each hydrogen atom in triazolyl, pyridyl, pyridyl, pyrimidinyl, pyridyl or triazolyl is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ - C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O) NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S( O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S (O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O) NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution.

。 In some embodiments, Ring B is

.

In some embodiments, Z ¹ is N. ^In some embodiments, Z2 is N. ^In some embodiments, Z3 is N. In some embodiments, ^Z4 is N. ^In some embodiments, Z5 is N. In some embodiments, ^Z6 is N. In some embodiments, Z ¹ is C(R ⁶ ). In some embodiments, Z ² is C(R ⁷ ). In some embodiments, Z ³ is C(R ⁸ ). In some embodiments, Z ⁴ is C(R ⁹ ). In some embodiments, Z ⁵ is C(R ¹⁰ ). In some embodiments, Z ⁶ is C(R ¹¹ ). In some embodiments, any of the possible combinations of Z ¹ to Z ⁷ as provided above may be combined. In some embodiments, Z ¹ is N, Z ² is C(R ⁷ ), Z ³ is C(R ⁸ ), Z ⁴ is N, Z ⁵ is C(R ¹⁰ ), and Z ⁶ is C(R 8 ). ¹¹ ). In some embodiments, Z ¹ is N, Z ² is C(R ⁷ ), Z ³ is C(R ⁸ ), Z ⁴ is C(R ⁹ ), Z ⁵ is C(R ¹⁰ ), and Z ⁶ is C(R ¹¹ ). In some embodiments, Z ¹ is N, Z ² is C(R ⁷ ), Z ³ is N, Z ⁴ is N, Z ⁵ is C(R ¹⁰ ), and Z ⁶ is C(R ¹¹ ). ^In some embodiments, Z1 is N, Z2 is C( ^{R7 )} , Z3 is N, ^Z4 is C( ^R9 ), ^Z5 is C( ^R10 ), and ^Z6 is C( ^{R 11} ). ^In some embodiments, Z1 is N, Z2 is C( ^{R7 )} , Z3 is C( ^R8 ), ^Z4 is C( ^R9 ), ^Z5 is N, and ^Z6 is C( ^{R 11} ). In some embodiments, Z ¹ is N, Z ² is C(R ⁷ ), Z ³ is C(R ⁸ ), Z ⁴ is C(R ⁹ ), Z ⁵ is C(R ¹⁰ ), and Z ⁶ for N. In some embodiments, R ⁶ is H. In some embodiments, ^R7 is H. ^In some embodiments, R is H. In some embodiments, ^R9 is H. In some embodiments, R ¹⁰ is H or -OCH ₃ . In some embodiments, R ¹¹ is H.

In some embodiments, each L is independently selected from the group consisting of -C(R ³ )(R ⁴ )-, -C(O)-, -O-, or -N(R ⁵ )-, with the proviso that (L) _n does not contain -OO- or -ON(R ⁵ )-bonds.

In some embodiments, -(L) _n - comprises one or more of: (CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₄ -, (CR ³ R ⁴ ) ₅ -, (CR ³ R ⁴ ) ₆ , (CR ³ R ⁴ ) ₇ -, (CR ³ R ⁴ ) ₈ -, C(O)N(R ⁵ )-(CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ - , CR ³ R ⁴ -C(O)N(R ⁵ )-(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ C(O)N(R ⁵ )-(CR ³ R ⁴ ) ₃ O-, N(R ⁵ )C(O)CR ³ R ⁴ O(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ N(R ⁵ )C(O)(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ N(R ⁵ )C(O)(CR ³ R ⁴ ) ₃ O-, CR ³ R ⁴ O(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ O(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₂ O-CR ³ R ⁴ -, (CR ³ R ⁴ ) ₃ O-CR ³ R ⁴ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₃ O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₅ O(CR ³ R ⁴ ) ₃ -, OCR ³ R ⁴ O(CR ³ R ⁴ ) ₃ -, CR ³ R ⁴ -O(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ -O(CR ³ R ⁴ ) ₃ O-, O (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₃ O-, O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ O-, -O-(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₃ O-, O(CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ -N(R ⁵ )(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₃ O(CR ³ R ⁴ )C(O)N(R ⁵ )(CR ³ R ⁴ )-, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ )C(O)N(R ⁵ )-(CR ³ R ⁴ )-, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ C(O)N(R ⁵ )-(CR ³ R ⁴ )-, (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₃ -, O(CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ N(R ⁵ )(CR ³ R ⁴ ) ₂ O- , (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₂ O- or (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₃ O-.

In some embodiments, -(L) _n - is (CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₄ -, (CR ³ R ⁴ ) ₅ -, (CR ³ R ⁴ ) ₆ , (CR ³ R ⁴ ) ₇ -, (CR ³ R ⁴ ) ₈ -, C(O)N(R ⁵ )-(CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ -C( O)N(R ⁵ )-(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ C(O)N(R ⁵ )-(CR ³ R ⁴ ) ₃ O-, N(R ⁵ )C(O )CR ³ R ⁴ O(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ N(R ⁵ )C(O)(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ N(R ⁵ )C(O )(CR ³ R ⁴ ) ₃ O-, CR ³ R ⁴ O(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ O(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₂ O-CR ³ R ⁴ -, (CR ³ R ⁴ ) ₃ O-CR ³ R ⁴ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₃ O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₅ O(CR ³ R ⁴ ) ₃ -, OCR ³ R ⁴ O (CR ³ R ⁴ ) ₃ -, CR ³ R ⁴ -O(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ -O(CR ³ R ⁴ ) ₃ O-, O(CR ³ R ⁴ ) ₂ O (CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₃ O-, O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ O-, -O- (CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₃ O-, O(CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ -N(R ⁵ )(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₃ O(CR ³ R ⁴ )C(O)N(R ⁵ )(CR ³ R ⁴ )-, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ )C(O)N(R ⁵ )-(CR ³ R ⁴ )-, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ C(O)N(R ⁵ )-(CR ³ R ⁴ )-, (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₃ -, O(CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ N(R ⁵ )(CR ³ R ⁴ ) ₂ O-, (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₂ O— or (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₃ O—.

In some embodiments, -(L) _n - comprises one or more of: (CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₄ -, (CR ³ R ⁴ ) ₅ , (CR ³ R ⁴ ) ₆ , (CR ³ R ⁴ ) ₇ -, (CR ³ R ⁴ ) ₈ -, C(O)N(R ⁵ )-(CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ -, N(R ⁵ )C(O)CR ³ R ⁴ O(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ O(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ O(CR ³ R ⁴ ) ₃ - , (CR ³ R ⁴ ) ₂ O-CR ³ R ⁴ -, (CR ³ R ⁴ ) ₃ O-CR ³ R ⁴ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₃ O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₃ -, OCR ³ R ⁴ -O(CR ³ R ⁴ ) ₃ -, CR ³ R ⁴ -O(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ -O(CR ³ R ⁴ ) ₃ O-, O(CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₃ O-, O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ O-, -O-(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₃ O-, O(CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ -N( R ⁵ )(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₂ -, O(CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ N(R ⁵ )(CR ³ R ⁴ ) ₂ O-, (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₂ O- or (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₂ O-.

In some embodiments, -(L) _n - is (CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₄ -, (CR ³ R ⁴ ) ₅ -, (CR ³ R ⁴ ) ₆ , (CR ³ R ⁴ ) ₇ , (CR ³ R ⁴ ) ₈ -, C(O)N(R ⁵ )-(CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ -, N(R ⁵ )C(O )CR ³ R ⁴ O(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ O(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ O(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₂ O-CR ³ R ⁴ -, (CR ³ R ⁴ ) ₃ O-CR ³ R ⁴ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₃ O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₃ -, OCR ³ R ⁴ -O(CR ³ R ⁴ ) ₃ -, CR ³ R ⁴ -O(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ -O(CR ³ R ⁴ ) ₃ O-, O(CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₃ O-, O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ O-, -O-(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₃ O-, O (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ -N(R ⁵ )(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₂ -, O(CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ N(R ⁵ )(CR ³ R ⁴ ) ₂ O-, (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₂ O- or (CR ³ R ⁴ ) ₂ N(R ⁵ ) (CR ³ R ⁴ ) ₂ O-.

^In some embodiments, each ^R3 and R4 are independently selected from the group consisting of H, deuterium, _C1 - _C6 alkyl, ^-NRcC (O) ^Rd , and -CN, wherein _C1 - _C6 Each hydrogen atom in the alkyl group is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O) NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S( O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O )NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f 、-P(O)R ^e R ^f 、-P(O) ₂ R ^e R ^f 、-P(O)NR ^e R ^f 、-P(O) ₂ NR ^e R ^f 、-P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substituted.

In some embodiments, -(L) _n - comprises one or more of: (CH ₂ ) ₃ -, (CH ₂ ) ₄ -, (CH ₂ ) ₅ -, (CH ₂ ) ₆ -, ( CH ₂ ) ₇ -, (CH ₂ ) ₈ -, C(O)NH(CH ₂ ) ₂ O(CH ₂ ) ₂ -, C(O)N(CH ₃ )-(CH ₂ ) ₂ O(CH ₂ ) ₂ -, NHC(O)CH ₂ O(CH ₂ ) ₂ -, N(CH ₃ )C(O)CH ₂ O(CH ₂ ) ₂ -, CH ₂ O(CH ₂ ) ₂ -, CH ₂ O (CH ₂ ) ₃ -, CH ₂ O(CH ₂ ) ₂ CH(CH ₃ )-, CH ₂ OCH ₂ CH(CH ₃ )-CH ₂ -, CH ₂ OCH(CH ₃ )-(CH ₂ ) ₂ - , CH(CN)O(CH ₂ ) ₃ -, CH(CH ₃ )O(CH ₂ ) ₃ -, CH ₂ O(CH ₂ ) ₂ -O-, (CH ₂ ) ₂ O(CH ₂ ) ₂ - , CH ₂ -C(CH ₃ ) ₂ -O(CH ₂ ) ₂ -, CH ₂ C(CH ₃ ) ₂ -O(CH ₂ ) ₃ -, (CH ₂ ) ₂ OCH ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₂ -, (CH ₂ ) ₃ O(CH ₂ ) ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₃ -, (CH ₂ ) ₂ OCH(CH ₃ )-(CH ₂ ) ₂ -, (CH ₂ ) ₂ OC(CH ₃ ) ₂ -(CH ₂ ) ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₂ -CH(CH ₃ )-, (CH ₂ ) ₂ O(CH ₂ ) ₂ -C(CH ₃ ) ₂ -CH ₂ CH(CH ₃ )-O-(CH ₂ ) ₃ -, CH ₂ CH(CH ₃ )O(CH ₂ ) ₂ -, CH(CH ₃ )CH ₂ O( CH ₂ ) ₂ -, O(CH ₂ ) ₂ -, -O-(CH ₂ ) ₃ -, OCH ₂ CH(OH)CH ₂ -, O(CH ₂ ) ₂ O(CH ₂ ) ₂ -, OCH ₂ CH(CH ₃ )-O(CH ₂ ) ₂ -, OCH(CH ₃ )CH ₂ O(CH ₂ ) ₂ -, (CH ₂ ) ₂ OCH ₂ CH(NHC(O)CH=CH ₂ )CH ₂ O -, (CH ₂ ) ₂ OCH ₂ CH(N(CH ₃ )-C(O)-CH=CH ₂ )C H ₂ O-, (CH ₂ ) ₂ OCH ₂ CH(NH-C(O)-CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ OCH ₂ CH(N(CH ₃ )-C(O) -CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ NH-CH ₂ CH(NH-C(O)-CH=CH ₂ )CH ₂ O-, (CH ₂ ) ₂ NHCH ₂ CH(N( CH ₃ )C(O)CH=CH ₂ )CH ₂ O-, (CH ₂ ) ₂ NHCH ₂ CH(NHC(O)CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ N(CH ₃ ) CH ₂ CH(N(CH ₃ )C(O)CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ N(CH ₃ )CH ₂ CH(N(CH ₃ )C(O)CH=CH ₂ )CH ₂ O-, (CH ₂ ) ₂ N(CH ₃ )CH ₂ CH(NHC(O)CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ N(CH ₃ )CH ₂ CH(N( CH ₃ )C(O)CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₃ O(CH ₂ )C(O)N(CH ₃ )CH ₂ -, (CH ₂ ) ₃ O(CH ₂ ) C(O)N(H)CH ₂ -, (CH ₂ ) ₂ O(CH ₂ )C(O)N(CH ₃ )CH ₂ -, (CH ₂ ) ₂ O(CH ₂ )C(O)N (H)CH ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₂ C(O)N(CH ₃ )CH ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₂ C(O)N(H) CH ₂ -, O(CH ₂ ) ₂ NH(CH ₂ ) ₂ -, OCH ₂ CH(CH ₃ )-NH-(CH ₂ ) ₂ -, OCH(CH ₃ )CH ₂ NH-(CH ₂ ) ₂ - , CH ₂ NH(CH ₂ ) ₂ -, (CH ₂ ) ₂ NH(CH ₂ ) ₂ -, (CH ₂ ) ₂ NH(CH ₂ ) ₃ -, (CH ₂ ) ₂ N(CH ₃ )(CH ₂ ) ₂ -, (CH ₂ ) ₂ N(CH ₃ )(CH ₂ ) ₃ -, CH ₂ CH(CH ₃ )NH(CH ₂ ) ₂ -, CH(CH ₃ )CH ₂ NH-(CH ₂ ) ₂ -, O(CH ₂ ) ₂ N(CH ₃ )(CH ₂ ) ₂ -, OCH ₂ CH(CH ₃ )-N( CH ₃ )-(CH ₂ ) ₂ -, OCH(CH ₃ )CH ₂ N(CH ₃ )(CH ₂ ) ₂ -, CH ₂ N(CH ₃ )(CH ₂ ) ₂ -, (CH ₂ ) ₂ N (CH ₃ )(CH ₂ ) ₂ -, CH ₂ C(O)N(H)(CH ₂ ) ₃ O-, CH ₂ C(O)N(CH ₃ )(CH ₂ ) ₃ O-, CH ₂ CH(CH ₃ )-N(CH ₃ )-(CH ₂ ) ₂ - or OCH(CH ₃ )CH ₂ N(CH ₃ )-(CH ₂ ) ₂ -.

In some embodiments, -(L) _n - is (CH ₂ ) ₃ -, (CH ₂ ) ₄ -, (CH ₂ ) ₅ -, (CH ₂ ) ₆ -, (CH ₂ ) ₇ -, (CH ₂ ) ₈ -, C(O)NH(CH ₂ ) ₂ O(CH ₂ ) ₂ -, C(O)N(CH ₃ )-(CH ₂ ) ₂ O(CH ₂ ) ₂ -, NHC(O) CH ₂ O(CH ₂ ) ₂ -, N(CH ₃ )C(O)CH ₂ O(CH ₂ ) ₂ -, CH ₂ O(CH ₂ ) ₂ -, CH ₂ O(CH ₂ ) ₃ -, CH ₂ O(CH ₂ ) ₂ CH(CH ₃ )-, CH ₂ OCH ₂ CH(CH ₃ )-CH ₂ -, CH ₂ OCH(CH ₃ )-(CH ₂ ) ₂ -, CH(CN)O(CH ₂ ) ₃ -, CH(CH ₃ )O(CH ₂ ) ₃ -, CH ₂ O(CH ₂ ) ₂ -O-, (CH ₂ ) ₂ O(CH ₂ ) ₂ -, CH ₂ -C(CH ₃ ) ₂ -O(CH ₂ ) ₂ -, CH ₂ C(CH ₃ ) ₂ -O(CH ₂ ) ₃ -, (CH ₂ ) ₂ OCH ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₂ -, (CH ₂ ) ₃ O(CH ₂ ) ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₃ -, (CH ₂ ) ₂ OCH(CH ₃ )-(CH ₂ ) ₂ -, (CH ₂ ) ₂ OC (CH ₃ ) ₂ -(CH ₂ ) ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₂ -CH(CH ₃ )-, (CH ₂ ) ₂ O(CH ₂ ) ₂ -C(CH ₃ ) ₂ -CH ₂ CH(CH ₃ )-O-(CH ₂ ) ₃ -, CH ₂ CH(CH ₃ )O(CH ₂ ) ₂ -, CH(CH ₃ )CH ₂ O(CH ₂ ) ₂ -, O( CH ₂ ) ₂ -, -O-(CH ₂ ) ₃ -, OCH ₂ CH(OH)CH ₂ -, O(CH ₂ ) ₂ O(CH ₂ ) ₂ -, OCH ₂ CH(CH ₃ )-O( CH ₂ ) ₂ -, OCH(CH ₃ )CH ₂ O(CH ₂ ) ₂ -, (CH ₂ ) ₂ OCH ₂ CH(NHC(O)CH=CH ₂ )CH ₂ O-, (CH ₂ ) ₂ OCH ₂ CH(N(CH ₃ )-C(O)-CH=CH ₂ )CH ₂ O-, (CH ₂ ) ₂ OCH ₂ CH(NH-C(O)-CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ OCH ₂ CH(N(CH ₃ )-C(O)-CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ NH-CH ₂ CH(NH-C(O)-CH=CH ₂ )CH ₂ O-, (CH ₂ ) ₂ NHCH ₂ CH(N(CH ₃ )C(O) CH=CH ₂ )CH ₂ O-, (CH ₂ ) ₂ NHCH ₂ CH(NHC(O)CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ N(CH ₃ )CH ₂ CH(N(CH ₃ )C(O)CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ N(CH ₃ )CH ₂ CH(N(CH ₃ )C(O)CH=CH ₂ )CH ₂ O-, ( CH ₂ ) ₂ N(CH ₃ )CH ₂ CH(NHC(O)CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ N(CH ₃ )CH ₂ CH(N(CH ₃ )C(O) CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₃ O(CH ₂ )C(O)N(CH ₃ )CH ₂ -, (CH ₂ ) ₃ O(CH ₂ )C(O)N(H )CH ₂ -, (CH ₂ ) ₂ O(CH ₂ )C(O)N(CH ₃ )CH ₂ -, (CH ₂ ) ₂ O(CH ₂ )C(O)N(H)CH ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₂ C(O)N(CH ₃ )CH ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₂ C(O)N(H)CH ₂ -, O(CH ₂ ) ₂ NH(CH ₂ ) ₂ -, OCH ₂ CH(CH ₃ )-NH-(CH ₂ ) ₂ -, OCH(CH ₃ )CH ₂ NH-(CH ₂ ) ₂ -, CH ₂ NH(CH ₂ ) ₂ -, (CH ₂ ) ₂ NH(CH ₂ ) ₂ -, (CH ₂ ) ₂ NH(CH ₂ ) ₃ -, (CH ₂ ) ₂ N(CH ₃ )(CH ₂ ) ₂ -, (CH ₂ ) ₂ N(CH ₃ )(CH ₂ ) ₃ -, CH ₂ CH(CH ₃ )NH(CH ₂ ) ₂ -, CH(CH ₃ )CH ₂ NH-(CH ₂ ) ₂ -, O(CH ₂ ) ₂ N(CH ₃ )(CH ₂ ) ₂ -, OCH ₂ CH(CH ₃ )-N(CH ₃ )-(CH ₂ ) ₂ -, OCH(CH ₃ )CH ₂ N(CH ₃ )(CH ₂ ) ₂ -, CH ₂ N(CH ₃ )(CH ₂ ) ₂ -, (CH ₂ ) ₂ N(CH ₃ )(CH ₂ ) ₂ -, CH ₂ C(O)N(H)(CH ₂ ) ₃ O-, CH ₂ C(O)N(CH ₃ )(CH ₂ ) ₃ O-, CH ₂ CH(CH ₃ )- N(CH ₃ )-(CH ₂ ) ₂ - or OCH(CH ₃ )CH ₂ N(CH ₃ )-(CH ₂ ) ₂ -.

In some embodiments, -(L) _n - comprises one or more of: (CH ₂ ) ₃ -, (CH ₂ ) ₄ -, (CH ₂ ) ₅ -, (CH ₂ ) ₆ -, ( CH ₂ ) ₇ -, (CH ₂ ) ₈ -, C(O)NH(CH ₂ ) ₂ O(CH ₂ ) ₂ -, C(O)N(CH ₃ )-(CH ₂ ) ₂ O(CH ₂ ) ₂ -, NHC(O)CH ₂ O(CH ₂ ) ₂ -, N(CH ₃ )C(O)CH ₂ O(CH ₂ ) ₂ -, CH ₂ O(CH ₂ ) ₂ -, CH ₂ O (CH ₂ ) ₃ -, CH ₂ O(CH ₂ ) ₂ CH(CH ₃ )-, CH ₂ OCH ₂ CH(CH ₃ )-CH ₂ -, CH ₂ OCH(CH ₃ )-(CH ₂ ) ₂ - , CH(CN)O(CH ₂ ) ₃ -, CH(CH ₃ )O(CH ₂ ) ₃ -, CH ₂ O(CH ₂ ) ₂ -O-, (CH ₂ ) ₂ O(CH ₂ ) ₂ - , CH ₂ -C(CH ₃ ) ₂ -O(CH ₂ ) ₂ -, (CH ₂ ) ₂ OCH ₂ -, (CH ₂ ) ₃ O(CH ₂ ) ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₃ -, -CH ₂ CH(CH ₃ )-O-(CH ₂ ) ₃ -, CH ₂ CH(CH ₃ )O(CH ₂ ) ₂ -, CH(CH ₃ )CH ₂ O(CH ₂ ) ₂ -, -O-(CH ₂ ) ₂ -, -O-(CH ₂ ) ₃ -, OCH ₂ CH(OH)CH ₂ -, O(CH ₂ ) ₂ O(CH ₂ ) ₂ -, OCH ₂ CH( CH ₃ )-O(CH ₂ ) ₂ -, OCH(CH ₃ )CH ₂ O(CH ₂ ) ₂ -, O(CH ₂ ) ₂ NH(CH ₂ ) ₂ -, OCH ₂ CH(CH ₃ )-NH -(CH ₂ ) ₂ -, OCH(CH ₃ )CH ₂ NH-(CH ₂ ) ₂ -, CH ₂ NH(CH ₂ ) ₂ -, (CH ₂ ) ₂ NH(CH ₂ ) ₂ -, CH ₂ CH (CH ₃ )NH(CH ₂ ) ₂ -, CH(CH ₃ )CH ₂ NH-(CH ₂ ) ₂ -, O(CH ₂ ) ₂ N(CH ₃ )(CH ₂ ) ₂ -, OCH ₂ CH( CH ₃ )-N(CH ₃ )-(CH ₂ ) ₂ -, OCH(CH ₃ )CH ₂ N (CH ₃ )(CH ₂ ) ₂ -, CH ₂ N(CH ₃ )(CH ₂ ) ₂ -, (CH ₂ ) ₂ N(CH ₃ )(CH ₂ ) ₂ -, CH ₂ CH(CH ₃ )- N(CH ₃ )-(CH ₂ ) ₂ - or OCH(CH ₃ )CH ₂ N(CH ₃ )-(CH ₂ ) ₂ -.

In some embodiments, -(L) _n - is (CH ₂ ) ₃ -, (CH ₂ ) ₄ -, (CH ₂ ) ₅ -, (CH ₂ ) ₆ -, (CH ₂ ) ₇ -, (CH ₂ ) ₈ , C(O)NH(CH ₂ ) ₂ O(CH ₂ ) ₂ -, C(O)N(CH ₃ )-(CH ₂ ) ₂ O(CH ₂ ) ₂ -, NHC(O)CH ₂ O(CH ₂ ) ₂ -, N(CH ₃ )C(O)CH ₂ O(CH ₂ ) ₂ -, CH ₂ O(CH ₂ ) ₂ -, CH ₂ O(CH ₂ ) ₃ -, CH ₂ O(CH ₂ ) ₂ CH(CH ₃ )-, CH ₂ OCH ₂ CH(CH ₃ )-CH ₂ -, CH ₂ OCH(CH ₃ )-(CH ₂ ) ₂ -, CH(CN)O(CH ₂ ) ₃ -, CH(CH ₃ )O(CH ₂ ) ₃ -, CH ₂ O(CH ₂ ) ₂ -O-, (CH ₂ ) ₂ O(CH ₂ ) ₂ -, CH ₂ -C(CH ₃ ) ₂ -O(CH ₂ ) ₂ -, (CH ₂ ) ₂ OCH ₂ -, (CH ₂ ) ₃ O(CH ₂ ) ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₃ -, -CH ₂ CH( CH ₃ )-O-(CH ₂ ) ₃ -, CH ₂ CH(CH ₃ )O(CH ₂ ) ₂ -, CH(CH ₃ )CH ₂ O(CH ₂ ) ₂ -, -O-(CH ₂ ) ₂ -, -O-(CH ₂ ) ₃ -, OCH ₂ CH(OH)CH ₂ -, O(CH ₂ ) ₂ O(CH ₂ ) ₂ -, OCH ₂ CH(CH ₃ )-O(CH ₂ ) ₂ -, OCH(CH ₃ )CH ₂ O(CH ₂ ) ₂ -, O(CH ₂ ) ₂ NH(CH ₂ ) ₂ -, OCH ₂ CH(CH ₃ )-NH-(CH ₂ ) ₂ -, OCH (CH ₃ )CH ₂ NH-(CH ₂ ) ₂ -, CH ₂ NH(CH ₂ ) ₂ -, (CH ₂ ) ₂ NH(CH ₂ ) ₂ -, CH ₂ CH(CH ₃ )NH(CH ₂ ) ₂ -, CH(CH ₃ )CH ₂ NH-(CH ₂ ) ₂ -, O(CH ₂ ) ₂ N(CH ₃ )(CH ₂ ) ₂ -, OCH ₂ CH(CH ₃ )-N(CH ₃ ) -(CH ₂ ) ₂ -, OCH(CH ₃ )CH ₂ N(CH ₃ )(CH ₂ ) ₂ -, CH ₂ N(CH ₃ )(CH ₂ ) ₂ -, (CH ₂ ) ₂ N(CH ₃ )(CH ₂ ) ₂ -, CH ₂ CH(CH ₃ )-N(CH ₃ )- (CH ₂ ) ₂ - or OCH(CH ₃ )CH ₂ N(CH ₃ )-(CH ₂ ) ₂ -.

In some embodiments, m is 0, 1 or 2. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

In some embodiments, n is 3, 4, 5, 6, 7, 8 or 9. In some embodiments, n is 3, 4, 5, 6, 7 or 8. In some embodiments, n is 4, 5, 6 or 7. In some embodiments, n is 4, 5 or 6. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9.

