TWI736134B - Diaryl macrocycles as modulators of protein kinases - Google Patents

Abstract

The present invention relates to certain diaryl macrocyclic compounds, pharmaceutical compositions containing them, and methods of using them, including methods for treating cancer, pain, neurological diseases, autoimmune diseases, and inflammation.

Description

Diaryl macrocycles as regulators of protein kinases

The present invention relates to certain diaryl macrocyclic derivatives, pharmaceutical compositions containing them, and their use in the treatment of cancer, pain, neurological diseases, autoimmune diseases and inflammation.

Protein kinase is a key regulator of cell growth, proliferation and survival. Genetic and epigenetic changes accumulate in cancer cells, which leads to abnormal activation of signal transduction pathways that drive malignant processes. Manning, G. et al., Science 2002, 298 , 1912-1934. The pharmacological inhibition of these signaling pathways represents a promising opportunity for intervention in targeted cancer therapies. Sawyers, C., Nature 2004, 432 , 294-297. MET and RON belong to a unique subfamily of receptor tyrosine kinases and are mainly produced in cells of epithelial or endothelial origin. Park, M. et al., Cell 1986, 45 , 895-904. Hepatocyte Growth Factor (HGF) (also known as Scattering Factor (SF)) is the only known natural high-affinity ligand of MET, and is mainly expressed in cells of mesenchymal origin. Bottaro, DP et al., Science 1991, 251 , 802-804. HGF/MET signal transduction controls the MET-dependent cell proliferation, survival and migration process critical to the invasive growth during embryonic development and organ regeneration after birth, and is only fully activated for wound healing and tissue regeneration in adults . Trusolino, L. et al., Nature Rev. Mol. Cell Biol. 2010, 11 , 834-848. The HGF/MET axis is often upregulated in many cancers through activating mutations, gene amplification, abnormal paracrine or autocrine ligands, and is strongly associated with tumorigenesis, invasive growth and metastasis. Gherardi, E. et al., Nature Rev. Cancer 2012, 12 , 89-103. In addition, the activation system of HGF/MET signaling is gradually becoming an important mechanism for resistance to EGFR and BRAF inhibitor therapy through MET amplification and/or matrix HGF up-regulation. Engelman, JA et al., Science 2007, 316 , 1039-1043; Wilson, TR et al., Nature 2012, 487 , 505-509. Due to the role of abnormal HGF/MET signaling in human tumorigenesis, invasion/metastasis and resistance, inhibiting the HGF/MET signaling pathway has great potential in cancer therapy. ALK and leukocyte tyrosine kinase (LTK) are grouped into the insulin receptor (IR) superfamily of receptor tyrosine kinase. ALK is mainly manifested in the central and peripheral nervous system, which indicates its potential role in the normal development and function of the nervous system. Pulford, K. et al., Cell Mol. Life Sci. 2004, 61 , 2939. ALK was discovered for the first time as the fusion protein NPM (nucleolar phosphate protein)-ALK, which is a fusion produced by the t(2;5)(p23;q35) chromosomal translocation in the anaplastic large cell lymphoma (ALCL) cell line Genetic code. Morris, SW et al., Science 1994, 263 , 1281. More than twenty different ALK translocation partners have been found in many cancers, including ALCL (60-90% incidence), inflammatory myofibroblastic tumor (IMT, 50-60%), non-small cell lung cancer (NSCLC) , 3-7%), colorectal cancer (CRC, 0-2.4%), breast cancer (0-2.4%) and other cancers. Grande, E. et al., Mol. Cancer Ther. 2011, 10 , 569-579. The ALK-fusion protein is located in the cytoplasm, and the fusion partner and ALK act in the dimerization or oligomerization of the fusion protein by means of helix-helix interaction to generate constitutive activation of ALK kinase function. Bischof, D. et al., Mol. Cell Biol., 1997, 17 , 2312-2325. EML4-ALK (which contains parts of the Echinoderm microtubule-associated protein-like 4 ( EML4 ) gene and ALK gene) was first discovered in NSCLC, is highly carcinogenic, and has been shown to cause lung adenocarcinoma in transgenic mice. Soda, M. et al., Nature 2007, 448 , 561-566. Oncogenic point mutations of ALK in both family and sporadic cases of neuroblastoma. Mossé, YP et al., Nature 2008, 455 , 930-935. ALK is an attractive molecular target for cancer therapeutic intervention due to its important role in hematopoietic, solid and stromal tumors. Grande, see above. The tropomyosin-related receptor tyrosine kinase (Trk) is a high-affinity receptor for neurotrophin (NT) (the nerve growth factor (NGF) family of proteins). Members of the Trk family are highly expressed in cells of neural origin. Trk (TrkA, TrkB and TrkC) mediates neuron development during development through the activation of its better neurotrophins (NGF to TrkA, brain-derived neurotrophic factor [BDNF] and NT4/5 to TrkB, and NT3 to TrkC) The survival and differentiation. The NT/Trk signaling pathway acts as an endogenous system that protects neurons after biochemical damage, temporary ischemia, or physical damage. Thiele, CJ et al., Clin. Cancer Res. 2009, 15 , 5962-5967. However, Trk was initially cloned in the extracellular domain as an oncogene fused to the tropomyosin gene. Activating mutations caused by chromosomal rearrangements or mutations in NTRK1 (TrkA) have been identified in papillary and bone marrow thyroid cancer, and recently in non-small cell lung cancer. Pierotti, MA, et al., Cancer Lett. 2006, 232 , 90-98; Vaishnavi, A., et al., Nat. Med. 2013, 19 , 1469-1472. Since Trk plays an important role in pain perception and tumor cell growth and survival signaling, inhibitors of Trk receptor kinase can provide benefits as a treatment for pain and cancer. The receptor tyrosine kinase AXL belongs to the TAM family of proteins and was initially detected as an unidentified transforming gene in patients with chronic myelogenous leukemia (CML). Verma, A. et al., Mol. Cancer Ther. 2011, 10 , 1763-1773. The main complex of TAM receptors is the growth arrest specific 6 protein (Gas6). AXL is extensively expressed and has been detected in various organs and cells, including hippocampus and cerebellum, monocytes, macrophages, platelets, endothelial cells (EC), heart, skeletal muscle, liver, kidney and testicles. Up-regulation of Gas6/AXL has been reported in many human cancers, including colon, esophagus, thyroid, breast, lung, liver, and astrocytoma-polymorphic malignant glioma. The references are the same as above. Increased activation of AXL and acquired resistance to erlotinib (erlotinib) in the absence of EGFR T790M changes or MET activation have been observed in EGFR-mutant lung cancer models in vitro and in vivo sex. Zhang, Z. et al., Nat. Genet. 2012, 44 , 852-860. In these models, the genetic or pharmacological inhibition of AXL repairs sensitivity to erlotinib. AXL was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to tyrosine kinase inhibitors, and in some cases the expression of its ligand, Gas6, was increased. The references are the same as above. Therefore, AXL is a promising therapeutic target for EGFR-mutant lung cancer patients who are resistant to EGFR inhibitors. Crizotinib (PF-02341066) is a tyrosine kinase drug targeting MET/ALK/ROS1/RON, which has intermediate activity against TRK and AXL. Cui, JJ et al., J. Med. Chem. 2011, 54 , 6342-6363. It has been approved for the treatment of certain patients with advanced (locally advanced or metastatic) NSCLC, which exhibits abnormal ALK fusion genes identified by the companion diagnostic test (Vysis ALK Break Apart FISH Probe Kit). Similar to imatinib and other kinase inhibitor drugs, resistance is always developed after treatment with crizotinib for a certain period of time. Resistance mechanisms include ALK gene amplification, secondary ALK mutations, and abnormal activation of other kinases (including KIT and EGFR). Katayama, R. et al., Sci. Transl. Med. 2012, 4 , 120ra17. Based on the clinical success of second-generation ABL inhibitors for the treatment of imatinib resistance in CML patients, second-generation ALK inhibitors are emerging. These drugs are aimed at treating patients with crizotinib refractory or resistant NSCLC, which have more effective inhibition of both wild and mutant ALK proteins. Gridelli, C. et al. Cancer Treat Rev. 2014, 40, 300-306. By modulating multiple targets in the group of structurally related tyrosine kinases MET, ALK, AXL, and TRK, the compounds described herein solve crizotinib resistance, EGFR inhibitor drug resistance and due to MET, ALK , AXL and/or TRK mutations and gene amplification and other major indications for abnormal cell signaling. The compounds described herein are inhibitors of MET, wild and mutant ALK, AXL, and TRK and will be used to treat cancer patients suffering from abnormal signaling from one or more of MET, ALK, AXL, or TRK. The Janus kinase family (JAK) includes JAK1, JAK2, JAK3 and TYK2, and is a cytoplasmic tyrosine kinase required for the physiological signal transduction of cytokines and growth factors. Quintas-Cardama, A. et al. Nat. Rev. Drug Discov. 2011, 10(2), 127-40; Pesu, M. et al., Immunol. Rev. 2008, 223, 132-142; Murray, PJ, J. Immunol. 2007, 178(5), 2623-2329. JAK is activated by ligand-induced oligomerization, which leads to the activation of a downstream transcription signal transduction pathway called STAT (signal transducers and activators of transcription). Phosphorylated STAT dimerizes and translocates into the nucleus to drive the expression of specific genes involved in proliferation, apoptosis, and differentiation, which are necessary for hematopoietic, inflammation, and immune response. Murray, see above. Knockout studies in mice have suggested the main role of JAK-STAT signal transduction, among which there is some overlap. JAK1 plays a key role in the signal transduction of various pro-inflammatory cytokines (such as IL-1, IL-4, IL-6) and tumor necrosis factor α (TNFα). Muller, M. et al., Nature 1993, 366(6451), 129-135. JAK2 is used for hematopoietic growth factor signal transduction (e.g. Epo, IL-3, IL-5, GM-CSF), thrombopoietin growth hormone and prolactin-mediated signal transduction. Neubauer, H. et al., Cell 1998 93(3), 397-409. JAK3 plays a role in mediating immune response, and TYK2 associates with JAK2 or JAK3 to transduce cytokine (such as IL-12) signals. Nosaka, T. et al., Science 1995, 270(5237), 800-802; Vainchenker, W. et al., Semin. Cell. Dev. Biol. 2008, 19(4), 385-393. The abnormal regulation of JAK/STAT pathway has been involved in a variety of human pathological diseases, including cancer (JAK2) and rheumatoid arthritis (JAK1, JAK3). Gain-of-function mutations in JAK2 (JAK2V617F) have been observed with high frequency in MPN patients. Levine, RL, et al., Cancer Cell 2005, 7(4), 387-397; Kralovics, R., et al., N. Engl. J. Med. 2005, 253(17), 1779-1790; James, C., et al. Human, Nature 2005, 434(7037), 1144-1148; Baxter, EJ et al., Lancet 2005, 365(9464), 1054-1061. Mutations in the JH2 pseudokinase domain of JAK2 result in constitutive kinase activity. Cells containing the JAK2V617F mutation acquire cytokine-independent growth ability and usually become tumors, which provides a strong basis for the development of JAK inhibitors as target therapies. Many JAK inhibitors have shown significant benefits in clinical trials for patients with myelofibrosis in terms of splenomegaly and disease-related systemic symptoms, including the first JAK2 inhibitor ruxolitinib approved by the FDA in 2011. Quintas-Cardama, see above; Sonbol, MB et al., Ther. Adv. Hematol. 2013, 4(1), 15-35; LaFave, LM et al., Trends Pharmacol. Sci. 2012, 33(11), 574 -582. Recently collected clinical data on Ruxolitinib treatment indicate that JAK inhibitors act on both JAK2 wild-type and JAK2 mutations. Verstovsek, S. et al., N. Engl. J. Med. 2012, 366(9), 799-807; Quintas-Cardama, A. et al., Blood 2010, 115(15), 3109-3117. The discovery of JAK2 as a selective inhibitor of JAK1/3 is still an unsolved challenge. In addition, JAK2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) is the cause of abnormal dendritic cell differentiation, which is the cause of abnormal dendritic cell differentiation and immunosuppressive bone marrow cell accumulation in cancer (Nefedova, Y. Et al., Cancer Res 2005;65(20):9525-35). In Pten-null senescent tumors, activation of the Jak2/Stat3 pathway establishes an immunosuppressive tumor microenvironment that contributes to tumor growth and chemoresistance (Toso, A. et al., Cell Reports 2014, 9, 75-89). Therefore, pharmacological inhibition of the JAK2/STAT3 pathway may be an important new treatment strategy to enhance anti-tumor activity through the regulation of anti-tumor immunity. ROS1 kinase is a receptor tyrosine kinase with an unknown ligand. The normal function of human ROS1 kinase is not yet fully understood. However, ROS1 kinase has been reported to undergo gene rearrangement to produce constitutively active fusion proteins in many human cancers, including glioblastoma, non-small cell lung cancer (NSCLC), cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer , Inflammatory myofibroblastic tumor, angiosarcoma and epithelioid hemangioendothelioma (Davies, KD et al., Clin Cancer Res 2013, 19 (15): 4040-4045). The use of crizotinib to target the ROS1 fusion protein has proven promising clinical efficacy in NSCLC patients whose tumors are positive for ROS1 genetic abnormalities (Shaw, AT et al., N Engl J Med. 2014, 371(21):1963- 1971). Acquired resistance mutations have been observed in crizotinib-treated patients (Awad, MM et al., N Engl J Med. 2013, 368(25): 2396-2401). There is an urgent need to develop second-generation ROS1 inhibitors to overcome crizotinib ROS1 resistance. The industry still needs small molecule inhibitors of these multiple proteins or tyrosine kinase targets with desired medicinal properties. In the context of the present invention, it has been found that certain diaryl macrocyclic compounds have this advantageous active property.

(I-A) 其中 環A’及環B’各自獨立地係單環或雙環芳基或雜芳基；其中環A’及環B’中之一者係單環芳基或雜芳基且另一者係雙環雜芳基；且環A’及環B’中之至少一者包含至少一個氮環成員； 每一L¹ 及L² 獨立地係-C(R^1’ )(R^2’ )-、-O-、-N(R^k’ )-、-S-、-S(O)-或-S(O)₂ -； 每一R^1’ 及R^2’ 獨立地係H、氘、鹵素、C_1-6 烷基、C_2-6 烯基、C_{2- 6} 炔基、C_3-6 環烷基、3至7員雜環烷基、C₆ -₁₀ 芳基或單或雙環雜芳基、-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或-NO₂ ，或R^1’ 及R^2’ 連同其所附接之一或多個碳一起形成C_3-6 環烷基或4至6員雜環烷基，其中C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、C₆ -₁₀ 芳基、單或雙環雜芳基、4至6員雜環烷基中之每一氫原子視情況獨立地經以下取代：氘、鹵素、C_1-6 烷基、C_1-6 鹵烷基、-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或-NO₂ ； 每一R^k’ 獨立地係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、C₆ -₁₀ 芳基或單或雙環雜芳基，其中C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、C₆ -₁₀ 芳基或單或雙環雜芳基中之每一氫原子視情況獨立地經以下取代：氘、鹵素、C_1-6 烷基、C_1-6 鹵烷基、-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或-NO₂ ； 每一R^3’ 及R^4’ 獨立地係氘、鹵素、-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’ 、-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、-NO₂ 、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、C₆ -₁₀ 芳基或單或雙環雜芳基，或任兩個R^3’ 基團或任兩個R^4’ 基團連同其所附接之環一起形成C_5-8 環烷基或5至8員雜環烷基，其中C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、C₆ -₁₀ 芳基、單或雙環雜芳基C_5-8 環烷基或5至8員雜環烷基中之每一氫原子視情況獨立地經以下取代：氘、鹵素、C_1-6 烷基、C_1-6 鹵烷基、-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或-NO₂ ； R^7’ 係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、C₆ -₁₀ 芳基或單或雙環雜芳基，其中C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、C₆ -₁₀ 芳基或單或雙環雜芳基中之每一氫原子視情況獨立地經以下取代：氘、鹵素、-OR^i’ 、-OC(O)R^i’ 、-OC(O)NR^i’ R^j’ 、-OS(O)R^i’ 、-OS(O)₂ R^i’ 、-OS(O)NR^i’ R^j’ 、-OS(O)₂ NR^i’ R^j’ 、-SR^i’ 、-S(O)R^i’ 、-S(O)₂ R^i’ 、-S(O)NR^i’ R^j’ 、-S(O)₂ NR^i’ R^j’ 、-NR^i’ R^j’ 、-NR^i’ C(O)R^j’ 、-NR^i’ C(O)OR^j’ 、-NR^i’ C(O)NR^i’ R^j’ 、-NR^i’ S(O)R^j’ 、-NR^i’ S(O)₂ R^j’ 、-NR^i’ S(O)NR^i’ R^j’ 、-NR^i’ S(O)₂ NR^i’ R^j’ 、-C(O)R^i’ 、-C(O)OR^i’ 、-C(O)NR^i’ R^j’ 、-PR^i’ R^j’ 、-P(O)R^i’ R^j’ 、-P(O)₂ R^i’ R^j’ 、-P(O)NR^i’ R^j’ 、-P(O)₂ NR^i’ R^j’ 、-P(O)OR^i’ 、-P(O)₂ OR^i’ 、-CN或-NO₂ ； 每一R^a’ 、R^b’ 、R^c’ 、R^d’ 、R^e’ 、R^f’ 、R^i’ 及R^j’ 獨立地選自由以下組成之群：H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、C₆ -₁₀ 芳基及雜芳基； m’係2、3、4或5； n’係2、3或4； p’係0、1、2、3或4；且 q’係0、1、2、3或4； 或其醫藥上可接受之鹽。 在一個態樣中，本發明係關於下式(I-A)之化學實體：

(I-A) 其中 環A’及環B’各自獨立地係單環或雙環芳基或雜芳基； 其中環A’及環B’中之一者係單環芳基或雜芳基且另一者係雙環雜芳基；且環A’及環B’中之至少一者包含至少一個氮環成員； 每一R^3’ 及R^4’ 獨立地係氘、鹵素、-OR^c’ 、-OC(O)R^c’ 、-OC(O)NR^c’ R^d’ 、-OC(=N)NR^c’ R^d’ 、-OS(O)_0-2 R^c’ 、-OS(O)_0-2 NR^c’ R^d’ 、-S(O)_0-2 R^c’ 、-S(O)_0-2 NR^c’ R^d’ 、-NR^c’ R^d’ 、-NR^c’ C(O)R^d’ 、-NR^c’ C(O)NR^c’ R^d’ 、-NR^c’ C(=N)NR^c’ R^d’ 、-NR^c’ S(O)_0-2 R^d’ 、-NR^c’ S(O)_{0- 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’ 、-P(O)_0-2 R^c’ R^d’ 、-P(O)_{0- 2} NR^c’ R^d’ 、-P(O)_0-2 OR^c’ 、-CN、-NO₂ 、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、苯基、萘基或單或雙環雜芳基；或任兩個R^3’ 基團或任兩個R^4’ 基團連同其所附接之環一起形成C_5-8 環烷基或5至8員雜環烷基； 其中每一烷基、烯基、炔基、環烷基、雜環烷基、苯基、萘基及單或雙環雜芳基未經取代或經一或多個選自由以下組成之群之取代基取代：氘、鹵素、C_1-6 烷基、C_1-6 鹵烷基、-OR^e’ 、-OC(O)R^e’ 、-OC(O)NR^e’ R^f’ 、-OS(O)_0-2 R^e’ 、-OS(O)_0-2 NR^e’ R^f’ 、-S(O)_0-2 R^e’ 、-S(O)_{0- 2} NR^e’ R^f’ 、-NR^e’ R^f’ 、-NR^e’ C(O)R^f’ 、-NR^e’ C(O)NR^e’ R^f’ 、-NR^e’ S(O)_0-2 R^f’ 、-NR^e’ S(O)_0-2 NR^e’ R^f’ 、-C(O)R^e’ 、-C(O)OR^e’ 、-C(O)NR^e’ R^f’ 、-P(O)_{0- 2} R^e’ R^f’ 、-P(O)_0-2 NR^e’ R^f’ 、-P(O)_0-2 OR^e’ 、-CN及-NO₂ ；且 每一R^c’ 、R^d’ 、R^e’ 及R^f’ 獨立地選自由以下組成之群：H、氘、C_{1- 6} 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、苯基、萘基及雜芳基； R^7’ 係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、苯基、萘基或單或雙環雜芳基； 其中每一烷基、烯基、炔基、環烷基、雜環烷基、苯基、萘基或雜芳基經一或多個選自由以下組成之群之取代基取代或未經取代：氘、鹵素、-OR^i’ 、-OC(O)R^i’ 、-OC(O)NR^i’ R^j’ 、-OS(O)_0-2 R^i’ 、-OS(O)_{0- 2} NR^i’ R^j’ 、-S(O)_0-2 R^i’ 、-S(O)_0-2 NR^i’ R^j’ 、-NR^i’ R^j’ 、-NR^i’ C(O)R^j’ 、-NR^i’ C(O)NR^i’ R^j’ 、-NR^i’ S(O)_0-2 R^j’ 、-NR^i’ S(O)_0-2 NR^i’ R^j’ 、-C(O)R^i’ 、-C(O)OR^i’ 、-C(O)NR^i’ R^j’ 、-P(O)_0-2 R^i’ R^j’ 、-P(O)_0-2 NR^i’ R^j’ 、-P(O)_{0- 2} OR^i’ 、-CN及-NO₂ ； 其中每一R^i’ 及R^j’ 獨立地係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、苯基、萘基或單或雙環雜芳基； 每一L¹ 及L² 獨立地係-C(R^1’ )(R^2’ )-、-O-、-N(R^k’ )-或-S(O)_0-2 ； 其中每一R^1’ 及R^2’ 獨立地係H、氘、鹵素、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、苯基、萘基或單或雙環雜芳基；或R^1’ 及R^2’ 連同其所附接之一或多個碳一起形成C_3-6 環烷基或4至6員雜環烷基； 每一R^k’ 獨立地係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、苯基、萘基或單或雙環雜芳基； 其中R^1’ 、R^2’ 或R^k’ 中之每一烷基、烯基、炔基、環烷基、雜環烷基、苯基、萘基或雜芳基獨立地未經取代或經一或多個選自由以下組成之群之取代基取代：氘、鹵素、C_1-6 烷基、C_1-6 鹵烷基、-OR^a’ 、-OC(O)R^a’ 、-OC(O)NR^a’ R^b’ 、-OS(O)_0-2 R^a’ 、-OS(O)_0-2 NR^a’ R^b’ 、-S(O)_{0- 2} R^a’ 、-S(O)_0-2 NR^a’ R^b’ 、-NR^a’ R^b’ 、-NR^a’ C(O)R^b’ 、-NR^a’ C(O)NR^a’ R^b’ 、-NR^a’ S(O)_0-2 R^b’ 、-NR^a’ S(O)_0-2 NR^a’ R^b’ 、-C(O)R^a’ 、-C(O)OR^a’ 、-C(O)NR^a’ R^b’ 、-P(O)_0-2 R^a’ R^b’ 、-P(O)_0-2 NR^a’ R^b’ 、-P(O)_0-2 OR^a’ 、-CN及-NO₂ ； 其中每一R^a’ 及R^b’ 獨立地係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、苯基、萘基或雜芳基； m’係3、4或5； n’係2、3或4； p’係0、1、2、3或4；且 q’係0、1、2、3或4； 或其醫藥上可接受之鹽。 在另一態樣中，本發明係關於下式(I)之化學實體：

(I) 其中 環A及環B各自獨立地係單環或雙環芳基或雜芳基；其中環A及環B中之一者係單環且另一者係雙環；且環包含至少一個氮環成員； R¹ 及R² 各自獨立地係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_{3- 6} 環烷基、3至7員雜環烷基、苯基、萘基或單或雙環雜芳基；或R¹ 及R² 連同其所附接之碳一起形成C_3-6 環烷基或4至6員雜環烷基； 其中每一烷基、烯基、炔基、環烷基、雜環烷基、苯基、萘基或雜芳基未經取代或經一或多個選自由以下組成之群之取代基取代：氘、鹵素、C_1-6 烷基、C_1-6 鹵烷基、-OR^a 、-OC(O)R^a 、-OC(O)NR^a R^b 、-OS(O)_0-2 R^a 、-OS(O)_0-2 NR^a R^b 、-NR^a R^b 、-NR^a C(O)R^b 、-NR^a C(O)NR^a R^b 、-NR^a S(O)_0-2 R^b 、-NR^a S(O)_0-2 NR^a R^b 、-C(O)R^a 、-C(O)OR^a 、-C(O)NR^a R^b 、-P(O)_0-2 R^a R^b 、-P(O)_0-2 NR^a R^b 、-P(O)_0-2 OR^a 、-CN及-NO₂ ； 其中每一R^a 及R^b 獨立地係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、苯基、萘基或雜芳基； 每一R³ 及R⁴ 獨立地係氘、鹵素、-OR^c 、-OC(O)R^c 、-OC(O)NR^c R^d 、-OC(=N)NR^c R^d 、-OS(O)_0-2 R^c 、-OS(O)_0-2 NR^c R^d 、-NR^c R^d 、-NR^c C(O)R^d 、-NR^c C(O)NR^c R^d 、-NR^c C(=N)NR^c R^d 、-NR^c S(O)_0-2 R^d 、-NR^c S(O)_0-2 NR^c R^d 、-C(O)R^c 、-C(O)OR^c 、-C(O)NR^c R^d 、-C(=N)NR^c R^d 、-P(O)_0-2 R^c R^d 、-P(O)_0-2 NR^c R^d 、-P(O)_{0- 2} OR^c 、-CN、-NO₂ 、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、苯基、萘基或單或雙環雜芳基； 其中每一烷基、烯基、炔基、環烷基、雜環烷基、苯基、萘基及單或雙環雜芳基未經取代或經一或多個選自由以下組成之群之取代基取代：氘、鹵素、C_1-6 烷基、C_1-6 鹵烷基、-OR^e 、-OC(O)R^e 、-OC(O)NR^e R^f 、-OS(O)_0-2 R^e 、-OS(O)_0-2 NR^e R^f 、-NR^e R^f 、-NR^e C(O)R^f 、-NR^e C(O)NR^e R^f 、-NR^e S(O)_0-2 R^f 、-NR^e S(O)_0-2 NR^e R^f 、-C(O)R^e 、-C(O)OR^e 、-C(O)NR^e R^f 、-P(O)_0-2 R^e R^f 、-P(O)_0-2 NR^e R^f 、-P(O)_0-2 OR^e 、-CN及-NO₂ ；且 每一R^c 、R^d 、R^e 及R^f 獨立地選自由以下組成之群：H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、苯基、萘基及雜芳基； R⁵ 及R⁶ 各自獨立地係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_{3- 6} 環烷基、3至7員雜環烷基、苯基、萘基或單或雙環雜芳基；或R⁵ 及R⁶ 連同其所附接之碳一起形成C_3-6 環烷基或4至6員雜環烷基； 其中每一烷基、烯基、炔基、環烷基、雜環烷基、苯基、萘基或雜芳基經一或多個選自由以下組成之群之取代基取代或未經取代：氘、鹵素、C_1-6 烷基、C_1-6 鹵烷基、-OR^g 、-OC(O)R^g 、-OC(O)NR^g R^h 、-OS(O)_0-2 R^g 、-OS(O)_0-2 NR^g R^h 、-NR^g R^h 、-NR^g C(O)R^h 、-NR^g C(O)NR^g R^h 、-NR^g S(O)_0-2 R^h 、-NR^g S(O)_0-2 NR^g R^h 、-C(O)R^g 、-C(O)OR^g 、-C(O)NR^g R^h 、-P(O)_0-2 R^g R^h 、-P(O)_0-2 NR^g R^h 、-P(O)_0-2 OR^g 、-CN及-NO₂ ； 其中每一R^g 及R^h 獨立地係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、苯基、萘基或單或雙環雜芳基； R⁷ 係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、苯基、萘基或單或雙環雜芳基； 其中每一烷基、烯基、炔基、環烷基、雜環烷基、苯基、萘基或雜芳基經一或多個選自由以下組成之群之取代基取代或未經取代：氘、鹵素、-ORⁱ 、-OC(O)Rⁱ 、-OC(O)NRⁱ R^j 、-OS(O)_0-2 Rⁱ 、-OS(O)_0-2 NRⁱ R^j 、-NRⁱ R^j 、-NRⁱ C(O)R^j 、-NRⁱ C(O)NRⁱ R^j 、-NRⁱ S(O)_0-2 R^j 、-NRⁱ S(O)_{0- 2} NRⁱ R^j 、-C(O)Rⁱ 、-C(O)ORⁱ 、-C(O)NRⁱ R^j 、-P(O)_0-2 Rⁱ R^j 、-P(O)_0-2 NRⁱ R^j 、-P(O)_0-2 ORⁱ 、-CN及-NO₂ ； 其中每一Rⁱ 及R^j 獨立地係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、苯基、萘基或單或雙環雜芳基； X及Y各自獨立地係-C(R^k )(R^k )-、-O-或-N(R^k )-； 其中每一R^k 獨立地係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_{3- 6} 環烷基、3至7員雜環烷基、苯基、萘基或單或雙環雜芳基； m係2、3或4； n係1、2或3； p係0、1、2、3或4；且 q係0、1、2、3或4； 或其醫藥上可接受之鹽。 在某些實施例中，式(I)或(I-A)之化合物係選自下文詳細說明中所闡述或例示之彼等物質中之化合物。 在某些實施例中，式(I)或(I-A)之化合物係具有下式之化合物

或其醫藥上可接受之鹽。 在某些實施例中，式(I)或(I-A)之化合物係具有下式之化合物

或其醫藥上可接受之鹽。 在某些實施例中，式(I)或(I-A)之化合物係下式之化合物

或其醫藥上可接受之鹽。 在某些實施例中，式(I)或(I-A)之化合物係具有下式之化合物

或其醫藥上可接受之鹽。 在某些實施例中，式(I)或(I-A)之化合物係具有下式之化合物

或其醫藥上可接受之鹽。 在某些實施例中，式(I)或(I-A)之化合物係具有下式之化合物

或其醫藥上可接受之鹽。 在其他態樣中，本發明係關於下式化合物之游離鹼的結晶形式

其具有實質上與圖XX相同之粉末X射線繞射圖案。在一些實施例中，下式化合物之游離鹼之結晶多晶形1

其中該粉末X射線繞射圖案具有在21.94之繞射角(2θ)處之峰。在一些實施例中，下式化合物之游離鹼之多晶形1

其中該粉末X射線繞射圖案具有在21.94及23.96之繞射角(2θ)處之峰。在一些實施例中，下式化合物之游離鹼之多晶形1

其中該粉末X射線繞射圖案具有在21.94、23.96及19.64之繞射角(2θ)處之峰。 在其他態樣中，本發明係關於醫藥組合物，其包含至少一種式(I)或(I-A)之化合物或其醫藥上可接受之鹽。本發明之醫藥組合物可進一步包含醫藥上可接受之賦形劑。本發明亦係關於式(I)或(I-A)之化合物或其醫藥上可接受之鹽，其用作藥劑。 在另一態樣中，本發明係關於治療癌症、疼痛、神經疾病、自體免疫疾病或發炎之方法，其包含向需要該治療之患者投與有效量之至少一種式(I)或(I-A)之化合物或其醫藥上可接受之鹽。 在另一態樣中，本發明係關於式(I)或(I-A)之化合物在製備用於治療該等疾病及醫學狀況之藥劑中之用途及該等化合物及鹽用於治療該等疾病及醫學狀況之用途。 在再另一態樣中，本發明係關於抑制蛋白質或酪胺酸激酶(包括MET、ALK、ROS1、AXL、TRK及JAK中之一或多者)之方法，其包含使包含該等激酶中之一或多者之細胞與有效量之至少一種式(I)或(I-A)之化合物或其鹽、及/或與至少一種本發明之醫藥組合物接觸，其中該接觸係在活體外、離體或在活體內。 本發明之額外實施例、特徵及優點將自詳細說明及藉助本發明之實踐顯而易見。 為簡便起見，本說明書中所列舉之出版物(包括專利)之揭示以引用的方式併入本文中。In one aspect, the present invention relates to compounds having the following formula (IA):

(IA) where ring A'and ring B'are independently monocyclic or bicyclic aryl or heteroaryl; wherein one of ring A'and ring B'is monocyclic aryl or heteroaryl and the other Is a bicyclic heteroaryl; and at least one of ring A'and ring B'contains at least one nitrogen ring member; each L ¹ and L ^{2 is} independently -C(R ^1' )(R ^2' )- , -O -, - N (R k ') -, - S -, - S (O) - or -S (O) ₂ -; each of R ^1' and R ^{2 'are} independently lines H, deuterium, halogen , C _1-6 alkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _3-6 cycloalkyl, 3-7 heterocycloalkyl, C ₆ - ₁₀ aryl or mono- or bicyclic heteroaryl group an aryl ^{group, -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 ^{1 'and} R ^2' together with their Attach one or more carbons together to form a C _3-6 cycloalkyl or 4 to 6 membered heterocycloalkyl, where C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _C3-6 cycloalkyl, 3-7 heterocycloalkyl, C ₆ - ₁₀ aryl group, a mono- or bicyclic heteroaryl group, 4-6 heterocycloalkyl of each hydrogen atom optionally independently substituted with the following substituted: deuterium, halo, C _1-6 alkyl, C _1-6 ^{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 R ^k'is independently H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3- 6-cycloalkyl,} 3-7 heterocycloalkyl, C ₆ - ₁₀ aryl or mono- or bicyclic heteroaryl, wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl group, C _3-6 cycloalkyl, 3-7 heterocycloalkyl, C ₆ - ₁₀ aryl or mono- or bicyclic heteroaryl group of each hydrogen atom is independently optionally substituted by the following: deuterium, halogen, C _{1 -6} alkyl, C _1-6 ^{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 R ^{3 'and} R ^4' independently fastened deuterium, ^{halogen, -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 ',} -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, C 1-6 alkyl, C _2-6 alkenyl group, C _{2 -6} alkynyl, C _3-6 cycloalkyl, 3-7 heterocycloalkyl, C ₆ - ₁₀ aryl or heteroaryl mono- or bicyclic aryl group, or any two of R ^{3 'group,} or any two of R ^The 4'group together with the ring to which it is attached forms a C _5-8 cycloalkyl group or a 5- to 8-membered heterocycloalkyl group, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne group, C _3-6 cycloalkyl, 3-7 heterocycloalkyl, C ₆ - ₁₀ aryl group, a mono- or bicyclic heteroaryl group or a C _5-8 cycloalkyl group 5-8 heterocycloalkyl of Each hydrogen atom is independently substituted by the following as appropriate: deuterium, halogen, C _1-6 alkyl, C _1-6 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; R ^{7 'based} H , deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-7 heterocycloalkyl, C ₆ - ₁₀ aryl group or a mono or bicyclic heteroaryl, wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-7 heterocycloalkyl, C ₆ - ₁₀ aryl mono- or bicyclic aryl or heteroaryl group of each hydrogen atom is independently optionally substituted by the following: deuterium, ^{halo, -OR i ', -OC (O} ) R i', -OC (O) NR i 'R j' ^{, -OS (O) R i '} , -OS (O) 2 R i', -OS (O) NR i 'R j', -OS (O) 2 NR i 'R j', -SR i ', ^{-S (O) R i ',} -S (O) 2 R i', -S (O) NR i 'R j', -S (O) 2 NR i 'R j', -NR i 'R j ^{', -NR i' C (O} ) R j ', -NR i' C (O) OR j ', -NR i' C (O) NR i 'R j', -NR i 'S (O) R ^{j ', -NR i' S (} O) 2 R j ', -NR i' S (O) NR i 'R j', -NR i 'S (O) 2 NR i' R j ', -C ( ^{O) R i ', -C (} O) OR i', -C (O) NR i 'R j', -PR i 'R j', -P (O) R i 'R j', -P ( _{^{O) 2 R i 'R j}} ', -P (O) NR i 'R j', -P (O) 2 NR i 'R j', -P (O) OR i ', -P (O) 2 OR ^i' , -CN or -NO ₂ ; each of Ra ^' , R ^b' , R ^c' , ^Rd' , Re ^' , R ^f' , R ^i'and R ^j'is independently selected from the group consisting of: H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-7 heterocycloalkyl, C ₆ - ₁₀ aryl group and heteroaryl Aryl; m'is 2, 3, 4, or 5; n'is 2, 3, or 4; p'is 0, 1, 2, 3, or 4; and q'is 0, 1, 2, 3, or 4; Or its pharmaceutically acceptable salt. In one aspect, the present invention relates to chemical entities of the following formula (IA):

(IA) wherein ring A'and ring B'are independently monocyclic or bicyclic aryl or heteroaryl; wherein one of ring A'and ring B'is monocyclic aryl or heteroaryl and the other donor line bicyclic heteroaryl group; and the ring a 'and ring B' contains at least one of the at least one nitrogen ring members; each R ^{3 'and} R ^4' independently based deuterium, halogen, -OR ^{c ',} -OC ^{(O) R c ', -OC} (O) NR c' R d ', -OC (= N) NR c' R d ', -OS (O) 0-2 R c', -OS (O) 0 _{^{-2 NR c 'R d',}} -S (O) 0-2 R c ', -S (O) 0-2 NR c' R d ', -NR c' R d ', -NR c' C ( ^{O) R d ', -NR c} ' C (O) NR c 'R d', -NR c 'C (= N) NR c' R d ', -NR c' S (O) 0-2 R d ^{', -NR c' S (O} ) 0- 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', -P (O) 0-2 R c 'R d', -P (O) 0- 2 NR c 'R d', -P (O) 0- ₂ OR ^c' , -CN, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, phenyl, naphthyl or mono- or bicyclic heteroaryl group; or any two of R ^{3 'group,} or any two of R ^4' groups form a C _5-8 cycloalkyl group or a 5- to which they are attached together with the ring 8-membered heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, naphthyl and mono- or bicyclic heteroaryl group is unsubstituted or selected by one or more Substitution free of substituents of the following group: deuterium, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ^e' , -OC(O)R ^e' , -OC(O)NR ^{e 'R f', -OS (O} ) 0-2 R e ', -OS (O) 0-2 NR e' R f ', -S (O) 0-2 R e', -S (O) 0 _{^{- 2 NR e 'R f'}} , -NR e 'R f', -NR e 'C (O) R f', -NR e 'C (O) NR e' R f ', -NR e' S ( ^{_{O) 0-2 R f ', -NR}} e' S (O) 0-2 NR e 'R f', -C (O) R e ', -C (O) OR e', -C (O) ^{NR e 'R f', -P} (O) 0- 2 R e 'R f', -P (O) 0-2 NR e 'R f', - P(O) _0-2 OR ^e' , -CN and -NO ₂ ; and each R ^c' , ^Rd' , Re ^' and R ^f'is independently selected from the group consisting of H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-7 heterocycloalkyl, phenyl, naphthyl, and heteroaryl; R ^{7 '} System H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 7 member heterocycloalkyl, phenyl, naphthyl or mono Or bicyclic heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, naphthyl or heteroaryl group has one or more substituents selected from the group consisting of a substituted or unsubstituted: deuterium, ^{halo, -OR i ', -OC (O} ) R i', -OC (O) NR i 'R j', -OS (O) 0-2 R i ', -OS ^{_{(O) 0- 2 NR i '}} R j', -S (O) 0-2 R i ', -S (O) 0-2 NR i' R j ', -NR i' R j ', -NR ^{i 'C (O) R j} ', -NR i 'C (O) NR i' R j ', -NR i' S (O) 0-2 R j ', -NR i' S (O) 0- _{^{2 NR i 'R j',}} -C (O) R i ', -C (O) OR i', -C (O) NR i 'R j', -P (O) 0-2 R i 'R _{^{j ', -P (O) 0-2}} NR i' R j ', -P (O) 0- 2 OR i', -CN and -NO _2; wherein each of R ^{i 'and} R ^j' is independently system H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, phenyl, naphthyl or mono-or Bicyclic heteroaryl; each L ¹ and L ^{2 is} independently -C(R ^1' )(R ^2' )-, -O-, -N(R ^k' )- or -S(O) _0-2 ; wherein each R ^{1 'and} R ^2' are independently lines H, deuterium, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 7-membered heterocycloalkyl, phenyl, naphthyl or mono- or bicyclic heteroaryl group; or R ^{1 'and} R ^2' together with one or more carbon attached form a C _3-6 cycloalkyl group or 4- to 6-membered heterocycloalkyl; each R ^k'is independently H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl or mono- or bicyclic heteroaryl; wherein each of R ^1' , R ^2'or R ^k'is alkyl, alkenyl, alkynyl, cycloalkyl , Heterocycloalkyl, phenyl, naphthyl or heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of deuterium, halogen, C _{1 -6} alkyl, C _1-6 ^{haloalkyl, -OR a ', -OC (O} ) R a', -OC (O) NR a 'R b', -OS (O) 0-2 R a ' ^{_{, -OS (O) 0-2 NR a}} 'R b', -S (O) 0- 2 R a ', -S (O) 0-2 NR a' R b ', -NR a' R b ' ^{, -NR a 'C (O)} R b', -NR a 'C (O) NR a' R b ', -NR a' S (O) 0-2 R b ', -NR a' S (O _{^{) 0-2 NR a 'R b'}} , -C (O) R a ', -C (O) OR a', -C (O) NR a 'R b', -P (O) 0-2 R ^{a 'R b', -P (} O) 0-2 NR a 'R b', -P (O) 0-2 OR a ', -CN and -NO _2; wherein each of R ^a' and R ^{b '} Independently H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, phenyl, naphthyl Or heteroaryl; m'is 3, 4, or 5; n'is 2, 3, or 4; p'is 0, 1, 2, 3, or 4; and q'is 0, 1, 2, 3, or 4; Or its pharmaceutically acceptable salt. In another aspect, the present invention relates to chemical entities of the following formula (I):

(I) wherein ring A and ring B are each independently a monocyclic or bicyclic aryl group or heteroaryl group; wherein one of ring A and ring B is a monocyclic ring and the other is a bicyclic ring; and the ring contains at least one nitrogen ring members; R ¹ and R ² are each independently based H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3- 6} cycloalkyl, hetero 3-7 Cycloalkyl, phenyl, naphthyl, or mono- or bicyclic heteroaryl; or R ¹ and R ² together with the carbon to which they are attached form a C _3-6 cycloalkyl group or a 4- to 6-membered heterocycloalkyl group; wherein Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, naphthyl, or heteroaryl group is unsubstituted or substituted with one or more substituents selected from the group consisting of deuterium , Halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ^a , -OC(O)R ^a , -OC(O)NR ^a R ^b , -OS(O) _0-2 R ^a , -OS(O) _0-2 NR ^a R ^b , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^a R ^b , -NR ^a S(O) _{0 -2} R ^b , -NR ^a S(O) _0-2 NR ^a R ^b , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -P(O _{^{) 0-2 R a R b, -P}} (O) 0-2 NR a R b, -P (O) 0-2 OR a, -CN and -NO _2; wherein each R ^a and R ^b are independently System H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 7 member heterocycloalkyl, phenyl, naphthyl or hetero Aryl; each R ³ and R ^{4 is} independently deuterium, halogen, -OR ^c , -OC(O)R ^c , -OC(O)NR ^c R ^d , -OC(=N)NR ^c R ^d , -OS(O) _0-2 R ^c , -OS(O) _0-2 NR ^c R ^d , -NR ^c R ^d , -NR ^c C(O)R ^d , -NR ^c C(O)NR ^c R ^d , -NR ^c C(=N)NR ^c R ^d , -NR ^c S(O) _0-2 R ^d , -NR ^c S(O) _0-2 NR ^c R ^d , -C(O)R ^c , -C(O)OR ^c , -C(O)NR ^c R ^d , -C(=N)NR ^c R ^d , -P(O) _0-2 R ^c R ^d , -P(O) _{0- ^{2 NR c R d, -P (}} O) 0- 2 OR c, -CN, -NO 2, C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl Alkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl or mono- or bicyclic heteroaryl; each of which is alkyl, alkenyl, alkynyl , Cycloalkyl, heterocycloalkyl, phenyl, naphthyl and mono- or bicyclic heteroaryl are unsubstituted or substituted with one or more substituents selected from the group consisting of deuterium, halogen, C _1-6 Alkyl, C _1-6 haloalkyl, -OR ^e , -OC(O)R ^e , -OC(O)NR ^e R ^f , -OS(O) _0-2 R ^e , -OS(O) _{0 -2} NR ^e R ^f , -NR ^e R ^f , -NR ^e C(O)R ^f , -NR ^e C(O)NR ^e R ^f , -NR ^e S(O) _0-2 R ^f , -NR ^e S(O) _0-2 NR ^e R ^f , -C(O)R ^e , -C(O)OR ^e , -C(O)NR ^e R ^f , -P(O) _0-2 R ^e R _{^{f, -P (O) 0-2 NR}} e R f, -P (O) 0-2 OR e, -CN and -NO _2; and each R ^c, R ^d, R ^e, and R ^f are independently selected from Free from the group consisting of: H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, phenyl , Naphthyl and heteroaryl; R ⁵ and R ⁶ are each independently H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3 6} cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl, or mono- or bicyclic heteroaryl; or R ⁵ and R ⁶ together with the carbon to which they are attached form a C _3-6 cycloalkyl or 4- to 6-membered hetero Cycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, naphthyl or heteroaryl group is substituted with one or more substituents selected from the group consisting of or Unsubstituted: Deuterium, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ^g , -OC(O)R ^g , -OC(O)NR ^g R ^h , -OS(O) _0-2 R ^g , -OS(O) _0-2 NR ^g R ^h , -NR ^g R ^h , -NR ^g C(O)R ^h , -NR ^g C(O)NR ^g R ^h , -NR ^g S(O) _0-2 R ^h , -NR ^g S(O) _0-2 NR ^g R ^h , -C(O)R ^g , -C(O)OR ^g , -C(O)NR ^g R ^h , -P(O) _0-2 R ^g R ^h , -P(O) _0-2 NR ^g R ^h , -P(O) _0-2 OR ^g , -CN and -NO ₂ ; where each R ^g And R ^{h are} independently H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, phenyl , Naphthyl or mono- or bicyclic heteroaryl; R ⁷ is H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 To 7-membered heterocycloalkyl, phenyl, naphthyl or mono- or bicyclic heteroaryl; each of which is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, naphthyl or heteroaryl The group is substituted or unsubstituted with one or more substituents selected from the group consisting of deuterium, halogen, -OR ⁱ , -OC(O)R ⁱ , -OC(O)NR ⁱ R ^j , -OS( O) _0-2 R ⁱ , -OS(O) _0-2 NR ⁱ R ^j , -NR ⁱ R ^j , -NR ⁱ C(O)R ^j , -NR ⁱ C(O)NR ⁱ R ^j ,- _{^{NR i S (O) 0-2 R}} j, -NR i S (O) 0- 2 NR i R j, -C (O) R i, -C (O) OR i, -C (O) NR i R ^j , -P(O) _0-2 R ⁱ R ^j , -P(O) _0-2 NR ⁱ R ^j , -P(O) _0-2 OR ⁱ , -CN and -NO ₂ ; each of them R ⁱ and R ^{j are} independently H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, Phenyl, naphthyl or mono- or bicyclic heteroaryl; X and Y are each independently -C(R ^k )(R ^k )-, -O- or -N(R ^k )-; wherein each R ^{k is} independent fastened H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3- 6} cycloalkyl, 3-7 heterocycloalkyl, phenyl, naphthyl or Mono- or bicyclic heteroaryl; m is 2, 3 or 4; n is 1, 2 or 3; p is 0, 1, 2, 3 or 4; and q is 0, 1, 2, 3 or 4; or Pharmaceutically acceptable salt. In some embodiments, the compound of formula (I) or (IA) is selected from the compounds described or exemplified in the detailed description below. In some embodiments, the compound of formula (I) or (IA) is a compound of the following formula

Or its pharmaceutically acceptable salt. In some embodiments, the compound of formula (I) or (IA) is a compound of the following formula

Or its pharmaceutically acceptable salt. In some embodiments, the compound of formula (I) or (IA) is a compound of the following formula

Or its pharmaceutically acceptable salt. In some embodiments, the compound of formula (I) or (IA) is a compound of the following formula

Or its pharmaceutically acceptable salt. In some embodiments, the compound of formula (I) or (IA) is a compound of the following formula

Or its pharmaceutically acceptable salt. In some embodiments, the compound of formula (I) or (IA) is a compound of the following formula

Or its pharmaceutically acceptable salt. In other aspects, the present invention relates to the crystalline form of the free base of the compound of the following formula

It has substantially the same powder X-ray diffraction pattern as in Figure XX. In some embodiments, the free base crystalline polymorph of the compound of the formula 1

The powder X-ray diffraction pattern has a peak at a diffraction angle (2θ) of 21.94. In some embodiments, the free base polymorph of the compound of the formula 1

The powder X-ray diffraction pattern has peaks at diffraction angles (2θ) of 21.94 and 23.96. In some embodiments, the free base polymorph of the compound of the formula 1

The powder X-ray diffraction pattern has peaks at diffraction angles (2θ) of 21.94, 23.96, and 19.64. In other aspects, the present invention relates to a pharmaceutical composition comprising at least one compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention may further include pharmaceutically acceptable excipients. The present invention also relates to a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof, which is used as a medicament. In another aspect, the present invention relates to a method for treating cancer, pain, neurological disease, autoimmune disease or inflammation, which comprises administering an effective amount of at least one formula (I) or (IA) to a patient in need of such treatment. ) Or a pharmaceutically acceptable salt thereof. In another aspect, the present invention relates to the use of compounds of formula (I) or (IA) in the preparation of medicaments for the treatment of such diseases and medical conditions and the use of such compounds and salts in the treatment of such diseases and Use of medical conditions. In yet another aspect, the present invention relates to a method for inhibiting protein or tyrosine kinase (including one or more of MET, ALK, ROS1, AXL, TRK, and JAK), which comprises the inclusion of these kinases One or more of the cells are contacted with an effective amount of at least one compound of formula (I) or (IA) or a salt thereof, and/or with at least one pharmaceutical composition of the present invention, wherein the contact is in vitro and in vitro Or in the living body. Additional embodiments, features and advantages of the present invention will be apparent from the detailed description and practice of the present invention. For brevity, the disclosures of publications (including patents) listed in this specification are incorporated herein by reference.

術語「鹵素」代表氯、氟、溴或碘。術語「鹵基」代表氯、氟、溴或碘。 術語「鹵烷基」係指具有一或多個鹵基取代基、或一個、兩個或三個鹵基取代基之烷基。鹵烷基之實例包括-CF₃ 、-(CH₂ )F、-CHF₂ 、-CH₂ Br、-CH₂ CF₃ 及-CH₂ CH₂ F。 術語「芳基」係指具有完全共軛π-電子系統之具有6至14個碳原子(C₆ -C₁₄ )之全碳單環或稠環多環基團。芳基包括具有6至10個碳原子(例如，「C₆ -₁₀ 芳基」)之全碳單環或稠環多環。芳基之實例係(但不限於)苯基、萘基及蒽基。芳基可如上文針對烷基所述經取代或未經取代。取代基亦包括彼等在本揭示內容之其他地方關於芳基所闡述者。 術語「雜環烷基」係指飽和或部分飽和且具有3至12個環原子之單環或多環結構，其中1至5環原子選自氮、氧及硫。多環系統包括稠合、橋接及螺系統。環結構可視情況在碳或硫環成員上含有至多兩個側氧基。雜環烷基之說明性實例包括以下呈適當鍵結部分形式之實體：

術語「雜芳基」係指每一雜環具有3至12個環原子之單環、稠合二環或稠合多環芳香族雜環(環結構具有選自碳原子及至多四個選自氮、氧及硫之雜原子之環原子)。雜芳基之說明性實例包含以下呈適當鍵結部分形式之實體：

「單環」雜芳基係芳香族5或6員雜環。5員雜芳基含有至多四個雜原子環原子，其中(a)一個環原子係氧及硫且0、1或2個環原子係氮，或(b) 0個環原子係氧或硫且至多4個環原子係氮。在一些實施例中，5員雜芳基係呋喃、噻吩、吡咯、噁唑、異噁唑、噻唑、異噻唑、吡唑、咪唑、噁二唑、噻二唑、三唑或四唑。6員雜芳基含有1或2個氮環原子。在一些實施例中，6員雜芳基係吡啶、吡嗪、嘧啶、噠嗪或三嗪。「雙環雜芳基」係包含一個稠合至苯基或另一雜芳基環之雜芳基環的稠合雙環系統。 術語「側氧基」代表羰基氧。舉例而言，經側氧基取代之環戊基係環戊酮。 術語「經取代」意指指定基團或部分具有一或多個取代基。術語「未經取代」意指指定基團不具取代基。在使用術語「經取代」來闡述結構系統時，取代意欲發生在系統上化合價允許之任何位置處。在一些實施例中，「經取代」意指指定基團或部分具有1、2或3個取代基。在其他實施例中，「經取代」意指指定基團或部分具有1或2個取代基。在再其他實施例中，「經取代」意指指定基團或部分具有1個取代基。 本文所描繪之任何式意欲代表化合物之結構式以及某些變化或形式。舉例而言，本文所給出之式意欲包括外消旋形式、或一或多個鏡像異構體、非鏡像異構體、或幾何異構體或其混合物。另外，本文所給出之任何式亦意欲指此化合物之水合物、溶劑合物或多晶型或其混合物。 本文所給出之任一式亦意欲代表化合物之未經標記形式以及經同位素標記之形式。經同位素標記之化合物具有由本文所給出式繪示之結構，只是一或多個原子由具有所選原子質量或質量數之原子替代。可納入本發明化合物中之同位素之實例包括氫、碳、氮、氧、磷、氟、氯及碘之同位素，例如分別為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及¹²⁵ I。該等經同位素標記之化合物可用於代謝研究(較佳利用¹⁴ C)、反應動力學研究(利用例如² H或³ H)、檢測或成像技術[例如正電子發射斷層掃描術(PET)或單光子發射電腦斷層掃描術(SPECT)](包括藥物或基質組織分佈分析)或患者之放射性治療。另外，使用較重同位素(例如氘，即² H)取代可提供某些源自較強代謝穩定性(例如，增加活體內半衰期或減少劑量需求)之治療優點。經同位素標記之本發明化合物及其前藥通常可藉由實施在方案中或在下文所述實例及製備中所揭示程序藉由用易於獲得之同位素標記試劑取代未經同位素標記之試劑來製備。 命名法「(原子)_i-j 」且j ＞ i在本文中應用於一類取代基時意欲指本發明之以下實施例：自i至j (包含i及j)之碳成員編號之各自及每一者係獨立地實現。例如，術語C_1-3 獨立地指具有一個碳成員(C₁ )之實施例、具有兩個碳成員(C₂ )之實施例及具有三個碳成員(C₃ )之實施例。 本文所提及之任何二取代基當允許一種以上之附接可能性時意欲涵蓋眾多該等可能性。舉例而言，提及二取代基-A-B- (其中A ≠ B)在本文中係指A附接至第一經取代成員且B附接至第二經取代成員之該二取代基，且其亦指A附接至第二成員且B附接至第一經取代成員之該二取代基。 本發明亦包括式(I)或(I-A)代表之化合物、較佳彼等上文所述者及本文例示之特定化合物的醫藥上接受之鹽、及包含該等鹽之醫藥組合物及使用該等鹽之方法。 「醫藥上可接受之鹽」意欲指本文所表示之化合物之游離酸或鹼之無毒、生物上可耐受或在其他方面生物學上適於投與個體之鹽。通常，參見S.M. Berge等人，「Pharmaceutical Salts」, J. Pharm. Sci., 1977, 66, 1-19。較佳醫藥上接受之鹽係彼等藥理學上有效且適於與個體之組織接觸而無過度毒性、刺激或過敏反應者。本文所述之化合物可具有足夠酸性基團、足夠鹼性基團、兩種類型之官能團或每一類型之多於一者，且因此與許多無機或有機鹼及無機及有機酸反應，以形成醫藥上可接受之鹽。 醫藥上可接受之鹽之實例包括硫酸鹽、焦硫酸鹽、硫酸氫鹽、亞硫酸鹽、亞硫酸氫鹽、磷酸鹽、磷酸氫鹽、磷酸二氫鹽、偏磷酸鹽、焦磷酸鹽、氯化物、溴化物、碘化物、乙酸鹽、硼酸鹽、硝酸鹽、丙酸鹽、癸酸鹽、辛酸鹽、丙烯酸鹽、甲酸鹽、異丁酸鹽、己酸鹽、庚酸鹽、丙炔酸鹽、草酸鹽、丙二酸鹽、琥珀酸鹽、辛二酸鹽、癸二酸鹽、富馬酸鹽、馬來酸鹽、丁炔-1,4-二酸鹽、己炔-1,6-二酸鹽、苯甲酸鹽、氯苯甲酸鹽、甲基苯甲酸鹽、二硝基苯甲酸鹽、羥基苯甲酸鹽、甲氧基苯甲酸鹽、鄰苯二甲酸鹽、磺酸鹽、甲磺酸鹽、丙磺酸鹽、甲苯磺酸鹽、二甲苯磺酸鹽、萘-1-磺酸鹽、萘-2-磺酸鹽、苯基乙酸鹽、苯基丙酸鹽、苯基丁酸鹽、檸檬酸鹽、乳酸鹽、γ-羥基丁酸鹽、羥乙酸鹽、酒石酸鹽及杏仁酸鹽。其他適宜醫藥上接受之鹽之列表可見於Remington's Pharmaceutical Sciences, 第17版, Mack Publishing Company, Easton, Pa., 1985。 對於含有鹼性氮之式(I)或(I-A)之化合物，醫藥上可接受之鹽可藉由業內可獲得之任何適宜方法來製備，例如使用以下各項處理游離鹼：無機酸，例如鹽酸、氫溴酸、硫酸、胺基磺酸、硝酸、硼酸、磷酸及諸如此類；或有機酸，例如乙酸、苯基乙酸、丙酸、硬脂酸、乳酸、抗壞血酸、馬來酸、羥基馬來酸、羥乙磺酸、琥珀酸、戊酸、富馬酸、丙二酸、丙酮酸、草酸、乙醇酸、水楊酸、油酸、棕櫚酸、月桂酸、吡喃糖基酸(pyranosidyl acid) (例如葡糖醛酸或半乳糖醛酸)、α-羥基酸(例如杏仁酸、檸檬酸或酒石酸)、胺基酸(例如天冬胺酸或麩胺酸)、芳香族酸(例如苯甲酸、2-乙醯氧基苯甲酸、萘甲酸或肉桂酸)、磺酸(例如月桂基磺酸、對甲苯磺酸、甲烷磺酸或乙烷磺酸)、或酸之任何相容混合物(諸如彼等在本文中以實例給出者)及根據此項技術之普通水準視為等效物或可接受之替代品之任何其他酸及其混合物。 本發明亦係關於式(I)或(I-A)之化合物的醫藥上接受之前藥及採用該等醫藥上接受之前藥之治療方法。術語「前藥」意指指定化合物在投與個體後經由化學或生理學過程(例如溶劑分解或酶促裂解)或在生理學條件下在活體內產生化合物之前體(例如，前藥在生理學pH下轉化成式(I)或(I-A)化合物)。「醫藥上可接受之前藥」係無毒、生物上可耐受且在其他方面生物學上適於投與個體之前藥。選擇及製備適宜前藥衍生物之說明性程序闡述於(例如)「Design of Prodrugs」，編輯H. Bundgaard, Elsevier, 1985中。 本發明亦係關於式(I)或(I-A)之化合物的醫藥活性代謝物及該等代謝物在本發明方法中之用途。「醫藥活性代謝物」意指式(I)或(I-A)化合物或其鹽在體內代謝之藥理學活性產物。化合物之前藥及活性代謝物可使用業內已知或可獲得之常規技術來測定。參見(例如) Bertolini等人，J. Med. Chem . 1997,40 , 2011-2016；Shan等人，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)；及Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen等人編輯，Harwood Academic Publishers, 1991)。 代表性實施例 在式(I-A)之一些實施例中，環A’係單環芳基或雜芳基且環B’係雙環雜芳基。在其他實施例中，環A’係雙環雜芳基且環B’係單環芳基或雜芳基。在一些實施例中，環A’係苯基或6員雜芳基。在其他實施例中，環B’係含有1、2或3個氮環原子之雙環雜芳基。在其他實施例中，環A’係苯基或吡啶基。 在再其他實施例中，環A’係苯基。在再其他實施例中，經-(R^3’ )_p’ 取代之環A’係

。在再其他實施例中，經-(R^3’ )_p’ 取代之環A’係

。在一些實施例中，環B’係：

其中Z¹ -Z⁷ 係如本文所述定義。在再其他實施例中，環B’係：

或

或

或

其中Z^1-7 係如本文所述以其他方式定義。在再其他實施例中，環B’係：

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

或

。 在再其他實施例中，環B’係

、

或

。在再其他實施例中，環B’係

。 在式(I-A)之其他實施例中，環A’係雙環雜芳基，且係：

其中Z¹ -Z⁷ 係如本文所述定義。在再其他實施例中，環A’係：

或

或

或

其中Z^1-7 係如本文所述以其他方式定義。在再其他實施例中，環A’係：

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

或

。 在再其他實施例中，環A’係

、

或

。在再其他實施例中，環A’係

。 在一些實施例中，環B’係單環芳基或雜芳基。在其他實施例中，環B’係苯基。在其他實施例中，環A’係吡啶基。 在一些實施例中，每一R^3’ 獨立地係氘、氟、氯、溴、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、異丙氧基、-CN、-CF₃ 、-NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-CO₂ C_1-4 烷基、-CO₂ H、-NHC(O)C_1-4 烷基、-SO₂ C_1-4 烷基、-C(O)NH₂ 、-C(O)NH(C_1-4 烷基)、-C(O)N(C_1-4 烷基)₂ 、環丙基、環丁基、環戊基、環己基、吡咯啶基、六氫吡啶基、六氫吡嗪基、嗎啉基或硫嗎啉基。在再其他實施例中，每一R^3’ 獨立地係氟、氯、溴、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、異丙氧基、-CN或-CF₃ 。在再其他實施例中，每一R^3’ 係氟或氯。 在一些實施例中，R^7’ 係H、氘、甲基、乙基、丙基、異丙基、環丙基、環丁基、環戊基、吡咯啶基、呋喃基、硫代呋喃基、六氫吡啶基、六氫吡嗪基、嗎啉基、苯基或單環雜芳基，其各自如式(I-A)中經取代或未經取代。在其他實施例中，R^7’ 係H，或係甲基、乙基、丙基、異丙基或環丙基，其各自如式(I-A)中未經取代或經取代。在再其他實施例中，R^7’ 係H或係甲基或乙基，其各自未經取代或經以下取代：鹵素、-OH、-OC_1-4 烷基、-NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-CO₂ H、-CO₂ C_1-4 烷基、-CONH₂ 、環烷基或單環雜環烷基。在再其他實施例中，R^7’ 係H、甲基、羥乙基、-CH₂ CONH₂ 或3-吡咯啶基甲基。在再其他實施例中，R^7’ 係H或甲基。 在一些實施例中，R^1’ 及R^2’ 各自獨立地係H、氘、甲基、乙基、丙基、異丙基、環丙基、環丁基、環戊基、吡咯啶基、呋喃基、硫代呋喃基、六氫吡啶基、六氫吡嗪基、嗎啉基、苯基或單環雜芳基，其各自如式(I-A)中經取代或未經取代。在其他實施例中，R^1’ 係H。在再其他實施例中，R^2’ 係氘、甲基、乙基、丙基、異丙基、環丙基、環丁基、環戊基、吡咯啶基、呋喃基、硫代呋喃基、六氫吡啶基、六氫吡嗪基、嗎啉基、苯基或單環雜芳基，其各自如式(I-A)中經取代或未經取代。在再其他實施例中，R^2’ 係H或係甲基或乙基，其各自未經取代或經以下取代：鹵素、-OH、-OC_1-4 烷基、-NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-CO₂ H、-CO₂ C_1-4 烷基、-CONH₂ 、環烷基或單環雜環烷基。在再其他實施例中，R^2’ 係H、甲基、氟甲基、羥甲基或環丙基。在再其他實施例中，R^2’ 係H。在再其他實施例中，R^2’ 係甲基。 在一些實施例中，每一R^k’ 獨立地係H、甲基、乙基、丙基、異丙基或環丙基。在其他實施例中，每一R^k’ 獨立地係H或甲基。 在一些實施例中，每一L¹ 及L² 獨立地係-CH₂ -或-CH(甲基)-、-CH(經取代甲基)-、-CH(C_3-6 環丙基)-、-CH(OH)-、-O-、-NH-、-N(C_{1- 4} 烷基)-、-N(C_3-6 環丙基)-、-S-、-S(O)-或-SO₂ -。在一些實施例中，-(L¹ )_n’ -係-CH₂ -O-、-CH(C_1-4 烷基)-O-或-CH(C_3-6 環烷基)-O-。在其他實施例中，-(L¹ )_n’ -係-CH(H或視情況經取代之C_1-4 烷基)-N(H或視情況經取代之C_1-4 烷基)-、-CH(CO₂ C_1-4 烷基或C(O)N(H或C_1-4 烷基)₂ )-N(H或視情況經取代之C_1-4 烷基)。在再其他實施例中，-(L¹ )_n’ -係-CH₂ S(O)_{0- 2} -。在其他實施例中，-(L¹ )_n’ -係-SO₂ -N(H或C_1-4 烷基)。在一些實施例中，-(L¹ )_n’ -係-(CH₂ )₃ -。在一些實施例中，-(L¹ )_n’ -係-(CH₂ )₂ -。在一些實施例中，-(L¹ )_n’ -係-CH(CH₃ )CH₂ -。 在一些實施例中，-(L² )_m’ 係-O-(C(R^1’ )(R^2’ ))_2-3 -。在其他實施例中，-(L² )_m’ 係-O-(CH₂ )_2-3 -。在其他實施例中，-(L² )_m’ 係-N(R^k’ )-(C(R^1’ )(R^2’ ))_2-3 -。在其他實施例中，-(L² )_m’ 係-N(H或C_1-4 烷基)-(CH₂ )_{2- 3} -。在其他實施例中，-(L² )_m’ 係-S-(C(R^1’ )(R^2’ ))_2-3 -。在其他實施例中，-(L² )_m’ 係-SO₂ -(C(R^1’ )(R^2’ ))_2-3 -。在再其他實施例中，-(L² )_m’ 係-SO₂ -N(R^k’ )-(C(R^1’ )(R^2’ ))₂ -。在再其他實施例中，-(L² )_m’ 係-(C(R^1’ )(R^2’ ))₃ -。 在一些實施例中，m’係3。在其他實施例中，m’係4。在再其他實施例中，m’係5。在一些實施例中，n’係2。在其他實施例中，n’係3。在再其他實施例中，n’係4。在一些實施例中，p’係0、1或2。在其他實施例中，p’係1或2。在一些實施例中，q’係0。在其他實施例中，q’係1。在再其他實施例中，q’係2。 在一些實施例中，式(I-A)係式(I)化合物或其醫藥上接受之鹽。在其他實施例中，式(I-A)化合物係式(I)化合物，其中每一變量獨立地如下文針對式(I)所示所定義。在一些實施例中，式(I-A)之變量如下映射於式(I)上：A’係A；B’係B；R^1’ 係R¹ ；R^2’ 係R² ；R^3’ 係R³ ；R^4’ 係R⁴ ；R^7’ 係R⁷ ；R^a’ -R^f’ 及R^i’ -R^k’ 分別映射於R^a -R^f 及Rⁱ -R^k 上；且L¹ 及L² 分別係-Y-(C(R⁵ )(R⁶ ))_m -及-C((R¹ )(R² ))_n -X-。 在式(I)之一些實施例中，環A係苯基或6員雜芳基。在其他實施例中，環A係苯基或吡啶基。在再其他實施例中，環A係苯基。在再其他實施例中，經-(R³ )_p 取代之環A係

。在再其他實施例中，經-(R³ )_p 取代之環A係

。 在一些實施例中，每一R³ 獨立地係氘、氟、氯、溴、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、異丙氧基、-CN、-CF₃ 、-NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-CO₂ C_1-4 烷基、-CO₂ H、-NHC(O)C_1-4 烷基、-SO₂ C_1-4 烷基、-C(O)NH₂ 、-C(O)NH(C_1-4 烷基)、-C(O)N(C_1-4 烷基)₂ 、環丙基、環丁基、環戊基、環己基、吡咯啶基、六氫吡啶基、六氫吡嗪基、嗎啉基或硫嗎啉基。在再其他實施例中，每一R³ 獨立地係氟、氯、溴、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、異丙氧基、-CN或-CF₃ 。在再其他實施例中，每一R³ 係氟或氯。 在再其他實施例中，經-(R³ )_p 取代之環A係

，其中R^3a 及R^3b 各自獨立地係H、氟或氯且M係CH或N。在一些實施例中，R^3a 係氟。 在一些實施例中，p係1或2。在其他實施例中，p係0。在再其他實施例中，p係1。在再其他實施例中，p係2。 在一些實施例中，環B係雙環雜芳基。在其他實施例中，環B係9員雙環雜芳基。 在一些實施例中，每一R⁴ 獨立地係氘、氟、氯、溴、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、異丙氧基、-CN、-CF₃ 、-NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-CO₂ C_1-4 烷基、-CO₂ H、-NHC(O)C_1-4 烷基、-SO₂ C_1-4 烷基、-C(O)NH₂ 、-C(O)NH(C_1-4 烷基)、-C(O)N(C_1-4 烷基)₂ 、環丙基、環丁基、環戊基、環己基、吡咯啶基、六氫吡啶基、六氫吡嗪基、嗎啉基或硫嗎啉基。在再其他實施例中，每一R⁴ 獨立地係氟、氯、溴、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、異丙氧基、-CN或-CF₃ 。 在其他實施例中，經-(R⁴ )_q 取代之環B係：

其中Z¹ 、Z² 、Z³ 及Z⁶ 各自獨立地係-C(R^x )-或N； 其中每一R^x 獨立地係H、氘、鹵素、C_1-4 烷基、-O-C_1-4 烷基、-OH、-NH₂ 、-NHC_1-4 烷基、-NH-苯基、-NH-雜芳基、CN或-CF₃ ； Z⁴ 及Z⁵ 各自獨立地係-C-或-N-；且 Z⁷ 係-CH-、-N-或-NH-。 在其他實施例中： (a) Z¹ , Z⁴ 及Z⁷ 各自係-N-； (b) Z¹ , Z⁵ 及Z⁷ 各自係-N-； (c) Z¹ 及Z³ 各自係-N-且Z⁷ 係-NH-； (d) Z³ 係-N-且Z⁷ 係-NH-； (e) Z³ 及Z⁶ 各自係-N-且Z⁷ 係-NH-； (f) Z² 、Z⁴ 及Z⁷ 各自係-N-； (g) Z¹ 、Z² 、Z⁴ 及Z⁷ 各自係-N-； (h) Z¹ 、Z³ 及Z⁴ 各自係-N-； (i) Z³ 及Z⁴ 各自係-N-； (j) Z¹ 、Z² 、Z⁵ 及Z⁷ 各自係-N-； (k) Z² 、Z⁵ 及Z⁷ 各自係-N-； (l) Z³ 及Z⁵ 各自係-N-； (m) Z³ 、Z⁵ 及Z⁶ 各自係-N-； (n) Z¹ 、Z⁵ 、Z⁶ 及Z⁷ 各自係-N-； (o) Z² 、Z⁵ 、Z⁶ 及Z⁷ 各自係-N-；或 (p) Z¹ 、Z³ 及Z⁶ 各自係-N-且Z⁷ 係-NH-。 在(a)-(p)之再其他實施例中，未明確定義之每一Z環原子獨立地係-C-或-C(R^x )- (與該環原子之定義一致)。在再其他實施例中，Z³ 係-N-。在其他實施例中，Z⁷ 係-N-或-NH-。在再其他實施例中，Z³ 係-N-且Z⁷ 係-N-或-NH-。在再其他實施例中，經-(R⁴ )_q 取代之環B係：

或

或

或

其中Z^1-7 係如上所述以其他方式定義。 在再其他實施例中，經-(R⁴ )_q 取代之環B係：

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

或

。 在再其他實施例中，經-(R⁴ )_q 取代之環B係

、

或

。在再其他實施例中，經-(R⁴ )_q 取代之環B係

。 在一些實施例中，q係0。在其他實施例中，q係1。 在一些實施例中，R¹ 及R² 各自獨立地係H、氘、甲基、乙基、丙基、異丙基、環丙基、環丁基、環戊基、吡咯啶基、呋喃基、硫代呋喃基、六氫吡啶基、六氫吡嗪基、嗎啉基、苯基或單環雜芳基，其各自如同在式(I)中經取代或未經取代。在其他實施例中，R¹ 係H。在再其他實施例中，R² 係氘、甲基、乙基、丙基、異丙基、環丙基、環丁基、環戊基、吡咯啶基、呋喃基、硫代呋喃基、六氫吡啶基、六氫吡嗪基、嗎啉基、苯基或單環雜芳基，其各自如同在式(I)中經取代或未經取代。在再其他實施例中，R² 係H或係甲基或乙基，其各自未經取代或經以下取代：鹵素、-OH、-OC_1-4 烷基、-NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-CO₂ H、-CO₂ C_1-4 烷基、-CONH₂ 、環烷基或單環雜環烷基。在再其他實施例中，R² 係H、甲基、氟甲基、羥甲基或環丙基。在再其他實施例中，R² 係H。在再其他實施例中，R² 係甲基。在再其他實施例中，R¹ 係H，且R² 不為H且呈如下所示立體化學構型：

。 在再其他實施例中，R¹ 及R² 一起形成C_3-6 環烷基。在其他實施例中，R¹ 及R² 一起形成視情況經C_1-4 烷基取代之5或6員雜環烷基。 在一些實施例中，n係1或2。在再其他實施例中，n係1。 在一些實施例中，R⁵ 及R⁶ 各自獨立地係H、氘、甲基、乙基、丙基、異丙基、環丙基、環丁基、環戊基、吡咯啶基、呋喃基、硫代呋喃基、六氫吡啶基、六氫吡嗪基、嗎啉基、苯基或單環雜芳基，其各自如同在式(I)中經取代或未經取代。在其他實施例中，每一R⁵ 係H。在再其他實施例中，每一R⁶ 獨立地係H，或係甲基、乙基或環丙基，其各自如同在式(I)中經取代或未經取代。在再其他實施例中，每一R⁶ 獨立地係H或未經取代或經-OH取代之甲基。在再其他實施例中，每一R⁶ 係H或甲基。在再其他實施例中，R⁵ 及R⁶ 一起形成C_3-6 環烷基。在其他實施例中，R⁵ 及R⁶ 一起形成視情況經C_1-4 烷基取代之5或6員雜環烷基。 在一些實施例中，m為2或3。在其他實施例中，m為2。 在一些實施例中，R⁷ 係H、氘、甲基、乙基、丙基、異丙基、環丙基、環丁基、環戊基、吡咯啶基、呋喃基、硫代呋喃基、六氫吡啶基、六氫吡嗪基、嗎啉基、苯基或單環雜芳基，其各自如同在式(I)中經取代或未經取代。在其他實施例中，R⁷ 係H，或係甲基、乙基、丙基、異丙基或環丙基，其各自未經取代或如同在式(I)中經取代。在再其他實施例中，R⁷ 係H或係甲基或乙基，其各自未經取代或經以下取代：鹵素、-OH、-OC_1-4 烷基、-NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-CO₂ H、-CO₂ C_1-4 烷基、-CONH₂ 、環烷基或單環雜環烷基。在再其他實施例中，R⁷ 係H、甲基、羥乙基、-CH₂ CONH₂ 或3-吡咯啶基甲基。在再其他實施例中，R⁷ 係H或甲基。 在一些實施例中，X及Y中之每一者獨立地係-O-或-N(R^k )-。在一些實施例中，X係-O-或-N(R^k )-。在一些實施例中，Y係-O-。在一些實施例中，每一R^k 獨立地係H、甲基、乙基、丙基、異丙基或環丙基。在其他實施例中，每一R^k 獨立地係H或甲基。 在一些實施例中，式(I)或(I-A)之化合物係式(II)之化合物：

(II) 其中M、R³ 、q、R² 、X、R⁷ 及Z^1-7 各自以上文所列舉若干方式中之任一者定義； R^5a 、R^5b 、R^6a 及R^6b 各自係R⁵ 且R⁶ 如上文以所列舉若干方式中之任一者所定義； 或其醫藥上可接受之鹽。 在一些實施例中，式(I)或(I-A)之化合物係式(III)之化合物：

(III) 其中 M係CH或N； R^3a 及R^3b 各自獨立地係H、氟、氯、溴、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、異丙氧基、-CN或-CF₃ ； R^2a 係H或係甲基或乙基，其各自未經取代或經以下取代：鹵素、-OH、-OC_1-4 烷基、-NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-CO₂ H、-CO₂ C_1-4 烷基、-CONH₂ 、環烷基或單環雜環烷基； X¹ 係O或-N(CH₃ )-； R^5a 、R^6a 、R^5b 及R^6b 各自獨立地係H、或甲基或乙基，其各自未經取代或經以下取代：鹵素、-OH、-OC_1-4 烷基、-NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-CO₂ H、-CO₂ C_1-4 烷基、-CONH₂ 、-CONH(C_1-4 烷基)、-CON(C_1-4 烷基)₂ 、環烷基或單環雜環烷基； R^7a 係H或係甲基或乙基，其各自未經取代或經以下取代：鹵素、-OH、-OC_1-4 烷基、-NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-CO₂ H、-CO₂ C_1-4 烷基、-CONH₂ 、-CONH(C_1-4 烷基)、-CON(C_1-4 烷基)₂ 、環烷基或單環雜環烷基； Z^1-7 各自以上文所列舉若干方式中之任一者定義； 或其醫藥上可接受之鹽。 在式(III)之一些實施例中，M係CH。 在其他實施例中，R^3a 及R^3b 各自獨立地係H、氟或氯。在再其他實施例中，R^3a 係H或氟。在再其他實施例中，R^3a 係氟。在再其他實施例中，R^3b 係H或氯。 在式(III)之一些實施例中，R^2a 係H、甲基、氟甲基或環丙基。 在式(III)之一些實施例中，X¹ 係O。在其他實施例中，X係-N(CH₃ )-。 在一些實施例中，R^7a 係H、甲基、羥乙基、-CH₂ CONH₂ 或3-吡咯啶基甲基。在其他實施例中，R^7a 係H或甲基。 在一些實施例中，式(I)或(I-A)之化合物係式(IV)化合物：

(IV) 其中 M係CH或N； X¹ 及X^1’ 獨立地係-C(R^1a )(R^2a )-、-S-、-S(O)-、-S(O)₂ -、-O-或-N(R^k’ )-； 每一R^1a 及R^2a 獨立地係H、氘、C_1-6 烷基、C_3-6 環烷基、C₆ -₁₀ 芳基、-C(O)OR^a’ 、-C(O)NR^a’ R^b’ 、-NR^a’ R^b’ 、-SR^a’ 、-S(O)R^a’ 、-S(O)NR^a’ 、-S(O)₂ R^a’ 、-S(O)₂ NR^a’ 或-OR^a’ ，其中C_1-6 烷基中之每一氫原子視情況獨立地經以下取代：氘、鹵素、-OH、-OC_1-4 烷基、-NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、NHC(O)C_1-4 烷基、-N(C_1-4 烷基)C(O)C_{1- 4} 烷基、-NHC(O)NHC_1-4 烷基、-N(C_1-4 烷基)C(O)NHC_1-4 烷基、NHC(O)N(C_1-4 烷基)₂ 、-N(C_1-4 烷基)C(O)N(C_1-4 烷基)₂ 、-NHC(O)OC_1-4 烷基、-N(C_1-4 烷基)C(O)OC_1-4 烷基、-CO₂ H、-CO₂ C_1-4 烷基、-CONH₂ 、-CONH(C_1-4 烷基)、-CON(C_1-4 烷基)₂ 、-SC_1-4 烷基、-S(O)C_1-4 烷基、-S(O)₂ C_1-4 烷基、-S(O)NH(C_1-4 烷基)、-S(O)₂ NH(C_1-4 烷基)、-S(O)N(C_1-4 烷基)₂ 、-S(O)₂ N(C_1-4 烷基)₂ 、C_3-6 環烷基或3至7員雜環烷基； R^3a 及R^3b 各自獨立地係H、氘、氟、氯、溴、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、異丙氧基、-CN或-CF₃ ； R^7a 係H、C_1-6 烷基或3至7員雜環烷基，其中C_1-6 烷基或3至7員雜環烷基中之每一氫原子視情況獨立地經以下取代：氘、鹵素、-CN、-OH、-OC_1-4 烷基、-NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-CO₂ H、-CO₂ C_1-4 烷基、-CONH₂ 、-CONH(C_1-4 烷基)、-CON(C_1-4 烷基)₂ 、環烷基或單環雜環烷基； 每一R^k’ 獨立地係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、C₆ -₁₀ 芳基或單或雙環雜芳基；其中R^k’ 中之C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、C₆ -₁₀ 芳基或單或雙環雜芳基中之每一氫原子視情況獨立地經以下取代：氘、鹵素、C_1-6 烷基、C_1-6 鹵烷基或-OR^a’ ； 其中每一R^a’ 及R^b’ 獨立地係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、C₆ -₁₀ 芳基或雜芳基； 每一Z¹ 、Z² 、Z³ 、Z⁴ 、Z⁵ 、Z⁶ 或Z⁷ 獨立地係N、NH或C(R^x )，其中每一R^x 當存在時獨立地係H、氘、鹵素、C_1-4 烷基、-O-C_1-4 烷基、-OH、-NH₂ 、-NH(C_1-4 烷基)、-NH(苯基)、-NH(雜芳基)、CN或-CF₃ ，前提條件係Z¹ 、Z² 、Z³ 、Z⁴ 、Z⁵ 、Z⁶ 或Z⁷ 中之至少一者係N或NH；且 m’係2或3； 或其醫藥上可接受之鹽。 在一些實施例中，Z¹ 、Z⁴ 及Z⁷ 係N且Z² 、Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 及Z³ 係N，Z⁷ 係NH且Z² 、Z⁴ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z³ 及Z⁶ 係N，Z⁷ 係NH且Z² 、Z⁴ 及Z⁵ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z³ 係N，Z⁷ 係NH且Z¹ 、Z² 、Z⁴ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z³ 及Z⁶ 係N，Z⁷ 係NH且Z¹ 、Z² 、Z⁴ 及Z⁵ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z² 、Z⁴ 及Z⁷ 係N且Z¹ 、Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z⁵ 及Z⁷ 係N且Z² 、Z³ 、Z⁴ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z² 、Z⁴ 及Z⁷ 係N且Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z² 、Z⁵ 及Z⁷ 係N且Z³ 、Z⁴ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z³ 、Z⁵ 及Z⁶ 係N且Z¹ 、Z² 、Z⁴ 及Z⁷ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z⁵ 、Z⁶ 及Z⁷ 係N且Z² 、Z³ 及Z⁴ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z² 及Z⁴ 係N且Z³ 、Z⁵ 、Z⁶ 及Z⁷ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z³ 及Z⁴ 係N且Z² 、Z⁵ 、Z⁶ 及Z⁷ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z³ 及Z⁴ 係N且Z¹ 、Z² 、Z⁵ 、Z⁶ 及Z⁷ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z² 、Z⁵ 及Z⁷ 係N且Z¹ 、Z³ 、Z⁴ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z³ 及Z⁵ 係N且Z¹ 、Z² 、Z⁴ 、Z⁶ 及Z⁷ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z² 、Z⁵ 、Z⁶ 及Z⁷ 係N且Z¹ 、Z³ 及Z⁴ 係C(R^x )，其中每一R^x 當存在時係H。 在一些實施例中，R^k’ 係選自由以下組成之群：H、甲基、乙基、丙基、異丙基、環丙基、2-羥乙基、2-羥基-2-甲基-丙基及N-甲基-吡咯-3-基。在一些實施例中，M係CH。在一些實施例中，M係CH，Z¹ 、Z⁴ 及Z⁷ 係N且Z² 、Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，M係CH，Z¹ 、Z⁴ 及Z⁷ 係N，Z² 、Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H，且X¹ 係-N(R^k’ )-。在一些實施例中，M係CH，Z¹ 、Z⁴ 及Z⁷ 係N，Z² 、Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H，X¹ 係-N(R^k’ )-，且X^1’ 係-O-。在一些實施例中，M係CH，Z¹ 、Z⁴ 及Z⁷ 係N，Z² 、Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H，X¹ 係-C(R^1a )(R^2a )-，且X^1’ 係-O-。 在一些實施例中，式(I)或(I-A)之化合物係式(V)化合物：

(V) 其中 M係CH或N； X¹ 及X^1’ 獨立地係-C(R^1a )(R^2a )-、-S-、-S(O)-、-S(O)₂ -、-O-或-N(R^k’ )-； 每一R^1a 及R^2a 獨立地係H、氘、C_1-6 烷基、C_3-6 環烷基、C₆ -₁₀ 芳基、-C(O)OR^a’ 、-C(O)NR^a’ R^b’ 、-NR^a’ R^b’ 、-SR^a’ 、-S(O)R^a’ 、-S(O)NR^a’ 、-S(O)₂ R^a’ 、-S(O)₂ NR^a’ 或-OR^a’ ，其中C_1-6 烷基中之每一氫原子視情況獨立地經以下取代：氘、鹵素、-OH、-OC_1-4 烷基、-NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、NHC(O)C_1-4 烷基、-N(C_1-4 烷基)C(O)C_{1- 4} 烷基、-NHC(O)NHC_1-4 烷基、-N(C_1-4 烷基)C(O)NHC_1-4 烷基、NHC(O)N(C_1-4 烷基)₂ 、-N(C_1-4 烷基)C(O)N(C_1-4 烷基)₂ 、-NHC(O)OC_1-4 烷基、-N(C_1-4 烷基)C(O)OC_1-4 烷基、-CO₂ H、-CO₂ C_1-4 烷基、-CONH₂ 、-CONH(C_1-4 烷基)、-CON(C_1-4 烷基)₂ 、-SC_1-4 烷基、-S(O)C_1-4 烷基、-S(O)₂ C_1-4 烷基、-S(O)NH(C_1-4 烷基)、-S(O)₂ NH(C_1-4 烷基)、-S(O)N(C_1-4 烷基)₂ 、-S(O)₂ N(C_1-4 烷基)₂ 、C_3-6 環烷基或3至7員雜環烷基； R^3a 及R^3b 各自獨立地係H、氟、氯、溴、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、異丙氧基、-CN或-CF₃ ； R^7a 係H、C_1-6 烷基或3至7員雜環烷基，其中C_1-6 烷基或3至7員雜環烷基中之每一氫原子視情況獨立地經以下取代：鹵素、-OH、-OC_{1- 4} 烷基、-NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-CO₂ H、-CO₂ C_1-4 烷基、-CONH₂ 、-CONH(C_1-4 烷基)、-CON(C_1-4 烷基)₂ 、環烷基或單環雜環烷基； 每一R^k’ 獨立地係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、C₆ -₁₀ 芳基或單或雙環雜芳基；其中R^k’ 中之C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、C₆ -₁₀ 芳基或單或雙環雜芳基中之每一氫原子之視情況獨立地經以下取代：氘、鹵素、C_1-6 烷基、C_1-6 鹵烷基或-OR^a’ ； 其中每一R^a’ 及R^b’ 獨立地係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、C₆ -₁₀ 芳基或雜芳基； 每一Z¹ 、Z² 、Z³ 、Z⁴ 、Z⁵ 、Z⁶ 或Z⁷ 獨立地係N、NH或C(R^x )，其中每一R^x 當存在時獨立地係H、氘、鹵素、C_1-4 烷基、-O-C_1-4 烷基、-OH、-NH₂ 、-NH(C_1-4 烷基)、-NH(苯基)、-NH(雜芳基)、CN或-CF₃ ，前提條件係Z¹ 、Z² 、Z³ 、Z⁴ 、Z⁵ 、Z⁶ 或Z⁷ 中之至少一者係N或NH；且 m’係2或3； 或其醫藥上可接受之鹽。 在一些實施例中，Z¹ 、Z⁴ 及Z⁷ 係N且Z² 、Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 及Z³ 係N，Z⁷ 係NH且Z² 、Z⁴ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z³ 及Z⁶ 係N，Z⁷ 係NH且Z² 、Z⁴ 及Z⁵ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z³ 係N，Z⁷ 係NH且Z¹ 、Z² 、Z⁴ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z³ 及Z⁶ 係N，Z⁷ 係NH且Z¹ 、Z² 、Z⁴ 及Z⁵ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z² 、Z⁴ 及Z⁷ 係N且Z¹ 、Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z⁵ 及Z⁷ 係N且Z² 、Z³ 、Z⁴ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z² 、Z⁴ 及Z⁷ 係N且Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z² 、Z⁵ 及Z⁷ 係N且Z³ 、Z⁴ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z³ 、Z⁵ 及Z⁶ 係N且Z¹ 、Z² 、Z⁴ 及Z⁷ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z⁵ 、Z⁶ 及Z⁷ 係N且Z² 、Z³ 及Z⁴ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z² 及Z⁴ 係N且Z³ 、Z⁵ 、Z⁶ 及Z⁷ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z³ 及Z⁴ 係N且Z² 、Z⁵ 、Z⁶ 及Z⁷ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z³ 及Z⁴ 係N且Z¹ 、Z² 、Z⁵ 、Z⁶ 及Z⁷ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z² 、Z⁵ 及Z⁷ 係N且Z¹ 、Z³ 、Z⁴ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z³ 及Z⁵ 係N且Z¹ 、Z² 、Z⁴ 、Z⁶ 及Z⁷ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z² 、Z⁵ 、Z⁶ 及Z⁷ 係N且Z¹ 、Z³ 及Z⁴ 係C(R^x )，其中每一R^x 當存在時係H。 在一些實施例中，R^k’ 係選自由以下組成之群：H、甲基、乙基、丙基、異丙基、環丙基、2-羥乙基、2-羥基-2-甲基-丙基及N-甲基-吡咯-3-基。在一些實施例中，M係CH。在一些實施例中，M係CH，Z¹ 、Z⁴ 及Z⁷ 係N且Z² 、Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，M係CH，Z¹ 、Z⁴ 及Z⁷ 係N，Z² 、Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H，且X¹ 係-N(R^k’ )-。在一些實施例中，M係CH，Z¹ 、Z⁴ 及Z⁷ 係N，Z² 、Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H，X¹ 係-N(R^k’ )-，且X^1’ 係-O-。在一些實施例中，M係CH，Z¹ 、Z⁴ 及Z⁷ 係N，Z² 、Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H，X¹ 係-C(R^1a )(R^2a )-，且X^1’ 係-O-。 在一些實施例中，式(I)或(I-A)之化合物係選自由以下組成之群之化合物：

其中 M係CH或N； X¹ 及X^1’ 獨立地係-C(R^1a )(R^2a )-、-S-、-S(O)-、-S(O)₂ -、-O-或-N(R^k’ )-； 每一R^1a 及R^2a 獨立地係H、氘、C_1-6 烷基、C_3-6 環烷基、C₆ -₁₀ 芳基、-C(O)OR^a’ 、-C(O)NR^a’ R^b’ 、-NR^a’ R^b’ 、-SR^a’ 、-S(O)R^a’ 、-S(O)NR^a’ 、-S(O)₂ R^a’ 、-S(O)₂ NR^a’ 或-OR^a’ ，其中C_1-6 烷基中之每一氫原子視情況獨立地經以下取代：氘、鹵素、-OH、-OC_1-4 烷基、-NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、NHC(O)C_1-4 烷基、-N(C_1-4 烷基)C(O)C_{1- 4} 烷基、-NHC(O)NHC_1-4 烷基、-N(C_1-4 烷基)C(O)NHC_1-4 烷基、NHC(O)N(C_1-4 烷基)₂ 、-N(C_1-4 烷基)C(O)N(C_1-4 烷基)₂ 、-NHC(O)OC_1-4 烷基、-N(C_1-4 烷基)C(O)OC_1-4 烷基、-CO₂ H、-CO₂ C_1-4 烷基、-CONH₂ 、-CONH(C_1-4 烷基)、-CON(C_1-4 烷基)₂ 、-SC_1-4 烷基、-S(O)C_1-4 烷基、-S(O)₂ C_1-4 烷基、-S(O)NH(C_1-4 烷基)、-S(O)₂ NH(C_1-4 烷基)、-S(O)N(C_1-4 烷基)₂ 、-S(O)₂ N(C_1-4 烷基)₂ 、C_3-6 環烷基或3至7員雜環烷基； R^3a 及R^3b 各自獨立地係H、氟、氯、溴、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、異丙氧基、-CN或-CF₃ ； R^7a 係H、C_1-6 烷基或3至7員雜環烷基，其中C_1-6 烷基或3至7員雜環烷基中之每一氫原子視情況獨立地經以下取代：鹵素、-OH、-OC_{1- 4} 烷基、-NH₂ 、-NH(C_1-4 烷基)、-N(C_1-4 烷基)₂ 、-CO₂ H、-CO₂ C_1-4 烷基、-CONH₂ 、-CONH(C_1-4 烷基)、-CON(C_1-4 烷基)₂ 、環烷基或單環雜環烷基； 每一R^k’ 獨立地係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、C₆ -₁₀ 芳基或單或雙環雜芳基；其中R^k’ 中之C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、C₆ -₁₀ 芳基或單或雙環雜芳基中之每一氫原子視情況獨立地經以下取代：氘、鹵素、C_1-6 烷基、C_1-6 鹵烷基或-OR^a’ ； 其中每一R^a’ 及R^b’ 獨立地係H、氘、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、3至7員雜環烷基、C₆ -₁₀ 芳基或雜芳基； 每一Z¹ 、Z² 、Z³ 、Z⁴ 、Z⁵ 、Z⁶ 或Z⁷ 獨立地係N、NH或C(R^x )，其中每一R^x 當存在時獨立地係H、氘、鹵素、C_1-4 烷基、-O-C_1-4 烷基、-OH、-NH₂ 、-NH(C_1-4 烷基)、-NH(苯基)、-NH(雜芳基)、CN或-CF₃ ，前提條件係Z¹ 、Z² 、Z³ 、Z⁴ 、Z⁵ 、Z⁶ 或Z⁷ 中之至少一者係N或NH；且 m’係2或3； 或其醫藥上可接受之鹽。 在一些實施例中，Z¹ 、Z⁴ 及Z⁷ 係N且Z² 、Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 及Z³ 係N，Z⁷ 係NH且Z² 、Z⁴ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z³ 及Z⁶ 係N，Z⁷ 係NH且Z² 、Z⁴ 及Z⁵ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z³ 係N，Z⁷ 係NH且Z¹ 、Z² 、Z⁴ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z³ 及Z⁶ 係N，Z⁷ 係NH且Z¹ 、Z² 、Z⁴ 及Z⁵ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z² 、Z⁴ 及Z⁷ 係N且Z¹ 、Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z⁵ 及Z⁷ 係N且Z² 、Z³ 、Z⁴ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z² 、Z⁴ 及Z⁷ 係N且Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z² 、Z⁵ 及Z⁷ 係N且Z³ 、Z⁴ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z³ 、Z⁵ 及Z⁶ 係N且Z¹ 、Z² 、Z⁴ 及Z⁷ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z⁵ 、Z⁶ 及Z⁷ 係N且Z² 、Z³ 及Z⁴ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z² 及Z⁴ 係N且Z³ 、Z⁵ 、Z⁶ 及Z⁷ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z¹ 、Z³ 及Z⁴ 係N且Z² 、Z⁵ 、Z⁶ 及Z⁷ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z³ 及Z⁴ 係N且Z¹ 、Z² 、Z⁵ 、Z⁶ 及Z⁷ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z² 、Z⁵ 及Z⁷ 係N且Z¹ 、Z³ 、Z⁴ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z³ 及Z⁵ 係N且Z¹ 、Z² 、Z⁴ 、Z⁶ 及Z⁷ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，Z² 、Z⁵ 、Z⁶ 及Z⁷ 係N且Z¹ 、Z³ 及Z⁴ 係C(R^x )，其中每一R^x 當存在時係H。 在一些實施例中，R^k’ 係選自由以下組成之群：H、甲基、乙基、丙基、異丙基、環丙基、2-羥乙基、2-羥基-2-甲基-丙基及N-甲基-吡咯-3-基。在一些實施例中，M係CH。在一些實施例中，M係CH，Z¹ 、Z⁴ 及Z⁷ 係N且Z² 、Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H。在一些實施例中，M係CH，Z¹ 、Z⁴ 及Z⁷ 係N，Z² 、Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H，且X¹ 係-N(R^k’ )-。在一些實施例中，M係CH，Z¹ 、Z⁴ 及Z⁷ 係N，Z² 、Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H，X¹ 係-N(R^k’ )-，且X^1’ 係-O-。在一些實施例中，M係CH，Z¹ 、Z⁴ 及Z⁷ 係N，Z² 、Z³ 、Z⁵ 及Z⁶ 係C(R^x )，其中每一R^x 當存在時係H，X¹ 係-C(R^1a )(R^2a )-，且X^1’ 係-O-。 在其他實施例中，式(I)或(I-A)之化合物係選自由以下組成之群：(13R)-5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；(13R)-11-氟-5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；11-氟-5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；(13R)-12-氯-11-氟-5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；12-氯-11-氟-5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；(13R)-12-氯-11-氟-5-(2-羥乙基)-13-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；12-氯-11-氟-5-(2-羥乙基)-13-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；2-[(13R)-12-氯-11-氟-13-甲基-4-側氧基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-5(4H)-基]乙醯胺；2-[12-氯-11-氟-13-甲基-4-側氧基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-5(4H)-基]乙醯胺；(13R)-12-氯-11-氟-13-甲基-5-(吡咯啶-2-基甲基)-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；12-氯-11-氟-13-甲基-5-(吡咯啶-2-基甲基)-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；(13R)-12-氯-11-氟-7-(羥甲基)-5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；12-氯-11-氟-7-(羥甲基)-5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；(13S)-11-氟-13-(氟甲基)-5-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；11-氟-13-(氟甲基)-5-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；(13R)-13-環丙基-11-氟-5-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；13-環丙基-11-氟-5-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；(13R)-11-氟-13-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；11-氟-13-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；(13R)-12-氯-11-氟-13-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；12-氯-11-氟-13-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；12-氯-11-氟-6-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；12-氯-11-氟-7-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；(8R)-9-氯-10-氟-8-甲基-15,16-二氫-8H-3,6-乙烯橋基咪唑并[5,1-f][1,10,4,7,8]苯并二氧雜三氮雜十三熳環-17(14H)-酮；9-氯-10-氟-8-甲基-15,16-二氫-8H-3,6-乙烯橋基咪唑并[5,1-f][1,10,4,7,8]苯并二氧雜三氮雜十三熳環-17(14H)-酮；(7R)-8-氯-9-氟-7-甲基-14,15-二氫-2H,7H-3,5-(次氮基亞甲橋基)吡咯并[3,4-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-16(13H)-酮；8-氯-9-氟-7-甲基-14,15-二氫-2H,7H-3,5-(次氮基亞甲橋基)吡咯并[3,4-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-16(13H)-酮；(5R)-3-氟-5-甲基-14,15-二氫-5H,10H-9,7-(次氮基亞甲橋基)吡啶并[2,3-k]吡咯并[3,4-d][1,10,3,7]二氧雜二氮雜十三熳環-12(13H)-酮；3-氟-5-甲基-14,15-二氫-5H,10H-9,7-(次氮基亞甲橋基)吡啶并[2,3-k]吡咯并[3,4-d][1,10,3,7]二氧雜二氮雜十三熳環-12(13H)-酮；(5R)-3-氟-5,16-二甲基-13,14,15,16-四氫-5H-9,7-(次氮基亞甲橋基)吡啶并[2,3-k]吡咯并[3,4-d][1,3,7,10]氧雜三氮雜十三熳環-12(10H)-酮；3-氟-5,16-二甲基-13,14,15,16-四氫-5H-9,7-(次氮基亞甲橋基)吡啶并[2,3-k]吡咯并[3,4-d][1,3,7,10]氧雜三氮雜十三熳環-12(10H)-酮；(13R)-12-氯-11-氟-5,13-二甲基-6,7-二氫-2H,13H-1,15-(次氮基亞甲橋基)吡咯并[3,4-f][1,10,4]苯并二氧雜氮雜十三熳環-4(5H)-酮；12-氯-11-氟-5,13-二甲基-6,7-二氫-2H,13H-1,15-(次氮基亞甲橋基)吡咯并[3,4-f][1,10,4]苯并二氧雜氮雜十三熳環-4(5H)-酮；(7R)-8-氯-9-氟-7,15-二甲基-14,15-二氫-2H,7H-3,5-(次氮基亞甲橋基)吡唑并[3,4-f][1,10,4]苯并二氧雜氮雜十三熳環-16(13H)-酮；8-氯-9-氟-7,15-二甲基-14,15-二氫-2H,7H-3,5-(次氮基亞甲橋基)吡唑并[3,4-f][1,10,4]苯并二氧雜氮雜十三熳環-16(13H)-酮；11-氟-14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；(13R)-12-氯-11-氟-13,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；12-氯-11-氟-13,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；12-氯-11-氟-5,14-二甲基-6,7,13,14-四氫-15,1-(次氮基亞甲橋基)吡唑并[4,3-f][1,4,10]苯并氧雜二氮雜十三熳環-4(5H)-酮；12-氯-11-氟-14-甲基-6,7,13,14-四氫-15,1-(次氮基亞甲橋基)吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；12-氯-11-氟-14-甲基-6,7,13,14-四氫-1,15-(次氮基亞甲橋基)吡咯并[3,2-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；12-氯-11-氟-14-甲基-6,7,13,14-四氫-1,15-(次氮基亞甲橋基)吡咯并[3,2-f][1,4,10]苯并氧雜二氮雜十三熳環-4(5H)-酮；9-氯-10-氟-7-甲基-7,8,15,16-四氫-3,6-乙烯橋基咪唑并[5,1-f][1,4,7,8,10]苯并氧雜四氮雜十三熳環-17(14H)-酮；9-氯-10-氟-7-甲基-7,8,15,16-四氫-6,3-(次氮基亞甲橋基)咪唑并[5,1-f][1,4,7,8,10]苯并氧雜四氮雜十三熳環-17(14H)-酮；9-氯-10-氟-7-甲基-7,8,15,16-四氫-6,3-(次氮基亞甲橋基)咪唑并[5,1-f][1,4,7,10]苯并氧雜三氮雜十三熳環-17(14H)-酮；9-氯-10-氟-7-甲基-7,8,15,16-四氫-3,6-(次氮基亞甲橋基)吡咯并[2,1-f][1,4,7,10]苯并氧雜三氮雜十三熳環-17(14H)-酮；9-氯-10-氟-7-甲基-7,8,15,16-四氫-3,6-(次氮基亞甲橋基)咪唑并[2,1-f][1,4,7,10]苯并氧雜三氮雜十三熳環-17(14H)-酮；9-氯-10-氟-7-甲基-7,8,15,16-四氫-3,6-乙烯橋基[1,2,4]三唑并[3,4-f][1,4,7,8,10]苯并氧雜四氮雜十三熳環-17(14H)-酮；9-氯-10-氟-7-甲基-7,8,15,16-四氫-6,3-(次氮基亞甲橋基)[1,2,4]三唑并[3,4-f][1,4,7,10]苯并氧雜三氮雜十三熳環-17(14H)-酮；8-氯-9-氟-6-甲基-6,7,14,15-四氫-2H-3,5-(次氮基亞甲橋基)吡咯并[3,4-f][1,4,8,10]苯并氧雜三氮雜十三熳環-16(13H)-酮；8-氯-9-氟-6-甲基-6,7,14,15-四氫-2H-3,5-(次氮基亞甲橋基)吡唑并[3,4-f][1,4,8,10]苯并氧雜三氮雜十三熳環-16(13H)-酮；8-氯-9-氟-6-甲基-6,7,14,15-四氫-2H-3,5-(次氮基亞甲橋基)吡唑并[3,4-f][1,4,10]苯并氧雜二氮雜十三熳環-16(13H)-酮；12-氯-11-氟-5,14-二甲基-6,7,13,14-四氫-2H-1,15-(次氮基亞甲橋基)吡咯并[3,4-f][1,4,10]苯并氧雜二氮雜十三熳環-4(5H)-酮；(8R)-10-氟-8,16-二甲基-15,16-二氫-8H-3,6-乙烯橋基咪唑并[5,1-f][1,10,4,7,8]苯并二氧雜三氮雜十三熳環-17(14H)-酮；10-氟-8,16-二甲基-15,16-二氫-8H-3,6-乙烯橋基咪唑并[5,1-f][1,10,4,7,8]苯并二氧雜三氮雜十三熳環-17(14H)-酮；(7R)-9-氟-7,15-二甲基-14,15-二氫-2H,7H-3,5-(次氮基亞甲橋基)吡咯并[3,4-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-16(13H)-酮；及9-氟-7,15-二甲基-14,15-二氫-2H,7H-3,5-(次氮基亞甲橋基)吡咯并[3,4-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-16(13H)-酮；或其醫藥上接受之鹽。 在其他實施例中，式(I)或(I-A)之化合物係選自由以下組成之群：12-氯-11-氟-14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；11-氟-3,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；10-氟-8-甲基-15,16-二氫-8H-3,6-乙烯橋基咪唑并[5,1-f][1,10,4,7,8]苯并二氧雜三氮雜十三熳環-17(14H)-酮；10-氟-7-甲基-7,8,15,16-四氫-3,6-乙烯橋基咪唑并[5,1-f][1,4,7,8,10]苯并氧雜四氮雜十三熳環-17(14H)-酮；14-乙基-11-氟-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；11-氟-14-丙基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；11-氟-14-(丙-2-基)-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；14-環丙基-11-氟-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；11-氟-14-(2-羥乙基)-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；11-氟-6,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；11-氟-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；11-氟-13-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；(13R )-11-氟-13-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；12-氯-11-氟-13-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；11-氟-14-甲基-4-側氧基-4,5,6,7,13,14-六氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-7-甲醯胺；11-氟-7-(羥甲基)-14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；11-氟-13-甲基-4-側氧基-4,5,6,7,13,14-六氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-7-甲醯胺；11-氟-7-(羥甲基)-13-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；11-氟-4-側氧基-4,5,6,7,13,14-六氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-7-甲醯胺；11-氟-7-(羥甲基)-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；11-氟-4-側氧基-4,5,6,7,13,14-六氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-13-甲酸甲酯；11-氟-4-側氧基-4,5,6,7,13,14-六氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-13-甲醯胺；11-氟-14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f]吡啶并[3,2-l][1,4,8,10]氧雜三氮雜十三熳環-4(5H)-酮；11-氟-13-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f]吡啶并[3,2-l][1,4,8,10]氧雜三氮雜十三熳環-4(5H)-酮；11-氟-13-(丙-2-基)-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f]吡啶并[3,2-l][1,4,8,10]氧雜三氮雜十三熳環-4(5H)-酮；13-環丙基-11-氟-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f]吡啶并[3,2-l][1,4,8,10]氧雜三氮雜十三熳環-4(5H)-酮；13-環丙基-11-氟-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；11-氟-13-(丙-2-基)-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；11-氟-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并氧雜硫雜二氮雜十三熳環-4(5H)-酮；11-氟-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并氧雜硫雜二氮雜十三熳環-4(5H)-酮14,14-二氧化物；6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][10,1,4,8]苯并氧雜硫雜二氮雜十三熳環-4(5H)-酮；14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并硫雜三氮雜十三熳環-4(5H)-酮；13-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并硫雜三氮雜十三熳環-4(5H)-酮；11-氟-6,7-二氫-5H-1,15-乙烯橋基吡唑并[3,4-e][11,1,2,4,8]苯并氧雜硫雜三氮雜十三熳環-4(14H)-酮13,13-二氧化物；11-氟-14-甲基-6,7-二氫-5H-1,15-乙烯橋基吡唑并[3,4-e][11,1,2,4,8]苯并氧雜硫雜三氮雜十三熳環-4(14H)-酮13,13-二氧化物；12-氟-15-甲基-5,6,7,8,14,15-六氫-4H-1,16-乙烯橋基吡唑并[4,3-g][1,5,9,11]苯并氧雜三氮雜十四熳環-4-酮；12-氟-14-甲基-5,6,7,8,14,15-六氫-4H-1,16-乙烯橋基吡唑并[4,3-g][1,5,9,11]苯并氧雜三氮雜十四熳環-4-酮；(14R )-12-氟-14-甲基-5,6,7,8,14,15-六氫-4H -1,16-乙烯橋基吡唑并[4,3-g ][1,5,9,11]苯并氧雜三氮雜十四熳環-4-酮；11-氟-7,14-二甲基-4,5,6,7,13,14-六氫-8H-1,15-乙烯橋基吡唑并[3,4-e][2,4,10]苯并三氮雜十三熳環-8-酮；11-氟-7,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[3,4-e][7,2,4,10]苯并氧雜三氮雜十三熳環-8(5H)-酮；11-氟-7,14-二甲基-4,5,6,7,13,14-六氫-8H-1,15-乙烯橋基吡唑并[3,4-e][2,4,7,10]苯并四氮雜十三熳環-8-酮；11-氟-4,7,14-三甲基-4,5,6,7,13,14-六氫-8H-1,15-乙烯橋基吡唑并[3,4-e][2,4,7,10]苯并四氮雜十三熳環-8-酮；11-氟-7,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[3,4-e][7,2,4,10]苯并硫雜三氮雜十三熳環-8(5H)-酮；11-氟-7,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[3,4-e][7,2,4,10]苯并硫雜三氮雜十三熳環-8(5H)-酮4,4-二氧化物；及12-氟-8,15-二甲基-5,6,7,8,14,15-六氫-9H-1,16-乙烯橋基吡唑并[3,4-e][7,2,4,8,11]苯并硫雜四氮雜十四熳環-9-酮4,4-二氧化物；或其醫藥上接受之鹽。 在其他實施例中，式(I)或(I-A)之化合物係選自由以下組成之群：11-氯-13-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；13-乙基-11-氟-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；13-環丁基-11-氟-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；11-氟-14-甲基(6,6,7,7-² H₄ )-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；11-氟-13-苯基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；13-(環丙基甲基)-11-氟-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；(7R ,14R )-12-氟-7-羥基-14-甲基-5,6,7,8,14,15-六氫-4H -1,16-乙烯橋基吡唑并[4,3-g ][1,5,9,11]苯并氧雜三氮雜十四熳環-4-酮；(7S ,14R )-12-氟-7-羥基-14-甲基-5,6,7,8,14,15-六氫-4H -1,16-乙烯橋基吡唑并[4,3-g ][1,5,9,11]苯并氧雜三氮雜十四熳環-4-酮；(7R ,13R )-11-氟-7,13-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；(7S ,13R )-11-氟-7,13-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；(7R )-11-氟-7,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；(6R )-11-氟-6,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；12-氟-7-羥基-15-甲基-5,6,7,8,14,15-六氫-4H -1,16-乙烯橋基吡唑并[4,3-g ][1,5,9,11]苯并氧雜三氮雜十四熳環-4-酮；(7S )-11-氟-7,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；11-氟-13-(羥甲基)-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；12-氟-14-(羥甲基)-5,6,7,8,14,15-六氫-4H -1,16-乙烯橋基吡唑并[4,3-g ][1,5,9,11]苯并氧雜三氮雜十四熳環-4-酮；11-氟-13,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；11-氟-14-(2-羥基-2-甲基丙基)-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；12-氟-5,6,7,8,14,15-六氫-4H -1,16-乙烯橋基吡唑并[4,3-g ][1,5,9]苯并氧雜二氮雜十四熳環-4-酮；11-氟-14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并硫雜三氮雜十三熳環-4(5H )-酮；11-氟-14-(1-甲基吡咯啶-3-基)-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；11-氟-14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并硫雜三氮雜十三熳環-4(5H )-酮8-氧化物；11-氟-14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并硫雜三氮雜十三熳環-4(5H )-酮8,8-二氧化物；(7S )-11-氟-7-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8]苯并氧雜二氮雜十三熳環-4(5H )-酮；(6S ,13R )-11-氟-6,13-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；(6R ,13R )-11-氟-6,13-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；(7S ,13S )-11-氟-13-(羥甲基)-7-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；及11-氟-6,7-二氫-13 H -1,15-乙烯橋基吡唑并[4,3- f ][1,10,4,8]苯并氧雜硫雜二氮雜十三熳環-4(5 H )-酮；或其醫藥上接受之鹽。 在其他實施例中，式(I)或(I-A)之化合物係選自由以下組成之群：(13R)-5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；(13R)-11-氟-5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；(13R)-12-氯-11-氟-5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；(13R)-12-氯-11-氟-5-(2-羥乙基)-13-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；2-[(13R)-12-氯-11-氟-13-甲基-4-側氧基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-5(4H)-基]乙醯胺；(13R)-12-氯-11-氟-13-甲基-5-(吡咯啶-2-基甲基)-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；(13R)-12-氯-11-氟-7-(羥甲基)-5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；(13S)-11-氟-13-(氟甲基)-5-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；(13R)-13-環丙基-11-氟-5-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；(13R)-11-氟-13-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；(13R)-12-氯-11-氟-13-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮；(8R)-9-氯-10-氟-8-甲基-15,16-二氫-8H-3,6-乙烯橋基咪唑并[5,1-f][1,10,4,7,8]苯并二氧雜三氮雜十三熳環-17(14H)-酮；(7R)-8-氯-9-氟-7-甲基-14,15-二氫-2H,7H-3,5-(次氮基亞甲橋基)吡咯并[3,4-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-16(13H)-酮；(5R)-3-氟-5-甲基-14,15-二氫-5H,10H-9,7-(次氮基亞甲橋基)吡啶并[2,3-k]吡咯并[3,4-d][1,10,3,7]二氧雜二氮雜十三熳環-12(13H)-酮；(5R)-3-氟-5,16-二甲基-13,14,15,16-四氫-5H-9,7-(次氮基亞甲橋基)吡啶并[2,3-k]吡咯并[3,4-d][1,3,7,10]氧雜三氮雜十三熳環-12(10H)-酮；(13R)-12-氯-11-氟-5,13-二甲基-6,7-二氫-2H,13H-1,15-(次氮基亞甲橋基)吡咯并[3,4-f][1,10,4]苯并二氧雜氮雜十三熳環-4(5H)-酮；(7R)-8-氯-9-氟-7,15-二甲基-14,15-二氫-2H,7H-3,5-(次氮基亞甲橋基)吡唑并[3,4-f][1,10,4]苯并二氧雜氮雜十三熳環-16(13H)-酮；(13R)-12-氯-11-氟-13,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮；(8R)-10-氟-8,16-二甲基-15,16-二氫-8H-3,6-乙烯橋基咪唑并[5,1-f][1,10,4,7,8]苯并二氧雜三氮雜十三熳環-17(14H)-酮；(7R)-9-氟-7,15-二甲基-14,15-二氫-2H,7H-3,5-(次氮基亞甲橋基)吡咯并[3,4-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-16(13H)-酮；(13R )-11-氟-13-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；(14R )-12-氟-14-甲基-5,6,7,8,14,15-六氫-4H -1,16-乙烯橋基吡唑并[4,3-g ][1,5,9,11]苯并氧雜三氮雜十四熳環-4-酮；(7R ,14R )-12-氟-7-羥基-14-甲基-5,6,7,8,14,15-六氫-4H -1,16-乙烯橋基吡唑并[4,3-g ][1,5,9,11]苯并氧雜三氮雜十四熳環-4-酮；(7S ,14R )-12-氟-7-羥基-14-甲基-5,6,7,8,14,15-六氫-4H -1,16-乙烯橋基吡唑并[4,3-g ][1,5,9,11]苯并氧雜三氮雜十四熳環-4-酮；(7R ,13R )-11-氟-7,13-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；(7S ,13R )-11-氟-7,13-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；(7R )-11-氟-7,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；(6R )-11-氟-6,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；(7S )-11-氟-7,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；(7S )-11-氟-7-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8]苯并氧雜二氮雜十三熳環-4(5H )-酮；(6S ,13R )-11-氟-6,13-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；(6R ,13R )-11-氟-6,13-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；及(7S ,13S )-11-氟-13-(羥甲基)-7-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮；或其醫藥上接受之鹽。 以下代表式(I)或(I-A)之化合物之說明性實施例： 實例 結構 化學名稱 1

(13R)-5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 1-1

5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 2

(13R)-11-氟-5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 2-1

11-氟-5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 3

(13R)-12-氯-11-氟-5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 3-1

12-氯-11-氟-5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 4

(13R)-12-氯-11-氟-5-(2-羥乙基)-13-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 4-1

12-氯-11-氟-5-(2-羥乙基)-13-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 5

2-[(13R)-12-氯-11-氟-13-甲基-4-側氧基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-5(4H)-基]乙醯胺 5-1

2-[12-氯-11-氟-13-甲基-4-側氧基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-5(4H)-基]乙醯胺 6

(13R)-12-氯-11-氟-13-甲基-5-(吡咯啶-2-基甲基)-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 6-1

12-氯-11-氟-13-甲基-5-(吡咯啶-2-基甲基)-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 7

(13R)-12-氯-11-氟-7-(羥甲基)-5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 7-1

12-氯-11-氟-7-(羥甲基)-5,13-二甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 8

(13S)-11-氟-13-(氟甲基)-5-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 8-1

11-氟-13-(氟甲基)-5-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 9

(13R)-13-環丙基-11-氟-5-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 9-1

13-環丙基-11-氟-5-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 10

(13R)-11-氟-13-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 10-1

11-氟-13-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 11

(13R)-12-氯-11-氟-13-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 11-1

12-氯-11-氟-13-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 12

12-氯-11-氟-6-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 13

12-氯-11-氟-7-甲基-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-4(5H)-酮 14

(8R)-9-氯-10-氟-8-甲基-15,16-二氫-8H-3,6-乙烯橋基咪唑并[5,1-f][1,10,4,7,8]苯并二氧雜三氮雜十三熳環-17(14H)-酮 14-1

9-氯-10-氟-8-甲基-15,16-二氫-8H-3,6-乙烯橋基咪唑并[5,1-f][1,10,4,7,8]苯并二氧雜三氮雜十三熳環-17(14H)-酮 15

(7R)-8-氯-9-氟-7-甲基-14,15-二氫-2H,7H-3,5-(次氮基亞甲橋基)吡咯并[3,4-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-16(13H)-酮 15-1

8-氯-9-氟-7-甲基-14,15-二氫-2H,7H-3,5-(次氮基亞甲橋基)吡咯并[3,4-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-16(13H)-酮 16

(5R)-3-氟-5-甲基-14,15-二氫-5H,10H-9,7-(次氮基亞甲橋基)吡啶并[2,3-k]吡咯并[3,4-d][1,10,3,7]二氧雜二氮雜十三熳環-12(13H)-酮 16-1

3-氟-5-甲基-14,15-二氫-5H,10H-9,7-(次氮基亞甲橋基)吡啶并[2,3-k]吡咯并[3,4-d][1,10,3,7]二氧雜二氮雜十三熳環-12(13H)-酮 17

(5R)-3-氟-5,16-二甲基-13,14,15,16-四氫-5H-9,7-(次氮基亞甲橋基)吡啶并[2,3-k]吡咯并[3,4-d][1,3,7,10]氧雜三氮雜十三熳環-12(10H)-酮 17-1

3-氟-5,16-二甲基-13,14,15,16-四氫-5H-9,7-(次氮基亞甲橋基)吡啶并[2,3-k]吡咯并[3,4-d][1,3,7,10]氧雜三氮雜十三熳環-12(10H)-酮 18

(13R)-12-氯-11-氟-5,13-二甲基-6,7-二氫-2H,13H-1,15-(次氮基亞甲橋基)吡咯并[3,4-f][1,10,4]苯并二氧雜氮雜十三熳環-4(5H)-酮 18-1

12-氯-11-氟-5,13-二甲基-6,7-二氫-2H,13H-1,15-(次氮基亞甲橋基)吡咯并[3,4-f][1,10,4]苯并二氧雜氮雜十三熳環-4(5H)-酮 19

(7R)-8-氯-9-氟-7,15-二甲基-14,15-二氫-2H,7H-3,5-(次氮基亞甲橋基)吡唑并[3,4-f][1,10,4]苯并二氧雜氮雜十三熳環-16(13H)-酮 19-1

8-氯-9-氟-7,15-二甲基-14,15-二氫-2H,7H-3,5-(次氮基亞甲橋基)吡唑并[3,4-f][1,10,4]苯并二氧雜氮雜十三熳環-16(13H)-酮 20

11-氟-14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 21

(13R)-12-氯-11-氟-13,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 21-1

12-氯-11-氟-13,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 22

12-氯-11-氟-5,14-二甲基-6,7,13,14-四氫-15,1-(次氮基亞甲橋基)吡唑并[4,3-f][1,4,10]苯并氧雜二氮雜十三熳環-4(5H)-酮 23

12-氯-11-氟-14-甲基-6,7,13,14-四氫-15,1-(次氮基亞甲橋基)吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 24

12-氯-11-氟-14-甲基-6,7,13,14-四氫-1,15-(次氮基亞甲橋基)吡咯并[3,2-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 25

12-氯-11-氟-14-甲基-6,7,13,14-四氫-1,15-(次氮基亞甲橋基)吡咯并[3,2-f][1,4,10]苯并氧雜二氮雜十三熳環-4(5H)-酮 26

9-氯-10-氟-7-甲基-7,8,15,16-四氫-3,6-乙烯橋基咪唑并[5,1-f][1,4,7,8,10]苯并氧雜四氮雜十三熳環-17(14H)-酮 27

9-氯-10-氟-7-甲基-7,8,15,16-四氫-6,3-(次氮基亞甲橋基)咪唑并[5,1-f][1,4,7,8,10]苯并氧雜四氮雜十三熳環-17(14H)-酮 28

9-氯-10-氟-7-甲基-7,8,15,16-四氫-6,3-(次氮基亞甲橋基)咪唑并[5,1-f][1,4,7,10]苯并氧雜三氮雜十三熳環-17(14H)-酮 29

9-氯-10-氟-7-甲基-7,8,15,16-四氫-3,6-(次氮基亞甲橋基)吡咯并[2,1-f][1,4,7,10]苯并氧雜三氮雜十三熳環-17(14H)-酮 30

9-氯-10-氟-7-甲基-7,8,15,16-四氫-3,6-(次氮基亞甲橋基)咪唑并[2,1-f][1,4,7,10]苯并氧雜三氮雜十三熳環-17(14H)-酮 31

9-氯-10-氟-7-甲基-7,8,15,16-四氫-3,6-乙烯橋基[1,2,4]三唑并[3,4-f][1,4,7,8,10]苯并氧雜四氮雜十三熳環-17(14H)-酮 32

9-氯-10-氟-7-甲基-7,8,15,16-四氫-6,3-(次氮基亞甲橋基)[1,2,4]三唑并[3,4-f][1,4,7,10]苯并氧雜三氮雜十三熳環-17(14H)-酮 33

8-氯-9-氟-6-甲基-6,7,14,15-四氫-2H-3,5-(次氮基亞甲橋基)吡咯并[3,4-f][1,4,8,10]苯并氧雜三氮雜十三熳環-16(13H)-酮 34

8-氯-9-氟-6-甲基-6,7,14,15-四氫-2H-3,5-(次氮基亞甲橋基)吡唑并[3,4-f][1,4,8,10]苯并氧雜三氮雜十三熳環-16(13H)-酮 35

8-氯-9-氟-6-甲基-6,7,14,15-四氫-2H-3,5-(次氮基亞甲橋基)吡唑并[3,4-f][1,4,10]苯并氧雜二氮雜十三熳環-16(13H)-酮 36

12-氯-11-氟-5,14-二甲基-6,7,13,14-四氫-2H-1,15-(次氮基亞甲橋基)吡咯并[3,4-f][1,4,10]苯并氧雜二氮雜十三熳環-4(5H)-酮 37

(8R)-10-氟-8,16-二甲基-15,16-二氫-8H-3,6-乙烯橋基咪唑并[5,1-f][1,10,4,7,8]苯并二氧雜三氮雜十三熳環-17(14H)-酮 37-1

10-氟-8,16-二甲基-15,16-二氫-8H-3,6-乙烯橋基咪唑并[5,1-f][1,10,4,7,8]苯并二氧雜三氮雜十三熳環-17(14H)-酮 38

(7R)-9-氟-7,15-二甲基-14,15-二氫-2H,7H-3,5-(次氮基亞甲橋基)吡咯并[3,4-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-16(13H)-酮 38-1

9-氟-7,15-二甲基-14,15-二氫-2H,7H-3,5-(次氮基亞甲橋基)吡咯并[3,4-f][1,10,4,8]苯并二氧雜二氮雜十三熳環-16(13H)-酮 及其醫藥上可接受之鹽。 以下代表式(I)或(I-A)之化合物之說明性實施例： 實例 結構 化學名稱 39