In some embodiments, the compound is selected from the group consisting of 1-(3-chloro-4-fluorophenyl)-17-methoxy-2,3,5,6,7,8-hexahydro- 10,12-Ethylidenepyrido[4,3- e ][1,4,7,10]oxatriazacyclotridecen-9( 1H )-one;

1-(3-Chloro-2-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-vinylidenepyrido[4,3- e ][1,4 ,7,10] oxatriazacyclotridecen-9( 1H )-one;

(3 R )-1-(3-chloro-4-fluorophenyl)-3-methyl-2,3,5,6,7,8-hexahydro-10,12-vinylidene pyrido[ 4,3- e ][1,4,7,10]oxatriazacyclotridecen-9(1 H )-one;

(3S)-1-(3-Chloro-4-fluorophenyl)-3-methyl-2,3,5,6,7,8-hexahydro-10,12-vinylidenepyrido[4 ,3- e ][1,4,7,10]oxatriazacyclotridecen-9(1 H )-one;

1-(3-Chloro-4-fluorophenyl)-3,3-dimethyl-2,3,5,6,7,8-hexahydro-10,12-vinylidenepyrido[4, 3- e ][1,4,7,10]oxatriazacyclotridecen-9(1 H )-one;

(5 S )-1-(3-chloro-4-fluorophenyl)-5-methyl-2,3,5,6,7,8-hexahydro-10,12-vinylidene pyrido[ 4,3- e ][1,4,7,10]oxatriazacyclotridecen-9(1 H )-one;

(7 R )-1-(3-chloro-4-fluorophenyl)-7-methyl-2,3,5,6,7,8-hexahydro-10,12-vinylidene pyrido[ 4,3- e ][1,4,7,10]oxatriazacyclotridecen-9(1 H )-one;

12-(3-Chloro-4-fluorophenyl)-1-methyl-4,13,14,16-tetrahydro-1 H -6,8-vinylidenepyrazolo[4,3- k ]pyrido[4,3- e ][1,4,7,10] oxatriazacyclotridecen -5(12H)-one;

14-(3-Chloro-4-fluorophenyl)-5-methyl-5,9,10,12,13,14-hexahydro-2,18-vinylidene-3,6-( Methenyl)pyrido[3,4- l ][1,4,7,8,11,14]oxapentaazacyclohexadecen-7( 8H )-one; and

1-(3-Chloro-4-fluorophenyl)-10-methyl-1,2,3,6,7,10-hexahydro-12,9-(oxazoenyl)-13,15-bridge Vinylidenepyrido[3,4- l ][1,4,7,14]oxatriazacyclohexadecen-8( 5H )-one;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is selected from the group consisting of 7-chloro-6-fluoro-15-methyl- 5,12,13,15 -tetrahydro-10H-1,18-vinylidene Pyrazolo[4,3- f ]pyrido[4,3- b ][8,11,1,4]benzodioxadiazacyclotetradecene;

7-Chloro-6-fluoro-15-methyl-5,12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- f ]pyrido[4, 3- b ][8,11,1]benzodioxazacyclotetradecene;

7-Chloro-15-methyl-5,12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- f ]pyrido[4,3- b ] [8,11,1]benzodioxazacyclotetradecene;

15-methyl-5,12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- f ]pyrimido[4,5- b ][8,11 ,1,4]benzodioxadiazacyclotetradecene;

7-Chloro-15-methyl-5,12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- f ]pyrimido[4,5- b ] [8,11,1]benzodioxazacyclotetradecene;

7,15-Dimethyl-5,12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- m ]pyrido[3,4- f ]pyrimidine And[4,5- i ][1,4,8]dioxazacyclotetradecene;

7-Chloro-6-fluoro-5,10,12,13-tetrahydro-1,19-vinylidenedipyrido[4,3- b :2',3'- f ][8,11, 1] Benzodioxazacyclotetradecene;

7-Chloro-6,17-difluoro-5,10,12,13-tetrahydro-1,19-vinylidene dibenzo[ e , l ]pyrido[3,4- i ][1, 4,8,11] dioxadiazacyclotetradecene;

7-Chloro-6-fluoro-14-methyl-5,13,14,17-tetrahydro-10 H -19,16-(azazoenyl)-1,20-vinylidenepyrido[4 ,3- b ][14,1,8,11]benzotriazacycloheptadecen-15(12 H )-one;

7-Chloro-6-fluoro-14,17-dimethyl-5,13,14,17-tetrahydro-10 H -19,16-(azazenyl)-1,20-vinylidenepyridine And[4,3- b ][14,1,8,11]benzotriazacycloheptadecen-15(12 H )-one;

7-Chloro-6-fluoro-14,17-dimethyl-5,13,14,17-tetrahydro-10 H -1,20-vinylidene-19,16-(methenylene) Pyrido[4,3- b ][14,1,4,7,8,11]benzozacyclohexadecen-15(12 H )-one;

7-Chloro-6-fluoro-14-methyl-13,14-dihydro-10 H ,17 H -19,16-(azazoenyl)-1,20-vinylidene pyrido[4, 3- b ][1,14,8,11]benzodioxadiazacyclohexadecen-15(12 H )-one;

[ _ _ 1,14,8,11] benzodioxadiazacyclohexadecen-15(12 H )-one;

[ _ _ 1,14,8,11] benzodioxadiazacyclohexadecen-15(12 H )-one;

7-Chloro-6-fluoro-14,17-dimethyl-13,14-dihydro-10 H ,17 H -19,16-(azazenyl)-1,20-vinylidene pyrido [4,3- b ][1,14,8,11]benzodioxadiazacyclohexadecen-15(12 H )-one;

16-Chloro-17-fluoro-8-methyl- 8,9,10,11,13,18 -hexahydro-7H-4,6-vinylidenepyrido[4,3- b ][11 ,1,4,7]benzotriazacyclotetradecen-7-one;

16-Chloro-17-fluoro-8,9,10,11,13,18-hexahydro-7H-4,6-vinylidenepyrido[4,3- b ][ 11,1,4 , 7] Benzotriazacyclotetradecen-7-one;

(13 R )-16-chloro-17-fluoro-13-methyl-8,9,10,11,13,18-hexahydro-7 H -4,6-vinylidenepyrido[4,3 - b ][11,1,4,7]benzotriazacyclotetradecen-7-one;

(13 S )-16-Chloro-17-fluoro-7-oxo- 8,9,10,11,13,18 -hexahydro-7H-4,6-vinylidenepyrido[4, 3- b ][11,1,4,7]benzotriazacyclotetradecene-13-carbonitrile;

(9 R )-16-Chloro-17-fluoro-9-methyl-8,9,10,11,13,18-hexahydro-7 H -4,6-vinylidenepyrido[4,3 - b ][11,1,4,7]benzotriazacyclotetradecen-7-one;

16-Chloro-17-fluoro-8-methyl-8,9,10,11-tetrahydro-7 H ,13 H -4,6-vinylidenepyrido[4,3- b ][1, 11,7] benzodioxazacyclotetradecen-7-one; and

16-Chloro-17-fluoro-8-methyl-8,9,10,11-tetrahydro-7 H ,13 H -4,6-vinylidenepyrido[4,3- b ][11, 1,7]Benzotriazacyclotetradecen-7-one;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is selected from the group consisting of 1-(3-chloro-4-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12- Vinylpyrido[4,3- e ][1,4,7,10]oxatriazacyclotridecen-9( 1H )-one;

1-(3-Chloro-4-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-vinylidenepyrido[4,3- e ][1,4 ,10] oxadiazacyclotridecen-9( 1H )-one;

15-(3-Chloro-4-fluorophenyl)-8,9,10,11,14,15-hexahydro-4,6-vinylidenepyrimido[4,5-e][1,4 ,10] Oxadiazacyclotridecen-7(13H)-one;

1-(3-Chloro-4-fluorophenyl)-11-methyl-1,2,3,5,6,7,8,11-octahydro-9H-14,16-vinylidene-13 , 10-(endomethylene)pyrido[4,3-e][1,4,10,11,14]oxa tetraazacycloheptadecen-9-one;

1-(3-Chloro-4-fluorophenyl)-8,11-dimethyl-1,2,3,5,6,7,8,11-octahydro-9H-14,16-vinylidene Base-13,10-(methenylene)pyrido[4,3-e][1,4,10,11,14]oxa tetraazacycloheptadecen-9-one;

1-(3-Chloro-4-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-vinylidene-13,10 -(methenylene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecen-9(2H)-one;

1-(3-Chloro-4-fluorophenyl)-7,10-dimethyl-1,2,3,6,7,10-hexahydro-13,15-vinylidene-12,9- (Methylene)pyrido[3,4-l][1,4,7,8,14]oxatetraazacyclohexadecen-8(5H)-one;

1-(3-Chloro-4-fluorophenyl)-8,11-dimethyl-1,3,4,8,9,11-hexahydro-2H-14,16-vinylidene-13, 10-(methenylene)pyrido[3,4-l][1,4,7,8,14]oxatetraazacyclohexadecen-7(6H)-one;

N-cyclopropyl-3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-vinylidene-13, 10-(methenylidene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecen-1(11H)-yl]benzamide;

3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-vinylidene-13,10-(methano Enyl)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecen-1(11H)-yl]-N-(prop-2-yl)benzyl Amide;

N-methyl-3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-vinylidene-13,10 -(methenylene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecen-1(11H)-yl]benzamide;

1-(3,4-Dichloro-2-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-vinylidene- 13,10-(methenylene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecen-9(2H)-one;

1-(3-Chloro-2-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-vinylidene-13,10 -(methenylene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecen-9(2H)-one;

2-[1-(3-Chloro-4-fluorophenyl)-11-methyl-9-oxo-1,2,3,4,5,6,7,11-octahydro-14,16 -Ethylene-13,10-(methenylene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecene-8(9H)- Base]-N-methylacetamide;

15-(3-Chloro-4-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene-3,6 -(methenylene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one;

N-[1-(3-Chloro-4-fluorophenyl)-2,3,6,7-tetrahydro-1H,5H-9,11-vinylidenepyrido[4,3-e][ 1,9,4]dioxazacyclododecen-6-yl]prop-2-enamide;

N-[1-(3-Chloro-4-fluorophenyl)-2,3,6,7-tetrahydro-1H,5H-9,11-vinylidenepyrido[4,3-e][ 1,9,4]dioxazacyclododecen-6-yl]acrylamide;

N-[1-(3-chloro-4-fluorophenyl)-4-methyl-2,3,4,5,6,7-hexahydro-1H-9,11-vinylidene pyrido[ 4,3-i][1,5,8]oxadiazacyclododecen-6-yl]prop-2-enamide;

15-(3-Chloro-4-fluorophenyl)-5,12-dimethyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene- 3,6-(methenylene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one;

15-(4-Chloro-3-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene-3,6 -(methenylene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one;

15-(3,4-Dichlorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene-3,6- (Ethomylenyl)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one;

15-(3-Chloro-4-fluorophenyl)-5,8-dimethyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene- 3,6-(methenylene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one;

10-(3-Chloro-4-fluorophenyl)-4,5,6,7,9,10-hexahydro-8H-2,14-vinylidenepyrido[3,4-d][1 ,3,6,9] oxatriazacyclododecen-8-one;

1-(3-Chloro-4-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-9,11-vinylidenepyrido[4,3-i][1 ,5,8] oxadiazacyclododecen-3-one;

15-(3,4-Dichloro-2-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene- 3,6-(methenylidene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one; and

7-Chloro-8-fluoro-17-methyl-5,13,14,17-tetrahydro-10H-1,20-vinylidene-19,16-(methenylidene)pyrido[4 ,3-b][14,1,4,7,8,11]benzo 㗁pentaazacyclohexadecen-15(12H)-one;

or a pharmaceutically acceptable salt thereof.

1-(3-氯-4-氟苯基)-2,3,5,6,7,8-六氫-10,12-橋亞乙烯基吡啶并[4,3- e][1,4,7,10]氧雜三氮雜環十三烯-9(1 H)-酮 2

1-(3-氯-4-氟苯基)-2,3,5,6,7,8-六氫-10,12-橋亞乙烯基吡啶并[4,3- e][1,4,10]氧雜二氮雜環十三烯-9(1 H)-酮 3

1-(3-氯-4-氟苯基)-17-甲氧基-2,3,5,6,7,8-六氫-10,12-橋亞乙烯基吡啶并[4,3- e][1,4,7,10]氧雜三氮雜環十三烯-9(1 H)-酮 4

1-(3-氯-2-氟苯基)-2,3,5,6,7,8-六氫-10,12-橋亞乙烯基吡啶并[4,3- e][1,4,7,10]氧雜三氮雜環十三烯-9(1 H)-酮 5

(3 R)-1-(3-氯-4-氟苯基)-3-甲基-2,3,5,6,7,8-六氫-10,12-橋亞乙烯基吡啶并[4,3- e][1,4,7,10]氧雜三氮雜環十三烯-9(1 H)-酮 6

(3S)-1-(3-氯-4-氟苯基)-3-甲基-2,3,5,6,7,8-六氫-10,12-橋亞乙烯基吡啶并[4,3- e][1,4,7,10]氧雜三氮雜環十三烯-9(1 H)-酮 7

1-(3-氯-4-氟苯基)-3,3-二甲基-2,3,5,6,7,8-六氫-10,12-橋亞乙烯基吡啶并[4,3- e][1,4,7,10]氧雜三氮雜環十三烯-9(1 H)-酮 8

(5 S)-1-(3-氯-4-氟苯基)-5-甲基-2,3,5,6,7,8-六氫-10,12-橋亞乙烯基吡啶并[4,3- e][1,4,7,10]氧雜三氮雜環十三烯-9(1 H)-酮 9

(7 R)-1-(3-氯-4-氟苯基)-7-甲基-2,3,5,6,7,8-六氫-10,12-橋亞乙烯基吡啶并[4,3- e][1,4,7,10]氧雜三氮雜環十三烯-9(1 H)-酮 10

12-(3-氯-4-氟苯基)-1-甲基-4,13,14,16-四氫-1 H-6,8-橋亞乙烯基吡唑并[4,3- k]吡啶并[4,3- e][1,4,7,10]氧雜三氮雜環十三烯-5(12 H)-酮 11

14-(3-氯-4-氟苯基)-5-甲基-5,9,10,12,13,14-六氫-2,18-橋亞乙烯基-3,6-(橋亞甲烯基)吡啶并[3,4- l][1,4,7,8,11,14]氧雜五氮雜環十六烯-7(8 H)-酮 12

1-(3-氯-4-氟苯基)-10-甲基-1,2,3,6,7,10-六氫-12,9-(橋氮烯基)-13,15-橋亞乙烯基吡啶并[3,4- l][1,4,7,14]氧雜三氮雜環十六烯-8(5 H)-酮 13

7-氯-6-氟-14-甲基-5,13,14,17-四氫-10 H-19,16-(橋氮烯基)-1,20-橋亞乙烯基吡啶并[4,3- b][14,1,8,11]苯并㗁三氮雜環十七烯-15(12 H)-酮 14

7-氯-6-氟-14,17-二甲基-5,13,14,17-四氫-10 H-19,16-(橋氮烯基)-1,20-橋亞乙烯基吡啶并[4,3- b][14,1,8,11]苯并㗁三氮雜環十七烯-15(12 H)-酮 15

7-氯-6-氟-14,17-二甲基-5,13,14,17-四氫-10 H-1,20-橋亞乙烯基-19,16-(橋亞甲烯基)吡啶并[4,3- b][14,1,4,7,8,11]苯并㗁五氮雜環十七烯-15(12 H)-酮 16

7-氯-6-氟-14-甲基-13,14-二氫-10 H,17 H-19,16-(橋氮烯基)-1,20-橋亞乙烯基吡啶并[4,3- b][1,14,8,11]苯并二氧雜二氮雜環十七烯-15(12 H)-酮 17

7-氯-8-氟-13,14-二氫-10 H,17 H-19,16-(橋氮烯基)-1,20-橋亞乙烯基吡啶并[4,3- b][1,14,8,11]苯并二氧雜二氮雜環十七烯-15(12 H)-酮 18

7-氯-6-氟-13,14-二氫-10 H,17 H-19,16-(橋氮烯基)-1,20-橋亞乙烯基吡啶并[4,3- b][1,14,8,11]苯并二氧雜二氮雜環十七烯-15(12 H)-酮 19

7-氯-6-氟-14,17-二甲基-13,14-二氫-10 H,17 H-19,16-(橋氮烯基)-1,20-橋亞乙烯基吡啶并[4,3- b][1,14,8,11]苯并二氧雜二氮雜環十七烯-15(12 H)-酮 20

16-氯-17-氟-8-甲基-8,9,10,11,13,18-六氫-7 H-4,6-橋亞乙烯基吡啶并[4,3- b][11,1,4,7]苯并㗁三氮雜環十四烯-7-酮 21

16-氯-17-氟-8,9,10,11,13,18-六氫-7 H-4,6-橋亞乙烯基吡啶并[4,3- b][11,1,4,7]苯并㗁三氮雜環十四烯-7-酮 22

(13 R)-16-氯-17-氟-13-甲基-8,9,10,11,13,18-六氫-7 H-4,6-橋亞乙烯基吡啶并[4,3- b][11,1,4,7]苯并㗁三氮雜環十四烯-7-酮 23

(13 S)-16-氯-17-氟-7-側氧基-8,9,10,11,13,18-六氫-7 H-4,6-橋亞乙烯基吡啶并[4,3- b][11,1,4,7]苯并㗁三氮雜環十四烯-13-甲腈 24

(9 R)-16-氯-17-氟-9-甲基-8,9,10,11,13,18-六氫-7 H-4,6-橋亞乙烯基吡啶并[4,3- b][11,1,4,7]苯并㗁三氮雜環十四烯-7-酮 25

16-氯-17-氟-8-甲基-8,9,10,11-四氫-7 H,13 H-4,6-橋亞乙烯基吡啶并[4,3- b][1,11,7]苯并二氧雜氮雜環十四烯-7-酮 26

16-氯-17-氟-8-甲基-8,9,10,11-四氫-7 H,13 H-4,6-橋亞乙烯基吡啶并[4,3- b][11,1,7]苯并㗁三氮雜環十四烯-7-酮 27

7-氯-6-氟-15-甲基-5,12,13,15-四氫-10 H-1,18-橋亞乙烯基吡唑并[4,3- f]吡啶并[4,3- b][8,11,1,4]苯并二氧雜二氮雜環十四烯 28

7-氯-6-氟-15-甲基-5,12,13,15-四氫-10 H-1,18-橋亞乙烯基吡唑并[4,3- f]吡啶并[4,3- b][8,11,1]苯并二氧雜氮雜環十四烯 29

7-氯-15-甲基-5,12,13,15-四氫-10 H-1,18-橋亞乙烯基吡唑并[4,3- f]吡啶并[4,3- b][8,11,1]苯并二氧雜氮雜環十四烯 30

15-甲基-5,12,13,15-四氫-10 H-1,18-橋亞乙烯基吡唑并[4,3- f]嘧啶并[4,5- b][8,11,1,4]苯并二氧雜二氮雜環十四烯 31

7-氯-15-甲基-5,12,13,15-四氫-10 H-1,18-橋亞乙烯基吡唑并[4,3- f]嘧啶并[4,5- b][8,11,1]苯并二氧雜氮雜環十四烯 32

7,15-二甲基-5,12,13,15-四氫-10 H-1,18-橋亞乙烯基吡唑并[4,3- m]吡啶并[3,4- f]嘧啶并[4,5- i][1,4,8]二氧雜氮雜環十四烯 33

7-氯-6-氟-5,10,12,13-四氫-1,19-橋亞乙烯基二吡啶并[4,3- b:2',3'- f][8,11,1]苯并二氧雜氮雜環十四烯 34

7-氯-6,17-二氟-5,10,12,13-四氫-1,19-橋亞乙烯基二苯并[ e, l]吡啶并[3,4- i][1,4,8,11]二氧雜二氮雜環十四烯 35

15-(3-氯-4-氟苯基)-8,9,10,11,14,15-六氫-4,6-橋亞乙烯基嘧啶并[4,5-e][1,4,10]氧雜二氮雜環十三烯-7(13H)-酮 36

1-(3-氯-4-氟苯基)-11-甲基-1,2,3,5,6,7,8,11-八氫-9H-14,16-橋亞乙烯基-13,10-(橋亞甲烯基)吡啶并[4,3-e][1,4,10,11,14]氧雜四氮雜環十七烯-9-酮 37

1-(3-氯-4-氟苯基)-8,11-二甲基-1,2,3,5,6,7,8,11-八氫-9H-14,16-橋亞乙烯基-13,10-(橋亞甲烯基)吡啶并[4,3-e][1,4,10,11,14]氧雜四氮雜環十七烯-9-酮 38

1-(3-氯-4-氟苯基)-11-甲基-1,3,4,5,6,7,8,11-八氫-14,16-橋亞乙烯基-13,10-(橋亞甲烯基)吡啶并[4,3-m][1,2,5,9,12]五氮雜環十七烯-9(2H)-酮 39

1-(3-氯-4-氟苯基)-7,10-二甲基-1,2,3,6,7,10-六氫-13,15-橋亞乙烯基-12,9-(橋亞甲烯基)吡啶并[3,4-l][1,4,7,8,14]氧雜四氮雜環十六烯-8(5H)-酮 40

1-(3-氯-4-氟苯基)-8,11-二甲基-1,3,4,8,9,11-六氫-2H-14,16-橋亞乙烯基-13,10-(橋亞甲烯基)吡啶并[3,4-l][1,4,7,8,14]氧雜四氮雜環十七烯-7(6H)-酮 41

7-氯-8-氟-17-甲基-5,13,14,17-四氫-10H-1,20-橋亞乙烯基-19,16-(橋亞甲烯基)吡啶并[4,3-b][14,1,4,7,8,11]苯并㗁五氮雜環十七烯-15(12H)-酮 42

N-環丙基-3-[11-甲基-9-側氧基-2,3,4,5,6,7,8,9-八氫-14,16-橋亞乙烯基-13,10-(橋亞甲烯基)吡啶并[4,3-m][1,2,5,9,12]五氮雜環十七烯-1(11H)-基]苯甲醯胺 43

3-[11-甲基-9-側氧基-2,3,4,5,6,7,8,9-八氫-14,16-橋亞乙烯基-13,10-(橋亞甲烯基)吡啶并[4,3-m][1,2,5,9,12]五氮雜環十七烯-1(11H)-基]-N-(丙-2-基)苯甲醯胺 44

N-甲基-3-[11-甲基-9-側氧基-2,3,4,5,6,7,8,9-八氫-14,16-橋亞乙烯基-13,10-(橋亞甲烯基)吡啶并[4,3-m][1,2,5,9,12]五氮雜環十七烯-1(11H)-基]苯甲醯胺 45

1-(3,4-二氯-2-氟苯基)-11-甲基-1,3,4,5,6,7,8,11-八氫-14,16-橋亞乙烯基-13,10-(橋亞甲烯基)吡啶并[4,3-m][1,2,5,9,12]五氮雜環十七烯-9(2H)-酮 46

1-(3-氯-2-氟苯基)-11-甲基-1,3,4,5,6,7,8,11-八氫-14,16-橋亞乙烯基-13,10-(橋亞甲烯基)吡啶并[4,3-m][1,2,5,9,12]五氮雜環十七烯-9(2H)-酮 47

2-[1-(3-氯-4-氟苯基)-11-甲基-9-側氧基-1,2,3,4,5,6,7,11-八氫-14,16-橋亞乙烯基-13,10-(橋亞甲烯基)吡啶并[4,3-m][1,2,5,9,12]五氮雜環十七烯-8(9H)-基]-N-甲基乙醯胺 48

15-(3-氯-4-氟苯基)-5-甲基-8,9,10,11,12,13,14,15-八氫-2,19-橋亞乙烯基-3,6-(橋亞甲烯基)吡啶并[3,4-f][1,2,5,8,11,15]六氮雜環十七烯-7(5H)-酮 49

N-[1-(3-氯-4-氟苯基)-2,3,6,7-四氫-1H,5H-9,11-橋亞乙烯基吡啶并[4,3-e][1,9,4]二氧雜氮雜環十二烯-6-基]丙-2-烯醯胺 50

N-[1-(3-氯-4-氟苯基)-2,3,6,7-四氫-1H,5H-9,11-橋亞乙烯基吡啶并[4,3-e][1,9,4]二氧雜氮雜環十二烯-6-基]丙醯胺 51

N-[1-(3-氯-4-氟苯基)-4-甲基-2,3,4,5,6,7-六氫-1H-9,11-橋亞乙烯基吡啶并[4,3-i][1,5,8]氧雜二氮雜環十二烯-6-基]丙-2-烯醯胺 52

15-(3-氯-4-氟苯基)-5,12-二甲基-8,9,10,11,12,13,14,15-八氫-2,19-橋亞乙烯基-3,6-(橋亞甲烯基)吡啶并[3,4-f][1,2,5,8,11,15]六氮雜環十七烯-7(5H)-酮 53

15-(4-氯-3-氟苯基)-5-甲基-8,9,10,11,12,13,14,15-八氫-2,19-橋亞乙烯基-3,6-(橋亞甲烯基)吡啶并[3,4-f][1,2,5,8,11,15]六氮雜環十七烯-7(5H)-酮 54

15-(3,4-二氯苯基)-5-甲基-8,9,10,11,12,13,14,15-八氫-2,19-橋亞乙烯基-3,6-(橋亞甲烯基)吡啶并[3,4-f][1,2,5,8,11,15]六氮雜環十七烯-7(5H)-酮 55

15-(3-氯-4-氟苯基)-5,8-二甲基-8,9,10,11,12,13,14,15-八氫-2,19-橋亞乙烯基-3,6-(橋亞甲烯基)吡啶并[3,4-f][1,2,5,8,11,15]六氮雜環十七烯-7(5H)-酮 56

10-(3-氯-4-氟苯基)-4,5,6,7,9,10-六氫-8H-2,14-橋亞乙烯基吡啶并[3,4-d][1,3,6,9]氧雜三氮雜環十二烯-8-酮 57

1-(3-氯-4-氟苯基)-1,2,4,5,6,7-六氫-3H-9,11-橋亞乙烯基吡啶并[4,3-i][1,5,8]氧雜二氮雜環十二烯-3-酮 58

15-(3,4-二氯-2-氟苯基)-5-甲基-8,9,10,11,12,13,14,15-八氫-2,19-橋亞乙烯基-3,6-(橋亞甲烯基)吡啶并[3,4-f][1,2,5,8,11,15]六氮雜環十七烯-7(5H)-酮 及其醫藥學上可接受之鹽。 Illustrative examples of compounds of formulas (I to XIV) are shown below: example structure name 1

1-(3-Chloro-4-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-vinylidenepyrido[4,3- e ][1,4 ,7,10]oxatriazacyclotridecen-9(1 H )-one 2

1-(3-Chloro-4-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-vinylidenepyrido[4,3- e ][1,4 ,10] Oxadiazatridecen-9(1 H )-one 3

1-(3-Chloro-4-fluorophenyl)-17-methoxy-2,3,5,6,7,8-hexahydro-10,12-vinylidenepyrido[4,3- e ][1,4,7,10]oxatriazacyclotridecen-9(1 H )-one 4

1-(3-Chloro-2-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-vinylidenepyrido[4,3- e ][1,4 ,7,10]oxatriazacyclotridecen-9(1 H )-one 5

(3 R )-1-(3-chloro-4-fluorophenyl)-3-methyl-2,3,5,6,7,8-hexahydro-10,12-vinylidene pyrido[ 4,3- e ][1,4,7,10]oxatriazacyclotridecen-9(1 H )-one 6

(3S)-1-(3-Chloro-4-fluorophenyl)-3-methyl-2,3,5,6,7,8-hexahydro-10,12-vinylidenepyrido[4 ,3- e ][1,4,7,10]oxatriazacyclotridecen-9(1 H )-one 7

1-(3-Chloro-4-fluorophenyl)-3,3-dimethyl-2,3,5,6,7,8-hexahydro-10,12-vinylidenepyrido[4, 3- e ][1,4,7,10]oxatriazacyclotridecen-9(1 H )-one 8

(5 S )-1-(3-Chloro-4-fluorophenyl)-5-methyl-2,3,5,6,7,8-hexahydro-10,12-vinylidene pyrido[ 4,3- e ][1,4,7,10]oxatriazacyclotridecen-9(1 H )-one 9

(7 R )-1-(3-chloro-4-fluorophenyl)-7-methyl-2,3,5,6,7,8-hexahydro-10,12-vinylidene pyrido[ 4,3- e ][1,4,7,10]oxatriazacyclotridecen-9(1 H )-one 10

12-(3-Chloro-4-fluorophenyl)-1-methyl-4,13,14,16-tetrahydro-1 H -6,8-vinylidenepyrazolo[4,3- k ]pyrido[4,3- e ][1,4,7,10]oxatriazacyclotridecen-5(12 H )-one 11

14-(3-Chloro-4-fluorophenyl)-5-methyl-5,9,10,12,13,14-hexahydro-2,18-vinylidene-3,6-( Methenyl)pyrido[3,4- l ][1,4,7,8,11,14]oxapentaazacyclohexadecen-7(8 H )-one 12

1-(3-Chloro-4-fluorophenyl)-10-methyl-1,2,3,6,7,10-hexahydro-12,9-(oxazoenyl)-13,15-bridge Vinylidenepyrido[3,4- l ][1,4,7,14]oxatriazacyclohexadecen-8(5 H )-one 13

7-Chloro-6-fluoro-14-methyl-5,13,14,17-tetrahydro-10 H -19,16-(azazoenyl)-1,20-vinylidenepyrido[4 ,3- b ][14,1,8,11]benzotriazacycloheptadecen-15(12 H )-one 14

7-Chloro-6-fluoro-14,17-dimethyl-5,13,14,17-tetrahydro-10 H -19,16-(azazenyl)-1,20-vinylidenepyridine And[4,3- b ][14,1,8,11]benzotriazacycloheptadecen-15(12 H )-one 15

7-Chloro-6-fluoro-14,17-dimethyl-5,13,14,17-tetrahydro-10 H -1,20-vinylidene-19,16-(methenylene) Pyrido[4,3- b ][14,1,4,7,8,11]benzozacyclohexadecen-15(12 H )-one 16

7-Chloro-6-fluoro-14-methyl-13,14-dihydro-10 H ,17 H -19,16-(azazoenyl)-1,20-vinylidene pyrido[4, 3- b ][1,14,8,11]benzodioxadiazacyclohexadecen-15(12 H )-one 17

[ _ _ 1,14,8,11]benzodioxadiazacyclohexadecen-15(12 H )-one 18

[ _ _ 1,14,8,11]benzodioxadiazacyclohexadecen-15(12 H )-one 19

7-Chloro-6-fluoro-14,17-dimethyl-13,14-dihydro-10 H ,17 H -19,16-(azazenyl)-1,20-vinylidene pyrido [4,3- b ][1,14,8,11]benzodioxadiazacyclohexadecen-15(12 H )-one 20

16-Chloro-17-fluoro-8-methyl- 8,9,10,11,13,18 -hexahydro-7H-4,6-vinylidenepyrido[4,3- b ][11 ,1,4,7]Benzotriazacyclotetradecen-7-one twenty one

16-Chloro-17-fluoro-8,9,10,11,13,18-hexahydro-7H-4,6-vinylidenepyrido[4,3- b ][ 11,1,4 , 7] Benzotriazacyclotetradecen-7-one twenty two

(13 R )-16-chloro-17-fluoro-13-methyl-8,9,10,11,13,18-hexahydro-7 H -4,6-vinylidenepyrido[4,3 - b ][11,1,4,7]benzotriazacyclotetradecen-7-one twenty three

(13 S )-16-Chloro-17-fluoro-7-oxo- 8,9,10,11,13,18 -hexahydro-7H-4,6-vinylidenepyrido[4, 3- b ][11,1,4,7]benzotriazacyclotetradecene-13-carbonitrile twenty four

(9 R )-16-Chloro-17-fluoro-9-methyl-8,9,10,11,13,18-hexahydro-7 H -4,6-vinylidenepyrido[4,3 - b ][11,1,4,7]benzotriazacyclotetradecen-7-one 25

16-Chloro-17-fluoro-8-methyl-8,9,10,11-tetrahydro-7 H ,13 H -4,6-vinylidenepyrido[4,3- b ][1, 11,7] Benzodioxazacyclotetradecen-7-one 26

16-Chloro-17-fluoro-8-methyl-8,9,10,11-tetrahydro-7 H ,13 H -4,6-vinylidenepyrido[4,3- b ][11, 1,7]Benzotriazacyclotetradecen-7-one 27

7-Chloro-6-fluoro-15-methyl-5,12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- f ]pyrido[4, 3- b ][8,11,1,4]benzodioxadiazacyclotetradecene 28

7-Chloro-6-fluoro-15-methyl-5,12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- f ]pyrido[4, 3- b ][8,11,1]benzodioxazacyclotetradecene 29

7-Chloro-15-methyl-5,12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- f ]pyrido[4,3- b ] [8,11,1]benzodioxazacyclotetradecene 30

15-methyl-5,12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- f ]pyrimido[4,5- b ][8,11 ,1,4]benzodioxadiazacyclotetradecene 31

7-Chloro-15-methyl-5,12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- f ]pyrimido[4,5- b ] [8,11,1]benzodioxazacyclotetradecene 32

7,15-Dimethyl-5,12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- m ]pyrido[3,4- f ]pyrimidine And[4,5- i ][1,4,8]dioxazacyclotetradecene 33

7-Chloro-6-fluoro-5,10,12,13-tetrahydro-1,19-vinylidenedipyrido[4,3- b :2',3'- f ][8,11, 1] Benzodioxazacyclotetradecene 34

7-Chloro-6,17-difluoro-5,10,12,13-tetrahydro-1,19-vinylidene dibenzo[ e , l ]pyrido[3,4- i ][1, 4,8,11] dioxadiazacyclotetradecene 35

15-(3-Chloro-4-fluorophenyl)-8,9,10,11,14,15-hexahydro-4,6-vinylidenepyrimido[4,5-e][1,4 ,10]Oxadiazatridecen-7(13H)-one 36

1-(3-Chloro-4-fluorophenyl)-11-methyl-1,2,3,5,6,7,8,11-octahydro-9H-14,16-vinylidene-13 ,10-(methenylidene)pyrido[4,3-e][1,4,10,11,14]oxatetraazacycloheptadecen-9-one 37

1-(3-Chloro-4-fluorophenyl)-8,11-dimethyl-1,2,3,5,6,7,8,11-octahydro-9H-14,16-vinylidene Base-13,10-(methenylene)pyrido[4,3-e][1,4,10,11,14]oxatetraazacycloheptadecen-9-one 38

1-(3-Chloro-4-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-vinylidene-13,10 -(methenylidene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecen-9(2H)-one 39

1-(3-Chloro-4-fluorophenyl)-7,10-dimethyl-1,2,3,6,7,10-hexahydro-13,15-vinylidene-12,9- (Ethomylenyl)pyrido[3,4-l][1,4,7,8,14]oxatetraazacyclohexadecen-8(5H)-one 40

1-(3-Chloro-4-fluorophenyl)-8,11-dimethyl-1,3,4,8,9,11-hexahydro-2H-14,16-vinylidene-13, 10-(Methenomylene)pyrido[3,4-l][1,4,7,8,14]oxatetraazacyclohexadecen-7(6H)-one 41

7-Chloro-8-fluoro-17-methyl-5,13,14,17-tetrahydro-10H-1,20-vinylidene-19,16-(methenylidene)pyrido[4 ,3-b][14,1,4,7,8,11]Benzopentaazacyclohexadecen-15(12H)-one 42

N-cyclopropyl-3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-vinylidene-13, 10-(methenylidene)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecen-1(11H)-yl]benzamide 43

3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-vinylidene-13,10-(methano Enyl)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecen-1(11H)-yl]-N-(prop-2-yl)benzyl Amide 44

N-methyl-3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-vinylidene-13,10 -(methenylene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecen-1(11H)-yl]benzamide 45

1-(3,4-Dichloro-2-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-vinylidene- 13,10-(Methylene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecen-9(2H)-one 46

1-(3-Chloro-2-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-vinylidene-13,10 -(methenylidene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecen-9(2H)-one 47

2-[1-(3-Chloro-4-fluorophenyl)-11-methyl-9-oxo-1,2,3,4,5,6,7,11-octahydro-14,16 -Ethylene-13,10-(methenylene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecene-8(9H)- base]-N-methylacetamide 48

15-(3-Chloro-4-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene-3,6 -(methenylene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one 49

N-[1-(3-Chloro-4-fluorophenyl)-2,3,6,7-tetrahydro-1H,5H-9,11-vinylidenepyrido[4,3-e][ 1,9,4]dioxazacyclododecen-6-yl]prop-2-enamide 50

N-[1-(3-Chloro-4-fluorophenyl)-2,3,6,7-tetrahydro-1H,5H-9,11-vinylidenepyrido[4,3-e][ 1,9,4]dioxazacyclododecen-6-yl]acrylamide 51

N-[1-(3-chloro-4-fluorophenyl)-4-methyl-2,3,4,5,6,7-hexahydro-1H-9,11-vinylidene pyrido[ 4,3-i][1,5,8]oxadiazacyclododecen-6-yl]prop-2-enamide 52

15-(3-Chloro-4-fluorophenyl)-5,12-dimethyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene- 3,6-(methenylene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one 53

15-(4-Chloro-3-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene-3,6 -(methenylene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one 54

15-(3,4-Dichlorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene-3,6- (Ethomylenyl)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one 55

15-(3-Chloro-4-fluorophenyl)-5,8-dimethyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene- 3,6-(methenylene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one 56

10-(3-Chloro-4-fluorophenyl)-4,5,6,7,9,10-hexahydro-8H-2,14-vinylidenepyrido[3,4-d][1 ,3,6,9]oxatriazacyclododecen-8-one 57

1-(3-Chloro-4-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-9,11-vinylidenepyrido[4,3-i][1 ,5,8]oxadiazacyclododecen-3-one 58

15-(3,4-Dichloro-2-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene- 3,6-(methenylene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one and pharmaceutically acceptable salts thereof.

Those skilled in the art will recognize that the materials listed or described herein are not exhaustive and that other materials within the scope of these defined terms may also be selected. pharmaceutical composition

For therapeutic purposes, pharmaceutical compositions comprising the compounds described herein may further comprise one or more pharmaceutically acceptable excipients. A pharmaceutically acceptable excipient is a substance that is nontoxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredients. Examples of pharmaceutically acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, colorants, bulking agents, emulsifiers or taste regulators. In a preferred embodiment, the pharmaceutical composition of the present invention is a sterile composition. Pharmaceutical compositions can be prepared using compounding techniques known or available to those skilled in the art.

The invention also encompasses sterile compositions, including compositions that comply with national and regional regulations governing such compositions.

The pharmaceutical compositions and compounds described herein can be formulated as solutions, emulsions, suspensions or dispersions in suitable pharmaceutical solvents or carriers according to conventional methods known in the art for the preparation of various dosage forms, or with Solid carriers are formulated together as pills, lozenges, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution or capsules. The pharmaceutical compositions of the invention may be administered by a suitable route of delivery such as oral, parenteral, rectal, nasal, topical or ocular routes, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.

For oral administration, the compounds of the invention may be provided in solid form such as tablets or capsules, or in the form of solutions, emulsions or suspensions. For preparation of oral compositions, the compounds of the invention may be formulated to yield, for example, a dosage of about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 to 250 mg per day, or about 250 mg to 1 g per day . Oral lozenges may contain the active ingredient in admixture with compatible pharmaceutically acceptable excipients such as diluents, disintegrants, binders, lubricating agents, sweeteners, flavoring agents, coloring agents, etc. agents and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, dextrose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral vehicles include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrants. Binders may include starch and gelatin. Lubricants, if present, can be magnesium stearate, stearic acid or talc. Tablets may, if desired, be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or with an enteric coating.

Capsules for oral administration include hard gelatin capsules and soft gelatin capsules. For the preparation of hard gelatin capsules, the active ingredient may be admixed with a solid, semi-solid or liquid diluent. Soft gelatin capsules can be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono- and diglycerides of short-chain fatty acids, polyethylene glycol 400, or propylene glycol.

Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid compositions optionally contain: pharmaceutically acceptable excipients such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose gelatin, aluminum stearate gel, and the like); non-aqueous vehicles such as oils (such as almond oil or fractionated coconut oil), propylene glycol, ethanol, or water; preservatives (such as methylparaben ester or propylparaben or sorbic acid); humectants such as lecithin; and flavoring or coloring agents if desired.

For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal or subcutaneous routes, the agents of the invention may be in the form of sterile aqueous solutions or suspensions buffered to appropriate pH and isotonicity or in parenterally acceptable oils. form available. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit dosage form, such as ampoules or disposable injection devices, in multidose form, such as vials from which the appropriate dose may be withdrawn, or in solid form or pre-concentrates useful in the preparation of injectable formulations. Illustrative infusion doses range from about 1 to 1000 μg/kg per minute of medicament mixed with pharmaceutical carrier over a period ranging from minutes to days.

For nasal, inhalation or oral administration, the pharmaceutical compositions of the invention may be administered, for example, using a spray formulation also containing a suitable carrier. Compositions of the invention may be formulated for rectal administration in the form of suppositories.

For topical administration, the compounds of the invention are preferably formulated in a cream or ointment or similar vehicle suitable for topical administration. For topical administration, the compounds of the invention may be mixed with a pharmaceutical carrier at a concentration of from about 0.1% to about 10% drug:vehicle. Another mode of administration of the agents of the invention may utilize patch formulations to achieve transdermal delivery.

As used herein, the terms "treat/treatment" encompass both "prophylactic" and "curative" treatments. "Prophylactic" treatment is intended to indicate the delay in the onset of a disease, disease symptoms or medical condition, the suppression of symptoms that may occur, or the reduction of the risk of the onset or recurrence of a disease or symptoms. "Curative" treatment includes reducing the severity or preventing the progression of an existing disease, symptom or condition. Thus, treatment includes amelioration of existing disease symptoms or preventing their worsening; preventing other symptoms from developing; To regress; to alleviate the condition caused by a disease or disorder; or to cause the symptoms of a disease or disorder to cease.

The term "subject" refers to a mammalian patient, such as a human, in need of such treatment.

Exemplary diseases include cancer, pain, neurological disease, autoimmune disease, and inflammation. As used herein, the term "cancer" includes, but is not limited to, ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER ⁺ breast cancer, colon adenocarcinoma , glioblastoma, glioblastoma multiforme, degenerative thyroid cancer, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelial hemangioendothelioma, Intrahepatic cholangiocarcinoma, papillary thyroid carcinoma, spitzoid neoplasm, sarcoma, astrocytoma, lower-grade glioma of the brain, secretory breast cancer, breast-like carcinoma, acute myeloid leukemia, Congenital mesodermal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, skin melanoma, head and neck squamous cell carcinoma, pediatric glioma CML, prostate cancer, lung squamous carcinoma, ovary Serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, and serous and clear cell endometrial carcinoma. In some embodiments, the cancer includes lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophagus-gastric cancer, glioblastoma, head and neck cancer, inflammatory myofibroblastic tumor, and degenerative Large cell lymphoma. Pain includes, for example, pain from any source or etiology, including cancer pain, pain from chemotherapeutic treatment, nerve pain, pain from injury, or pain from other sources. Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren syndrome, type 1 diabetes, and lupus. Exemplary neurological diseases include Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Huntington's disease. Exemplary inflammatory diseases include atherosclerosis, allergies, and inflammation from infection or injury.

In one aspect, the compounds and pharmaceutical compositions of the invention specifically target tyrosine receptor kinases, in particular EGFR. Accordingly, these compounds and pharmaceutical compositions are useful for preventing, reversing, slowing or inhibiting the activity of one or more of these kinases. In preferred embodiments, the method of treatment targets cancer. In other embodiments, the methods are used to treat lung cancer or non-small cell lung cancer.

In the inhibitory method of the present invention, "effective amount" means an amount sufficient to inhibit the target protein. Measuring such target adjustments can be performed by conventional analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cell is preferably a cancer cell with aberrant signaling due to upregulation of EGFR.

In the methods of treatment of the present invention, "effective amount" means an amount or dosage generally sufficient to produce the desired therapeutic benefit in a subject in need of such treatment. The effective amount or dose of a compound of the present invention can be determined by conventional methods such as modeling, dose escalation or clinical trials, taking into account conventional factors such as the mode or route of administration or drug delivery, pharmacokinetics of the agent, infection The severity and course of the disease, the individual's health status, condition and weight, and the judgment of the treating physician. Exemplary dosages range from about 0.1 mg to 1 g per day, or from about 1 mg to 50 mg per day, or from about 50 to 250 mg per day, or from about 250 mg to 1 g per day. The total dose can be administered in single or divided dose units (eg, BID, TID, QID).

Once the patient's disease improves, the dose can be adjusted for prophylaxis or maintenance therapy. For example, the dosage or frequency of administration, or both, may be reduced as symptoms vary to maintain the desired therapeutic or prophylactic effect. Of course, treatment may be discontinued if symptoms have been relieved to an appropriate level. However, patients may require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require long-term ongoing treatment. drug combination

The compounds of the invention described herein may be used in combination with one or more other active ingredients in pharmaceutical compositions or methods to treat the diseases and conditions described herein. Other active ingredients include other therapies or agents that moderate the adverse effects of therapy for the intended disease target. Such combinations can be used to increase efficacy, ameliorate other disease symptoms, reduce one or more side effects, or reduce the required dosage of the compounds of the invention. The other active ingredient may be administered in a separate pharmaceutical composition from the compound of the invention or may be included with the compound of the invention in a single pharmaceutical composition. The other active ingredient may be administered simultaneously with, prior to, or subsequent to the administration of the compound of the invention.

Combination medicaments include other active ingredients that are known or found to be effective in treating the diseases and conditions described herein, including active ingredients that are active against another target associated with the disease. For example, the compositions and formulations and methods of treatment of the invention may further comprise other drugs or agents, such as other active agents useful in the treatment or alleviation of the target disease or associated symptoms or conditions. For cancer indications, other such agents include, but are not limited to, kinase inhibitors such as ALK inhibitors (e.g. crizotinib), Raf inhibitors (e.g. vemurafenib), VEGFR inhibitors agents (e.g. sunitinib); standard chemotherapeutic agents such as alkylating agents, antimetabolites, antineoplastic antibiotics, topoisomerase inhibitors, platinums, mitotic inhibitors, antibodies, hormones therapy or corticosteroids. For pain indications, suitable combination agents include anti-inflammatory drugs, such as NSAIDs. The pharmaceutical compositions of the invention may additionally comprise one or more such active agents, and methods of treatment may further comprise administering an effective amount of one or more such active agents. chemical synthesis method

The following examples are offered to illustrate, not limit, the invention. Those skilled in the art will recognize that the following synthetic reactions and schemes can be modified by selection of appropriate starting materials and reagents to obtain other compounds of formulas (I) to (XIV).

The proposed targets can be prepared by conventional chemical methods or following the general procedures shown below, which are illustrated using selected examples:

Process I

Process II

Process III

Process IV

Process V

Abbreviations: Examples described herein use materials including, but not limited to, described by the following abbreviations known to those skilled in the art: g Gram eq equivalent mmol millimolar mL ml EtOAc ethyl acetate MHz megahertz ppm millionth δ chemical shift the s Unimodal d double peak t triple peak q quartet quince quintet br broad peak m multiplet Hz hertz THF Tetrahydrofuran ℃ Celsius PE petroleum ether EA ethyl acetate _f blocking factor N equivalent J Coupling constant DMSO- d ₆ deuterated dimethyloxide n-BuOH Butanol DIEA n,n-Diisopropylethylamine TMS Trimethylsilyl min minute hr Hour Me methyl Et Ethyl i-Pr Isopropyl TLC TLC m mole Compd# Compound number MS mass spectrometry m/z mass-to-charge ratio Mrs. Methylsulfonyl FDPP pentafluorophenyl diphenyl phosphate Boc tertiary butoxycarbonyl TFA Trifluoroacetate Tos Tosyl DMAP 4-(Dimethylamino)pyridine mM micromole ATP Adenosine triphosphate _IC50 half maximum inhibitory concentration U/mL Units of activity per milliliter KHMDS Potassium bis(trimethylsilyl)amide DIAD Diisopropyl azodicarboxylate MeTHF 2-Methyltetrahydrofuran MOM Methoxymethyl DCM Dichloromethane DMF N , N -Dimethylformamide DPPA diphenylphosphoryl azide DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DIPEA N , N -Diisopropylethylamine SEM [2-(Trimethylsilyl)ethoxy]methylacetal Hex Hexane Pd(dppf)Cl ₂ [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) MeCN (ACN) Acetonitrile Pd ₂ (dba) ₃ Ginseng(dibenzylideneacetone)dipalladium(0) Hunig's Base N , N -Diisopropylethylamine TBAF Tertiary butylammonium fluoride PPh ₃ Triphenylphosphine RT room temperature p-TSA p-toluenesulfonic acid t-BuOH Tertiary butanol Pd(amphos)Cl ₂ Dichlorobis[di-tertiary butyl(4-dimethylaminophenyl)phosphine]palladium(II) mCPBA m-chloroperoxybenzoic acid AcOH Acetic acid DMAc N , N -Dimethylformamide BPD 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3, 2-dioxaborolane MTBE Methyl tertiary butyl ether BINAP 2,2'-bis(diphenylphosphino)-1,1-binaphthalene dppp 1,3-bis(diphenylphosphino)propane DME Dimethoxyethane LAH lithium aluminum hydride HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate T ₃ P Propylphosphonic anhydride LCMS liquid chromatography mass spectrometry NMR NMR spectroscopy NBS N-Bromobutanediamide AIBN Azobisisobutyronitrile TBAI tetrabutylammonium iodide ACN Acetonitrile FA formic acid HPLC HPLC Cbz Benzyloxycarbonyl DMS Dimethyl sulfide TBS Tertiary butyldimethylsilyl TEA Triethylamine Tf Trifluoromethanesulfonyl

General Method A

To a solution of A1-1 (1 equiv) and A1-2 (1.1 equiv) in ethanol (0.5M) was added a catalytic amount of KI and aqueous HCl (2N, 0.5% by volume ethanol). The solution was refluxed for 12 hours and the product A-1 precipitated, filtered and washed by ethanol.

Alternatively, A-1 can be prepared under palladium-catalyzed conditions:

To a mixture of A1-1 (1.0 eq) and A1-2 (1.1 eq) in anhydrous dioxane (0.1 M) was added Pd(dba) ₂ (0.04 eq), 2,2'-bis (Diphenylphosphino)-1,1-binaphthyl (0.045 equivalents) and sodium tertiary butoxide (1.5 equivalents). The mixture was refluxed for 7 hours or until the reaction was complete. The mixture was cooled, diluted with EtOAc, filtered through a pad of celite and concentrated. The residue was purified by silica gel column to obtain A-1.

A-1 to A-13 were prepared by general method A:

General Method B

To a solution of A2-1 (1 equiv) and B1-2 (1.1 equiv) in DMF (0.5M) was added _Cs2CO3 ( ₂ equiv). The mixture was heated at 100°C until the reaction was complete. The mixture was cooled, diluted with EtOAc, washed with water and brine, and dried _{over Na2SO4} . After filtration and condensation, the residue was purified by silica gel column to obtain B-1.

B-1 to B-4 were prepared by general method B:

General Method C

To a solution of A-1 (1.0 equiv) in DMF (1 M) was added phosphoryl chloride (2.0 equiv) dropwise at 0 °C. The solution was heated at 80 °C until the reaction was complete. After cooling, the reaction was quenched with methanol, diluted with EtOAc, and washed with water, _saturated aqueous _Na2CO3 and brine. The organic layer was dried _{over Na2SO4} , filtered and concentrated. The residue was purified by silica gel column to obtain C-1.

C-1 to C-6 were prepared by general method C:

General Method D

The alcohol starting material (1.0 equiv) was added to a suspension of NaH (60% in mineral oil, 1.1 equiv) in anhydrous THF (0.5 M) at ambient temperature. After 30 minutes, the halide compound (1.0 eq) was added to the above suspension. After the reaction was complete, the reaction was quenched with saturated aqueous ammonium chloride and extracted three times with EtOAc. The combined extracts were washed with brine, dried _{over Na2SO4} , filtered, concentrated and purified by silica gel column to give the product.

D-1 to D-12 were prepared by general method D:

General Method E

C-1 (1.0 equiv), Pd(OAc) ₂ (0.025 equiv), 1,3-bis(diphenylphosphino)propane (0.0325 equiv) and _Et3N ( 2 equivalents) in 1:1 MeOH/MeCN (0.1 M) was pumped into the reactor at a flow rate of 2.4 mL/min, and CO was pumped into the reactor at a flow rate of 12 mL _n /min middle. The reaction solution was concentrated and purified by silica gel column to obtain E-1.

E-1 to E-9 were prepared by general method E:

General Method F

To a solution of C- ₁ (1.0 equiv) and F1-2 (1.2 equiv) and _Cs2CO3 ( ₃ equiv) in DME/ _H2O (5:1, 0.2 M) was added Pd under N2 ( dppf)Cl2 ₍ 0.05 equiv). The mixture was stirred overnight at 85 °C, cooled to ambient temperature, and quenched with _H2O . The resulting mixture was extracted three times with EtOAc. The combined extracts were washed with brine and dried _over anhydrous _Na2SO4 . After filtration and condensation, the resulting residue was purified by silica gel chromatography to yield the desired product F-1.

F-1 to F-16 were prepared by General Method F:

General method G

E-1 (1.0 equiv) was added to a suspension of NaH (60% in mineral oil, 1.1 equiv) in anhydrous DMF (0.5 M) at ambient temperature. After 30 minutes, the alkyl halide G1-2 (1.0 eq) was added to the above suspension. After the reaction was complete, the reaction was quenched with saturated aqueous ammonium chloride and extracted three times with EtOAc. The combined extracts were washed with brine, dried _{over Na2SO4} , filtered, concentrated and purified by silica gel column to afford G-1.

G-1 to G-20 were prepared by general method G:

General method H

Step 1. To a solution of F-1 (1.0 equiv) in MeOH (0.2 M) was added LiOH (3 eq) in _H2O (1 M). The mixture was stirred at 60 °C until the hydrolysis reaction was complete. The solution was cooled to ambient temperature, concentrated to remove methanol, acidified by aqueous HCl ( ₁ N) until pH ~4-5, and then extracted with _CH2Cl2 . The combined extracts _were dried over _Na2SO4 , concentrated and dried in vacuo to give crude product.

Step _2. The crude solid was dissolved in _CH2Cl2 (0.2 M) and to the solution was added HCl in dioxane (4 eq HCl). The solution was stirred at 40 °C until de-Boc was complete. The solvent was removed in a rotary evaporator and the residue was dried in vacuo to give a crude solid which was used in the next step without purification.

Step 3. To a solution of the crude solid (1 equiv, assuming 100% yield from Step 1 and Step 2) in DMF (0.2 M) was added DIPEA (3 equiv) and pentafluorophenyl diphenylphosphate (FDPP) (1.1 eq). The solution was stirred at ambient temperature until amide formation was complete. The mixture was diluted with water and extracted three times with EtOAc. The combined extracts were washed three times with water, with aq. HCl (1 N), sat. _aq . _Na2CO3 and brine, dried _{over Na2SO4} and concentrated. The resulting residue was purified by silica gel column to obtain Example 1.

Examples 1 to 26 were prepared using General Method H:

General Method I

Step 1. To a solution of F-9 (1.0 equiv) in methanol (1.0 M) was added sodium borohydride (0.5 equiv) at ambient temperature, and the mixture was stirred until the reaction was complete. The reaction solution was quenched with aqueous HCl (1 M), followed by extraction with ethyl acetate. The combined organic layers were washed with brine and dried _{over Na2SO4} . After filtration and condensation, the residue was purified by silica gel column to obtain F9-2.

Step 2. To a solution of F9-2 (1.0 eq) and triphenylphosphine (1.1 eq) in anhydrous THF (0.1 M) was added dropwise diisopropyl azodicarboxylate (1.1 eq) in anhydrous THF ( 2 M) solution. The resulting mixture was stirred at ambient temperature under nitrogen until the reaction was complete. The mixture was concentrated under reduced pressure, diluted in EtOAc, washed with 2M aqueous NaOH (100 mL), and dried _{over Na2SO4} . After filtration and condensation, the residue was purified with a silica gel column to give the product Example 27.

Examples 27 to 34 were prepared using General Method I:

Preparation of tertiary butyl N-[3-[2-(3-chloro-4-fluoro-anilino)ethoxy]propyl]carbamate (J1)

Step 1. Add N-(3-hydroxypropyl)-carbamate tertiary butyl ester (9.25 g, 52.84 mmol, 1 eq) and diacetoxyrhodium (1.17 g, 2.64 mmol, 0.05 eq) To a solution in DCM (100 mL) was added a solution of ethyl 2-diazoacetate (30.15 g, 264.20 mmol, 5 eq) in DCM (15 mL) dropwise. The mixture was stirred at 20°C for 12 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column (PE to PE/EtOAc = 40:1) to give ethyl 2-[3-[tertiary butoxycarbonylamino]propoxy]acetate as a yellow oil ( 5.8 g, crude material).

Step 2. Dissolve ethyl 2-[3-(tertiary butoxycarbonylamino)propoxy]acetate (4.00 g, 15.3 mmol, 1.00 eq ) in MeOH (30.0 mL) and H ₂ O (3.00 mL) To the mixture in was added LiOH•H ₂ O (1.28 g, 30.6 mmol, 2.00 eq ) in one portion. The mixture was stirred at 20°C for 2 hours. Upon completion, the mixture was concentrated in vacuo to afford [2-[3-(tertiary-butoxycarbonylamino)-propoxy]acetyl]oxylithium (4.00 g, crude) as a yellow solid.

Step 3. Add [2-[3-(tertiary butoxycarbonylamino)propoxy]acetyl]oxylithium (4.00 g, crude material, 1 eq ) and 3-chloro-4-fluoro- To a mixture of aniline (2.43 g, 16.7 mmol, 1.00 eq ) in DMF (40.0 mL) was added DIEA (6.48 g, 50.2 mmol, 8.74 mL, 3.00 eq ) followed by HATU (9.54 g, 25.1 mmol, 1.50 eq ) . The mixture was stirred at 20°C for 1 hour. Upon completion, the residue was poured into ice water (50.0 mL). The aqueous phase was extracted with ethyl acetate (60.0 mL*3). The combined organic phases were washed with brine (30.0 mL*3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=30/1 to 15/1) to give N-[3-[2-(3-chloro-4-fluoro-anilino) as a white solid )-tert-butyl 2-oxo-ethoxy]propyl]carbamate (4.20 g, 11.6 mmol, 69.3% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.18 - 8.92 (m, 1H), 7.99 - 7.86 (m, 1H), 7.73 - 7.59 (m, 1H), 7.10 (t, J = 8.8 Hz, 1H) , 4.66 (br s, 1H), 4.07 (s, 2H), 3.65 (t, J = 5.6 Hz, 2H), 3.40 (br d, J = 5.6 Hz, 2H), 1.82 (quin, J = 5.6 Hz, 2H), 1.44 (s, 9H). LC-MS: m/z 383.1 (M+Na) ⁺ .