12-氯-11-氟-14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 40

11-氟-3,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 41

10-氟-8-甲基-15,16-二氫-8H-3,6-乙烯橋基咪唑并[5,1-f][1,10,4,7,8]苯并二氧雜三氮雜十三熳環-17(14H)-酮 42

10-氟-7-甲基-7,8,15,16-四氫-3,6-乙烯橋基咪唑并[5,1-f][1,4,7,8,10]苯并氧雜四氮雜十三熳環-17(14H)-酮 43

14-乙基-11-氟-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 44

11-氟-14-丙基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 45

11-氟-14-(丙-2-基)-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 46

14-環丙基-11-氟-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 47

11-氟-14-(2-羥乙基)-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 48

11-氟-6,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 49

14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 50

11-氟-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 51

11-氟-13-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 51-1

(13R )-11-氟-13-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮 52

12-氯-11-氟-13-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 53

11-氟-14-甲基-4-側氧基-4,5,6,7,13,14-六氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-7-甲醯胺 54

11-氟-7-(羥甲基)-14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 55

11-氟-13-甲基-4-側氧基-4,5,6,7,13,14-六氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-7-甲醯胺 56

11-氟-7-(羥甲基)-13-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 57

11-氟-4-側氧基-4,5,6,7,13,14-六氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-7-甲醯胺 58

11-氟-7-(羥甲基)-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 59

11-氟-4-側氧基-4,5,6,7,13,14-六氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-13-甲酸甲酯 60

11-氟-4-側氧基-4,5,6,7,13,14-六氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-13-甲醯胺 61

11-氟-14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f]吡啶并[3,2-l][1,4,8,10]氧雜三氮雜十三熳環-4(5H)-酮 62

11-氟-14-(丙-2-基)-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f]吡啶并[3,2-l][1,4,8,10]氧雜三氮雜十三熳環-4(5H)-酮 63

11-氟-13-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f]吡啶并[3,2-l][1,4,8,10]氧雜三氮雜十三熳環-4(5H)-酮 64

11-氟-13-(丙-2-基)-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f]吡啶并[3,2-l][1,4,8,10]氧雜三氮雜十三熳環-4(5H)-酮 65

13-環丙基-11-氟-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f]吡啶并[3,2-l][1,4,8,10]氧雜三氮雜十三熳環-4(5H)-酮 66

13-環丙基-11-氟-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 67

11-氟-13-(丙-2-基)-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮 68

11-氟-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并氧雜硫雜二氮雜十三熳環-4(5H)-酮 69

11-氟-6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][1,10,4,8]苯并氧雜硫雜二氮雜十三熳環-4(5H)-酮14,14-二氧化物 70

6,7-二氫-13H-1,15-乙烯橋基吡唑并[4,3-f][10,1,4,8]苯并氧雜硫雜二氮雜十三熳環-4(5H)-酮 71

14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并硫雜三氮雜十三熳環-4(5H)-酮 72

13-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并硫雜三氮雜十三熳環-4(5H)-酮 73

11-氟-6,7-二氫-5H-1,15-乙烯橋基吡唑并[3,4-e][11,1,2,4,8]苯并氧雜硫雜三氮雜十三熳環-4(14H)-酮13,13-二氧化物 74

11-氟-14-甲基-6,7-二氫-5H-1,15-乙烯橋基吡唑并[3,4-e][11,1,2,4,8]苯并氧雜硫雜三氮雜十三熳環-4(14H)-酮13,13-二氧化物 75

12-氟-15-甲基-5,6,7,8,14,15-六氫-4H-1,16-乙烯橋基吡唑并[4,3-g][1,5,9,11]苯并氧雜三氮雜十四熳環-4-酮 76

12-氟-14-甲基-5,6,7,8,14,15-六氫-4H-1,16-乙烯橋基吡唑并[4,3-g][1,5,9,11]苯并氧雜三氮雜十四熳環-4-酮 76-1

(14R )-12-氟-14-甲基-5,6,7,8,14,15-六氫-4H -1,16-乙烯橋基吡唑并[4,3-g ][1,5,9,11]苯并氧雜三氮雜十四熳環-4-酮 77

11-氟-7,14-二甲基-4,5,6,7,13,14-六氫-8H-1,15-乙烯橋基吡唑并[3,4-e][2,4,10]苯并三氮雜十三熳環-8-酮 78

11-氟-7,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[3,4-e][7,2,4,10]苯并氧雜三氮雜十三熳環-8(5H)-酮 79

11-氟-7,14-二甲基-4,5,6,7,13,14-六氫-8H-1,15-乙烯橋基吡唑并[3,4-e][2,4,7,10]苯并四氮雜十三熳環-8-酮 80

11-氟-4,7,14-三甲基-4,5,6,7,13,14-六氫-8H-1,15-乙烯橋基吡唑并[3,4-e][2,4,7,10]苯并四氮雜十三熳環-8-酮 81

11-氟-7,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[3,4-e][7,2,4,10]苯并硫雜三氮雜十三熳環-8(5H)-酮 82

11-氟-7,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[3,4-e][7,2,4,10]苯并硫雜三氮雜十三熳環-8(5H)-酮4,4-二氧化物 83

12-氟-8,15-二甲基-5,6,7,8,14,15-六氫-9H-1,16-乙烯橋基吡唑并[3,4-e][7,2,4,8,11]苯并硫雜四氮雜十四熳環-9-酮4,4-二氧化物 及其醫藥上可接受之鹽。 以下代表式(I)或(I-A)之化合物之說明性實施例： 實例 結構 化學名稱 84

11-氯-13-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮    85

13-乙基-11-氟-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮 86

13-環丁基-11-氟-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮 87

11-氟-14-甲基(6,6,7,7-² H₄ )-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮 88

11-氟-13-苯基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮 89

13-(環丙基甲基)-11-氟-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮 90

(7R ,14R )-12-氟-7-羥基-14-甲基-5,6,7,8,14,15-六氫-4H -1,16-乙烯橋基吡唑并[4,3-g ][1,5,9,11]苯并氧雜三氮雜十四熳環-4-酮 91

(7S ,14R )-12-氟-7-羥基-14-甲基-5,6,7,8,14,15-六氫-4H -1,16-乙烯橋基吡唑并[4,3-g ][1,5,9,11]苯并氧雜三氮雜十四熳環-4-酮 92

(7R ,13R )-11-氟-7,13-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮 93

(7S ,13R )-11-氟-7,13-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮 94

(7R )-11-氟-7,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮 95

(6R )-11-氟-6,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮 96

12-氟-7-羥基-15-甲基-5,6,7,8,14,15-六氫-4H -1,16-乙烯橋基吡唑并[4,3-g ][1,5,9,11]苯并氧雜三氮雜十四熳環-4-酮 97

(7S )-11-氟-7,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮 98

11-氟-13-(羥甲基)-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮 99

12-氟-14-(羥甲基)-5,6,7,8,14,15-六氫-4H -1,16-乙烯橋基吡唑并[4,3-g ][1,5,9,11]苯并氧雜三氮雜十四熳環-4-酮 100

11-氟-13,14-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮 101

11-氟-14-(2-羥基-2-甲基丙基)-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮 102

11-氟-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8]苯并氧雜二氮雜十三熳環-4(5H )-酮 103

12-氟-5,6,7,8,14,15-六氫-4H -1,16-乙烯橋基吡唑并[4,3-g ][1,5,9]苯并氧雜二氮雜十四熳環-4-酮 104

11-氟-14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并硫雜三氮雜十三熳環-4(5H )-酮 105

11-氟-14-(1-甲基吡咯啶-3-基)-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮 106

11-氟-14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并硫雜三氮雜十三熳環-4(5H )-酮8-氧化物 107

11-氟-14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并硫雜三氮雜十三熳環-4(5H )-酮8,8-二氧化物 108

(7S )-11-氟-7-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8]苯并氧雜二氮雜十三熳環-4(5H )-酮 109

(6S ,13R )-11-氟-6,13-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮 110

(6R ,13R )-11-氟-6,13-二甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮 111

(7S ,13S )-11-氟-13-(羥甲基)-7-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f ][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H )-酮 112

11-氟-6,7-二氫-13 H -1,15-乙烯橋基吡唑并[4,3- f ][1,10,4,8]苯并氧雜硫雜二氮雜十三熳環-4(5 H )-酮 及其醫藥上可接受之鹽。 彼等熟悉此項技術者將意識到，本文所列示或說明之種類並不詳盡，且亦可選擇在該等所定義術語範圍內之其他種類。 醫藥組合物 出於治療目的，包含本文所述化合物之醫藥組合物可進一步包含一或多種醫藥上可接受之賦形劑。醫藥上可接受之賦形劑係無毒性且其他方面生物上適用於投與個體之物質。該等賦形劑促進本文所述化合物之投與且與活性成份相容。醫藥上可接受之賦形劑之實例包括穩定劑、潤滑劑、表面活性劑、稀釋劑、抗氧化劑、黏合劑、著色劑、增量劑、乳化劑或味道修飾劑。在較佳實施例中，本發明之醫藥組合物係無菌組合物。醫藥組合物可使用已知或熟悉此項技術者可用之混合技術製備。 本發明亦涵蓋無菌組合物，包括符合管控該等組合物之國家及地方法規之組合物。 本文所述之醫藥組合物及化合物可根據此項技術中已知製備各種劑型之習用方法調配成於適宜醫藥溶劑或載劑中之溶液、乳液、懸浮液或分散液，或作為丸劑、錠劑、菱形錠劑、栓劑、藥囊、糖衣丸、顆粒、粉末、重構粉末或膠囊連同固體載劑。本發明之醫藥組合物可藉由適宜遞送途徑(例如經口、非經腸、經直腸、經鼻、局部或經眼途徑或藉由吸入)投與。較佳地，組合物經調配用於經靜脈內或口服投與。 對於口服投與，本發明之化合物可以固體形式(例如錠劑或膠囊)、或作為溶液、乳液或懸浮液提供。為製備口服組合物，本發明化合物可經調配以獲得(例如)約0.1 mg至1 g每天、或約1 mg至50 mg每天、或約50 mg至250 mg每天、或約250 mg至1 g每天。口服錠劑可包括活性成份與相容醫藥上接受之賦形劑之混合物，例如稀釋劑、崩解劑、黏合劑、潤滑劑、甜味劑、矯味劑、著色劑及防腐劑。適宜惰性填充劑包括碳酸鈉及碳酸鈣、磷酸鈉及磷酸鈣、乳糖、澱粉、糖、葡萄糖、甲基纖維素、硬脂酸鎂、甘露醇、山梨醇及諸如此類。實例性液體口服賦形劑包括乙醇、甘油、水及諸如此類。澱粉、聚乙烯基吡咯啶酮(PVP)、羥乙酸澱粉鈉、微晶纖維素及海藻酸係實例性崩解劑。黏合劑可包括澱粉及明膠。潤滑劑(若存在)可為硬脂酸鎂、硬脂酸或滑石粉。若期望，錠劑可經材料(例如單硬脂酸甘油酯或二硬脂酸甘油酯)塗覆以延遲在胃腸道中之吸收，或可經腸溶包衣塗覆。 口服投與之膠囊包括硬質及軟質明膠膠囊。為製備硬質明膠膠囊，活性成份可與固體、半固體或液體稀釋劑混合。軟質明膠膠囊可藉由將活性成份與水、油(例如花生油或橄欖油)、液體石蠟、短鏈脂肪酸之單及二甘油酯之混合物、聚乙二醇400或丙二醇。 經口投與之液體可呈(例如)懸浮液、溶液、乳液或糖漿之形式，或可凍乾或呈現為在使用前與水或其他適宜媒劑重構之乾產物。該等液體組合物可視情況含有：醫藥上可接受之賦形劑，例如懸浮劑(例如，山梨醇、甲基纖維素、海藻酸鈉、明膠、羥乙基纖維素、羧甲基纖維素、硬脂酸鋁凝膠及諸如此類)；非水性媒劑，例如油(例如，杏仁油或分餾椰子油)、丙二醇、乙醇或水；防腐劑(例如，對羥基苯甲酸甲酯或對羥基苯甲酸丙酯或山梨酸)；潤濕劑，例如卵磷脂；及若期望，矯味劑或著色劑。 對於非經腸使用(包括經靜脈內、經肌內、經腹膜內、經鼻內或皮下途徑)，本發明試劑可以無菌水溶液或懸浮液形式提供，其經緩衝至適當pH且等滲或於非經腸可接受油中。適宜水性媒劑包括林格氏溶液(Ringer's solution)及等滲氯化鈉。該等形式可以單位劑量形式(例如安瓿或可棄式注射裝置)、多劑量形式(例如可自其去除適當劑量之小瓶)或以可用於製備可注射調配物之固體形式或預濃縮物呈現。說明性注射劑量在於數分鐘至數天範圍內之時期約1至1000 μg/kg/分鐘藥劑與醫藥載劑之混合物。 對於經鼻吸入或口服投與而言，本發明醫藥組合物可使用(例如)亦含有適宜載劑之噴霧調配物來投與。本發明組合物可經調配作為栓劑用於直腸投與。 對於局部投與而言，本發明化合物較佳調配成乳霜或軟膏或適用於局部投與之類似媒劑。對於局部投與而言，本發明化合物可與醫藥載劑以約0.1%至約10%藥物對媒劑之濃度混合。投與本發明藥劑之另一方式可利用貼片調配物來實施經皮遞送。 如本文所用，術語「治療(treat, treatment)」涵蓋「預防性」及 「治癒性」治療二者。「預防性」治療意欲指延遲疾病、疾病症狀或醫學狀況之發展、抑制可出現之症狀或降低疾病或症狀發展或復發之風險。「治癒性」治療包括降低現有疾病、症狀或病況之嚴重性或抑制其惡化。因此，治療包括改善現有疾病症狀或阻止其惡化、阻止其他症狀出現、改善或預防症狀之潛在系統性病因、抑制病症或疾病(例如阻滯病症或疾病之發展、減輕病症或疾病、使病症或疾病消退、減輕由疾病或病症造成之狀況或終止疾病或病症之症狀)。 術語「個體」係指需要該治療之哺乳動物患者，例如人類。 實例性疾病包括癌症、疼痛、神經疾病、自體免疫疾病及發炎。癌症包括(例如)肺癌、結腸癌、乳癌、前列腺癌、肝細胞癌、腎細胞癌、胃及食管癌、神經膠質母細胞瘤、頭頸癌、發炎性肌纖維母細胞腫瘤及間變性大細胞淋巴瘤。疼痛包括(例如)任一源或病因之疼痛，包括癌症疼痛、化學治療之疼痛、神經疼痛、損傷疼痛或其他源。自體免疫疾病包括(例如)類風濕性關節炎、休格倫氏症候群(Sjogren syndrome)、I型糖尿病及狼瘡。實例性神經疾病包括阿爾茨海默病(Alzheimer’s Disease), 帕金森氏病(Parkinson’s Disease), 肌萎縮性側束硬化症及亨廷頓氏病(Huntington’s disease)。實例性發炎疾病包括動脈粥樣硬化、過敏及因感染或損傷而發炎。 在一個態樣中，本發明之化合物及醫藥組合物特定靶向酪胺酸受體激酶、具體而言MET、ALK、AXL、TRK及JAK。因此，該等化合物及醫藥組合物可用於阻止、逆轉、減緩或抑制該等激酶中之一或多者之活性。在較佳實施例中，治療方法靶向癌症。在其他實施例中，方法用於治療肺癌或非小細胞肺癌。 在本發明之抑制方法中，「有效量」意指有效抑制靶標蛋白質之量。該等靶標調節量測可藉由常規分析方法(例如彼等下文所述者)實施。該調節可用於各種設置中，包括活體外分析。在該等方法中，細胞較佳係由於MET、ALK、AXL、TRK及/或JAK上調具有異常信號傳導之癌症細胞。 在本發明之治療方法中，「有效量」意指足以在需要改治療之個體中產生期望治療益處之量或劑量。本發明化合物之有效量或計量可藉由常規方法(例如模型化、劑量遞增或臨床試驗)慮及常規因素(例如投與或藥物遞送之模式或途徑、藥劑之藥代動力學、感染之嚴重程度及過程、個體之健康狀況及體重、及治療醫師之判斷)來確定。實例性劑量係在約0.1 mg至1 g每天、或約1 mg至50 mg每天、或約50 mg至250 mg每天或約250 mg至1 g每天之範圍內。總劑量可以單一或分開劑量單位(例如，BID、TID、QID)。 在患者之疾病發生改善後，可調整劑量以便預防性或維持性治療。例如，可根據症狀將投與劑量或投與頻率或二者降低至維持期望治療或預防效應之量。當然，若症狀已減輕至適當程度，則可停止治療。然而，任一症狀復發時，患者可能需要長期間歇治療。患者亦可需要長期緩慢治療。 藥物組合 本文所述之本發明化合物可與一或多種其他活性成份組合用於醫藥組合物或方法中以治療本文所述之疾病及病症。其他額外活性成份包括其他治療劑或緩和治療劑針對預期疾病靶標之不利效應之藥劑。該等組合可用於增加功效，改善其他疾病症狀，降低一或多種負效應，或降低本發明化合物之所需劑量。額外活性成份可調配成與本發明化合物分開之醫藥組合物或可與本發明化合物包括在單一醫藥組合物中。額外活性成份可與本發明化合物之投與同時、在其之前或在其之後投與。 組合藥劑包括彼等已知或觀察到在治療本文所述疾病及病症中有效之額外活性成份，包括彼等有效針對於疾病相關之另一靶標者。舉例而言，本發明之組合物及調配物、以及治療方法可進一步包含其他藥劑或醫藥，例如其他可用於治療或緩解目標疾病或相關症狀或狀況之活性劑。對於癌症適應症而言，其他該等藥劑包括(但不限於)激酶抑制劑，例如EGFR抑制劑(例如，埃羅替尼(erlotinib)、吉非替尼(gefitinib))；Raf抑制劑(例如，維羅非尼(vemurafenib))、VEGFR抑制劑(例如，舒尼替尼(sunitinib))；標準化學治療劑，例如烷基化劑、抗代謝物、抗腫瘤抗生素、拓撲異構酶抑制劑、鉑藥物、有絲分裂抑制劑、抗體、激素療法或皮質類固醇。對於疼痛適應症而言，適宜組合藥劑包括消炎劑，例如NSAID。本發明之醫藥組合物可另外包含一或多種該等活性劑，且治療方法可另外包含投與有效量之一或多種該等活性劑。 化學合成 現將參考下文用於其一般製備之說明性合成方案及下文特定實例來闡述可用於本發明方法中之實例性化學實體。熟悉此項技術者將認識到，為獲得本文之各種化合物，可適宜地選擇起始材料，以使最終期望取代基將經由在具或不具有適當保護之反應方案攜載以產生期望產物。另一選擇為，可能需要或期望採用可經由反應方案攜載且在適當時經期望取代基替代之適宜基團來替代最終期望取代基。而且，熟悉此項技術者將認識到，以下方案中所示之轉化可以與具體側基之官能性相容之任何順序實施。一般方案中所描繪反應中之每一者較佳在約0℃至所用有機溶劑之回流溫度之溫度下實施。除非另有說明，否則變量係如上文參考式(I)所定義。本文所述之同位素標記化合物係根據下文所述之方法使用適當標記之起始材料來製備。該等材料一般可自放射性標記之化學試劑之商業供應商獲得。 一般方法A：

將瞭解，式A或A-1化合物可根據一般方法A使用適當官能化起始材料及中間體來製得。 步驟1. 可在適當溫度(例如0℃)下向適當官能化之化合物A-1 (約1.00 eq.)(其中R^A 及R^B 係與本文所述之反應條件相容之基團且Nu係親核基團，例如陰離子或能夠形成親核試劑之基團(例如鹵化物))存於能夠促進A-1 與A-2 之偶合的試劑(例如酸(例如TfOH (0.6 M))或烷基鹵化物(例如n-BuLi))中之溶液中添加A-2 (其中R^C 係與本文所述之反應條件相容之基團且X² 係(例如)離去基團)(約1.00 eq.)。可將混合物在適當溫度(例如60℃)下攪拌，直至反應完成為止。然後可使反應返回至環境溫度，且可使反應混合物驟冷，中和，洗滌，萃取，乾燥及/或視需要在真空下濃縮，獲得A-3 。 步驟2. 可將A-3 (其中R^A 、R^B 及R^C 係與本文所述之反應條件相容之基團)(在本文所述之一些實例性實施例中，A-3可為市售醛或酮，或A-3 可自步驟1製得，約1.00 eq.)與市售胺A-4 (其中R^C 係與本文所述之反應條件相容之基團) (約1.50 eq.)於適當溶劑(例如甲醇(0.5 M))中之混合物在適當溫度(例如環境溫度)下攪拌適當時間量或直至藉由TLC或LC-MS亞胺形成完成為止。可向反應溶液中逐部分添加還原劑(例如NaBH₄ (約2.00 eq.))。可將混合物在適當溫度(例如環境溫度)下攪拌，直至TLC或LC-MS顯示反應完成為止。反應可經驟冷，洗滌，萃取，乾燥及或視需要在真空下濃縮，以提供A-5 。 步驟3. 經製備或市售A-5 (其中R^A 、R^B 及R^C 係與本文所述之反應條件相容之基團) (約1 eq.)、市售5-氯吡唑并[1,5-a]嘧啶-3-甲酸乙酯(A-6 ，約1 eq.)及適當鹼(例如二異丙基乙胺(約5 eq.))於適當溶劑(例如丁醇(0.4 M))中之混合物可在適當溫度(例如110℃)下攪拌設定時間長度或直至反應顯示完成為止。反應可返回至環境溫度並視需要用水稀釋。混合物可經萃取，洗滌，乾燥，在減壓下濃縮及/或視需要藉由層析方法純化，以提供A 。 在一些實例性方法中，一般方法A可如下實施：

步驟1. 可於0℃下向A-1 (1.00 eq.)於TfOH (0.6 M)中之溶液中添加A-2 (1.00 eq.)。可將混合物於60℃下攪拌4小時或直至反應完成為止。冷卻至環境溫度之後，可將反應混合物傾倒於冰-水(w/w = 1/1)中，用NaHCO₃ 中和至pH約9，並視需要用EtOAc萃取三次。合併之有機層可用鹽水洗滌，視需要經無水Na₂ SO₄ 乾燥，並濃縮以獲得A-3 。 步驟2. 可將A-3 (市售醛或酮、或自步驟1製備，1.00 eq.)及市售胺A-4 (1.50 eq.)於甲醇(0.5 M)中之混合物於環境溫度下攪拌2小時或藉由TLC或LC-MS顯示亞胺形成完成為止。可向反應溶液中逐部分添加NaBH₄ (2.00 eq.)。可將混合物於環境溫度下攪拌，直至TLC或LC-MS顯示反應完成為止。可將反應用水驟冷並視需要用二氯甲烷萃取三次。可將合併之有機相用鹽水洗滌，利用無水Na₂ SO₄ 乾燥，過濾並在真空中濃縮以獲得A-5 。 步驟3. 可將所製備或市售A-5 (1 eq.)、5-氯吡唑并[1,5-a]嘧啶-3-甲酸乙酯(A-6 , 1 eq.)及二異丙基乙胺(5 eq.)於丁醇(0.4 M)中於110℃下加熱30分鐘或直至反應顯示完成為止。反應可經冷卻並用水稀釋。混合物可用二氯甲烷萃取四次(視需要)且合併之萃取物可經無水硫酸鈉乾燥。過濾後，混合物可在減壓下濃縮且殘餘物可經由急驟層析純化，以提供A 。 替代一般方法A：

偶合步驟1. 可將適當官能化之AA-1 (約1.00 eq.)、適當官能化之乙烯基偶合試劑(約1.00-1.50 eq.)及鈀觸媒(約0.05 eq.)之混合物在適當反應條件下在惰性氣氛下加熱至適當溫度(例如約90℃)達適當時間量，直至TLC指示起始材料完全消耗為止。可視需要將反應混合物傾倒於H₂ O中。可將混合物萃取且將有機相洗滌，乾燥，濃縮，並視需要經由矽膠管柱層析純化，以獲得AA-2 。 偶合步驟2. 可將AA-2 型化合物(約1.00 eq.)、5-氯吡唑并[1,5-a]嘧啶-3-甲酸乙酯(A-6 , 約1.00 eq.)及鈀觸媒在適當反應條件下在惰性氣氛下加熱至適當溫度(例如120℃)達適當時間長度，直至TLC指示起始材料完全消耗為止。可視需要將反應混合物傾倒於H₂ O中。可將混合物萃取且有機相可經洗滌，乾燥，濃縮，並視需要經由矽膠管柱層析純化，以獲得AA-3 。 步驟3. 在適當溫度下在惰性氣氛下向AA-3 (約1.00 eq.)及4-甲基苯磺醯肼(呈莫耳過量)於適宜溶劑中之混合物中添加適當鹼(呈莫耳過量)。可將混合物加熱至適當溫度(例如65℃)並攪拌適當時間量，直至TLC指示反應完成為止。可將混合物冷卻並視需要在減壓下濃縮。可視需要將經濃縮反應混合物用水稀釋，並萃取。合併之有機相可經洗滌，乾燥，過濾，在真空中濃縮，並純化以獲得AA-4 。 一般方法B：

步驟1. 可將醛B-1 (約1.0 eq)(其中R^A 及R^B 係與本文所述之反應條件相容之基團)、B-2 (約1.0 eq) (其中X¹ 係離去基團且PG係保護基團)、適宜鹼(呈莫耳過量)及觸媒於適宜溶劑中之溶液加熱並攪拌適當時間量，直至反應完成為止。可添加額外的B-2 且視需要進一步加熱。可將混合物冷卻至環境溫度並視需要用水稀釋。混合物可經萃取，且合併之萃取物可經洗滌，乾燥，並視需要在減壓下濃縮。可經由急驟層析純化粗製反應產物，以提供B-3 。 步驟2. 可將存於適當溶劑中之醛B-3 (約1.0 eq)及適當官能化之胺(約2.0-4.0 eq)(其中R^C 係與本文所述之反應條件相容之基團)加熱並攪拌適當時間量。可將混合物冷卻至環境溫度且可添加適宜還原劑(約1.0 eq)。可將混合物攪拌適當時間量，然後視需要藉由添加水驟冷。混合物可利用適當有機溶劑萃取，且合併之萃取物可經洗滌，乾燥並視需要在減壓下濃縮。可視需要經由急驟層析純化粗製反應產物，以提供B-4 。 步驟3. 可將存於適宜溶劑中之化合物B-4 (約1.0 eq)、5-氯吡唑并[1,5-a]嘧啶-3-甲酸乙酯(A-6 , 約1.0 eq)及適宜鹼(呈莫耳過量)加熱適宜時間量。反應可經冷卻並視需要用水稀釋。混合物可利用適宜有機溶劑萃取，且合併之萃取物可經乾燥並視需要在減壓下濃縮。可經由急驟層析純化粗製反應產物，以提供B1 。 在一些實例性方法中，一般方法B可如下實施：

步驟1. 可將醛B-1 (約1.0 eq)(其中R^A 及R^B 係與本文所述之反應條件相容之基團)、B-2 (約1.0 eq)(其中X¹ 係離去基團且PG係保護基團)、碳酸鉀(呈莫耳過量)及碘化鉀(催化量)於DMF中之溶液加熱至60℃並攪拌約15小時。可添加額外氯化物B-2 且可視需要進一步於80℃下加熱，直至反應顯示完成為止。可將混合物冷卻至環境溫度並視需要藉由添加水(250 mL)稀釋。混合物可利用乙酸乙酯(3 × 300 mL)萃取且合併之萃取物可用水(200 mL)及鹽水(100 mL)洗滌，可利用硫酸鈉乾燥，並視需要在減壓下濃縮。可經由急驟層析純化粗製反應產物，以提供B-3 。 步驟2. 可將存於甲醇中之醛B-3 (約1.0 eq)及甲胺(約2.5 eq)加熱至60℃並攪拌約1小時。可將混合物冷卻至環境溫度且可添加硼氫化鈉(約1.0 eq)。可將混合物攪拌約30分鐘，然後視需要藉由添加水(200 mL)驟冷。混合物可用二氯甲烷萃取且合併之萃取物可利用鹽水(50 mL)洗滌，可經硫酸鈉乾燥並視需要在減壓下濃縮。可經由急驟層析純化粗製反應產物，以提供B-4 。 步驟3. 可將存於丁醇中之胺B-4 (約1.0 eq)、5-氯吡唑并[1,5-a]嘧啶-3-甲酸乙酯(A-6 , 約1.0 eq)及hünig鹼(呈莫耳過量)於110℃下加熱約25分鐘。反應可經冷卻並用水(250 mL)稀釋。混合物可用二氯甲烷萃取且合併之萃取物可視需要用硫酸鈉乾燥。混合物可視需要在減壓下濃縮。可經由急驟層析純化粗製反應產物，以提供B 。 一般方法C

步驟1. 可向C-1 (約1.0 eq.) (其中R^A 、R^B 、R^C 、R^D 及R^E 係與本文所述之反應條件相容之基團)、X¹ AlkNHPG (約1.5-2.0 eq.) (其中X¹ 係離去基團，Alk係適當官能化之烷基且PG係保護基團)於適宜溶劑中之溶液中添加適宜鹼(約3.0 eq.)。可將混合物在惰性氣氛下加熱至適當溫度達適當時間量，直至LC-MS顯示起始材料完全轉化為產物。可將混合物冷卻至環境溫度，用水稀釋並視需要用適宜有機溶劑萃取。合併之有機萃取物可用水及鹽水洗滌，經Na₂ SO₄ 乾燥，並視需要濃縮。所得殘餘物可視需要經由矽膠管柱層析純化，以獲得C-2 。 步驟2. 可向C-2 (1 eq.) (其中R^A 、R^C 、R^D 及R^E 係與本文所述之反應條件相容之基團，Alk係適當官能化之烷基且PG係保護基團)於適宜溶劑中之溶液添加適宜鹼(呈莫耳過量)。可將溶液加熱至適當溫度達適當時間量。反應可利用適宜酸中和至pH＜5，且反應混合物可用適宜有機溶劑萃取。合併之有機物可經洗滌且可視需要經乾燥。粗製反應產物混合物可經過濾，在減壓下濃縮，並視需要在高真空下乾燥以提供C-3 。 步驟3. 可在適當溫度(例如0℃)下向C-3 (約1.0 eq.)於適宜有機溶劑中之溶液添加適宜酸(約4 eq.)。可將反應混合物在適當溫度下攪拌適當時間量，直至藉由LC-MS顯示反應完成為止。粗製產物可經過濾，洗滌，且可在高真空下乾燥，以提供C-4 。 步驟4a. 可向C-4 (約1.0 eq.)於適宜溶劑中之溶劑中添加適宜鹼(呈莫耳過量)。可將溶液於冰水浴中冷卻且可添加適宜偶合劑(約1.5 eq.)以產生經活化酯。可將溶液緩慢升溫至環境溫度並攪拌，直至藉由LC-MS 顯示起始材料轉化為期望產物為止。混合物可用水稀釋並視需要用適宜有機溶劑萃取。合併之有機萃取物可經洗滌，乾燥，並視需要在減壓下濃縮。所得殘餘物可藉由矽膠管柱層析純化，以獲得C 。 在一些實例性方法中，一般方法C可如下實施：

步驟1. 可向C-1 (約1.0 eq.)(其中R^A 、R^B 、R^C 、R^D 及R^E 係與本文所述之反應條件相容之基團)、X¹ AlkNHPG (約1.5-2.0 eq.) (其中X¹ 係離去基團，Alk係適當官能化之烷基且PG係保護基團)於DMF (0.5 M)中之溶液中添加K₂ CO₃ (約3.0 eq.)。可將混合物於約80℃下加熱約2小時或直至藉由LC-MS可顯示起始材料完全轉化為產物為止。可將混合物冷卻至環境溫度，視需要用水稀釋並視需要用EtOAc萃取三次。然後，合併之有機層可用水及鹽水洗滌，可經Na₂ SO₄ 乾燥，並視需要濃縮。所得殘餘物可經由矽膠管柱層析用EtOAc/己烷(5-100%, 10CV)溶析來純化，以獲得C-2 。 步驟2. 可向C-2 (約1 eq.)於甲醇/THF/H2O (3:1:1, 0.2M)中之溶液中添加LiOH.H2O (約5.0 eq.)。可將溶液於約70℃下加熱約2小時。可將反應於約0℃下利用HCl水溶液(2 M)中和至pH＜5，並視需要用CH₂ Cl₂ 萃取四次。合併之有機萃取物可用鹽水洗滌，且視需要可經Na₂ SO₄ 乾燥。粗製產物混合物可經過濾，在減壓下濃縮，並視需要在高真空下乾燥，以提供C-3 。 步驟3. 可於約0℃下向C-3 (約1.0 eq.)於CH₂ Cl₂ (0.25 M)中之溶液添加於二噁烷中之HCl (4 M, 約4 eq.)。可將反應攪拌並允許自0℃升溫至室溫達約27小時或直至藉由LC-MS可顯示反應完成為止。所得反應混合物可經過濾，用CH₂ Cl₂ 洗滌，並視需要在高真空下乾燥，以提供C-4 。 步驟4a. 利用HATU環化。可向C-4 (約1.0 eq.)於約10 mL DMF (約0.005 M)中之溶液中添加DIPEA (約5.0 eq.)。將溶液於冰水浴中冷卻且可添加HATU (約1.5 eq.)。可使溶液升溫至環境溫度並攪拌直至藉由LC-MS可顯示起始材料完全轉化為期望產物之時。混合物可用水稀釋並視需要用EtOAc萃取三次。合併之有機相可用水及鹽水洗滌，經Na₂ SO₄ 乾燥，並視需要在減壓下濃縮。所得殘餘物可經由矽膠管柱層析(0-5% MeOH/DCM)純化，以獲得C 。 步驟4b. 利用FDPP環化. 可向DIPEA (約5 eq.)於DMF/CH₂ Cl₂ (3:1, 約0.005M)中之溶液中添加C-4 (約1.00 eq.)。C-4 完全溶解之後，可添加二苯基次膦酸五氟苯基酯(FDPP, 約1.05 eq.)。可允許將偶合攪拌30分鐘或直至藉由LC-MS顯示反應完成之時。反應溶液可利用CH₂ Cl₂ 稀釋，用水、Na₂ CO₃ 水溶液(2 M)及鹽水洗滌三次，可視需要經Na₂ SO₄ 乾燥。過濾及在減壓下濃縮之後，殘餘物可經由矽膠管柱層析利用MeOH/CH₂ Cl₂ (0-5%)溶析來純化，以提供C 。 實例 提供以下實例以說明而非限制本發明。熟悉此項技術者將認識到，以下合成反應及方案可藉由選擇適宜起始材料及試劑經修改以獲得其他式(I)或(I-A)化合物。用於合成方法中之具有適宜官能性之雙環雜芳香族市面有售。縮寫 本文所述實例使用各種材料，包括(但不限於)彼等由以下熟悉此項技術者已知之縮寫所述者： 縮寫 名稱 TLC 薄層層析 PLC 製備型液體層析 HPLC 高效液體層析 LCMS、LC-MS 液體層析質譜 LRESIMS 低解析度電噴霧離子化質譜 ELISA 酶聯免疫分析 DCM 二氯甲烷 DMSO 二甲基亞碸 DIPEA, DIEA 二異丙基乙胺 CDI 1,1'-羰基二咪唑 THF 四氫呋喃 XantPhos 4,5-雙(二苯基膦基)-9,9-二甲基呫噸 TBSCl 第三丁基二甲基矽基氯化物 DMF N,N-二甲基甲醯胺 HATU 六氟磷酸1-[雙(二甲基胺基)亞甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物鹽 ACN 乙腈 EtOAc 乙酸乙酯 DTAD 偶氮二羧酸二第三丁基酯 FDFF 二苯基次膦酸五氟苯基酯 FBS 胎牛血清 BSA 牛血清白蛋白 PBS 磷酸鹽緩衝鹽水 DMEM 杜貝克氏改良鷹氏培養基(Dulbecco’s modified eagle medium) EDTA 乙二胺四乙酸 RIPA 放射免疫沈澱分析 HEPES (4-(2-羥乙基)-1-哌嗪乙磺酸) 實例 A6

步驟1. 於16℃下在N₂ 下向5-氟-2-羥基苯甲醛(500.00 mg, 3.57 mmol, 1.00 eq.)於MeOH (20.00 mL)中之溶液一次性添加1-甲基吡咯啶-3-胺(357.43 mg, 3.57 mmol, 1.00 eq.)。將混合物於16℃下於N₂ 下攪拌10小時。然後，添加NaBH₄ (270.00 mg, 7.14 mmol, 2.00 eq.)並將混合物於16℃下在N₂ 下攪拌6小時。TLC (DCM:MeOH=15:1)顯示反應完成。將反應混合物在減壓下濃縮以移除MeOH。使用水(50 mL)稀釋殘餘物並使用DCM (20 mL × 3)萃取。將合併之有機層用鹽水(50 mL)洗滌，經Na₂ SO₄ 乾燥，過濾並在減壓下濃縮，以獲得呈黃色固體之A6-5 (350.00 mg, 1.56 mmol, 43.71%產率)。¹ HNMR (300 MHz, DMSO-d ₆ ) δ 6.94 (dd,J =2.7, 9.3 Hz, 1H), 6.86 (dt,J =3.0, 8.6 Hz, 1H), 6.67 (dd,J =4.7, 8.7 Hz, 1H), 3.71 (s, 2H), 3.24 - 3.09 (m, 1H), 2.58 (dd,J =7.1, 8.8 Hz, 1H), 2.48 - 2.32 (m, 2H), 2.30 - 2.17 (m, 4H), 2.05 - 1.82 (m, 1H), 1.60 - 1.43 (m, 1H)。 步驟2. 於16℃下在N₂ 下向A6-5 (300.00 mg, 1.34 mmol, 1.00 eq.)及5-氯吡唑并[1,5-a]嘧啶-3-甲酸乙酯(302.34 mg, 1.34 mmol, 1.00 eq.)於n-BuOH (40.00 mL)中之溶液添加DIPEA (1.04 g, 8.04 mmol, 6.00 eq.)。將混合物於120℃下攪拌2小時。TLC (PE: EtOAc =1:1)顯示反應已完成。將混合物傾倒於水(50 mL)中並藉由DCM (50 mL×3)萃取。將混合物藉由Pre-PLC純化，以獲得呈白色固體之A6甲酸鹽(290.00 mg, 701.43 umol, 52.35%產率)。實例 A8

向5-氯吡唑并[1,5-a]嘧啶-3-甲酸乙酯(1.25 g, 5.54 mmol)及(R )-2-(1-胺基乙基)-4-氟苯酚HCl鹽(自NetChem公司購得)於EtOH (15.83 mL)中之溶液添加Hunig鹼(3.58 g, 27.70 mmol)並加熱至70℃達1.5小時。將反應旋轉蒸發至乾燥，懸浮於水中，並用DCM (5 x 50 mL)萃取。將合併之萃取物經Na₂ SO₄ 乾燥，且在減壓下濃縮。急驟層析(ISCO系統，二氧化矽(40 g)，0-5%甲醇於二氯甲烷中)提供A8 (1.89 g, 5.49 mmol, 99%產率)。實例 A9

步驟1. 於0℃下向4-氟苯酚(2.00 g, 17.84 mmol, 1.00 eq.)於TfOH (30.00 mL)中之溶液添加丙醯氯(1.65 g, 17.84 mmol, 1.00 eq.)。將混合物於60℃下攪拌4小時。TLC顯示反應完成。將混合物冷卻至25℃，傾倒於冰-水(w/w = 1/1) (120 mL)中，用NaHCO₃ 中和以使得pH為約9，並用EtOAc (120 mL×3)萃取。將合併之有機層藉由鹽水(50 mL)洗滌，利用無水Na₂ SO₄ 乾燥，並濃縮以獲得呈無色油狀物之A9-3 (1.80 g, 10.70 mmol, 59.98%產率)。¹ HNMR (400 MHz, CDCl₃ ) δ 12.09 (s, 1H), 7.45 (dd,J =3.0, 9.0 Hz, 1H), 7.26 - 7.20 (m, 1H), 6.97 (dd,J =4.5, 9.0 Hz, 1H), 3.02 (q,J =7.3 Hz, 2H), 1.27 (t,J =7.2 Hz, 3H)。 步驟2. 於-78℃下將氨氣鼓泡於MeOH (20 mL)中達10分鐘。將A9-3 (1.00 g, 5.95 mmol, 1.00 eq.)添加至溶液並於25℃下攪拌1小時。向反應混合物中添加Ti(i-PrO)₄ (1.63 g, 7.14 mmol, 1.20 eq.)，並將混合物再攪拌1小時。然後，添加NaBH₄ (449.93 mg, 11.89 mmol, 2.00 eq.)。將混合物於25℃下攪拌12小時。TLC顯示起始材料完全消耗。將殘餘物傾倒於水(50 mL)中並攪拌30分鐘。將混合物過濾且濾液用HCl (1 M)調整至pH約1並用EtOAc (50 mL×2)萃取。將碳酸氫鈉添加至水相以調整pH為約9並用DCM (50 mLx2)萃取。將合併之有機層用飽和鹽水(50 mL)洗滌，利用無水Na₂ SO₄ 乾燥，過濾並在真空中濃縮以獲得呈黃色固體之A9-5 (310.00 mg, 1.83 mmol, 30.79%產率)。¹ HNMR (400 MHz, CDCl₃ )  δ 6.86 (dt,J =3.0, 8.4 Hz, 1H), 6.79 - 6.74 (m, 1H), 6.67 (dd,J =2.9, 8.9 Hz, 1H), 3.98 (t,J =7.0 Hz, 1H), 1.92 - 1.81 (m, 1H), 1.80 - 1.68 (m, 1H), 0.95 (t,J =7.4 Hz, 3H)。 步驟3. 如一般方法A中所述，使A9-5與5-氯吡唑并[1,5-a]嘧啶-3-甲酸乙酯在DIPEA之存在下於n-BuOH中偶合以提供A9。實例 A13-5 ： 2-(1- 胺基 -2- 環丙基乙基 )-4- 氟苯酚 之製備

步驟1. 於25℃下在N₂ 下向2-環丙基乙酸(4.47 g, 44.60 mmol, 1.00 eq.)於DCM (150.00 mL)中之混合物中一次性添加CDI (7.96 g, 49.10 mmol, 1.10 eq.)。將混合物於25℃下攪拌1小時。然後添加N-甲氧基甲胺鹽酸鹽(4.79 g, 49.06 mmol, 1.10 eq.)。將混合物於25℃下再攪拌12小時。將反應用1N鹽酸水溶液(50 mL)驟冷，並分離為各層。水層用DCM (30 mLx2)萃取。合併之有機層用50%飽和碳酸鈉水溶液(50 mL)及飽和鹽水(30 mL)洗滌，利用無水Na₂ SO₄ 乾燥，過濾並在真空中濃縮以獲得呈油狀物之2-環丙基-N -甲氧基-N -甲基乙醯胺(6.00 g, 41.91 mmol, 93.96%產率)。¹ H NMR (400 MHz, CDCl₃ ) δ 3.65 (s, 1H), 3.18 (s, 1H), 2.33 (d,J =6.8 Hz, 2H), 1.13 - 1.02 (m, 1H), 0.57 - 0.49 (m, 2H), 0.19 - 0.11 (m, 2H)。 步驟2. 於-78℃下在N₂ 下向2-環丙基-N -甲氧基-N -甲基乙醯胺(6.00 g, 29.27 mmol, 1.00 eq.)於THF (100.00 mL)中之混合物中逐滴添加n-BuLi (2.5 M, 12.88 mL, 1.10 eq.)。混合物於-78℃下攪拌10分鐘。然後以20分鐘時間，利用於THF (20 mL)中之2-溴-4-氟-1-甲氧基苯(4.19 g, 29.27 mmol, 1.00 eq.)處理混合物。於-78℃下攪拌1小時之後，使混合物升溫至25℃並再攪拌1小時。TLC顯示反應完成。將混合物傾倒於10% HCl水溶液(100 mL)中並攪拌10分鐘。水相用乙酸乙酯(300 mL×3)萃取。將合併之有機相用鹽水(200 mL)洗滌，經無水Na₂ SO₄ 乾燥，過濾並在真空中濃縮。殘餘物藉由矽膠層析(石油醚/乙酸乙酯=50/1, 10/1)純化，獲得呈無色油狀物之2-環丙基-1-(5-氟-2-甲氧基苯基)乙-1-酮(2.4 g, 39.38%產率)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.42 (dd,J =3.3, 8.8 Hz, 1H), 7.15 (ddd,J =3.3, 7.5, 9.0 Hz, 1H), 6.91 (dd,J =4.0, 9.0 Hz, 1H), 3.91 - 3.85 (m, 3H), 2.89 (d,J =6.8 Hz, 2H), 1.18 - 1.05 (m, 1H), 0.61 - 0.50 (m, 2H), 0.20 - 0.09 (m, 2H)。 步驟3. 於-78℃下在N₂ 下向2-環丙基-1-(5-氟-2-甲氧基苯基)乙-1-酮(500.00 mg, 2.40 mmol, 1.00 eq.)於DCM (10.00 mL)中之溶液中逐滴添加BCl₃ (1 M, 3.00 mL, 1.25 eq.)。混合物於-78℃下攪拌2小時。TLC顯示反應完成。將混合物升溫至25℃並傾倒於冰-水(w/w = 1/1) (10 mL)中並攪拌10分鐘。水相用乙酸乙酯(30 mL×3)萃取。合併之有機相用飽和鹽水(30 mL)洗滌，經無水Na₂ SO₄ 乾燥，過濾並在真空中濃縮以獲得呈油狀物之2-環丙基-1-(5-氟-2-羥基苯基)乙-1-酮(430.00 mg, 2.21 mmol, 92.3%產率)。¹ H NMR (400 MHz, CDCl₃ ) δ 12.12 (s, 1H), 7.40 (dd,J =3.0, 8.8 Hz, 1H), 7.24 (ddd,J =3.0, 7.8, 9.0 Hz, 1H), 6.98 (dd,J =4.5, 9.3 Hz, 1H), 2.88 (d,J =6.8 Hz, 2H), 1.23 - 1.11 (m, 1H), 0.70 - 0.63 (m, 2H), 0.25 (q,J =5.0 Hz, 2H)。 步驟4. 於25℃下於N₂ 下向2-環丙基-1-(5-氟-2-羥基苯基)乙-1-酮(400.00 mg, 1.92 mmol, 1.00 eq.)於MeOH (20.00 mL)中之溶液中添加NH₂ OH.HCl (160.18 mg, 2.31 mmol, 1.20 eq.)及AcONa (189.09 mg, 2.31 mmol, 1.20 eq.)達12小時。TLC (石油醚/乙酸乙酯=3:1)顯示起始材料完全消耗。使用水驟冷反應，然後用DCM (30 mL×3)萃取。合併之有機相用鹽水(30 mL)洗滌，經無水Na₂ SO₄ 乾燥，過濾並在真空中濃縮，以獲得呈白色固體之純產物2-環丙基-1-(5-氟-2-羥基苯基)乙-1-酮肟(400.00 mg, 1.79 mmol, 93.32%產率)。固體未經進一步純化即用於下一步驟中。 步驟5. 在N₂ 下向2-環丙基-1-(5-氟-2-羥基苯基)乙-1-酮肟(260.00 mg, 1.16 mmol, 1.00eq. )於MeOH/HCl (10.00 mL, 4N)中之溶液中添加Pd-C (10%, 100 mg)。將懸浮液在真空下脫氣，並使用H₂ 吹掃若干次。將混合物於H₂ (50 psi)下在50℃下攪拌12小時。LC-MS顯示起始材料完全消耗。將反應混合物過濾且濾液濃縮，以獲得呈白色固體之2-(1-胺基-2-環丙基乙基)-4-氟苯酚(200.00 mg, 955.75 umol, 82.39%產率)。¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.44 - 9.82 (m, 1H), 8.52 (br. s., 2H), 7.36 (dd,J =2.8, 9.5 Hz, 1H), 7.07-6.93 (m, 2H), 4.49 (d,J =5.5 Hz, 1H), 1.82-1.72 (m, 2H), 0.67 - 0.55 (m, 1H), 0.43 - 0.28 (m, 2H), 0.12-0.06 (m, 1H), (-0.03)-(-0.09) (m, 1H)。實例 A14-5 ： 2-( 胺基 ( 苯基 ) 甲基 )-4- 氟苯酚之製備

步驟1. 於25℃下在N₂ 下向A14-3 (2.00 g, 9.25 mmol, 1.00 eq.)及AcOK (1.10 g, 11.20 mmol, 1.20 eq.)於乙醇(30.00 mL)中之溶液中一次性添加NH₂ OH.HCl (642.80 mg, 9.25 mmol, 1.00 eq.)。將混合物於25℃下攪拌30分鐘，然後加熱至90℃並攪拌5小時。TLC顯示反應完成。將混合物濃縮且添加水(50 mL)。用乙酸乙酯(50 mL ×3)萃取混合物。將合併之有機相藉由鹽水(50 mL)洗滌，經無水Na₂ SO₄ 乾燥，過濾，並濃縮以獲得呈黃色固體之(5-氟-2-羥基苯基)(苯基)甲酮肟(1.50 g, 6.49 mmol, 70.13%產率)。¹ HNMR (400 MHz, CDCl₃ ) δ 7.50 - 7.37 (m, 5H), 7.19 - 7.07 (m, 2H), 6.71 (dd,J =2.9, 8.9 Hz, 1H)。 步驟2. 於25℃下在N₂ 下向(5-氟-2-羥基苯基)(苯基)甲酮肟(900.00 mg, 4.18 mmol, 1.00 eq.)及Zn粉末(1.09 g, 16.73 mmol, 4 eq.)於THF (10.00 mL)中之混合物中一次性添加NH₄ Cl (2.24 g, 41.82 mmol, 10.00 eq.)。將混合物於25℃下攪拌30分鐘，然後加熱至60℃並攪拌15小時。將混合物濃縮並添加水(100 mL)，隨後用乙酸乙酯(50 mL×3)萃取。合併之有機層藉由鹽水洗滌，經無水Na₂ SO₄ 乾燥，過濾，並濃縮以獲得呈黃色固體之A14-5 (630.00 mg, 2.90 mmol, 69.38%產率)。¹ HNMR (400 MHz, CDCl₃ ) δ 7.42 (d,J =7.5 Hz, 2H), 7.33 (t,J =7.5 Hz, 2H), 7.27 - 7.20 (m, 1H), 6.93 - 6.80 (m, 2H), 6.70 (dd,J =4.9, 8.7 Hz, 1H), 5.28 (s, 1H)。實例 A17

步驟1. 向5-((2-溴-5-氟苄基)(甲基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(根據一般方法A製備) (300.00 mg, 0.736 mmol, 1.00 eq.)、2-甲基丙烷-2-硫醇(166.10 mg, 1.84 mmol, 2.50 eq.)、Pd₂ (dba)₃ (84.72 mg, 0.147 mmol, 0.20 eq.)於二噁烷(8.00 mL)之溶液中添加XantPhos (127.87 mg, 0.221 mmol, 0.30 eq.)及K₂ CO₃ (101.81 mg, 0.736 mmol, 1.00 eq.)。將混合物脫氣並在N₂ 下加熱至120℃達24小時。TLC (石油醚/乙酸乙酯=1:1)顯示起始材料完全消耗。將反應混合物傾倒於H₂ O (20 mL)中並用乙酸乙酯(50 mLx3)萃取。有機相用鹽水(30 mL)洗滌，經無水Na₂ SO₄ 乾燥，濃縮，並藉由矽膠管柱層析(石油醚/乙酸乙酯=2:1至1:1)純化 ，獲得呈黃色固體之5-((2-(第三丁基硫基)-5-氟苄基)(甲基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(200.00 mg, 0.48 mmol, 65.18%產率)。¹ H NMR (400 MHz, CDCl₃ ) δ 8.34 (s, 1H), 8.29 (br. s., 1H), 7.60 (dd,J =5.9, 8.4 Hz, 1H), 7.00 (t,J =7.7 Hz, 1H), 6.29 (br. s., 2H), 5.00 (br. s., 2H), 4.37 (d,J =6.8 Hz, 2H), 3.41 (br. s., 3H), 1.36-1.20 (m, 12H)。 步驟2. 於0℃下在N₂ 下向5-((2-(第三丁基硫基)-5-氟苄基)(甲基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(300.00 mg, 0.720 mmol, 1.00 eq. )於DCM (8.00 mL)中之溶液中逐滴添加BBr₃ (902.21 mg, 3.60 mmol, 5.00 eq.)。將反應混合物於0℃下攪拌2.5小時。TLC (石油醚: 乙酸乙酯=1:1)顯示反應完成。將混合物傾倒於水(20 mL)中。將水相用二氯甲烷(50 mL×3)萃取。將合併之有機相用鹽水(30 mL)洗滌，經無水Na₂ SO₄ 乾燥，過濾並在真空中濃縮。殘餘物藉由pre-HPLC (管柱：Phenomenex Synergi C18 150*30mm*4um且條件：0.05% HCl-ACN)純化並凍乾，以獲得呈白色固體之A17 HCl鹽(38.00 mg, 0.098 mmol, 13.61%產率)。實例 A18

步驟1. 將2-溴-4-氟苯酚(10.00 g, 52.36 mmol, 1.00 eq.)、三氟(乙烯基)-硼烷鉀鹽(9.84 g, 66.50 mmol, 1.27 eq.)、Cs₂ CO₃ (51.18 g, 157.08 mmol, 3.00 eq.)及Pd(PPh₃ )₂ Cl₂ (1.84 g, 2.62 mmol, 0.05 eq.)於THF (90.00 mL)及H₂ O (10.00 mL)中之混合物脫氣且然後在N₂ 下加熱至90℃達12小時。TLC (石油醚/乙酸乙酯=10/1)顯示起始材料完全消耗。將反應混合物傾倒於H₂ O (100 mL)中。混合物用乙酸乙酯(300 mL × 3)萃取。將有機相用飽和鹽水(200 mL)洗滌，經無水Na₂ SO₄ 乾燥，濃縮，並利用矽膠管柱層析(藉由EtOAc/石油醚=1/30溶析)純化，以獲得呈無色油狀物之4-氟-2-乙烯基苯酚(3.50 g, 25.34 mmol, 48.39%產率)。¹ H NMR (400 MHz, CDCl₃ ) δ 7.12 (dd,J =3.0, 9.5 Hz, 1H), 6.89 - 6.81 (m, 1H), 6.79 - 6.73 (m, 1H), 5.75 (d,J =17.6 Hz, 1H), 5.64 (s, 1H), 5.39 (d,J =11.3 Hz, 1H)。 步驟2. 在N₂ 下將4-氟-2-乙烯基苯酚(1.95 g, 14.12 mmol, 1.00eq. )、TBSCl (6.38 g, 42.35 mmol, 3.00 eq.)及1H-咪唑(5.77 g, 84.70 mmol, 6.00 eq.)於DCM (20.00 mL)中之混合物於20℃下攪拌5小時。TLC (石油醚/乙酸乙酯=10:1)顯示起始材料完全消耗。將反應混合物傾倒於H₂ O (30 mL)中。用二氯甲烷(50 mLx3)萃取混合物。有機相用鹽水(50 mL)洗滌，經無水Na₂ SO₄ 乾燥，濃縮，並藉由矽膠管柱層析用石油醚溶析來純化，以獲得呈無色油狀物之三丁基(4-氟-2-乙烯基苄基)矽烷(2.30 g, 9.11 mmol, 64.54%產率)。 步驟3. 將三丁基(4-氟-2-乙烯基苄基)矽烷(2.30 g, 9.11 mmol, 1.00 eq.)、5-氯吡唑并[1,5-a]嘧啶-3-甲酸乙酯(2.06 g, 9.11 mmol, 1.00 eq.)、Pd(PhCN)₂ Cl₂ (118.20 mg, 0.455.63 mmol, 0.05 eq.)及叁-鄰甲苯基磷烷(277.36 mg, 0.911 mmol, 0.10 eq.)、DIPEA (7.07 g, 54.68 mmol, 6.00 eq.)於DMF (25.00 mL)中之混合物脫氣且然後在N₂ 下加熱至120℃達24小時。TLC (石油醚/乙酸乙酯=1:1)顯示起始材料完全消耗。將反應混合物傾倒於H₂ O (30 mL)中。混合物用乙酸乙酯(100 mL × 3)萃取。The 有機相用飽和鹽水(30 mL)洗滌，經無水Na₂ SO₄ 乾燥，濃縮，並藉由矽膠管柱層析(EtOAc: 石油醚=1:3)純化，以獲得呈白色固體之(E )-5-(5-氟-2-羥基苯乙烯基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(1.00 g, 2.26 mmol, 24.86%產率)。¹ H NMR (400 MHz, CDCl₃ ) δ 9.29 (br. s., 1H), 8.50 (d,J =7.0 Hz, 1H), 8.28 (br. s., 1H), 7.84 (d,J =16.6 Hz, 1H), 7.20 - 7.04 (m, 3H), 6.69 (d,J =5.8 Hz, 2H), 4.20 (q,J =6.9 Hz, 2H), 1.30 - 1.19 (m, 3H)。 步驟4. 於20℃在N₂ 下向(E )-5-(5-氟-2-羥基苯乙烯基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(378.22 mg, 1.04 mmol, 1.00 eq.)及4-甲基苯磺醯肼(3.29 g, 17.68 mmol, 17.00 eq.)於THF (4.00 mL)中之混合物中一次性添加NaOAc (1.71 g, 20.80 mmol, 20.00 eq.)。然後將混合物加熱至65℃並攪拌12小時。TLC顯示反應完成。將混合物冷卻至20℃並於45℃下在減壓下濃縮。將水(100 mL)添加至殘餘物。水相用乙酸乙酯(300 mLx2)萃取。合併之有機相用飽和鹽水(50 mL)洗滌，利用無水Na₂ SO₄ 乾燥，過濾，在真空中濃縮，並藉由pre-HPLC (管柱：Phenomenex Synergi Max-RP 250*50 mm*10 um，0.225%FA-ACN)純化，以獲得呈白色固體之A18 (120.00 mg, 0.347 mmol, 33.42%產率)。實例 A20

向4-氟-2-甲基胺基甲基-苯酚(305.2 mg, 1.97 mmol)及6-氯-咪唑并[1,2-b]噠嗪-3-甲酸乙酯(230 mg, 1.02 mmol)於DMSO (5 mL)中之混合物中添加KF (180 mg, 3.01 mmol)。將反應混合物於120℃下在氮氣下攪拌18小時。然後將溶液冷卻至環境溫度，用水(20 mL)稀釋並用EtOAc (3 x 50 mL)萃取。合併之有機相進一步用水(3 × 50 mL)及鹽水(50 mL)洗滌，經Na₂ SO₄ 乾燥並濃縮。然後將殘餘物藉由矽膠管柱用EtOAc/己烷(0-50%, 10 CV)溶析來純化，以獲得呈白色固體之期望產物 (240 mg, 69%)。實例 A22

A22-1係根據一般方法A合成。向A22-1 (150 mg, 0.387 mmol)於乙醇(2 mL)中之溶液中添加4M於二噁烷中之HCl (2 mL)並將反應溶液於75℃下加熱2小時。將溶劑蒸發且殘餘物用Et3N中和，並於矽膠筒上用甲醇/CH₂ Cl₂ (0-12.5%)溶析來純化，以提供A22 (144 mg, 100%)。實例 A23

步驟1. 向(5-氟-2-甲氧基苯基)甲硫醇(496.1 mg, 2.88 mmol)及6-氯-咪唑并[1,2-b]噠嗪-3-甲酸乙酯(650.0 mg, 2.88 mmol)於乙醇(14.4 mL)中之混合物中添加DIPEA (1.12 g, 8.64 mmol)。將反應混合物於80℃下攪拌1小時。將反應混合物冷卻至環境溫度，用水(50 mL)稀釋並用DCM(3 × 50 mL)萃取。合併之萃取物經Na₂ SO₄ 乾燥，並在減壓下濃縮。殘餘物用急驟層析(ISCO系統、二氧化矽(120 g)用EtOAc/己烷(0-50%)溶析來純化，以獲得A23-2 (560 mg, 54%產率)。在純化期間A23-2 自管柱析出。 步驟2. 向A23-2 ( 498.7 mg, 1.38 mmol)於甲醇(100 mL)中之溶液中添加4M於二噁烷中之HCl (10 mL)並將反應溶液於75℃下加熱2小時。將溶劑蒸發且殘餘物用Et3N中和，並於矽膠筒上利用甲醇/CH₂ Cl₂ (0-12.5%)溶析來純化，以提供A23 (470 mg, 98%)。 A1-A24係根據一般方法A及本文所述之方法製備。 實例 結構 名稱 分析數據 A1

5-((5-氟-2-羥基苄基)(甲基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 345.2 (M+H)⁺ ；¹ H NMR (500 MHz, 氯仿-d ) δ 9.71 (bs, 1H), 8.32 (d,J = 7.9 Hz, 1H), 8.30 (s, 1H), 6.98 - 6.87 (m, 3H), 6.37 (d,J = 7.9 Hz, 1H), 4.82 (s, 2H), 4.42 (q,J = 7.1 Hz, 2H), 3.21 (s, 3H), 1.39 (t,J = 7.1 Hz, 3H)。 A2

5-(乙基(5-氟-2-羥基苄基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 359.3 (M+H)⁺ ；¹ H NMR (300 MHz, 氯仿-d ) δ 9.75 (bs, 1H), 8.30 - 8.27 (m, 2H), 6.95 - 6.86 (m, 3H), 6.34 (d,J = 7.9 Hz, 1H), 4.79 (s, 2H), 4.40 (q,J = 7.2 Hz, 2H), 3.56 (q,J = 7.2 Hz, 2H), 1.38 (t,J = 7.2 Hz, 3H), 1.25 (t,J = 7.2 Hz, 3H)。 A3

5-((5-氟-2-羥基苄基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 331.3 (M+H)⁺ ；¹ H NMR (300 MHz, 氯仿-d ) δ 9.61 (bs, 1H), 8.52 (d,J = 7.5 Hz, 1H), 8.28 (bt,J = 5.1 Hz, 1H), 8.13 (s, 1H), 7.25 - 7.23 (m, 1H), 6.93 - 6.86 (m, 1H), 6.81 - 6.77 (m, 1H), 6.44 (d,J = 7.5 Hz, 1H), 4.51 (d,J = 5.1 Hz, 2H), 4.20 (q,J = 6.9 Hz, 2H), 1.39 (t,J = 6.9 Hz, 3H)。 A4

5-((2-羥基苄基)(甲基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 327.5 (M+H)⁺ ；¹ H NMR (300 MHz, 氯仿-d ) δ 9.79 (s, 1H), 8.30 - 8.27 (m, 2H), 7.26 - 7.21 (m, 2H), 6.96 (d,J = 7.8 Hz, 1H), 6.84 (t,J = 7.5 Hz, 1H), 6.34 (d,J = 8.1 Hz, 1H), 4.85 (s, 2H), 4.42 (q,J = 6.9 Hz, 2H), 3.18 (s, 3H), 1.40 (t,J = 6.9 Hz, 3H)。 A5