Step 4. To N-[3-[2-(3-chloro-4-fluoro-anilino)-2-oxo-ethoxy]propyl]carbamate at 0 °C under _N2 To a mixture of tert-butyl ester (1.70 g, 4.71 mmol, 1.00 eq ) in THF (15.0 mL) was added LiAlH ₄ (268 mg, 7.07 mmol, 1.50 eq ) in three portions. The mixture was stirred at 20°C for 6 hours. After completion, water (0.26 mL) was added dropwise to the mixture at 0 °C. Aqueous NaOH (15%, 0.78 mL) was then slowly added to the mixture followed by water (0.26 mL). The mixture was dried over anhydrous Na ₂ SO ₄ (5.00 g), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=30/1 to 15/1) to give N-[3-[2-(3-chloro-4-fluoro-aniline) as a yellow oil yl)ethoxy]propyl]carbamate (865 mg, 2.49 mmol, 52.9% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ = 6.97 (t, J = 8.8 Hz, 1H), 6.76 (br d, J = 3.2 Hz, 1H), 6.64 - 6.53 (m, 1H), 4.72 (br s , 1H), 3.66 (t, J = 4.8 Hz, 2H), 3.53 (t, J = 5.6 Hz, 2H), 3.33 - 3.19 (m, 4H), 1.79 - 1.73 (m, 2H), 1.45 (s, 9H). LC-MS: m/z 347.1 (M+H) ⁺ .

Preparation of tertiary butyl N-[3-[2-(3-chloro-4-fluoro-anilino)ethoxy]propyl]-N-methyl-carbamate (J2)

Using a method similar to J1, using N-(3-hydroxypropyl)-N-methyl-carbamic acid tertiary butyl ester as starting material instead of N-(3-hydroxypropyl)-carbamic acid tertiary Butyl ester to prepare J2. LCMS: m/z 361.1 (M+H) ⁺ .

Preparation of (3-((tertiary butoxycarbonyl)amino)propyl)(2-((3-chloro-4-fluorophenyl)amino)ethyl)benzyl carbamate (J3)

Step 1. To a solution of 3-chloro-4-fluoro-aniline (13 g, 89.3 mmol, 1 eq ) in DMSO (100 mL) was added DIEA (23.1 g, 178.62 mmol, 2 eq) and 2-bromoacetic acid Ethyl ester (16.4 g, 98.2 mmol, 1.1 eq). The mixture was stirred at 90°C for 2 hours. The reaction mixture was partitioned between ethyl acetate (100 mL x 3) and water (300 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give 2-(3-chloro -Ethyl 4-fluoro-anilino)acetate (21 g, crude material). LCMS: m/z 231.8 (M+H) ⁺ .

Step 2. To a solution of ethyl 2-(3-chloro-4-fluoro-anilino)acetate (21 g, 90.7 mmol, 1 eq) in MeOH (150 mL) was added LiOH.H ₂ O (11.4 g , 272 mmol, 3 eq) and H ₂ O (50 mL). The mixture was stirred at 40°C for 1 hour. The mixture was concentrated in vacuo to remove MeOH, acidified with 2M HCl to pH = 4, the solid was filtered and the filter cake was concentrated to give 2-(3-chloro-4-fluoro-anilino)acetic acid (15.5 g, 74.6 mmol, 82% yield). LCMS: m/z 204.2 (M+H) ⁺ .

Step 3. To a solution of 2-(3-chloro-4-fluoro-anilino)acetic acid (15.5 g, 76.1 mmol, 1 eq) in THF (200 mL) was added DIEA (29.5 g, 228 mmol, 39.8 mL , 3 eq). Then tert-butyl N-(3-aminopropyl)carbamate (15.9 g, 91.4 mmol, 16 mL, 1.2 eq), T ₃ P (29.1 g, 91.4 mmol, 27.2 mL, 1.2 eq) was added to the mixture. The mixture was stirred at 25°C for 2 hours. The reaction mixture was partitioned between ethyl acetate (50 mL x 3) and water (200 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1:0 to 0:1) to give N-[3-[[2-(3-chloro-4 -Fluoro-anilino)acetyl]amino]propyl]carbamate (20 g, 55.6 mmol, 73% yield). 1H NMR (400 MHz, DMSO- d ₆ ) δ = 7.91 (t, J = 4.8 Hz, 1H), 7.11 (t, J = 9.2 Hz, 1H), 6.74 (s, 1H), 6.62 (dd, J = 2.4, 6.0 Hz, 1H), 6.48 (td, J = 3.2, 8.8 Hz, 1H), 6.17 (br t, J = 6.0 Hz, 1H), 3.60 (d, J = 6.0 Hz, 2H), 3.06 (q , J = 6.0 Hz, 2H), 2.88 (q, J = 6.0 Hz, 2H), 1.47 (m, 2H), 1.36 (s, 9H); LCMS: m/z 360.0 (M+H) ⁺ .

Step 4. Add tertiary butyl N-[3-[[2-(3-chloro-4-fluoro-anilino)acetyl]amino]propyl]carbamate (5 g, To a mixture of 13.9 mmol, 1 eq) in THF (50 mL) was added BH3.THF ( ₁ M, 34.7 mL, 2.5 eq) dropwise. The mixture was stirred at 25 °C for 12 h, and then quenched by the addition of MeOH (20 mL) at 0 °C, followed by stirring for 30 min. The mixture was concentrated, and the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1:0 to ethyl acetate/methanol=5:1) to give N-[ Tert-butyl 3-[2-(3-chloro-4-fluoro-anilino)ethylamino]propyl]carbamate (3 g, 8.24 mmol, 59% yield). LCMS: m/z 346.2 (M+H) ⁺ .

Step 5. Add tertiary butyl N-[3-[2-(3-chloro-4-fluoro-anilino)ethylamino]propyl]carbamate (3 g, 8.67 mmol, 1 eq) to To a solution in EtOAc (20 mL) and _H2O (10 mL) was added _NaHCO3 (1.09 g, 13.0 mmol, 1.5 eq) and CbzCl (888 mg, 5.20 mmol, 0.6 eq). The mixture was stirred at 25°C for 1 hour. Concentrate the mixture. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5:1 to 1:1) to obtain N-[3-(tertiary butoxycarbonylamino) as a yellow oil )propyl]-N-[2-(3-chloro-4-fluoro-anilino)ethyl]benzylcarbamate (2.7 g, 5.57 mmol, 64.2% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.41 - 7.28 (m, 5H), 7.13 - 6.93 (m, 1H), 6.83 - 6.61 (m, 2H), 6.58 - 6.40 (m, 1H), 5.88 (t, J = 5.6 Hz, 1H), 5.07 (s, 2H), 3.30 (s, 2H), 3.24 (t, J = 6.8 Hz, 2H), 3.16 (s, 2H), 2.90 (d, J = 5.2 Hz, 2H), 1.61 (t, J = 6.8 Hz, 2H), 1.37 (s, 9H); LCMS: m/z 480.0 (M+H) ⁺ .

Preparation of tertiary butyl N-[3-[2-(3-chloro-4-fluoro-anilino)ethoxy]ethyl]-N-methyl-carbamate (J4)

Using a method similar to J1, using N-(3-hydroxyethyl)-N-methyl-carbamic acid tertiary butyl ester as starting material instead of N-(3-hydroxypropyl)-carbamic acid tertiary Butyl ester to prepare J4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.09 - 7.06 (m, 1H), 6.71 - 6.68 (m, 1H), 6.57 - 6.54 (m, 1H), 5.78 - 5.76 (m, 1H), 3.55 - 3.49 (m, 4H), 3.32 - 3.31 (m, 2H), 3.16 - 3.15 (m, 2H), 2.79 (s, 3H), 1.38 (s, 9H). LCMS: m/z 347.2 (M+H) ⁺ .

Preparation of ethyl 2-[3-(3-chloro-4-fluoro-anilino)propoxy]acetate (J5)

Step 1. Add 3-bromopropan-1-ol (10.0 g, 71.9 mmol, 6.49 mL, 1 eq ) and diacetyloxyrhodium (318 mg, 1.44 mmol, 0.02 eq ) in DCM (50 A solution of ethyl 2-diazoacetate (20.0 g, 175 mmol, 2.44 eq ) in DCM (50 mL) was slowly added dropwise to the mixture in mL), and the resulting mixture was stirred at 25 °C for 12 h. The residue was diluted with H ₂ O (20 mL) and extracted with DCM (20 mL*3). The combined organic layers were washed with brine (20 mL* ₃ ), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give ethyl 2-(3-bromopropoxy)acetate (30.0 g , crude matter). ¹ H NMR (400 MHz, CDCl ₃ - d ) δ = 4.23 - 4.20 (m, 2H), 4.07 (s, 2H), 3.66 (t, J = 5.6 Hz, 2H), 3.54 (t, J = 6.4 Hz , 2H), 2.15 (quin, J = 6.4 Hz, 2H), 1.30 - 1.28 (m, 3H).

Step 2. To 3-chloro-4-fluoro-aniline (3.00 g, 20.6 mmol, 1 eq) and KI (342 mg, 2.06 mmol, 0.1 eq) and DIEA (7.99 g, 61.8 mmol, 10.7 mL, 3 eq) To a mixture in DMSO (40 mL) was added ethyl 2-(3-bromopropoxy)acetate (11.6 g, 51.5 mmol, 2.5 eq), and the resulting mixture was stirred at 110° C. for 12 hrs. The residue was diluted with H ₂ O (20 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were washed with brine (10 mL* ₃ ), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give 2-[3-(3-chloro-4-fluoro-anilino) as a brown oil )propoxy]ethyl acetate (J5, 2.76 g, 8.97 mmol, 43.5% yield, 94.2% purity). ¹ H NMR (400 MHz, CDCl ₃ - d ) δ = 6.93 (t, J = 8.8 Hz, 1H), 6.62 (dd, J = 2.8, 6.0 Hz, 1H), 6.46 (td, J = 3.2, 8.8 Hz , 1H), 4.24 (q, J = 7.2 Hz, 2H), 4.08 (s, 2H), 3.65 (t, J = 5.6 Hz, 2H), 3.25 (t, J = 6.4 Hz, 2H), 1.90 (quin , J = 6.0 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H). LCMS: m/z 290.0 (M+1).

Preparation of tertiary butyl N-[2-[(2-amino-4-chloro-5-fluoro-phenyl)methoxy]ethyl]carbamate (J6)

Step 1. To a mixture of 1-chloro-2-fluoro-4-methyl-5-nitro-benzene (25.0 g, 131 mmol, 1 eq ) in ACN (200 mL) was added AIBN (2.17 g, 13.1 mmol, 0.1 eq ) and NBS (37.5 g, 211 mmol, 1.6 eq ). The mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0) to obtain a crude compound. The crude compound was further purified by reverse phase HPLC (0.1% FA condition) to give 1-(bromomethyl)-4-chloro-5-fluoro-2-nitro-benzene (17.0 g, 62.6 mmol, 47.5% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.22 (d, J = 6.4 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 4.80 (s, 2H).

Step 2. To a mixture of tert-butyl N-(2-hydroxyethyl)carbamate (10.1 g, 62.9 mmol, 9.76 mL, 1.3 eq ) in DCM (200 mL) was added TBAI (8.94 g, 24.2 mmol, 0.5 eq ) and KOH (1.36 g, 24.2 mmol, 0.5 eq ) and Na ₂ CO ₃ (2.57 g, 24.2 mmol, 0.5 eq ), the mixture was stirred at 25°C for 1 hour. Then 1-(bromomethyl)-4-chloro-5-fluoro-2-nitro-benzene (13.0 g, 48.4 mmol, 1 eq ) was added and the mixture was stirred at 50°C for 12 hours. The reaction was filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 15/1). The product was further purified by reverse phase HPLC to give N-[2-[(4-chloro-5-fluoro-2-nitro-phenyl)-methoxy]ethyl]-carbamic acid as a yellow solid Tertiary butyl ester (1.50 g, 3.89 mmol, 8.04% yield). LCMS: m/z 249 (M-100) ⁺ .

Step 3. Add N-[2-[(4-chloro-5-fluoro-2-nitro-phenyl)-methoxy] ethyl] carbamate tertiary butyl ester (1.50 g, 4.30 mmol, 1 eq ) To a mixture in H ₂ O (4.00 mL) and EtOH (20.0 mL) was added Fe (720 mg, 12.9 mmol, 3 eq ) and NH ₄ Cl (1.15 g, 21.5 mmol, 5 eq ). The mixture was stirred at 85 °C for ₂ h under N2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to remove EtOH. The reaction mixture was partitioned between H2O ( ₂ mL) and EtOAc (5 mL). The organic phase was separated, washed with brine (3 mL*3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to afford N-[2-[(2-amino-4-chloro-5-fluoro-phenyl)-methoxy]ethyl]amino as a yellow oil Tert-butyl formate (J6, 1.00 g, 2.17 mmol, 50.4% yield). LCMS: m/z 341.0 (M+Na) ⁺ .

Preparation of 3-[2-[benzyloxycarbonyl-[3-(tertiary butoxycarbonylamino)propyl]-amino]ethylamino]benzoic acid methyl ester (J7)

Step 1. Methyl 3-aminobenzoate (10 g, 66.1 mmol, 1 eq ), tertiary butyl 2-bromoacetate (14.2 g, 72.8 mmol, 1.1 eq ) and DIEA (17.1 g, 132 mmol, 2 eq ) in DMSO (100 mL) was stirred at 80°C for 2 hours. The reaction mixture was diluted with H ₂ O (1000 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (500 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 3-((2-(tertiary-butoxy)-2-oxo as a yellow oil. (ethyl)amino)benzoate (19 g, crude), and it was used directly in the next step. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.24 - 7.11 (m, 3H), 6.83 - 6.78 (m, 1H), 6.32 (t, J = 6.4 Hz, 1H), 3.84 - 3.77 (m, 5H), 1.41 (s, 9H)

Step 2. Methyl 3-((2-(tertiary butoxy)-2-oxoethyl)amino)benzoate (19 g, 71.6 mmol, 1 eq ) in TFA (100 mL) and The solution in DCM (100 mL) was stirred at 20 °C for 2 hours. The reaction mixture was diluted with H ₂ O (100 mL) and extracted with DCM (100 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 2-(3-methoxycarbonylanilino)acetic acid (J7-3, 11 g, 49.9 mmol, 69.7% yield, 95% purity) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.25 - 7.10 (m, 3H), 6.82 (d, J = 7.6 Hz, 1H), 3.84 (s, 2H), 3.81 (s, 3H); LCMS : m/z 210.3 (M+H) ⁺ .

Following a procedure similar to J3-2 to J3, J7 was prepared from J7-3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.37 - 7.26 (m, 6H), 7.18 (s, 1H), 7.11 (s, 1H), 6.89 - 6.69 (m, 2H), 6.02 (s, 1H), 5.08 (s, 2H), 3.37 - 3.31 (m, 5H), 3.28 - 3.17 (m, 4H), 2.90 (d, J = 5.2 Hz, 2H), 1.62 (d, J = 6.4 Hz, 2H ), 1.36 (s, 9H); LCMS: m/z 486.8 (M+H) ⁺ .

Benzyl N-[3-(tertiary butoxycarbonylamino)propyl]-N-[2-(3,4-dichloro-2-fluoro-anilino)ethyl]carbamate (J8 ) preparation

Following a similar procedure to J3, J8 was prepared using 3,4-dichloro-2-fluoro-aniline as starting material. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.39 - 7.29 (m, 6H), 7.21 - 6.91 (m, 1H), 6.78 (s, 1H), 6.07 (s, 1H), 5.05 (d, J = 17.2 Hz, 2H), 3.39 - 3.32 (m, 2H), 3.30 - 3.17 (m, 4H), 2.89 (s, 2H), 1.66 - 1.53 (m, 2H), 1.36 (s, 9H).

Preparation of N-[3-(tertiary butoxycarbonylamino)propyl]-N-[2-(3-chloro-2-fluoro-anilino)ethyl]carbamate (J9)

Following a similar procedure to J3, J8 was prepared using 3-chloro-2-fluoro-aniline as starting material. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.41 - 7.28 (m, 5H), 6.83 - 6.69 (m, 2H), 6.68 - 6.57 (m, 1H), 5.88 (s, 1H), 5.06 ( d, J =12.0 Hz, 2H), 3.38 - 3.34 (m, 1H), 3.32 - 3.28 (m, 1H), 3.24 (s, 4H), 2.89 (s, 2H), 1.65 - 1.55 (m, 2H) , 1.36 (s, 9H); LCMS: m/z 480.2 (M+H) ⁺ .

Preparation of N-[2-[tertiary butyl(dimethyl)silyl]oxyethyl]-3-chloro-4-fluoro-aniline (J10)

Step 1. To a solution of 3-chloro-4-fluoroaniline (2 g, 13.7 mmol, 1 eq ) in THF (20 mL) was added NaH (0.6 g, 15.0 mmol, 60% purity, 1.09 eq ). 1,3,2-Dioxathiolane 2,2-dioxide (2 g, 16.1 mmol, 1.17 eq ) was then added to the reaction. The reaction mixture was stirred at 20 °C for 12 h, and then quenched with aqueous _NH4Cl (100 mL) at 0 °C. The reaction mixture was diluted with 400 mL H ₂ O and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (50 mL), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give crude 2-(3-chloro-4-fluoro-anilino)hydrogensulfate as a yellow oil Ethyl ester (3.71 g, crude material).

Step 2. To a solution of 2-(3-chloro-4-fluoro-anilino)ethyl hydrogensulfate (3.71 g, 13.7 mmol, 1 eq ) in MeOH (40 mL) was added concentrated H ₂ SO ₄ (674 mg, 6.88 mmol, 0.5 eq ). The reaction was stirred at 60°C for 2 hours. The reaction mixture was diluted with H ₂ O (100 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 0/1) to give 2-(3-chloro-4-fluoro-anilino)ethanol as a yellow solid (2 g, 10.44 mmol, 76% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.31 (t, J = 9.2 Hz, 1H), 7.14 (d, J = 4.0 Hz, 1H), 7.01 - 6.92 (m, 1H), 3.60 - 3.54 (m, 2H), 3.21 (t, J = 5.6 Hz, 2H); LCMS: m/z 190.0 (M+H) ⁺ .

Step 3. To a solution of 2-(3-chloro-4-fluoro-anilino)ethanol (1.5 g, 7.91 mmol, 1 eq ) in DCM (20 mL) was added TBSCl (1.40 g, 9.29 mmol, 1.17 eq ) and TEA (2.40 g, 23.73 mmol, 3 eq ). The reaction was stirred at 20°C for 2 hours. The reaction mixture was diluted with H ₂ O (100 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 4/1) to obtain N-[2-[tertiary butyl(dimethyl )silyl]oxyethyl]-3-chloro-4-fluoro-aniline (1.9 g, 6.19 mmol, 78.2% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.07 (t, J = 9.2 Hz, 1H), 6.69 (dd, J = 2.8, 6.4 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H ), 5.75 (t, J = 6.0 Hz, 1H), 3.68 (t, J = 6.0 Hz, 2H), 3.11 (q, J = 6.0 Hz, 2H), 0.85 (s, 9H), 0.02 (s, 6H ); LCMS: m/z 304.2 (M+H) ⁺ .

Preparation of tertiary butyl N-[2-(3-chloro-4-fluoro-anilino)ethyl]carbamate (J11)

To a solution of 3-chloro-4-fluoroaniline (5 g, 34.35 mmol, 1 eq ) in THF (50 mL) was added NaH (1.50 g, 37.50 mmol, 60% purity, 1.09 eq ) at 0°C. Then tert-butyl 2,2-dioxathiazolidine-3-carboxylate (8.00 g, 35.8 mmol, 1.04 eq ) was added to the reaction. The reaction was stirred at 20°C for 12 hours. The reaction was quenched by adding to aqueous _NH4Cl (100 mL) at 0 °C. The crude product was purified by reverse phase HPLC (0.1% TFA condition). The compound tert-butyl N-[2-(3-chloro-4-fluoro-anilino)ethyl]carbamate (6.7 g, 22.04 mmol, 64% yield, 95% purity) was obtained as a yellow oil ). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.09 (t, J = 9.2 Hz, 1H), 6.84 (s, 1H), 6.65 (d, J = 3.6 Hz, 1H), 6.57 - 6.48 (m , 1H), 3.04 (s, 4H), 1.37 (s, 9H); LCMS: m/z 288.8 (M+H) ⁺ .

Preparation of tertiary butyl N-[3-[2-(3-chloro-4-fluoro-anilino)ethyl-methyl-amino]propyl]carbamate (J12)

Using a method similar to J3-4 in J3, J12 was prepared as a colorless oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.08 (t, J = 9.2 Hz, 1H), 6.77 (t, J = 5.2 Hz, 1H), 6.69 (d, J = 6.0 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 5.56 (t, J = 5.2 Hz, 1H), 3.03 (q, J = 6.4 Hz, 2H), 2.95 (q, J = 6.4 Hz, 2H), 2.46 ( t, J = 6.4 Hz, 2H), 2.31 (t, J = 6.8 Hz, 2H), 2.15 (s, 3H), 1.56 - 1.46 (m, 2H), 1.36 (s, 9H); LCMS: m/z 359.9 (M+H) ⁺ .

Preparation of (3-((tertiary butoxycarbonyl)amino)propyl)(2-((4-chloro-3-fluorophenyl)amino)ethyl)benzyl carbamate (J13)

In a similar manner to J3, using 4-chloro-3-fluoro-aniline instead of 3-chloro-4-fluoro-aniline, J13 was prepared as a colorless oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.40 - 7.27 (m, 5H), 6.77 (s, 1H), 6.50 - 6.39 (m, 1H), 6.19 (t, J = 5.6 Hz, 1H) , 5.06 (d, J = 11.2 Hz, 2H), 3.29 (s, 1H), 3.24 (t, J = 6.4 Hz, 2H), 3.17 (d, J = 5.2 Hz, 2H), 2.89 (d, J = 4.8 Hz, 2H), 2.52 (d, J = 2.0 Hz, 2H), 1.65 - 1.55 (m, 2H), 1.36 (s, 9H); LCMS: m/z (M+H) ⁺ .

Preparation of N-[3-(tertiary butoxycarbonylamino)propyl]-N-[2-(3,4-dichloroanilino)ethyl]carbamate (J14)

In a similar manner to J3, using 3,4-dichloroaniline instead of 3-chloro-4-fluoro-aniline, J14 was prepared as a brown gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.34 (d, J = 7.2 Hz, 5H), 7.25 - 7.07 (m, 1H), 6.84 - 6.69 (m, 2H), 6.63 - 6.44 (m, 1H), 6.16 (s, 1H), 5.06 (s, 2H), 3.32 - 3.15 (m, 6H), 2.89 (br s, 2H), 1.65 - 1.56 (m, 2H), 1.36 (s, 9H); LCMS: m/z 496.0 (M+H) ⁺ .

N-[3-[benzyloxycarbonyl-[2-(3-chloro-4-fluoro-anilino) ethyl] amino] propyl]-N-methyl-carbamic acid tertiary butyl ester ( Preparation of J15)

Using a method similar to J3, using N-(3-aminopropyl)-N-methyl-carbamic acid tertiary butyl ester instead of N-(3-aminopropyl)-carbamic acid tertiary butyl ester , J15 was prepared as a colorless oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.44 - 7.26 (m, 5H), 7.13 - 6.91 (m, 1H), 6.76 - 6.60 (m, 1H), 6.60 - 6.39 (m, 1H), 5.89 (s, 1H), 5.07 (s, 2H), 3.35 - 3.10 (m, 8H), 2.78 - 2.61 (m, 3H), 1.74 - 1.62 (m, 2H), 1.36 (s, 9H); LCMS: m/z 494.0 (M+H) ⁺ .

In a similar manner to J3, using 3,4-dichloro-2-fluoro-aniline instead of 3-chloro-4-fluoro-aniline, J16 was prepared as a colorless oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.37 - 7.30 (m, 5H), 6.76 (s, 1H), 6.09 - 5.98 (m, 1H), 5.04 (d, J = 16.4 Hz, 2H) , 3.31 (s, 3H), 2.88 (d, J = 2.8 Hz, 2H), 1.67 - 1.53 (m, 2H), 1.35 (s, 9H); LCMS: m/z 513.9 (M+H) ⁺ .

2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrazole-3-carboxylic acid methyl ester (K1) preparation

Step 1. To a solution of TEA (48.0 g, 475 mmol, 66.1 mL, 2.25 eq ) in MeOH (300 mL) and H ₂ O (150 mL) was added methylhydrazinesulfuric acid (30.4 g, 211 mmol, 1 eq ). The mixture was stirred at 25°C for 1 hour. Then dimethyl but-2-ynedioate (30.0 g, 211 mmol, 1 eq ) was added, and the mixture was stirred at 70°C for 13 hours. The reaction mixture was concentrated in vacuo to remove MeOH. The crude product was triturated with _H2O (200 mL) at 25 °C for 1 h. The filter cake was then triturated with MeOH (100 mL) at 25 °C for 1 h. The filter cake was dried under vacuum to afford methyl 5-hydroxy-2-methyl-pyrazole-3-carboxylate (18.0 g, 115 mmol, 54.6% yield, 100% purity) as a white solid.

Step 2. To a mixture of methyl 5-hydroxy-2-methyl-pyrazole-3-carboxylate (8.00 g, 51.2 mmol, 1 eq ) in DCM (100 mL) was added pyridine (4.86 g , 61.4 mmol, 4.96 mL, 1.2 eq ), then Tf ₂ O (15.9 g, 56.3 mmol, 9.30 mL, 1.1 eq ) was added dropwise at 0°C, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was partitioned between _H2O (30 mL) and DCM (60 mL*2). The organic phase was separated, washed with brine (50 mL*3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 2-methyl-5-(trifluoromethylsulfonyloxy yl) pyrazole-3-carboxylic acid methyl ester (13.4 g, 45.0 mmol, 87.8% yield, 96.8% purity). LCMS: m/z 289.0 (M+H) ⁺ .

Step 3. Methyl 2-methyl-5-(trifluoromethylsulfonyloxy)pyrazole-3-carboxylate (13.4 g, 46.5 mmol, 1 eq ), 4,4,5,5-tetra Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolane Alkane (13.0 g, 51.1 mmol, 1.1 eq ), KOAc (13.6 g, 139 mmol, 3 eq ), Pd(dppf)Cl ₂ (3.40 g, 4.65 mmol, 0.1 eq ) in dioxane (150 mL) The mixture was degassed and purged with _N2 for 3 h, then the mixture was stirred at 100 °C under _N2 for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography to give 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)pyrazole-3-carboxylic acid methyl ester (14.0 g, crude material). ¹ H NMR (400 MHz, CDCl ₃ - d ) δ = 7.22 - 7.22 (m, 1H), 7.23 (s, 1H), 4.22 (s, 3H), 3.85 (s, 3H), 1.34 (s, 12H) .

Preparation of 5-dihydroxyboryl-2-methyl-pyrazole-3-carboxylic acid (K2)

To 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrazole-3-carboxylic acid methyl ester (2 g , 7.52 mmol, 1 eq) in THF (40 mL) were added LiOH (360 mg, 15.0 mmol, 2 eq) and _H2O (10 mL). The mixture was stirred at 25°C for 2 hours. The mixture was concentrated to afford 5-boronyl-2-methyl-pyrazole-3-carboxylic acid (3 g, crude) as a white solid, which was used directly in the next step. LCMS: m/z 619.2 (M+H) ⁺ .

Preparation of 5-(4-chloro-6-quinolyl)-2-methyl-pyrazole-3-carboxylic acid methyl ester (M1)

6-Bromo-4-chloro-quinoline (5.00 g, 20.6 mmol, 1 eq ), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Borolol-2-yl)pyrazole-3-carboxylic acid methyl ester (6.04 g, 22.6 mmol, 1.1 eq ), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (1.68 g, 2.06 mmol, 0.1 eq ) and a mixture of K ₂ CO ₃ (7.12 g, 51.5 mmol, 2.5 eq ) in dioxane (60 mL) and H ₂ O (6 mL) was stirred at 80° C. under N ₂ for 4 h. The residue was diluted with H ₂ O (20 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were washed with brine (15 mL* ₃ ), dried over _Na2SO4 . The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/0 to 3/1) to obtain 5-(4-chloro-6-quinolyl)-2-methanol as a white solid Methyl-pyrazole-3-carboxylate (M1, 5.60 g, 18.0 mmol, 87.40% yield). LCMS: m/z 302.0 (M+H) ⁺ .

Preparation of 5-(8-chloro-1,5-phenidin-2-yl)-2-methyl-pyrazole-3-carboxylic acid methyl ester (M2)

Step 1. To a solution of 6-chloropyridin-3-amine (5 g, 38.9 mmol, 1 eq) in i -PrOH (100 mL) was added 5-(methoxymethylene)-2,2- Dimethyl-1,3-dioxane-4,6-dione (7.24 g, 38.9 mmol, 1 eq). The mixture was stirred at 80 °C for 5 hours, cooled to room temperature and concentrated to give 5-[[(6-chloro-3-pyridyl)amino]methylene]-2,2-bis as a yellow solid Methyl-1,3-dioxane-4,6-dione (8.8 g, 30.8 mmol, 79% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.29 (d, J = 14.4 Hz, 1H), 8.66 (d, J = 2.8 Hz, 1H), 8.57 (d, J = 14.4 Hz, 1H), 8.11 (dd, J = 2.8, 8.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 1.68 (s, 6H); LCMS: m/z 282.9 (M+H) ⁺ .

Step 2. Diphenyl ether (400 mL) was heated to 220°C, and 5-[[(6-chloro-3-pyridyl)amino]methylene]-2,2-dimethyl-1 ,3-Dioxane-4,6-dione (8.8 g, 31.1 mmol, 1 eq) was added portionwise to the mixture. After the addition was complete, the mixture was stirred at 220°C for 10 minutes. After the reaction was completed, the reaction solution was cooled to room temperature, and petroleum ether (1 L) was added to the reaction mixture to precipitate a large amount of solid. The precipitate was collected by filtration, washed with petroleum ether and dried under reduced pressure. The crude product was triturated with ethyl acetate (30 mL) at 25 °C to afford 6-chloro-1,5-phenidin-4-ol (3.4 g, 16.9 mmol, 54% yield) as a brown solid . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.21 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.23 (dd, J = 2.0, 8.8 Hz, 1H), 8.11 (t , J = 7.2 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.74 (s, 1H), 7.63 - 7.58 (m, 1H), 7.39 - 7.31 (m, 2H), 6.68 (d, J = 4.8 Hz, 1H), 4.07 (s, 3H), 3.92 (s, 2H), 3.30 (s, 4H), 2.88 - 2.81 (m, 2H), 1.93 - 1.82 (m, 2H); LCMS: 181.1 (M+H) ⁺ .

Step 3. To a solution of 6-chloro-1,5-phenidin-4-ol (1.6 g, 8.86 mmol, 1 eq) in ACN (15 mL) was added TMSBr (10.9 g, 70.9 mmol, 8 eq). The mixture was stirred at 85°C for 16 hours. The mixture was cooled and filtered. The filtrate was concentrated to afford 6-bromo-1,5-phenidin-4-ol (2.8 g, crude) as a brown solid. LCMS: 226.7 (M+H) ⁺ .

Step 4. To a solution of 6-bromo-1,5-phenidin-4-ol (2.8 g, 12.4 mmol, 1 eq) in toluene (30 mL) was added DIEA (6.43 g, 49.8 mmol, 8.7 mL, 4 eq) and _POCl3 (5.72 g, 37.3 mmol, 3.47 mL, 3 eq). The mixture was stirred at 110°C for 2 hours, cooled and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 0:1 to 1:1) to give 2-bromo-8-chloro-1,5-oxidine ( 1.7 g, 5.93 mmol, 47.7% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.99 - 8.93 (m, 1H), 8.42 (d, J = 8.8 Hz, 1H), 8.10 - 8.02 (m, 2H); LCMS: 244.8 (M+ H) ⁺ .

Step 5. Combine 2-bromo-8-chloro-1,5-oxidine (1.7 g, 6.98 mmol, 1 eq), 2-methyl-5-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborol-2-yl)pyrazole-3-carboxylic acid methyl ester (2.42 g, 9.08 mmol, 1.3 eq), KOAc (2.06 g, 21 mmol, 3 eq), Pd( dppf)Cl ₂ .CH ₂ Cl ₂ (570 mg, 698 μmol, 0.1 eq) in dioxane (20 mL) and H ₂ O (10 mL) was degassed and purged 3 times with N ₂ . The mixture was stirred at 70 °C under _N2 atmosphere for 16 h. The reaction mixture was partitioned between ethyl acetate (30 mL x 3) and water (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1:0 to 0:1) to give 5-(8-chloro-1,5-phenidine-2 as a yellow solid -yl)-2-methyl-pyrazole-3-carboxylic acid methyl ester (800 mg, 2.40 mmol, 34% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.21 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.23 (dd, J = 2.0, 8.8 Hz, 1H), 8.11 (t , J = 7.2 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.74 (s, 1H), 7.63 - 7.58 (m, 1H), 7.39 - 7.31 (m, 2H), 6.68 (d, J = 4.8 Hz, 1H), 4.07 (s, 3H), 3.92 (s, 2H), 3.30 (s, 4H), 2.88 - 2.81 (m, 2H), 1.93 - 1.82 (m, 2H); LCMS: m /z 303.0 (M+H) ⁺ .

1-(3-Chloro-4-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-vinylidenepyrido[4,3- e ][1,4 ,7,10] Preparation of oxatriazacyclotridecen-9( 1H )-ketone (Example 1)

Step 1. Mix 8-bromo-2-methoxy-1,5-butyridine (120 mg, 0.502 mmol, 1.00 eq ), N-[3-[2-(3-chloro-4-fluoro-anilino ) ethoxy] propyl] tertiary butyl carbamate (192 mg, 0.552 mmol, 1.10 eq ), RuPhos Pd G3 (42.0 mg, 0.0502 mmol, 0.10 eq ) and Cs ₂ CO ₃ (491 mg, 1.51 mmol , 3.00 eq ) in toluene (3.00 mL) was stirred at 110° C. under N ₂ for 20 h. Upon completion, the mixture was concentrated in vacuo. The mixture was purified by preparative TLC (petroleum ether:ethyl acetate=1:1) to give N-[3-[2-(3-chloro-4-fluoro-N-(6-methoxy yl-1,5-phenidin-4-yl)anilino)ethoxy]propyl]carbamate (70.0 mg, 0.139 mmol, 27.6% yield). LCMS: m/z 505.2 (M+H) ⁺ .

Step 2. To N-[3-[2-(3-chloro-4-fluoro-N-(6-methoxy-1,5-phenidin-4-yl)anilino)ethoxy]propyl ] To a mixture of tert-butyl carbamate (115 mg, 0.228 mmol, 1.00 eq ) in DCM (1.00 mL) was slowly added HBr (1.49 g, 6.08 mmol, 1.00 mL, 33% purity, 27.0 eq ) in HOAc solution in. The mixture was stirred at 25°C for 12 hours. The mixture was concentrated in vacuo to afford 8-[N-[2-(3-aminopropoxy)ethyl]-3-chloro-4-fluoro-anilino]-1,5-pyridine as a yellow solid -2-ol (105 mg, crude, HBr). LCMS: m/z 391.1 (M+1) ⁺ .

Step 3. To 8-[N-[2-(3-aminopropoxy)ethyl]-3-chloro-4-fluoro-anilino]-1,5-pyridin-2-ol (105 mg , 0.223 mmol, 1.00 eq , HBr) and DIEA (144 mg, 1.11 mmol, 0.194 mL, 5.00 eq ) in DCM (2.00 mL) were slowly added Boc ₂ O (97.2 mg, 0.445 mmol, 0.102 mL, 2.00 eq ). The mixture was stirred at 25°C for 2 hours. Upon completion, the mixture was concentrated in vacuo. The residue was purified by prep-TLC (ethyl acetate) to afford N-[3-[2-(3-chloro-4-fluoro-N-(6-hydroxy-1,5-oxidine) as a yellow solid -4-yl)anilino)ethoxy]propyl]carbamate (105 mg, 0.210 mmol, 94.4% yield). LCMS: m/z 491.2 (M+H) ⁺ .

Step 4. To N-[3-[2-(3-chloro-4-fluoro-N-(6-hydroxy-1,5-phenidin-4-yl)anilino)ethoxy] at 0°C Propyl]carbamate tertiary butyl ester (105 mg, 0.214 mmol, 1.00 eq ), 2,6-lutidine (920 mg, 8.59 mmol, 1.00 mL, 40.0 eq ) and DMAP (52.0 mg, 0.428 mmol , 2.00 eq ) in DCM (1.00 mL) was added trifluoromethylsulfonyl triflate (121 mg, 0.428 mmol, 2.00 eq ). The mixture was stirred at 20°C for 20 hours. Upon completion, DCM (10.0 mL) was added to the mixture. The organic phase was washed with water (10.0 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether/ethyl acetate=1/1) to give trifluoromethanesulfonate [8-[N-[2-[3-(tertiary butoxy Carbonylamino)-propoxy]ethyl]-3-chloro-4-fluoro-anilino]-1,5-phenidin-2-yl]ester (70.0 mg, 0.109 mmol, 51.1% yield). LCMS: m/z 623.1 (M+H) ⁺ .

Step 5. Triflate [8-[N-[2-[3-(tertiary butoxycarbonylamino)propoxy]ethyl]-3-chloro-4-fluoro-anilino] -1,5-phenidine-2-yl] ester (70.0 mg, 0.112 mmol, 1.00 eq ), Pd(dppf)Cl ₂ (17.0 mg, 0.0225 mmol, 0.2 eq ), TEA (510 mg, 5.03 mmol, 45.0 eq ) in DMF (5.00 mL) and MeOH (10.0 mL) was stirred at 80 °C under CO (50 psi) for 12 h. Upon completion, the mixture was concentrated in vacuo and purified by preparative TLC (petroleum ether: ethyl acetate = 1:3) to afford 8-[N-[2-[3-(tertiary butoxy Carbonylamino)propoxy]ethyl]-3-chloro-4-fluoro-anilino]-1,5-pyridine-2-carboxylic acid methyl ester (60.0 mg, 0.110 mmol, 98.3% yield). LCMS: m/z 533.2 (M+1) ⁺ .

Step 6-1. To 8-[N-[2-[3-(tertiary butoxycarbonylamino)propoxy]ethyl]-3-chloro-4-fluoro-anilino]-1,5 To a mixture of -methidine-2-carboxylate (60.0 mg, 0.113 mmol, 1.00 eq ) in MeOH (3.00 mL) and H ₂ O (1.00 mL) was added LiOH·H ₂ O (23.6 mg, 0.563 mmol, 5.00eq ). The mixture was stirred at 25°C for 2 hours. Upon completion, the MeOH was removed in vacuo. Water (5.00 mL) and HCl (1 N) were added to the mixture until pH=5-6. The mixture was extracted with DCM (15.0 mL*3). The combined organic phases _were dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to afford 8-[N-[2-[3-(tertiary butoxycarbonylamino)propoxy]ethyl as a yellow solid ]-3-Chloro-4-fluoro-anilino]-1,5-pyridine-2-carboxylic acid (50.0 mg, 0.0964 mmol, 85.6% yield). LCMS: m/z 519.2 (M+1) ⁺ .

Step 6-2. To 8-[N-[2-[3-(tertiary butoxycarbonylamino)propoxy]ethyl]-3-chloro-4-fluoro-anilino] at 0°C - To a mixture of 1,5-pyridine-2-carboxylic acid (50.0 mg, 0.0964 mmol, 1.00 eq ) and DCM (2.00 mL) was slowly added HCl/dioxane (4 M, 1.72 mL, 71.6 eq ). The mixture was stirred at 20°C for 1 hour. Upon completion, the mixture was concentrated in vacuo to afford 8-[N-[2-(3-aminopropoxy)ethyl]-3-chloro-4-fluoro-anilino]-1,5 as a yellow solid - Furidine-2-carboxylic acid (43.0 mg, 94.4 μmol, 98.0% yield, HCl). LCMS: m/z 419.1 (M+H) ⁺ .

Step 7. To 8-[N-[2-(3-aminopropoxy)ethyl]-3-chloro-4-fluoro-anilino]-1,5-pyridine-2-carboxylic acid (37.0 mg , 0.0813 mmol, 1.00 eq , HCl) in DCM (2.00 mL) was slowly added DIEA (110 mg, 0.850 mmol, 10.0 eq ) followed by FDPP (38.0 mg, 0.0975 mmol, 1.20 eq ). The mixture was stirred at 25°C for 1 hour. Upon completion, the mixture was concentrated in vacuo. The mixture was purified by preparative HPLC to afford Example 1 (14.7 mg, 0.0358 mmol, 44.1% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.00 - 9.83 (m, 1H), 8.57 (d, J = 5.2 Hz, 1H), 8.48 (d, J = 8.8 Hz, 1H), 8.24 (d , J = 8.8 Hz, 1H), 7.71 - 7.63 (m, 1H), 7.51 - 7.45 (m, 1H), 7.41 - 7.32 (m, 1H), 6.76 (d, J = 5.2 Hz, 1H), 4.48 - 4.31 (m, 2H), 3.89 (br s, 2H), 3.79 (br s, 2H), 3.53 - 3.46 (m, 2H), 1.88 - 1.80 (m, 2H); LCMS: m/z 401.1 (M+ H) ⁺ .

1-(3-Chloro-4-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-vinylidenepyrido-[4,3- e ][1, 4,10] Preparation of oxadiazatridecen-9( 1H )-one (Example 2)

Step 1. N-[3-[2-(3-chloro-4-fluoro-anilino) ethoxy] propyl] carbamate tertiary butyl ester (90 mg, 0.260 mmol, 1.15 eq ), 4 -Methyl chloroquinoline-6-carboxylate (50.0 mg, 0.226 mmol, 1.00 eq ), Pd ₂ (dba) ₃ (15.0 mg, 0.0164 mmol, 0.07 eq ), tri-tertiary butylphosphonium; tetrafluoroborate (10.0 mg, 0.0345 mmol, 0.15 eq ) and K ₂ CO ₃ (94.0 mg, 0.680 mmol, 3.01 eq ) in toluene (2.00 mL) was stirred at 110° C. under N ₂ for 15 h. Upon completion, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10/1 to 1/1) to obtain 4-[N-[2-[3-(tertiary butoxycarbonyl Amino)propoxy]ethyl]-3-chloro-4-fluoro-anilino]quinoline-6-carboxylic acid methyl ester (2-2, 75.0 mg, 0.124 mmol, 54.9% yield). ¹ H NMR (400 MHz, CDCl ₃ -d) δ = 8.89 - 8.74 (m, 1H), 8.44 - 8.35 (m, 1H), 8.20 - 7.97 (m, 2H), 7.24 (br d, J = 5.2 Hz , 1H), 7.04 - 6.86 (m, 2H), 6.79 - 6.60 (m, 1H), 4.76 - 4.56 (m, 1H), 4.04 (br t, J = 4.8 Hz, 2H), 3.82 (s, 3H) , 3.57 (t, J = 5.2 Hz, 2H), 3.38 (t, J = 6.0 Hz, 2H), 3.16 - 3.01 (m, 2H), 1.68 - 1.61 (m, 2H), 1.32 (s, 9H); LCMS: 532.2 (M+H) ⁺ .

Example 2 was prepared from 2-2 after ester hydrolysis, de-Boc and macrocyclamide formation as described in the conversion of 1-6 to Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.71 (s, 1H), 8.82 - 8.11 (m, 2H), 8.04 - 7.68 (m, 2H), 7.46 - 7.14 (m, 2H), 7.14 - 6.31 (m, 2H), 4.18 - 3.86 (m, 2H), 3.80 (br s, 2H), 3.72 - 3.49 (m, 2H), 3.47 - 3.37 (m, 2H), 1.79 - 1.63 (m, 2H) . LCMS: m/z 400.0 (M+H) ⁺ .

15-(3-Chloro-4-fluorophenyl)-8,9,10,11,14,15-hexahydro-4,6-vinylidenepyrimido[4,5-e][1,4 ,10] Preparation of oxadiazacyclotridecen-7(13H)-one (Example 35)

Example 35 was prepared using a procedure similar to Example 2, substituting methyl 4-chloroquinazoline-6-carboxylate in Step 1 for methyl 4-chloroquinazoline-6-carboxylate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.75 (s, 1H), 8.74 (s, 1H), 8.35 (dd, J = 1.6, 5.6 Hz, 1H), 8.11 (br d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 2.4, 6.4 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.41 - 7.37 (m, 1H), 4.72 (s, 2H), 4.40 (s, 2H), 3.92 (s, 2H), 3.76 (br d, J = 2.0 Hz, 2H), 1.88 - 1.83 (m, 1H). LCMS: m/z 401.1 (M+H) ⁺ .

1-(3-Chloro-4-fluorophenyl)-11-methyl-1,2,3,5,6,7,8,11-octahydro-9H-14,16-vinylidene-13 , Preparation of 10-(methenidelidene)pyrido[4,3-e][1,4,10,11,14]oxa tetraazacycloheptadecen-9-one (Example 36)

5-(4-Chloro-6-quinolinyl)-2-methyl-pyrazole-3-carboxylic acid methyl ester (M1, 200 mg, 0.663 mmol, 1 eq ), N-[3-[2-( 3-Chloro-4-fluoro-anilino)ethoxy]propyl]carbamate tert-butyl ester (J1, 300 mg, 0.865 mmol, 1.3 eq ), RuPhos-Pd-G3 (55.4 mg, 0.0663 mmol, 0.1 eq ), _Cs2CO3 (647.91 mg, 1.99 mmol, ₃ eq ) in toluene (8 mL) was stirred at 110 °C under _N2 atmosphere for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 5-[4-[N-[2-[3-(tertiary butoxycarbonylamino)propoxy]ethyl]-3-chloro as a yellow solid -methyl 4-fluoro-anilino]-6-quinolinyl]-2-methyl-pyrazole-3-carboxylate (110 mg, 0.180 mmol, 27.1% yield). ¹ H NMR (400 MHz, CDCl ₃ - d ) δ = 8.84 - 8.54 (m, 2H), 8.36 - 8.07 (m, 1H), 8.02 - 7.79 (m, 1H), 7.60 (br d, J = 5.2 Hz , 1H), 7.54 - 7.28 (m, 1H), 7.25 - 7.03 (m, 2H), 6.81 (s, 1H), 5.31 (s, 1H), 4.32 (br d, J = 1.2 Hz, 1H), 4.22 - 4.12 (m, 3H), 3.94 (s, 3H), 3.74 (br s, 2H), 3.61 - 3.45 (m, 3H), 3.19 (br d, J = 5.6 Hz, 2H), 2.37 - 2.16 (m , 1H), 1.93 - 1.69 (m, 9H), 1.65 - 1.53 (m, 1H). LCMS: m/z 612.3 (M+H) ⁺ .

36-1 was further converted to Example 36 following hydrolysis, de-Boc and macrocyclamide formation as described in the conversion of 1-6 to Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.99 (s, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.23 - 8.15 (m, 2H), 8.09 - 8.00 (m, 1H) , 7.60 - 7.44 (m, 2H), 7.43 - 7.28 (m, 1H), 7.23 - 7.14 (m, 1H), 6.70 - 6.62 (m, 1H), 4.08 (s, 3H), 3.99 (br s, 2H ), 3.70 (br s, 2H), 3.47 - 3.46 (m, 4H), 2.03 - 1.97 (m, 2H). LCMS: m/z 480.2 (M+H) ⁺ .

1-(3-Chloro-4-fluorophenyl)-8,11-dimethyl-1,2,3,5,6,7,8,11-octahydro-9H-14,16-vinylidene Base-13,10-(methenylene)pyrido[4,3-e][1,4,10,11,14]oxatetraazacyclohexadecen-9-one (Example 37) preparation

Using a method similar to Example 36, using J2 in Step 1, Example 37 was prepared. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.97 (d, J = 1.6 Hz, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.20 (dd, J = 1.6, 8.8 Hz, 1H ), 8.04 (d, J = 8.8 Hz, 1H), 7.49 (dd, J = 2.8, 6.4 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.21 (td, J = 3.6, 8.8 Hz, 1H) , 6.69 (d, J = 4.8 Hz, 1H), 4.04 (s, 3H), 3.98 (br s, 2H), 3.69 (br s, 4H), 3.49 (br s, 2H), 3.01 (s, 3H) , 2.16 (br d, J = 5.2 Hz, 2H) LCMS: m/z 494.2 (M+H) ⁺ .

1-(3-Chloro-4-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-vinylidene-13,10 Preparation of -(methenylidene)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecen-9(2H)-one (Example 38)

38-1 was prepared following a procedure similar to Example 36, using J3 instead of J1.

To a solution of 38-1 (50 mg, 0.0814 mmol, 1 eq) in DCM (3 mL) was added HBr/AcOH (1 mL). The mixture was stirred at 25 °C for 1 h, then partitioned between dichloromethane (5 mL x 3) and water (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The crude product was purified by reverse phase HPLC to afford Example 38 (4.04 mg, 0.0842 mmol, 10% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.41 (d, J = 5.2 Hz, 1H), 8.36 - 8.27 (m, 2H), 7.95 (t, J = 7.6 Hz, 1H), 7.75 - 7.68 (m, 1H), 7.64 (s, 1H), 7.57 - 7.47 (m, 1H), 7.41 (dd, J = 4.0, 6.8 Hz, 1H), 6.60 (d, J = 5.6 Hz, 1H), 4.38 ( d, J = 7.6 Hz, 2H), 4.10 (s, 3H), 3.54 - 3.48 (m, 2H), 3.11 - 3.05 (m, 2H), 2.65 (d, J = 4.4 Hz, 2H), 1.70 - 1.63 (m, 2H); LCMS: m/z 480.2 (M+1:480.2).

1-(3-Chloro-4-fluorophenyl)-7,10-dimethyl-1,2,3,6,7,10-hexahydro-13,15-vinylidene-12,9- Preparation of (methenylidene)pyrido[3,4-l][1,4,7,8,14]oxatetraazacyclohexadecen-8(5H)-one (Example 39)

Example 39 was prepared following a procedure similar to Example 36, using J4 instead of J1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.86 - 8.67 (m, 1H), 8.10 - 7.80 (m, 3H), 7.50 - 7.30 (m, 1H), 7.12 - 6.91 (m, 2H), 6.71 - 6.47 (m, 2H), 4.14 - 3.97 (m, 2H), 3.67 (s, 3H), 3.61 - 3.39 (m, 6H), 2.91 - 2.79 (m, 3H); LCMS: m/z 480.2 ( M+H) ⁺ .

1-(3-Chloro-4-fluorophenyl)-8,11-dimethyl-1,3,4,8,9,11-hexahydro-2H-14,16-vinylidene-13, 10-(methenylidene)pyrido[3,4-l][1,4,7,8,14]oxa tetraazacycloheptadecen-7(6H)-one (Example 40) preparation

Step 1. Add 5-(4-chloro-6-quinolyl)-2-methyl-pyrazole-3-carboxylic acid methyl ester (2.00 g, 6.63 mmol, 1 eq ) and CaCl ₂ (2.21 g, 19.89 mmol, 3 eq ) in EtOH (40 mL) was slowly added NaBH ₄ (501 mg, 13.3 mmol, 2 eq ). The mixture was stirred at 25°C for 12 hours. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to give compound [5-(4-chloro-6-quinolyl) as a white solid -2-Methyl-pyrazol-3-yl]methanol (1.70 g, 5.96 mmol, 89.8% yield). LCMS: m/z 274.1 (M+H) ⁺ .

Step 2. Add [5-(4-chloro-6-quinolinyl)-2-methyl-pyrazol-3-yl]methanol (1.30 g, 4.75 mmol, 1 eq ) and TEA (1.44 g, 14.3 mmol, 1.98 mL, 3 eq ) in DCM (13 mL) was added MsCl (670 mg, 5.85 mmol, 1.23 eq ) and the mixture was stirred at 25 °C for 1 h. Additional MsCl (652 mg, 5.70 mmol, 1.2 eq ) was added at 0°C, and the mixture was stirred at 25°C for a further 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 4-chloro-6-[ 5-(Chloromethyl)-1-methyl-pyrazol-3-yl]quinoline (1.60 g, 4.69 mmol, 98.8% yield, 85.7% purity). LCMS: m/z 291.9 (M+H) ⁺ .

Step 3. Add 4-chloro-6-[5-(chloromethyl)-1-methyl-pyrazol-3-yl]quinoline (1.33 g, 4.55 mmol, 1 eq ) in THF (20 mL) To the mixture was added MeNH ₂ (2 M, 30 mL, 13.2 eq ), and the mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated in vacuo to afford 1-[5-(4-chloro-6-quinolinyl)-2-methyl-pyrazol-3-yl]-N-methyl-methylamine as a yellow solid ( 1.20 g, 3.85 mmol, 84.6% yield). LCMS: m/z 287.1 (M+H) ⁺ .

Step 4. To 1-[5-(4-chloro-6-quinolinyl)-2-methyl-pyrazol-3-yl]-N-methyl-methylamine (1.15 g, 4.01 mmol, 1 eq ) to a mixture in DCM (12 mL) was added DIEA (1.55 g, 12.0 mmol, 2.09 mL, 3 eq ). The mixture was stirred at 0 °C. Then Boc ₂ O (2.62 g, 12.0 mmol, 2.76 mL, 3 eq ) was added and the mixture was stirred at 25°C for 2 hours. The reaction was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to afford N-[[5-(4-chloro-6-quinolinyl)-2-methyl-pyrazol-3-yl]methyl] as a yellow oil - tert-butyl N-methyl-carbamate (720 mg, 1.75 mmol, 43.6% yield, 94.0% purity). LCMS: m/z 388.1 (M+H) ⁺ .

Step 5. To N-[[5-(4-chloro-6-quinolyl)-2-methyl-pyrazol-3-yl]methyl]-N-methyl-carbamic acid tertiary butyl ester (300 mg, 0.775 mmol, 1 eq ) and ethyl 2-[3-(3-chloro-4-fluoro-anilino)propoxy]acetate (270 mg, 0.931 mmol, 1.20 eq ) in toluene (5 mL ) were added Cs ₂ CO ₃ (757 mg, 2.33 mmol, 3 eq ) and RuPhos Pd G ₃ (64.0 mg, 0.0775 mmol, 0.1 eq ). The mixture was stirred at 120 °C for 12 h under _N2 . The reaction was filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=50/0 to 1/1) to obtain 2 as a yellow oil. -[3-(N-[6-[5-[[tertiary butoxycarbonyl (methyl)amino]methyl]-1-methyl-pyrazol-3-yl]-4-quinolinyl ]-3-Chloro-4-fluoro-anilino)propoxy]acetate (68.0 mg, 0.957 mmol, 12.3% yield). LCMS: m/z 640.4 (M+H) ⁺ .

Example 40 was obtained from 40-5 after ester hydrolysis, de-Boc and macrocyclamide formation as described in the conversion of 1-6 to Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.64 - 8.55 (m, 1H), 8.34 (s, 1H), 8.31 - 8.24 (m, 1H), 8.21 (br d, J = 8.4 Hz, 1H ), 8.05 (br d, J = 8.8 Hz, 1H), 7.63 - 7.55 (m, 1H), 7.50 - 7.41 (m, 1H), 7.36 - 7.30 (m, 1H), 6.81 (br d, J = 5.2 Hz, 1H), 6.53 (s, 1H), 5.17 (br d, J = 16.8 Hz, 1H), 4.74 (br d, J = 12.8 Hz, 1H), 4.15 - 4.00 (m, 2H), 3.89 (s , 3H), 3.80 - 3.66 (m, 3H), 3.64 - 3.55 (m, 5H), 2.67 - 2.65 (m, 2H). LCMS: m/z 480.2 (M+H) ⁺ .

7-Chloro-8-fluoro-17-methyl-5,13,14,17-tetrahydro-10H-1,20-vinylidene-19,16-(methenylidene)pyrido[4 ,3-b] [14,1,4,7,8,11] benzo 㗁 pentaazacyclohexadecen-15 (12H) -one (example 41) preparation

41-1 was prepared using a method similar to 2-2 in Example 2. Using the transformation method as in 1-2 to 1-5 in Example 1, 41-1 was transformed into 41-4 in three steps. Using a method similar to 36-1 to 36-2 in Example 36, 41-4 was coupled with K1 to afford 41-5. Example 41 was obtained from 41-5 after ester hydrolysis, de-Boc and macrocyclamide formation as described in the conversion of 1-6 to Example 1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.61 (s, 1H), 8.72 (d, J = 4.8 Hz, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.94 - 7.89 (m, 2H), 7.64 (d, J = 9.2 Hz, 1H), 7.55 (d, J = 4.8 Hz, 1H), 5.32 (s, 2H), 4.72 (s , 2H), 4.15 (s, 3H), 3.94 (br t, J = 7.2 Hz, 2H). LCMS: m/z 453.2 (M+H) ⁺ .