5-((5-氟-2-羥基苄基)(2-羥基-2-甲基丙基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 403.2 (M+H)⁺ ；¹ H NMR (400 MHz, 氯仿-d ) δ 8.32 (s, 1H), 8.26 (d,J =8.0 Hz, 1H), 7.05 - 6.80 (m, 3H), 6.59 (br. s., 1H), 5.06 (br. s., 2H), 4.43 (q,J =7.1 Hz, 2H), 3.62 (br. s., 2H), 1.60 (s, 1H), 1.46 - 1.36 (m, 9H)。 A6

5-((5-氟-2-羥基苄基)(1-甲基吡咯啶-3-基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 414.2 (M+H)⁺ ；¹ H NMR (400 MHz, 氯仿-d ) δ 8.67 (br. s., 2H), 8.35 (d,J =8.0 Hz, 1H), 8.24 (s, 1H), 7.14 - 7.07 (m, 1H), 6.83 (dt,J =2.8, 8.4 Hz, 1H), 6.73 (br. s., 1H), 6.60 (br. s., 1H), 5.13 (br. s., 1H), 4.75 - 4.62 (m, 2H), 4.34 (q,J =6.9 Hz, 2H), 3.88 (br. s., 3H), 3.41 (br. s., 1H), 3.04 (br. s., 3H), 2.54 (br. s., 2H), 1.40 (t,J =7.2 Hz, 3H)。 A7

5-((1-(5-氟-2-羥基苯基)乙基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 345.3 (M+H)⁺ ；¹ H NMR (300 MHz, 氯仿-d ) δ 9.61 (bs, 1H), 8.24 (s, 1H), 8.17 (d,J = 7.2 Hz, 1H), 6.96 - 6.91 (m, 2H), 6.88 - 6.81 (m, 1H), 6.09 (d,J = 7.8 Hz, 1H), 5.72 - 5.63 (m, 1H), 5.45 (bd,J = 8.7 Hz, 1H), 4.43 (q,J = 7.2 Hz, 2H), 1.64 (d,J = 6.9 Hz, 3H), 1.41 (t,J = 7.2 Hz, 3H)。 A8

(R)-5-((1-(5-氟-2-羥基苯基)乙基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 345.2 (M+H)⁺ . A9

5-((1-(5-氟-2-羥基苯基)丙基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 359.2 (M+H)⁺ ；¹ H NMR (400 MHz, 氯仿-d ) δ 8.99 (br. s., 1H), 8.27 (s, 1H), 8.20 (d,J =7.5 Hz, 1H), 6.98 (dd,J =5.0, 8.8 Hz, 1H), 6.94 - 6.84 (m, 2H), 6.13 (d,J =7.5 Hz, 1H), 5.41 (br. s., 2H), 4.57 - 4.40 (m, 2H), 2.11 - 1.95 (m, 2H), 1.44 (t,J =7.2 Hz, 3H), 1.02 (t,J =7.4 Hz, 3H)。 A10

5-((1-(5-氟-2-羥基苯基)-2-甲基丙基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 373.2 (M+H)⁺ ；¹ H NMR (400 MHz, 氯仿-d ) δ 8.25 (s, 1H), 8.19 (d,J =7.5 Hz, 1H), 6.99 (dd,J =5.1, 8.7 Hz, 1H), 6.91 - 6.81 (m, 2H), 6.14 (d,J =7.5 Hz, 1H), 5.11 (t,J =9.7 Hz, 1H), 4.62 - 4.37 (m, 2H), 2.22 (qd,J =6.5, 17.1 Hz, 1H), 1.43 (t,J =7.2 Hz, 3H), 1.22 (d,J =6.5 Hz, 3H), 0.89 (d,J =6.5 Hz, 3H)。 A11

5-((環丙基(5-氟-2-羥基苯基)甲基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 371.2 (M+H)⁺ ；¹ H NMR (400 MHz, 氯仿-d ) δ 8.25 (s, 1H), 8.21 (d,J =7.5 Hz, 1H), 7.13 (dd,J =3.0, 9.4 Hz, 1H), 7.00 - 6.94 (m, 1H), 6.91 - 6.84 (m, 1H), 6.14 (d,J =7.7 Hz, 1H), 5.69 (d,J =8.0 Hz, 1H), 4.70 (t,J =8.3 Hz, 1H), 4.49 - 4.38 (m, 2H), 1.42 (t,J =7.1 Hz, 4H), 0.83 - 0.74 (m, 1H), 0.72 - 0.63 (m, 1H), 0.57 (qd,J =4.8, 9.6 Hz, 1H), 0.48 - 0.40 (m, 1H)。 A12

5-((環丁基(5-氟-2-羥基苯基)甲基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 385.2 (M+H)⁺ ；¹ H NMR (400 MHz, 氯仿-d ) δ 9.09 (br. s., 1H), 8.27 (s, 1H), 8.20 (d,J =7.5 Hz, 1H), 6.98 (dd,J =5.0, 8.8 Hz, 1H), 6.91 - 6.78 (m, 2H), 6.12 (d,J =7.5 Hz, 1H), 5.45 (t,J =9.4 Hz, 1H), 5.27 (d,J =8.4 Hz, 1H), 4.51 - 4.45 (m, 2H), 2.98 - 2.89 (m, 1H), 2.29 (dd,J =3.8, 7.5 Hz, 1H), 2.07 - 1.90 (m, 4H), 1.75 - 1.66 (m, 1H), 1.45 (t,J =7.1 Hz, 3H)。 A13

5-((2-環丙基-1-(5-氟-2-羥基苯基)乙基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 385.2 (M+H)⁺ ；¹ H NMR (400 MHz, 氯仿-d ) δ 9. 00 (br. s., 1H), 8.27 (s, 1H), 8.19 (d,J =7.5 Hz, 1H), 7.00 - 6.82 (m, 3H), 6.15 (d,J =7.5 Hz, 1H), 5.57 (br. s., 2H), 4.52 - 4.40 (m, 2H), 2.01 - 1.77 (m, 2H), 1.44 (t,J =7.2 Hz, 3H), 0.72 (d,J =6.5 Hz, 1H), 0.56 - 0.41 (m, 2H), 0.24 - 0.07 (m, 2H)。 A14

5-(((5-氟-2-羥基苯基)(苯基)甲基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 407.2 (M+H)⁺ ；¹ H NMR (400 MHz, 氯仿-d ) δ 9.66 (s, 1H), 8.64 - 8.55 (m, 2H), 8.16 (s, 1H), 7.33 (d,J =4.4 Hz, 4H), 7.25 (qd,J =4.3, 8.5 Hz, 1H), 7.11 (dd,J =3.1, 9.7 Hz, 1H), 6.98 - 6.91 (m, 1H), 6.88 - 6.78 (m, 2H), 6.58 (d,J =7.5 Hz, 1H), 4.18 (q,J =7.0 Hz, 2H), 1.30 (t,J =7.1 Hz, 4H)。 A15

5-((1-(5-氯-2-羥基苯基)乙基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 361.2 (M+H)⁺ ；¹ H NMR (400 MHz, 氯仿-d ) δ 9.42 (br. s., 1H), 8.27 (s, 1H), 8.20 (d,J =7.5 Hz, 1H), 7.28 (s, 1H), 7.25 (d,J =2.5 Hz, 1H), 7.13 (dd,J =2.5, 8.8 Hz, 1H), 6.95 (d,J =8.5 Hz, 1H), 6.11 (d,J =7.5 Hz, 1H), 5.75 - 5.64 (m, 1H), 5.46 (d,J =8.3 Hz, 1H), 4.52 - 4.40 (m, 2H), 1.68 (d,J =6.8 Hz, 3H), 1.61 (s, 2H), 1.44 (t,J =7.2 Hz, 3H)。 A16

5-((1-(5-氟-2-羥基苯基)乙基)(甲基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 359.2 (M+H)⁺ ；¹ H NMR (400 MHz, 氯仿-d ) δ 9.61 (s, 1H), 8.35 - 8.29 (m, 2H), 7.08 - 7.03 (m, 1H), 6.92 (dd,J =1.3, 6.1 Hz, 2H), 6.45 (q,J =6.9 Hz, 1H), 6.35 (d,J =7.9 Hz, 1H), 4.51 - 4.36 (m, 2H), 3.00 (s, 3H), 1.65 (d,J =7.0 Hz, 3H), 1.41 (t,J =7.2 Hz, 3H)。 A17

5-((5-氟-2-巰基苄基)(甲基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 361.2 (M+H)⁺ ；¹ H NMR (400 MHz, 氯仿-d ) δ 9.19 (br. s., 1H), 9.09 (d,J =7.3 Hz, 1H), 8.51 (s, 1H), 7.91 - 7.81 (m, 2H), 7.48 (dt,J =2.8, 8.5 Hz, 1H), 7.14 (d,J =7.3 Hz, 1H), 4.29 (br. s., 2H), 4.18 (q,J =7.0 Hz, 2H), 2.56 (br. s., 3H), 1.16 (t,J =7.2 Hz, 3H)。 A18

5-(5-氟-2-羥基苯乙基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 330.2 (M+H)⁺ ；¹ H NMR (400 MHz, 氯仿-d ) δ 9.42 (s, 1H), 9.14 (d,J =7.0 Hz, 1H), 8.55 (s, 1H), 7.18 (d,J =7.0 Hz, 1H), 7.05 (dd,J =3.0, 9.5 Hz, 1H), 6.86 - 6.80 (m, 1H), 6.79 - 6.74 (m, 1H), 4.30 (q,J =7.2 Hz, 2H), 3.21 - 3.13 (m, 2H), 3.06 - 2.99 (m, 2H), 1.33 (t,J =7.2 Hz, 3H)。 A19

5-((5-氟-2-羥基苄基)(甲基)胺基)-2-甲基吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 359.2 (M+H)⁺ . A20

6-((5-氟-2-羥基苄基)(甲基)胺基)咪唑并[1,2-b]噠嗪-3-甲酸乙酯 MS: 345.2 (M+H)⁺ ；¹ H NMR (500 MHz, 氯仿-d ) δ 8.61 (s, 1H), 8.17 (s, 1H), 7.91 (d,J = 10.0 Hz, 1H), 7.00 - 6.86 (m, 4H), 4.78 (s, 2H), 4.47 (qd,J = 7.2, 0.5 Hz, 2H), 3.17 (s, 3H), 1.41 (td,J = 7.1, 0.5 Hz, 3H)。 A21

5-(((5-氟-2-羥基吡啶-3-基)甲基)(甲基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 346.2 (M+H)⁺ . A22

5-(((5-氟-2-羥基吡啶-3-基)甲基)(異丙基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 374.2 (M+H)⁺ . A23

5-((5-氟-2-羥基苄基)硫基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 348.2 (M+H)⁺ . A24

5-((1-(5-氟-2-羥基苯基)-2-羥乙基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 361.2 (M+H)⁺ . 實例 B7

步驟1. 向1-(5-氟-2-羥基-苯基)-乙酮(773 mg, 5.0 mmol)及(2-氯-乙基)-胺基甲酸第三丁基酯(1.80 g, 10.0 mmol)於DMF (20 mL)中之混合物中添加KI (2.0 mg, 0.012 mmol)及Cs₂ CO₃ (3.26 g, 10.0 mmol)。將混合物在80℃下攪拌過夜。然後將混合物冷卻至環境溫度，用EtOAc稀釋，並用1N NaOH (5 x 10 mL)洗滌，直至LCMS顯示無1-(5-氟-2-羥基-苯基)-乙酮峰為止。將有機層經Na₂ SO₄ 乾燥並濃縮。然後將殘餘物藉由矽膠管柱用EtOAc/己烷(0-30%, 10 CV)溶析來純化，以獲得呈黃色固體之期望產物B7-2 (1.1 g, 73.8%)：LC-MS (ESI)m/z 320.3 (M+Na)⁺ 。 步驟2. 向B7-2 (1.0 g, 3.36 mmol)於MeOH (10 mL)中之溶液中逐份添加NaBH₄ (640 mg, 16.8 mmol)。將混合物於環境溫度下攪拌2小時，直至藉由LCMS起始材料無剩餘為止。然後將溶液用水(50 mL)稀釋並用DCM (3 × 20 mL)萃取。合併之DCM層經Na₂ SO₄ 乾燥並濃縮。殘餘物藉由矽膠管柱用EtOAc/己烷(0-50%, 10 CV)溶析來純化，以獲得呈淺黃色固體之期望產物B7-3 (0.75g, 75%)。LC-MS (ESI)m/z 322.3 (M+Na)⁺ ；¹ H NMR (500 MHz, 氯仿-d ) δ 7.11 (dd,J = 9.2, 3.4 Hz, 1H), 6.89 (ddd,J = 9.0, 7.9, 3.2 Hz, 1H), 6.77 (dd,J = 8.9, 4.4 Hz, 1H), 5.09 (q,J = 6.6 Hz, 1H), 4.92 (d,J = 4.4 Hz, 1H), 4.03 (t,J = 5.2 Hz, 2H), 3.62 - 3.50 (m, 2H), 1.49 (d,J = 6.4 Hz, 3H), 1.45 (s, 9H)。 步驟3：於-78℃下向B7-3 (600 mg, 2.0 mmol)及{2-[4-氟-2-(1-羥基-乙基)-苯氧基]-乙基}-胺基甲酸第三丁基酯(450 mg, 2.0 mmol)於無水THF (40.0 mL)中之溶液中分部分添加NaH (60%, 80 mg, 2.0 mmol)。將懸浮液於-78℃下攪拌4小時並使其升溫至0℃並再攪拌4小時。然後將混合物置於冰箱中於-20℃下過夜。LC-MS顯示至期望產物之良好轉化。然後將混合物用冰及1N HCl之混合物驟冷並用EtOAc (3 x 20 mL)萃取。有機層經Na₂ SO₄ 乾燥，濃縮並純化兩次，以獲得呈黃色固體之期望產物B7 (240 mg, 25%)： B1-B7係根據一般方法B及本文所述之方法製備。 實例 結構 名稱 分析數據 B1

5-((2-(2-((第三丁氧基羰基)胺基)乙氧基)-5-氟苄基)(甲基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 488.3.1 (M+H)⁺ ；¹ H NMR (500 MHz, 氯仿-d ) δ 8.30 (s, 1H), 8.26 (s, 1H), 6.92 (td,J = 8.6, 3.3 Hz, 1H), 6.83 - 6.76 (m, 1H), 6.31 (s, 1H), 4.93 (s, 2H), 4.51 - 4.44 (m, 1H), 4.36 (q,J = 7.2 Hz, 2H), 4.03 (t,J = 4.9 Hz, 2H), 3.69 - 3.63 (m, 1H), 3.51 (s, 2H), 3.30 (s, 2H), 1.44 (s, 9H), 1.41 - 1.35 (t,J = 7.2 Hz, 3H)。 B2

5-((2-(2-((第三丁氧基羰基)胺基)乙氧基)-5-氟苄基)(乙基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 502.2 (M+H)⁺ . B3

5-((2-(2-((第三丁氧基羰基)胺基)乙氧基)-5-氟苄基)(丙基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 516.3 (M+H)⁺ . B4

5-((2-(2-((第三丁氧基羰基)胺基)乙氧基)-5-氟苄基)(環丙基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 514.2 (M+H)⁺ . B5

5-((2-(2-((第三丁氧基羰基)胺基)乙氧基)-5-氟苄基)(2-羥乙基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 518.3 (M+H)⁺ . B6

   5-((6-(2-((第三丁氧基羰基)胺基)乙氧基)-2-氯-3-氟苄基)(甲基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯 MS: 522.5 (M+H)⁺ . B7

6-(1-(2-(2-((第三丁氧基羰基)胺基)乙氧基)-5-氟苯基)乙氧基)咪唑并[1,2-b]噠嗪-3-甲酸乙酯 LC-MS (ESI)m/z 511.6 (M+Na)⁺ ；¹ H NMR (500 MHz, 氯仿-d ) δ 8.16 (s, 1H), 7.90 (d,J = 9.7 Hz, 1H), 7.16 (dd,J = 9.0, 3.2 Hz, 1H), 0.95 (d,J = 9.5 Hz, 1H), 6.90 - 6.88 (m, 1H), 6.81 - 6.78 (m, 1H), 6.68 (q,J = 6.2 Hz, 1H), 5.84 - 5.68 (m, 1H), 4.38 (q,J = 7.2 Hz, 2H), 4.15 - 4.09 (m, 2H), 3.60 - 3.52 (m, 2H), 1.65 (d,J = 6.4 Hz, 3H), 1.38 (d,J = 7.2 Hz, 3H), 1.35 (s, 9H)。 實例 2 及 2-1.

合成 A ： 實例2可如以下方案中所示以外消旋或鏡像異構體富集之起始材料開始來製備：

步驟1. 向化合物2A (1當量)及2B (1.2當量)於無水DMF (0.2 M)中之混合物中添加Cs₂ CO₃ (1.5當量)並將反應於油浴中於80℃下在氮氣下加熱過夜。將混合物冷卻，傾倒於水中，並用EtOAc萃取三次。將合併之有機層用水洗滌五次，用鹽水洗滌，並經Na₂ SO₄ 乾燥。濃縮之後，將殘餘物於急驟管柱上用EtOAc/己烷溶析來純化，以提供化合物2C。 步驟2. 向化合物2C (1當量)於無水THF (0.2 M)中之溶液中添加NaH (1.2當量)。將反應混合物於環境溫度下攪拌0.5小時。向混合物中添加化合物2D並將反應於回流下在氮氣下加熱過夜。將反應冷卻至環境溫度並用一部分水(1/3之THF體積)及NaOH (3當量)稀釋。將混合物攪拌並於70℃下加熱2小時或直至酯完全水解成相應酸為止。冷卻之後，將有機層分離且將水層中和至pH約5。將所得沈澱過濾，用水洗滌三次，並在真空下乾燥以提供化合物2E，其未經進一步純化即使用。 步驟3. 向化合物2E (1當量)於CH₂ Cl₂ (0.2 M)中之溶液中添加4 M HCl/二噁烷(10當量)並將混合物攪拌，直至化合物2E完全轉化為化合物2F為止。將混合物濃縮，且殘餘物藉由反相製備型HPLC純化以提供化合物2F。 步驟4. 於0℃下將化合物2F (1當量)及DIPEA (10當量)於DMF (0.2 M)中之溶液逐滴添加至HATU (1.4當量)於DMF (0.1 M)中之溶液中。添加完成後，將混合物於0℃下再攪拌30分鐘。添加水並將混合物用EtOAc萃取三次。將合併之有機層用飽和NaHCO₃ 洗滌兩次，然後用鹽水洗滌，經Na₂ SO₄ 乾燥並濃縮。將殘餘物於矽膠管柱上用EtOAc/己烷溶析來純化，以提供實例2。合成 B ： 實例2及2-1亦可根據以下方案使用外消旋或鏡像異構體富集之起始材料來製備：

步驟1. 化合物2C與化合物2G在合成A、步驟2中所述之條件下反應，以提供化合物2H。 步驟2. 化合物2H在合成A、步驟3中所述之條件下轉化為化合物2I。 步驟3. 向化合物2I (1當量)及DIPEA (2當量)於甲苯(0.01 M)中之溶液中添加Pd(P-tBu₃ )₂ (1當量)。將反應混合物於100℃下在4巴CO下加熱過夜，且然後濃縮。將殘餘物於矽膠管柱上用EtOAc/己烷溶析來純化，以提供實例2。實例 10 及 10-1.

實例10及10-1可如以下方案中所示使用外消旋或鏡像異構體富集之起始材料來製備：

步驟1. 化合物10C係自化合物10A及10B使用實例2、合成A、步驟1中所述之方法製備。 步驟2. 化合物10E係自化合物10C及10D使用實例2、合成A、步驟2中所述之方法製備。 步驟3. 將化合物10E (1當量)及NH₂ -NH₂ (10當量)於甲醇(0.2 M)中之混合物於回流下加熱直至化合物10E完全轉化為化合物10F為止。將混合物濃縮且殘餘物於反相製備型HPLC中純化，以提供化合物10F。 步驟4. 化合物10F係根據針對實例2、合成A、步驟4所述之方法轉化為實例10。實例 11-1

步驟1：向2-氯-3-氟-6-羥基-苯甲醛(175 mg, 1.0 mmol)、雙-tos乙二醇(740 mg, 2.0 mmol)於ACN (5 mL)中之溶液中添加K₂ CO₃ (276 mg, 2.0 mmol)及KI (2 mg)。將混合物於120℃下攪拌24小時。將固體濾除並將濾液濃縮且藉由管柱層析純化，以獲得呈白色固體之期望產物11-1B。此材料直接用於下一步驟中。 步驟2：向11-1B (373 mg, 1 mmol)於ACN (5 mL)中之溶液中添加NaN₃ (650 mg, 10 mmol)並將混合物於120℃下攪拌24小時。將固體濾除並將殘餘物濃縮且藉由管柱層析純化，以獲得呈白色固體之11-1C (200 mg, 82%)。¹ H NMR (500 MHz, 氯仿-d ) δ 10.49 (d,J = 1.1 Hz, 1H), 7.31 (dd,J = 9.2, 8.2 Hz, 1H), 6.88 (dd,J = 9.2, 3.7 Hz, 1H), 4.21 (dd,J = 5.4, 4.5 Hz, 2H), 3.67 (dd,J = 5.4, 4.5 Hz, 2H)。 步驟3：於-78℃下向11-1C (100 mg, 0.41 mmol)於無水THF (5 mL)中之溶液中添加甲基溴化鎂(1N於Et₂ O中, 0.82 mL, 0.82 mmol)。使混合物升溫至室溫並攪拌2小時，直至TLC顯示不存在起始材料為止。然後將溶液冷卻至0℃並用飽和NH₄ OAc水溶液驟冷，且用EtOAc (20 mL x 3)萃取。合併之有機物經Na₂ SO₄ 乾燥並濃縮。殘餘物11-1D直接用於下一步驟中。¹ H NMR (500 MHz, 氯仿-d ) δ 6.97 (dd,J = 9.2, 8.3 Hz, 1H), 6.77 (dd,J = 9.1, 4.1 Hz, 1H), 5.27 (q,J = 6.7 Hz, 1H), 4.34 - 4.29 (m, 1H), 4.22 - 4.16 (m, 1H), 4.04 - 3.98 (m, 1H), 3.95 - 3.88 (m, 2H), 1.51 (d,J = 6.7 Hz, 3H)。 步驟4：於-78℃下向5-氯-吡唑并[1,5-a]嘧啶-3-甲酸乙酯(100 mg, 0.44 mmol)及11-1D (110 mg, 0.41 mmol)於無水THF (5.0 mL)中之溶液中添加NaH (60%, 17 mg, 0.44 mmol)。使混合物升溫至室溫並攪拌8小時，直至形成大量期望產物為止。然後將混合物用水/冰稀釋並用DCM (3×20 mL)萃取。有機層經Na₂ SO₄ 乾燥，濃縮並藉由矽膠管柱層析純化，以獲得呈黃色液體之11-1E (20 mg, 0.045 mmol, 6%)，其直接用於下一步驟中。 步驟5：向11-1E (20 mg, 0.045 mmol)於MeOH (1mL)中之溶液中添加LiOH (16 mg, 0.38 mmol)，隨後添加1 mL H₂ O。將混合物於60℃下攪拌4小時，直至LCMS及TLC顯示反應完成為止。將溶液冷卻至室溫，部分濃縮並藉由1N HCl酸化，直至pH為2-3為止。將水性混合物用DCM (3x10 mL)萃取。將有機層經Na₂ SO₄ 乾燥並濃縮。殘餘物11-1F直接用於下一步驟中。 步驟6：向11-1F (20 mg, 0.045 mmol)於DCM (5mL)中之溶液中添加PPh₃ (24 mg, 0.09 mmol)。將溶液攪拌1小時，直至TLC顯示起始材料完全轉化為期望產物為止。然後混合物未經進一步表徵直接用於下一步驟。11-1G MS ESI⁺ m/z 417.7 (M+Na)⁺ 。 步驟7：向自以上步驟中所獲得之11-1G於DMF (10 mL)中之溶液中添加DIPEA (0.20 mL, 1.15 mmol)。將溶液用乾冰/丙酮浴冷凍並添加HATU (40.0 mg, 0.11 mmol)。使溶液緩慢升溫至室溫且LCMS顯示起始材料清潔轉化為期望產物。然後將混合物用水(50 mL)稀釋且用EtOAc (3 × 50 mL)萃取。將合併之有機層用水(3 x 50mL)及鹽水(50 mL)洗滌並經Na₂ SO₄ 乾燥。將溶劑移除且所得殘餘物藉由矽膠管柱層析(0-5% MeOH/DCM)純化，獲得呈白色固體之期望產物(2.6 mg, 20%產率)。實例 14 及 14-1.

實例14及14-1可根據以下方案使用外消旋或鏡像異構體富集之起始材料來製備：

步驟1. 向化合物14A (1當量)及14B (1.2當量)於無水DMF (0.2 M)中之混合物中添加Cs₂ CO₃ (1.5當量)並將反應於油浴中於80℃下在氮氣下加熱過夜。將混合物冷卻，傾倒於水中，並用EtOAc萃取三次。將合併之有機層用水洗滌五次，用鹽水洗滌，並經Na₂ SO₄ 乾燥。濃縮之後，將殘餘物於急驟矽膠管柱上用EtOAc/己烷溶析來純化，以提供14C。 步驟2. 向14C (1當量)於無水THF (0.2 M)中之冷卻(-78℃)溶液中添加MeMgBr (3當量，3 M於二乙基醚中)。將反應自-78℃至0℃攪拌2小時，並用飽和NH₄ Cl水溶液驟冷，且然後用EtOAc (2x)萃取。有機物經MgSO₄ 乾燥，過濾並濃縮。將此殘餘物藉由矽膠管柱層析用EtOAc/己烷溶析來純化，以獲得14D。 步驟3. 向化合物14D (1當量)於無水THF (0.2 M)中之溶液中添加NaH (1.2當量)。將反應混合物於環境溫度下攪拌0.5小時。向混合物中添加14E並將反應在氮氣下加熱至回流過夜。將反應冷卻至環境溫度，且然後傾倒於水中。將產物用EtOAc萃取三次。用鹽水洗滌合併之有機物，經Na₂ SO₄ 乾燥並濃縮。殘餘物用矽膠管柱用EtOAc/己烷溶析來純化，以提供產物14F。 步驟4. 向化合物14F (1當量)於CH₂ Cl₂ (0.2 M)中之溶液中添加4 M HCl/二噁烷(10當量)並將混合物攪拌直至所有14F均轉化為14G為止。濃縮之後，殘餘物於反相製備型HPLC中純化，以提供14G。 步驟5. 向14G (1當量)及DIPEA (2當量)於甲苯(0.01 M)中之溶液添加Pd(P-t-Bu₃ )₂ (1當量)。將反應混合物於100℃下在4巴CO下加熱過夜，且然後濃縮。將殘餘物於矽膠管柱上用EtOAc/己烷溶析來純化，以提供14。實例 15 及 15-1.

實例15及15-1可根據以下方案使用外消旋或鏡像異構體富集之起始材料來製備：

步驟1. 向15A (1.0當量)於THF (0.15 M)中之懸浮液中添加2.0 M NaOH水溶液(3當量)。將均質反應混合物攪拌過夜，且然後在減壓下去除有機物。使用1.0 M HCl水溶液使水性殘餘物達到pH 4。藉由過濾收集所得沈澱物並用H₂ O沖洗，以獲得15B之固體。濾液用EtOAc (2 ×)萃取，且在減壓下濃縮有機物以提供額外部分之15B。 步驟2. 藉由將濃H₂ SO₄ (2.3 mL)小心添加至CrO₃ (2.67 g)中且然後使用10 mL H₂ O稀釋來製備瓊斯試劑(Jones reagent)之儲備溶液(2.67 M)。向15B (1.0當量)於丙酮中之懸浮液(0.067 M)中緩慢添加瓊斯試劑(1.2當量)。將反應混合物攪拌15分鐘且然後用i-PrOH萃取並藉助矽藻土墊用丙酮沖洗來過濾。將濾液濃縮以提供15C，其未經進一步純化即使用。 步驟4. 於0℃下向15C (1.0當量)於DMF (0.40 M)中之溶液中添加NaH (60%於礦物油中, 1.5當量)。將反應混合物在室溫下攪拌30分鐘，且然後冷卻返回至0℃，且緩慢添加2-(三甲基矽基)乙氧基甲基氯(4.3 mL, 1.2當量)。使反應混合物升溫至室溫，攪拌1小時，且然後使用H₂ O驟冷並使用EtOAc (3 ×)萃取。使用H₂ O (3 ×)及鹽水洗滌合併之有機物，且然後經MgSO₄ 乾燥並濃縮。將殘餘物藉由急驟矽膠層析用20-30% EtOAc/己烷溶析來純化，以獲得15D。 步驟5. 於氮氣氛下向14D (1.0當量)、碘化銅(I) (0.05當量)、8-羥基喹啉(0.1當量)及磷酸三鉀(2.0當量)於DMF (0.2 M)中之反應混合物中添加15D (1.2當量)並將反應混合物於120℃下加熱24小時。將反應混合物冷卻至室溫且然後用EtOAc稀釋。藉助矽藻土墊過濾混合物並在真空下蒸發濾液。將粗製殘餘物於矽膠管柱上用EtOAC/己烷溶析來純化，以獲得15E。 步驟6. 將15E (1.0當量)於1,4-二噁烷(0.062 M)及水(THF之1/3)中之0℃懸浮液用磺胺酸(6.0當量)處理。經由滴液漏斗經20分鐘添加亞氯酸鈉(1.3當量)及磷酸二氫鉀(12當量)於水(1.2 M)中之溶液。添加完成後，移除冰浴並將反應混合物於室溫下攪拌3小時。添加THF，且然後將反應混合物於室溫下再攪拌3小時。將反應混合物用水稀釋並用EtOAc (2x)萃取。將合併之有機層用水及鹽水洗滌，且然後經Na₂ SO₄ 乾燥，過濾，並濃縮。將殘餘物用乙酸乙酯/己烷研磨，以獲得15F。 步驟7. 向化合物15F (1當量)於CH₂ Cl₂ (0.2 M)中之溶液中添加4 M HCl/二噁烷(10當量)並將混合物攪拌，直至所有15F均轉化為15G為止。濃縮之後，將殘餘物於反相製備型HPLC中純化，以提供15G。 步驟8. 於0℃下將化合物15G (1當量)及DIPEA (10當量)於DMF (0.2 M)中之溶液逐滴添加至HATU (1.4當量)於DMF (0.1 M)中之溶液。添加完成後，將混合物於0℃下再攪拌30分鐘。添加水並將混合物用EtOAc萃取三次。合併之有機物用飽和NaHCO₃ 洗滌兩次、用鹽水洗滌，經Na₂ SO₄ 乾燥，並蒸發。將殘餘物用矽膠管柱利用EtOAc/己烷溶析來純化，以提供15。實例 18 及 18-1.

實例18及18-1可根據以下方案使用外消旋或鏡像異構體富集之起始材料來製備：

步驟1. 在氮氣氛下向14D (1.0當量)、18A (1.2當量)及碘化銅(I) (0.05當量)於DMF (0.2 M)中之反應混合物中添加NaH (3.0當量)。將反應混合物在120℃下加熱24小時，且然後冷卻至室溫並用EtOAc稀釋。藉助矽藻土墊過濾混合物並在真空下蒸發濾液。將粗製殘餘物於矽膠管柱上用EtOAc/己烷溶析來純化，以獲得18B。 步驟2. 向18B (1.0當量)於DMF (0.2 M)中之反應混合物中添加KOH (2當量)及I₂ (1.1當量)。將反應混合物於室溫下攪拌1小時，且然後用NaHSO₃ 驟冷並用EtOAc萃取。合併之有機物用飽和NaHCO₃ 洗滌兩次、用鹽水洗滌，經Na₂ SO₄ 乾燥，並蒸發。將殘餘物利用矽膠管柱用EtOAc/己烷溶析來純化，以提供18C。 步驟3. 向化合物18C (1當量)於CH₂ Cl₂ (0.2 M)中之溶液中添加4 M HCl/二噁烷(10當量)並將混合物攪拌直至所有18C均轉化為18D為止。濃縮之後，將殘餘物於反相製備型HPLC中純化，以提供18D。 步驟4. 向18D (1當量)及DIPEA (2當量)於甲苯(0.01 M)中之溶液中添加Pd(P-t-Bu₃ )₂ (1當量)。將反應混合物於100℃下在4巴CO下加熱過夜，且然後濃縮。將殘餘物於矽膠管柱上用EtOAc/己烷溶析來純化，以提供18。實例 20

實例20係根據以下方案製備：

步驟1. (2-(4-氟-2-甲醯基苯氧基)乙基)胺基甲酸第三丁基酯(20C)。將醛20A (1.5 g, 11 mmol)、氯化物20B (2.1 g, 12 mmol)、碳酸鉀(7.4 g, 54 mmol)及碘化鉀(36 mg, 0.2 mmol)於DMF (11 mL)中之溶液加熱至60℃並攪拌15小時。額外氯化物20B (1.0 g, 6 mmol)並於80℃下再加熱5小時完成反應。將混合物冷卻至室溫並藉由添加水(250 mL)稀釋。將混合物用乙酸乙酯(3 × 300 mL)萃取且合併之萃取物用水(200 mL)及鹽水(100 mL)洗滌，用硫酸鈉乾燥，並在減壓下濃縮。急驟層析(ISCO系統，二氧化矽，0-20%乙酸乙酯於己烷中)提供呈黏稠油狀物之20C (3.0 g, 99%)。LRESIMSm/z 306.1 [M+Na]⁺ ，C₁₄ H₁₈ F₁ N₁ Na₁ O₄ 之計算值，306.1。 步驟2. (2-(4-氟-2-((甲基胺基)甲基)苯氧基)乙基)胺基甲酸第三丁基酯(20D)。將於甲醇(88 mL)中之醛20C (2.5 g, 8.8 mmol)及甲胺(0.69 g, 22 mmol)加熱至60℃並攪拌1小時。將混合物冷卻至室溫並添加硼氫化鈉(0.33 g, 8.8 mmol)。將混合物攪拌30分鐘，然後藉由添加水(200 mL)驟冷。將混合物用二氯甲烷(4 × 100 mL)萃取且合併之萃取物用鹽水(50 mL)、硫酸鈉乾燥並在減壓下濃縮。急驟層析(ISCO系統，二氧化矽，0-100%之(10%甲醇於乙酸乙酯中)於己烷中)提供呈凝膠之目標化合物(2.1 g, 80%)。LRESIMSm/z 299.2 [M+H]⁺ ，C₁₅ H₂₄ F₁ N₂ O₃ 之計算值，299.2。 步驟3. 5-((2-(2-((第三丁氧基羰基)胺基)乙氧基)-5-氟苄基)(甲基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(20F)。將於丁醇(17 mL)中之胺20D (2.1 g, 7.0 mmol)、酯20E (1.59 g, 7.0 mmol)及Hünig鹼(7.0 mL, 5.2 g, 40 mmol)於110℃下加熱25分鐘。將反應冷卻並用水(250 mL)稀釋。將混合物用二氯甲烷(4 × 100 mL)萃取且合併之萃取物用硫酸鈉乾燥。將混合物在減壓下濃縮。急驟層析(ISCO系統，二氧化矽，20-100%乙酸乙酯於己烷中)提供呈固體之目標化合物(2.1 g, 75%)。LRESIMSm/z 488.3 [M+H]⁺ ，C₂₄ H₃₁ F₁ N₅ O₅ 之計算值，488.2。 步驟4. 5-((2-(2-((第三丁氧基羰基)胺基)乙氧基)-5-氟苄基)(甲基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸(20G)。於室溫下將氫氧化鈉(40 mL, 2 M於水中)添加至酯20F (2.1 g, 4.3 mmol)於四氫呋喃:甲醇(3:2, 100 mL)中之攪拌溶液中。將反應加熱至60℃並攪拌6.5小時。將混合物冷卻至0℃並用鹽酸(45 mL, 2 M於水中)酸化，然後用水(100 mL)稀釋。將混合物用乙酸乙酯(4 × 150 mL)萃取且合併之萃取物用鹽水(50 mL)及硫酸鈉乾燥。將混合物在減壓下濃縮以提供呈固體之目標化合物(1.92 g, 97%)。LRESIMSm/z 460.2 [M+H]⁺ ，C₂₂ H₂₇ F₁ N₅ O₅ 之計算值，460.2。 步驟5. 5-((2-(2-胺基乙氧基)-5-氟苄基)(甲基)胺基)吡唑并[1,5-a]嘧啶-3-甲酸(20H)。於室溫下將鹽酸(5 mL, 4M於二噁烷中)添加至羧酸20G (1.92 g, 4.2 mmol)於二氯甲烷(25 mL)中之攪拌溶液中。將反應攪拌2小時，然後在減壓下濃縮，以提供呈固體之目標化合物。LRESIMSm/z 360.2 [M+H]⁺ ，C₁₇ H₁₀ F₁ N₅ O₃ 之計算值，360.2。 步驟6. 在氬氣氛下，於-78℃下將HATU (1.67 g, 4.4 mmol)添加至羧酸20H (1.50 g, 4.2 mmol)及Hünig鹼(7.28 mL, 5.40 g, 41.8 mmol)於DMF:二氯甲烷(5:1, 60 mL)中之攪拌溶液中。使反應緩慢升溫至室溫並攪拌3小時，然後用水(300 mL)驟冷。將混合物用乙酸乙酯(3 × 100 mL)、然後二氯甲烷(2 × 100 mL)萃取，且合併之萃取物用鹽水(50 mL)及硫酸鈉乾燥。將混合物在減壓下濃縮。急驟層析(ISCO系統，二氧化矽，1-4%甲醇於二氯甲烷中)、隨後自乙酸乙酯/甲醇重結晶提供呈固體之實例20 (0.98 g, 68%, 2步)。LRESIMSm/z 342.2 [M+H]⁺ ，C₁₇ H₁₇ F₁ N₅ O₂ 之計算值， 342.1；¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.43 (dd,J = 6.9, 2.7 Hz, 1 H), 8.76 (d,J = 7.9 Hz, 1 H), 8.10 (s, 1 H), 7.19 - 7.25 (m, 1 H), 7.03 - 7.07 (m, 2 H), 6.72 (d,J = 7.9 Hz, 1 H), 5.64 (dd,J = 14.9, 1.5 Hz, 1 H), 4.48 (dt,J = 10.2, 4.3 Hz, 1 H), 4.04 - 4.10 (m, 2 H), 3.81 - 3.87 (m, 1 H), 3.58 (s, 3 H), 3.38 - 3.46 (m, 1 H)。實例 20 之替代合成 ： 實例20亦藉由以下替代途徑製備：

步驟1. 5-側氧基-4H -吡唑并[1,5-a]嘧啶-3-甲酸乙酯(20J)。於20℃下在N₂ 下向20I (150.00 g, 1.08 mmol)及(E )-3-乙氧基丙-2-烯酸乙酯(292.16 g, 2.03 mol)於DMF (3.2 L)中之溶液中一次性添加Cs₂ CO₃ (656.77 g, 2.02 mol)。將混合物於110℃下攪拌6小時。將混合物冷卻至20℃並藉助矽藻土墊過濾。濾餅用乙酸乙酯(3 × 30 mL)洗滌。將濾液添加至H₂ O (2 L)並用HOAc酸化至pH=4。將所得沈澱物過濾，以獲得呈白色固體之20J (173.00 g, 834.98 mmol, 86.36%產率)。¹ H NMR (400 MHz, DMSO-d₆ ) δ 8.54 (d,J =7.91 Hz, 1H), 8.12 (s, 1H), 6.13 (d,J =7.91 Hz, 1H), 4.27 (q,J =7.11 Hz, 2H), 1.28 (t,J =7.09 Hz, 3H)。 步驟2. 5-氯吡唑并[1,5-a]嘧啶-3-甲酸乙酯(20K)。於20℃下在N₂ 下向20J (158.00 g, 762.59 mmol)於MeCN (1.6 L)中之混合物中添加POCl₃ (584.64 g, 3.81 mol)。將混合物於100℃下攪拌2小時。將混合物冷卻至20℃並於0℃下分批傾倒於冰-水(5000 mL)中並攪拌20分鐘。將沈澱物過濾並乾燥，以獲得呈白色固體之20K (110.00 g, 487.52 mmol, 63.93%產率)。¹ H NMR (400 MHz, DMSO-d₆ ) δ 9.33 (d,J =7.28 Hz, 1H), 8.66 (s, 1H), 7.41 (d,J =7.15 Hz, 1H), 4.31 (q,J =7.15 Hz, 2H), 1.32 (t,J =7.09 Hz, 3H)。 步驟3. 4-氟-2-甲基胺基甲基-苯酚(20M)。於25℃下在N₂ 下向20 L (5.00 g, 35.69 mmol, 1.00eq. )於MeOH (50.00 mL)中之溶液中一次性添加水性甲胺(8.8 mL, 71.38 mmol, 25%, 2.00eq )。將混合物於25℃下攪拌3小時，然後逐部分添加NaBH₄ (2.70 g, 71.38 mmol, 2.00eq ) 。並將混合物於25℃下再攪拌9小時。TLC顯示反應完成。將混合物於45℃下於減壓下濃縮。將殘餘物傾倒於水(50 mL)中。水相用二氯甲烷(3 x 200 mL)萃取且合併之有機相用鹽水(200 mL)洗滌，經無水Na₂ SO₄ 乾燥，過濾並在真空中濃縮以獲得呈無色固體之20M (5.10 g, 32.87 mmol, 92.09%產率)。¹ H NMR (400MHz, CDCl₃ ) δ 6.86 (dt,J =3.0, 8.7 Hz, 1H), 6.78 - 6.69 (m, 2H), 3.93 (s, 2H), 2.48 (s, 3H)。 步驟4. 5-[(5-氟-2-羥基-苄基)-甲基-胺基]-吡唑并[1,5-a]嘧啶-3-甲酸乙酯(A1)。向20M (33.70 g, 217.17 mmol, 1.00 eq.)及20K (49.00 g, 217.17 mmol, 1.00 eq.)於n-BuOH (740.00 mL)中之懸浮液中添加DIPEA (159.98 g, 1.24 mol, 5.70 eq.)。在氮氣下將混合物於120℃下攪拌2小時。TLC顯示反應完成。將溶液冷卻至25℃，且然後移除溶劑。將殘餘物用水(500 mL)稀釋且用二氯甲烷(3 × 500 mL)萃取。將合併之有機萃取物用鹽水(300 mL)洗滌，經無水Na₂ SO₄ 乾燥，並於真空下濃縮。殘餘物藉由EtOAc(100 mL)研磨以獲得呈白色固體之A1 (60.00 g, 174.25 mmol, 80.24%產率)。¹ H NMR (500 MHz, 氯仿-d ) δ 9.71 (s, 1H), 8.32 (d,J = 7.9 Hz, 1H), 8.30 (s, 1H), 6.98 - 6.87 (m, 3H), 6.37 (d,J = 7.9 Hz, 1H), 4.82 (s, 2H), 4.42 (q,J = 7.1 Hz, 2H), 3.21 (s, 3H), 1.39 (t,J = 7.1 Hz, 3H)。 步驟5. 5-{[2-(2-第三丁氧基羰基胺基-乙氧基)-5-氟-苄基]-甲基-胺基}-吡唑并[1,5-a]嘧啶-3-甲酸乙酯(B1)。向A1 (102.85g, 298.6 mmol, 1 eq.)、(2-氯-乙基)-胺基甲酸第三丁基酯(56.33 g, 313.5 mmol, 1.05 eq.)於DMF (854 mL)中之溶液中添加K₂ CO₃ (206.41 g, 1493 mmol, 5.0 eq.)。將混合物於80℃下加熱20小時，其中藉由LC-MS，起始材料至產物之轉化率為約85%。向反應燒瓶中添加額外部分之(2-氯-乙基)-胺基甲酸第三丁基酯(5.633 g, 31.35 mmol, 0.1 eq.)及K₂ CO₃ (41.282 g, 298.6 mmol, 1 eq.)。將反應在80℃下再繼續攪拌21小時。然後將混合物冷卻至室溫，用水(1000 ml)驟冷並用EtOAc (3 x 900 mL)萃取。然後將合併之有機萃取物用水(3 x 700mL)及鹽水(500 mL)洗滌，經Na₂ SO₄ 乾燥，並濃縮。將所得殘餘物藉由矽膠管柱用EtOAc/己烷(0-70%)溶析來純化，以獲得呈白色固體之B1 (128.74 g, 96.7%產率)。LC-MS (ESI)m/z 510.1 (M+Na)⁺ ；¹ H NMR (500 MHz, 氯仿-d ) δ 8.30 (s, 1H), 8.26 (s, 1H), 6.92 (td,J = 8.6, 3.3 Hz, 1H), 6.83 - 6.76 (m, 1H), 6.31 (s, 1H), 4.93 (s, 2H), 4.51 - 4.44 (m, 1H), 4.36 (q,J = 7.2 Hz, 2H), 4.03 (t,J = 4.9 Hz, 2H), 3.69 - 3.63 (m, 1H), 3.51 (s, 2H), 3.30 (s, 2H), 1.44 (s, 9H), 1.41 - 1.35 (t,J = 7.2 Hz, 3H)。 步驟6. 11-氟-14-甲基-6,7,13,14-四氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-4(5H)-酮(20)。向B1 (128.74 g, 264.07 mmol, 1 eq.)於甲醇(750 mL)及THF (250 mL)中之溶液中添加於H₂ O (250 mL)中之LiOH^. H₂ O (55.40 g, 1320 mmol, 5.0 eq.)。將澄清溶液於70℃下加熱2小時。將反應於0℃下下利用HCl水溶液(2M, 250 mL)中和至pH＜5，且然後用CH₂ Cl₂ (1x1000 mL, 3x500 mL)萃取。合併之有機物用鹽水(300 mL)洗滌，且經Na₂ SO₄ 乾燥。過濾後，蒸發，高真空乾燥，獲得白色固體(126.47 g, 275.25 mmol, 104%產率)。於0℃下向酸(121.30 g, 264 mmol)於CH₂ Cl₂ (996 mL)中之溶液中添加於二噁烷中之HCl (4 M, 204 mL)。自0℃至室溫持續攪拌27小時，直至藉由LC-MS完成去Boc。將白色固體過濾，用DCM (400 mL)洗滌，並高真空乾燥以提供胺3HCl鹽之白色固體(123.55 gram)，其未經進一步純化直接使用。向DIPEA (169.4 g, 228 mL, 1310毫莫耳)於DMF (3.7 L)及CH₂ Cl₂ (1.0 L)中之溶液中添加酸胺HCl鹽(22.92 g, 49.0 mmol, 1.00 eq.)。固體完全溶解之後，添加於CH₂ Cl₂ 中之二苯基次膦酸五氟苯基酯(FDPP) (1.1 M, 19.76 g, 51.44 mmol, 1.05 eq.)。藉由LC-MS，偶合在30分鐘內完成，且然後根據與第一部分相同之程序添加第二部分鹽及FDPP。鹽、隨後FDPP之添加每30分鐘重複且藉由LC-MS監測每一添加循環。將所有鹽(123.55 g, 264 mmol, 1.00 eq)及FDPP (106.44 g, 277 mmol, 1.05 eq.)分批添加至反應燒瓶中。將反應溶液濃縮至約500 mL之體積且形成大量沈澱物。將固體產物20過濾並用DMF (50 mL×3)洗滌。將濾液傾倒於水(2L)中且沈澱出額外產物。將固體產物過濾並用水(100 mL×3)洗滌。將合併之固體產物乾燥，且重新溶解於10%於二氯甲烷中之甲醇(1.5 L)且然後添加乙酸乙酯(1 L)。將溶液濃縮至約500 mL且形成大量白色固體。過濾並高真空乾燥之後，獲得白色固體化合物20 (74.58 g, 83%產率)。實例 20 之粉末 X- 射線繞射 (PXRD). 將實例20之試樣結晶多晶形1轉移至零背景板中用於PXRD分析。PXRD數據係使用Bruker D8 X-射線繞射儀根據製造商建議程序獲得。用於掃描之參數：2-θ範圍：4.5至39.1度；步階大小：0.02度；步階時間：1秒；分析時間：180秒。 繞射峰通常經量測具有±0.1度 (2θ)之誤差。 結果顯示於圖1總。數據匯總於表1中。 表1 2-θ (度數) d-值 峰強度(計數) 峰強度(%) 10.68 9.611 31.15 5.2 11.96 8.586 19.11 2.9 15.26 6.737 20.92 4.4 19.64 5.244 27.57 6.4 21.94 4.701 452.41 100 23.96 4.309 91.85 18.2 26.82 3.857 10.92 2.2 實例 20 之差示掃描量熱法 (DSC). 圖2中所示之DSC量測係使用Seiko Model SSC/5200差示掃描量熱計實施。使7.92 mg實例20之試樣結晶多晶形1於36℃下平衡，且然後以10℃/min之速率斜坡升溫至380℃。實例20之試樣結晶多晶形1顯示熔點為298.9℃。實例 26.

實例26可根據以下方案來製備：

步驟1. 將異丙醇鈦(IV) (1.3當量)添加至甲胺於甲醇中之市售溶液(2 M, 3當量)中，隨後添加起始醛14C (1.0當量)。將反應混合物於環境溫度下攪拌5小時，此後添加硼氫化鈉(1.0當量)並將所得混合物進一步再攪拌2小時之時期。然後藉由添加水使反應驟冷，將所得無機沈澱物過濾並用EtOAc洗滌。將有機層分離且水性部分進一步用EtOAc (x2)萃取。將合併之萃取物乾燥(K₂ CO₃ )並在真空中濃縮，以獲得26A。 步驟2. 將化合物26A (1當量)及DIPEA (2當量)於n-BuOH (0.2 M)中之混合物於120℃下加熱過夜，冷卻至環境溫度，且然後濃縮。將殘餘物用矽膠管柱用EtOAc/己烷溶析來純化，以提供產物26B。 步驟3. 向化合物26B (1當量)於CH₂ Cl₂ (0.2 M)中之溶液中添加4 M HCl/二噁烷(10當量)並將混合物攪拌，直至所有26B轉化為26C為止。濃縮之後，將殘餘物於反相製備型HPLC中純化，以提供26C。 步驟4. 向26C (1當量)及DIPEA (2當量)於甲苯(0.01 M)中之溶液中添加Pd(P-t-Bu₃ )₂ (1當量)。將反應混合物於100℃下在4巴CO下加熱過夜，且然後濃縮。將殘餘物於矽膠管柱上用EtOAc/己烷溶析量純化，以提供26。實例 37 及 37-1.

實例37及37-1可根據以下方案自外消旋或鏡像異構體富集之起始材料來製備：

步驟1. 化合物37B係自化合物2C及化合物37A使用針對實例2、合成A、步驟2所述之方法來製備。 步驟2. 化合物37C係自化合物37B使用實例2、合成A、步驟3中所述之方法來製備。 步驟3. 實例37係自化合物37C使用實例2、合成A、步驟4中所述之方法來製備。實例 38 及 38-1.

實例38及38-1可根據以下方案自外消旋或鏡像異構體富集之起始材料來製備：

步驟1. 化合物38B係自化合物2C及38A 如實例2、合成A、步驟2中所述製備。 步驟2. 化合物38C係自化合物38B使用實例2、合成A、步驟3中所述之方法製備。 步驟3. 實例38係自化合物38C使用實例2、合成B、步驟4中所述之方法製備。實例 39

實例39係根據以下方案製備：

步驟1. 2-(3-氯-4-氟-2-甲醯基-苯氧基)-乙基]-胺基甲酸第三丁基酯(39B)。向2-氯-3-氟-6-羥基-苯甲醛(39A, 53 mg, 0.3 mmol)及(2-氯-乙基)-胺基甲酸第三丁基酯(135 mg, 0.75 mmol)於DMF (5 mL)中之溶液中添加KI (2.0 mg, 0.012 mmol)及K₂ CO₃ (105 mg, 0.75 mmol)。將混合物於100℃下微波處理2小時。然後將混合物用水(20 mL)稀釋並用EtOAc (3x20 mL)萃取。將合併之有機層用水(3x20 mL)及鹽水(20 mL)洗滌，經Na₂ SO₄ 乾燥並濃縮，以獲得39B。粗殘餘物直接用於下一步驟中。LC-MS: (ESI)m/z 340.3 (M+Na)⁺ 。 步驟2. {[2-(3-氯-4-氟-2-甲基胺基甲基-苯氧基)-乙基]-胺基甲酸第三丁基酯(39C)。向39B (95.4 mg, 0.3 mmol)於MeOH (3 ml)中之溶液中添加甲胺鹽酸鹽(50.7 mg, 0.75 mmol)。將混合物於60℃下攪拌30分鐘。然後將溶液冷卻至環境溫度並添加NaBH₄ (11.1 mg, 0.3 mmol)。將混合物於環境溫度下攪拌2小時。然後將溶液用水(50 mL)稀釋並用DCM(3 × 20 mL)萃取。將合併之有機層經Na₂ SO₄ 乾燥並濃縮，以獲得39C。粗製殘餘物直接用於下一步驟中。LC-MS: (ESI)m/z 333.3 (M+H)⁺ 。 步驟3. 5-{[6-(2-第三丁氧基羰基胺基-乙氧基)-2-氯-3-氟-苄基]-甲基-胺基}-吡唑并[1,5-a]嘧啶-3-甲酸乙酯(39D)。向20K (67.5 mg, 0.3 mmol)及39C (99.9 mg, 0.3 mmol)於n -BuOH (2.0 mL)中之溶液中添加DIEA (1.0 mL)。將混合物於微波下於150℃下加熱2小時。然後將混合物用水稀釋並用DCM (3x20 mL)萃取。有機層經Na₂ SO₄ 乾燥，濃縮並藉由純化矽膠管柱層析，以獲得呈黃色液體之17。LC-MS: (ESI)m/z 522.5 (M+H)⁺ 。 步驟4. 5-{[6-(2-第三丁氧基羰基胺基-乙氧基)-2-氯-3-氟-苄基]-甲基-胺基}-吡唑并[1,5-a]嘧啶-3-甲酸(39E)。向39D (40 mg, 0.0776 mmol)於MeOH (1mL)中之溶液中添加LiOH (16 mg, 0.38 mmol)及H₂ O (1 mL)。將混合物於60℃下攪拌4小時。將溶液冷卻至環境溫度，部分濃縮並藉由HCl水溶液(1 N)酸化，直至pH 2-3。將水性混合物用DCM (3x10 mL)萃取。將有機層經Na₂ SO₄ 乾燥並濃縮，以獲得39E。粗製殘餘物直接用於下一步驟中。LC-MS: (ESI)m/z 494.3 (M+H)⁺ 。 步驟5. 5-{[6-(2-胺基-乙氧基)-2-氯-3-氟-苄基]-甲基-胺基}-吡唑并[1,5-a]嘧啶-3-甲酸(39F)。向39E (40 mg, 0.0776 mmol)於DCM (2 mL)中之溶液中添加TFA (0.4 mL)。將溶液攪拌1小時。在旋轉蒸發下移除溶劑。將殘餘物利用DCM重新溶解並重新濃縮(3X)，以獲得呈泡沫狀固體之39F。LC-MS: (ESI)m/z 393.5 (M+H)⁺ 。 步驟6. 向39F (36 mg, 0.078mmol)於10 mL DCM中之溶液中添加DIEA (0.20 mL, 1.15 mmol)。將溶液用乾冰/丙酮浴冷凍並添加HATU (40.0 mg, 0.11 mmol)。使溶液緩慢升溫至環境溫度。將混合物用水(50 mL)稀釋且用EtOAc (3 x 50 mL)萃取。將合併之有機層用水(3 × 50 mL)及鹽水(50 mL)洗滌，經Na₂ SO₄ 乾燥並濃縮。將所得殘餘物藉由矽膠管柱(0-5% MeOH/DCM)純化，獲得呈白色固體之實例39 (6.2 mg, 23.4%)。LC-MS (ESI)m/z 376.5 (M+H)⁺ 。¹ H NMR (500 MHz, 氯仿-d ) δ 9.51 (s, 1H), 8.40 - 8.33 (m, 2H), 7.03 (ddd, J = 8.9, 8.0, 0.7 Hz, 1H), 6.78 (dd, J = 9.3, 4.2 Hz, 1H), 6.40 (d, J = 7.9 Hz, 1H), 5.97 (dd, J = 15.0, 2.1 Hz, 1H), 4.49 - 4.43(m, 1H), 4.31 (ddd, J = 10.9, 6.4, 4.5 Hz, 1H), 4.12 - 4.03 (m, 1H), 3.91 (d, J = 14.9 Hz, 1H), 3.72 - 3.63 (m, 1H), 3.56 (s, 3H)。實例 40

實例40係如以下方案中所示製備：

步驟1. 5-[(5-氟-2-羥基-苄基)-甲基-胺基]-2-甲基-吡唑并[1,5-a]嘧啶-3-甲酸(40B)。向19A (75 mg, 0.14 mmol)於甲醇(2 mL)中之溶液中添加LiOH (60 mg, 1.4 mmol)及H₂ O (2 mL)。將混合物於60℃下攪拌4小時。將溶液冷卻至環境溫度，部分濃縮並藉由HCl水溶液(1 N)酸化直至pH 2-3。將所得懸浮液用EtOAc (3 x 20mL)萃取。將有機層經Na₂ SO₄ 乾燥並濃縮，以獲得40A。LC-MS (ESI)m/z 331.6 (M+H)⁺ 。 步驟2. 5-[(5-氟-2-羥基-苄基)-甲基-胺基]-2-甲基-吡唑并[1,5-a]嘧啶-3-甲酸(2-羥基-乙基)-醯胺(40B)。於0℃下向40A (140 mg, 0.42 mmol)及2-胺基-乙醇(244 mg, 4 mmol)於DCM (5 mL)中之溶液中添加DIEA (0.20 mL, 1.15 mmol)及HATU (380.0 mg, 1.0 mmol)。將溶液緩慢升溫至環境溫度。然後將混合物用水(25 mL)稀釋且用EtOAc (3 × 25 mL)萃取。將合併之有機層用HCl (1N, 3 x 20mL)及鹽水(50 mL)洗滌，經Na₂ SO₄ 乾燥並濃縮。將所得殘餘物藉由矽膠管柱用0-5% MeOH/DCM (10 CV)溶析純化，獲得呈白色固體之40B (74 mg, 47%)。LC-MS (ESI)m/z 374.3 (M+H)⁺ 。 步驟3. 於0℃下向40B (74 mg, 0.2 mmol)於THF (3 mL) 及DCM (3 mL)中之溶液中添加PPh₃ (131 mg, 0.5 mmol)及偶氮二羧酸二第三丁基酯(DTAD) (115 mg, 0.5 mmol)。使混合物升溫至環境溫度並再攪拌4小時。將溶劑移除且殘餘物藉由矽膠管柱用0-10%, MeOH/DCM (10 CV)溶析、隨後製備型TLC純化，以獲得呈白色固體之實例40 (15 mg)。LC-MS (ESI)m/z 356.5 (M+H)⁺ ；¹ H NMR (500 MHz, 氯仿-d ) δ 8.12 (d,J = 7.7 Hz, 1H), 6.93 (ddd,J = 9.0, 3.1, 0.9 Hz, 1H), 6.78 (ddd,J = 9.0, 7.3, 3.0 Hz, 1H), 6.71 (dd,J = 9.1, 4.5 Hz, 1H), 6.28 (d,J = 7.7 Hz, 1H), 5.77 (dd,J = 15.2, 1.7 Hz, 1H), 4.38 - 4.33 (m, 1H), 3.98 (s, 1H), 3.91 (d,J = 1.4 Hz, 1H), 3.78 (dd,J = 15.1, 0.9 Hz, 1H), 3.45 (s, 3H), 3.43 - 3.36 (m, 1H), 2.45 (s, 3H)。實例 41

實例41係使用以下方案中所示之方法製備：

步驟1：[2-(2-乙醯基-4-氟-苯氧基)-乙基]-胺基甲酸第三丁基酯(41B). 向1-(5-氟-2-羥基-苯基)-乙酮(41A, 773 mg, 5.0 mmol)及(2-氯-乙基)-胺基甲酸第三丁基酯(1.80 g, 10.0 mmol)於DMF (20 mL)中之混合物中添加KI (2.0 mg, 0.012 mmol)及Cs₂ CO₃ (3.26 g, 10.0 mmol)。將混合物在80℃下攪拌過夜。然後將混合物冷卻至環境溫度，用EtOAc稀釋，並用1 N NaOH (5 x 10 mL)洗滌，直至LCMS顯示無1-(5-氟-2-羥基-苯基)-乙酮峰為止。將有機層經Na₂ SO₄ 乾燥並濃縮。然後將殘餘物藉由矽膠管柱用EtOAc/己烷(0-30%, 10 CV)溶析來純化，以獲得呈黃色固體之期望產物41B (1.1 g, 73.8%)。MS (ESI) m/z：320.3 (M+Na)⁺ 。 步驟2. (2-(4-氟-2-(1-羥乙基)苯氧基)乙基)胺基甲酸第三丁基酯(41C)。向41B (1.0 g, 3.36 mmol)於MeOH (10 mL)中之溶液中分批添加NaBH₄ (640 mg, 16.8 mmol)。將混合物在環境溫度下攪拌2小時。然後將溶液用水(50 mL)稀釋並用DCM (3 × 20 mL)萃取。合併之DCM層經Na₂ SO₄ 乾燥並濃縮。殘餘物藉由矽膠管柱用EtOAc/己烷(0-50%, 10 CV)溶析來純化，以獲得呈淺黃色固體之期望產物 (0.75g, 75%)。LC-MS (ESI)m/z 322.3 (M+Na)⁺ ；¹ H NMR (500 MHz, 氯仿-d ) δ 7.11 (dd,J = 9.2, 3.4 Hz, 1H), 6.89 (ddd,J = 9.0, 7.9, 3.2 Hz, 1H), 6.77 (dd,J = 8.9, 4.4 Hz, 1H), 5.09 (q,J = 6.6 Hz, 1H), 4.92 (d,J = 4.4 Hz, 1H), 4.03 (t,J = 5.2 Hz, 2H), 3.62 - 3.50 (m, 2H), 1.49 (d,J = 6.4 Hz, 3H), 1.45 (s, 9H)。 步驟3. 6-{1-[2-(2-第三丁氧基羰基胺基-乙氧基)-5-氟-苯基]-乙氧基}-咪唑并[1,2-b]噠嗪-3-甲酸乙酯(41D)。於-78℃下向41C (600 mg, 2.0 mmol)及{2-[4-氟-2-(1-羥基-乙基)-苯氧基]-乙基}-胺基甲酸第三丁基酯(450 mg, 2.0 mmol)於無水THF (40.0 mL)中之溶液中分批添加NaH (60%, 80 mg, 2.0 mmol)。將懸浮液於-78℃下攪拌4小時並使其升溫至0℃，並再攪拌4小時。然後將混合物置於冰箱中於-20℃下過夜。然後將混合物用冰與1 N HCl之混合物驟冷並用EtOAc (3 x 20 mL)萃取。有機層經Na₂ SO₄ 乾燥，濃縮並純化兩次，以獲得呈黃色固體之期望產物(240 mg, 25%)。LC-MS (ESI)m/z 511.6 (M+Na)⁺ ；¹ H NMR (500 MHz, 氯仿-d ) δ 8.16 (s, 1H), 7.90 (d,J = 9.7 Hz, 1H), 7.16 (dd,J = 9.0, 3.2 Hz, 1H), 0.95 (d,J = 9.5 Hz, 1H), 6.90 - 6.88 (m, 1H), 6.81 - 6.78 (m, 1H), 6.68 (q,J = 6.2 Hz, 1H), 5.84 - 5.68 (m, 1H), 4.38 (q,J = 7.2 Hz, 2H), 4.15 - 4.09 (m, 2H), 3.60 - 3.52 (m, 2H), 1.65 (d,J = 6.4 Hz, 3H), 1.38 (d,J = 7.2 Hz, 3H), 1.35 (s, 9H)。 步驟4. 化合物41D係使用類似於彼等本文所述之方法轉化為實例41。MS: 343.2 (M+H)⁺ ；¹ H NMR (500 MHz, 氯仿-d ) δ 9.82 (d,J = 7.0 Hz, 1H), 8.27 (s, 1H), 8.09 (d,J = 9.5 Hz, 1H), 7.18 (dd,J = 8.9, 3.2 Hz, 1H), 7.01 - 6.94 (m, 2H), 6.83 (dd,J = 9.0, 4.3 Hz, 1H), 6.60 - 6.53 (m, 1H), 4.63 - 4.52 (m, 1H), 4.27 - 4.16 (m, 1H), 4.16 - 4.04 (m, 1H), 3.70 - 3.56 (m, 1H), 1.70 (d,J = 6.4 Hz, 3H)實例 42