N-cyclopropyl-3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-vinylidene-13, 10-(methenylidene)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecen-1(11H)-yl]benzamide (example 42) Preparation

Step 1. To a solution of 6-chloroquinolin-4-ol (1 g, 5.57 mmol, 1 eq) in DMF (15 mL) was added _PBr3 (1.96 g, 7.24 mmol, 1.3 eq) at 0 °C. The reaction was stirred at 20°C for 2 hours. The reaction mixture was poured into 50 mL of water and the solid was filtered to give 4-bromo-6-chloro-quinoline (0.85 g, 3.15 mmol, 56% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.74 (d, J = 4.4 Hz, 1H), 8.12 - 8.07 (m, 2H), 7.99 (d, J = 4.4 Hz, 1H), 7.87 (d , J = 8.8 Hz, 1H)

Step 2. Combine 4-bromo-6-chloro-quinoline (200 mg, 0.824 mmol, 1 eq ), 3-[2-[benzyloxycarbonyl-[3-(tertiary butoxycarbonylamino) Propyl]amino]ethylamino]methylbenzoate (400 mg, 0.824 mmol, 1 eq ), RuPhos Pd G ₃ (68.8 mg, 0.0824 mmol, 0.1 eq ) and Cs ₂ CO ₃ (805.2 mg, 2.28 mmol, 3 eq ) in toluene (8 mL) was stirred at 120°C for 12 hours. The reaction mixture was diluted with H ₂ O (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to give 3-[2-[benzyloxycarbonyl-[3- Methyl (tertiary butoxycarbonylamino)propyl]amino]ethyl-(6-chloro-4-quinolyl)amino]benzoate (160 mg, 123.6 μmol, 30% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.98 - 8.76 (m, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.59 - 7.40 (m, 3H), 7.32 - 7.18 (m, 6H), 7.00 (d, J = 7.2 Hz, 1H), 6.73 (s, 1H), 4.98 (s, 2H), 4.14 - 4.03 (m, 2H), 3.75 (s, 3H), 3.55 (d, J = 6.4 Hz, 2H), 3.23 - 3.08 (m, 2H), 2.84 (d, J = 6.8 Hz, 2H), 1.55 (d, J = 5.6 Hz, 2H ), 1.37 - 1.27 (m, 9H)

Step 3. Add 3-[2-[benzyloxycarbonyl-[3-(tertiary butoxycarbonylamino)propyl]amino]ethyl-(6-chloro-4-quinolyl)amine A solution of methyl]benzoate (160 mg, 0.243 mmol, 1 eq ) in DCM (5 mL) and HCl/dioxane (2 mL) was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated to afford crude 3-[2-[3-aminopropyl(benzyloxycarbonyl)amino]ethyl-(6-chloro-4-quinolyl)amine as a yellow oil [0010] methyl]benzoate (170 mg, crude material).

Step 4. To methyl 3-[2-[3-aminopropyl(benzyloxycarbonyl)amino]ethyl-(6-chloro-4-quinolyl)amino]benzoate (170 mg , 0.310 mmol, 1 eq ), 3-dihydroxyboryl-1-methyl-1H-pyrazole-5-carboxylic acid (118 mg, 0.696 mmol, 2.24 eq ) and DIEA (80.3 mg, 0.621 mmol, 2 eq ) To a solution in DMF ( ₂₀ mL) was added T3P (148 mg, 0.466 mmol, 1.5 eq ). The reaction was stirred at 20°C for 0.5 hours. The reactant was used directly in the next step without manipulation.

酸(175 mg，0.279 mmol，1 eq)、K ₃PO ₄(179.6 mg，3 eq)及[2-(2-胺基苯基)苯基]-氯-鈀;二環己基-[3-(2,4,6-三異丙基苯基)苯基]膦(21.9 mg，0.1 eq)於THF (20 mL)及H ₂O (4 mL)中之溶液在70℃下攪拌1小時。反應混合物用H ₂O (50 mL)稀釋且用EtOAc (30 mL × 3)萃取。合併之有機層用鹽水(50 mL)洗滌，經Na ₂SO ₄乾燥，過濾且減壓濃縮，得到殘餘物。殘餘物藉由管柱層析(SiO ₂，石油醚/乙酸乙酯=1/1至1/0)純化，得到呈黃色固體狀之42-6 (75 mg，39.9%產率)。LCMS：m/z 619.2) (M+H) ⁺。 Step 5. Adding [5-[3-[benzyloxycarbonyl-[2-(N-(6-chloro-4-quinolyl)-3-methoxycarbonyl-anilino)ethyl]amino ]Propylaminoformyl]-1-methyl-pyrazol-3-yl]

acid (175 mg, 0.279 mmol, 1 eq ), K ₃ PO ₄ (179.6 mg, 3 eq ) and [2-(2-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl-[3- A solution of (2,4,6-triisopropylphenyl)phenyl]phosphine (21.9 mg, 0.1 eq ) in THF (20 mL) and H ₂ O (4 mL) was stirred at 70° C. for 1 hour. The reaction mixture was diluted with H ₂ O (50 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/1 to 1/0) to afford 42-6 (75 mg, 39.9% yield) as a yellow solid. LCMS: m/z 619.2) (M+H) ⁺ .

Step 6. 42-6 (25 mg, 0.0404 mmol, 1 eq ) and LiOH.H ₂ O (3.39 mg, 0.0808 mmol, 2 eq ) were dissolved in THF (1 mL), MeOH (1 mL) and H ₂ O ( 0.5 mL) was stirred at 20°C for 1 hour. The reaction mixture was concentrated to afford crude 42-7 (25 mg, crude) as a yellow solid.

Step 7. To a solution of 42-7 (25 mg, 0.0413 mmol, 1 eq ) and cyclopropylamine (4.72 mg, 0.0826 mmol, 2 eq ) in THF (1 mL) was added DIEA (10.6 mg, 0.0826 eq ) and T ₃ P (19.7 mg, 0.0620 mmol, 1.5 eq ). The reaction was stirred at 20°C for 0.5 hours. The reaction mixture was diluted with aqueous NaHCO ₃ (10 mL) and extracted with DCM (5 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give crude 42-8 (27 mg, crude) as a yellow solid.

Step 8. To a solution of 42-8 (27 mg, 0.0419 mmol, 1 eq ) in DCM (3 mL) was added HBr/HOAc (0.5 mL). The reaction was stirred at 20°C for 0.5 hours. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford Example 42 (1.86 mg, 0.0335 μmol, 7.98% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.21 (s, 1H), 8.56 (d, J = 5.2 Hz, 1H), 8.43 (d, J = 4.0 Hz, 1H), 8.36 (s, 2H ), 8.23 (d, J = 8.8 Hz, 1H), 8.10 (t, J = 7.6 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.74 (s, 1H), 7.63 (s, 1H ), 7.57 (d, J = 7.6 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.41 - 7.36 (m, 1H), 6.62 (d, J = 5.2 Hz, 1H), 4.06 (s, 3H) , 3.91 (d, J = 2.8 Hz, 2H), 3.44 (s, 2H), 2.87 (s, 3H), 2.80 ( J = 3.6, 7.2 Hz, 2H), 1.87 (d, J = 8.0 Hz, 2H) , 0.66 (d, J = 7.2 Hz, 2H), 0.58 - 0.49 (m, 2H); LCMS: m/z 510.2 (M+H) ⁺ .

3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-vinylidene-13,10-(methano Enyl)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecen-1(11H)-yl]-N-(prop-2-yl)benzyl Preparation of Amide (Example 43)

Following a procedure similar to Example 42, Example 43 was prepared in Step 7 using 2-propylamine for amide coupling with 42-7. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.21 (d, J = 1.2 Hz, 1H), 8.56 (d, J = 4.8 Hz, 1H), 8.33 (s, 1H), 8.25 - 8.19 (m , 2H), 8.14 - 8.08 (m, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.67 - 7.60 (m, 2H), 7.48 - 7.42 (m, 1H), 7.41 - 7.37 (m, 1H), 6.62 (d, J = 4.8 Hz, 1H), 4.11 - 4.04 (m, 4H), 3.98 - 3.88 (m, 2H), 3.21 (d, J = 4.0 Hz, 4H) , 2.87 ( s, 2H), 1.92 - 1.82 (m, 2H), 1.14 (d, J = 6.4 Hz, 6H); LCMS: m/z 512.5 (M+H) ⁺ .

N -methyl-3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-vinylidene-13,10 -(methenylidene)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecen-1(11H)-yl]benzamide (Example 44 ) preparation

Following a procedure similar to Example 42, Example 44 was prepared in Step 7 using methylamine for amide coupling with 42-7. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.22 (s, 1H), 8.57 (d, J = 4.8 Hz, 1H), 8.49 - 8.37 (m, 1H), 8.24 (d, J = 8.8 Hz , 1H), 8.12 (t, J = 7.2 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.69 - 7.63 (m, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.41 - 7.34 (m, 1H), 6.65 (d, J = 5.2 Hz, 1H), 4.07 (s, 3H), 3.99 - 3.86 ( m, 2H), 3.25 (s, 4H), 2.93 - 2.85 (m, 2H), 2.75 (d, J = 4.4 Hz, 3H), 1.93 - 1.84 (m, 2H); LCMS: m/z 484.2 (M +H) ⁺ .

1-(3,4-Dichloro-2-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-vinylidene- 13,10-(methenidene)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecen-9(2H)-one (Example 45) preparation

Example 45 was prepared following a procedure similar to Example 36, using J8 in place of J1, followed by de-Cbz as in Example 38. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.22 (d, J = 1.6 Hz, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.24 (dd, J = 1.6, 8.8 Hz, 1H ), 8.12 (t, J = 7.2 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.74 (s, 1H), 7.68 - 7.58 (m, 2H), 6.77 (d, J = 4.8 Hz , 1H), 4.07 (s, 3H), 3.91 (d, J = 0.8 Hz, 2H), 3.53 - 3.35 (m, 2H), 2.83 (s, 2H), 2.61 - 2.54 (m, 2H), 1.92 - 1.83 (m, 2H). LCMS: m/z 513.0 (M+H) ⁺ .

1-(3-Chloro-2-fluorophenyl)-11-methyl-1,3,4,5,6,7,8,11-octahydro-14,16-vinylidene-13,10 Preparation of -(methenomethylene)pyrido[4,3-m][1,2,5,9,12]pentaazacycloheptadecen-9(2H)-one (Example 46)

Example 46 was prepared following a procedure similar to Example 36, using J9 in place of J1, followed by de-Cbz as in Example 38. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.21 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.23 (dd, J = 2.0, 8.8 Hz, 1H), 8.11 (t , J = 7.2 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.74 (s, 1H), 7.63 - 7.58 (m, 1H), 7.39 - 7.31 (m, 2H), 6.68 (d, J = 4.8 Hz, 1H), 4.07 (s, 3H), 3.92 (s, 2H), 3.30 (s, 4H), 2.88 - 2.81 (m, 2H), 1.93 - 1.82 (m, 2H); LCMS: m /z 479.3 (M+H) ⁺ .

2-[1-(3-Chloro-4-fluorophenyl)-11-methyl-9-oxo-1,2,3,4,5,6,7,11-octahydro-14,16 -Ethylene-13,10-(methenylene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecene-8(9H)- Preparation of]-N-methylacetamide (Example 47)

47-1 was prepared in a similar manner to 36-1 in Example 36, using J3 instead of J1.

Step 1. To 5-[4-[N-[2-[benzyloxycarbonyl-[3-(tertiary butoxycarbonylamino)propyl]amino]ethyl]-3-chloro-4 -Fluoro-anilino]-6-quinolinyl]-2-methyl-pyrazole-3-carboxylic acid methyl ester (380 mg, 0.509 mmol, 1 eq ) in DCM (2 mL) and HCl/dioxane ( 2 mL) in the solution. The mixture was stirred at 25°C for 0.5 hours. The mixture was concentrated to give a residue. The compound was used in the next step without further purification to give 5-[4-[N-[2-[3-aminopropyl(benzyloxycarbonyl)amino]ethyl as a yellow oil ]-4-Chloro-3-fluoro-anilino]-6-quinolinyl]-2-methyl-pyrazole-3-carboxylic acid methyl ester (328 mg, 0.509 mmol, 100% yield).

Step 2. To 5-[4-[N-[2-[3-aminopropyl(benzyloxycarbonyl)-amino]ethyl]-4-chloro-3-fluoro-anilino]-6 -Quinolinyl]-2-methyl-pyrazole-3-carboxylic acid methyl ester (289 mg, 0.448 mmol, 1 eq ) and 2-bromo-N-methyl-acetamide (68.1 mg, 0.448 mmol, 1 eq eq ) To a solution in DMSO (4 mL) was added DIEA (289 mg, 2.24 mmol, 5 eq ). The mixture was stirred at 50 °C for 16 h, quenched with water (40 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography ( _SiO2 , EtOAc:MeOH = 1:0 to 1:1) to give 5-[4-[N-[2-[benzyloxycarbonyl- [3-[[2-(Methylamino)-2-oxo-ethyl]amino]propyl]amino]ethyl]-3-chloro-4-fluoro-anilino]-6- Quinolinyl]-2-methyl-pyrazole-3-carboxylic acid methyl ester (70 mg, 0.0661 mmol, 14% yield). LCMS: m/z 716.4 (MS+H) ⁺ .

Step 3. To 5-[4-[N-[2-[benzyloxycarbonyl-[3-[[2-(methylamino)-2-oxo-ethyl]amino]propyl ]amino]ethyl]-3-chloro-4-fluoro-anilino]-6-quinolinyl]-2-methyl-pyrazole-3-carboxylic acid methyl ester (70 mg, 0.0977 mmol, 1 eq ) To a solution in MeOH (1 mL), H ₂ O (0.5 mL) and THF (1 mL) was added LiOH.H ₂ O (12.3 mg, 293 μmol, 3 eq ). The mixture was stirred at 25°C for 0.5 hours. The mixture was concentrated to remove MeOH. The compound was used in the next step without further purification.

Step 4. To 5-[4-[N-[2-[benzyloxycarbonyl-[3-[[2-(methylamino)-2-oxo-ethyl]amino]propyl ]amino]ethyl]-3-chloro-4-fluoro-anilino]-6-quinolinyl]-2-methyl-pyrazole-3-carboxylic acid (68.6 mg, 0.0977 mmol, 1 eq ) in THF (40 mL) was added T ₃ P (46.6 mg, 0.146 mmol, 1.5 eq ) and DIEA (37.9 mg, 0.293 mmol, 3 eq ). The mixture was stirred at 0°C for 3 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-TLC ( _Si02 , EtOAc:MeOH = 4:1) to afford 47-5 (10 mg, 0.0139 mmol, 14% yield) as a white solid. LCMS: m/z 684.2 (MS+H) ⁺ .

Step 5. To a solution of 47-5 (10 mg, 0.0146 mmol, 1 eq ) in DCM (3 mL) and HBr/AcOH (1 mL). The mixture was stirred at 25°C for 1 hour. The mixture was quenched with saturated NaHCO ₃ solution (10 mL) and extracted with dichloromethane (5 mL×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to afford Example 47 (0.93 mg) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.22 (d, J = 1.6 Hz, 1H), 8.58 (d, J = 4.8 Hz, 1H), 8.21 (dd, J = 1.6, 8.8 Hz, 1H ), 8.03 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 4.4 Hz, 1H), 7.69 (s, 1H), 7.47 - 7.38 (m, 2H), 7.26 - 7.22 (m, 1H) , 6.68 (d, J = 4.4 Hz, 1H), 4.02 (s, 3H), 3.86 (d, J = 4.4 Hz, 2H), 3.75 - 3.54 (m, 2H), 2.84 - 2.77 (m, 2H), 2.60 (s, 7H), 1.98-1.96 (m, 2H). LCMS: m/z 550.2 (MS+H) ⁺ .

15-(3-Chloro-4-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene-3,6 Preparation of -(methenylidene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one (Example 48)

Following a procedure similar to Example 36, using M2 in place of M1, followed by de-Cbz as in Example 38, Example 48 was prepared as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.41 (d, J = 5.2 Hz, 1H), 8.36 - 8.27 (m, 2H), 7.95 (t, J = 7.6 Hz, 1H), 7.75 - 7.68 (m, 1H), 7.64 (s, 1H), 7.57 - 7.47 (m, 1H), 7.41 (dd, J = 4.0, 6.8 Hz, 1H), 6.60 (d, J = 5.6 Hz, 1H), 4.38 ( d, J = 7.6 Hz, 2H), 4.10 (s, 3H), 3.54 - 3.48 (m, 2H), 3.11 - 3.05 (m, 2H), 2.65 (d, J = 4.4 Hz, 2H), 1.70 - 1.63 (m, 2H); LCMS: 480.2 (M+H) ⁺ .

N-[1-(3-Chloro-4-fluorophenyl)-2,3,6,7-tetrahydro-1H,5H-9,11-vinylidenepyrido[4,3-e][ Preparation of 1,9,4]dioxazacyclododecen-6-yl]prop-2-enamide (Example 49)

Step 1. Mix N-[2-[tertiary butyl(dimethyl)silyl]oxyethyl]-3-chloro-4-fluoro-aniline (1.7 g, 5.59 mmol, 1 eq ), 4- Chloro-6-methoxy-quinoline (1.1 g, 5.68 mmol, 1.02 eq ), RuPhos Pd G ₃ (200 mg, 0.239 mmol, 0.043 eq ) and Cs ₂ CO ₃ (5.47 g, 16.7 mmol, 3 eq ) The solution in toluene (20 mL) was stirred at 120 °C for 12 hours. The reaction mixture was diluted with H ₂ O (200 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to obtain N-[2-[tertiary butyl(dimethyl )silyl]oxyethyl]-N-(3-chloro-4-fluoro-phenyl)-6-methoxy-quinolin-4-amine (2.2 g, 3.34 mmol, 59% yield, 70 %purity). LCMS: m/z 461.4 (M+H) ⁺ .

Step 2. N-[2-[tertiary butyl(dimethyl)silyl]oxyethyl]-N-(3-chloro-4-fluoro-phenyl)-6-methoxy-quinoline A solution of phenin-4-amine (2.2 g, 4.77 mmol, 1 eq ) and CsF (2.17 g, 14.3 mmol, 3 eq ) in DMSO (20 mL) was stirred at 20° C. for 12 h. The reaction mixture was washed with H ₂ O ( 400 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 0/1) to give 2-(3-chloro-4-fluoro-N-( 6-methoxy-4-quinolinyl)anilino)ethanol (850 mg, 2.45 mmol, 51.37% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.73 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.46 (d, J = 4.8 Hz, 1H), 7.36 (dd, J = 2.8, 9.2 Hz, 1H), 7.20 (t, J = 9.2 Hz, 1H), 7.03 - 6.97 (m, 2H), 6.65 (td, J = 3.6, 9.2 Hz, 1H), 4.94 (t, J = 5.2 Hz, 1H), 3.95 (t, J = 5.6 Hz, 2H), 3.64 - 3.58 (m, 5H); LCMS: m/z 346.8 (M+H) ⁺ .

Step 3. Add 2-(3-chloro-4-fluoro-N-(6-methoxy-4-quinolyl)anilino)ethanol (800 mg, 2.31 mmol, 1 eq ) in DCM at 0 °C (20 mL) was added BBr ₃ (1 M, 6.92 mL, 3 eq ). The reaction was stirred at 20 °C for 12 h under _N2 . The reaction mixture was quenched by adding aqueous NaHCO ₃ (10 mL). The reaction mixture was diluted with H ₂ O (100 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 4-[3-chloro-4-fluoro-N-(2-hydroxyethyl ) anilino]quinolin-6-ol (600 mg, 1.73 mmol, 75.03% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.94 (s, 1H), 8.69 (d, J = 4.8 Hz, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.44 (d, J = 4.4 Hz, 1H), 7.25 (dd, J = 2.4, 9.2 Hz, 1H), 7.16 (t, J = 9.2 Hz, 1H), 6.89 (dd, J = 3.2, 6.4 Hz, 1H), 6.85 (d , J = 2.4 Hz, 1H), 6.54 - 6.46 (m, 1H), 4.88 (t, J = 5.2 Hz, 1H), 3.90 (t, J = 6.0 Hz, 2H), 3.59 (q, J = 6.0 Hz , 2H); LCMS: m/z 332.9 (M+H) ⁺ .

Step 4. Combine 4-[3-chloro-4-fluoro-N-(2-hydroxyethyl)anilino]quinolin-6-ol (600 mg, 1.80 mmol, 1 eq ), 3-chloro-2- A solution of (chloromethyl)prop-1-ene (600 mg, 4.80 mmol, 2.66 eq ) and K ₂ CO ₃ (747 mg, 5.41 mmol, 3 eq ) in DMF (10 mL) was stirred at 40°C for 12 Hour. The reaction mixture was diluted with H ₂ O (100 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/1 to 0/1) to give 2-(3-chloro-N-[6-[2 -(Chloromethyl)allyloxy]-4-quinolinyl]-4-fluoro-anilino)ethanol (350 mg, 0.797 mmol, 44% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.75 (d, J = 4.8 Hz, 1H), 7.97 (s, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.41 (dd, J = 2.8, 9.2 Hz, 1H), 7.18 (t, J = 9.2 Hz, 1H), 7.03 (d, J = 2.8 Hz, 1H), 6.96 (dd, J = 2.8, 6.2 Hz, 1H), 6.59 (td , J = 3.6, 8.8 Hz, 1H), 5.32 (s, 1H), 5.19 (d, J = 1.2 Hz, 1H), 4.93 (t, J = 5.2 Hz, 1H), 4.52 (s, 2H), 4.22 (s, 2H), 3.94 (t, J = 6.0 Hz, 2H), 3.61 (q, J = 6.0 Hz, 2H); LCMS: m/z 420.9 (M+H) ⁺ .

Step 5. Add 2-(3-chloro-N-[6-[2-(chloromethyl)allyloxy]-4-quinolyl]-4-fluoro-anilino)ethanol ( To a solution of 300 mg, 0.712 mmol, 1 eq ) in THF (60 mL) was added NaH (60.0 mg, 1.50 mmol, 60% purity, 2.11 eq ). The reaction was stirred at 20°C for 6 hours. The reaction was quenched with aqueous NH ₄ Cl (50 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to obtain 49-5 (170 mg, 0.441 mmol, 62% yield) as a yellow oil ). LCMS: m/z 384.9 (M+H) ⁺ .

Step 6. 49-5 (170 mg, 0.441 mmol, 1 eq ), K ₂ OsO ₄ .2H ₂ O (8.14 mg, 0.022 mmol, 0.05 eq ) and NMO (155 mg, 1.33 mmol, 3 eq ) were dissolved in THF (3 mL) and _H2O (0.5 mL) was stirred at 20 °C for 12 h. The reaction mixture was diluted with aqueous Na ₂ SO ₃ (100 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give crude product 49-6 (180 mg, 0.412 mmol, 93.3% yield) as a brown solid, which It was used in the next step without further purification. LCMS: m/z 418.9 (M+H) ⁺ .

Step 7. To a solution of 49-6 (180 mg, 0.429 mmol, 1 eq ) in THF (2 mL) and H ₂ O (1 mL) was added NaIO ₄ (137 mg, 0.644 mmol, 1.5 eq ). The reaction was stirred at 20°C for 1 hour. The reaction mixture was diluted with H ₂ O (100 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% TFA condition) to afford 49-7 (50 mg, 0.116 mmol, 27.0% yield) as a yellow oil. LCMS: m/z 405.0 (M+H) ⁺ .

Step 8. To a solution of 49-7 (35 mg, 0.0905 mmol, 1 eq ) and ammonium acetate (13.9 mg, 0,180 mmol, 2 eq ) in THF (1 mL) and MeOH (1 mL) was added NaBH ₃ CN (8.53 mg, 0.135 mmol, 1.5 eq ). The reaction was stirred at 20°C for 12 hours. The reaction mixture was concentrated to give crude product 49-8 (30 mg, crude) as a yellow solid, which was used without further purification.

Step 9. To a solution of 49-8 (30 mg, 0.077 mmol, 1 eq ) and NaHCO ₃ (6.50 mg, 0.077 mmol, 1 eq ) in THF (1 mL) and H ₂ O (1 mL) was added propane -2-enyl chloride (8 mg, 0.088 mmol, 1.14 eq ). The reaction was stirred at 20°C for 0.1 hour. The reaction mixture was concentrated and purified by preparative HPLC to afford Example 49 (7.14 mg, 0.016 μmol, 21% yield) as a yellow gum. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.92 (d, J = 2.4 Hz, 1H), 8.65 (d, J = 6.0 Hz, 1H), 8.43 (br d, J = 7.2 Hz, 1H) , 8.02 (d, J = 9.2 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.49 (t, J = 8.8 Hz, 1H), 7.38 - 7.30 (m, 1H), 7.08 (d, J = 6.0 Hz, 1H), 6.37 (dd, J = 10.2, 17.2 Hz, 1H), 6.15 (dd, J = 2.0, 17.2 Hz, 1H), 5.64 (dd, J = 2.0, 10.0 Hz, 1H), 4.36 (br s, 2H), 4.02 (br s, 2H), 3.53 (br s, 2H), 3.51 (br s, 1H), 2.07 (s, 2H); LCMS: m/z 442.0 (M+1).

N-[1-(3-Chloro-4-fluorophenyl)-2,3,6,7-tetrahydro-1H,5H-9,11-vinylidenepyrido[4,3-e][ 1,9,4] Preparation of dioxazacyclododecen-6-yl]acrylamide (Example 50)

A suspension of Example 49 (1.05 mg, 0.00238 mmol) and 10% Pd/C (0.25 mg, 0.00024 mmol) in ethanol (0.1 mL) was stirred under a hydrogen balloon for 1 h. The mixture was filtered, concentrated and purified by reverse phase HPLC to afford Example 50 (0.62 mg, 0.0014 mmol, 59%) as a colorless oil. LCMS: m/z 443.9 (M+H) ⁺ .

N-[1-(3-chloro-4-fluorophenyl)-4-methyl-2,3,4,5,6,7-hexahydro-1H-9,11-vinylidene pyrido[ Preparation of 4,3-i][1,5,8]oxadiazacyclododecen-6-yl]prop-2-enamide (Example 51)

Step 1. In a similar manner to 49-1 in Example 49, 51-1 was prepared using J11 instead of J10. LCMS: m/z 445.8 (M+H) ⁺ .

Step 2. To tertiary butyl N-[2-(3-chloro-4-fluoro-N-(6-methoxy-4-quinolyl)anilino)ethyl]carbamate at 0°C (1.6 g, 3.59 mmol, 1 eq ) in DMF (20 mL) were added NaH (260 mg, 6.50 mmol, 60% purity, 1.81 eq ) and CH ₃ I (611 mg, 4.31 mmol, 1.2 eq ) . The reaction was stirred at 20°C for 2 hours. The reaction was quenched with water (50 ml), diluted with H ₂ O (100 mL), and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 0% to 20%) to give N-[2-(3-chloro-4-fluoro-N- (6-Methoxy-4-quinolinyl)anilino)ethyl]-N-methyl-carbamic acid tert-butyl ester (1.5 g, 1.08 mmol, 30% yield). LCMS: m/z 460.0 (M+H) ⁺ .

Step 3. N-[2-(3-Chloro-4-fluoro-N-(6-methoxy-4-quinolyl)anilino)ethyl]-N-methyl-carbamic acid A solution of butyl ester (1.5 g, 3.26 mmol, 1 eq ) in HCl/dioxane (10 mL) and DCM (10 mL) was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated to give the crude product N'-(3-chloro-4-fluoro-phenyl)-N'-(6-methoxy-4-quinolinyl)-N-methyl- Ethane-1,2-diamine (1.2 g, crude material), which was used without further purification.

Step 4. To N'-(3-chloro-4-fluoro-phenyl)-N'-(6-methoxy-4-quinolyl)-N-methyl-ethane-1 at 0°C , To a solution of 2-diamine (1.2 g, 3.33 mmol, 1 eq ) in DMSO (20 mL) was added DIEA (1.29 g, 10.00 mmol, 3 eq ). 3-Chloro-2-(chloromethyl)prop-1-ene (4.32 g, 34.5 mmol, 10.4 eq ) was then added to the reaction. The reaction was stirred at 50°C for 12 hours. The reaction was concentrated and purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 0% to 60%) to give N'-(3-chloro-4-fluoro-phenyl as a yellow oil )-N-[2-(chloromethyl)allyl]-N'-(6-methoxy-4-quinolyl)-N-methyl-ethane-1,2-diamine (0.9 g, 1.89 mmol, 56% yield). ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 8.64 (d, J = 5.2 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.40 (d, J = 5.2 Hz, 1H), 7.33 (dd, J = 2.4, 9.2 Hz, 1H), 7.11 (t, J = 8.8 Hz, 1H), 6.99 (dd, J = 2.4, 6.0 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H ), 6.83 - 6.76 (m, 1H), 5.15 (s, 1H), 5.06 (s, 1H), 4.26 (s, 3H), 4.20 - 4.15 (m, 2H), 4.06 (br t, J = 6.4 Hz , 2H), 3.98 (s, 2H), 3.08 (s, 2H), 2.25 (s, 3H); LCMS: m/z 447.9 (M+H) ⁺ .

Step 5. To N'-(3-chloro-4-fluoro-phenyl)-N-[2-(chloromethyl)allyl]-N'-(6-methoxy-4-quinolyl )-N-Methyl-ethane-1,2-diamine (0.9 g, 2.01 mmol, 1 eq ) in DCM (20 mL) was added BBr ₃ (1 M, 6.02 mL, 3 eq ). The reaction was stirred at 40°C for 2 hours. The reaction mixture was diluted with aqueous NaHCO ₃ (100 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product 4-[3-chloro-N-[2-[2-(chloro Methyl)allyl-methyl-amino]ethyl]-4-fluoro-anilino]quinolin-6-ol (0.42 g, 0.928 mmol, 46% yield), which was obtained directly without further purification use. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 8.58 (d, J = 6.4 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 6.4 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.30 - 7.24 (m, 1H), 7.11 (qd, J = 4.0, 7.6 Hz, 1H), 6.77 (d , J = 2.4 Hz, 1H), 5.28 - 5.21 (m, 1H), 5.14 (s, 1H), 4.26 (t, J = 6.4 Hz, 2H), 4.05 - 3.96 (m, 2H), 3.20 (s, 2H), 2.84 (s, 2H), 2.37 (s, 3H); LCMS: m/z 434.0 (M+H) ⁺ .

Step 6. To 4-[3-chloro-N-[2-[2-(chloromethyl)allyl-methyl-amino]ethyl]-4-fluoro-anilino]quinoline-6- To a solution of the alcohol (0.3 g, 0.690 mmol, 1 eq ) in DMF (60 mL) was added K ₂ CO ₃ (114 mg, 0.828 mmol, 1.2 eq ). The reaction was stirred at 80 °C for 1 h, diluted with H ₂ O (300 mL), and extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give 51-6 (0.1 g, 0.238 mmol, 34% yield) as a white solid . LCMS: m/z 398.0 (M+H) ⁺ .

Example 51 was obtained from 51-6 following a procedure similar to that of 49-5 to Example 49. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.24 - 9.12 (m, 1H), 8.54 (d, J = 4.0 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.95 - 7.85 (m, 1H), 7.44 - 7.38 (m, 1H), 7.35 - 7.25 (m, 2H), 7.03 (s, 1H), 6.93 (d, J = 4.8 Hz, 1H), 6.41 - 6.22 (m, 1H ), 6.20 - 6.07 (m, 1H), 5.70 - 5.56 (m, 1H), 4.59 - 4.40 (m, 2H), 4.34 (t, J = 4.8 Hz, 2H), 3.96 - 3.82 (m, 1H), 3.50 - 3.41 (m, 2H), 3.30 - 3.29 (m, 3H), 2.91 - 2.77 (m, 2H); LCMS: m/z 454.9 (M+H) ⁺ .

15-(3-Chloro-4-fluorophenyl)-5,12-dimethyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene- 3,6-(methenylidene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one (Example 52 ) preparation

Following a procedure similar to Example 36, using M2 in place of M1 and J12 in place of J1, Example 52 was prepared as a yellow solid.

15-(4-Chloro-3-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene-3,6 Preparation of -(methenylidene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one (Example 53)

Following a procedure similar to Example 36, using M2 instead of M1 and J13 instead of J1 , followed by de-Cbz as in Example 38, Example 53 was prepared as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.49 (d, J = 5.2 Hz, 1H), 8.38 - 8.34 (m, 1H), 8.32 - 8.28 (m, 1H), 7.96 (t, J = 7.2 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.52 (d, J = 11.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 5.2 Hz, 1H) , 4.36 - 4.29 (m, 2H), 4.10 (s, 3H), 3.51 - 3.47 (m, 2H), 3.13 - 3.08 (m, 2H), 2.65 (d, J = 4.8 Hz, 2H), 1.71 - 1.65 (m, 2H); LCMS: m/z 480.2 (M+H) ⁺ .

15-(3,4-Dichlorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene-3,6- Preparation of (methenylidene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one (Example 54)

Following a procedure similar to Example 36, using M2 instead of M1 and J14 instead of J1 , followed by de-Cbz as in Example 38, Example 54 was prepared as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.47 (d, J = 5.2 Hz, 1H), 8.37 - 8.34 (m, 1H), 8.30 - 8.25 (m, 1H), 7.98 - 7.92 (m, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.66 - 7.61 (m, 2H), 7.35 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 5.2 Hz, 1H), 4.37 - 4.30 (m, 2H), 4.10 (s, 3H), 3.49 (d, J = 5.6 Hz, 2H), 3.11 - 3.05 (m, 2H), 2.66 - 2.62 (m, 2H), 1.70 - 1.59 (m, 2H); LCMS: 495.9 (M+H) ⁺ .

15-(3-Chloro-4-fluorophenyl)-5,8-dimethyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene- 3,6-(methenidelidene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one (Example 55 ) preparation

Following a procedure similar to Example 36, using M2 instead of M1 and J15 instead of J1 , followed by de-Cbz as in Example 38, Example 55 was prepared as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.42 (d, J = 5.2 Hz, 1H), 8.35 - 8.19 (m, 2H), 7.69 (d, J = 6.4 Hz, 1H), 7.55 - 7.45 (m, 2H), 7.43 - 7.36 (m, 1H), 6.62 (d, J = 5.2 Hz, 1H), 4.32 (t, J = 7.2 Hz, 2H), 4.07 (s, 3H), 3.67 (s, 2H), 3.11 - 3.02 (m, 2H), 2.99 (s, 3H), 2.65 (d, J = 8.8 Hz, 2H), 1.84 (d, J = 5.6 Hz, 2H); LCMS: m/z 494.2 ( M+H)+.

10-(3-Chloro-4-fluorophenyl)-4,5,6,7,9,10-hexahydro-8H-2,14-vinylidenepyrido[3,4-d][1 ,3,6,9] Preparation of oxatriazacyclododecen-8-one (Example 56)

Step 1. Combine ethyl 2-(3-chloro-4-fluoro-anilino)acetate (2 g, 8.63 mmol, 1 eq ), 8-chloro-2-methoxy-1,5-phenidine (1.85 g, 9.50 mmol, 1.1 eq ), Cs ₂ CO ₃ (8.44 g, 25.9 mmol, 3 eq ), XPhos (412 mg, 0.863 mmol, 0.1 eq ) and Pd(dba) ₂ (496 mg, 0.863 mmol, 0.1 eq ) in dioxane (20 mL) was degassed and purged 3 times with N ₂ . The mixture was stirred at 100 °C for 12 h under _N2 atmosphere. The reaction mixture was partitioned between ethyl acetate (30 mL x 3) and water (40 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1:0 to 1:1) to obtain 2-(3-chloro-4-fluoro-N-( 6-Methoxy-1,5-phenidin-4-yl)anilino)ethyl acetate (2 g, 4.41 mmol, 51% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.52 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.39 - 7.34 (m, 1H), 7.34 - 7.30 (m, 1H), 7.17 - 7.13 (m, 1H), 7.12 - 7.07 (m, 1H), 7.03 (d, J = 5.2 Hz, 1H), 5.02 (s, 2H), 4.10 (q, J = 7.2 Hz, 2H), 3.52 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H); LCMS: m/z 391.0 (M+H) ⁺ .

Step 2. Ethyl 2-(3-chloro-4-fluoro-N-(6-methoxy-1,5-phenidin-4-yl)anilino)acetate (1.9 g, 4.87 To a solution of mmol, 1 eq ) in DCM (2 mL) was added BBr ₃ (1 M, 14.62 mL, 3 eq ). The reaction was stirred at 40 °C for ₂ h under N2. The reaction mixture was partitioned between ethyl acetate (30 mL x 3) and water (30 mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1:0 to 5:1) to obtain 2-(3-chloro-4-fluoro-N-( 6-Hydroxy-1,5-(5-phenidin-4-yl)anilino)acetic acid methyl ester (600 mg, 1.33 mmol, 27% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.53 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 9.6 Hz, 1H), 7.55 - 7.49 (m, 1H), 7.26 - 7.15 (m, 1H), 6.79 (d, J = 9.6 Hz, 1H), 6.69 (d, J = 5.8 Hz, 1H), 6.40 (d, J = 3.2, 6.0 Hz, 1H), 4.56 (s, 2H) , 3.70 (s, 3H); LCMS: m/z 361.9 (M+H) ⁺ .

Step 3. To the To a solution in MeOH (5 mL) and _H2O ( ₂ mL) was added LiOH.H2O (174 mg, 4.15 mmol, 3 eq ). The mixture was stirred at 25°C for 1 hour. The mixture was concentrated to give crude 2-(3-chloro-4-fluoro-N-(6-hydroxy-1,5-phenidin-4-yl)anilino)acetic acid (400 mg, crude ), and it is used directly in the next step. LCMS: m/z 347.7 (M+H) ⁺ .

Step 4. Add 2-(3-chloro-4-fluoro-N-(6-hydroxy-1,5-phenidin-4-yl)anilino)acetic acid (400 mg, 1.15 mmol, 1 eq ) and 3- To a solution of aminopropan-1-ol (86.4 mg, 1.15 mmol, 1 eq ) in DMF (5 mL) was added T ₃ P (439 mg, 1.38 mmol, 1.2 eq ) and DIEA (446 mg, 3.45 mmol, 3eq ). The mixture was stirred at 25°C for 2 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , ethyl acetate/MeOH=1:0 to 5:1) to give 2-(3-chloro-4-fluoro-N-(6- Hydroxy-1,5-(5-(3-hydroxypropyl)-4-yl)anilino)-N-(3-hydroxypropyl)acetamide (100 mg, 0.246 mmol, 22% yield). LCMS: m/z 404.8 (M+H) ⁺ .

Step 5. 2-(3-chloro-4-fluoro-N-(6-hydroxyl-1,5-phenidin-4-yl)anilino)-N-(3-hydroxypropyl)acetamide ( A mixture of 100 mg, 0.247 mmol, 1 eq ), DIAD (150 mg, 0.741 mmol, 3 eq ), PPh ₃ (194 mg, 0.741 mmol, 3 eq ) in THF (1 mL) was degassed and blown with N ₂ Sweep 3 times. The mixture was stirred at 25 °C under _N2 atmosphere for 16 h. The reaction mixture was partitioned between ethyl acetate (20 mL x 3) and water (40 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-TLC ( _Si02 , EtOAc:MeOH = 10:1) to afford Example 56 (60 mg, 0.152 mmol, 61% yield) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ= 8.56 (d, J = 5.2 Hz, 1H), 8.51 (s, 1H), 8.27 (d, J = 9.2 Hz, 1H), 7.43 - 7.40 (m , 1H), 7.39- 7.36 (m, 1H), 7.25 (d, J = 9.2 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 5.2 Hz, 1H), 4.48 (s, 2H), 4.43 (t, J = 6.4Hz, 2H), 3.22 (s, 2H), 1.96 - 1.85 (m, 2H); LCMS: m/z 386.6 (M+H) ⁺ .

1-(3-Chloro-4-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-9,11-vinylidenepyrido[4,3-i][1 ,5,8] Preparation of oxadiazacyclododecen-3-one (Example 57)

Following a procedure similar to Example 56, using 4-bromo-6-methoxyquinoline in place of 8-chloro-2-methoxy-1,5-fidine, Example 57 was prepared as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.69 (d, J = 4.8 Hz, 1H), 8.24 (t, J = 5.6 Hz, 1H), 7.95 (s, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 7.29 (d, J = 4.8 Hz, 1H), 7.14 (t, J = 9.2 Hz, 1H), 6.83 (d, J = 6.0 Hz, 1H), 6.58 (d, J = 8.8 Hz, 1H), 4.33 (s, 2H), 4.03 (t, J = 6.0 Hz, 2H), 3.28 - 3.21 (m, 2H), 1.91 - 1.81 (m , 2H); LCMS: m/z 386.6 (M+H) ⁺ .

15-(3,4-Dichloro-2-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene- 3,6-(methenylidene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one (Example 58 ) preparation

Following a procedure similar to Example 36, using M2 instead of M1 and J16 instead of J1 , followed by de-Cbz as in Example 38, Example 58 was prepared as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.43 (d, J = 5.2 Hz, 1H), 8.36 - 8.33 (m, 1H), 8.32 - 8.26 (m, 1H), 8.23 (s, 1H) , 7.93 (t, J = 6.8 Hz, 1H), 7.73 (s, 1H), 7.71 (s, 1H), 7.64 (s, 1H), 6.55 (d, J = 5.6 Hz, 1H), 4.40 (s, 2H), 4.18 - 4.06 (m, 5H), 3.10 - 3.04 (m, 2H), 2.63 (d, J = 2.8 Hz, 2H), 1.69 - 1.64 (m, 2H); LCMS: m/z 514.1 (M +H) ⁺ . Screening Assays Kinase Binding Assays

Kinase binding assays were performed on Eurofins/DiscoveRx using the general KINOME scan protocol (Fabian, MA et al., "A small molecule-kinase interaction map for clinical kinase inhibitors", Nat. Biotechnol. 2005, 23(3):329-36) . For most analyses, kinase-tagged T7 phage strains were prepared in E. coli hosts derived from the BL21 strain. E. coli was grown to log phase and infected with T7 phage and incubated at 32°C with shaking until lysis. Lysates were centrifuged and filtered to remove cellular debris. The remaining kinases were produced in HEK-293 cells and subsequently labeled with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotin-labeled small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. Ligandated beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and reduce non- specific binding. Binding reactions were assembled by combining kinase, liganded affinity beads, and test compounds in 1X binding buffer (20% SeaBlock, 0.17X PBS, 0.05% Tween 20, 6 mM DTT). All reactions were performed in polystyrene 96-well assay plates in a final volume of 0.135 mL. The assay plate was incubated for 1 hour at room temperature with shaking, and the affinity beads were washed with wash buffer (1×PBS, 0.05% Tween 20). Beads were then resuspended in elution buffer (1×PBS, 0.05% Tween 20, 0.5 μM non-biotin-labeled affinity ligand) and incubated for 30 minutes at room temperature with shaking. The kinase concentration in the eluate was measured by qPCR. Results for compounds tested at a given concentration in this assay are reported as "% of Control", with lower numbers indicating stronger binding in the matrix.

Calculation against %: biochemical analysis

Reaction Biology Corporation (www.reactionbiology.com) will use the HotSpot assay platform, a radiometric assay based on conventional filter-binding assays that directly measure kinase catalytic activity against specific substrates, to evaluate targeting of enzymatic kinases. (Anastassiadis T et al. Comprehensive Assay of Kinase Catalytic Activity Reveals Features of Kinase Inhibitor Selectivity. Nat Biotechnol. 2011, 29:1039-45). Briefly, in reaction buffer (20 mM Hepes pH 7.5, 10 mM MgCl ₂ , 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na ₃ VO ₄ , 2 mM DTT, 1% DMSO) Preparation of specific kinase/substrate pairs and necessary cofactors. Compounds were delivered to the reaction, and then a mixture of ATP (Sigma, St. Louis MO) and ³³ P ATP (Perkin Elmer, Waltham MA) was added after approximately 20 minutes to a final concentration of 10 μΜ. The reaction was carried out at room temperature for 120 minutes, and then the reaction was spotted onto P81 ion exchange filter paper (Whatman Inc., Piscataway, NJ). Unbound phosphate was removed by washing the filter extensively in 0.75% phosphoric acid. Kinase activity data were expressed as the percentage of kinase activity remaining in the test samples compared to the vehicle (dimethyloxide) reaction after subtracting background from control reactions containing inactive enzyme. _IC50 values and curve fitting were obtained using Prism (GraphPad Software). cell analysis

Inhibition of cellular activity of wild-type and mutant EGFR will be assessed using ProQinase's cellular phosphorylation assay at ProQinase GmbH (www.proqinase.com), which assays have been designed to measure compounds that respond to physiological substrates in a physiological environment active. Cellular kinase assays include EGFR wild type, EGFR L858R mutant, EGFR T790M mutant, EGFR G719S mutant, EGFR L861Q mutant, EGFR Δ752-759 mutant, EGFR L858R/T790M mutant, EGFR Δ746-750/T790M mutant , EGFR Δ746-750/C797S mutant, EGFR T790M/C797S/L858R mutant, EGFR Δ746-750/T790M/C797S mutant and EGFR Δ747-749/A750P mutant. Detailed protocols are available on the ProQinase GmbH website.

Table 1. Inhibitory activity against WT and mutant EGFR kinases instance number EGFR Wt IC ₅₀ (nM) EGFR (d746-750) _IC50 (nM) EGFR (d746-750/C797S) IC ₅₀ (nM) EGFR (L858R) IC ₅₀ (nM) EGFR (L858R, C797S) IC ₅₀ (nM) EGFR (D770_N771insNPG) _IC50 (nM) 1 153.70 2 334.80 366.00 132.10 147.90 144.30 1911.00 35 189.90 215.50 78.99 92.58 99.06 6084.00 36 114.10 146.40 68.66 27.44 214.00 1336.00 37 112.30 38 5.59 3.87 2.16 3.92 6.68 20.64 39 >1000.00 40 18.70 82.52 22.48 6.77 28.11 250.00 41 >1000.00 42 >1000 43 >1000 44 >1000.00 >1000.00 >1000.00 >1000.00 45 0.51 8.55 0.54 1.19 1.67 0.92 46 1.85 19.51 1.90 4.13 3.70 27.17 47 101.00 885.70 524.40 96.73 820.30 >1000 48 0.10 1.73 1.36 0.12 3.26 3.73 49 9.28 61.72 9.84 213.20 50 782.70 1675.00 448.60 1000.00 51 42.99 156.40 34.16 856.90 52 6.98 11.34 3.85 2.42 15.16 36.38 53 2.12 7.94 1.34 0.85 3.73 7.64 54 0.32 4.99 0.45 0.23 0.96 1.34 55 0.85 1.77 0.64 0.29 0.79 5.78 56 >1000 >1000 >1000 2407.00 >1000 >1000 57 1659.00 >1000 1295.00 581.40 1551.00 >1000 58 0.25 1.18 0.10 0.57

Table 2. Inhibitory activity against WT and mutant HER2 kinase and HER4 kinase instance number ERBB2 IC ₅₀ (nM) ERBB2 (A775_G776insYVMA) IC ₅₀ (nM) ERBB2 (D769H) IC ₅₀ (nM) ERBB2 (D769Y) IC ₅₀ (nM) ERBB2 (V777L) IC ₅₀ (nM) ERBB4 IC ₅₀ (nM) 1 246.90 636.7 2 776.60 1549.00 >1000 35 3181.00 5249.00 >1000 36 267.00 259.00 130.00 146.00 162.00 37 270.80 920.2 38 13.39 14.79 7.92 10.59 12.48 16.85 39 1000.00 1000 40 73.75 460.2 41 1981.00 1000 42 >1000.00 >1000.00 43 >1000.00 >1000.00 44 >1000.00 >1000.00 45 0.80 0.20 1.22 0.47 0.25 46 27.38 42.51 22.95 24.65 22.28 47 18.56 12.82 14.91 6.81 5.42 48 0.94 0.66 0.95 0.39 0.42 49 87.84 123.50 50 1000.00 51 430.50 52 8.66 5.21 73.83 53 1.57 1.60 23.81 54 0.25 0.32 1.83 55 0.85 0.68 17.16 56 >1000 >1000 >1000 57 >1000 1086.00 >1000 58 0.37 0.14 1.16

Claims (52)

A compound of formula I or a pharmaceutically acceptable salt thereof,

wherein X is -X ¹ - or -X ¹ -(ring A)-; X ¹ is -O-, -S-, -NR ¹ -; each Y is independently ring B or -C(O)NR ² - ; Ring A is C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl, and wherein each hydrogen atom in C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently optional Deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ - C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , - C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substituted; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 Each hydrogen atom in the 10-membered heteroaryl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , - OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C( O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O) R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C( O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ ; each ring B is C ₆ -C ₁₀ aryl Or 5 to 10 membered heteroaryl, wherein C ₆ -C ₁₀ aryl or each hydrogen atom in the 5 to 10 membered heteroaryl is independently deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a 、-C(O)NR ^a R ^b 、-PR ^a R ^b 、-P(O)R ^a R ^b 、-P(O) ₂ R ^a R ^b 、-P(O)NR ^a R ^b 、- Substituted by P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ ; where C ₁ -C ₆ alkyl, C ₂ -C ₆ alkene Each hydrogen atom in radical, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently Optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O )R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S (O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C (O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ are substituted; each L is independently -C(R ³ )(R ⁴ )-, -C (O)-, -O-, -N(R ⁵ )-, -S-, -S(O)- or -S(O) ₂ -, the restriction is that (L) _n does not contain -OO-, -OS-, -SS- or -ON (R ⁵ )-bond; Z ¹ is N or C (R ⁶ ); Z ² is N or C (R ⁷ ); Z ³ is N or C (R ⁸ ); Z ⁴ is N or C (R ⁹ ); Z ⁵ is N or C (R ¹⁰ ); Z ⁶ is N or C (R ¹¹ ); the limitation is that at least one of Z ¹ to Z ⁶ is N; Each of R ¹ , R ² and R ⁵ is independently H, deuterium, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ ring Alkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ Each hydrogen atom in alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently optionally replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS( O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S (O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S( O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e' , -CN or -NO ₂ substitution; each R ³ and R ⁴ are independently H, deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ - C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^c , -OC(O)R ^c , -OC(O)NR ^c R ^d , -OC(=N)NR ^c R ^d , -OS(O)R ^c , -OS(O) ₂ R ^c , -OS(O)NR ^c R ^d , -OS(O) ₂ NR ^c R ^d , -SR ^c , -S(O)R ^c , -S(O) ₂ R ^c , -S(O)NR ^c R ^d , -S(O) ₂ NR ^c R ^d , -NR ^c R ^d , -NR ^c C(O)R ^d , -N(C(O)R ^c )(C(O)R ^d ), -NR ^c C(O)OR ^d , -NR ^c C(O)NR ^c R ^d , -NR ^c C(=N)NR ^c R ^d , -NR ^c S(O)R ^d , -NR ^c S(O) ₂ R ^d , -NR ^c S(O)NR ^c R ^d , -NR ^c S(O) ₂ NR ^c R ^d , -C(O)R ^c , -C(O)OR ^c , -C(O)NR ^c R ^d , -C(=N)NR ^c R ^d , -PR ^c R ^d , -P(O)R ^c R ^d , -P(O) ₂ R ^c R ^d , -P(O)NR ^c R ^d , -P(O) ₂ NR ^c R ^d , -P(O) OR ^c , -P(O) ₂ OR ^c , -CN, -NO ₂ , or both R ³ and R ⁴ form a C ₃ -C ₆ cycloalkyl group or 4 to 6 membered heterocycloalkyl, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C Each hydrogen atom in ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl or 4 to 6 membered heterocycloalkyl independently depends on In case of deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O) R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f 、-NR ^e C(O)NR ^e R ^f 、-NR ^e S(O)R ^f 、-NR ^e S(O) ₂ R ^f 、-NR ^e S(O)NR ^e R ^f 、-NR ^e S (O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution; each of R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ is independently H, deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ - C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S (O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , - NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , - C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O ) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ ; or R ⁶ and R ⁷ , R ⁷ and R ⁸ or R ¹⁰ and R ¹¹ are formed together with the carbon to which they are attached C ₄ -C ₆ cycloalkyl, 4 to 7 membered heterocycloalkyl, 5 to 10 membered heteroaryl or C ₆ -C ₁₀ aryl, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl , C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl Each hydrogen atom in a group or a 4- to 7-membered heterocycloalkyl group is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O) R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , - NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substituted; each R ^a , R ^b , R ^c , R ^d , ^Re and R ^f are independently selected from the following composition Groups: H, deuterium, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkyl-C ₆ -C ₁₀ aryl and 5 to 10 membered heteroaryl, wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkylene -C ₆ -C ₁₀ aryl or 5 Each hydrogen atom in the 10-membered heteroaryl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OH, -OC ₁ -C ₆ alkyl, -OC(O)-(H or C ₁ -C ₆ alkyl), -OC(O)N(H or C ₁ -C ₆ alkyl) ₂ , -OC(O)N(C ₂ -C ₆ Alkyl), -OS(O)-(H or C ₁ -C ₆ alkyl), -OS(O) ₂ -(H or C ₁ -C ₆ alkyl), -OS(O)N(H or C ₁ -C ₆ alkyl) ₂ , -OS(O)N(C ₂ -C ₆ alkylene), -OS(O) ₂ N(H or C ₁ -C ₆ alkyl) ₂ , -OS( O) ₂ N(C ₂ -C ₆ alkylene), -S(H or C ₁ -C ₆ alkyl), -S(O) (H or C ₁ -C ₆ alkyl), -S(O ) ₂ (H or C ₁ -C ₆ alkyl), -S(O)N(H or C ₁ -C ₆ alkyl) ₂ , -S(O)N(C ₂ -C ₆ alkylene), -S(O) ₂ N(H or C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ N(C ₂ -C ₆ alkylene), -N(H or C ₁ -C ₆ alkyl ) ₂ , -N(C ₂ -C ₆ alkylene), -N(H or C ₁ -C ₆ alkyl)C(O)-(H or C ₁ -C ₆ alkyl), -N(H or C ₁ -C ₆ alkyl)C(O)O(H or C ₁ -C ₆ alkyl), -N(H or C ₁ -C ₆ alkyl)C(O)N(H or C ₁ - C ₆ alkyl) ₂ , -N(H or C ₁ -C ₆ alkyl)C(O)N(C ₂ -C ₆ alkylene), -N(H or C ₁ -C ₆ alkyl)S (O)-(H or C ₁ -C ₆ alkyl), -N(H or C ₁ -C ₆ alkyl)S(O) ₂ (H or C ₁ -C ₆ alkyl), -N(H or C ₁ -C ₆ alkyl)S(O)N(H or C ₁ -C ₆ alkyl) ₂ , -N(H or C ₁ -C ₆ alkyl)S(O)N(C ₂ -C ₆ alkylene), -N(H or C ₁ -C ₆ alkyl)S(O) ₂ N(H or C ₁ -C ₆ alkyl) ₂ , -N(H or C ₁ -C ₆ alkyl )S(O) ₂ N(C ₂ -C ₆ alkylene), -C(O)-(H or C ₁ -C ₆ alkyl), -C(O)O(H or C ₁ -C ₆ Alkyl), -C(O)N(C ₂ -C ₆ alkylene), -P(H or C ₁ -C ₆ alkyl) ₂ , -P(C ₂ -C ₆ alkylene), - P(O)(H or C ₁ -C ₆ alkyl) ₂ , -P(O)(C ₂ -C ₆ alkylene), -P(O) ₂ (H or C ₁ -C ₆ alkyl) _2. -P(O) ₂ (C ₂ -C ₆ alkylene), -P(O)N(H or C ₁ -C ₆ alkyl) ₂ , -P(O)N(C ₂ -C ₆ alkylene), -P(O) ₂ N(H or C ₁ -C ₆ alkylene) ₂ , -P(O) ₂ N(C ₂ -C ₆ alkylene), -P(O )O(H or C ₁ -C ₆ alkyl), -P(O) ₂ O(H or C ₁ -C ₆ alkyl), -CN or -NO ₂ substituted; m is 0, 1 or 2; and n is 3, 4, 5, 6, 7, 8 or 9. As the compound of claim 1, it has formula II

or a pharmaceutically acceptable salt thereof. As the compound of claim 1, it has formula III

or a pharmaceutically acceptable salt thereof. As the compound of claim 1, it has formula IV

or a pharmaceutically acceptable salt thereof. As the compound of claim 1, it has formula V

or a pharmaceutically acceptable salt thereof. As the compound of claim 1, it has formula VI

or a pharmaceutically acceptable salt thereof. As the compound of claim 1, it has formula VII

or a pharmaceutically acceptable salt thereof. As the compound of claim 1, it has formula VIII

or a pharmaceutically acceptable salt thereof. As the compound of claim 1, it has formula IX

or a pharmaceutically acceptable salt thereof. The compound as claimed in item 1, which has formula X

or a pharmaceutically acceptable salt thereof. As the compound of claim 1, it has formula XI

or a pharmaceutically acceptable salt thereof. The compound as claimed in item 1, which has formula XII

or a pharmaceutically acceptable salt thereof. The compound as claimed in item 1, which has formula XIII

or a pharmaceutically acceptable salt thereof. The compound as claimed in item 1, which has formula XIV

or a pharmaceutically acceptable salt thereof. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 14, wherein ring A (if present) is phenylene, furyl, thienyl, pyrrolyl, oxazolyl , Extended isoxazolyl, extended thiazolyl, extended isothiazolyl, extended pyrazolyl, extended imidazolyl, extended diazolyl, extended thiadiazolyl, extended triazolyl, extended pyridyl, extended pyridyl, pyrimidinyl, pyrimidinyl or trisulphinyl, wherein phenylene, furyl, thienyl, pyrrolyl, azolyl, isoxazolyl, thiazolyl, isothiazolyl, Each hydrogen in pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrimidinyl, diazolyl or triazolyl The atoms are independently optionally deuterium, fluorine, chlorine, bromine, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS(O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S( O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , - CN or -NO ₂ substitution; wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, Each hydrogen atom in C ₆ -C ₁₀ aryl or 5- to 10-membered heteroaryl is independently optionally replaced by deuterium, fluorine, chlorine, bromine, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , - OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O ) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A (if present) is phenylene or pyridyl, wherein each hydrogen atom in phenylene or pyridyl is independently is optionally substituted with deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A (if present) is a phenylene or pyridinyl group having the following formula

, wherein each hydrogen atom is independently optionally substituted by deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring A (if present) is

. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X ¹ is -NR ¹ -. A compound or a pharmaceutically acceptable salt thereof as in any one of the preceding claims, wherein R ¹ (if present) is hydrogen, C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, or 5 to 10 members Heteroaryl, wherein each hydrogen atom in C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl is independently optionally replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS (O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , - NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O) R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P Substituted by (O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e' , -CN or -NO ₂ . The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R ¹ , if present, is hydrogen. The compound or pharmaceutically acceptable salt thereof as any one of claims 1 to 20, wherein R ¹ (if present) is phenyl or pyridyl, wherein each hydrogen atom in phenyl or pyridyl is independently In case of deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O) R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f 、-NR ^e C(O)NR ^e R ^f 、-NR ^e S(O)R ^f 、-NR ^e S(O) ₂ R ^f 、-NR ^e S(O)NR ^e R ^f 、-NR ^e S (O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e' , -CN or -NO ₂ substitution. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 20 or 22, wherein R ¹ (if present) is phenyl or pyridyl, wherein each hydrogen atom in phenyl or pyridyl is independently is optionally substituted with deuterium, fluorine, chlorine, bromine or C ₁ -C ₆ alkyl. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 20, 22 or 23, wherein R ¹ (if present) has the following formula

. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein X ¹ is -O-. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein X ¹ is -S-. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring B (if present) is a 5 to 10 membered heteroaryl, wherein 5 to 10 members are each hydrogen in the heteroaryl Atoms are independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkane radical, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O)R ^a , -OS (O) ₂ R ^a , -SR ^a , -S(O)R ^a , -S(O) ₂ R ^a , -S(O)NR ^a R ^b , -S(O) ₂ NR ^a R ^b , - OS(O)NR ^a R ^b , -OS(O) ₂ NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -NR ^a C (O)NR ^a R ^b , -NR ^a S(O)R ^b , -NR ^a S(O) ₂ R ^b , -NR ^a S(O)NR ^a R ^b , -NR ^a S(O) ₂ NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -PR ^a R ^b , -P(O)R ^a R ^b , -P(O ) ₂ R ^a R ^b , -P(O)NR ^a R ^b , -P(O) ₂ NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN or -NO ₂ substitution; wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ -C Each hydrogen atom in ₁₀ aryl or 5 to 10 membered heteroaryl is independently optionally replaced by deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O )R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ replace. A compound or a pharmaceutically acceptable salt thereof as in any one of the preceding claims, wherein ring B (if present) is phenylene, furyl, thienyl, pyrrolyl, oxazolyl, Isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, diazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl, pyrimidine phenylene, furyl, thienyl, pyrrolyl, azolyl, isoxazolyl, thiazolyl, isothiazolyl, pyryl Each hydrogen atom in the azole group, imidazolyl group, diazolyl group, thiadiazolyl group, triazolyl group, pyridyl group, pyrimidyl group, pyrimidinyl group, diazolyl group or triazoyl group is independent Optionally via deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS( O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S( O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O) OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -PR ^e R ^f , -P(O)R ^e R ^f , -P(O) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ substitution. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring B (if present) is

. The compound according to any one of the preceding claims, or ^a pharmaceutically acceptable salt thereof, wherein Z is N. A compound or a pharmaceutically acceptable salt thereof as in any one of the preceding claims, wherein Z ² is C(R ⁷ ), Z ³ is C(R ⁸ ), Z ⁴ is N, and Z ⁵ is C(R 8 ). ¹⁰ ), and Z ⁶ is C(R ¹¹ ). The compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, wherein Z ² is C(R ⁷ ), Z ³ is C(R ⁸ ), Z ⁴ is C(R ⁹ ), Z ⁵ is C(R ¹⁰ ), and Z ⁶ is C(R ¹¹ ). The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein Z ² is C(R ⁷ ), Z ³ is N, Z ⁴ is N, Z ⁵ is C(R ¹⁰ ) , and Z ⁶ is C(R ¹¹ ). A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 30, wherein Z ² is C(R ⁷ ), Z ³ is N, Z ⁴ is C(R ⁹ ), and Z ⁵ is C (R ¹⁰ ), and Z ⁶ is C(R ¹¹ ). The compound according to any one of the preceding claims, wherein R ⁶ (if present) is H, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding claims, wherein R ⁷ (if present) is H, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding claims, wherein R ⁸ (if present) is H, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding claims, wherein R ⁹ (if present) is H, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ (if present) is H or —OCH ₃ . The compound according to any one of the preceding claims, wherein R ¹¹ (if present) is H, or a pharmaceutically acceptable salt thereof. A compound or a pharmaceutically acceptable salt thereof as in any one of the preceding claims, wherein each L is independently selected from -C(R ³ )(R ⁴ )-, -C(O)-, -O- or The group consisting of -N(R ⁵ )-, with the proviso that (L) _n does not contain a -OO- or -ON(R ⁵ )- bond. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein -(L) _n - is (CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₄ -, (CR ³ R ⁴ ) ₅ -, (CR ³ R ⁴ ) ₆ , (CR ³ R ⁴ ) ₇ -, (CR ³ R ⁴ ) ₈ -, C(O)N(R ⁵ )-(CR ³ R ⁴ ) ₂ O( CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ -C(O)N(R ⁵ )-(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ C(O)N(R ⁵ )-(CR ³ R ⁴ ) ₃ O-, N(R ⁵ )C(O)CR ³ R ⁴ O(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ N(R ⁵ )C(O)(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ N(R ⁵ )C(O)(CR ³ R ⁴ ) ₃ O-, CR ³ R ⁴ O(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ O(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₂ O-CR ³ R ⁴ -, (CR ³ R ⁴ ) ₃ O-CR ³ R ⁴ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ - , (CR ³ R ⁴ ) ₃ O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₅ O(CR ³ R ⁴ ) ₃ -, OCR ³ R ⁴ -O(CR ³ R ⁴ ) ₃ -, CR ³ R ⁴ -O(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ -O(CR ³ R ⁴ ) ₃ O-, O(CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₃ O-, O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ O-, -O-(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₃ O-, O(CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ O-, CR ³ R ⁴ -N(R ⁵ )(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₂ -, (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₃ -, (CR ³ R ⁴ ) ₃ O(CR ³ R ⁴ )C(O)N(R ⁵ )(CR ³ R ⁴ )-, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ )C(O)N(R ⁵ )-(CR ³ R ⁴ )-, (CR ³ R ⁴ ) ₂ O(CR ³ R ⁴ ) ₂ C(O)N(R ⁵ )-(CR ³ R ⁴ )-, (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₃ -, O(CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₂ -, CR ³ R ⁴ N(R ⁵ )(CR ³ R ⁴ ) ₂ O-, (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₂ O- or (CR ³ R ⁴ ) ₂ N(R ⁵ )(CR ³ R ⁴ ) ₃ O-. A compound or a pharmaceutically acceptable salt thereof as in any one of the preceding claims, wherein each R ³ and R ⁴ are independently selected from the group consisting of H, deuterium, C ₁ -C ₆ alkyl, -NR ^c C (O) R ^d and -CN, wherein each hydrogen atom in C ₁ -C ₆ alkyl is independently optionally deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O)R ^e , -OS(O) ₂ R ^e , -OS(O)NR ^e R ^f , - OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)OR ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O)R ^f , -NR ^e S(O) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e 、-C(O)NR ^e R ^f 、-PR ^e R ^f 、-P(O)R ^e R ^f 、-P(O) ₂ R ^e R ^f 、-P(O)NR ^e R ^f 、- Substituted by P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN or -NO ₂ . A compound or a pharmaceutically acceptable salt thereof as in any one of the preceding claims, wherein -(L) _n -includes (CH ₂ ) ₃ -, (CH ₂ ) ₄ -, (CH ₂ ) ₅ -, ( CH ₂ ) ₆ -, (CH ₂ ) ₇ -, (CH ₂ ) ₈ -, C(O)NH(CH ₂ ) ₂ O(CH ₂ ) ₂ -, C(O)N(CH ₃ )-(CH ₂ ) ₂ O(CH ₂ ) ₂ -, NHC(O)CH ₂ O(CH ₂ ) ₂ -, N(CH ₃ )C(O)CH ₂ O(CH ₂ ) ₂ -, CH ₂ O(CH ₂ ) ₂ -, CH ₂ O(CH ₂ ) ₃ -, CH ₂ O(CH ₂ ) ₂ CH(CH ₃ )-, CH ₂ OCH ₂ CH(CH ₃ )-CH ₂ -, CH ₂ OCH(CH ₃ ) -(CH ₂ ) ₂ -, CH(CN)O(CH ₂ ) ₃ -, CH(CH ₃ )O(CH ₂ ) ₃ -, CH ₂ O(CH ₂ ) ₂ -O-, (CH ₂ ) ₂ O(CH ₂ ) ₂ -, CH ₂ -C(CH ₃ ) ₂ -O(CH ₂ ) ₂ -, CH ₂ C(CH ₃ ) ₂ -O(CH ₂ ) ₃ -, (CH ₂ ) ₂ OCH ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₂ -, (CH ₂ ) ₃ O(CH ₂ ) ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₃ -, (CH ₂ ) ₂ OCH(CH ₃ )-(CH ₂ ) ₂ -, (CH ₂ ) ₂ OC(CH ₃ ) ₂ -(CH ₂ ) ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₂ -CH(CH ₃ )-, (CH ₂ ) ₂ O(CH ₂ ) ₂ -C(CH ₃ ) ₂ -CH ₂ CH(CH ₃ )-O-(CH ₂ ) ₃ -, CH ₂ CH(CH ₃ )O(CH ₂ ) ₂ -, CH( CH ₃ )CH ₂ O(CH ₂ ) ₂ -, O(CH ₂ ) ₂ -, -O-(CH ₂ ) ₃ -, OCH ₂ CH(OH)CH ₂ -, O(CH ₂ ) ₂ O(CH ₂ ) ₂ -, OCH ₂ CH(CH ₃ )-O(CH ₂ ) ₂ -, OCH(CH ₃ )CH ₂ O(CH ₂ ) ₂ -, (CH ₂ ) ₂ OCH ₂ CH(NHC(O)CH =CH ₂ )CH ₂ O-, (CH ₂ ) ₂ OCH ₂ CH(N(CH ₃ )-C(O) -CH=CH ₂ )CH ₂ O-, (CH ₂ ) ₂ OCH ₂ CH(NH-C(O)-CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ OCH ₂ CH(N(CH ₃ )-C(O)-CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ NH-CH ₂ CH(NH-C(O)-CH=CH ₂ )CH ₂ O-, (CH ₂ ) ₂ NHCH ₂ CH(N(CH ₃ )C(O)CH=CH ₂ )CH ₂ O-, (CH ₂ ) ₂ NHCH ₂ CH(NHC(O)CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ N(CH ₃ )CH ₂ CH(N(CH ₃ )C(O)CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ N(CH ₃ )CH ₂ CH(N(CH ₃ )C( O)CH=CH ₂ )CH ₂ O-, (CH ₂ ) ₂ N(CH ₃ )CH ₂ CH(NHC(O)CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₂ N(CH ₃ ) CH ₂ CH(N(CH ₃ )C(O)CH ₂ CH ₂ )CH ₂ O-, (CH ₂ ) ₃ O(CH ₂ )C(O)N(CH ₃ )CH ₂ -, (CH ₂ ) ₃ O(CH ₂ )C(O)N(H)CH ₂ -, (CH ₂ ) ₂ O(CH ₂ )C(O)N(CH ₃ )CH ₂ -, (CH ₂ ) ₂ O(CH ₂ )C(O)N(H)CH ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₂ C(O)N(CH ₃ )CH ₂ -, (CH ₂ ) ₂ O(CH ₂ ) ₂ C( O)N(H)CH ₂ -, O(CH ₂ ) ₂ NH(CH ₂ ) ₂ -, OCH ₂ CH(CH ₃ )-NH-(CH ₂ ) ₂ -, OCH(CH ₃ )CH ₂ NH- (CH ₂ ) ₂ -, CH ₂ NH(CH ₂ ) ₂ -, (CH ₂ ) ₂ NH(CH ₂ ) ₂ -, (CH ₂ ) ₂ NH(CH ₂ ) ₃ -, (CH ₂ ) ₂ N( CH ₃ )(CH ₂ ) ₂ -, (CH ₂ ) ₂ N(CH ₃ )(CH ₂ ) ₃ -, CH ₂ CH(CH ₃ )NH(CH ₂ ) ₂ -, CH(CH ₃ )CH ₂ NH -(CH ₂ ) ₂ -, O(CH ₂ ) ₂ N(CH ₃ )(CH ₂ ) ₂ -, OCH ₂ C H(CH ₃ )-N(CH ₃ )-(CH ₂ ) ₂ -, OCH(CH ₃ )CH ₂ N(CH ₃ )(CH ₂ ) ₂ -, CH ₂ N(CH ₃ )(CH ₂ ) ₂ -, (CH ₂ ) ₂ N(CH ₃ )(CH ₂ ) ₂ -, CH ₂ C(O)N(H)(CH ₂ ) ₃ O-, CH ₂ C(O)N(CH ₃ )(CH ₂ ) ₃ O-, CH ₂ CH(CH ₃ )-N(CH ₃ )-(CH ₂ ) ₂ - or OCH(CH ₃ )CH ₂ N(CH ₃ )-(CH ₂ ) ₂ -. Such as the compound of claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 1-(3-chloro-4-fluorophenyl)-17-methoxy-2,3,5 ,6,7,8-Hexahydro-10,12-vinylidenepyrido[4,3- e ][1,4,7,10]oxatriazacyclotridecene-9(1 H )-one; 1-(3-chloro-2-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-vinylidenepyrido[4,3- e ] [1,4,7,10]oxatriazacyclotridecen-9(1 H )-one; (3 R )-1-(3-chloro-4-fluorophenyl)-3-methyl -2,3,5,6,7,8-Hexahydro-10,12-vinylidenepyrido[4,3- e ][1,4,7,10]oxatriazacyclotridecane En-9(1 H )-one; (3S)-1-(3-chloro-4-fluorophenyl)-3-methyl-2,3,5,6,7,8-hexahydro-10, 12-vinylidenepyrido[4,3- e ][1,4,7,10]oxatriazacyclotridecen-9( 1H )-one; 1-(3-chloro-4 -fluorophenyl)-3,3-dimethyl-2,3,5,6,7,8-hexahydro-10,12-vinylidenepyrido[4,3- e ][1,4 ,7,10] Oxatriazacyclotridecen-9(1 H )-one; (5 S )-1-(3-chloro-4-fluorophenyl)-5-methyl-2,3 ,5,6,7,8-hexahydro-10,12-vinylidene pyrido[4,3- e ][1,4,7,10]oxatriazacyclotridecene-9( 1 H )-one; (7 R )-1-(3-chloro-4-fluorophenyl)-7-methyl-2,3,5,6,7,8-hexahydro-10,12-bridge Vinylidenepyrido[4,3- e ][1,4,7,10]oxatriazacyclotridecen-9( 1H )-one; 12-(3-chloro-4-fluorobenzene Base)-1-methyl-4,13,14,16-tetrahydro-1 H -6,8-vinylidenepyrazolo[4,3- k ]pyrido[4,3- e ][ 1,4,7,10] oxatriazacyclotridecen -5(12H)-one; 14-(3-chloro-4-fluorophenyl)-5-methyl-5,9,10 ,12,13,14-hexahydro-2,18-vinylidene-3,6-(methenylene)pyrido[3,4- l ][1,4,7,8,11, 14] Oxapentaazacyclohexadecen-7( 8H )-one; and 1-(3-chloro-4-fluorophenyl)-10-methyl-1,2,3,6,7, 10-Hexahydro-12,9-(oxazoenyl)-13,15-vinylidene pyrido[3,4- l ][1,4,7,14]oxatriazacyclohexadecane En-8( 5H )-one. Such as the compound of claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 7-chloro-6-fluoro-15-methyl-5,12,13,15-tetrahydro-10 H -1,18-Ethylidenepyrazolo[4,3- f ]pyrido[4,3- b ][8,11,1,4]benzodioxadiazacyclotetradecene ; 7-Chloro-6-fluoro-15-methyl- 5,12,13,15 -tetrahydro-10H-1,18-vinylidenepyrazolo[4,3- f ]pyrido[4 ,3- b ][8,11,1]benzodioxazacyclotetradecene; 7-chloro-15-methyl- 5,12,13,15 -tetrahydro-10H-1,18 -vinylidenepyrazolo[4,3- f ]pyrido[4,3- b ][8,11,1]benzodioxazacyclotetradecene; 15-methyl-5, 12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- f ]pyrimido[4,5- b ][8,11,1,4]benzo Dioxadiazacyclotetradecene; 7-Chloro-15-methyl-5,12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- f ]pyrimido[4,5- b ][8,11,1]benzodioxazacyclotetradecene; 7,15-dimethyl-5,12,13,15-tetrahydro-10 H -1,18-vinylidenepyrazolo[4,3- m ]pyrido[3,4- f ]pyrimido[4,5- i ][1,4,8]dioxazepine Cyclotetradecene; 7-Chloro-6-fluoro-5,10,12,13-tetrahydro-1,19-vinylidenedipyrido[4,3- b :2',3'- f ] [8,11,1]benzodioxazacyclotetradecene; 7-chloro-6,17-difluoro-5,10,12,13-tetrahydro-1,19-vinylidene di Benzo[ e , l ]pyrido[3,4- i ][1,4,8,11]dioxadiazacyclotetradecene; 7-chloro-6-fluoro-14-methyl-5 ,13,14,17-Tetrahydro-10 H -19,16-(azazenyl)-1,20-vinylidenepyrido[4,3- b ][14,1,8,11] Benzotriazacycloheptadecen-15(12 H )-one; 7-chloro-6-fluoro-14,17-dimethyl-5,13,14,17-tetrahydro-10 H -19 ,16-(Azazenyl)-1,20-vinylidenepyrido[4,3- b ][14,1,8,11]benzo-triazacycloheptadecene-15(12 H )-ketone; 7-chloro-6-fluoro-14,17-dimethyl-5,13,14,17-tetrahydro-10H-1,20-vinylidene- 19,16- (bridge Methylene)pyrido[4,3 - b ][14,1,4,7,8,11]benzo(o)pentaazacycloheptadecen-15(12 H )-one; 7-chloro-6-fluoro-14-methyl-13, 14-Dihydro-10 H , 17 H -19,16-(azazoenyl)-1,20-vinylidenepyrido[4,3- b ][1,14,8,11]benzo Dioxadiazacyclohexadecen -15(12H)-one; 7-Chloro-8-fluoro-13,14-dihydro-10H,17H- 19,16- ( oxazoenyl ) -1,20-vinylidenepyrido[4,3- b ][1,14,8,11]benzodioxadiazacyclohexadecen-15(12 H )-one; 7- Chloro-6-fluoro-13,14-dihydro-10 H ,17 H -19,16-(azazoenyl)-1,20-vinylidene pyrido[4,3- b ][1, 14,8,11] benzodioxadiazacyclohexadecen-15(12 H )-one; 7-chloro-6-fluoro-14,17-dimethyl-13,14-dihydro- 10 H , 17 H -19,16-(azozenyl)-1,20-vinylidenepyrido[4,3- b ][1,14,8,11]benzodioxadiazepine Heterocyclic heptadecen-15(12 H )-one; 16-chloro-17-fluoro-8-methyl-8,9,10,11,13,18-hexahydro-7 H -4,6-bridge Vinylidenepyrido[4,3- b ][11,1,4,7]benzotriazacyclotetradecen-7-one; 16-chloro-17-fluoro-8,9,10, 11,13,18 -Hexahydro-7H-4,6-vinylidenepyrido[4,3- b ][11,1,4,7]benzotriazacyclotetradecene-7 -ketone ; (13R)-16-chloro-17-fluoro-13-methyl-8,9,10,11,13,18-hexahydro- 7H -4,6-vinylidenepyrido[ 4,3- b ][11,1,4,7]benzotriazacyclotetradecen-7-one; ( 13S )-16-chloro-17-fluoro-7-oxo-8 , 9,10,11,13,18 -Hexahydro-7H-4,6-vinylidenepyrido[4,3- b ][11,1,4,7]benzo-triazine Tetradecene-13-carbonitrile; (9 R )-16-chloro-17-fluoro-9-methyl-8,9,10,11,13,18-hexahydro-7 H -4,6-bridge Vinylidenepyrido[4,3- b ][11,1,4,7]benzotriazacyclotetradecen-7-one; 16-chloro-17-fluoro-8-methyl-8 ,9,10,11-tetrahydro-7 H ,13 H -4,6-vinylidenepyrido[4,3- b ][1,11,7]benzodioxazepinetetradecyl en-7-one; and 16-chloro-17-fluoro-8-methyl-8,9,10,11-tetrahydro-7 H , 13 H -4,6-vinylidene pyrido[4,3- b ][11 ,1,7]Benzotriazacyclotetradecen-7-one. Such as the compound of claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 1-(3-chloro-4-fluorophenyl)-2,3,5,6,7,8 -Hexahydro-10,12-vinylidenepyrido[4,3- e ][1,4,7,10]oxatriazacyclotridecen-9(1 H )-one; 1- (3-Chloro-4-fluorophenyl)-2,3,5,6,7,8-hexahydro-10,12-vinylidenepyrido[4,3- e ][1,4,10 ]oxadiazacyclodecen-9( 1H )-one; 15-(3-chloro-4-fluorophenyl)-8,9,10,11,14,15-hexahydro-4, 6-vinylidenepyrimido[4,5-e][1,4,10]oxadiazatridecen-7(13H)-one; 1-(3-chloro-4-fluorobenzene base)-11-methyl-1,2,3,5,6,7,8,11-octahydro-9H-14,16-vinylidene-13,10-(methenylidene)pyridine And[4,3-e][1,4,10,11,14]oxa tetraazacycloheptadecen-9-one; 1-(3-chloro-4-fluorophenyl)-8,11 -Dimethyl-1,2,3,5,6,7,8,11-octahydro-9H-14,16-vinylidene-13,10-(vinylidene)pyrido[4 ,3-e][1,4,10,11,14]oxa tetraazacycloheptadecen-9-one; 1-(3-chloro-4-fluorophenyl)-11-methyl-1 ,3,4,5,6,7,8,11-Octahydro-14,16-vinylidene-13,10-(methenylene)pyrido[4,3-m][1, 2,5,9,12]pentaazacyclohexadecen-9(2H)-one; 1-(3-chloro-4-fluorophenyl)-7,10-dimethyl-1,2,3 ,6,7,10-Hexahydro-13,15-vinylidene-12,9-(methenylene)pyrido[3,4-l][1,4,7,8,14] Oxatetraazacyclohexadecen-8(5H)-one; 1-(3-Chloro-4-fluorophenyl)-8,11-dimethyl-1,3,4,8,9,11 -Hexahydro-2H-14,16-vinylidene-13,10-(methenylene)pyrido[3,4-l][1,4,7,8,14]oxa-tetraaze Heterocyclic heptadecen-7(6H)-one; N-cyclopropyl-3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octa Hydrogen-14,16-vinylidene-13,10-(methenylene)pyrido[4,3-m][1,2,5,9,12]pentaazacyclohexadecene- 1(11H)-yl]benzamide; 3-[11-methyl-9-oxo-2,3,4,5,6,7,8,9-octahydro-14,16-bridge Vinylidene-13,10-(methenylene)pyrido[4,3-m][1,2,5,9,1 2] Pentaazacycloheptadecen-1(11H)-yl]-N-(prop-2-yl)benzamide; N-methyl-3-[11-methyl-9-oxo -2,3,4,5,6,7,8,9-octahydro-14,16-vinylidene-13,10-(methenylene)pyrido[4,3-m][ 1,2,5,9,12]pentaazacycloheptadecen-1(11H)-yl]benzamide; 1-(3,4-dichloro-2-fluorophenyl)-11-methanol Base-1,3,4,5,6,7,8,11-octahydro-14,16-vinylidene-13,10-(methenylene)pyrido[4,3-m] [1,2,5,9,12]pentaazacyclohexadecen-9(2H)-one; 1-(3-chloro-2-fluorophenyl)-11-methyl-1,3,4 ,5,6,7,8,11-octahydro-14,16-vinylidene-13,10-(methenylene)pyrido[4,3-m][1,2,5, 9,12] Pentaazacycloheptadecen-9(2H)-one; 2-[1-(3-chloro-4-fluorophenyl)-11-methyl-9-oxo-1,2 ,3,4,5,6,7,11-octahydro-14,16-vinylidene-13,10-(methenylene)pyrido[4,3-m][1,2, 5,9,12] Pentaazacyclohexadecen-8(9H)-yl]-N-methylacetamide; 15-(3-chloro-4-fluorophenyl)-5-methyl-8 ,9,10,11,12,13,14,15-Octahydro-2,19-vinylidene-3,6-(methenylene)pyrido[3,4-f][1, 2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one; N-[1-(3-chloro-4-fluorophenyl)-2,3,6,7- Tetrahydro-1H,5H-9,11-vinylidenepyrido[4,3-e][1,9,4]dioxazacyclododecen-6-yl]prop-2-ene Amide; N-[1-(3-chloro-4-fluorophenyl)-2,3,6,7-tetrahydro-1H,5H-9,11-vinylidenepyrido[4,3- e][1,9,4]dioxazacyclododecen-6-yl]propionamide; N-[1-(3-chloro-4-fluorophenyl)-4-methyl-2 ,3,4,5,6,7-Hexahydro-1H-9,11-vinylidenepyrido[4,3-i][1,5,8]oxadiazacyclododecene- 6-yl]prop-2-enamide; 15-(3-chloro-4-fluorophenyl)-5,12-dimethyl-8,9,10,11,12,13,14,15- Octahydro-2,19-vinylidene-3,6-(methenylidene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclodeca Heptaen-7(5H)-one; 15-(4-chloro-3-fluorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2, 19-Ethylene-3,6-(methenylene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecene-7( 5H)-ketone; 15-(3,4-dichlorophenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene -3,6-(methenylene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one; 15 -(3-Chloro-4-fluorophenyl)-5,8-dimethyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene-3 ,6-(methenidelidene)pyrido[3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one; 10-( 3-Chloro-4-fluorophenyl)-4,5,6,7,9,10-hexahydro-8H-2,14-vinylidenepyrido[3,4-d][1,3, 6,9] Oxatriazacyclododecen-8-one; 1-(3-Chloro-4-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-9 ,11-vinylidene pyrido[4,3-i][1,5,8]oxadiazacyclododecen-3-one; 15-(3,4-dichloro-2-fluoro Phenyl)-5-methyl-8,9,10,11,12,13,14,15-octahydro-2,19-vinylidene-3,6-(methenylidene)pyrido [3,4-f][1,2,5,8,11,15]hexaazacyclohexadecen-7(5H)-one; and 7-chloro-8-fluoro-17-methyl-5 ,13,14,17-tetrahydro-10H-1,20-vinylidene-19,16-(methenylene)pyrido[4,3-b][14,1,4,7, 8,11] Benzozacyclohexadecen-15(12H)-one. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients. A method of treating a disease such as cancer, comprising administering to an individual in need of such treatment an effective amount of a compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof. A compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in an individual. A compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, for use in treating cancer in an individual. A use of the compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer in an individual.