實例42係使用以下方案中所示之方法製備：

步驟1. 6-[(5-氟-2-羥基-苄基)-甲基-胺基]-咪唑并[1,2-b]噠嗪-3-甲酸乙酯(42B)。向4-氟-2-甲基胺基甲基-苯酚(20L, 305.2 mg, 1.97 mmol)及6-氯-咪唑并[1,2-b]噠嗪-3-甲酸乙酯(42A, 230 mg, 1.02 mmol)於DMSO (5 mL)中之混合物中添加KF (180 mg, 3.01 mmol)。將反應混合物於120℃下在氮氣下攪拌18小時。然後將溶液冷卻至環境溫度，用水(20 mL)稀釋並用EtOAc (3 x 50 mL)萃取。將合併之有機層進一步用水(3 × 50 mL)及鹽水(50 mL)洗滌，經Na₂ SO₄ 乾燥並濃縮。然後將殘餘物藉由矽膠管柱用EtOAc/己烷(0-50%, 10 CV)溶析來純化，以獲得呈白色固體之期望產物 (240 mg, 69%)。LC-MS (ESI)m/z 345.2 (M+H)⁺ ；¹ H NMR (500 MHz, 氯仿-d ) δ 8.61 (s, 1H), 8.17 (s, 1H), 7.91 (d,J = 10.0 Hz, 1H), 7.00 - 6.86 (m, 4H), 4.78 (s, 2H), 4.47 (qd,J = 7.2, 0.5 Hz, 2H), 3.17 (s, 3H), 1.41 (td,J = 7.1, 0.5 Hz, 3H)。 步驟2. 6-{[2-(2-第三丁氧基羰基胺基-乙氧基)-5-氟-苄基]-甲基-胺基}-咪唑并[1,2-b]噠嗪-3-甲酸乙酯(42C)。向6-[(5-氟-2-羥基-苄基)-甲基-胺基]-咪唑并[1,2-b]噠嗪-3-甲酸乙酯(2B, 200 mg, 0.58 mmol)及(2-氯-乙基)-胺基甲酸第三丁基酯(209 mg, 1.16 mmol)於DMF (5 mL)中之溶液總添加K₂ CO₃ (200 mg, 1.45 mmol)及KI (2.0 mg, 0.012 mmol)。將混合物在氮氣下於90℃下加熱4小時。然後混合物用水(20 mL)稀釋且用EtOAc (3 × 10 mL)萃取。然後將合併之有機層用水(3 x 5mL)及鹽水(2 x 5mL)洗滌。將有機層經Na₂ SO₄ 乾燥並濃縮。將所得殘餘物藉由矽膠管柱用EtOAc/己烷(0-100%, 10 CV)溶析純化，以獲得呈白色固體之42C (203 mg, 76%)。LC-MS (ESI)m/z 510.1 (M+Na)⁺ ；¹ H NMR (500 MHz, 氯仿-d ) δ (ppm) 8.16 (s, 1H), 7.85 (d,J = 9.9 Hz, 1H), 7.00 (dd,J = 8.9, 3.2 Hz, 1H), 6.95 - 6.87 (m, 2H), 6.80 (dd,J = 8.9, 4.3 Hz, 1H), 4.95 (s, 1H), 4.74 (s, 2H), 4.41 (q,J = 7.2 Hz, 2H), 4.04 (t,J = 5.2 Hz, 2H), 3.56 - 3.50 (m, 2H), 3.26 (s, 3H), 1.43 (s, 9H), 1.40 (t,J = 7.2 Hz, 3H)。 步驟3. 化合物42C係使用類似於彼等本文所述之方法轉化為實例42。MS: 342.5 (M+H)⁺ ；¹ H NMR (500 MHz, 氯仿-d ) δ 10.01 (d,J = 6.9 Hz, 1H), 8.17 (s, 1H), 8.04 (d,J = 10.0 Hz, 1H), 7.07 - 7.04 (m, 1H), 7.00 (d,J = 10.0 Hz, 1H), 6.96 - 6.92 (m, 1H), 6.84 (dd,J = 9.1, 4.5 Hz, 1H), 5.69 (dd,J = 15.8, 1.6 Hz, 1H), 4.55 (dt,J = 9.9, 3.7 Hz, 1H), 4.20 - 4.09 (m, 2H), 3.98 (dd,J = 15.9, 1.0 Hz, 1H), 3.66 - 3.62 (m, 1H), 3.61 (s,3H)。實例 51-1

步驟1 向A8 (399.4 mg, 1.16 mmol)及(2-氯乙基)胺基甲酸第三丁基酯(260.5 mg, 1.45 mmol)於DMF (5.8 mL)中之溶液中添加K₂ CO₃ (801.6 mg, 5.80 mmol)並在攪拌的同時於80℃下加熱6小時。使反應冷卻至環境溫度並用DCM (3 mL)稀釋，藉助注射器式過濾器過濾，並在減壓下濃縮。急驟層析(ISCO系統，二氧化矽(12 g), 0-70%乙酸乙酯於己烷中)提供51-1A (407.4 mg, 0.836 mmol, 72%產率)。 步驟2. 於環境溫度下向51-1A (407.4 mg, 0.836 mmol)於MeOH (6 mL)及THF (4 mL)中之溶液中添加LiOH水溶液(2M, 4.0 mL)。將反應溶液於70℃下加熱2小時。將反應燒瓶冷卻至環境溫度，用水及甲醇稀釋，且然後用HCl水溶液(2 M, 4 mL)驟冷至pH ＜5。將混合物用DCM (3 x 5 mL)萃取，經Na₂ SO₄ 乾燥，在減壓下濃縮，並在高真空下乾燥過夜。向酸產物於DCM (6 mL)中之溶液中添加4 M於1,4-二噁烷中之HCl (2.97 mL)。將混合物於室溫下攪拌3小時，且然後在減壓下濃縮並在高真空下乾燥。於室溫下向de-Boc產物及FDPP (352.9 mg, 0.918 mmol)於DMF (21 mL)中之溶液中添加Hunig鹼(539.5 mg, 0.327 mmol)。將混合物攪拌2.5小時，且然後用2 M Na₂ CO₃ 溶液(21 mL)使反應驟冷。將混合物攪拌15分鐘且然後用DCM (4 × 10 mL)萃取。合併之萃取物經Na₂ SO₄ 乾燥，且在減壓下濃縮。殘餘物用急驟層析(ISCO系統，二氧化矽(12 g), 0-11.25%甲醇於二氯甲烷中)純化，以提供51-1 (164.0 mg, 0.480 mmol, 57.55 %產率，三步)。實例 53

實例53係使用以下方案中所示之方法製備：

步驟1. 5-[1-(5-氟-2-羥基-苯基)-乙基胺基]-吡唑并[1,5-a]嘧啶-3-甲酸(53A)。向5-[(5-氟-2-羥基-苄基)-甲基-胺基]-吡唑并[1,5-a]嘧啶-3-甲酸乙酯(20M, 300 mg, 0.87 mmol)於MeOH (5 mL)中之溶液中添加LiOH (420 mg, 10 mmol)，隨後添加5 mL H₂ O。將混合物於60℃下攪拌4小時。將溶液冷卻至環境溫度，部分濃縮並用1 N HCl酸化直至pH 2-3。將所得懸浮液用EtOAc (3 x 20 mL)萃取。經Na₂ SO₄ 乾燥合併之有機層並濃縮。殘餘物直接用於下一步驟中。LCMS (ESI⁺ )m/z 317.4 (M+H)⁺ 。 步驟2. 3-({5-[(5-氟-2-羥基-苄基)-甲基-胺基]-吡唑并[1,5-a]嘧啶-3-羰基}-胺基)-2-羥基-丙酸甲酯(53B)。於0℃下向53A (80 mg, 0.25 mmol)及3-胺基-2-羥基-丙酸甲酯鹽酸鹽(70 mg, 0.5 mmol)於DCM (5 mL)中之溶液中添加DIPEA (1.0 mL, 5.7 mmol)，隨後添加HATU (140.0 mg, 0.5 mmol)。將溶液緩慢升溫至環境溫度。將混合物用水(25 mL)稀釋且用EtOAc (3 x 25 mL)萃取。將合併之有機層用1 N HCl (3 x 20 mL)及鹽水(50 mL)洗滌，並經Na₂ SO₄ 乾燥。將溶劑移除且且所得白色固體直接用於下一步驟。LC-MS (ESI⁺ )m/z 418.4 (M+H)⁺ 。 步驟3. 11-氟-14-甲基-4-側氧基-4,5,6,7,13,14-六氫-1,15-乙烯橋基吡唑并[4,3-f][1,4,8,10]苯并氧雜三氮雜十三熳環-7-甲酸甲酯(53C)。向53B (83 mg, 0.2 mmol)於DCM (5 mL)中之溶液中添加PPh₃ (263 mg, 1.0 mmol)，隨後添加CBr₄ (332 mg, 1.0 mmol)。將混合物在環境溫度下攪拌過夜。將溶劑移除且並將殘餘物重新溶解於DMF (5 mL)中，隨後添加K₂ CO₃ (116.8 mg, 0.84 mmol)。然後將混合物於80℃下攪拌，直至完全形成期望產物為止。將混合物用EtOAc稀釋且用水洗滌。將有機層經Na₂ SO₄ 乾燥並濃縮。殘餘物藉由矽膠管柱(0-10%, MeOH/DCM)純化，以獲得呈白色固體之53C (40 mg)。LC-MS (ESI⁺ )m/z 400.2 (M+H)⁺ 。 步驟4. 向53C (20 mg, 0.05 mmol)中添加NH₃ 之MeOH溶液(7 N, 2 mL)。將混合物在60℃下攪拌過夜。將溶劑移除且殘餘物藉由矽膠管柱(0-10%, MeOH/DCM)純化，以獲得呈灰白色固體之實例53 (8 mg)。LC-MS (ESI⁺ )m/z 385.5 (M+H)⁺ ；¹ H NMR (300 MHz, 氯仿-d ) δ 8.41 (s, 1H), 8.34 (d,J = 7.9 Hz, 1H), 8.17 (s, 1H), 6.99 - 6.92 (m, 2H), 6.77 (dd,J = 6.2, 3.5 Hz, 1H), 6.38 (d,J = 7.9 Hz, 1H), 5.63 - 5.44 (m, 2H), 5.09 (dd,J = 11.0, 8.4 Hz, 1H), 4.38 (dd,J = 14.7, 11.0 Hz, 1H), 4.28 - 4.17 (m, 1H), 4.17 - 4.07 (m, 2H), 3.22 (s, 3H)。實例 54

實例54係使用以下方案中所示之方法製備：

向化合物53C (20 mg, 0.05 mmol)於MeOH (2 mL)中之溶液中逐份添加NaBH₄ (19 mg, 0.5 mmol)。將混合物攪拌4 小時。將溶劑移除且殘餘物藉由矽膠管柱(0-10%, MeOH/DCM)純化，以獲得呈白色固體之期望產物 (8 mg)。LC-MS (ESI⁺ )m/z 372.5 (M+H)⁺ ；¹ H NMR (300 MHz, 氯仿-d ) δ 8.39 (s, 1H), 8.32 (d,J = 7.9 Hz, 1H), 7.01 - 6.85 (m, 3H), 6.35 (d,J = 8.0 Hz, 1H), 5.55 - 5.43 (m, 1H), 4.92 - 4.82 (m, 1H), 4.09 - 3.98 (m, 2H), 3.80 - 3.70 (m, 3H), 3.23 (s, 3H)。實例 93

步驟1. 向(R )-(2-羥基丙基)胺基甲酸第三丁基酯(1.00 g, 5.71 mmol)及對甲苯磺醯氯(1.14 g, 6.00 mmol)於DCM (29 mL)中之溶液中添加三乙胺(1.44 g, 14.28 mmol)並將混合物於室溫下攪拌48小時。將反應溶液在減壓下濃縮且殘餘物用急驟層析(ISCO系統，二氧化矽(40 g), 0-20%乙酸乙酯於己烷中)純化，以提供(R )-4-甲基苯磺酸1-((第三丁氧基羰基)胺基)丙-2-基酯(1.12 g, 3.40 mmol, 59.54%產率)。 步驟2. 向A8 (100.00 mg, 0.290 mmol)及(R )-4-甲基苯磺酸1-((第三丁氧基羰基)胺基)丙-2-基酯(143.50 mg, 0.436 mmol)於DMF (1.45 mL)中之溶液中添加K₂ CO₃ (200.7 mg, 1.45 mmol)並在攪拌的同時在80℃下加熱16小時。使反應冷卻至環境溫度並用DCM (3 mL)稀釋，藉助注射器式過濾器過濾，並在減壓下濃縮。急驟層析(ISCO系統，二氧化矽(12 g), 0-60%乙酸乙酯於己烷中)提供93A (32.90 mg, 0.0656 mmol, 22.59%產率)。 步驟3. 於環境溫度下向93A (32.90 mg, 0.0656 mmol)於MeOH (3 mL)及THF (2 mL)中之溶液中添加LiOH水溶液(2M, 2 mL)。將反應溶液於70℃下加熱2小時。將反應燒瓶冷卻至環境溫度，用水及甲醇稀釋，且然後用HCl水溶液(2 M, 2 mL)驟冷至pH ＜5。將混合物用DCM (3 x 5 mL)萃取，經Na₂ SO₄ 乾燥，在減壓下濃縮，並在高真空下乾燥過夜。向酸產物於DCM (4 mL)中之溶液中添加4 M於1,4-二噁烷中之HCl (2.0 mL)。將混合物於室溫下攪拌3小時，且然後在減壓下濃縮並在高真空下乾燥。於室溫下向de-Boc產物及FDPP (27.62 mg, 0.0719 mmol)於DMF (1.6 mL)中之溶液中添加Hunig鹼(42.23 mg, 0.327 mmol)。將混合物攪拌2.5小時，且然後用2 M Na₂ CO₃ 溶液(2 mL)使反應驟冷。將混合物攪拌15分鐘，然後用DCM (4 × 10 mL)萃取。合併之萃取物經Na₂ SO₄ 乾燥，且在減壓下濃縮。殘餘物用急驟層析(ISCO系統，二氧化矽(12 g), 0-10%甲醇於二氯甲烷中)純化，以提供93 (10.1 mg, 0.0284 mmol, 43.49%產率，三步)。實例 104 、 106 及 107

步驟1. 向A17^. HCl (38 mg, 0.096 mmol)及(2-氯乙基)胺基甲酸第三丁基酯(12.9 mg, 0.072 mmol)於DMF (0.5 mL)中之溶液中添加K₂ CO₃ (33.1 mg, 0.24 mmol)並在攪拌的同時在80℃下攪拌1.5小時。使反應冷卻至環境溫度並用DCM (3 mL)稀釋，藉助注射器式過濾器過濾，並在減壓下濃縮。急驟層析(ISCO系統，二氧化矽(12 g), 0-60%乙酸乙酯於己烷中)提供104A (20.8 mg, 0.0413 mmol, 86.3%產率)。 步驟2. 104係根據一般方法C自呈白色固體之104A製備。 步驟3. 向104 (4.6 mg, 0.0129 mmol)於DCM (0.3 mL)中之溶液中添加3-氯過氧苯甲酸甲酯(2.2 mg, 0.0129 mmol)並將反應攪拌20分鐘，隨後添加飽和NaHCO₃ 水溶液(3 mL)並用DCM (4 x 4mL)萃取。合併之萃取物經Na₂ SO₄ 乾燥，且在減壓下濃縮。急驟層析(ISCO系統，二氧化矽(12 g), 0-12.5%甲醇於二氯甲烷中)提供106 (0.5 mg, 10.4%產率)及107 (1.7 mg, 33.9%產率)。 以下實例係使用類似於彼等本文特定闡述之一般方法A、B及C之方法來製備，如本文所述。 實例 分析數據 11-1 MS: 377.7 (M+H)⁺ ；¹ H NMR (500 MHz, 氯仿-d ) δ 8.49 (d,J = 7.9 Hz, 1H), 8.29 (s, 1H), 7.13 (dd,J = 9.2, 7.8 Hz, 1H), 7.02 (d,J = 7.3 Hz, 1H), 6.92 (dd,J = 9.4, 3.9 Hz, 1H), 6.82 (d,J = 7.7 Hz, 1H), 4.63 - 4.55 (m, 1H), 4.45 (dd,J = 10.8, 5.4 Hz, 1H), 4.31 - 4.23 (m, 1H), 4.00 (dd,J = 16.2, 8.7 Hz, 1H), 1.70 (d,J = 6.9 Hz, 3H)。 20 MS: 342.2 [M+H]⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) 9.43 (dd,J = 6.9, 2.7 Hz, 1 H), 8.76 (d,J = 7.9 Hz, 1 H), 8.10 (s, 1 H), 7.19 - 7.25 (m, 1 H), 7.03 - 7.07 (m, 2 H), 6.72 (d,J = 7.9 Hz, 1 H), 5.64 (dd,J = 14.9, 1.5 Hz, 1 H), 4.48 (dt,J = 10.2, 4.3 Hz, 1 H), 4.04 - 4.10 (m, 2 H), 3.81 - 3.87 (m, 1 H), 3.58 (s, 3 H), 3.38 - 3.46 (m, 1 H)。 39 LC-MS (ESI)m/z 376.5 (M+H)⁺ .¹ H NMR (500 MHz, 氯仿-d ) δ 9.51 (s, 1H), 8.40 - 8.33 (m, 2H), 7.03 (ddd,J = 8.9, 8.0, 0.7 Hz, 1H), 6.78 (dd, J = 9.3, 4.2 Hz, 1H), 6.40 (d, J = 7.9 Hz, 1H), 5.97 (dd, J = 15.0, 2.1 Hz, 1H), 4.49 - 4.43(m, 1H), 4.31 (ddd, J = 10.9, 6.4, 4.5 Hz, 1H), 4.12 - 4.03 (m, 1H), 3.91 (d, J = 14.9 Hz, 1H), 3.72 - 3.63 (m, 1H), 3.56 (s, 3H)。 40 MS: 356.5 (M+H)⁺ ；¹ H NMR (500 MHz, 氯仿-d ) δ 8.12 (d,J = 7.7 Hz, 1H), 6.93 (ddd,J = 9.0, 3.1, 0.9 Hz, 1H), 6.78 (ddd,J = 9.0, 7.3, 3.0 Hz, 1H), 6.71 (dd,J = 9.1, 4.5 Hz, 1H), 6.28 (d,J = 7.7 Hz, 1H), 5.77 (dd,J = 15.2, 1.7 Hz, 1H), 4.38 - 4.33 (m, 1H), 3.98 (s, 1H), 3.91 (d,J = 1.4 Hz, 1H), 3.78 (dd,J = 15.1, 0.9 Hz, 1H), 3.45 (s, 3H), 3.43 - 3.36 (m, 1H), 2.45 (s, 3H)。 41 MS: 343.2 (M+H)⁺ ；¹ H NMR (500 MHz, 氯仿-d ) δ 9.82 (d,J = 7.0 Hz, 1H), 8.27 (s, 1H), 8.09 (d,J = 9.5 Hz, 1H), 7.18 (dd,J = 8.9, 3.2 Hz, 1H), 7.01 - 6.94 (m, 2H), 6.83 (dd,J = 9.0, 4.3 Hz, 1H), 6.60 - 6.53 (m, 1H), 4.63 - 4.52 (m, 1H), 4.27 - 4.16 (m, 1H), 4.16 - 4.04 (m, 1H), 3.70 - 3.56 (m, 1H), 1.70 (d,J = 6.4 Hz, 3H)。 42 MS: 342.5 (M+H)⁺ ；¹ H NMR (500 MHz, 氯仿-d ) δ 10.01 (d,J = 6.9 Hz, 1H), 8.17 (s, 1H), 8.04 (d,J = 10.0 Hz, 1H), 7.07 - 7.04 (m, 1H), 7.00 (d,J = 10.0 Hz, 1H), 6.96 - 6.92 (m, 1H), 6.84 (dd,J = 9.1, 4.5 Hz, 1H), 5.69 (dd,J = 15.8, 1.6 Hz, 1H), 4.55 (dt,J = 9.9, 3.7 Hz, 1H), 4.20 - 4.09 (m, 2H), 3.98 (dd,J = 15.9, 1.0 Hz, 1H), 3.66 - 3.62 (m, 1H), 3.61 (s, 3H)。 43 MS: 356.6 (M+H)⁺ ；¹ H NMR (500 MHz, 氯仿-d ) δ 8.27 (d,J = 7.9 Hz, 1H), 8.17 (s, 1H), 6.96 (ddd,J = 9.0, 3.1, 0.9 Hz, 1H), 6.88-6.81 (m, 1H), 6.77 (dd,J = 9.0, 4.7 Hz, 1H), 6.41 (d,J = 7.9 Hz, 1H), 5.71-5.63 (m, 1H), 4.43 (dt,J = 10.0, 4.4 Hz, 1H), 4.09 (ddd,J = 10.3, 8.4, 4.0 Hz, 1H), 3.96-3.92 (m, 1H), 3.87 (dd,J = 15.0, 0.8 Hz, 1H), 3.77 (dd,J = 15.0, 7.2 Hz, 1H), 3.55-3.51 (m, 2H), 1.33 (t,J = 7.2 Hz, 3H)。 44 MS: 370.1 (M+H)⁺ ；¹ H NMR (500 MHz, DMSO-d ₆ ) 9.28 (dd,J = 5.8, 4.0 Hz, 1H), 8.71 (d,J = 7.9 Hz, 1 H), 8.08 (s, 1 H), 7.16 (dd,J = 9.5, 3.0 Hz, 1 H), 6.98 - 7.09 (m, 2 H), 6.82 (d,J = 8.0 Hz, 1 H), 5.48 (d,J = 15.0 Hz, 1 H), 4.42 - 4.51 (m, 1 H), 4.16 - 4.23 (m, 1 H), 4.04 - 4.14 (m, 2 H), 3.74 - 3.82 (m, 2 H), 3.39 - 3.46 (m, 1 H), 1.58 - 1.81 (m, 2 H), 0.97 (t,J = 7.3 Hz, 3 H)。 45 MS: 370.1 (M+H)⁺ ；¹ H NMR (500 MHz, DMSO-d ₆ ) 8.87 - 8.98 (m, 1 H), 8.69 - 8.79 (m, 1 H), 8.04 - 8.12 (m, 1 H), 7.10 - 7.18 (m, 1 H), 6.92 - 7.04 (m, 3 H), 5.09 - 5.18 (m, 1 H), 4.61 - 4.69 (m, 1 H), 4.50 - 4.56 (m, 1 H), 4.41 - 4.49 (m, 1 H), 4.16 (d,J = 15.30 Hz, 1 H), 3.57 - 3.68 (m, 2 H), 1.23 - 1.27 (m, 6 H)。 46 MS: 368.1 (M+H)⁺ ；¹ H NMR (500 MHz, DMSO-d ₆ ) 9.35 (dd,J = 7.0, 2.7 Hz, 1 H), 8.81 (d,J = 7.8 Hz, 1 H), 8.07 - 8.15 (m, 1 H), 7.19 (dd,J =9.2, 2.3 Hz, 1 H), 7.01 - 7.08 (m, 2 H), 6.98 (d,J = 7.8 Hz, 1 H), 5.53 (dd,J = 15.1, 1.5 Hz, 1 H), 4.47 (dt,J = 10.22, 4.25 Hz, 1 H), 4.34 (t,J = 5.08 Hz, 1 H), 4.14 (d,J = 15.30 Hz, 1 H), 4.02 - 4.10 (m, 2 H), 3.79 - 3.92 (m, 1 H), 1.12 - 1.16 (m, 1 H), 1.03 - 1.08 (m, 2 H), 0.81 - 0.86 (m, 1 H)。 47 MS: 372.1 (M+H)⁺ ；¹ H NMR (500 MHz, DMSO-d ₆ ) 9.25 (t,J = 4.9 Hz, 1 H), 8.71 (d,J = 7.9 Hz, 1 H), 8.07 (s, 1 H), 7.22 (dd,J = 9.5, 3.0 Hz, 1 H), 7.05 - 7.11 (m, 1 H), 6.96 - 7.04 (m, 1 H), 6.83 (d,J = 8.0 Hz, 1 H), 5.51 (d,J = 14.6 Hz, 1 H), 4.96 (t,J = 5.4 Hz, 1 H), 4.42 - 4.51 (m, 1 H), 4.24 (ddd,J = 10.9, 6.8, 4.2 Hz, 1 H), 4.09 - 4.20 (m, 2 H), 3.91 (dt,J = 15.2, 5.5 Hz, 1 H), 3.67 - 3.82 (m, 3 H), 3.39 - 3.51 (m, 1 H)。 48 MS: 356.1 (M+H)⁺ ；¹ H NMR (500 MHz, DMSO-d ₆ ) 9.70 (d,J = 8.6 Hz, 1 H), 8.76 (d,J = 8.0 Hz, 1 H), 8.09 (s, 1 H), 7.25 (dd,J = 9.5, 3.0 Hz, 1 H), 7.01 - 7.11 (m, 1 H), 6.94 - 7.00 (m, 1 H), 6.71 (d,J = 8.0 Hz, 1 H), 5.64 - 5.73 (m, 1 H), 4.34 (d,J = 9.6 Hz, 1 H), 4.28 (t,J = 8.9 Hz, 1 H), 4.10 (d,J = 15.0 Hz, 1 H), 3.94 (dd,J = 9.6, 3.6 Hz, 1 H), 3.58 (s, 3 H), 1.36 (d,J = 6.8 Hz, 3 H)。 49 MS: 324.1 (M+H)⁺ ；¹ H NMR (500 MHz, DMSO-d ₆ ) 9.52 (d,J = 4.5 Hz, 1 H), 8.74 (d,J = 7.9 Hz, 1 H), 8.09 (s, 1 H), 7.44 (d,J = 7.6 Hz, 1 H), 7.18 - 7.25 (m, 1 H), 7.02 (d,J = 7.9 Hz, 1 H), 6.93 (t,J = 7.4 Hz, 1 H), 6.71 (d,J = 7.9 Hz, 1 H), 5.69 (d,J = 14.8 Hz, 1 H), 4.47 (dt,J = 10.1, 4.1 Hz, 1 H), 4.01 - 4.13 (m, 2 H), 3.83 - 3.90 (m, 1 H), 3.54 - 3.61 (m, 3 H), 3.38 - 3.46 (m, 1 H)。 50 MS: 328.1 (M+H)⁺ ；¹ H NMR (500 MHz, DMSO-d ₆ ) 9.80 (d,J = 7.82 Hz, 1 H), 8.89 (t,J = 6.00 Hz, 1 H), 8.58 (d,J = 7.62 Hz, 1 H), 8.03 - 8.08 (m, 1 H), 7.12 - 7.18 (m, 1 H), 6.99 - 7.05 (m, 2 H), 6.39 (d,J = 7.62 Hz, 1 H), 5.13 - 5.21 (m, 1 H), 4.46 - 4.53 (m, 1 H), 3.87 - 4.00 (m, 4 H)。 51 MS: 342.3 (M+H)⁺ ；¹ H NMR (500 MHz, 含有CD₃ OD之氯仿-d ) δ 8.14 (s, 1H), 7.81 - 7.72 (m, 1H), 7.10 (dd,J = 9.0, 3.0 Hz, 1H), 6.88 (ddd,J = 9.0, 7.6, 3.0 Hz, 1H), 6.80 (dd,J = 9.2, 4.4 Hz, 1H), 6.20 (d,J = 7.4 Hz, 1H), 5.75 (td,J = 7.2, 1.9 Hz, 1H), 4.52 - 4.46 (m, 1H), 4.09 (tdd,J = 9.6, 6.4, 3.9 Hz, 2H), 3.60 - 3.52 (m, 1H), 1.52 (d,J = 7.0 Hz, 3H)。 51-1 MS: 342.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.71 (br d,J =5.21 Hz, 1 H), 8.77 (br d,J =6.86 Hz, 1 H), 8.57 (d,J =7.41 Hz, 1 H), 8.04 (s, 1 H), 7.11 - 7.22 (m, 1 H), 6.96 - 7.04 (m, 2 H), 6.36 (d,J =7.68 Hz, 1 H), 5.63 (br dd,J =6.86, 5.49 Hz, 1 H), 4.50 (dt,J =10.15, 3.98 Hz, 1 H), 4.01 (td,J =9.61, 3.84 Hz, 1H), 3.87 (dt,J =10.09, 3.74 Hz, 1 H), 3.35 - 3.46 (m, 1 H), 1.45 (d,J =7.14 Hz, 3 H)。 52 MS: 376.5 (M+H)⁺ ；¹ HNMR (500 MHz, 氯仿-d ) δ 9.92 (s, 1H), 8.29 - 8.18 (m, 2H), 7.01 (dd,J = 9.2, 8.2 Hz, 1H), 6.77 (dd,J = 9.2, 4.2 Hz, 1H), 6.37 - 6.26 (m, 1H), 6.19 (d,J = 7.6 Hz, 1H), 6.12 (s, 1H), 4.53 - 4.45 (m, 1H), 4.14 (d,J = 6.3 Hz, 1H), 4.04 - 3.98 (m, 1H), 3.57 (s, 1H), 1.74 (d,J = 7.3 Hz, 3H)。 55 MS: 385.6 (M+H)⁺ ；¹ H NMR (300 MHz, 甲醇-d ₄ ) 8.35 (d,J = 7.6 Hz, 1 H), 8.24 (s, 1 H), 7.24 - 6.96 (m, 1 H), 6.82 (m, 2 H), 6.41 (dd,J = 7.7, 4.8 Hz, 1 H), 5.59 (m, 1 H), 5.31—5.05 (m, 1 H), 4.39 - 4.21 (m, 1 H), 3.17 - 3.02 (m, 1 H), 1.58 (d,J = 6.9 Hz, 3H)。 56 MS: 372.3 (M+H)⁺ ；¹ H NMR (300 MHz, 甲醇-d ₄ ) δ 8.35 (d,J = 7.6 Hz, 1 H), 8.18 (s, 1 H), 7.05 (d,J = 9.4 Hz, 1 H), 6.82 (dd,J = 6.5, 1.8 Hz, 1 H), 6.39 (d,J = 7.6 Hz, 1 H), 5.60 (m, 1 H), 4.92 (m, 2H), 4.08 (dd,J = 13.1, 9.9 Hz, 1 H), 3.91 - 3.81 (m, 2 H), 3.73 (dd,J = 12.6, 5.1 Hz, 1 H), 1.58 (d,J = 6.9 Hz, 3H)。 57 MS: 371.4 (M+H)⁺ .¹ H NMR (300 MHz, 甲醇-d ₄ ) δ 8.46 (d,J = 7.6 Hz, 1H), 8.41 (s, 1H), 7.00 (dd,J = 9.1, 2.9 Hz, 1H), 6.88 - 6.78 (m, 2H), 6.58 (d,J = 7.7 Hz, 1H), 5.20 (s, 1H), 4.65 (s, 2H), 3.49 (q,J = 7.3 Hz, 2H)。 58 MS: 358.5 (M+H)⁺ . )⁺ .¹ H NMR (300 MHz, 氯仿-d ) δ 8.37 (s, 1H), 8.21 (d,J = 7.6 Hz, 1H), 6.90 (d,J = 7.5 Hz, 3H), 6.10 (d,J = 7.6 Hz, 1H), 5.88 (s, 1H), 5.11 - 4.85 (m, 3H), 4.20 (dd,J = 15.1, 5.7 Hz, 1H), 4.05 (dd,J = 14.0, 9.9 Hz, 1H), 3.83 - 3.68 (m, 3H), 3.44 (d,J = 7.3 Hz, 1H)。 59 MS: 386.1 (M+H)⁺ ；¹ H NMR (500 MHz, DMSO-d ₆ ) 9.97 (s, 1 H), 8.57 (d,J = 7.6 Hz, 1 H), 8.40 (d,J = 5.9 Hz, 1 H), 8.10 (s, 1 H), 6.85 (dd,J = 8.9, 4.8 Hz, 1 H), 6.60 (d,J = 7.6 Hz, 1 H), 7.23 (dd,J = 9.3, 3.2 Hz, 1 H), 7.00 (td,J = 8.6, 3.2 Hz, 1 H), 5.90 (d,J = 6.4 Hz, 1 H), 4.27 - 4.34 (m, 2 H), 3.90 (t,J = 9.33 Hz, 2 H), 3.66 (s, 3 H)。 60 MS: 371.1 (M+H)⁺ ；¹ H NMR (500 MHz, DMSO-d ₆ ) 9.98 (bs, 1H), 8.54 (d,J = 7.6 Hz, 1 H), 8.33 (d,J = 6.24 Hz, 1 H), 8.07 (s, 1 H), 7.44 (bs, 1 H), 7.28 (bs, 1 H), 7.18 (dd,J = 9.6, 3.2 Hz, 1 H), 6.94 (td,J = 8.5, 3.2 Hz, 1 H), 6.83 (dd,J = 8.9, 4.9 Hz, 1 H), 6.66 (d,J = 7.5 Hz, 1 H), 5.86 (d,J = 6.4 Hz, 1 H), 4.22 - 4.36 (m, 2 H), 3.84 - 3.97 (m, 2 H)。 61 MS: 343.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.22 (dd,J =6.87, 2.86 Hz, 1 H), 8.78 (d,J =7.45 Hz, 1 H), 8.10 (s, 1 H), 8.06 (d,J =3.44 Hz, 1 H), 7.80 (dd,J =8.59, 2.86 Hz, 1 H), 6.74 (d,J =8.02 Hz, 1 H), 5.44 (dd,J =14.89, 1.72 Hz, 1 H), 4.69 (ddd,J =10.88, 8.59, 4.58 Hz, 1 H), 4.32 - 4.39 (m, 1 H), 4.21 (d,J =15.47 Hz, 1 H), 3.80 - 3.88 (m, 1 H), 3.58 (s, 3 H), 3.41 - 3.49 (m, 1 H)。 62 MS: 371.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.72 - 8.80 (m, 2 H), 8.08 (s, 1 H), 8.01 (d,J =2.74 Hz, 1 H), 7.49 (dd,J =8.78, 2.74 Hz, 1 H), 7.00 (d,J =8.23 Hz, 1 H), 4.94 - 5.06 (m, 2 H), 4.57 - 4.68 (m, 1 H), 4.26 - 4.39 (m, 2 H), 3.66 - 3.77 (m, 1 H), 3.49 - 3.55 (m, 1 H), 1.56 (d,J =6.59 Hz, 3 H), 1.22 (d,J =6.60 Hz, 3 H)。 66 MS: 368.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.56 (dd,J =6.87, 2.86 Hz, 1 H), 9.02 (d,J =6.87 Hz, 1 H), 8.58 (d,J =8.02 Hz, 1 H), 8.03 (s, 1 H), 7.18 (dd,J =9.74, 2.86 Hz, 1 H), 6.97 - 7.08 (m, 2 H), 6.41 (d,J =7.45 Hz, 1 H), 4.68 - 4.80 (m, 1 H), 4.48 (dt,J =10.60, 4.15 Hz, 1 H), 4.05 (ddd,J =10.45, 8.45, 4.01 Hz, 1 H), 3.75 - 3.84 (m, 1 H), 3.36 - 3.43 (m, 1 H), 1.26 - 1.38 (m, 1 H)。0.63 (tt,J =8.74, 4.44 Hz, 1 H), 0.37 - 0.49 (m, 2 H), 0.28 (dq,J =9.31,4.53 Hz, 1 H)。 67 MS: 370.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.75 (br d,J =6.30 Hz, 1 H), 8.78 (d,J =7.45 Hz, 1 H), 8.57 (d,J =8.02 Hz, 1 H) 8.04 (s, 1 H), 7.06 (dt,J =9.16, 1.43 Hz, 1 H), 6.98 - 7.02 (m, 2 H), 6.39 (d,J =7.45 Hz, 1 H), 5.13 (ddd,J =10.02, 7.73, 1.72 Hz, 1 H), 4.51 (dt,J =9.88, 3.65 Hz, 1 H) 3.94 (td,J =9.88, 3.72 Hz, 1 H), 3.82 - 3.90 (m, 1 H), 3.39 - 3.43 (m, 1 H), 1.96 - 2.09 (m, 1 H), 1.12 (d,J =6.30 Hz, 3 H), 0.68 (d,J =6.30 Hz, 3 H)。 75 MS: 356.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.73 (d,J =8.02 Hz, 1 H), 8.25 (t,J =4.30 Hz, 1 H), 8.10 (s, 1 H), 7.14 - 7.21 (m, 1 H), 7.00 - 7.04 (m, 2 H), 6.68 (d,J =8.02 Hz, 1 H), 5.75 (br d,J =14.32 Hz, 1 H), 4.33 - 4.43 (m, 1 H), 4.22 (br d,J =6.87 Hz, 1 H), 4.05 (br d,J =14.89 Hz, 1 H), 3.59 - 3.68 (m, 1 H), 3.59 - 3.68 (m, 1 H), 3.37 - 3.45 (m, 1 H), 1.98 - 2.17 (m, 2 H)。 76-1 MS: 356.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.68 (d,J =7.45 Hz, 1 H), 8.53 (d,J =7.45 Hz, 1 H), 8.40 (s, 1 H), 8.03 (s, 1 H), 7.11 - 7.18 (m, 1 H), 6.96 - 7.00 (m, 2 H), 6.32 (d,J =7.45 Hz, 1 H), 5.65 - 5.74 (m, 1 H), 4.29 - 4.36 (m, 1 H), 4.20 - 4.26 (m, 1 H), 3.54 - 3.62 (m, 1 H), 3.39 - 3.47 (m, 1 H), 1.98 - 2.17 (m, 2 H), 1.41 (d,J =7.45 Hz, 3 H)。 84 MS: 358.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.78 (d,J =6.79 Hz, 1 H), 8.58 (d,J =7.62 Hz, 1 H), 8.05 (s, 1 H), 7.36 (d,J =2.61 Hz, 1 H), 7.21 (dd,J =8.85, 2.68 Hz, 1 H), 7.03 (d,J =8.85 Hz, 1 H), 6.36 (d,J =7.68 Hz, 1 H), 5.62 (quin,J =6.90 Hz, 1 H), 4.52 (dt,J =10.15, 3.98 Hz, 1 H), 3.98 - 4.11 (m, 1 H), 3.80 - 3.92 (m, 1 H), 3.35 - 3.47 (m, 1 H), 1.45 (d,J =7.07 Hz, 3 H)。 85 MS: 356.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.73 (br d,J =5.49 Hz, 1 H), 8.74 (d,J =7.14 Hz, 1 H), 8.57 (d,J =7.68 Hz, 1 H), 8.04 (s, 1 H), 7.06 - 7.14 (m, 1 H), 6.97 - 7.03 (m, 2 H), 6.37 (d,J =7.68 Hz, 1 H), 5.33 - 5.45 (m, 1 H), 4.51 (dt,J =10.15, 3.43 Hz, 1 H), 3.98 (td,J =9.88, 3.84 Hz, 1 H), 3.82 - 3.93 (m, 1 H), 3.39 (td,J =9.61, 2.74 Hz, 1 H), 1.85 - 1.99 (m, 1 H), 1.62 - 1.76 (m, 1 H), 0.87 (t,J =7.14 Hz, 3 H)。 86 MS: 382.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.74 (dd,J =7.16, 2.00 Hz, 1 H), 8.64 (d,J =6.87 Hz, 1 H), 8.57 (d,J =7.45 Hz, 1 H) 8.05 (s, 1 H), 6.95 - 7.06 (m, 3 H), 6.38 (d,J =8.02 Hz, 1 H), 5.47 (ddd,J =10.60, 7.16, 1.15 Hz, 1 H), 4.54 (dt,J =10.17, 3.79 Hz, 1 H), 4.01 (td,J =9.59, 3.72 Hz, 1 H), 3.80 - 3.90 (m, 1 H), 3.39 - 3.48 (m, 1 H), 2.66 - 2.77 (m, 1 H), 2.12 - 2.23 (m, 1 H), 1.83 (br d,J =2.29 Hz, 3 H), 1.55 - 1.73 (m, 2 H)。 87 MS: 346.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.40 (s, 1 H), 8.77 (d,J =8.23 Hz, 1 H), 8.10 (s, 1 H), 7.19 - 7.26 (m, 1 H), 7.01 - 7.08 (m, 2 H), 6.72 (d,J =8.23 Hz, 1 H), 5.64 (dd,J =15.09, 1.37 Hz, 1 H), 4.08 (d,J =14.82 Hz, 1 H), 3.58 (s, 3 H)。 88 MS: 404.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.70 (dd,J =6.87, 2.86 Hz, 1 H), 9.26 (d,J =7.45 Hz, 1 H), 8.66 (d,J =7.45 Hz, 1 H), 8.09 (s, 1 H), 7.35 - 7.45 (m, 4 H), 7.28 - 7.34 (m, 1 H), 7.15 (dd,J =9.16, 3.44 Hz, 1 H), 7.09 - 7.13 (m, 1 H), 7.04 - 7.09 (m, 1 H), 6.92 (d,J =6.87 Hz, 1 H), 6.52 (d,J =7.45 Hz, 1 H), 4.56 (dt,J =10.31, 4.01 Hz, 1 H), 4.08 - 4.14 (m, 1 H), 3.87 (ddt,J =13.75, 7.59, 3.94, 3.94 Hz, 1 H), 3.44 - 3.49 (m, 1 H)。 89 MS: 382.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.76 (dd,J =7.45, 2.29 Hz, 1 H), 8.77 (d,J =7.45 Hz, 1 H), 8.58 (d,J =8.02 Hz, 1 H), 8.05 (s, 1 H), 7.09 (dt,J =9.74, 1.72 Hz, 1 H), 7.00 (dd,J =6.30, 1.72 Hz, 2 H), 6.38 (d,J =7.45 Hz, 1 H), 5.56 - 5.63 (m, 1 H), 4.51 (dt,J =10.17, 3.79 Hz, 1 H), 3.99 (td,J =9.59, 3.72 Hz, 1 H), 3.86 (ddt,J =13.75, 7.45, 3.72, 3.72 Hz, 1 H), 3.38 - 3.43 (m, 1 H), 1.94 (ddd,J =13.89, 7.88, 6.30 Hz, 1 H) 1.44 (dt,J =14.03, 7.30 Hz, 1 H), 0.63 - 0.73 (m, 1 H), 0.37 - 0.45 (m, 1 H), 0.27 - 0.34 (m, 1 H), 0.18 (dq,J =9.24, 4.75 Hz, 1 H), -0.12 - -0.04 (m, 1 H)。 90 MS: 372.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.68 (d,J =8.02 Hz, 1 H), 8.52 (d,J =7.45 Hz, 1 H), 8.36 (t,J =4.01 Hz, 1 H), 8.04 (s, 1 H), 7.16 (dd,J =9.45, 3.15 Hz, 1 H), 7.06 (dd,J =9.17, 4.58 Hz, 1 H), 6.95 - 7.02 (m, 1 H), 6.30 (d,J =8.02 Hz, 1 H), 5.66 - 5.75 (m, 1 H), 5.45 (d,J =4.58 Hz, 1 H), 4.12 - 4.25 (m, 2 H), 4.05 (d,J =9.16 Hz, 1 H), 3.60 - 3.67 (m, 1 H), 3.28 - 3.31 (m, 1 H), 1.42 (d,J =6.87 Hz, 3 H)。 91 MS: 372.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.70 (d,J =6.87 Hz, 1 H), 8.53 (d,J =7.45 Hz, 1 H), 8.47 (dd,J =8.31, 2.00 Hz, 1 H), 8.03 (s, 1 H), 7.07 - 7.13 (m, 1 H), 6.97 - 7.03 (m, 2 H), 6.34 (d,J =7.45 Hz, 1 H), 5.60 (quind,J =7.02, 7.02, 7.02, 7.02, 1.72 Hz, 1 H), 5.36 (d,J =4.01 Hz, 1 H), 4.42 (br d,J =10.88 Hz, 1 H), 4.01 - 4.14 (m, 2 H), 3.88 - 3.97 (m, 1 H), 3.10 - 3.17 (m, 1 H), 1.41 (d,J =7.45 Hz, 3 H)。 92 MS: 356.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.41 (dd,J =6.01, 3.72 Hz, 1 H), 8.71 (d,J =7.45 Hz, 1 H), 8.58 (d,J =7.45 Hz, 1 H), 8.06 (s, 1 H), 7.14 (dd,J =9.74, 3.44 Hz, 1 H), 7.07 (dd,J =9.17, 4.58 Hz, 1 H), 6.96 (ddd,J =9.17, 8.02, 3.44 Hz, 1 H), 6.35 (d,J =7.45 Hz, 1 H), 5.63 - 5.74 (m, 1 H), 4.77 -4.89 (m, 1 H), 3.73 - 3.85 (m, 1 H), 3.52 - 3.58 (m, 1 H), 1.43 (d,J =6.87 Hz, 3 H), 1.19 (br d,J =6.30 Hz, 3 H)。 93 MS: 356.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.82 (dd,J =8.02, 2.29 Hz, 1 H), 8.81 (d,J =6.87 Hz, 1 H), 8.58 (d,J =7.45 Hz, 1 H), 8.04 (s, 1 H), 7.12 (dd,J =9.45, 3.15 Hz, 1 H), 6.99 - 7.05 (m, 1 H), 6.94 - 6.99 (m, 1 H), 6.36 (d,J =7.45 Hz, 1 H), 5.53 (quind,J =6.87, 6.87, 6.87, 6.87, 1.15 Hz, 1 H), 4.45 - 4.52 (m, 1 H), 3.90 (ddd,J =13.46, 8.31, 4.01 Hz, 1 H), 3.10 - 3.17 (m, 1 H), 1.46 (d,J =6.30 Hz, 3 H), 1.44 (d,J =7.45 Hz, 3 H)。 94 MS: 356.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.49 (dd,J =7.45, 2.86 Hz, 1 H), 8.77 (d,J =7.45 Hz, 1 H), 8.09 (s, 1 H), 7.15 (dd,J =9.45, 3.15 Hz, 1 H), 7.04 - 7.09 (m, 1 H), 6.97 - 7.03 (m, 1 H), 6.73 (d,J =8.02 Hz, 1 H), 5.54 (dd,J =14.89, 1.72 Hz, 1 H), 4.55 (ddd,J =7.59, 5.87, 4.30 Hz, 1 H), 4.08 (d,J =14.89 Hz, 1 H), 3.85 - 3.92 (m, 1 H), 3.59 (s, 3 H), 3.16 (ddd,J =13.60, 7.88, 3.15 Hz, 1 H), 1.45 (d,J =6.30 Hz, 3 H)。 95 MS: 356.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.71 (d,J =8.59 Hz, 1 H) 8.76 (d,J =8.02 Hz, 1 H) 8.09 (s, 1 H) 7.25 (dd,J =9.45, 3.15 Hz, 1 H) 7.02 - 7.09 (m, 1 H) 6.95 - 7.00 (m, 1 H) 6.71 (d,J =8.02 Hz, 1 H) 5.68 (dd,J =14.89, 1.15 Hz, 1 H) 4.34 (dd,J =9.45, 1.43 Hz, 1 H) 4.24 - 4.30 (m, 1 H) 4.10 (d,J =14.89 Hz, 1 H) 3.94 (dd,J =9.74, 4.01 Hz, 1 H) 3.58 (s, 3 H) 1.36 (d,J =6.87 Hz, 3 H)。 96 MS: 372.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.64 (d,J =8.23 Hz, 1 H) 8.27 (br s, 1 H) 8.08 (s, 1 H) 7.15 (br d,J =6.59 Hz, 1 H) 7.04 - 7.10 (m, 1 H) 6.96 - 7.02 (m, 1 H) 6.66 (d,J =8.23 Hz, 1 H) 5.11 (br s, 1 H) 4.28 (br s, 2 H) 4.15 (br s, 1 H) 4.06 (br s, 1 H) 3.90 (br s, 2 H) 3.57 (s, 3 H) 3.29 (br s, 1 H)。 97 MS: 356.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.49 (dd,J =7.45, 2.86 Hz, 1 H), 8.77 (d,J =8.02 Hz, 1 H), 8.09 (s, 1 H), 7.15 (dd,J =9.74, 2.86 Hz, 1 H), 7.04 - 7.10 (m, 1 H), 6.97 - 7.03 (m, 1 H), 6.73 (d,J =8.02 Hz, 1 H), 5.54 (dd,J =14.89, 1.72 Hz, 1 H), 4.50 - 4.60 (m, 1 H), 4.08 (d,J =15.47 Hz, 1 H), 3.84 - 3.92 (m, 1 H), 3.59 (s, 3 H), 3.16 (ddd,J =13.46, 7.73, 2.86 Hz, 1 H), 1.45 (d,J =6.30 Hz, 3 H)。 98 MS: 358.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.76 (dd,J =7.45, 2.29 Hz, 1 H), 8.82 (d,J =6.87 Hz, 1 H), 8.58 (d,J =7.45 Hz, 1 H), 8.05 (s, 1 H), 7.06 - 7.15 (m, 1 H), 6.99 - 7.04 (m, 2 H), 6.45 (d,J =8.02 Hz, 1 H), 5.57 - 5.66 (m, 1 H), 5.16 - 5.25 (m, 1 H), 4.52 (dt,J =10.17, 3.79 Hz, 1 H), 3.99 (td,J =9.74, 4.01 Hz, 1 H), 3.87 (ddt,J =13.82, 7.52, 3.94, 3.94 Hz, 1 H), 3.71 (ddd,J =11.17, 8.31, 6.30 Hz, 1 H), 3.59 (dt,J =11.17, 5.01 Hz, 1 H), 3.36 - 3.45 (m, 1 H)。 99 MS: 372.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.72 (d,J =8.02 Hz, 1 H), 8.53 (d,J =7.45 Hz, 1 H), 8.40 (t,J =4.01 Hz, 1 H), 8.04 (s, 1 H), 7.09 (dd,J =9.16, 2.86 Hz, 1 H), 6.95 - 7.05 (m, 2 H), 6.42 (d,J =7.45 Hz, 1 H), 5.63 - 5.72 (m, 1 H), 5.16 (t,J =5.44 Hz, 1 H), 4.29 - 4.37 (m, 1 H), 4.19 - 4.27 (m, 1 H), 3.65 (ddd,J =11.17, 8.31, 6.30 Hz, 1 H), 3.53 - 3.61 (m, 2 H), 3.41 - 3.48 (m, 1 H), 2.00 - 2.18 (m, 2 H)。 100 MS: 356.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.46 (dd,J =7.16, 2.58 Hz, 1 H), 8.77 (d,J =8.02 Hz, 1 H), 8.11 (s, 1 H), 7.22 (dd,J =9.74, 2.29 Hz, 1 H), 7.01 - 7.06 (m, 2 H), 6.74 (d,J =8.02 Hz, 1 H), 6.20 - 6.30 (m, 1 H), 4.50 (dt,J =10.31, 4.01 Hz, 1 H), 4.05 (ddd,J =10.31, 9.16, 4.01 Hz, 1 H), 3.85 (ddt,J =13.68, 7.52, 3.72, 3.72 Hz, 1 H), 3.38 - 3.49 (m, 4 H), 1.53 (d,J =7.45 Hz, 3 H)。 101 MS: 400.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.58 (dd,J =7.45, 2.86 Hz, 1 H), 8.50 (s, 1 H), 8.01 (s, 1 H), 7.36 (dd,J =9.16, 2.86 Hz, 1 H), 7.00 - 7.14 (m, 2 H), 5.61 (dd,J =14.61, 1.43 Hz, 1 H), 4.44 - 4.52 (m, 1 H), 4.14 (d,J =12.60 Hz, 1 H), 4.00 - 4.09 (m, 2 H), 3.81 - 3.92 (m, 2 H), 3.39 - 3.47 (m, 1 H), 1.40 (s, 3 H), 1.38 (s, 3 H)。 102 MS: 327.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.58 - 9.70 (m, 1 H), 9.09 (d,J =6.87 Hz, 1 H), 8.42 (s, 1 H), 7.22 (dd,J =9.74, 2.86 Hz, 1 H), 7.11 (d,J =7.45 Hz, 1 H), 6.84 - 6.97 (m, 2 H), 4.37 - 4.50 (m, 1 H), 3.90 - 4.06 (m, 3 H), 3.42 - 3.64 (m, 3 H), 2.54 - 2.62 (m, 1 H)。 103 MS: 341.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.04 (d,J =6.87 Hz, 1 H), 8.56 (t,J =4.01 Hz, 1 H), 8.40 (s, 1 H), 7.19 (dd,J =9.74, 2.86 Hz, 1 H), 7.06 (d,J =6.87 Hz, 1 H), 6.81 - 6.96 (m, 2 H), 4.19 - 4.29 (m, 2 H), 3.53 - 3.63 (m, 4 H), 3.24 - 3.31 (m, 2 H), 2.09 - 2.21 (m, 2 H)。 104 MS: 358.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.79 (d,J =8.02 Hz, 1 H), 8.70 (dd,J =7.45, 2.86 Hz, 1 H), 8.07 (s, 1 H), 7.59 (dd,J =8.59, 5.73 Hz, 1 H), 7.10 (td,J =8.59, 2.86 Hz, 1 H), 7.04 (dd,J =10.02, 2.58 Hz, 1 H), 6.78 (d,J =8.02 Hz, 1 H), 5.79 (dd,J =15.75, 1.43 Hz, 1 H), 4.17 (d,J =16.04 Hz, 1 H), 3.73 - 3.82 (m, 1 H), 3.59 (s, 3 H), 3.52 - 3.58 (m, 1 H), 3.26 - 3.30 (m, 1 H), 3.18 - 3.23 (m, 1 H)。 105 MS: 411.2 (M+H)⁺ . 106 MS: 374.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.84 (d,J =8.02 Hz, 1 H), 8.09 - 8.19 (m, 2 H), 8.07 (s, 1 H), 7.35 (td,J =8.45, 2.58 Hz, 1 H), 7.22 (dd,J =10.31, 2.29 Hz, 1 H), 6.86 (d,J =8.02 Hz, 1 H), 5.75 (d,J =16.61 Hz, 1 H), 4.57 (d,J =16.61 Hz, 1 H), 4.11 - 4.15 (m, 1 H), 3.79 - 3.87 (m, 2 H), 3.59 (s, 3 H), 3.48 - 3.57 (m, 1 H)。 107 MS: 390.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.83 (d,J =8.02 Hz, 1 H), 8.12 (dd,J =9.16, 5.73 Hz, 1 H), 8.07 (s, 1 H), 7.82 (br t,J =5.16 Hz, 1 H), 7.39 (td,J =8.59, 2.86 Hz, 1 H), 7.14 - 7.21 (m, 1 H), 6.84 (d,J =7.45 Hz, 1 H), 5.37 - 5.54 (m, 1 H), 4.61 - 4.76 (m, 1 H), 3.83 - 3.93 (m, 1 H), 3.57 - 3.63 (m, 5H), 3.46 - 3.54 (m, 1 H)。 108 MS: 371.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.73 (br d,J =6.87 Hz, 1 H) 9.09 (d,J =8.00 Hz, 1 H) 8.41 (s, 1 H) 7.20 (dd,J =9.74, 2.86 Hz, 1 H) 7.11 (d,J =6.87 Hz, 1 H) 6.94 (dd,J =9.16, 4.58 Hz, 1 H) 6.78 - 6.88 (m, 1 H) 4.44 (ddd,J =8.88, 5.44, 4.01 Hz, 1 H) 3.99 - 4.06 (m, 1 H) 3.88 - 3.97 (m, 1H) 3.67 - 3.73 (m, 1 H) 3.47 - 3.53 (m, 1 H) 3.12 - 3.21 (m, 1 H) 2.54 - 2.62 (m, 1 H) 1.43 (d,J =6.30 Hz, 3 H)。 109 MS: 371.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.43 (d,J =2.29 Hz, 1 H) 8.73 (d,J =6.87 Hz, 1 H) 8.57 (d,J =7.50 Hz, 1 H) 8.01 (s, 1 H) 7.16 (dd,J =9.17, 2.86 Hz, 1 H) 7.00 - 7.11 (m, 2 H) 6.34 (d,J =7.45 Hz, 1 H) 5.61 - 5.73 (m, 1 H) 4.37 (dd,J =10.31, 4.01 Hz, 1 H) 4.00 (ddt,J =8.45, 4.30, 2.22, 2.22 Hz, 1 H) 3.88 - 3.96 (m, 1 H) 1.48 (d,J =6.87 Hz, 3 H) 1.42 (d,J =7.45 Hz, 3 H)。 110 MS: 371.2 (M+H)⁺ .¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.95 (d,J =8.59 Hz, 1 H) 8.79 (d,J =6.87 Hz, 1 H) 8.58 (d,J =7.45 Hz, 1 H) 8.04 (s, 1 H) 7.16 (dd,J =9.45, 3.15 Hz, 1 H) 6.98 - 7.05 (m, 1 H) 6.92 - 6.97 (m, 1 H) 6.34 (d,J =8.02 Hz, 1 H) 5.67 (quind,J =7.02, 7.02, 7.02, 7.02, 1.72 Hz, 1 H) 4.35 (dd,J =9.45, 1.43 Hz, 1 H) 4.20 - 4.30 (m, 1 H) 3.93 (dd,J =9.74, 4.01 Hz, 1 H) 1.47 (d,J =7.45 Hz, 3 H) 1.37 (d,J =6.87 Hz, 3 H) 111 MS: 371.2 (M+H)⁺ . 112 MS: 345.2 (M+H)⁺ . 額外實例係使用類似於上文所述之方法製備。生物實例 1 ：生物化學激酶分析 . MET/ALK/AXL/TRK激酶抑制可藉由Omnia (Invitrogen有限公司)連續螢光分析來量測。反應係於30℃下於96孔板中以50 μL體積實施。混合物含有1 nM人類重組靶標激酶結構域、2 μM磷酸基受體肽、測試化合物(11劑量，3倍連續稀釋液，2% DMSO最終)或僅DMSO、0.2 mM DTT及於20 mM Hepes中之10 mM MgCl₂ ，pH 7.5，且藉由添加ATP (100 μM最終濃度)、隨後20 min預培育來起始反應。在20 min內使用Tecan Safire微板讀取器量測磷肽形成之初始速率，其中激發波長設定為360 nm且發射為485 nm。K_i 值係使用非線性回歸方法(GraphPad Prism, GraphPad Software, San Diego, CA)藉由將數據擬合至競爭抑制之方程式來計算。生物實例 2 ：細胞激酶磷酸化 ELISA 分析 實驗係基於出版物中所述之程序實施(Christensen, J.等人，「Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma」, Mol. Cancer Ther. 2007, 6 (12)：3314-3322。)所有實驗均係在標準條件(37℃及5% CO₂ )下實施。IC₅₀ 值係使用基於Microsoft Excel之四參數方法藉由濃度/反應曲線擬合來計算。將細胞接種於96孔板中補充有10%胎牛血清(FBS)之培養基中並在24小時後轉移至無血清培養[具有0.04%牛血清白蛋白(BSA)]中，在研究配體依賴性RTK磷酸化之實驗，添加相應生長因子長達20分鐘。將細胞與抑制劑一起培育1 h及/或與適當配體一起培育指定時間後，將細胞用補充有1 mmol/L Na₃ VO₄ 之HBSS洗滌一次，並自細胞生成蛋白質溶解產物。隨後，使用特定捕獲抗體塗覆96孔板及特異性針對磷酸化酪胺酸殘基之檢測抗體藉由夾心ELISA方法評價所選蛋白質激酶之磷酸化。將抗體塗覆之板(a)在蛋白質溶解產物之存在下在4℃下過夜，(b) 在1%於PBS中之Tween 20中洗滌七次，(c) 在山葵過氧化酶偶聯抗總磷酸酪胺酸(PY-20)抗體(1:500)中培育30 min，(d) 再洗滌七次，(e) 在3,3,5,5-四甲基聯苯胺過氧化物酶受質(Bio-Rad)中培養以起始顯色反應，該反應藉由添加0.09 N H₂ SO₄ 終止，及(f) 使用分光光度計量測在450 nm下之吸光度。用於個別激酶之細胞系包括用於MET之A549、用於ALK之Karpas 299、用於AXL之293-AXL、用於TRKA之PAET RKA及用於TRKB之PAE-TRKB。生物實例 3 ：激酶結合分析 . 激酶結合分析係在DiscoveRx處使用一般KINOMEscan K_d 方案實施(Fabian, M. A.等人，「A small molecule-kinase interaction map for clinical kinase inhibitors」, Nat. Biotechnol. 2005, 23(3)：329-36)。對於大多數分析而言，在源自BL21菌株之大腸桿菌(E. coli )宿主中製備激酶標記之T7噬菌體菌株。使大腸桿菌生長至對數期且用T7噬菌體感染並在32℃下振盪培育直至溶解。將溶解產物離心且過濾以去除細胞碎片。在HEK-293細胞中產生剩餘激酶且隨後用DNA標記以供qPCR檢測。在室溫下用生物素化小分子配體將抗生蛋白鏈菌素塗覆之磁性珠粒處理30分鐘以產生親和樹脂以供激酶分析。用過量生物素封阻配體化珠粒且用封阻緩衝液(SeaBlock (Pierce)，1% BSA、0.05% Tween 20、1 mM DTT)洗滌以去除未結合配體且減少非特異性結合。藉由在1×結合緩衝液(20% SeaBlock、0.17x PBS、0.05% Tween 20、6 mM DTT)中組合激酶、配體化親和珠粒及測試化合物來彙集結合反應。所有反應皆係在聚苯乙烯96孔板中以0.135 mL之最終體積實施。在室溫下將分析板振盪培育1小時且用洗滌緩衝液(1× PBS、0.05% Tween 20)洗滌親和珠粒。然後將珠粒再懸浮於溶析緩衝液(1x PBS、0.05% Tween 20、0.5 μM未生物素化親和配體)中且在室溫下振盪培育30分鐘。藉由qPCR量測溶析液中之激酶之濃度。在此分析中所測試化合物之結果呈現於表2中。利用此方法，實例20亦與PLK4激酶具有結合親和性(K_d 2.9 nM)。 表2. 實例 TRKAK _d (nM) TRKBK _d (nM) TRKCK _d (nM) JAK1K _d (nM) JAK2K _d (nM) JAK3K _d (nM) ALKK _d (nM) ROS1K _d (nM) 11-1 1900                ＞30000 1900 20 0.031 0.18 0.30 ＞1000 4.8 120 80 21 39 0.23          27    180 4.7 40                   600 410 41 6.00       280 2.6 33 200    42 0.088                      43 0.086          3.7          45 0.082          7.8          49 0.14          24          50 0.20          0.57          51 0.065       65 0.15 4.3       51-1 0.051       37 0.048 1.8 6.8 0.73 52 6.5                270 62 75 0.015          6.5          92             0.12    8.2    93             0.082    5.7    98             0.74    14    103             1.9    28    生物實例 4 ： Ba/F3 細胞增殖分析 . TRKA Ba/F3細胞增殖分析係藉由ACD (Advanced Cellular Dynamics)實施。將Ba/F3細胞系維持於含有10%胎牛血清及抗生素之RPMI-1640培養基中。收穫對數期生長之細胞並將5,000個細胞分佈於384孔板中之每一孔中於50 µL生長培養基中。將50毫微升經稀釋化合物一式兩份添加於適當孔中，並將細胞於37℃下在加濕5% CO₂ 培養箱中培養48小時。藉由添加15 µL CellTiter-Glo並量測發光來測定生存力，其報告為以每秒技術量測之相對光單位(RLU)。將每一化合物之數據(RLU)正規化為在僅媒劑(DMSO)存在下獲得之平均最大反應。該等數據用於推導抑制% (100 – 最大反應%)且兩個數據點/濃度之平均值用於使用GraphPad Prism軟體(GraphPad有限公司, San Diego, CA)經由非線性回歸分析計算IC₅₀ 值(造成細胞存活之一半最大抑制之濃度)。利用此方法，實例20以3.0 nM之IC₅₀ 抑制TRKA Ba/F3細胞之細胞增殖。此分析中所測試化合物之數據呈現於表3中。生物實例 5 ： EML4-ALK Ba/F3 穩定細胞系產生及細胞增殖分析 . EML4-ALK野生型基因(變體1)係在GenScript處合成並選殖於pCDH-CMV-MCS-EF1-Puro質粒(System Biosciences有限公司)中。Ba/F3-EML4-ALK野生型細胞系係藉由用含有EML4-ALK野生型之慢病毒轉染Ba/F3細胞產生。穩定細胞系係藉由嘌呤黴素處理、隨後IL-3撤退來選擇。將5000個細胞接種於384孔白色板中過夜，然後用化合物處理。細胞增殖係根據製造商方案在各種濃度之化合物培育48小時之後使用CellTiter-Glo基於螢光素酶之ATP檢測分析(Promega)量測。IC₅₀ 測定係使用GraphPad Prism軟體(GraphPad有限公司, San Diego, CA.)實施。此分析中所測試化合物之數據呈現於表3中。生物實例 6 ：細胞增殖分析 . 將結腸直腸細胞系KM 12 (具有內源性TPM3-TRKA融合基因)細胞在補充有10%胎牛血清及100 U/mL青黴素/鏈黴素之DMEM培養基中培養。將5000個細胞接種於384孔白色板中達24小時，然後用化合物處理。細胞增殖係根據製造商方案在培育72小時之後使用CellTiter-Glo基於螢光素酶之ATP檢測分析(Promega)量測。IC₅₀ 測定係使用GraphPad Prism軟體(GraphPad有限公司, San Diego, CA.)實施。 另一選擇為：將結腸直腸細胞系KM 12 (具有內源性TPM3-TRKA融合基因)細胞在補充有10%胎牛血清及100 U/mL青黴素/鏈黴素之DMEM培養基中培養。將原發性血小板過多症細胞系SET-2細胞(具有內源性JAK2 V618F點突變)或T細胞淋巴瘤Karpas-299細胞系(具有內源性NPM-ALK融合基因)在補充有10%胎牛血清及100 U/mL青黴素/鏈黴素之RPMI培養基中培養。將5000個細胞接種於384孔白色板中達24小時，然後用化合物處理。細胞增殖係根據製造商方案在培育72小時之後使用CellTiter-Glo基於螢光素酶之ATP檢測分析(Promega)量測。IC₅₀ 測定係使用GraphPad Prism軟體(GraphPad有限公司, San Diego, CA.)實施。 該等分析中所測試之化合物數據呈現於表3中。 表3 實例 KM 12細胞增殖IC₅₀ (nM) SET2細胞增殖IC₅₀ (nM) Karpas 299細胞增殖IC₅₀ (nM) EML4-ALK Ba/F3細胞增殖IC₅₀ (nM) 11-1 ＞10000 ＞10000 ＞10000    20 0.86 2000 1000    39 3.8 8800 3800    40 204 ＞10000 ＞10000    41 118 1500 3900    42 4.0 2000 3400    43 2.6 1700 2800    44 9.9 2030 4100    45 0.35 8000 ＞10000    46 1.5 7000 7100    47 31 ＞10000 ＞10000    48 62 6000 6000    49 6.7 7000 3900    50 74 6000 4100    51 3.2 425 832    51-1 1.3 234 289 248 52 52 3600 7800    59 ＞1000          60 ＞1000          61 0.6 3747 3900    62 0.9    4000    66 17.5 1543 1900    67 2.8 1231 1200    75 0.6 4436 3900    76-1 5.8 1003 3800    84 0.8 3146 4200    85 0.9 928 1080    86    1998 1000    87 0.3 2734 1591    88 50.4 1900 3129    89 0.2 859 1398    90 1.8 5911 1653    91 1.8 1536 961    92 0.3 142 88.7 78.6 93 0.5 242 23.7 21.1 94 0.2 ＞10000 ＞10000    95 0.4 2673 4107    96 0.6 6000 5000    97 0.3 6500 1419    98 7.4 808 281    99 6.3 6848 506    100 0.6 5834 5364    101 ＞1000 6000 ＞10000    102 1.2 2450 2304    103 15 ＞10000 1956    104 0.3 2353 5747    105 500 ＞10000 ＞5000    106 176 ＞10000 ＞10000    107 75.6 3000 ＞10000    108 3.6 870 619    109 0.86 398 225    110 0.7 219 163    111 76 1996 329    生物實例 7 ：細胞作用機制研究 -TRKA 及下游信號靶標磷酸化分析 . 將結腸直腸細胞系KM 12 (具有內源性TPM3-TRKA融合基因)細胞在補充有10%胎牛血清及100 U/mL青黴素/鏈黴素之DMEM培養基中培養。將一百萬個細胞接種於6孔板中達24小時，然後用化合物處理。將細胞用1xPBS洗滌並在5小時處理後收集，且在補充有10 mM EDTA、Halt蛋白酶及磷酸酶抑制劑(Thermo Scientific)之RIPA緩衝液(50 mM Tris, pH 7.4, 150 mM NaCl、1% NP-40、0.5%去氧膽酸鹽、0.1% SDS)中溶胞。蛋白質溶解產物(20 µg)在4-12% Bolt Bis-Tris預製凝膠上，使用MES操作緩衝液(Life Technologies)解析，使用Trans-Blot Turbo轉移系統(Bio-Rad)轉移至硝基纖維素膜並利用靶向磷酸化TRK A (Cell Signaling Technology, Y496, Y680, Y681, 純系C50F3；稀釋1:1000)、總TRK A (Santa Cruz Biotechnology, sc-11；純系C-14, 稀釋1:2000)、磷酸化AKT (Cell signaling, S473, D9E, #9271；稀釋1:5000)、總AKT (Cell Signaling Technology, 40D4；稀釋1:2000)、磷酸化ERK (Cell Signaling Technology, Thr 202/204, D13.14.4E, #4370；稀釋1:2000)、總ERK (Cell Signaling Technology；稀釋1:1000)及微管蛋白(Sigma, T4026, 稀釋1:5000)之抗體檢測。抗體通常在4℃下輕柔振盪培育過夜，隨後洗滌並與適當HRP偶聯二級抗體一起培育。將膜於室溫下暴露於化學發光受質達5 min (SuperSignal West Femto, Thermo Scientific)。利用 C-Digit成像系統(LI-COR Biosciences)獲得影像。直接經由LICOR之Image Studio Digits獲得該條帶之相對密度。藉助GraphPad Prism軟體(GraphPad有限公司, San Diego, CA)使用非線性回歸分析法計算半抑制濃度(IC₅₀ )值。利用此方法，實例20抑制KM12細胞中之TPM3-TRKA之自體磷酸化，其IC₅₀ 為1.07 nM，且抑制其下游信號靶標AKT及ERK之磷酸化，其IC₅₀ 分別為2.80 nM及2.00 nM。生物實例 8 ：半胱天冬酶活性分析 . 將KM12細胞維持於含有10%胎牛血清及抗生素之DMEM培養基中。將500,000個細胞接種於12孔板中並引入各種濃度之化合物達72小時。對於星形孢菌素處理法而言，在60小時時添加500 nM STS並培育12小時作為陽性對照。收集所有細胞並用1xPBS洗滌兩次，且然後在補充有Halt蛋白酶及磷酸酶抑制劑(Thermo Scientific)之溶胞緩衝液(20mM HEPES、150 mM NaCl、10 mM KCl、5 mM EDTA、1% NP40)中溶胞。對於半胱天冬酶分析而言，將約20 μL (20 µg)細胞溶解產物與20 µL半胱天冬酶3 glo試劑(Promega)一起培育，於37℃下培育20 min之後藉由發光釋放量測酶活性。對於西方印跡(western blotting)而言，將細胞溶解產物煮沸並藉由SDS-PAGE/免疫印跡使用PARP或肌動蛋白抗體來分析。利用此方法，實例20誘導KM 12細胞之細胞凋亡。Cross reference of related applications According to 35 USC § 119(e), this application claims against the U.S. Provisional Application No. 61/931,506 filed on January 24, 2014, No. 62/049,326 filed on September 11, 2014, and January 2015. The priority of No. 62/106,301 filed on 22nd, the entire content of which is incorporated into this article by way of reference in its entirety. Before further explaining the present invention, it should be understood that the present invention is not limited to the specific embodiments described, as these can of course be changed. It should also be understood that the terms used herein are only for the purpose of describing specific embodiments and are not intended to be limited, because the scope of the present invention will only be limited to the scope of the attached patent application. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those familiar with the art in the present invention. All patents, applications, public applications and other publications mentioned in this article are incorporated into this article by reference in their entirety. If the definitions in this section are contrary or inconsistent with the definitions in patents, applications or other publications incorporated herein by reference, the definitions in this section shall take precedence over the incorporation by reference Definition in this article. Unless the context clearly dictates otherwise, the singular forms "一 (a, an)" and "the" used in the scope of the patent application herein and the accompanying applications include plural indicators. It should be further noted that the scope of patent application can be designed to not contain any optional elements. Therefore, this statement, together with the statement of the elements of the patented scope, is intended to serve as a basis for the use of exclusive terms (such as "alone", "only" and the like) or the use of "negative" restrictions. As used herein, the terms "including," "including," and "including" are used in their open, non-limiting meanings. In order to provide a more concise description, some of the quantitative expressions given in this article are not limited by the term "about". It should be understood that regardless of whether the term "about" is used explicitly or not, each quantity given herein is intended to refer to the actual value given, and it is also intended to refer to the approximate value of the given value that will be reasonably inferred based on those familiar with the art. , Including the equivalent and approximate values of the experimental and/or measurement conditions attributable to the given value. Whenever the yield is given as a percentage, the yield refers to the mass of the entity giving the yield relative to the maximum amount of the same entity that can be obtained under specific stoichiometric conditions. Unless otherwise specified, the concentrations given in percentages refer to mass ratios. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those familiar with the art in the present invention. Although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe methods and/or materials in combination with the cited publications. Unless otherwise specified, the methods and techniques of the present invention are generally implemented according to conventional methods well known in the industry and as described in various general and more specific references cited and discussed throughout this specification. See, for example, Loudon, Organic Chemistry, 4th 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. The chemical nomenclature of the compounds described herein is usually derived from the use of commercially available ACD/Name 2014 (ACD/Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer). It should be understood that certain features of the invention set forth in the context of separate embodiments for the sake of clarity can also be provided in combination in a single embodiment. Conversely, the various features of the invention set forth in the context of a single embodiment for brevity can also be provided individually or in any suitable subcombination. All combinations with respect to the embodiments of chemical groups represented by variables are specifically covered by the present invention and are covered by these combinations to produce compounds that produce stable compounds (i.e., separable, separable, The extent of characterization and testing of biologically active compounds) is disclosed herein. In addition, all the sub-combinations of the chemical groups listed in the embodiments that illustrate these variables are also specifically covered by the present invention and are disclosed herein as if each and the sub-combinations of each chemical group are individually and explicitly disclosed herein. . Chemical definition The term "alkyl" refers to a straight or branched alkyl group having 1 to 12 carbon atoms in the chain. Examples of alkyl groups include (but are not limited to) methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, second butyl, tertiary butyl (tBu), Pentyl, isopentyl, tertiary pentyl, hexyl, isohexyl, and herein based on those skilled in the art and the teachings provided herein will be regarded as equivalent groups to any of the foregoing examples. The term "alkenyl" refers to a straight or branched hydrocarbon group having 2 to 12 carbon atoms in the chain and having one or more double bonds. Examples of alkenyl groups include ethenyl (vinyl), allyl and but-3-en-1-yl. The term includes cis and trans isomers and mixtures thereof. The term "alkynyl" refers to a straight or branched hydrocarbon group having 2 to 12 carbon atoms in the chain and having one or more triple bonds. Examples of alkynyl groups include ethynyl (-C≡CH) and propynyl (-CH₂ C≡CH). The term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic carbocyclic ring having 3 to 12 ring atoms. Polycyclic carbocyclic rings include fused, bridged and spiro polycyclic ring systems. Illustrative examples of cycloalkyl groups include the following entities in the form of appropriate bonding moieties:

The term "halogen" represents chlorine, fluorine, bromine or iodine. The term "halo" represents chlorine, fluorine, bromine or iodine. The term "haloalkyl" refers to an alkyl group having one or more halo substituents, or one, two or three halo substituents. Examples of haloalkyl groups include -CF₃ , -(CH₂ )F, -CHF₂ , -CH₂ Br, -CH₂ CF₃ And -CH₂ CH₂ F. The term "aryl" refers to a fully conjugated π-electron system with 6 to 14 carbon atoms (C₆ -C₁₄ ) Is an all-carbon monocyclic or fused-ring polycyclic group. Aryl groups include those having 6 to 10 carbon atoms (e.g., "C₆ -₁₀ "Aryl") is an all-carbon monocyclic ring or a fused-ring polycyclic ring. Examples of aryl groups are (but not limited to) phenyl, naphthyl and anthracenyl. Aryl groups can be substituted or unsubstituted as described above for alkyl groups. Substituents also include those described with respect to aryl groups elsewhere in this disclosure. The term "heterocycloalkyl" refers to a saturated or partially saturated monocyclic or polycyclic structure having 3 to 12 ring atoms, wherein 1 to 5 ring atoms are selected from nitrogen, oxygen and sulfur. Polycyclic systems include fused, bridged and spiro systems. The ring structure may optionally contain up to two pendant oxy groups on the carbon or sulfur ring members. Illustrative examples of heterocycloalkyl groups include the following entities in the form of appropriate bonding moieties:

The term "heteroaryl" refers to a monocyclic, fused bicyclic or fused polycyclic aromatic heterocyclic ring with each heterocyclic ring having 3 to 12 ring atoms (the ring structure has selected from carbon atoms and up to four selected from (Ring atoms of heteroatoms of nitrogen, oxygen and sulfur). Illustrative examples of heteroaryl groups include the following entities in the form of appropriate bonding moieties:

"Monocyclic" heteroaryl is an aromatic 5- or 6-membered heterocyclic ring. 5-membered heteroaryl groups contain up to four heteroatom ring atoms, of which (a) one ring atom is oxygen and sulfur and 0, 1 or 2 ring atoms are nitrogen, or (b) 0 ring atoms are oxygen or sulfur and Up to 4 ring atoms are nitrogen. In some embodiments, the 5-membered heteroaryl group is furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. The 6-membered heteroaryl group contains 1 or 2 nitrogen ring atoms. In some embodiments, the 6-membered heteroaryl group is pyridine, pyrazine, pyrimidine, pyridazine, or triazine. "Bicyclic heteroaryl" is a fused bicyclic ring system containing a heteroaryl ring fused to a phenyl or another heteroaryl ring. The term "pendant oxy" represents a carbonyl oxygen. For example, the cyclopentyl group substituted by the pendant oxy group is cyclopentanone. The term "substituted" means that the specified group or moiety has one or more substituents. The term "unsubstituted" means that the specified group has no substituents. When the term "substitution" is used to describe a structural system, the substitution is intended to occur at any position allowed by the valence on the system. In some embodiments, "substituted" means that the specified group or moiety has 1, 2, or 3 substituents. In other embodiments, "substituted" means that the specified group or moiety has 1 or 2 substituents. In still other embodiments, "substituted" means that the specified group or part has 1 substituent. Any formula described herein is intended to represent the structural formula of the compound as well as certain variations or forms. For example, the formulas given herein are intended to include racemic forms, or one or more mirror image isomers, diastereomers, or geometric isomers or mixtures thereof. In addition, any formula given herein is also intended to refer to the hydrate, solvate, or polymorphic form of the compound or a mixture thereof. Any formula given herein is also intended to represent the unlabeled form as well as the isotope-labeled form of the compound. The isotope-labeled compound has the structure depicted by the formula given herein, except that one or more atoms are replaced by atoms having the selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as² 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 and¹²⁵ I. These isotopically-labeled compounds can be used for metabolism studies (better use¹⁴ C), reaction kinetics research (using e.g.² H or³ H), detection or imaging technology [such as positron emission tomography (PET) or single photon emission computed tomography (SPECT)] (including drug or matrix tissue distribution analysis) or radiotherapy of patients. In addition, use heavier isotopes (such as deuterium, which is² H) Substitution can provide certain therapeutic advantages derived from greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). The isotopically-labeled compounds of the present invention and their prodrugs can generally be prepared by implementing the procedures disclosed in the scheme or in the examples and preparations described below by substituting readily available isotope-labeled reagents for non-isotopically-labeled reagents. Nomenclature "(atom)_ij "And j>i when applied to a type of substituent herein is intended to refer to the following embodiments of the present invention: each and each of the carbon member numbers from i to j (including i and j) are implemented independently. For example, the term C_1-3 Independently refers to having one carbon member (C₁ ) Embodiment, with two carbon members (C₂ ) Examples and having three carbon members (C₃ ) Of the embodiment. Any di-substituent mentioned herein when allowing more than one attachment possibility is intended to cover a multitude of such possibilities. For example, a reference to a di-substituent -AB- (where A ≠ B) means herein that A is attached to the first substituted member and B is attached to the second substituted member, and which It also refers to the di-substituent where A is attached to the second member and B is attached to the first substituted member. The present invention also includes compounds represented by formula (I) or (IA), preferably pharmaceutically acceptable salts of the specific compounds described above and exemplified herein, and pharmaceutical compositions containing these salts and using the same The method of waiting for salt. "Pharmaceutically acceptable salt" is intended to mean a salt that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to an individual in the free acid or base of the compound represented herein. Generally, see S.M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66, 1-19. Preferably, the pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with individual tissues without excessive toxicity, irritation or allergic reactions. 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 therefore react with many inorganic or organic bases and inorganic and organic acids to form Pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chlorine Compounds, bromide, iodide, acetate, borate, nitrate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propyne Salt, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne- 1,6-Diacid salt, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, o-benzene Diformate, sulfonate, methanesulfonate, propanesulfonate, toluenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate , Phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate and mandelic acid. A list of other suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985. For compounds of formula (I) or (IA) containing basic nitrogen, pharmaceutically acceptable salts can be prepared by any suitable method available in the industry, for example, using the following to treat the free base: inorganic acid, such as hydrochloric acid , Hydrobromic acid, sulfuric acid, aminosulfonic acid, nitric acid, boric acid, phosphoric acid and the like; or organic acids, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, 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, pyranosidyl acid (pyranosidyl acid) (E.g. glucuronic acid or galacturonic acid), α-hydroxy acids (e.g. mandelic acid, citric acid or tartaric acid), amino acids (e.g. aspartic acid or glutamine acid), aromatic acids (e.g. benzoic acid) , 2-acetoxy benzoic acid, naphthoic acid or cinnamic acid), sulfonic acid (e.g. lauryl sulfonic acid, p-toluene sulfonic acid, methane sulfonic acid or ethane sulfonic acid), or any compatible mixture of acids (such as They are given as examples herein) and any other acids and mixtures thereof that are considered equivalents or acceptable substitutes according to the ordinary level of this technology. The present invention also relates to the medically accepted prodrug of the compound of formula (I) or (I-A) and the method of treatment using the medically accepted prodrug. The term "prodrug" means that the specified compound produces a compound precursor in the living body through a chemical or physiological process (for example, solvolysis or enzymatic cleavage) or under physiological conditions (for example, a prodrug in physiological It is converted into a compound of formula (I) or (IA) at pH). A "pharmaceutically acceptable prodrug" is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to an individual. Illustrative procedures for selecting and preparing suitable prodrug derivatives are described in (for example) "Design of Prodrugs", edited by H. Bundgaard, Elsevier, 1985. The present invention also relates to the pharmaceutically active metabolites of the compounds of formula (I) or (I-A) and the use of these metabolites in the method of the present invention. "Pharmaceutically active metabolite" means a pharmacologically active product metabolized in the body by a compound of formula (I) or (I-A) or its salt. The prodrug and active metabolite of the compound can be determined using conventional techniques known or available in the industry. See (for example) 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 (edited by Krogsgaard-Larsen et al., Harwood Academic Publishers, 1991). Representative embodiment In some embodiments of formula (I-A), ring A'is a monocyclic aryl or heteroaryl and ring B'is a bicyclic heteroaryl. In other embodiments, ring A'is a bicyclic heteroaryl and ring B'is a monocyclic aryl or heteroaryl. In some embodiments, ring A'is a phenyl group or a 6-membered heteroaryl group. In other embodiments, ring B'is a bicyclic heteroaryl group containing 1, 2, or 3 nitrogen ring atoms. In other embodiments, ring A'is phenyl or pyridyl. In still other embodiments, ring A'is a phenyl group. In still other embodiments, after -(R^3' )_p' The substituted ring A’ system

. In still other embodiments, after -(R^3' )_p' The substituted ring A’ system

. In some embodiments, ring B'is:

Where Z¹ -Z⁷ Is defined as described herein. In still other embodiments, ring B'is:

or

or

or

Where Z^1-7 Is defined in other ways as described herein. In still other embodiments, ring B'is:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

. In still other embodiments, ring B’ is

,

or

. In still other embodiments, ring B’ is

. In other embodiments of formula (I-A), ring A'is a bicyclic heteroaryl group, and is:

Where Z¹ -Z⁷ Is defined as described herein. In still other embodiments, ring A'is:

or

or

or

Where Z^1-7 Is defined in other ways as described herein. In still other embodiments, ring A'is:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

. In still other embodiments, ring A’ is

,

or

. In still other embodiments, ring A’ is

. In some embodiments, ring B'is a monocyclic aryl or heteroaryl. In other embodiments, ring B'is a phenyl group. In other embodiments, ring A'is pyridyl. In some embodiments, each R^3' Independently deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN, -CF₃ , -NH₂ , -NH(C_1-4 Alkyl), -N(C_1-4 alkyl)₂ , -CO₂ C_1-4 Alkyl, -CO₂ H, -NHC(O)C_1-4 Alkyl, -SO₂ C_1-4 Alkyl, -C(O)NH₂ , -C(O)NH(C_1-4 Alkyl), -C(O)N(C_1-4 alkyl)₂ , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, hexahydropyridyl, hexahydropyrazinyl, morpholinyl or thiomorpholinyl. In still other embodiments, each R^3' Independently fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN or -CF₃ . In still other embodiments, each R^3' It is fluorine or chlorine. In some embodiments, R^7' System H, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl, thiofuranyl, hexahydropyridinyl, hexahydropyridine Azinyl, morpholinyl, phenyl or monocyclic heteroaryl, each of which is substituted or unsubstituted as in formula (IA). In other embodiments, R^7' It is H, or methyl, ethyl, propyl, isopropyl or cyclopropyl, each of which is unsubstituted or substituted as in formula (I-A). In still other embodiments, R^7' It is H or methyl or ethyl, each of which is unsubstituted or substituted by: halogen, -OH, -OC_1-4 Alkyl, -NH₂ , -NH(C_1-4 Alkyl), -N(C_1-4 alkyl)₂ , -CO₂ H, -CO₂ C_1-4 Alkyl, -CONH₂ , Cycloalkyl or monocyclic heterocycloalkyl. In still other embodiments, R^7' H, methyl, hydroxyethyl, -CH₂ CONH₂ Or 3-pyrrolidinylmethyl. In still other embodiments, R^7' It is H or methyl. In some embodiments, R^1' And R^2' Each independently is H, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl, thiofuranyl, hexahydropyridyl, Hexahydropyrazinyl, morpholinyl, phenyl or monocyclic heteroaryl, each of which is substituted or unsubstituted as in formula (IA). In other embodiments, R^1' Department H. In still other embodiments, R^2' Deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl, thiofuranyl, hexahydropyridinyl, hexahydropyrazinyl , Morpholinyl, phenyl or monocyclic heteroaryl, each of which is substituted or unsubstituted as in formula (IA). In still other embodiments, R^2' It is H or methyl or ethyl, each of which is unsubstituted or substituted by: halogen, -OH, -OC_1-4 Alkyl, -NH₂ , -NH(C_1-4 Alkyl), -N(C_1-4 alkyl)₂ , -CO₂ H, -CO₂ C_1-4 Alkyl, -CONH₂ , Cycloalkyl or monocyclic heterocycloalkyl. In still other embodiments, R^2' It is H, methyl, fluoromethyl, hydroxymethyl or cyclopropyl. In still other embodiments, R^2' Department H. In still other embodiments, R^2' Department of methyl. In some embodiments, each R^k' Independently H, methyl, ethyl, propyl, isopropyl or cyclopropyl. In other embodiments, each R^k' Independently H or methyl. In some embodiments, each L¹ And L² Independently Department-CH₂ -Or -CH(methyl)-, -CH(substituted methyl)-, -CH(C_3-6 Cyclopropyl)-, -CH(OH)-, -O-, -NH-, -N(C_{1- 4} Alkyl)-, -N(C_3-6 Cyclopropyl)-, -S-, -S(O)- or -SO₂ -. In some embodiments, -(L¹ )_n' -Department-CH₂ -O-, -CH(C_1-4 Alkyl) -O- or -CH(C_3-6 Cycloalkyl) -O-. In other embodiments, -(L¹ )_n' -Is -CH (H or C replaced as appropriate_1-4 Alkyl)-N(H or optionally substituted C_1-4 Alkyl)-, -CH(CO₂ C_1-4 Alkyl or C(O)N(H or C_1-4 alkyl)₂ )-N(H or C replaced as appropriate_1-4 alkyl). In still other embodiments, -(L¹ )_n' -Department-CH₂ S(O)_{0- 2} -. In other embodiments, -(L¹ )_n' -Department-SO₂ -N(H or C_1-4 alkyl). In some embodiments, -(L¹ )_n' -Department-(CH₂ )₃ -. In some embodiments, -(L¹ )_n' -Department-(CH₂ )₂ -. In some embodiments, -(L¹ )_n' -Department-CH (CH₃ )CH₂ -. In some embodiments, -(L² )_m' Department-O-(C(R^1' )(R^2' ))_2-3 -. In other embodiments, -(L² )_m' Department-O-(CH₂ )_2-3 -. In other embodiments, -(L² )_m' Department-N(R^k' )-(C(R^1' )(R^2' ))_2-3 -. In other embodiments, -(L² )_m' Department-N (H or C_1-4 Alkyl)-(CH₂ )_{2- 3} -. In other embodiments, -(L² )_m' Department-S-(C(R^1' )(R^2' ))_2-3 -. In other embodiments, -(L² )_m' Department-SO₂ -(C(R^1' )(R^2' ))_2-3 -. In still other embodiments, -(L² )_m' Department-SO₂ -N(R^k' )-(C(R^1' )(R^2' ))₂ -. In still other embodiments, -(L² )_m' Department-(C(R^1' )(R^2' ))₃ -. In some embodiments, m'is 3. In other embodiments, m'is 4. In still other embodiments, m'is 5. In some embodiments, n'is 2. In other embodiments, n'is 3. In still other embodiments, n'is 4. In some embodiments, p'is 0, 1, or 2. In other embodiments, p'is 1 or 2. In some embodiments, q'is zero. In other embodiments, q'is 1. In still other embodiments, q'is 2. In some embodiments, formula (I-A) is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of formula (I-A) is a compound of formula (I), wherein each variable is independently defined as shown below for formula (I). In some embodiments, the variables of formula (I-A) are mapped to formula (I) as follows: A'is A; B'is B; R^1' Department of R¹ ; R^2' Department of R² ; R^3' Department of R³ ; R^4' Department of R⁴ ; R^7' Department of R⁷ ; R^a' -R^f' And R^i' -R^k' Mapped to R respectively^a -R^f And Rⁱ -R^k On; and L¹ And L² Respectively -Y-(C(R⁵ )(R⁶ ))_m -And-C((R¹ )(R² ))_n -X-. In some embodiments of Formula (I), Ring A is phenyl or 6-membered heteroaryl. In other embodiments, ring A is phenyl or pyridyl. In still other embodiments, ring A is phenyl. In still other embodiments, after -(R³ )_p Substituted ring A system

. In still other embodiments, after -(R³ )_p Substituted ring A system

. In some embodiments, each R³ Independently deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN, -CF₃ , -NH₂ , -NH(C_1-4 Alkyl), -N(C_1-4 alkyl)₂ , -CO₂ C_1-4 Alkyl, -CO₂ H, -NHC(O)C_1-4 Alkyl, -SO₂ C_1-4 Alkyl, -C(O)NH₂ , -C(O)NH(C_1-4 Alkyl), -C(O)N(C_1-4 alkyl)₂ , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, hexahydropyridyl, hexahydropyrazinyl, morpholinyl or thiomorpholinyl. In still other embodiments, each R³ Independently fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN or -CF₃ . In still other embodiments, each R³ It is fluorine or chlorine. In still other embodiments, after -(R³ )_p Substituted ring A system

, Where R^3a And R^3b Each is independently H, fluorine or chlorine and M is CH or N. In some embodiments, R^3a Department of fluorine. In some embodiments, p is 1 or 2. In other embodiments, p is 0. In still other embodiments, p is 1. In still other embodiments, p is 2. In some embodiments, Ring B is a bicyclic heteroaryl group. In other embodiments, Ring B is a 9-membered bicyclic heteroaryl group. In some embodiments, each R⁴ Independently deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN, -CF₃ , -NH₂ , -NH(C_1-4 Alkyl), -N(C_1-4 alkyl)₂ , -CO₂ C_1-4 Alkyl, -CO₂ H, -NHC(O)C_1-4 Alkyl, -SO₂ C_1-4 Alkyl, -C(O)NH₂ , -C(O)NH(C_1-4 Alkyl), -C(O)N(C_1-4 alkyl)₂ , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, hexahydropyridyl, hexahydropyrazinyl, morpholinyl or thiomorpholinyl. In still other embodiments, each R⁴ Independently fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN or -CF₃ . In other embodiments, after -(R⁴ )_q Replaced ring B series:

Where Z¹ ,Z² ,Z³ And Z⁶ Each independently of -C(R^x )-Or N; Where each R^x Independently H, Deuterium, Halogen, C_1-4 Alkyl, -O-C_1-4 Alkyl, -OH, -NH₂ , -NHC_1-4 Alkyl, -NH-phenyl, -NH-heteroaryl, CN or -CF₃ ； Z⁴ And Z⁵ Each is independently -C- or -N-; and Z⁷ It is -CH-, -N- or -NH-. In other embodiments: (a) Z¹ , Z⁴ And Z⁷ Respectively -N-; (b) Z¹ , Z⁵ And Z⁷ Respectively -N-; (c) Z¹ And Z³ Respectively -N-and Z⁷ Department -NH-; (d) Z³ Department-N-and Z⁷ Department -NH-; (e) Z³ And Z⁶ Respectively -N-and Z⁷ Department -NH-; (f) Z² ,Z⁴ And Z⁷ Respectively -N-; (g) Z¹ ,Z² ,Z⁴ And Z⁷ Respectively -N-; (h) Z¹ ,Z³ And Z⁴ Respectively -N-; (i) Z³ And Z⁴ Respectively -N-; (j) Z¹ ,Z² ,Z⁵ And Z⁷ Respectively -N-; (k) Z² ,Z⁵ And Z⁷ Respectively -N-; (l) Z³ And Z⁵ Respectively -N-; (m) Z³ ,Z⁵ And Z⁶ Respectively -N-; (n) Z¹ ,Z⁵ ,Z⁶ And Z⁷ Respectively -N-; (o) Z² ,Z⁵ ,Z⁶ And Z⁷ Each is -N-; or (p) Z¹ ,Z³ And Z⁶ Respectively -N-and Z⁷ Department -NH-. In still other embodiments of (a)-(p), each Z ring atom that is not clearly defined is independently -C- or -C(R^x )- (consistent with the definition of the ring atom). In still other embodiments, Z³ Department-N-. In other embodiments, Z⁷ It is -N- or -NH-. In still other embodiments, Z³ Department-N-and Z⁷ It is -N- or -NH-. In still other embodiments, after -(R⁴ )_q Replaced ring B series:

or

or

or

Where Z^1-7 Department is defined in other ways as described above. In still other embodiments, after -(R⁴ )_q Replaced ring B series:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

. In still other embodiments, after -(R⁴ )_q Substituted ring B system

,

or

. In still other embodiments, after -(R⁴ )_q Substituted ring B system

. In some embodiments, q is zero. In other embodiments, q is 1. In some embodiments, R¹ And R² Each independently is H, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl, thiofuranyl, hexahydropyridyl, Hexahydropyrazinyl, morpholinyl, phenyl or monocyclic heteroaryl, each of which is substituted or unsubstituted as in formula (I). In other embodiments, R¹ Department H. In still other embodiments, R² Deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl, thiofuranyl, hexahydropyridinyl, hexahydropyrazinyl , Morpholinyl, phenyl or monocyclic heteroaryl, each of which is substituted or unsubstituted as in formula (I). In still other embodiments, R² It is H or methyl or ethyl, each of which is unsubstituted or substituted by: halogen, -OH, -OC_1-4 Alkyl, -NH₂ , -NH(C_1-4 Alkyl), -N(C_1-4 alkyl)₂ , -CO₂ H, -CO₂ C_1-4 Alkyl, -CONH₂ , Cycloalkyl or monocyclic heterocycloalkyl. In still other embodiments, R² It is H, methyl, fluoromethyl, hydroxymethyl or cyclopropyl. In still other embodiments, R² Department H. In still other embodiments, R² Department of methyl. In still other embodiments, R¹ Department H, and R² It is not H and has the following stereochemical configuration:

. In still other embodiments, R¹ And R² Together to form C_3-6 Cycloalkyl. In other embodiments, R¹ And R² Together form as the case by C_1-4 Alkyl substituted 5- or 6-membered heterocycloalkyl. In some embodiments, n is 1 or 2. In still other embodiments, n is 1. In some embodiments, R⁵ And R⁶ Each independently is H, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl, thiofuranyl, hexahydropyridyl, Hexahydropyrazinyl, morpholinyl, phenyl or monocyclic heteroaryl, each of which is substituted or unsubstituted as in formula (I). In other embodiments, each R⁵ Department H. In still other embodiments, each R⁶ Independently H, or methyl, ethyl or cyclopropyl, each of which is substituted or unsubstituted as in formula (I). In still other embodiments, each R⁶ Independently H or unsubstituted or substituted methyl with -OH. In still other embodiments, each R⁶ It is H or methyl. In still other embodiments, R⁵ And R⁶ Together to form C_3-6 Cycloalkyl. In other embodiments, R⁵ And R⁶ Together form as the case by C_1-4 Alkyl substituted 5- or 6-membered heterocycloalkyl. In some embodiments, m is 2 or 3. In other embodiments, m is 2. In some embodiments, R⁷ System H, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl, thiofuranyl, hexahydropyridinyl, hexahydropyridine Azinyl, morpholinyl, phenyl or monocyclic heteroaryl, each of which is substituted or unsubstituted as in formula (I). In other embodiments, R⁷ Is H, or is methyl, ethyl, propyl, isopropyl or cyclopropyl, each of which is unsubstituted or substituted as in formula (I). In still other embodiments, R⁷ It is H or methyl or ethyl, each of which is unsubstituted or substituted by: halogen, -OH, -OC_1-4 Alkyl, -NH₂ , -NH(C_1-4 Alkyl), -N(C_1-4 alkyl)₂ , -CO₂ H, -CO₂ C_1-4 Alkyl, -CONH₂ , Cycloalkyl or monocyclic heterocycloalkyl. In still other embodiments, R⁷ H, methyl, hydroxyethyl, -CH₂ CONH₂ Or 3-pyrrolidinylmethyl. In still other embodiments, R⁷ It is H or methyl. In some embodiments, each of X and Y is independently -O- or -N(R^k )-. In some embodiments, X is -O- or -N(R^k )-. In some embodiments, Y is -O-. In some embodiments, each R^k Independently H, methyl, ethyl, propyl, isopropyl or cyclopropyl. In other embodiments, each R^k Independently H or methyl. In some embodiments, the compound of formula (I) or (I-A) is a compound of formula (II):

(II) Where M, R³ , Q, R² , X, R⁷ And Z^1-7 Each is defined in any of the several methods listed above; R^5a , R^5b , R^6a And R^6b Respectively R⁵ And R⁶ As defined above in any of the several ways listed; Or its pharmaceutically acceptable salt. In some embodiments, the compound of formula (I) or (I-A) is a compound of formula (III):

(III) in M is CH or N; R^3a And R^3b Each independently is H, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN or -CF₃ ； R^2a It is H or methyl or ethyl, each of which is unsubstituted or substituted by: halogen, -OH, -OC_1-4 Alkyl, -NH₂ , -NH(C_1-4 Alkyl), -N(C_1-4 alkyl)₂ , -CO₂ H, -CO₂ C_1-4 Alkyl, -CONH₂ , Cycloalkyl or monocyclic heterocycloalkyl; X¹ Department O or -N (CH₃ )-; R^5a , R^6a , R^5b And R^6b Each is independently H, or methyl or ethyl, each of which is unsubstituted or substituted by: halogen, -OH, -OC_1-4 Alkyl, -NH₂ , -NH(C_1-4 Alkyl), -N(C_1-4 alkyl)₂ , -CO₂ H, -CO₂ C_1-4 Alkyl, -CONH₂ , -CONH(C_1-4 Alkyl), -CON(C_1-4 alkyl)₂ , Cycloalkyl or monocyclic heterocycloalkyl; R^7a It is H or methyl or ethyl, each of which is unsubstituted or substituted by: halogen, -OH, -OC_1-4 Alkyl, -NH₂ , -NH(C_1-4 Alkyl), -N(C_1-4 alkyl)₂ , -CO₂ H, -CO₂ C_1-4 Alkyl, -CONH₂ , -CONH(C_1-4 Alkyl), -CON(C_1-4 alkyl)₂ , Cycloalkyl or monocyclic heterocycloalkyl; Z^1-7 Each is defined in any of the several methods listed above; Or its pharmaceutically acceptable salt. In some embodiments of formula (III), M is CH. In other embodiments, R^3a And R^3b Each is independently H, fluorine or chlorine. In still other embodiments, R^3a It is H or fluorine. In still other embodiments, R^3a Department of fluorine. In still other embodiments, R^3b It is H or chlorine. In some embodiments of formula (III), R^2a It is H, methyl, fluoromethyl or cyclopropyl. In some embodiments of formula (III), X¹ Department O. In other embodiments, X series -N (CH₃ )-. In some embodiments, R^7a H, methyl, hydroxyethyl, -CH₂ CONH₂ Or 3-pyrrolidinylmethyl. In other embodiments, R^7a It is H or methyl. In some embodiments, the compound of formula (I) or (I-A) is a compound of formula (IV):

(IV) in M is CH or N; X¹ And X^1' Independently Department-C(R^1a )(R^2a )-, -S-, -S(O)-, -S(O)₂ -, -O- or -N(R^k' )-; Every R^1a And R^2a Independently of H, Deuterium, C_1-6 Alkyl, C_3-6 Cycloalkyl, C₆ -₁₀ Aryl, -C(O)OR^a' , -C(O)NR^a' R^b' , -NR^a' R^b' , -SR^a' , -S(O)R^a' , -S(O)NR^a' , -S(O)₂ R^a' , -S(O)₂ NR^a' Or -OR^a' , Where C_1-6 Each hydrogen atom in the alkyl group is independently substituted by the following as appropriate: deuterium, halogen, -OH, -OC_1-4 Alkyl, -NH₂ , -NH(C_1-4 Alkyl), -N(C_1-4 alkyl)₂ , NHC(O)C_1-4 Alkyl, -N(C_1-4 Alkyl)C(O)C_{1- 4} Alkyl, -NHC(O)NHC_1-4 Alkyl, -N(C_1-4 Alkyl)C(O)NHC_1-4 Alkyl, NHC(O)N(C_1-4 alkyl)₂ , -N(C_1-4 Alkyl)C(O)N(C_1-4 alkyl)₂ , -NHC(O)OC_1-4 Alkyl, -N(C_1-4 Alkyl)C(O)OC_1-4 Alkyl, -CO₂ H, -CO₂ C_1-4 Alkyl, -CONH₂ , -CONH(C_1-4 Alkyl), -CON(C_1-4 alkyl)₂ , -SC_1-4 Alkyl, -S(O)C_1-4 Alkyl, -S(O)₂ C_1-4 Alkyl, -S(O)NH(C_1-4 Alkyl), -S(O)₂ NH(C_1-4 Alkyl), -S(O)N(C_1-4 alkyl)₂ , -S(O)₂ N(C_1-4 alkyl)₂ , C_3-6 Cycloalkyl or 3 to 7 membered heterocycloalkyl; R^3a And R^3b Each independently is H, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN or -CF₃ ； R^7a Department H, C_1-6 Alkyl or 3 to 7 membered heterocycloalkyl, where C_1-6 Each hydrogen atom in an alkyl group or a 3- to 7-membered heterocycloalkyl group is independently substituted by the following as appropriate: deuterium, halogen, -CN, -OH, -OC_1-4 Alkyl, -NH₂ , -NH(C_1-4 Alkyl), -N(C_1-4 alkyl)₂ , -CO₂ H, -CO₂ C_1-4 Alkyl, -CONH₂ , -CONH(C_1-4 Alkyl), -CON(C_1-4 alkyl)₂ , Cycloalkyl or monocyclic heterocycloalkyl; Every R^k' Independently of H, Deuterium, C_1-6 Alkyl, C_2-6 Alkenyl, C_2-6 Alkynyl, C_3-6 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C₆ -₁₀ Aryl or mono- or bicyclic heteroaryl; wherein R^k' C in_1-6 Alkyl, C_2-6 Alkenyl, C_2-6 Alkynyl, C_3-6 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C₆ -₁₀ Each hydrogen atom in an aryl group or a mono- or bicyclic heteroaryl group is independently substituted by the following as appropriate: deuterium, halogen, C_1-6 Alkyl, C_1-6 Haloalkyl or -OR^a' ； Where each R^a' And R^b' Independently of H, Deuterium, C_1-6 Alkyl, C_2-6 Alkenyl, C_2-6 Alkynyl, C_3-6 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C₆ -₁₀ Aryl or heteroaryl; Every Z¹ ,Z² ,Z³ ,Z⁴ ,Z⁵ ,Z⁶ Or Z⁷ Independently of N, NH or C(R^x ), where each R^x When present, it is independently H, deuterium, halogen, C_1-4 Alkyl, -O-C_1-4 Alkyl, -OH, -NH₂ , -NH(C_1-4 Alkyl), -NH (phenyl), -NH (heteroaryl), CN or -CF₃ , The prerequisite is Z¹ ,Z² ,Z³ ,Z⁴ ,Z⁵ ,Z⁶ Or Z⁷ At least one of them is N or NH; and m’ is 2 or 3; Or its pharmaceutically acceptable salt. In some embodiments, Z¹ ,Z⁴ And Z⁷ Department N and Z² ,Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ And Z³ Department N, Z⁷ Department NH and Z² ,Z⁴ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z³ And Z⁶ Department N, Z⁷ Department NH and Z² ,Z⁴ And Z⁵ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z³ Department N, Z⁷ Department NH and Z¹ ,Z² ,Z⁴ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z³ And Z⁶ Department N, Z⁷ Department NH and Z¹ ,Z² ,Z⁴ And Z⁵ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z² ,Z⁴ And Z⁷ Department N and Z¹ ,Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z⁵ And Z⁷ Department N and Z² ,Z³ ,Z⁴ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z² ,Z⁴ And Z⁷ Department N and Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z² ,Z⁵ And Z⁷ Department N and Z³ ,Z⁴ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z³ ,Z⁵ And Z⁶ Department N and Z¹ ,Z² ,Z⁴ And Z⁷ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z⁵ ,Z⁶ And Z⁷ Department N and Z² ,Z³ And Z⁴ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z² And Z⁴ Department N and Z³ ,Z⁵ ,Z⁶ And Z⁷ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z³ And Z⁴ Department N and Z² ,Z⁵ ,Z⁶ And Z⁷ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z³ And Z⁴ Department N and Z¹ ,Z² ,Z⁵ ,Z⁶ And Z⁷ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z² ,Z⁵ And Z⁷ Department N and Z¹ ,Z³ ,Z⁴ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z³ And Z⁵ Department N and Z¹ ,Z² ,Z⁴ ,Z⁶ And Z⁷ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z² ,Z⁵ ,Z⁶ And Z⁷ Department N and Z¹ ,Z³ And Z⁴ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, R^k' It is selected from the group consisting of: H, methyl, ethyl, propyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-hydroxy-2-methyl-propyl and N-methyl- Pyrrol-3-yl. In some embodiments, M is CH. In some embodiments, M is CH, Z¹ ,Z⁴ And Z⁷ Department N and Z² ,Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, M is CH, Z¹ ,Z⁴ And Z⁷ Department N, Z² ,Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H, and X¹ Department-N(R^k' )-. In some embodiments, M is CH, Z¹ ,Z⁴ And Z⁷ Department N, Z² ,Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H, X¹ Department-N(R^k' )-, and X^1' Department-O-. In some embodiments, M is CH, Z¹ ,Z⁴ And Z⁷ Department N, Z² ,Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H, X¹ Department-C(R^1a )(R^2a )-, and X^1' Department-O-. In some embodiments, the compound of formula (I) or (I-A) is a compound of formula (V):

(V) in M is CH or N; X¹ And X^1' Independently Department-C(R^1a )(R^2a )-, -S-, -S(O)-, -S(O)₂ -, -O- or -N(R^k' )-; Every R^1a And R^2a Independently of H, Deuterium, C_1-6 Alkyl, C_3-6 Cycloalkyl, C₆ -₁₀ Aryl, -C(O)OR^a' , -C(O)NR^a' R^b' , -NR^a' R^b' , -SR^a' , -S(O)R^a' , -S(O)NR^a' , -S(O)₂ R^a' , -S(O)₂ NR^a' Or -OR^a' , Where C_1-6 Each hydrogen atom in the alkyl group is independently substituted by the following as appropriate: deuterium, halogen, -OH, -OC_1-4 Alkyl, -NH₂ , -NH(C_1-4 Alkyl), -N(C_1-4 alkyl)₂ , NHC(O)C_1-4 Alkyl, -N(C_1-4 Alkyl)C(O)C_{1- 4} Alkyl, -NHC(O)NHC_1-4 Alkyl, -N(C_1-4 Alkyl)C(O)NHC_1-4 Alkyl, NHC(O)N(C_1-4 alkyl)₂ , -N(C_1-4 Alkyl)C(O)N(C_1-4 alkyl)₂ , -NHC(O)OC_1-4 Alkyl, -N(C_1-4 Alkyl)C(O)OC_1-4 Alkyl, -CO₂ H, -CO₂ C_1-4 Alkyl, -CONH₂ , -CONH(C_1-4 Alkyl), -CON(C_1-4 alkyl)₂ , -SC_1-4 Alkyl, -S(O)C_1-4 Alkyl, -S(O)₂ C_1-4 Alkyl, -S(O)NH(C_1-4 Alkyl), -S(O)₂ NH(C_1-4 Alkyl), -S(O)N(C_1-4 alkyl)₂ , -S(O)₂ N(C_1-4 alkyl)₂ , C_3-6 Cycloalkyl or 3 to 7 membered heterocycloalkyl; R^3a And R^3b Each independently is H, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN or -CF₃ ； R^7a Department H, C_1-6 Alkyl or 3 to 7 membered heterocycloalkyl, where C_1-6 Each hydrogen atom in an alkyl group or a 3- to 7-membered heterocycloalkyl group is independently substituted with the following as appropriate: halogen, -OH, -OC_{1- 4} Alkyl, -NH₂ , -NH(C_1-4 Alkyl), -N(C_1-4 alkyl)₂ , -CO₂ H, -CO₂ C_1-4 Alkyl, -CONH₂ , -CONH(C_1-4 Alkyl), -CON(C_1-4 alkyl)₂ , Cycloalkyl or monocyclic heterocycloalkyl; Every R^k' Independently of H, Deuterium, C_1-6 Alkyl, C_2-6 Alkenyl, C_2-6 Alkynyl, C_3-6 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C₆ -₁₀ Aryl or mono- or bicyclic heteroaryl; wherein R^k' C in_1-6 Alkyl, C_2-6 Alkenyl, C_2-6 Alkynyl, C_3-6 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C₆ -₁₀ Each hydrogen atom in an aryl group or a mono- or bicyclic heteroaryl group is independently substituted by the following as appropriate: deuterium, halogen, C_1-6 Alkyl, C_1-6 Haloalkyl or -OR^a' ； Where each R^a' And R^b' Independently of H, Deuterium, C_1-6 Alkyl, C_2-6 Alkenyl, C_2-6 Alkynyl, C_3-6 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C₆ -₁₀ Aryl or heteroaryl; Every Z¹ ,Z² ,Z³ ,Z⁴ ,Z⁵ ,Z⁶ Or Z⁷ Independently of N, NH or C(R^x ), where each R^x When present, it is independently H, deuterium, halogen, C_1-4 Alkyl, -O-C_1-4 Alkyl, -OH, -NH₂ , -NH(C_1-4 Alkyl), -NH (phenyl), -NH (heteroaryl), CN or -CF₃ , The prerequisite is Z¹ ,Z² ,Z³ ,Z⁴ ,Z⁵ ,Z⁶ Or Z⁷ At least one of them is N or NH; and m’ is 2 or 3; Or its pharmaceutically acceptable salt. In some embodiments, Z¹ ,Z⁴ And Z⁷ Department N and Z² ,Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ And Z³ Department N, Z⁷ Department NH and Z² ,Z⁴ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z³ And Z⁶ Department N, Z⁷ Department NH and Z² ,Z⁴ And Z⁵ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z³ Department N, Z⁷ Department NH and Z¹ ,Z² ,Z⁴ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z³ And Z⁶ Department N, Z⁷ Department NH and Z¹ ,Z² ,Z⁴ And Z⁵ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z² ,Z⁴ And Z⁷ Department N and Z¹ ,Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z⁵ And Z⁷ Department N and Z² ,Z³ ,Z⁴ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z² ,Z⁴ And Z⁷ Department N and Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z² ,Z⁵ And Z⁷ Department N and Z³ ,Z⁴ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z³ ,Z⁵ And Z⁶ Department N and Z¹ ,Z² ,Z⁴ And Z⁷ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z⁵ ,Z⁶ And Z⁷ Department N and Z² ,Z³ And Z⁴ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z² And Z⁴ Department N and Z³ ,Z⁵ ,Z⁶ And Z⁷ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z³ And Z⁴ Department N and Z² ,Z⁵ ,Z⁶ And Z⁷ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z³ And Z⁴ Department N and Z¹ ,Z² ,Z⁵ ,Z⁶ And Z⁷ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z² ,Z⁵ And Z⁷ Department N and Z¹ ,Z³ ,Z⁴ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z³ And Z⁵ Department N and Z¹ ,Z² ,Z⁴ ,Z⁶ And Z⁷ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z² ,Z⁵ ,Z⁶ And Z⁷ Department N and Z¹ ,Z³ And Z⁴ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, R^k' It is selected from the group consisting of: H, methyl, ethyl, propyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-hydroxy-2-methyl-propyl and N-methyl- Pyrrol-3-yl. In some embodiments, M is CH. In some embodiments, M is CH, Z¹ ,Z⁴ And Z⁷ Department N and Z² ,Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, M is CH, Z¹ ,Z⁴ And Z⁷ Department N, Z² ,Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H, and X¹ Department-N(R^k' )-. In some embodiments, M is CH, Z¹ ,Z⁴ And Z⁷ Department N, Z² ,Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H, X¹ Department-N(R^k' )-, and X^1' Department-O-. In some embodiments, M is CH, Z¹ ,Z⁴ And Z⁷ Department N, Z² ,Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H, X¹ Department-C(R^1a )(R^2a )-, and X^1' Department-O-. In some embodiments, the compound of formula (I) or (I-A) is a compound selected from the group consisting of:

in M is CH or N; X¹ And X^1' Independently Department-C(R^1a )(R^2a )-, -S-, -S(O)-, -S(O)₂ -, -O- or -N(R^k' )-; Every R^1a And R^2a Independently of H, Deuterium, C_1-6 Alkyl, C_3-6 Cycloalkyl, C₆ -₁₀ Aryl, -C(O)OR^a' , -C(O)NR^a' R^b' , -NR^a' R^b' , -SR^a' , -S(O)R^a' , -S(O)NR^a' , -S(O)₂ R^a' , -S(O)₂ NR^a' Or -OR^a' , Where C_1-6 Each hydrogen atom in the alkyl group is independently substituted by the following as appropriate: deuterium, halogen, -OH, -OC_1-4 Alkyl, -NH₂ , -NH(C_1-4 Alkyl), -N(C_1-4 alkyl)₂ , NHC(O)C_1-4 Alkyl, -N(C_1-4 Alkyl)C(O)C_{1- 4} Alkyl, -NHC(O)NHC_1-4 Alkyl, -N(C_1-4 Alkyl)C(O)NHC_1-4 Alkyl, NHC(O)N(C_1-4 alkyl)₂ , -N(C_1-4 Alkyl)C(O)N(C_1-4 alkyl)₂ , -NHC(O)OC_1-4 Alkyl, -N(C_1-4 Alkyl)C(O)OC_1-4 Alkyl, -CO₂ H, -CO₂ C_1-4 Alkyl, -CONH₂ , -CONH(C_1-4 Alkyl), -CON(C_1-4 alkyl)₂ , -SC_1-4 Alkyl, -S(O)C_1-4 Alkyl, -S(O)₂ C_1-4 Alkyl, -S(O)NH(C_1-4 Alkyl), -S(O)₂ NH(C_1-4 Alkyl), -S(O)N(C_1-4 alkyl)₂ , -S(O)₂ N(C_1-4 alkyl)₂ , C_3-6 Cycloalkyl or 3 to 7 membered heterocycloalkyl; R^3a And R^3b Each independently is H, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN or -CF₃ ； R^7a Department H, C_1-6 Alkyl or 3 to 7 membered heterocycloalkyl, where C_1-6 Each hydrogen atom in an alkyl group or a 3- to 7-membered heterocycloalkyl group is independently substituted with the following as appropriate: halogen, -OH, -OC_{1- 4} Alkyl, -NH₂ , -NH(C_1-4 Alkyl), -N(C_1-4 alkyl)₂ , -CO₂ H, -CO₂ C_1-4 Alkyl, -CONH₂ , -CONH(C_1-4 Alkyl), -CON(C_1-4 alkyl)₂ , Cycloalkyl or monocyclic heterocycloalkyl; Every R^k' Independently of H, Deuterium, C_1-6 Alkyl, C_2-6 Alkenyl, C_2-6 Alkynyl, C_3-6 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C₆ -₁₀ Aryl or mono- or bicyclic heteroaryl; wherein R^k' C in_1-6 Alkyl, C_2-6 Alkenyl, C_2-6 Alkynyl, C_3-6 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C₆ -₁₀ Each hydrogen atom in an aryl group or a mono- or bicyclic heteroaryl group is independently substituted by the following as appropriate: deuterium, halogen, C_1-6 Alkyl, C_1-6 Haloalkyl or -OR^a' ； Where each R^a' And R^b' Independently of H, Deuterium, C_1-6 Alkyl, C_2-6 Alkenyl, C_2-6 Alkynyl, C_3-6 Cycloalkyl, 3 to 7 membered heterocycloalkyl, C₆ -₁₀ Aryl or heteroaryl; Every Z¹ ,Z² ,Z³ ,Z⁴ ,Z⁵ ,Z⁶ Or Z⁷ Independently of N, NH or C(R^x ), where each R^x When present, it is independently H, deuterium, halogen, C_1-4 Alkyl, -O-C_1-4 Alkyl, -OH, -NH₂ , -NH(C_1-4 Alkyl), -NH (phenyl), -NH (heteroaryl), CN or -CF₃ , The prerequisite is Z¹ ,Z² ,Z³ ,Z⁴ ,Z⁵ ,Z⁶ Or Z⁷ At least one of them is N or NH; and m’ is 2 or 3; Or its pharmaceutically acceptable salt. In some embodiments, Z¹ ,Z⁴ And Z⁷ Department N and Z² ,Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ And Z³ Department N, Z⁷ Department NH and Z² ,Z⁴ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z³ And Z⁶ Department N, Z⁷ Department NH and Z² ,Z⁴ And Z⁵ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z³ Department N, Z⁷ Department NH and Z¹ ,Z² ,Z⁴ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z³ And Z⁶ Department N, Z⁷ Department NH and Z¹ ,Z² ,Z⁴ And Z⁵ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z² ,Z⁴ And Z⁷ Department N and Z¹ ,Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z⁵ And Z⁷ Department N and Z² ,Z³ ,Z⁴ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z² ,Z⁴ And Z⁷ Department N and Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z² ,Z⁵ And Z⁷ Department N and Z³ ,Z⁴ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z³ ,Z⁵ And Z⁶ Department N and Z¹ ,Z² ,Z⁴ And Z⁷ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z⁵ ,Z⁶ And Z⁷ Department N and Z² ,Z³ And Z⁴ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z² And Z⁴ Department N and Z³ ,Z⁵ ,Z⁶ And Z⁷ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z¹ ,Z³ And Z⁴ Department N and Z² ,Z⁵ ,Z⁶ And Z⁷ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z³ And Z⁴ Department N and Z¹ ,Z² ,Z⁵ ,Z⁶ And Z⁷ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z² ,Z⁵ And Z⁷ Department N and Z¹ ,Z³ ,Z⁴ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z³ And Z⁵ Department N and Z¹ ,Z² ,Z⁴ ,Z⁶ And Z⁷ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, Z² ,Z⁵ ,Z⁶ And Z⁷ Department N and Z¹ ,Z³ And Z⁴ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, R^k' It is selected from the group consisting of: H, methyl, ethyl, propyl, isopropyl, cyclopropyl, 2-hydroxyethyl, 2-hydroxy-2-methyl-propyl and N-methyl- Pyrrol-3-yl. In some embodiments, M is CH. In some embodiments, M is CH, Z¹ ,Z⁴ And Z⁷ Department N and Z² ,Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H. In some embodiments, M is CH, Z¹ ,Z⁴ And Z⁷ Department N, Z² ,Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H, and X¹ Department-N(R^k' )-. In some embodiments, M is CH, Z¹ ,Z⁴ And Z⁷ Department N, Z² ,Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H, X¹ Department-N(R^k' )-, and X^1' Department-O-. In some embodiments, M is CH, Z¹ ,Z⁴ And Z⁷ Department N, Z² ,Z³ ,Z⁵ And Z⁶ Department C (R^x ), where each R^x When it exists, it is H, X¹ Department-C(R^1a )(R^2a )-, and X^1' Department-O-. In other embodiments, the compound of formula (I) or (IA) is selected from the group consisting of (13R)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethylene Bridging group pyrazolo[4,3-f][1,10,4,8]benzodioxadiaazatridecyclo-4(5H)-one; 5,13-dimethyl-6 ,7-Dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine-4(5H )-Ketone; (13R)-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10 ,4,8]benzodioxadiazepine tridecane-4(5H)-one; 11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15- Vinyl bridge pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine-4(5H)-one; (13R)-12-chloro- 11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzodi Oxadiazepine tridecane-4(5H)-one; 12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-vinylpyridine Azolo[4,3-f][1,10,4,8]benzodioxadiazepine-4(5H)-one; (13R)-12-chloro-11-fluoro- 5-(2-hydroxyethyl)-13-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8] Benzodioxadiazepine tridecane-4(5H)-one; 12-chloro-11-fluoro-5-(2-hydroxyethyl)-13-methyl-6,7-dihydro- 13H-1,15-vinyl bridging group pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine-4(5H)-one; 2- [(13R)-12-chloro-11-fluoro-13-methyl-4- pendant oxy-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f] [1,10,4,8]benzodioxadiazepine-5(4H)-yl]acetamide; 2-[12-chloro-11-fluoro-13-methyl-4 -Pendant oxy-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine Cyclo-5(4H)-yl]acetamide; (13R)-12-chloro-11-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro -13H-1,15-vinyl bridging group pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine tridecane-4(5H)-one; 12 -Chloro-11-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro -13H-1,15-vinyl bridge group pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine tridecane-4(5H)-one; ( 13R)-12-chloro-11-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-vinylpyrazolo[4,3 -f][1,10,4,8]benzodioxadiazepine tridecane-4(5H)-one; 12-chloro-11-fluoro-7-(hydroxymethyl)-5, 13-Dimethyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine Tricyclic-4(5H)-one; (13S)-11-fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-vinylpyrazole And [4,3-f][1,10,4,8]benzodioxadiazepine-4(5H)-one; 11-fluoro-13-(fluoromethyl)-5 -Methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine Cyclo-4(5H)-one; (13R)-13-cyclopropyl-11-fluoro-5-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4, 3-f][1,10,4,8]benzodioxadiazepine tridecane-4(5H)-one; 13-cyclopropyl-11-fluoro-5-methyl-6, 7-Dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine-4(5H) -Ketone; (13R)-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8 ]Benzodioxadiazepine tridecane-4(5H)-one; 11-fluoro-13-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[ 4,3-f][1,10,4,8]benzodioxadiazepine tridecane-4(5H)-one; (13R)-12-chloro-11-fluoro-13-methyl -6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine- 4(5H)-one; 12-chloro-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10 ,4,8] benzodioxadiazepine tridecane-4(5H)-one; 12-chloro-11-fluoro-6-methyl-6,7-dihydro-13H-1,15 -Vinyl pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine-4(5H)-one; 12-chloro-11-fluoro -7-Methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,1 0,4,8] benzodioxadiazepine tridecane-4(5H)-one; (8R)-9-chloro-10-fluoro-8-methyl-15,16-dihydro- 8H-3,6-vinyl imidazo[5,1-f][1,10,4,7,8]benzodioxatriazatridecyclic-17(14H)-one; 9 -Chloro-10-fluoro-8-methyl-15,16-dihydro-8H-3,6-vinyl imidazo[5,1-f][1,10,4,7,8]benzo Dioxatriazatriazone-17(14H)-one; (7R)-8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5- (Nitrilomethylene bridging group) pyrrolo[3,4-f][1,10,4,8]benzodioxadiazepine-16(13H)-one; 8-chloro -9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5-(nitrilomethylene bridging group)pyrrolo[3,4-f][1,10,4, 8] Benzodioxadiazepine tridecane-16(13H)-one; (5R)-3-fluoro-5-methyl-14,15-dihydro-5H,10H-9,7- (Nitrilomethylene bridging group)pyrido[2,3-k]pyrrolo[3,4-d][1,10,3,7]dioxadiazepine-12(13H )-Ketone; 3-fluoro-5-methyl-14,15-dihydro-5H,10H-9,7-(nitrilomethylene bridging group)pyrido[2,3-k]pyrrolo[3 ,4-d][1,10,3,7]dioxadiazepine-12(13H)-one; (5R)-3-fluoro-5,16-dimethyl-13, 14,15,16-Tetrahydro-5H-9,7-(nitrilomethylene bridge) pyrido[2,3-k]pyrrolo[3,4-d][1,3,7,10 ]Oxatriazatriazone-12(10H)-one; 3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H-9,7-(nitrilo Glymethylene bridge) pyrido[2,3-k]pyrrolo[3,4-d][1,3,7,10]oxatriazatridecane-12(10H)-one; (13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-2H,13H-1,15-(nitrilomethylene bridging group)pyrrolo[3,4 -f][1,10,4]benzodioxazepine-4(5H)-one; 12-chloro-11-fluoro-5,13-dimethyl-6,7-di Hydrogen-2H,13H-1,15-(nitrilomethylene bridging group)pyrrolo[3,4-f][1,10,4]benzodioxazepine tridecane-4(5H )-Ketone; (7R)-8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(nitrilomethylene bridge group)pyrazole And [3,4-f][1,10,4]benzodioxazepine ring-16(13 H)-ketone; 8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(nitrilomethylene bridging group) pyrazolo [3 ,4-f][1,10,4]benzodioxazepine-16(13H)-one; 11-fluoro-14-methyl-6,7,13,14-tetrahydro -1,15-Vinyl pyrazolo[4,3-f][1,4,8,10]benzoxatriazatridecyclic-4(5H)-one; (13R)- 12-chloro-11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8 ,10] Benzooxatriazatriazone-4(5H)-one; 12-chloro-11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1 ,15-Vinyl pyrazolo[4,3-f][1,4,8,10]benzoxatriazatridecyclo-4(5H)-one; 12-chloro-11- Fluoro-5,14-dimethyl-6,7,13,14-tetrahydro-15,1-(nitrilomethylene bridging group)pyrazolo[4,3-f][1,4,10 ]Benzoxadiazepine tridecane-4(5H)-one; 12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-15,1-(times Nitromethylene bridging group) pyrazolo[4,3-f][1,4,8,10]benzoxatriazatridecyclo-4(5H)-one; 12-chloro-11 -Fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-(nitrilomethylene bridging group)pyrrolo[3,2-f][1,4,8,10] Benzoxatriazatriazone-4(5H)-one; 12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-(nitrilo Glymethylene bridging group) pyrrolo[3,2-f][1,4,10]benzoxadiaazatridecyclo-4(5H)-one; 9-chloro-10-fluoro-7 -Methyl-7,8,15,16-tetrahydro-3,6-vinyl imidazo[5,1-f][1,4,7,8,10]benzoxatetraazade Tricyclic-17(14H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(nitrilomethylene bridge) imidazo [5,1-f][1,4,7,8,10]benzoxazepine -17(14H)-one; 9-chloro-10-fluoro-7-methyl- 7,8,15,16-Tetrahydro-6,3-(nitrilomethylene bridge) imidazo[5,1-f][1,4,7,10]benzoxatriazade Tricyclic-17(14H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-(nitrilomethylene bridge) pyrrolo [2,1-f][1,4,7,10] benzoxatriazatriazone-17(14H)-one; 9-chloro-10-fluoro- 7-Methyl-7,8,15,16-tetrahydro-3,6-(nitrilomethylene bridge) imidazo[2,1-f][1,4,7,10]benzox Heterotriaza-tridecan ring-17(14H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-vinyl bridging group [1, 2,4]triazolo[3,4-f][1,4,7,8,10]benzoxazepine-17(14H)-one; 9-chloro-10- Fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(nitrilomethylene bridging group)[1,2,4]triazolo[3,4-f][1 ,4,7,10] benzoxatriazatridecarin-17(14H)-one; 8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro- 2H-3,5-(Nitrilomethylene bridging group)pyrrolo[3,4-f][1,4,8,10]benzoxatriazatridecane-16(13H)- Ketone; 8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(nitrilomethylene bridging group)pyrazolo[3,4-f ][1,4,8,10]benzoxatriazatriazone-16(13H)-one; 8-chloro-9-fluoro-6-methyl-6,7,14,15- Tetrahydro-2H-3,5-(nitrilomethylene bridging group)pyrazolo[3,4-f][1,4,10]benzoxadiazepine -16(13H )-Ketone; 12-chloro-11-fluoro-5,14-dimethyl-6,7,13,14-tetrahydro-2H-1,15-(nitrilomethylene bridging group)pyrrolo[3 ,4-f][1,4,10]benzoxadiazepine tridecane-4(5H)-one; (8R)-10-fluoro-8,16-dimethyl-15,16 -Dihydro-8H-3,6-vinyl bridging imidazo[5,1-f][1,10,4,7,8]benzodioxatriazatridecane-17(14H) -Ketone; 10-Fluoro-8,16-dimethyl-15,16-dihydro-8H-3,6-vinyl imidazo[5,1-f][1,10,4,7,8 ] Benzodioxatriazatridecene-17(14H)-one; (7R)-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3, 5-(Nitrilomethylene bridging group)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazepine tridecane-16(13H)-one; and 9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(nitrilomethylene bridging group)pyrrolo[3,4-f][1,10, 4,8] Benzodioxadiazepine -16(13H)-one; or a pharmaceutically acceptable salt thereof. In other embodiments, the compound of formula (I) or (IA) is selected from the group consisting of: 12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1, 15-Vinyl pyrazolo[4,3-f][1,4,8,10]benzoxatriazatridecyclo-4(5H)-one; 11-fluoro-3,14 -Dimethyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzoxatriazade Tricyclic-4(5H)-one; 10-fluoro-8-methyl-15,16-dihydro-8H-3,6-vinyl imidazo[5,1-f][1,10, 4,7,8] Benzodioxatriazatriazone-17(14H)-one; 10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6- Vinyl bridge imidazo[5,1-f][1,4,7,8,10]benzoxatetraazatridecyclic-17(14H)-one; 14-ethyl-11-fluoro -6,7,13,14-Tetrahydro-1,15-vinyl bridge pyrazolo[4,3-f][1,4,8,10]benzoxatriazatriazin ring- 4(5H)-one; 11-fluoro-14-propyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8 ,10] Benzooxatriazatriazone-4(5H)-one; 11-fluoro-14-(prop-2-yl)-6,7,13,14-tetrahydro-1,15 -Vinyl bridge pyrazolo[4,3-f][1,4,8,10]benzoxatriazatridecyclo-4(5H)-one; 14-cyclopropyl-11- Fluoro-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzoxatriazatriazin ring -4(5H)-one; 11-fluoro-14-(2-hydroxyethyl)-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f] [1,4,8,10] Benzoxatriazatriazone-4(5H)-one; 11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro -1,15-Vinyl pyrazolo[4,3-f][1,4,8,10]benzoxatriazatridecyclo-4(5H)-one; 14-methyl -6,7,13,14-Tetrahydro-1,15-vinyl bridge pyrazolo[4,3-f][1,4,8,10]benzoxatriazatriazin ring- 4(5H)-one; 11-fluoro-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzo Oxatriazatridecene-4(5H)-one; 11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo [4, 3-f][1,4,8,10]benzoxatriazatriazone-4(5H)-one; (13R )-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; 12-chloro-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4, 8,10] benzoxatriazatridecan ring-4(5H)-one; 11-fluoro-14-methyl-4- pendant oxy-4,5,6,7,13,14- Hexahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzoxatriazatridecyclo-7-methamide; 11-fluoro -7-(hydroxymethyl)-14-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10 ] Benzooxatriazatriazone-4(5H)-one; 11-fluoro-13-methyl-4- pendant oxy-4,5,6,7,13,14-hexahydro- 1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzoxatriazatridecyclo-7-methamide; 11-fluoro-7- (Hydroxymethyl)-13-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzo Oxatriazatridecene-4(5H)-one; 11-fluoro-4- pendant oxy-4,5,6,7,13,14-hexahydro-1,15-vinylpyridine Azolo[4,3-f][1,4,8,10]benzoxatriazatriazepine-7-methanamide; 11-fluoro-7-(hydroxymethyl)-6, 7,13,14-Tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzoxatriazatridecane-4(5H )-Ketone; 11-fluoro-4- pendant oxy-4,5,6,7,13,14-hexahydro-1,15-vinyl pyrazolo[4,3-f][1,4 ,8,10] Benzooxatriazatriazone-13-methyl carboxylate; 11-fluoro-4- pendant oxy-4,5,6,7,13,14-hexahydro-1, 15-Vinyl pyrazolo[4,3-f][1,4,8,10]benzoxatriazatridecyclic-13-methamide; 11-fluoro-14-methyl -6,7,13,14-Tetrahydro-1,15-vinyl pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatri Azatridecine-4(5H)-one; 11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f ]Pyrido[3,2-l][1,4,8,10]oxatriazatriadecine-4(5H)-one; 11-fluoro-13-(prop-2-yl)- 6,7,13,14-Tetrahydro-1,15-vinyl pyrazolo[4,3-f]pyrido[3,2-l][1,4,8,10]oxatriazide Heterotridecene-4(5H)-one; 13-cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f ]Pyrido[3,2-l][1,4,8,10]oxatriazatridecyclo-4(5H)-one; 13-cyclopropyl-11-fluoro-6,7, 13,14-Tetrahydro-1,15-vinyl bridge group pyrazolo[4,3-f][1,4,8,10]benzoxatriazatridecane-4(5H)- Ketone; 11-fluoro-13-(prop-2-yl)-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8 ,10] benzoxatriazatridecan ring-4(5H)-one; 11-fluoro-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3- f][1,10,4,8]Benzoxathiadiazepine-4(5H)-one; 11-fluoro-6,7-dihydro-13H-1,15-ethylene Bridging group pyrazolo[4,3-f][1,10,4,8]benzoxathiadiazepine tridecane-4(5H)-one 14,14-dioxide; 6 ,7-Dihydro-13H-1,15-vinyl pyrazolo[4,3-f][10,1,4,8]benzoxadiazepine-4( 5H)-ketone; 14-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzosulfide Heterotriazatridecene-4(5H)-one; 13-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][ 1,4,8,10]benzothiatriazatridecyclo-4(5H)-one; 11-fluoro-6,7-dihydro-5H-1,15-vinylpyrazolo [3,4-e][11,1,2,4,8]benzoxathiatriazatridecane-4(14H)-one 13,13-dioxide; 11-fluoro- 14-Methyl-6,7-dihydro-5H-1,15-vinyl pyrazolo[3,4-e][11,1,2,4,8]benzoxathiatriazide Heterotridecene-4(14H)-ketone 13,13-dioxide; 12-fluoro-15-methyl-5,6,7,8,14,15-hexahydro-4H-1,16- Vinyl bridge pyrazolo[4,3-g][1,5,9,11]benzoxatriazatetradecen-4-one; 12-fluoro-14-methyl-5,6 ,7,8,14,15-hexahydro-4H-1,16-vinyl pyrazolo[4,3-g][1,5,9,11] benzoxatriazatetrazepine Cyclo-4-one; (14R )-12-fluoro-14-methyl-5,6,7,8,14,15-hexahydro-4H -1,16-vinyl pyrazolo [4,3-g ][1,5,9,11] benzoxatriazatetradecen-4-one; 11-fluoro-7,14-dimethyl-4,5,6,7,13,14- Hexahydro-8H-1,15-vinyl pyrazolo[3,4-e][2,4,10]benzotriazepine-8-one; 11-fluoro-7,14 -Dimethyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[3,4-e][7,2,4,10]benzoxatriazade Tricyclic-8(5H)-one; 11-fluoro-7,14-dimethyl-4,5,6,7,13,14-hexahydro-8H-1,15-vinyl pyrazolo [3,4-e][2,4,7,10]benzotetraazatridecane-8-one; 11-fluoro-4,7,14-trimethyl-4,5,6, 7,13,14-Hexahydro-8H-1,15-vinyl pyrazolo[3,4-e][2,4,7,10]benzotetraazatridecyclo-8-one ; 11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[3,4-e][7,2,4,10] Benzothiatriazatriazide ring-8(5H)-one; 11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyridine Azolo[3,4-e][7,2,4,10]benzothiatriazatridecyclo-8(5H)-one 4,4-dioxide; and 12-fluoro-8 ,15-Dimethyl-5,6,7,8,14,15-hexahydro-9H-1,16-vinyl pyrazolo[3,4-e][7,2,4,8, 11] Benzothiatetraazatetraazatetracycline-9-one 4,4-dioxide; or its pharmaceutically acceptable salt. In other embodiments, the compound of formula (I) or (IA) is selected from the group consisting of: 11-chloro-13-methyl-6,7,13,14-tetrahydro-1,15-ethylene bridge Pyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; 13-ethyl-11-fluoro-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo [4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; 13-cyclobutyl-11-fluoro-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo [4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; 11-fluoro-14-methyl(6,6,7,7-² H₄ )-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; 11-fluoro-13-phenyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo [4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; 13-(cyclopropylmethyl)-11-fluoro-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; (7R ,14R )-12-fluoro-7-hydroxy-14-methyl-5,6,7,8,14,15-hexahydro-4H -1,16-vinyl pyrazolo [4,3-g ][1,5,9,11]benzoxatriazatetradecen-4-one; (7S ,14R )-12-fluoro-7-hydroxy-14-methyl-5,6,7,8,14,15-hexahydro-4H -1,16-vinyl pyrazolo [4,3-g ][1,5,9,11]benzoxatriazatetradecen-4-one; (7R ,13R )-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; (7S ,13R )-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; (7R )-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; (6R )-11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; 12-fluoro-7-hydroxy-15-methyl-5,6,7,8,14,15-hexahydro-4H -1,16-vinyl pyrazolo [4,3-g ][1,5,9,11]benzoxatriazatetradecen-4-one; (7S )-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; 11-fluoro-13-(hydroxymethyl)-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; 12-fluoro-14-(hydroxymethyl)-5,6,7,8,14,15-hexahydro-4H -1,16-vinyl pyrazolo [4,3-g ][1,5,9,11] benzoxatriazatetradecen-4-one; 11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1 ,15-vinyl pyrazolo [4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; 11-fluoro-14-(2-hydroxy-2-methylpropyl)-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; 12-fluoro-5,6,7,8,14,15-hexahydro-4H -1,16-vinyl pyrazolo [4,3-g ][1,5,9] benzoxadiazepine tetradecen-4-one; 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethylene bridge Pyrazolo[4,3-f ][1,4,8,10]benzothiatriazepine-4(5H )-Ketone; 11-fluoro-14-(1-methylpyrrolidin-3-yl)-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo [4,3-f ][1,4,8,10]benzothiatriazepine-4(5H )-Ketone 8-oxide; 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo [4,3-f ][1,4,8,10]benzothiatriazepine-4(5H )-Ketone 8,8-dioxide; (7S )-11-fluoro-7-methyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8]benzoxadiazepine-4(5H )-Ketone; (6S ,13R )-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; (6R ,13R )-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; (7S ,13S )-11-fluoro-13-(hydroxymethyl)-7-methyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; and 11-fluoro-6,7-dihydro-13 H -1,15-vinyl pyrazolo [4,3- f ][1,10,4,8]Benzoxathiadiazepine-4(5 H )-Ketone; or its pharmaceutically acceptable salt. In other embodiments, the compound of formula (I) or (IA) is selected from the group consisting of (13R)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethylene Bridging group pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine-4(5H)-one; (13R)-11-fluoro-5 ,13-Dimethyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine Tridecyl ring-4(5H)-one; (13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-vinylpyrazole And [4,3-f][1,10,4,8] benzodioxadiazepine tridecane-4(5H)-one; (13R)-12-chloro-11-fluoro-5 -(2-Hydroxyethyl)-13-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzene And dioxadiazepine tridecane-4(5H)-one; 2-[(13R)-12-chloro-11-fluoro-13-methyl-4-oxo-6,7-di Hydrogen-13H-1,15-vinyl bridging group pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine-5(4H)-yl] Acetamide; (13R)-12-chloro-11-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro-13H-1,15-vinyl Pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine-4(5H)-one; (13R)-12-chloro-11-fluoro -7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4, 8] Benzodioxadiazepine tridecane-4(5H)-one; (13S)-11-fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro- 13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine-4(5H)-one; (13R )-13-cyclopropyl-11-fluoro-5-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4, 8] Benzodioxadiazepine tridecane-4(5H)-one; (13R)-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethylene bridge Pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine-4(5H)-one; (13R)-12-chloro-11- Fluoro-13-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine Tridecane-4(5H)-one; (8R)-9-chloro-10-fluoro -8-Methyl-15,16-dihydro-8H-3,6-vinyl imidazo[5,1-f][1,10,4,7,8]benzodioxatriazane Tridecyl ring-17(14H)-one; (7R)-8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5-(nitrilomethylene Bridging group) pyrrolo[3,4-f][1,10,4,8]benzodioxadiazepine-16(13H)-one; (5R)-3-fluoro-5 -Methyl-14,15-dihydro-5H,10H-9,7-(nitrilomethylene bridge) pyrido[2,3-k]pyrrolo[3,4-d][1,10 ,3,7]Dioxadiazepine-12(13H)-one; (5R)-3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro- 5H-9,7-(nitrilomethylene bridging group)pyrido[2,3-k]pyrrolo[3,4-d][1,3,7,10]oxatriazine Cyclo-12(10H)-ketone; (13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-2H,13H-1,15-(nitrilomethylene Bridging group) pyrrolo[3,4-f][1,10,4]benzodioxazepine-4(5H)-one; (7R)-8-chloro-9-fluoro- 7,15-Dimethyl-14,15-dihydro-2H,7H-3,5-(nitrilomethylene bridging group)pyrazolo[3,4-f][1,10,4]benzene Dioxazepine tridecane-16(13H)-one; (13R)-12-chloro-11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1 ,15-Vinyl pyrazolo[4,3-f][1,4,8,10]benzoxatriazatridecyclo-4(5H)-one; (8R)-10- Fluoro-8,16-dimethyl-15,16-dihydro-8H-3,6-vinyl imidazo[5,1-f][1,10,4,7,8]benzodiox Heterotriazatriazide ring-17(14H)-one; (7R)-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(nitrilo Ylmethylene bridging group) pyrrolo[3,4-f][1,10,4,8]benzodioxadiazepine -16(13H)-one; (13R )-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; (14R )-12-fluoro-14-methyl-5,6,7,8,14,15-hexahydro-4H -1,16-vinyl pyrazolo [4,3-g ][1,5,9,11]benzoxatriazatetradecen-4-one; (7R ,14R )-12-fluoro-7-hydroxy-14-methyl-5,6,7,8,14,15-hexahydro-4H -1,16-vinyl pyrazolo [4,3-g ][1,5,9,11]benzoxatriazatetradecen-4-one; (7S ,14R )-12-fluoro-7-hydroxy-14-methyl-5,6,7,8,14,15-hexahydro-4H -1,16-vinyl pyrazolo [4,3-g ][1,5,9,11]benzoxatriazatetradecen-4-one; (7R ,13R )-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; (7S ,13R )-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; (7R )-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; (6R )-11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; (7S )-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; (7S )-11-fluoro-7-methyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8]benzoxadiazepine-4(5H )-Ketone; (6S ,13R )-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; (6R ,13R )-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; and (7S ,13S )-11-fluoro-13-(hydroxymethyl)-7-methyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f ][1,4,8,10]benzoxatriazatriazin-4(5H )-Ketone; or its pharmaceutically acceptable salt. The following represent illustrative examples of compounds of formula (I) or (I-A): Instance structure Chemical Name 1

(13R)-5,13-Dimethyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzodi Oxadiazepine-4(5H)-one 1-1

5,13-Dimethyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzodioxadiazepine Heterotridecane-4(5H)-one 2

(13R)-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8 ]Benzodioxadiazepine tridecane-4(5H)-one 2-1

11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzodi Oxadiazepine-4(5H)-one 3

(13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10 ,4,8]benzodioxadiazepine-4(5H)-one 3-1

12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8 ]Benzodioxadiazepine tridecane-4(5H)-one 4

(13R)-12-chloro-11-fluoro-5-(2-hydroxyethyl)-13-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3 -f][1,10,4,8]benzodioxadiazepine tridecane-4(5H)-one 4-1

12-chloro-11-fluoro-5-(2-hydroxyethyl)-13-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][ 1,10,4,8]benzodioxadiazepine tridecane-4(5H)-one 5

2-[(13R)-12-chloro-11-fluoro-13-methyl-4- pendant oxy-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3- f][1,10,4,8]benzodioxadiazepine-5(4H)-yl]acetamide 5-1

2-[12-chloro-11-fluoro-13-methyl-4- pendant oxy-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1 ,10,4,8]benzodioxadiazepine-5(4H)-yl)acetamide 6

(13R)-12-chloro-11-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro-13H-1,15-vinylpyrazolo[ 4,3-f][1,10,4,8]benzodioxadiazepine tridecane-4(5H)-one 6-1

12-Chloro-11-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3- f][1,10,4,8]benzodioxadiazepine tridecane-4(5H)-one 7

(13R)-12-chloro-11-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-vinylpyrazolo[4, 3-f][1,10,4,8]benzodioxadiazepine tridecane-4(5H)-one 7-1

12-chloro-11-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f] [1,10,4,8]benzodioxadiazepine tridecane-4(5H)-one 8

(13S)-11-Fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1, 10,4,8]benzodioxadiazepine-tridecyl-4(5H)-one 8-1

11-Fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4, 8] benzodioxadiazepine tridecane-4(5H)-one 9

(13R)-13-cyclopropyl-11-fluoro-5-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10, 4,8]benzodioxadiazepine tridecane-4(5H)-one 9-1

13-Cyclopropyl-11-fluoro-5-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8] Benzodioxadiazepine tridecane-4(5H)-one 10

(13R)-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzo Dioxadiazepine-4(5H)-one 10-1

11-fluoro-13-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzodioxane Azepine-4(5H)-one 11

(13R)-12-chloro-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4, 8] benzodioxadiazepine tridecane-4(5H)-one 11-1

12-chloro-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzo Dioxadiazepine-4(5H)-one 12

12-chloro-11-fluoro-6-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzo Dioxadiazepine-4(5H)-one 13

12-chloro-11-fluoro-7-methyl-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzo Dioxadiazepine-4(5H)-one 14

(8R)-9-chloro-10-fluoro-8-methyl-15,16-dihydro-8H-3,6-vinyl imidazo[5,1-f][1,10,4,7 ,8]benzodioxatriazatriazone-17(14H)-one 14-1

9-chloro-10-fluoro-8-methyl-15,16-dihydro-8H-3,6-vinyl imidazo[5,1-f][1,10,4,7,8]benzene Dioxatriazatriazone-17(14H)-one 15

(7R)-8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5-(nitrilomethylene bridging group)pyrrolo[3,4-f] [1,10,4,8]benzodioxadiazepine tridecane-16(13H)-one 15-1

8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5-(nitrilomethylene bridging group)pyrrolo[3,4-f][1,10 ,4,8]benzodioxadiazepine-16(13H)-one 16

(5R)-3-fluoro-5-methyl-14,15-dihydro-5H,10H-9,7-(nitrilomethylene bridging group)pyrido[2,3-k]pyrrolo[3 ,4-d][1,10,3,7]dioxadiazepine-12(13H)-one 16-1

3-Fluoro-5-methyl-14,15-dihydro-5H,10H-9,7-(nitrilomethylene bridging group)pyrido[2,3-k]pyrrolo[3,4-d ][1,10,3,7]dioxadiazepine-12(13H)-one 17

(5R)-3-Fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H-9,7-(nitrilomethylene bridge)pyrido(2,3-k ]Pyrrolo[3,4-d][1,3,7,10]oxatriazatridecyclic-12(10H)-one 17-1

3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H-9,7-(nitrilomethylene bridging group)pyrido[2,3-k]pyrrolo[ 3,4-d][1,3,7,10]oxatriazatriazin-12(10H)-one 18

(13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-2H,13H-1,15-(nitrilomethylene bridging group)pyrrolo[3,4 -f][1,10,4]benzodioxazepine tridecane-4(5H)-one 18-1

12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-2H,13H-1,15-(nitrilomethylene bridging group)pyrrolo[3,4-f][ 1,10,4]benzodioxazepine-tridecyl-4(5H)-one 19

(7R)-8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(nitrilomethylene bridging group)pyrazolo(3, 4-f][1,10,4]benzodioxazepine-16(13H)-one 19-1

8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(nitrilomethylene bridging group)pyrazolo[3,4-f] [1,10,4]benzodioxazepine tridecane-16(13H)-one 20

11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzoxa Triazatridecine-4(5H)-one twenty one

(13R)-12-chloro-11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1 ,4,8,10]benzoxatriazatriazone-4(5H)-one 21-1

12-chloro-11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8 ,10]benzoxatriazatriazin-4(5H)-one twenty two

12-chloro-11-fluoro-5,14-dimethyl-6,7,13,14-tetrahydro-15,1-(nitrilomethylene bridging group)pyrazolo[4,3-f] [1,4,10] benzoxadiazepine tridecane-4(5H)-one twenty three

12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-15,1-(nitrilomethylene bridging group)pyrazolo[4,3-f][1, 4,8,10]benzoxatriazatriazepine-4(5H)-one twenty four

12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-(nitrilomethylene bridging) pyrrolo[3,2-f][1,4 ,8,10]benzoxatriazatriazin-4(5H)-one 25

12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-(nitrilomethylene bridging) pyrrolo[3,2-f][1,4 ,10] benzoxadiazepine tridecane-4(5H)-one 26

9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-vinyl imidazo[5,1-f][1,4,7,8,10 ]Benzoxatetraazatridecane-17(14H)-one 27

9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(nitrilomethylene bridge) imidazo[5,1-f][1,4 ,7,8,10]benzoxazepine -17(14H)-one 28

9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(nitrilomethylene bridge) imidazo[5,1-f][1,4 ,7,10)benzoxatriazatriazin-17(14H)-one 29

9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-(nitrilomethylene bridge) pyrrolo[2,1-f][1,4 ,7,10)benzoxatriazatriazin-17(14H)-one 30

9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-(nitrilomethylene bridge) imidazo[2,1-f][1,4 ,7,10)benzoxatriazatriazin-17(14H)-one 31

9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-vinyl[1,2,4]triazolo[3,4-f][1 ,4,7,8,10]benzoxatetraazatridecyclic-17(14H)-one 32

9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(nitrilomethylene bridging group)[1,2,4]triazolo[3, 4-f][1,4,7,10]benzoxatriazatriazin-17(14H)-one 33

8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(nitrilomethylene bridging group)pyrrolo[3,4-f][1 ,4,8,10]benzoxatriazatriazin-16(13H)-one 34

8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(nitrilomethylene bridging group)pyrazolo[3,4-f][ 1,4,8,10)benzoxatriazatriazin-16(13H)-one 35

8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5-(nitrilomethylene bridging group)pyrazolo[3,4-f][ 1,4,10]benzoxadiazepine tridecane-16(13H)-one 36

12-chloro-11-fluoro-5,14-dimethyl-6,7,13,14-tetrahydro-2H-1,15-(nitrilomethylene bridge) pyrrolo[3,4-f ][1,4,10] benzoxadiazepine tridecane-4(5H)-one 37

(8R)-10-fluoro-8,16-dimethyl-15,16-dihydro-8H-3,6-vinyl imidazo[5,1-f][1,10,4,7, 8) Benzodioxatriazatriazone-17(14H)-one 37-1

10-Fluoro-8,16-dimethyl-15,16-dihydro-8H-3,6-vinyl imidazo[5,1-f][1,10,4,7,8]benzo Dioxatriazatriazone-17(14H)-one 38

(7R)-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(nitrilomethylene bridging group)pyrrolo[3,4-f][ 1,10,4,8]benzodioxadiazepine -16(13H)-one 38-1

9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(nitrilomethylene bridging group)pyrrolo[3,4-f][1,10, 4,8]benzodioxadiazepine tridecane-16(13H)-one And its pharmaceutically acceptable salts. The following represent illustrative examples of compounds of formula (I) or (I-A): Instance structure Chemical Name 39

12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10] Benzoxatriazatriazin-4(5H)-one 40

11-fluoro-3,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzene P-oxatriazatriazone-4(5H)-one 41

10-Fluoro-8-methyl-15,16-dihydro-8H-3,6-vinyl imidazo[5,1-f][1,10,4,7,8]benzodioxa Triazatride ring-17(14H)-one 42

10-Fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-vinyl imidazo[5,1-f][1,4,7,8,10]benzooxy Tetraaza-tridecan ring-17(14H)-one 43

14-Ethyl-11-fluoro-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzoxa Triazatridecine-4(5H)-one 44

11-fluoro-14-propyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzoxa Triazatridecine-4(5H)-one 45

11-fluoro-14-(prop-2-yl)-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10 ] Benzoxatriazatriazone-4(5H)-one 46

14-Cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzooxy Triazine-4(5H)-one 47

11-fluoro-14-(2-hydroxyethyl)-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10 ] Benzoxatriazatriazone-4(5H)-one 48

11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzene P-oxatriazatriazone-4(5H)-one 49

14-Methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzoxatriazade Tricyclic-4(5H)-one 50

11-Fluoro-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzoxatriazatriazide熳环-4(5H)-one 51

11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzoxa Triazatridecine-4(5H)-one 51-1

(13 R )-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3- f ][1,4,8,10 ] Benzoxatriazatriazin-4(5 H )-one 52

12-chloro-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10] Benzoxatriazatriazin-4(5H)-one 53

11-fluoro-14-methyl-4- pendant oxy-4,5,6,7,13,14-hexahydro-1,15-vinyl pyrazolo[4,3-f][1, 4,8,10]benzoxatriazatriazin-7-methanamide 54

11-Fluoro-7-(hydroxymethyl)-14-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4, 8,10] benzoxatriazatriazone-4(5H)-one 55

11-fluoro-13-methyl-4- pendant oxy-4,5,6,7,13,14-hexahydro-1,15-vinyl pyrazolo[4,3-f][1, 4,8,10]benzoxatriazatriazin-7-methanamide 56

11-Fluoro-7-(hydroxymethyl)-13-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4, 8,10] benzoxatriazatriazone-4(5H)-one 57

11-fluoro-4- pendant oxy-4,5,6,7,13,14-hexahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10 ] Benzoxatriazatriazone-7-methanamide 58

11-Fluoro-7-(hydroxymethyl)-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzene P-oxatriazatriazone-4(5H)-one 59

11-fluoro-4- pendant oxy-4,5,6,7,13,14-hexahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10 ] Benzooxatriazatriazone-13-methyl carboxylate 60

11-fluoro-4- pendant oxy-4,5,6,7,13,14-hexahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10 ]Benzoxatriazatriazin-13-methanamide 61

11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f]pyrido[3,2-l][1,4 ,8,10]oxatriazatriazin-4(5H)-one 62

11-fluoro-14-(prop-2-yl)-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f]pyrido[3,2-l ][1,4,8,10]oxatriazatriazone-4(5H)-one 63

11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f]pyrido[3,2-l][1,4 ,8,10]oxatriazatriazin-4(5H)-one 64

11-fluoro-13-(prop-2-yl)-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f]pyrido[3,2-l ][1,4,8,10]oxatriazatriazone-4(5H)-one 65

13-Cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f]pyrido[3,2-l][1, 4,8,10]oxatriazatriazin-4(5H)-one 66

13-Cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzooxy Triazine-4(5H)-one 67

11-fluoro-13-(prop-2-yl)-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10 ] Benzoxatriazatriazone-4(5H)-one 68

11-fluoro-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzoxadiazepine熳环-4(5H)-one 69

11-fluoro-6,7-dihydro-13H-1,15-vinyl pyrazolo[4,3-f][1,10,4,8]benzoxadiazepine Cyclo-4(5H)-one 14,14-dioxide 70

6,7-Dihydro-13H-1,15-vinyl pyrazolo[4,3-f][10,1,4,8]benzoxadiazepine-4 (5H)-ketone 71

14-Methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzothiatriazide Tricyclic-4(5H)-one 72

13-Methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzothiatriazide Tricyclic-4(5H)-one 73

11-fluoro-6,7-dihydro-5H-1,15-vinyl pyrazolo[3,4-e][11,1,2,4,8]benzoxathiatriaza Tridecane-4(14H)-ketone 13,13-dioxide 74

11-fluoro-14-methyl-6,7-dihydro-5H-1,15-vinyl pyrazolo[3,4-e][11,1,2,4,8]benzoxa Thiotriazatriazone-4(14H)-one 13,13-dioxide 75

12-fluoro-15-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-vinyl pyrazolo[4,3-g][1,5,9, 11] Benzoxatriazatetradecacyclo-4-one 76

12-fluoro-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-vinyl pyrazolo[4,3-g][1,5,9, 11] Benzoxatriazatetradecacyclo-4-one 76-1

(14 R )-12-fluoro-14-methyl- 5,6,7,8,14,15-hexahydro-4 H -1,16-vinyl pyrazolo[4,3- g ][ 1,5,9,11]benzoxatriazatetradecen-4-one 77

11-fluoro-7,14-dimethyl-4,5,6,7,13,14-hexahydro-8H-1,15-vinyl pyrazolo[3,4-e][2,4 ,10] benzotriazatriazepine-8-one 78

11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[3,4-e][7,2,4,10]benzene P-oxatriazatriazone-8(5H)-one 79

11-fluoro-7,14-dimethyl-4,5,6,7,13,14-hexahydro-8H-1,15-vinyl pyrazolo[3,4-e][2,4 ,7,10]benzotetraazatridecane-8-one 80

11-fluoro-4,7,14-trimethyl-4,5,6,7,13,14-hexahydro-8H-1,15-vinyl pyrazolo[3,4-e][2 ,4,7,10]benzotetraazatridecyclo-8-one 81

11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[3,4-e][7,2,4,10]benzene Tetraazatriazatriazin-8(5H)-one 82

11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[3,4-e][7,2,4,10]benzene Thiotriazatriazide ring-8(5H)-one 4,4-dioxide 83

12-Fluoro-8,15-dimethyl-5,6,7,8,14,15-hexahydro-9H-1,16-vinyl pyrazolo[3,4-e][7,2 ,4,8,11] Benzothiatetraazatetraazatetracycline-9-one 4,4-dioxide And its pharmaceutically acceptable salts. The following represent illustrative examples of compounds of formula (I) or (I-A): Instance structure Chemical Name 84

11-chloro-13-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3- f ][1,4,8,10]benzoxa Triaza Tridecine-4(5 H )-one 85

13-Ethyl-11-fluoro-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3- f ][1,4,8,10]benzoxa Triaza Tridecine-4(5 H )-one 86

13-Cyclobutyl-11-fluoro-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3- f ][1,4,8,10]benzox Triazine-4(5 H )-one 87

11-fluoro-14-methyl(6,6,7,7- ² H ₄ )-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3- f ] [1,4,8,10] benzoxatriazatriazone-4(5 H )-one 88

11-fluoro-13-phenyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3- f ][1,4,8,10]benzoxa Triaza Tridecine-4(5 H )-one 89

13-(Cyclopropylmethyl)-11-fluoro-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3- f ][1,4,8,10 ] Benzoxatriazatriazin-4(5 H )-one 90

(7 R ,14 R )-12-fluoro-7-hydroxy-14-methyl- 5,6,7,8,14,15-hexahydro-4 H -1,16-vinyl pyrazolo[ 4,3- g ][1,5,9,11]benzoxatriazatetradecen-4-one 91

(7 S ,14 R )-12-fluoro-7-hydroxy-14-methyl- 5,6,7,8,14,15-hexahydro-4 H -1,16-vinylpyrazolo[ 4,3- g ][1,5,9,11]benzoxatriazatetradecen-4-one 92

(7 R ,13 R )-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3- f ][1 ,4,8,10]benzoxatriazatriazin-4(5 H )-one 93

(7 S ,13 R )-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3- f ][1 ,4,8,10]benzoxatriazatriazin-4(5 H )-one 94

(7 R )-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3- f ][1,4, 8,10]benzoxatriazatriazin-4(5 H )-one 95

(6 R )-11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3- f ][1,4, 8,10]benzoxatriazatriazin-4(5 H )-one 96

12-Fluoro-7-hydroxy-15-methyl- 5,6,7,8,14,15-hexahydro-4 H -1,16-vinyl pyrazolo[4,3- g ][1 ,5,9,11]benzoxatriazatetradecen-4-one 97

(7 S )-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3- f ][1,4, 8,10]benzoxatriazatriazin-4(5 H )-one 98

11-Fluoro-13-(hydroxymethyl)-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3- f ][1,4,8,10]benzene P-oxatriazatriazone-4(5 H )-one 99

12-Fluoro-14-(hydroxymethyl)-5,6,7,8,14,15-hexahydro-4 H -1,16-vinyl pyrazolo[4,3- g ][1, 5,9,11]benzoxazepine tetradecen-4-one 100

11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3- f ][1,4,8,10]benzene P-oxatriazatriazone-4(5 H )-one 101

11-fluoro-14-(2-hydroxy-2-methylpropyl)-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3- f ][1, 4,8,10]benzoxatriazatriazin-4(5 H )-one 102

11-Fluoro-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3- f ][1,4,8]benzoxadiazepine -4(5 H )-ketone 103

12-Fluoro- 5,6,7,8,14,15-hexahydro-4 H -1,16-vinyl pyrazolo[4,3- g ][1,5,9]benzoxa Diazatetracycline-4-one 104

11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3- f ][1,4,8,10]benzothia Triaza Tridecine-4(5 H )-one 105

11-fluoro-14-(1-methylpyrrolidin-3-yl)-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3- f ][1, 4,8,10]benzoxatriazatriazin-4(5 H )-one 106

11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3- f ][1,4,8,10]benzothia Triazatridecyclic-4(5 H )-one 8-oxide 107

11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3- f ][1,4,8,10]benzothia Triazatride ring-4(5 H )-one 8,8-dioxide 108

(7 S )-11-fluoro-7-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3- f ][1,4,8]benzene P-oxadiazepine-4(5 H )-one 109

(6 S ,13 R )-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3- f ][1 ,4,8,10]benzoxatriazatriazin-4(5 H )-one 110

(6 R ,13 R )-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3- f ][1 ,4,8,10]benzoxatriazatriazin-4(5 H )-one 111

(7 S ,13 S )-11-fluoro-13-(hydroxymethyl)-7-methyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3 -f ][1,4,8,10]benzoxatriazatriazepine-4(5 H )-one 112

11-Fluoro-6,7-dihydro-13 H -1,15-vinyl pyrazolo[4,3- f ][1,10,4,8]benzoxadiazepine Tricyclic-4( 5H )-one And its pharmaceutically acceptable salts. Those familiar with the technology will realize that the types listed or described in this article are not exhaustive, and other types within the scope of these defined terms may also be selected. Pharmaceutical composition For therapeutic purposes, the pharmaceutical composition comprising the compounds described herein may further comprise one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are substances that are non-toxic and are otherwise biologically suitable for administration to individuals. These excipients facilitate the 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, extenders, emulsifiers, or taste modifiers. In a preferred embodiment, the pharmaceutical composition of the present invention is a sterile composition. The pharmaceutical composition can be prepared using mixing techniques that are known or familiar to those skilled in the art. The present invention also covers sterile compositions, including compositions that comply with national and local regulations governing such compositions. The pharmaceutical compositions and compounds described herein can be formulated into solutions, emulsions, suspensions or dispersions in suitable pharmaceutical solvents or carriers according to conventional methods known in the art for preparing various dosage forms, or as pills or lozenges , Lozenges, suppositories, sachets, dragees, granules, powders, reconstituted powders or capsules together with solid carriers. The pharmaceutical composition of the present invention can be administered by a suitable delivery route (for example, oral, parenteral, rectal, nasal, topical or ocular route, or by inhalation). Preferably, the composition is formulated for intravenous or oral administration. For oral administration, the compounds of the present invention can be provided in solid form (for example, tablets or capsules), or as solutions, emulsions, or suspensions. To prepare an oral composition, the compound of the present invention can be formulated to obtain, for example, about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 mg to 250 mg per day, or about 250 mg to 1 g. every day. Oral lozenges may include a mixture of active ingredients and compatible pharmaceutically acceptable excipients, such as diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, coloring agents, and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerin, water, and the like. Exemplary disintegrants of starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose and alginic acid. The binder may include starch and gelatin. The lubricant (if present) can be magnesium stearate, stearic acid or talc. If desired, the lozenge may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating. Oral capsules include hard and soft gelatin capsules. To prepare hard gelatin capsules, the active ingredient can be mixed with solid, semi-solid or liquid diluents. Soft gelatin capsules can be prepared by combining the active ingredients with water, 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. The liquid for oral administration may be in the form of, for example, a suspension, solution, emulsion, or syrup, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. These liquid compositions may optionally contain: pharmaceutically acceptable excipients, such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, Aluminum stearate gel and the like); non-aqueous vehicles such as oils (for example, almond oil or fractionated coconut oil), propylene glycol, ethanol or water; preservatives (for example, methyl paraben or paraben Propyl ester or sorbic acid); wetting agents, such as lecithin; and if desired, flavoring or coloring agents. For parenteral use (including intravenous, intramuscular, intraperitoneal, intranasal or subcutaneous routes), the reagents of the present invention can be provided in the form of a sterile aqueous solution or suspension, which is buffered to an appropriate pH and isotonic or in Acceptable in oil parenterally. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms can be presented in unit dosage form (e.g., ampoules or disposable injection devices), multiple-dose form (e.g. vials from which appropriate doses can be removed), or in solid forms or pre-concentrates that can be used to prepare injectable formulations. The illustrative injection dose is about 1 to 1000 μg/kg/minute of the mixture of the medicament and the pharmaceutical carrier for a period in the range of several minutes to several days. For nasal inhalation or oral administration, the pharmaceutical composition of the present invention can be administered using, for example, a spray formulation that also contains a suitable carrier. The composition of the present invention can be formulated as a suppository for rectal administration. For topical administration, the compound of the present invention is preferably formulated as a cream or ointment or a similar vehicle suitable for topical administration. For topical administration, the compound of the invention can be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% drug to vehicle. Another way to administer the agents of the present invention can utilize patch formulations to implement transdermal delivery. As used herein, the term "treat, treatment" encompasses both "preventive" and "curative" treatments. "Prophylactic" treatment is intended to mean delaying the development of disease, disease symptoms, or medical conditions, inhibiting symptoms that may appear, or reducing the risk of disease or symptoms developing or recurring. "Curative" treatment includes reducing the severity or inhibiting the deterioration of an existing disease, symptom or condition. Therefore, treatment includes improving the symptoms of the existing disease or preventing its deterioration, preventing the appearance of other symptoms, improving or preventing the underlying systemic cause of the symptoms, inhibiting the disease or disease (such as blocking the development of the disease or disease, reducing the disease or disease, making the disease or The disease subsides, reduces the condition caused by the disease or disease, or terminates the symptoms of the disease or disease). The term "individual" refers to a mammalian patient in need of such treatment, such as a human. Exemplary diseases include cancer, pain, neurological diseases, autoimmune diseases, and inflammation. Cancers include, for example, lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophageal cancer, glioblastoma, head and neck cancer, inflammatory myofibroblastic tumor, and anaplastic large cell lymphoma . Pain includes, for example, pain from any source or cause, including cancer pain, chemotherapy pain, nerve pain, injury pain, or other sources. Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren syndrome, type I 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 due to infection or injury. In one aspect, the compounds and pharmaceutical compositions of the present invention specifically target tyrosine receptor kinases, specifically MET, ALK, AXL, TRK, and JAK. Therefore, the compounds and pharmaceutical compositions can be used to prevent, reverse, slow down or inhibit the activity of one or more of these kinases. In a preferred embodiment, the treatment method targets cancer. In other embodiments, the method is used to treat lung cancer or non-small cell lung cancer. In the inhibition method of the present invention, "effective amount" means an amount effective to inhibit the target protein. These target adjustment measurements can be implemented by conventional analysis methods (such as those described below). This adjustment can be used in a variety of settings, including in vitro analysis. In these methods, the cells are preferably cancer cells with abnormal signal transduction due to the up-regulation of MET, ALK, AXL, TRK and/or JAK. In the treatment method of the present invention, "effective amount" means an amount or dose sufficient to produce the desired therapeutic benefit in an individual in need of modification. The effective amount or measurement of the compound of the present invention can be determined by conventional methods (e.g., modeling, dose escalation, or clinical trials), taking into account conventional factors (e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, and the severity of infection. The degree and process, the individual’s health and weight, and the judgment of the treating physician). Exemplary dosages are in the range of about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 mg to 250 mg per day or about 250 mg to 1 g per day. The total dose can be single or divided dose units (e.g., BID, TID, QID). After the patient's disease has improved, the dosage can be adjusted for preventive or maintenance treatment. For example, the dosage or frequency of administration or both can be reduced according to symptoms to an amount that maintains the desired therapeutic or prophylactic effect. Of course, if the symptoms have alleviated to an appropriate level, the treatment can be stopped. However, when either symptom recurs, the patient may require long-term intermittent treatment. Patients may also need long-term slow treatment. Drug combination The compounds of the invention described herein can be used in pharmaceutical compositions or methods in combination with one or more other active ingredients to treat the diseases and conditions described herein. Other additional active ingredients include other therapeutic agents or agents that mitigate the adverse effects of the therapeutic agents on the intended disease target. These combinations can be used to increase efficacy, improve symptoms of other diseases, reduce one or more negative effects, or reduce the required dosage of the compounds of the present invention. The additional active ingredient can be formulated into a pharmaceutical composition separate from the compound of the present invention or can be included in a single pharmaceutical composition with the compound of the present invention. The additional active ingredient can be administered at the same time, before or after the administration of the compound of the invention. Combination agents include additional active ingredients known or observed to be effective in the treatment of the diseases and conditions described herein, including those that are effective against another target related to the disease. For example, the compositions and formulations and treatment methods of the present invention may further include other agents or medicines, such as other active agents that can be used to treat or alleviate the target disease or related symptoms or conditions. For cancer indications, other such agents include (but are not limited to) kinase inhibitors, such as EGFR inhibitors (e.g., erlotinib, gefitinib); Raf inhibitors (e.g. , Vemurafenib), VEGFR inhibitors (for example, sunitinib); standard chemotherapeutic agents, such as alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors , Platinum drugs, mitotic inhibitors, antibodies, hormone therapy or corticosteroids. For pain indications, suitable combination agents include anti-inflammatory agents, such as NSAIDs. The pharmaceutical composition of the present invention may additionally include one or more of these active agents, and the treatment method may additionally include administering an effective amount of one or more of these active agents. Chemical synthesis Exemplary chemical entities that can be used in the methods of the present invention will now be described with reference to the following illustrative synthetic schemes for their general preparation and specific examples below. Those skilled in the art will recognize that in order to obtain the various compounds herein, the starting materials can be appropriately selected so that the final desired substituent will be carried through a reaction scheme with or without proper protection to produce the desired product. Alternatively, it may be necessary or desirable to replace the final desired substituent with a suitable group that can be carried through the reaction scheme and replaced by the desired substituent when appropriate. Moreover, those skilled in the art will recognize that the transformations shown in the following schemes can be performed in any order that is compatible with the functionality of the specific pendant groups. Each of the reactions depicted in the general scheme is preferably carried out at a temperature ranging from about 0°C to the reflux temperature of the organic solvent used. Unless otherwise stated, the variables are as defined above with reference to formula (I). The isotopically labeled compounds described herein are prepared according to the methods described below using appropriately labeled starting materials. These materials are generally available from commercial suppliers of radiolabeled chemical reagents. General method A:

It will be understood that the compound of formula A or A-1 can be prepared according to general method A using appropriate functionalized starting materials and intermediates. Step 1. The compound can be functionalized at a suitable temperature (for example, 0℃)A-1 (About 1.00 eq.) (where R^A And R^B Is a group compatible with the reaction conditions described herein, and Nu is a nucleophilic group, such as an anion or a group capable of forming a nucleophile (such as a halide), which can promoteA-1 andA-2 The coupling reagent (e.g. acid (e.g. TfOH (0.6 M)) or alkyl halide (e.g. n-BuLi)) is added to the solutionA-2 (Where R^C Is a group compatible with the reaction conditions described herein and X² Is (for example) a leaving group) (about 1.00 eq.). The mixture can be stirred at an appropriate temperature (e.g., 60°C) until the reaction is complete. The reaction can then be returned to ambient temperature, and the reaction mixture can be quenched, neutralized, washed, extracted, dried and/or concentrated under vacuum as necessary to obtainA-3 . Step 2. You canA-3 (Where R^A , R^B And R^C Is a group compatible with the reaction conditions described herein) (in some exemplary embodiments described herein, A-3 may be a commercially available aldehyde or ketone, orA-3 Can be prepared from step 1, about 1.00 eq.) and commercially available amineA-4 (Where R^C It is a group compatible with the reaction conditions described herein) (about 1.50 eq.) in a suitable solvent (e.g. methanol (0.5 M)) and stirred at an appropriate temperature (e.g. ambient temperature) for an appropriate amount of time or until the The imine formation is completed by TLC or LC-MS. Reducing agent (e.g. NaBH₄ (About 2.00 eq.)). The mixture can be stirred at an appropriate temperature (for example, ambient temperature) until TLC or LC-MS shows that the reaction is complete. The reaction can be quenched, washed, extracted, dried and, if necessary, concentrated under vacuum to provideA-5 . Step 3. Prepared or commercially availableA-5 (Where R^A , R^B And R^C Is a group compatible with the reaction conditions described herein) (about 1 eq.), commercially available 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (A-6 , About 1 eq.) and a suitable base (such as diisopropylethylamine (about 5 eq.)) in a suitable solvent (such as butanol (0.4 M)) can be stirred at a suitable temperature (such as 110 ℃) Set the length of time or until the reaction display is complete. The reaction can be returned to ambient temperature and diluted with water as needed. The mixture can be extracted, washed, dried, concentrated under reduced pressure and/or purified by chromatography as necessary to provideA . In some exemplary methods, general method A can be implemented as follows:

Step 1. It can be turned at 0℃A-1 (1.00 eq.) added to the solution in TfOH (0.6 M)A-2 (1.00 eq.). The mixture can be stirred at 60°C for 4 hours or until the reaction is complete. After cooling to ambient temperature, the reaction mixture can be poured into ice-water (w/w = 1/1) with NaHCO₃ Neutralized to pH about 9, and extracted three times with EtOAc as needed. The combined organic layer can be washed with brine, if necessary, with anhydrous Na₂ SO₄ Dried and concentrated to obtainA-3 . Step 2. You canA-3 (Commercially available aldehydes or ketones, or prepared from step 1, 1.00 eq.) and commercially available aminesA-4 (1.50 eq.) The mixture in methanol (0.5 M) was stirred at ambient temperature for 2 hours or until the imine formation was completed by TLC or LC-MS. NaBH can be added part by part to the reaction solution₄ (2.00 eq.). The mixture can be stirred at ambient temperature until TLC or LC-MS shows that the reaction is complete. The reaction can be quenched with water and extracted three times with dichloromethane as necessary. The combined organic phase can be washed with brine, using anhydrous Na₂ SO₄ Dry, filter and concentrate in vacuum to obtainA-5 . Step 3. Can be prepared or sold commerciallyA-5 (1 eq.), 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (A-6 , 1 eq.) and diisopropylethylamine (5 eq.) were heated in butanol (0.4 M) at 110°C for 30 minutes or until the reaction showed completion. The reaction can be cooled and diluted with water. The mixture can be extracted with dichloromethane four times (as needed) and the combined extract can be dried over anhydrous sodium sulfate. After filtration, the mixture can be concentrated under reduced pressure and the residue can be purified via flash chromatography to provideA . Alternative to general method A:

Coupling step 1. It can be appropriately functionalizedAA-1 (About 1.00 eq.), a mixture of appropriately functionalized vinyl coupling reagent (about 1.00-1.50 eq.) and palladium catalyst (about 0.05 eq.) under appropriate reaction conditions and heated to an appropriate temperature under an inert atmosphere (e.g. Approximately 90°C) for an appropriate amount of time until TLC indicates complete consumption of the starting material. Optionally pour the reaction mixture into H₂ O in. The mixture can be extracted and the organic phase can be washed, dried, concentrated, and purified by silica gel column chromatography as necessary to obtainAA-2 . Coupling step 2. Can beAA-2 Type compound (about 1.00 eq.), 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (A-6 , About 1.00 eq.) and the palladium catalyst are heated to an appropriate temperature (for example, 120°C) under an inert atmosphere under appropriate reaction conditions for an appropriate length of time, until TLC indicates that the starting material is completely consumed. Optionally pour the reaction mixture into H₂ O in. The mixture can be extracted and the organic phase can be washed, dried, concentrated, and optionally purified by silica gel column chromatography to obtainAA-3 . Step 3. In an inert atmosphere at an appropriate temperatureAA-3 (Approximately 1.00 eq.) and 4-methylbenzenesulfonamide (in molar excess) are added to the mixture in a suitable solvent with an appropriate base (in molar excess). The mixture can be heated to an appropriate temperature (e.g. 65°C) and stirred for an appropriate amount of time until TLC indicates that the reaction is complete. The mixture can be cooled and, if necessary, concentrated under reduced pressure. If necessary, the concentrated reaction mixture is diluted with water and extracted. The combined organic phase can be washed, dried, filtered, concentrated in vacuo, and purified to obtainAA-4 . General method B:

Step 1. Aldehydes can beB-1 (About 1.0 eq) (where R^A And R^B Is a group compatible with the reaction conditions described herein),B-2 (About 1.0 eq) (where X¹ A solution of a leaving group and PG a protecting group), a suitable base (in molar excess) and a catalyst in a suitable solvent are heated and stirred for a suitable amount of time until the reaction is completed. Can add additionalB-2 And if necessary, further heating. The mixture can be cooled to ambient temperature and diluted with water as needed. The mixture can be extracted, and the combined extracts can be washed, dried, and optionally concentrated under reduced pressure. The crude reaction product can be purified by flash chromatography to provideB-3 . Step 2. Aldehydes can be stored in appropriate solventsB-3 (About 1.0 eq) and appropriately functionalized amine (about 2.0-4.0 eq) (where R^C The group compatible with the reaction conditions described herein) is heated and stirred for an appropriate amount of time. The mixture can be cooled to ambient temperature and a suitable reducing agent (about 1.0 eq) can be added. The mixture can be stirred for an appropriate amount of time, and then quenched by adding water as needed. The mixture can be extracted with a suitable organic solvent, and the combined extracts can be washed, dried and, if necessary, concentrated under reduced pressure. If necessary, the crude reaction product may be purified by flash chromatography to provideB-4 . Step 3. The compound can be stored in a suitable solventB-4 (About 1.0 eq), 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (A-6 , About 1.0 eq) and a suitable base (in molar excess) for heating for a suitable amount of time. The reaction can be cooled and diluted with water as needed. The mixture can be extracted with a suitable organic solvent, and the combined extract can be dried and, if necessary, concentrated under reduced pressure. The crude reaction product can be purified by flash chromatography to provideB1 . In some exemplary methods, general method B can be implemented as follows:

Step 1. Aldehydes can beB-1 (About 1.0 eq) (where R^A And R^B Is a group compatible with the reaction conditions described herein),B-2 (About 1.0 eq) (where X¹ A solution of (a leaving group and PG is a protecting group), potassium carbonate (in molar excess), and potassium iodide (catalytic amount) in DMF is heated to 60°C and stirred for about 15 hours. Additional chloride can be addedB-2 If necessary, it can be further heated at 80°C until the reaction is complete. The mixture can be cooled to ambient temperature and diluted by adding water (250 mL) as needed. The mixture can be extracted with ethyl acetate (3×300 mL) and the combined extracts can be washed with water (200 mL) and brine (100 mL), dried with sodium sulfate, and concentrated under reduced pressure if necessary. The crude reaction product can be purified by flash chromatography to provideB-3 . Step 2. Aldehydes stored in methanol can be convertedB-3 (About 1.0 eq) and methylamine (about 2.5 eq) are heated to 60°C and stirred for about 1 hour. The mixture can be cooled to ambient temperature and sodium borohydride (about 1.0 eq) can be added. The mixture can be stirred for about 30 minutes and then quenched by adding water (200 mL) as needed. The mixture can be extracted with dichloromethane and the combined extracts can be washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure if necessary. The crude reaction product can be purified by flash chromatography to provideB-4 . Step 3. The amine in butanol can beB-4 (About 1.0 eq), 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (A-6 , About 1.0 eq) and hünig base (in molar excess) are heated at 110°C for about 25 minutes. The reaction can be cooled and diluted with water (250 mL). The mixture can be extracted with dichloromethane and the combined extracts can be dried with sodium sulfate if necessary. The mixture can be concentrated under reduced pressure if necessary. The crude reaction product can be purified by flash chromatography to provideB . General Method C

Step 1. Available toC-1 (About 1.0 eq.) (where R^A , R^B , R^C , R^D And R^E Is a group compatible with the reaction conditions described herein), X¹ AlkNHPG (about 1.5-2.0 eq.) (where X¹ It is a leaving group, Alk is a suitably functionalized alkyl group and PG is a protecting group) in a solution in a suitable solvent and a suitable base (about 3.0 eq.) is added. The mixture can be heated to an appropriate temperature under an inert atmosphere for an appropriate amount of time until LC-MS shows that the starting material is completely converted into a product. The mixture can be cooled to ambient temperature, diluted with water and extracted with a suitable organic solvent if necessary. The combined organic extracts can be washed with water and brine, and subjected to Na₂ SO₄ Dry and concentrate as needed. The obtained residue may be purified by silica gel column chromatography as needed to obtainC-2 . Step 2. Available toC-2 (1 eq.) (where R^A , R^C , R^D And R^E It is a group compatible with the reaction conditions described herein, Alk is a suitably functionalized alkyl group and PG is a protecting group) in a suitable solvent with a suitable base (in molar excess). The solution can be heated to an appropriate temperature for an appropriate amount of time. The reaction can be neutralized to pH<5 with a suitable acid, and the reaction mixture can be extracted with a suitable organic solvent. The combined organics can be washed and optionally dried. The crude reaction product mixture can be filtered, concentrated under reduced pressure, and optionally dried under high vacuum to provideC-3 . Step 3. It can be turned at an appropriate temperature (for example, 0℃)C-3 (About 1.0 eq.) Add a suitable acid (about 4 eq.) to a solution in a suitable organic solvent. The reaction mixture can be stirred at an appropriate temperature for an appropriate amount of time until the completion of the reaction is indicated by LC-MS. The crude product can be filtered, washed, and dried under high vacuum to provideC-4 . Step 4a. Available toC-4 (About 1.0 eq.) Add a suitable base (in molar excess) to the solvent in a suitable solvent. The solution can be cooled in an ice water bath and a suitable coupling agent (about 1.5 eq.) can be added to produce an activated ester. The solution can be slowly warmed to ambient temperature and stirred until the conversion of the starting material into the desired product is shown by LC-MS. The mixture can be diluted with water and, if necessary, extracted with a suitable organic solvent. The combined organic extracts can be washed, dried, and optionally concentrated under reduced pressure. The resulting residue can be purified by silica gel column chromatography to obtainC . In some exemplary methods, general method C can be implemented as follows:

Step 1. Available toC-1 (About 1.0 eq.) (where R^A , R^B , R^C , R^D And R^E Is a group compatible with the reaction conditions described herein), X¹ AlkNHPG (about 1.5-2.0 eq.) (where X¹ Is a leaving group, Alk is an appropriately functionalized alkyl group and PG is a protecting group) in the solution of DMF (0.5 M), add K₂ CO₃ (About 3.0 eq.). The mixture can be heated at about 80°C for about 2 hours or until the complete conversion of the starting material into the product can be shown by LC-MS. The mixture can be cooled to ambient temperature, diluted with water as needed and extracted with EtOAc three times as needed. Then, the combined organic layer can be washed with water and brine, and can be washed with Na₂ SO₄ Dry and concentrate as needed. The residue obtained can be purified by silica gel column chromatography with EtOAc/hexane (5-100%, 10CV) elution to obtainC-2 . Step 2. Available toC-2 (Approximately 1 eq.) LiOH.H2O (approximately 5.0 eq.) was added to the solution in methanol/THF/H2O (3:1:1, 0.2M). The solution can be heated at about 70°C for about 2 hours. The reaction can be neutralized with HCl aqueous solution (2 M) at about 0°C to pH<5, and if necessary, CH₂ Cl₂ Extract four times. The combined organic extracts can be washed with brine, and optionally with Na₂ SO₄ dry. The crude product mixture can be filtered, concentrated under reduced pressure, and dried under high vacuum as necessary to provideC-3 . Step 3. It can be turned at about 0℃C-3 (About 1.0 eq.) in CH₂ Cl₂ Add HCl (4 M, about 4 eq.) in dioxane to the solution in (0.25 M). The reaction can be stirred and allowed to warm from 0°C to room temperature for about 27 hours or until the completion of the reaction can be shown by LC-MS. The resulting reaction mixture can be filtered with CH₂ Cl₂ Wash and dry under high vacuum as needed to provideC-4 . Step 4a. Cyclization using HATU. Available toC-4 (About 1.0 eq.) DIPEA (about 5.0 eq.) was added to the solution in about 10 mL DMF (about 0.005 M). The solution was cooled in an ice water bath and HATU (approximately 1.5 eq.) could be added. The solution can be warmed to ambient temperature and stirred until it can be shown by LC-MS that the starting material is completely converted to the desired product. The mixture can be diluted with water and extracted three times with EtOAc as necessary. The combined organic phase can be washed with water and brine, and subjected to Na₂ SO₄ Dry and, if necessary, concentrate under reduced pressure. The resulting residue can be purified by silica gel column chromatography (0-5% MeOH/DCM) to obtainC . Step 4b. Cyclization using FDPP. DIPEA (approximately 5 eq.) in DMF/CH₂ Cl₂ (3:1, about 0.005M) in the solutionC-4 (About 1.00 eq.).C-4 After complete dissolution, pentafluorophenyl diphenylphosphinate (FDPP, about 1.05 eq.) can be added. The coupling may be allowed to stir for 30 minutes or until the completion of the reaction is indicated by LC-MS. Reaction solution can use CH₂ Cl₂ Dilute with water, Na₂ CO₃ Wash three times with aqueous solution (2 M) and brine, optionally with Na₂ SO₄ dry. After filtration and concentration under reduced pressure, the residue can be subjected to silica gel column chromatography using MeOH/CH₂ Cl₂ (0-5%) elution to purify to provideC . Instance The following examples are provided to illustrate but not limit the invention. Those familiar with the art will recognize that the following synthesis reactions and schemes can be modified by selecting appropriate starting materials and reagents to obtain other compounds of formula (I) or (I-A). Bicyclic heteroaromatics with suitable functionality for use in synthetic methods are commercially available.abbreviation The examples described herein use a variety of materials, including (but not limited to) those described by the following abbreviations known to those skilled in the art: abbreviation name TLC Thin layer chromatography PLC Preparative liquid chromatography HPLC High performance liquid chromatography LCMS, LC-MS Liquid Chromatography Mass Spectrometry LRESIMS Low-resolution electrospray ionization mass spectrometry ELISA Enzyme-linked immunoassay DCM Dichloromethane DMSO Dimethyl sulfoxide DIPEA, DIEA Diisopropylethylamine CDI 1,1'-Carbonyl diimidazole THF Tetrahydrofuran XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene TBSCl Tert-butyldimethylsilyl chloride DMF N,N-Dimethylformamide HATU Hexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide salt ACN Acetonitrile EtOAc Ethyl acetate DTAD Di-tert-butyl azodicarboxylate FDFF Pentafluorophenyl diphenylphosphinate FBS Fetal Bovine Serum BSA Bovine serum albumin PBS Phosphate buffered saline DMEM Dulbecco's modified eagle medium EDTA Ethylenediaminetetraacetic acid RIPA Radioimmunoprecipitation analysis HEPES (4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid) Instance A6

Step 1. At 16℃ in N₂ To a solution of 5-fluoro-2-hydroxybenzaldehyde (500.00 mg, 3.57 mmol, 1.00 eq.) in MeOH (20.00 mL) was added 1-methylpyrrolidine-3-amine (357.43 mg, 3.57 mmol , 1.00 eq.). Put the mixture at 16°C in N₂ Stir for 10 hours. Then, add NaBH₄ (270.00 mg, 7.14 mmol, 2.00 eq.) and the mixture at 16 ℃ in N₂ Stir for 6 hours. TLC (DCM:MeOH=15:1) showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with water (50 mL) and extracted with DCM (20 mL×3). The combined organic layer was washed with brine (50 mL) and washed with Na₂ SO₄ Dry, filter and concentrate under reduced pressure to obtain A6-5 (350.00 mg, 1.56 mmol, 43.71% yield) as a yellow solid.¹ HNMR (300 MHz, DMSO-d ₆ ) δ 6.94 (dd,J =2.7, 9.3 Hz, 1H), 6.86 (dt,J =3.0, 8.6 Hz, 1H), 6.67 (dd,J =4.7, 8.7 Hz, 1H), 3.71 (s, 2H), 3.24-3.09 (m, 1H), 2.58 (dd,J =7.1, 8.8 Hz, 1H), 2.48-2.32 (m, 2H), 2.30-2.17 (m, 4H), 2.05-1.82 (m, 1H), 1.60-1.43 (m, 1H). Step 2. At 16℃ in N₂ Downward A6-5 (300.00 mg, 1.34 mmol, 1.00 eq.) and 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (302.34 mg, 1.34 mmol, 1.00 eq.) in n Add DIPEA (1.04 g, 8.04 mmol, 6.00 eq.) to the solution in BuOH (40.00 mL). The mixture was stirred at 120°C for 2 hours. TLC (PE: EtOAc =1:1) shows that the reaction is complete. The mixture was poured into water (50 mL) and extracted by DCM (50 mL×3). The mixture was purified by Pre-PLC to obtain A6 formate (290.00 mg, 701.43 umol, 52.35% yield) as a white solid.Instance A8

To 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (1.25 g, 5.54 mmol) and (R )-2-(1-Aminoethyl)-4-fluorophenol HCl salt (purchased from NetChem) in EtOH (15.83 mL), add Hunig base (3.58 g, 27.70 mmol) and heat to 70℃ Up to 1.5 hours. The reaction was rotary evaporated to dryness, suspended in water, and extracted with DCM (5 x 50 mL). The combined extracts were subjected to Na₂ SO₄ Dry and concentrate under reduced pressure. Flash chromatography (ISCO system, silica (40 g), 0-5% methanol in dichloromethane) provided A8 (1.89 g, 5.49 mmol, 99% yield).Instance A9

Step 1. Add propyl chloride (1.65 g, 17.84 mmol, 1.00 eq.) to a solution of 4-fluorophenol (2.00 g, 17.84 mmol, 1.00 eq.) in TfOH (30.00 mL) at 0°C. The mixture was stirred at 60°C for 4 hours. TLC showed that the reaction was complete. The mixture was cooled to 25°C, poured into ice-water (w/w = 1/1) (120 mL), and NaHCO₃ It was neutralized so that the pH was about 9, and extracted with EtOAc (120 mL×3). The combined organic layer was washed with brine (50 mL), using anhydrous Na₂ SO₄ Dry and concentrate to obtain A9-3 (1.80 g, 10.70 mmol, 59.98% yield) as a colorless oil.¹ HNMR (400 MHz, CDCl₃ ) δ 12.09 (s, 1H), 7.45 (dd,J =3.0, 9.0 Hz, 1H), 7.26-7.20 (m, 1H), 6.97 (dd,J =4.5, 9.0 Hz, 1H), 3.02 (q,J =7.3 Hz, 2H), 1.27 (t,J =7.2 Hz, 3H). Step 2. Bubble ammonia in MeOH (20 mL) for 10 minutes at -78°C. A9-3 (1.00 g, 5.95 mmol, 1.00 eq.) was added to the solution and stirred at 25°C for 1 hour. Add Ti(i-PrO) to the reaction mixture₄ (1.63 g, 7.14 mmol, 1.20 eq.), and the mixture was stirred for another hour. Then, add NaBH₄ (449.93 mg, 11.89 mmol, 2.00 eq.). The mixture was stirred at 25°C for 12 hours. TLC showed that the starting material was completely consumed. The residue was poured into water (50 mL) and stirred for 30 minutes. The mixture was filtered and the filtrate was adjusted to pH about 1 with HCl (1 M) and extracted with EtOAc (50 mL×2). Sodium bicarbonate was added to the aqueous phase to adjust the pH to about 9 and extracted with DCM (50 mL×2). The combined organic layer was washed with saturated brine (50 mL), using anhydrous Na₂ SO₄ Dry, filter and concentrate in vacuo to obtain A9-5 (310.00 mg, 1.83 mmol, 30.79% yield) as a yellow solid.¹ HNMR (400 MHz, CDCl₃ ) Δ 6.86 (dt,J =3.0, 8.4 Hz, 1H), 6.79-6.74 (m, 1H), 6.67 (dd,J =2.9, 8.9 Hz, 1H), 3.98 (t,J =7.0 Hz, 1H), 1.92-1.81 (m, 1H), 1.80-1.68 (m, 1H), 0.95 (t,J =7.4 Hz, 3H). Step 3. As described in general method A, couple A9-5 with ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate in n-BuOH in the presence of DIPEA to provide A9 .Instance A13-5 : 2-(1- Amino -2- Cyclopropylethyl )-4- Fluorophenol Preparation

Step 1. At 25℃ in N₂ To a mixture of 2-cyclopropylacetic acid (4.47 g, 44.60 mmol, 1.00 eq.) in DCM (150.00 mL) was added CDI (7.96 g, 49.10 mmol, 1.10 eq.) in one portion. The mixture was stirred at 25°C for 1 hour. Then N-methoxymethylamine hydrochloride (4.79 g, 49.06 mmol, 1.10 eq.) was added. The mixture was stirred for another 12 hours at 25°C. The reaction was quenched with 1N aqueous hydrochloric acid (50 mL) and separated into layers. The aqueous layer was extracted with DCM (30 mL×2). The combined organic layer was washed with 50% saturated aqueous sodium carbonate (50 mL) and saturated brine (30 mL), using anhydrous Na₂ SO₄ Dry, filter and concentrate in vacuo to obtain 2-cyclopropyl- as an oilN -Methoxy-N -Methylacetamide (6.00 g, 41.91 mmol, 93.96% yield).¹ H NMR (400 MHz, CDCl₃ ) δ 3.65 (s, 1H), 3.18 (s, 1H), 2.33 (d,J =6.8 Hz, 2H), 1.13-1.02 (m, 1H), 0.57-0.49 (m, 2H), 0.19-0.11 (m, 2H). Step 2. At -78℃ in N₂ Downward 2-cyclopropyl-N -Methoxy-N -To a mixture of methylacetamide (6.00 g, 29.27 mmol, 1.00 eq.) in THF (100.00 mL) was added n-BuLi (2.5 M, 12.88 mL, 1.10 eq.) dropwise. The mixture was stirred at -78°C for 10 minutes. The mixture was then treated with 2-bromo-4-fluoro-1-methoxybenzene (4.19 g, 29.27 mmol, 1.00 eq.) in THF (20 mL) for 20 minutes. After stirring at -78°C for 1 hour, the mixture was warmed to 25°C and stirred for another 1 hour. TLC showed that the reaction was complete. The mixture was poured into 10% aqueous HCl (100 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (300 mL×3). The combined organic phase was washed with brine (200 mL), and subjected to anhydrous Na₂ SO₄ Dry, filter and concentrate in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=50/1, 10/1) to obtain 2-cyclopropyl-1-(5-fluoro-2-methoxy) as a colorless oil Phenyl)ethan-1-one (2.4 g, 39.38% yield).¹ H NMR (400 MHz, CDCl₃ ) δ 7.42 (dd,J =3.3, 8.8 Hz, 1H), 7.15 (ddd,J =3.3, 7.5, 9.0 Hz, 1H), 6.91 (dd,J =4.0, 9.0 Hz, 1H), 3.91-3.85 (m, 3H), 2.89 (d,J =6.8 Hz, 2H), 1.18-1.05 (m, 1H), 0.61-0.50 (m, 2H), 0.20-0.09 (m, 2H). Step 3. At -78℃ in N₂ Downward 2-cyclopropyl-1-(5-fluoro-2-methoxyphenyl)ethan-1-one (500.00 mg, 2.40 mmol, 1.00 eq.) in a solution of DCM (10.00 mL) Add BCl dropwise₃ (1 M, 3.00 mL, 1.25 eq.). The mixture was stirred at -78°C for 2 hours. TLC showed that the reaction was complete. The mixture was warmed to 25°C and poured into ice-water (w/w = 1/1) (10 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with saturated brine (30 mL), and subjected to anhydrous Na₂ SO₄ Dry, filter and concentrate in vacuo to obtain 2-cyclopropyl-1-(5-fluoro-2-hydroxyphenyl)ethan-1-one (430.00 mg, 2.21 mmol, 92.3% yield as an oil) ).¹ H NMR (400 MHz, CDCl₃ ) δ 12.12 (s, 1H), 7.40 (dd,J =3.0, 8.8 Hz, 1H), 7.24 (ddd,J =3.0, 7.8, 9.0 Hz, 1H), 6.98 (dd,J =4.5, 9.3 Hz, 1H), 2.88 (d,J =6.8 Hz, 2H), 1.23-1.11 (m, 1H), 0.70-0.63 (m, 2H), 0.25 (q,J =5.0 Hz, 2H). Step 4. At 25℃ in N₂ Add NH to a solution of 2-cyclopropyl-1-(5-fluoro-2-hydroxyphenyl)ethan-1-one (400.00 mg, 1.92 mmol, 1.00 eq.) in MeOH (20.00 mL)₂ OH.HCl (160.18 mg, 2.31 mmol, 1.20 eq.) and AcONa (189.09 mg, 2.31 mmol, 1.20 eq.) for 12 hours. TLC (petroleum ether/ethyl acetate=3:1) showed that the starting material was completely consumed. The reaction was quenched with water, and then extracted with DCM (30 mL×3). The combined organic phase was washed with brine (30 mL), and washed with anhydrous Na₂ SO₄ Dry, filter and concentrate in vacuo to obtain the pure product 2-cyclopropyl-1-(5-fluoro-2-hydroxyphenyl)ethan-1-one oxime (400.00 mg, 1.79 mmol, 93.32) as a white solid %Yield). The solid was used in the next step without further purification. Step 5. In N₂ Downward 2-cyclopropyl-1-(5-fluoro-2-hydroxyphenyl)ethan-1-one oxime (260.00 mg, 1.16 mmol, 1.00eq. ) Pd-C (10%, 100 mg) was added to the solution in MeOH/HCl (10.00 mL, 4N). Degas the suspension under vacuum and use H₂ Purge several times. Put the mixture in H₂ (50 psi) and stir at 50°C for 12 hours. LC-MS showed complete consumption of starting material. The reaction mixture was filtered and the filtrate was concentrated to obtain 2-(1-amino-2-cyclopropylethyl)-4-fluorophenol (200.00 mg, 955.75 umol, 82.39% yield) as a white solid.¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.44-9.82 (m, 1H), 8.52 (br. s., 2H), 7.36 (dd,J =2.8, 9.5 Hz, 1H), 7.07-6.93 (m, 2H), 4.49 (d,J =5.5 Hz, 1H), 1.82-1.72 (m, 2H), 0.67-0.55 (m, 1H), 0.43-0.28 (m, 2H), 0.12-0.06 (m, 1H), (-0.03)-(- 0.09) (m, 1H).Instance A14-5 : 2-( Amino ( Phenyl ) methyl )-4- Preparation of fluorophenol

Step 1. At 25℃ in N₂ To the solution of A14-3 (2.00 g, 9.25 mmol, 1.00 eq.) and AcOK (1.10 g, 11.20 mmol, 1.20 eq.) in ethanol (30.00 mL), add NH at a time₂ OH.HCl (642.80 mg, 9.25 mmol, 1.00 eq.). The mixture was stirred at 25°C for 30 minutes, then heated to 90°C and stirred for 5 hours. TLC showed that the reaction was complete. The mixture was concentrated and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (50 mL), and then washed with anhydrous Na₂ SO₄ Dry, filter, and concentrate to obtain (5-fluoro-2-hydroxyphenyl)(phenyl)methanone oxime (1.50 g, 6.49 mmol, 70.13% yield) as a yellow solid.¹ HNMR (400 MHz, CDCl₃ ) δ 7.50-7.37 (m, 5H), 7.19-7.07 (m, 2H), 6.71 (dd,J =2.9, 8.9 Hz, 1H). Step 2. At 25℃ in N₂ Downward (5-fluoro-2-hydroxyphenyl) (phenyl) ketone oxime (900.00 mg, 4.18 mmol, 1.00 eq.) and Zn powder (1.09 g, 16.73 mmol, 4 eq.) in THF (10.00 mL Add NH to the mixture in) at one time₄ Cl (2.24 g, 41.82 mmol, 10.00 eq.). The mixture was stirred at 25°C for 30 minutes, then heated to 60°C and stirred for 15 hours. The mixture was concentrated and water (100 mL) was added, followed by extraction with ethyl acetate (50 mL×3). The combined organic layer was washed with brine and anhydrous Na₂ SO₄ Dry, filter, and concentrate to obtain A14-5 (630.00 mg, 2.90 mmol, 69.38% yield) as a yellow solid.¹ HNMR (400 MHz, CDCl₃ ) δ 7.42 (d,J =7.5 Hz, 2H), 7.33 (t,J =7.5 Hz, 2H), 7.27-7.20 (m, 1H), 6.93-6.80 (m, 2H), 6.70 (dd,J =4.9, 8.7 Hz, 1H), 5.28 (s, 1H).Instance A17

Step 1. To 5-((2-bromo-5-fluorobenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (prepared according to general method A) ( 300.00 mg, 0.736 mmol, 1.00 eq.), 2-methylpropane-2-thiol (166.10 mg, 1.84 mmol, 2.50 eq.), Pd₂ (dba)₃ (84.72 mg, 0.147 mmol, 0.20 eq.) XantPhos (127.87 mg, 0.221 mmol, 0.30 eq.) and K₂ CO₃ (101.81 mg, 0.736 mmol, 1.00 eq.). Degas the mixture and degas it in N₂ Heat to 120°C for 24 hours. TLC (petroleum ether/ethyl acetate=1:1) showed that the starting material was completely consumed. Pour the reaction mixture into H₂ O (20 mL) and extract with ethyl acetate (50 mLx3). The organic phase was washed with brine (30 mL), and washed with anhydrous Na₂ SO₄ Dry, concentrate, and purify by silica gel column chromatography (petroleum ether/ethyl acetate=2:1 to 1:1) to obtain 5-((2-(tertiary butylthio)- as a yellow solid 5-fluorobenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (200.00 mg, 0.48 mmol, 65.18% yield).¹ H NMR (400 MHz, CDCl₃ ) δ 8.34 (s, 1H), 8.29 (br. s., 1H), 7.60 (dd,J =5.9, 8.4 Hz, 1H), 7.00 (t,J =7.7 Hz, 1H), 6.29 (br. s., 2H), 5.00 (br. s., 2H), 4.37 (d,J =6.8 Hz, 2H), 3.41 (br. s., 3H), 1.36-1.20 (m, 12H). Step 2. At 0℃ in N₂ Downward 5-((2-(tertiary butylthio)-5-fluorobenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (300.00 mg , 0.720 mmol, 1.00 eq. ) Add BBr dropwise to the solution in DCM (8.00 mL)₃ (902.21 mg, 3.60 mmol, 5.00 eq.). The reaction mixture was stirred at 0°C for 2.5 hours. TLC (petroleum ether: ethyl acetate=1:1) showed that the reaction was complete. The mixture was poured into water (20 mL). The aqueous phase was extracted with dichloromethane (50 mL×3). The combined organic phase was washed with brine (30 mL), and subjected to anhydrous Na₂ SO₄ Dry, filter and concentrate in vacuo. The residue was purified by pre-HPLC (column: Phenomenex Synergi C18 150*30mm*4um and condition: 0.05% HCl-ACN) and lyophilized to obtain a white solidA17 HCl salt (38.00 mg, 0.098 mmol, 13.61% yield).Instance A18

Step 1. Combine 2-bromo-4-fluorophenol (10.00 g, 52.36 mmol, 1.00 eq.), trifluoro(vinyl)-borane potassium salt (9.84 g, 66.50 mmol, 1.27 eq.), Cs₂ CO₃ (51.18 g, 157.08 mmol, 3.00 eq.) and Pd(PPh₃ )₂ Cl₂ (1.84 g, 2.62 mmol, 0.05 eq.) in THF (90.00 mL) and H₂ The mixture in O (10.00 mL) is degassed and then in N₂ Heat to 90°C for 12 hours. TLC (petroleum ether/ethyl acetate=10/1) showed that the starting material was completely consumed. Pour the reaction mixture into H₂ O (100 mL). The mixture was extracted with ethyl acetate (300 mL × 3). The organic phase was washed with saturated brine (200 mL), and subjected to anhydrous Na₂ SO₄ Dry, concentrate, and purify by silica gel column chromatography (eluted with EtOAc/petroleum ether=1/30) to obtain 4-fluoro-2-vinylphenol (3.50 g, 25.34 mmol) as a colorless oil , 48.39% yield).¹ H NMR (400 MHz, CDCl₃ ) δ 7.12 (dd,J =3.0, 9.5 Hz, 1H), 6.89-6.81 (m, 1H), 6.79-6.73 (m, 1H), 5.75 (d,J =17.6 Hz, 1H), 5.64 (s, 1H), 5.39 (d,J =11.3 Hz, 1H). Step 2. In N₂ Add 4-fluoro-2-vinylphenol (1.95 g, 14.12 mmol, 1.00eq. ), a mixture of TBSCl (6.38 g, 42.35 mmol, 3.00 eq.) and 1H-imidazole (5.77 g, 84.70 mmol, 6.00 eq.) in DCM (20.00 mL) was stirred at 20°C for 5 hours. TLC (petroleum ether/ethyl acetate=10:1) showed that the starting material was completely consumed. Pour the reaction mixture into H₂ O (30 mL). The mixture was extracted with dichloromethane (50 mL×3). The organic phase was washed with brine (50 mL), and washed with anhydrous Na₂ SO₄ Dry, concentrate, and purify by silica gel column chromatography with petroleum ether to obtain tributyl (4-fluoro-2-vinylbenzyl) silane (2.30 g, 9.11 mmol) as a colorless oil , 64.54% yield). Step 3. Combine tributyl (4-fluoro-2-vinylbenzyl) silane (2.30 g, 9.11 mmol, 1.00 eq.), 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid Ethyl ester (2.06 g, 9.11 mmol, 1.00 eq.), Pd(PhCN)₂ Cl₂ (118.20 mg, 0.455.63 mmol, 0.05 eq.) and tri-o-tolylphosphorane (277.36 mg, 0.911 mmol, 0.10 eq.), DIPEA (7.07 g, 54.68 mmol, 6.00 eq.) in DMF (25.00 mL ) In the degassed mixture and then in N₂ Heat to 120°C for 24 hours. TLC (petroleum ether/ethyl acetate=1:1) showed that the starting material was completely consumed. Pour the reaction mixture into H₂ O (30 mL). The mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (30 mL), and washed with anhydrous Na₂ SO₄ Dry, concentrate, and purify by silica gel column chromatography (EtOAc: petroleum ether=1:3) to obtain (E )-5-(5-fluoro-2-hydroxystyryl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (1.00 g, 2.26 mmol, 24.86% yield).¹ H NMR (400 MHz, CDCl₃ ) δ 9.29 (br. s., 1H), 8.50 (d,J =7.0 Hz, 1H), 8.28 (br. s., 1H), 7.84 (d,J =16.6 Hz, 1H), 7.20-7.04 (m, 3H), 6.69 (d,J =5.8 Hz, 2H), 4.20 (q,J =6.9 Hz, 2H), 1.30-1.19 (m, 3H). Step 4. At 20℃ in N₂ Downward (E )-5-(5-fluoro-2-hydroxystyryl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (378.22 mg, 1.04 mmol, 1.00 eq.) and 4-methylbenzene To a mixture of sulfazide (3.29 g, 17.68 mmol, 17.00 eq.) in THF (4.00 mL) was added NaOAc (1.71 g, 20.80 mmol, 20.00 eq.) in one portion. The mixture was then heated to 65°C and stirred for 12 hours. TLC showed that the reaction was complete. The mixture was cooled to 20°C and concentrated under reduced pressure at 45°C. Water (100 mL) was added to the residue. The aqueous phase was extracted with ethyl acetate (300 mL×2). The combined organic phase was washed with saturated brine (50 mL), using anhydrous Na₂ SO₄ Dry, filter, concentrate in vacuo, and purify by pre-HPLC (column: Phenomenex Synergi Max-RP 250*50 mm*10 um, 0.225% FA-ACN) to obtain A18 (120.00 mg) as a white solid , 0.347 mmol, 33.42% yield).Instance A20

To 4-fluoro-2-methylaminomethyl-phenol (305.2 mg, 1.97 mmol) and 6-chloro-imidazo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (230 mg, 1.02 mmol) ) Add KF (180 mg, 3.01 mmol) to the mixture in DMSO (5 mL). The reaction mixture was stirred at 120°C under nitrogen for 18 hours. The solution was then cooled to ambient temperature, diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was further washed with water (3 × 50 mL) and brine (50 mL), and then washed with Na₂ SO₄ Dry and concentrate. The residue was then purified by elution with EtOAc/hexane (0-50%, 10 CV) through a silica gel column to obtain the desired product (240 mg, 69%) as a white solid.Instance A22

A22-1 is synthesized according to general method A. To a solution of A22-1 (150 mg, 0.387 mmol) in ethanol (2 mL) was added 4M HCl in dioxane (2 mL) and the reaction solution was heated at 75°C for 2 hours. The solvent was evaporated and the residue was neutralized with Et3N, and methanol/CH was used on the silica gel cylinder₂ Cl₂ (0-12.5%) was purified by elution to provide A22 (144 mg, 100%).Instance A23

Step 1. To (5-fluoro-2-methoxyphenyl) methyl mercaptan (496.1 mg, 2.88 mmol) and 6-chloro-imidazo[1,2-b]pyridazine-3-carboxylic acid ethyl ester ( 650.0 mg, 2.88 mmol) DIPEA (1.12 g, 8.64 mmol) was added to a mixture of ethanol (14.4 mL). The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with DCM (3×50 mL). The combined extract is Na₂ SO₄ Dry and concentrate under reduced pressure. The residue was purified by flash chromatography (ISCO system, silica (120 g) eluted with EtOAc/hexane (0-50%) to obtainA23-2 (560 mg, 54% yield). During purificationA23-2 Precipitated from the column. Step 2. ToA23-2 (498.7 mg, 1.38 mmol) in methanol (100 mL) was added 4M HCl in dioxane (10 mL) and the reaction solution was heated at 75°C for 2 hours. The solvent was evaporated and the residue was neutralized with Et3N, and methanol/CH was used on the silica gel cylinder₂ Cl₂ (0-12.5%) elution to purify to provideA23 (470 mg, 98%). A1-A24 are prepared according to general method A and the methods described herein. Instance structure name analyze data A1

5-((5-Fluoro-2-hydroxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 345.2 (M+H) ⁺ ; ¹ H NMR (500 MHz, chloroform- d ) δ 9.71 (bs, 1H), 8.32 (d, J = 7.9 Hz, 1H), 8.30 (s, 1H), 6.98- 6.87 (m, 3H), 6.37 (d, J = 7.9 Hz, 1H), 4.82 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 3.21 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). A2

5-(Ethyl(5-fluoro-2-hydroxybenzyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 359.3 (M+H) ⁺ ; ¹ H NMR (300 MHz, chloroform- d ) δ 9.75 (bs, 1H), 8.30-8.27 (m, 2H), 6.95-6.86 (m, 3H), 6.34 (d , J = 7.9 Hz, 1H), 4.79 (s, 2H), 4.40 (q, J = 7.2 Hz, 2H), 3.56 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H ), 1.25 (t, J = 7.2 Hz, 3H). A3

5-((5-Fluoro-2-hydroxybenzyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 331.3 (M+H) ⁺ ; ¹ H NMR (300 MHz, chloroform- d ) δ 9.61 (bs, 1H), 8.52 (d, J = 7.5 Hz, 1H), 8.28 (bt, J = 5.1 Hz, 1H), 8.13 (s, 1H), 7.25-7.23 (m, 1H), 6.93-6.86 (m, 1H), 6.81-6.77 (m, 1H), 6.44 (d, J = 7.5 Hz, 1H), 4.51 (d, J = 5.1 Hz, 2H), 4.20 (q, J = 6.9 Hz, 2H), 1.39 (t, J = 6.9 Hz, 3H). A4

5-((2-Hydroxybenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 327.5 (M+H) ⁺ ; ¹ H NMR (300 MHz, chloroform- d ) δ 9.79 (s, 1H), 8.30-8.27 (m, 2H), 7.26-7.21 (m, 2H), 6.96 (d , J = 7.8 Hz, 1H), 6.84 (t, J = 7.5 Hz, 1H), 6.34 (d, J = 8.1 Hz, 1H), 4.85 (s, 2H), 4.42 (q, J = 6.9 Hz, 2H ), 3.18 (s, 3H), 1.40 (t, J = 6.9 Hz, 3H). A5

5-((5-Fluoro-2-hydroxybenzyl)(2-hydroxy-2-methylpropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 403.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, chloroform- d ) δ 8.32 (s, 1H), 8.26 (d, J =8.0 Hz, 1H), 7.05-6.80 (m, 3H), 6.59 (br. s., 1H), 5.06 (br. s., 2H), 4.43 (q, J =7.1 Hz, 2H), 3.62 (br. s., 2H), 1.60 (s, 1H), 1.46 -1.36 (m, 9H). A6

5-((5-Fluoro-2-hydroxybenzyl)(1-methylpyrrolidin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 414.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, chloroform- d ) δ 8.67 (br. s., 2H), 8.35 (d, J =8.0 Hz, 1H), 8.24 (s, 1H) , 7.14-7.07 (m, 1H), 6.83 (dt, J =2.8, 8.4 Hz, 1H), 6.73 (br. s., 1H), 6.60 (br. s., 1H), 5.13 (br. s. , 1H), 4.75-4.62 (m, 2H), 4.34 (q, J =6.9 Hz, 2H), 3.88 (br. s., 3H), 3.41 (br. s., 1H), 3.04 (br. s ., 3H), 2.54 (br. s., 2H), 1.40 (t, J =7.2 Hz, 3H). A7

5-((1-(5-Fluoro-2-hydroxyphenyl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 345.3 (M+H) ⁺ ; ¹ H NMR (300 MHz, chloroform- d ) δ 9.61 (bs, 1H), 8.24 (s, 1H), 8.17 (d, J = 7.2 Hz, 1H), 6.96- 6.91 (m, 2H), 6.88-6.81 (m, 1H), 6.09 (d, J = 7.8 Hz, 1H), 5.72-5.63 (m, 1H), 5.45 (bd, J = 8.7 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 1.64 (d, J = 6.9 Hz, 3H), 1.41 (t, J = 7.2 Hz, 3H). A8

(R)-5-((1-(5-Fluoro-2-hydroxyphenyl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 345.2 (M+H) ⁺ . A9

5-((1-(5-Fluoro-2-hydroxyphenyl)propyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 359.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, chloroform- d ) δ 8.99 (br. s., 1H), 8.27 (s, 1H), 8.20 (d, J =7.5 Hz, 1H) , 6.98 (dd, J =5.0, 8.8 Hz, 1H), 6.94-6.84 (m, 2H), 6.13 (d, J =7.5 Hz, 1H), 5.41 (br. s., 2H), 4.57-4.40 ( m, 2H), 2.11-1.95 (m, 2H), 1.44 (t, J =7.2 Hz, 3H), 1.02 (t, J =7.4 Hz, 3H). A10

5-((1-(5-Fluoro-2-hydroxyphenyl)-2-methylpropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 373.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, chloroform- d ) δ 8.25 (s, 1H), 8.19 (d, J =7.5 Hz, 1H), 6.99 (dd, J =5.1, 8.7 Hz, 1H), 6.91-6.81 (m, 2H), 6.14 (d, J =7.5 Hz, 1H), 5.11 (t, J =9.7 Hz, 1H), 4.62-4.37 (m, 2H), 2.22 (qd , J =6.5, 17.1 Hz, 1H), 1.43 (t, J =7.2 Hz, 3H), 1.22 (d, J =6.5 Hz, 3H), 0.89 (d, J =6.5 Hz, 3H). A11

5-((Cyclopropyl(5-fluoro-2-hydroxyphenyl)methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 371.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, chloroform- d ) δ 8.25 (s, 1H), 8.21 (d, J =7.5 Hz, 1H), 7.13 (dd, J =3.0, 9.4 Hz, 1H), 7.00-6.94 (m, 1H), 6.91-6.84 (m, 1H), 6.14 (d, J =7.7 Hz, 1H), 5.69 (d, J =8.0 Hz, 1H), 4.70 (t , J =8.3 Hz, 1H), 4.49-4.38 (m, 2H), 1.42 (t, J =7.1 Hz, 4H), 0.83-0.74 (m, 1H), 0.72-0.63 (m, 1H), 0.57 ( qd, J =4.8, 9.6 Hz, 1H), 0.48-0.40 (m, 1H). A12

5-((Cyclobutyl(5-fluoro-2-hydroxyphenyl)methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 385.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, chloroform- d ) δ 9.09 (br. s., 1H), 8.27 (s, 1H), 8.20 (d, J =7.5 Hz, 1H) , 6.98 (dd, J =5.0, 8.8 Hz, 1H), 6.91-6.78 (m, 2H), 6.12 (d, J =7.5 Hz, 1H), 5.45 (t, J =9.4 Hz, 1H), 5.27 ( d, J =8.4 Hz, 1H), 4.51-4.45 (m, 2H), 2.98-2.89 (m, 1H), 2.29 (dd, J =3.8, 7.5 Hz, 1H), 2.07-1.90 (m, 4H) , 1.75-1.66 (m, 1H), 1.45 (t, J =7.1 Hz, 3H). A13

5-((2-Cyclopropyl-1-(5-fluoro-2-hydroxyphenyl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 385.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, chloroform- d ) δ 9. 00 (br. s., 1H), 8.27 (s, 1H), 8.19 (d, J =7.5 Hz, 1H), 7.00-6.82 (m, 3H), 6.15 (d, J =7.5 Hz, 1H), 5.57 (br. s., 2H), 4.52-4.40 (m, 2H), 2.01-1.77 (m, 2H ), 1.44 (t, J =7.2 Hz, 3H), 0.72 (d, J =6.5 Hz, 1H), 0.56-0.41 (m, 2H), 0.24-0.07 (m, 2H). A14

5-(((5-Fluoro-2-hydroxyphenyl)(phenyl)methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 407.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, chloroform- d ) δ 9.66 (s, 1H), 8.64-8.55 (m, 2H), 8.16 (s, 1H), 7.33 (d, J =4.4 Hz, 4H), 7.25 (qd, J =4.3, 8.5 Hz, 1H), 7.11 (dd, J =3.1, 9.7 Hz, 1H), 6.98-6.91 (m, 1H), 6.88-6.78 (m, 2H), 6.58 (d, J =7.5 Hz, 1H), 4.18 (q, J =7.0 Hz, 2H), 1.30 (t, J =7.1 Hz, 4H). A15

5-((1-(5-chloro-2-hydroxyphenyl)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 361.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, chloroform- d ) δ 9.42 (br. s., 1H), 8.27 (s, 1H), 8.20 (d, J =7.5 Hz, 1H) , 7.28 (s, 1H), 7.25 (d, J =2.5 Hz, 1H), 7.13 (dd, J =2.5, 8.8 Hz, 1H), 6.95 (d, J =8.5 Hz, 1H), 6.11 (d, J =7.5 Hz, 1H), 5.75-5.64 (m, 1H), 5.46 (d, J =8.3 Hz, 1H), 4.52-4.40 (m, 2H), 1.68 (d, J =6.8 Hz, 3H), 1.61 (s, 2H), 1.44 (t, J =7.2 Hz, 3H). A16

5-((1-(5-Fluoro-2-hydroxyphenyl)ethyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 359.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, chloroform- d ) δ 9.61 (s, 1H), 8.35-8.29 (m, 2H), 7.08-7.03 (m, 1H), 6.92 (dd , J =1.3, 6.1 Hz, 2H), 6.45 (q, J =6.9 Hz, 1H), 6.35 (d, J =7.9 Hz, 1H), 4.51-4.36 (m, 2H), 3.00 (s, 3H) , 1.65 (d, J =7.0 Hz, 3H), 1.41 (t, J =7.2 Hz, 3H). A17

5-((5-Fluoro-2-mercaptobenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 361.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, chloroform- d ) δ 9.19 (br. s., 1H), 9.09 (d, J =7.3 Hz, 1H), 8.51 (s, 1H) , 7.91-7.81 (m, 2H), 7.48 (dt, J =2.8, 8.5 Hz, 1H), 7.14 (d, J =7.3 Hz, 1H), 4.29 (br. s., 2H), 4.18 (q, J =7.0 Hz, 2H), 2.56 (br. s., 3H), 1.16 (t, J =7.2 Hz, 3H). A18

5-(5-Fluoro-2-hydroxyphenethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 330.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, chloroform- d ) δ 9.42 (s, 1H), 9.14 (d, J =7.0 Hz, 1H), 8.55 (s, 1H), 7.18 ( d, J =7.0 Hz, 1H), 7.05 (dd, J =3.0, 9.5 Hz, 1H), 6.86-6.80 (m, 1H), 6.79-6.74 (m, 1H), 4.30 (q, J =7.2 Hz , 2H), 3.21-3.13 (m, 2H), 3.06-2.99 (m, 2H), 1.33 (t, J =7.2 Hz, 3H). A19

5-((5-Fluoro-2-hydroxybenzyl)(methyl)amino)-2-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 359.2 (M+H) ⁺ . A20

6-((5-Fluoro-2-hydroxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid ethyl ester MS: 345.2 (M+H) ⁺ ; ¹ H NMR (500 MHz, chloroform- d ) δ 8.61 (s, 1H), 8.17 (s, 1H), 7.91 (d, J = 10.0 Hz, 1H), 7.00- 6.86 (m, 4H), 4.78 (s, 2H), 4.47 (qd, J = 7.2, 0.5 Hz, 2H), 3.17 (s, 3H), 1.41 (td, J = 7.1, 0.5 Hz, 3H). A21

5-(((5-Fluoro-2-hydroxypyridin-3-yl)methyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 346.2 (M+H) ⁺ . A22

5-(((5-Fluoro-2-hydroxypyridin-3-yl)methyl)(isopropyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 374.2 (M+H) ⁺ . A23

5-((5-Fluoro-2-hydroxybenzyl)thio)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 348.2 (M+H) ⁺ . A24

5-((1-(5-Fluoro-2-hydroxyphenyl)-2-hydroxyethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester MS: 361.2 (M+H) ⁺ . Instance B7

Step 1. To 1-(5-fluoro-2-hydroxy-phenyl)-ethanone (773 mg, 5.0 mmol) and (2-chloro-ethyl)-carbamic acid tert-butyl ester (1.80 g, 10.0 mmol) Add KI (2.0 mg, 0.012 mmol) and Cs to the mixture in DMF (20 mL)₂ CO₃ (3.26 g, 10.0 mmol). The mixture was stirred at 80°C overnight. The mixture was then cooled to ambient temperature, diluted with EtOAc, and washed with 1 N NaOH (5 x 10 mL) until LCMS showed no 1-(5-fluoro-2-hydroxy-phenyl)-ethanone peak. Pass the organic layer through Na₂ SO₄ Dry and concentrate. Then the residue was purified by elution with EtOAc/hexane (0-30%, 10 CV) through a silica gel column to obtain the desired product B7-2 (1.1 g, 73.8%) as a yellow solid: LC-MS (ESI)m/z 320.3 (M+Na)⁺ . Step 2. To a solution of B7-2 (1.0 g, 3.36 mmol) in MeOH (10 mL), add NaBH portion by portion₄ (640 mg, 16.8 mmol). The mixture was stirred at ambient temperature for 2 hours until no starting material remained by LCMS. Then the solution was diluted with water (50 mL) and extracted with DCM (3×20 mL). The combined DCM layer is passed through Na₂ SO₄ Dry and concentrate. The residue was purified by elution with EtOAc/hexane (0-50%, 10 CV) on a silica gel column to obtain the desired product B7-3 (0.75 g, 75%) as a pale yellow solid. LC-MS (ESI)m/z 322.3 (M+Na)⁺ ；¹ H NMR (500 MHz, chloroform-d ) δ 7.11 (dd,J = 9.2, 3.4 Hz, 1H), 6.89 (ddd,J = 9.0, 7.9, 3.2 Hz, 1H), 6.77 (dd,J = 8.9, 4.4 Hz, 1H), 5.09 (q,J = 6.6 Hz, 1H), 4.92 (d,J = 4.4 Hz, 1H), 4.03 (t,J = 5.2 Hz, 2H), 3.62-3.50 (m, 2H), 1.49 (d,J = 6.4 Hz, 3H), 1.45 (s, 9H). Step 3: Add B7-3 (600 mg, 2.0 mmol) and {2-[4-fluoro-2-(1-hydroxy-ethyl)-phenoxy]-ethyl}-amino group at -78℃ To a solution of tert-butyl formate (450 mg, 2.0 mmol) in anhydrous THF (40.0 mL) was added NaH (60%, 80 mg, 2.0 mmol) in portions. The suspension was stirred at -78°C for 4 hours and allowed to warm to 0°C and stirred for another 4 hours. The mixture was then placed in the refrigerator at -20°C overnight. LC-MS showed good conversion to the desired product. Then the mixture was quenched with a mixture of ice and 1N HCl and extracted with EtOAc (3 x 20 mL). Organic layer by Na₂ SO₄ Dry, concentrate and purify twice to obtain the desired product B7 (240 mg, 25%) as a yellow solid: B1-B7 are prepared according to general method B and the methods described herein. Instance structure name analyze data B1

5-((2-(2-((Third-butoxycarbonyl)amino)ethoxy)-5-fluorobenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine Ethyl -3-formate MS: 488.3.1 (M+H) ⁺ ; ¹ H NMR (500 MHz, chloroform- d ) δ 8.30 (s, 1H), 8.26 (s, 1H), 6.92 (td, J = 8.6, 3.3 Hz, 1H ), 6.83-6.76 (m, 1H), 6.31 (s, 1H), 4.93 (s, 2H), 4.51-4.44 (m, 1H), 4.36 (q, J = 7.2 Hz, 2H), 4.03 (t, J = 4.9 Hz, 2H), 3.69-3.63 (m, 1H), 3.51 (s, 2H), 3.30 (s, 2H), 1.44 (s, 9H), 1.41-1.35 (t, J = 7.2 Hz, 3H ). B2

5-((2-(2-((Third-butoxycarbonyl)amino)ethoxy)-5-fluorobenzyl)(ethyl)amino)pyrazolo[1,5-a]pyrimidine Ethyl -3-formate MS: 502.2 (M+H) ⁺ . B3

5-((2-(2-((Third-butoxycarbonyl)amino)ethoxy)-5-fluorobenzyl)(propyl)amino)pyrazolo[1,5-a]pyrimidine Ethyl -3-formate MS: 516.3 (M+H) ⁺ . B4

5-((2-(2-((Third-butoxycarbonyl)amino)ethoxy)-5-fluorobenzyl)(cyclopropyl)amino)pyrazolo[1,5-a] Ethyl pyrimidine-3-carboxylate MS: 514.2 (M+H) ⁺ . B5

5-((2-(2-((Third-butoxycarbonyl)amino)ethoxy)-5-fluorobenzyl)(2-hydroxyethyl)amino)pyrazolo[1,5- a] Ethyl pyrimidine-3-carboxylate MS: 518.3 (M+H) ⁺ . B6

5-((6-(2-((Third-butoxycarbonyl)amino)ethoxy)-2-chloro-3-fluorobenzyl)(methyl)amino)pyrazolo[1,5 -a] Ethyl pyrimidine-3-carboxylate MS: 522.5 (M+H) ⁺ . B7

6-(1-(2-(2-((Third-butoxycarbonyl)amino)ethoxy)-5-fluorophenyl)ethoxy)imidazo[1,2-b]pyridazine- Ethyl 3-formate LC-MS (ESI) m/z 511.6 (M+Na) ⁺ ; ¹ H NMR (500 MHz, chloroform- d ) δ 8.16 (s, 1H), 7.90 (d, J = 9.7 Hz, 1H), 7.16 ( dd, J = 9.0, 3.2 Hz, 1H), 0.95 (d, J = 9.5 Hz, 1H), 6.90-6.88 (m, 1H), 6.81-6.78 (m, 1H), 6.68 (q, J = 6.2 Hz , 1H), 5.84-5.68 (m, 1H), 4.38 (q, J = 7.2 Hz, 2H), 4.15-4.09 (m, 2H), 3.60-3.52 (m, 2H), 1.65 (d, J = 6.4 Hz, 3H), 1.38 (d, J = 7.2 Hz, 3H), 1.35 (s, 9H). Instance 2 and 2-1.

synthesis A : Example 2 can be prepared starting from the racemic or spiegelmer enriched starting material as shown in the following scheme:

Step 1. Add Cs to the mixture of 2A (1 equivalent) and 2B (1.2 equivalent) in anhydrous DMF (0.2 M)₂ CO₃ (1.5 equivalents) and the reaction was heated in an oil bath at 80°C under nitrogen overnight. The mixture was cooled, poured into water, and extracted three times with EtOAc. The combined organic layer was washed five times with water, washed with brine, and subjected to Na₂ SO₄ dry. After concentration, the residue was purified by EtOAc/hexane elution on a flash column to provide compound 2C. Step 2. To a solution of compound 2C (1 equivalent) in anhydrous THF (0.2 M) was added NaH (1.2 equivalent). The reaction mixture was stirred at ambient temperature for 0.5 hours. Compound 2D was added to the mixture and the reaction was heated under reflux under nitrogen overnight. The reaction was cooled to ambient temperature and diluted with a portion of water (1/3 of the volume of THF) and NaOH (3 equivalents). The mixture was stirred and heated at 70°C for 2 hours or until the ester was completely hydrolyzed to the corresponding acid. After cooling, the organic layer was separated and the aqueous layer was neutralized to pH about 5. The resulting precipitate was filtered, washed three times with water, and dried under vacuum to provide compound 2E, which was used without further purification. Step 3. Add compound 2E (1 equivalent) to CH₂ Cl₂ Add 4 M HCl/dioxane (10 equivalents) to the solution in (0.2 M) and stir the mixture until compound 2E is completely converted to compound 2F. The mixture was concentrated, and the residue was purified by reverse phase preparative HPLC to provide compound 2F. Step 4. Add the solution of compound 2F (1 equivalent) and DIPEA (10 equivalent) in DMF (0.2 M) dropwise to the solution of HATU (1.4 equivalent) in DMF (0.1 M) at 0°C. After the addition was complete, the mixture was stirred for another 30 minutes at 0°C. Water was added and the mixture was extracted three times with EtOAc. Use saturated NaHCO for the combined organic layer₃ Washed twice, then washed with brine, after Na₂ SO₄ Dry and concentrate. The residue was purified by EtOAc/hexane elution on a silica gel column to provide Example 2.synthesis B : Examples 2 and 2-1 can also be prepared using racemic or spiegelmer enriched starting materials according to the following scheme:

Step 1. Compound 2C is reacted with compound 2G under the conditions described in Synthesis A, Step 2 to provide compound 2H. Step 2. Compound 2H is converted to Compound 2I under the conditions described in Synthesis A, Step 3. Step 3. To compound 2I (1 equivalent) and DIPEA (2 equivalents) in toluene (0.01 M) with Pd(P-tBu₃ )₂ (1 equivalent). The reaction mixture was heated at 100°C under 4 bar CO overnight, and then concentrated. The residue was purified by EtOAc/hexane elution on a silica gel column to provide Example 2.Instance 10 and 10-1.

Examples 10 and 10-1 can be prepared using racemic or spiegelmer enriched starting materials as shown in the following scheme:

Step 1. Compound 10C was prepared from compounds 10A and 10B using the method described in Example 2, Synthesis A, Step 1. Step 2. Compound 10E is prepared from the method described in Compound 10C and 10D using the method described in Example 2, Synthesis A, Step 2. Step 3. Combine compound 10E (1 equivalent) and NH₂ -NH₂ The mixture (10 equivalents) in methanol (0.2 M) was heated under reflux until compound 10E was completely converted to compound 10F. The mixture was concentrated and the residue was purified in reverse phase preparative HPLC to provide compound 10F. Step 4. Compound 10F was converted to Example 10 according to the method described for Example 2, Synthesis A, Step 4.Instance 11-1

Step 1: Add 2-chloro-3-fluoro-6-hydroxy-benzaldehyde (175 mg, 1.0 mmol), bis-tos ethylene glycol (740 mg, 2.0 mmol) in ACN (5 mL) K₂ CO₃ (276 mg, 2.0 mmol) and KI (2 mg). The mixture was stirred at 120°C for 24 hours. The solid was filtered off and the filtrate was concentrated and purified by column chromatography to obtain the desired product 11-1B as a white solid. This material is used directly in the next step. Step 2: Add NaN to the solution of 11-1B (373 mg, 1 mmol) in ACN (5 mL)₃ (650 mg, 10 mmol) and the mixture was stirred at 120°C for 24 hours. The solid was filtered off and the residue was concentrated and purified by column chromatography to obtain 11-1C (200 mg, 82%) as a white solid.¹ H NMR (500 MHz, chloroform-d ) δ 10.49 (d,J = 1.1 Hz, 1H), 7.31 (dd,J = 9.2, 8.2 Hz, 1H), 6.88 (dd,J = 9.2, 3.7 Hz, 1H), 4.21 (dd,J = 5.4, 4.5 Hz, 2H), 3.67 (dd,J = 5.4, 4.5 Hz, 2H). Step 3: Add methylmagnesium bromide (1N in Et₂ In O, 0.82 mL, 0.82 mmol). The mixture was warmed to room temperature and stirred for 2 hours until TLC showed no starting material. Then cool the solution to 0℃ and use saturated NH₄ The aqueous OAc solution was quenched and extracted with EtOAc (20 mL x 3). The combined organic matter is passed through Na₂ SO₄ Dry and concentrate. The residue 11-1D was used directly in the next step.¹ H NMR (500 MHz, chloroform-d ) δ 6.97 (dd,J = 9.2, 8.3 Hz, 1H), 6.77 (dd,J = 9.1, 4.1 Hz, 1H), 5.27 (q,J = 6.7 Hz, 1H), 4.34-4.29 (m, 1H), 4.22-4.16 (m, 1H), 4.04-3.98 (m, 1H), 3.95-3.88 (m, 2H), 1.51 (d,J = 6.7 Hz, 3H). Step 4: Add 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (100 mg, 0.44 mmol) and 11-1D (110 mg, 0.41 mmol) in anhydrous at -78℃ Add NaH (60%, 17 mg, 0.44 mmol) to the solution in THF (5.0 mL). The mixture was warmed to room temperature and stirred for 8 hours until a large amount of the desired product formed. The mixture was then diluted with water/ice and extracted with DCM (3×20 mL). Organic layer by Na₂ SO₄ It was dried, concentrated and purified by silica gel column chromatography to obtain 11-1E (20 mg, 0.045 mmol, 6%) as a yellow liquid, which was used directly in the next step. Step 5: Add LiOH (16 mg, 0.38 mmol) to the solution of 11-1E (20 mg, 0.045 mmol) in MeOH (1mL), followed by 1 mL of H₂ O. The mixture was stirred at 60°C for 4 hours, until LCMS and TLC showed that the reaction was complete. The solution was cooled to room temperature, partially concentrated and acidified by 1N HCl until the pH was 2-3. The aqueous mixture was extracted with DCM (3x10 mL). Pass the organic layer through Na₂ SO₄ Dry and concentrate. The residue 11-1F was used directly in the next step. Step 6: Add PPh to a solution of 11-1F (20 mg, 0.045 mmol) in DCM (5mL)₃ (24 mg, 0.09 mmol). The solution was stirred for 1 hour until TLC showed complete conversion of the starting material to the desired product. The mixture was then used directly in the next step without further characterization. 11-1G MS ESI⁺ m/z 417.7 (M+Na)⁺ . Step 7: Add DIPEA (0.20 mL, 1.15 mmol) to the solution of 11-1G obtained in the above step in DMF (10 mL). The solution was frozen with a dry ice/acetone bath and HATU (40.0 mg, 0.11 mmol) was added. The solution was slowly warmed to room temperature and LCMS showed that the starting material was cleanly converted to the desired product. Then the mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layer was washed with water (3 x 50mL) and brine (50 mL) and washed with Na₂ SO₄ dry. The solvent was removed and the resulting residue was purified by silica gel column chromatography (0-5% MeOH/DCM) to obtain the desired product (2.6 mg, 20% yield) as a white solid.Instance 14 and 14-1.

Examples 14 and 14-1 can be prepared using racemic or spiegelmer enriched starting materials according to the following scheme:

Step 1. Add Cs to the mixture of 14A (1 equivalent) and 14B (1.2 equivalent) in anhydrous DMF (0.2 M)₂ CO₃ (1.5 equivalents) and the reaction was heated in an oil bath at 80°C under nitrogen overnight. The mixture was cooled, poured into water, and extracted three times with EtOAc. The combined organic layer was washed five times with water, washed with brine, and subjected to Na₂ SO₄ dry. After concentration, the residue was purified by EtOAc/hexane elution on a flash silica gel column to provide 14C. Step 2. To a cooled (-78°C) solution of 14C (1 equivalent) in dry THF (0.2 M) was added MeMgBr (3 equivalents, 3 M in diethyl ether). The reaction was stirred from -78°C to 0°C for 2 hours, and saturated NH₄ The aqueous Cl solution was quenched and then extracted with EtOAc (2x). Organic matter by MgSO₄ Dry, filter and concentrate. The residue was purified by silica gel column chromatography with EtOAc/hexane elution to obtain 14D. Step 3. To a solution of compound 14D (1 equivalent) in anhydrous THF (0.2 M) was added NaH (1.2 equivalent). The reaction mixture was stirred at ambient temperature for 0.5 hours. 14E was added to the mixture and the reaction was heated to reflux under nitrogen overnight. The reaction was cooled to ambient temperature and then poured into water. The product was extracted three times with EtOAc. The combined organics were washed with brine, and subjected to Na₂ SO₄ Dry and concentrate. The residue was purified using a silica gel column with EtOAc/hexane to provide the product 14F. Step 4. Add compound 14F (1 equivalent) to CH₂ Cl₂ Add 4 M HCl/dioxane (10 equivalents) to the solution in (0.2 M) and stir the mixture until all 14F is converted to 14G. After concentration, the residue was purified in reverse phase preparative HPLC to provide 14G. Step 5. Add Pd(P-t-Bu) to a solution of 14G (1 equivalent) and DIPEA (2 equivalent) in toluene (0.01 M)₃ )₂ (1 equivalent). The reaction mixture was heated at 100°C under 4 bar CO overnight, and then concentrated. The residue was purified by EtOAc/hexane elution on a silica gel column to provide 14.Instance 15 and 15-1.

Examples 15 and 15-1 can be prepared using racemic or spiegelmer enriched starting materials according to the following scheme:

Step 1. To a suspension of 15A (1.0 equivalent) in THF (0.15 M) was added 2.0 M NaOH aqueous solution (3 equivalents). The homogeneous reaction mixture was stirred overnight, and then the organics were removed under reduced pressure. The aqueous residue was brought to pH 4 using 1.0 M aqueous HCl. Collect the resulting precipitate by filtration and use H₂ O rinse to obtain 15B solids. The filtrate was extracted with EtOAc (2×), and the organics were concentrated under reduced pressure to provide an additional portion of 15B. Step 2. By adding thick H₂ SO₄ (2.3 mL) Carefully add to CrO₃ (2.67 g) and then use 10 mL H₂ Dilute with O to prepare a stock solution (2.67 M) of Jones reagent. To a suspension (0.067 M) of 15B (1.0 equivalent) in acetone was slowly added Jones reagent (1.2 equivalent). The reaction mixture was stirred for 15 minutes and then extracted with i-PrOH and filtered with the aid of a Celite pad rinsing with acetone. The filtrate was concentrated to provide 15C, which was used without further purification. Step 4. Add NaH (60% in mineral oil, 1.5 equivalents) to a solution of 15C (1.0 equivalent) in DMF (0.40 M) at 0°C. The reaction mixture was stirred at room temperature for 30 minutes, and then cooled back to 0°C, and 2-(trimethylsilyl)ethoxymethyl chloride (4.3 mL, 1.2 equivalents) was slowly added. The reaction mixture was allowed to warm to room temperature, stirred for 1 hour, and then used H₂ O was quenched and extracted with EtOAc (3×). Use H₂ O (3 ×) and brine wash the combined organics, and then MgSO₄ Dry and concentrate. The residue was purified by flash silica gel chromatography with 20-30% EtOAc/hexane to obtain 15D. Step 5. Add 14D (1.0 equivalent), copper(I) iodide (0.05 equivalent), 8-hydroxyquinoline (0.1 equivalent) and tripotassium phosphate (2.0 equivalent) in DMF (0.2 M) under a nitrogen atmosphere. 15D (1.2 equivalents) was added to the reaction mixture and the reaction mixture was heated at 120°C for 24 hours. The reaction mixture was cooled to room temperature and then diluted with EtOAc. The mixture was filtered through a pad of Celite and the filtrate was evaporated under vacuum. The crude residue was purified by EtOAC/hexane elution on a silica gel column to obtain 15E. Step 6. A 0°C suspension of 15E (1.0 equivalent) in 1,4-dioxane (0.062 M) and water (1/3 of THF) was treated with sulfanilic acid (6.0 equivalent). A solution of sodium chlorite (1.3 equivalent) and potassium dihydrogen phosphate (12 equivalent) in water (1.2 M) was added via a dropping funnel over 20 minutes. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 3 hours. THF was added, and then the reaction mixture was stirred at room temperature for another 3 hours. The reaction mixture was diluted with water and extracted with EtOAc (2x). The combined organic layer was washed with water and brine, and then subjected to Na₂ SO₄ Dry, filter, and concentrate. The residue was triturated with ethyl acetate/hexane to obtain 15F. Step 7. Add compound 15F (1 equivalent) to CH₂ Cl₂ Add 4 M HCl/dioxane (10 equivalents) to the solution in (0.2 M) and stir the mixture until all 15F is converted to 15G. After concentration, the residue was purified in reverse phase preparative HPLC to provide 15G. Step 8. Add a solution of compound 15G (1 equivalent) and DIPEA (10 equivalent) in DMF (0.2 M) to a solution of HATU (1.4 equivalent) in DMF (0.1 M) at 0°C. After the addition was complete, the mixture was stirred for another 30 minutes at 0°C. Water was added and the mixture was extracted three times with EtOAc. Saturated NaHCO for combined organics₃ Wash twice, wash with brine, and pass Na₂ SO₄ Dry and evaporate. The residue was purified with a silica gel column using EtOAc/hexane elution to provide 15.Instance 18 and 18-1.

Examples 18 and 18-1 can be prepared using racemic or spiegelmer enriched starting materials according to the following scheme:

Step 1. Add NaH (3.0 equivalent) to the reaction mixture of 14D (1.0 equivalent), 18A (1.2 equivalent) and copper(I) (0.05 equivalent) in DMF (0.2 M) under a nitrogen atmosphere. The reaction mixture was heated at 120°C for 24 hours, and then cooled to room temperature and diluted with EtOAc. The mixture was filtered through a pad of Celite and the filtrate was evaporated under vacuum. The crude residue was purified by EtOAc/hexane elution on a silica gel column to obtain 18B. Step 2. Add KOH (2 equivalents) and I to the reaction mixture of 18B (1.0 equivalent) in DMF (0.2 M)₂ (1.1 equivalent). The reaction mixture was stirred at room temperature for 1 hour, and then NaHSO₃ Quench and extract with EtOAc. Saturated NaHCO for combined organics₃ Wash twice, wash with brine, and pass Na₂ SO₄ Dry and evaporate. The residue was purified using a silica gel column with EtOAc/hexane to provide 18C. Step 3. Add compound 18C (1 equivalent) to CH₂ Cl₂ Add 4 M HCl/dioxane (10 equivalents) to the solution in (0.2 M) and stir the mixture until all 18C is converted to 18D. After concentration, the residue was purified in reverse phase preparative HPLC to provide 18D. Step 4. Add Pd(P-t-Bu) to the solution of 18D (1 equivalent) and DIPEA (2 equivalent) in toluene (0.01 M)₃ )₂ (1 equivalent). The reaction mixture was heated at 100°C under 4 bar CO overnight, and then concentrated. The residue was purified by EtOAc/hexane elution on a silica gel column to provide 18.Instance 20

Example 20 was prepared according to the following scheme:

Step 1. Tertiary butyl (2-(4-fluoro-2-methanylphenoxy)ethyl)carbamate (20C). Heat a solution of aldehyde 20A (1.5 g, 11 mmol), chloride 20B (2.1 g, 12 mmol), potassium carbonate (7.4 g, 54 mmol) and potassium iodide (36 mg, 0.2 mmol) in DMF (11 mL) Bring to 60°C and stir for 15 hours. Additional chloride 20B (1.0 g, 6 mmol) was added and heated at 80°C for another 5 hours to complete the reaction. The mixture was cooled to room temperature and diluted by adding water (250 mL). The mixture was extracted with ethyl acetate (3×300 mL) and the combined extracts were washed with water (200 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-20% ethyl acetate in hexane) provides 20C (3.0 g, 99%) as a viscous oil. LRESIMSm/z 306.1 [M+Na]⁺ , C₁₄ H₁₈ F₁ N₁ Na₁ O₄ The calculated value, 306.1. Step 2. Tertiary butyl (2-(4-fluoro-2-((methylamino)methyl)phenoxy)ethyl)carbamate (20D). The aldehyde 20C (2.5 g, 8.8 mmol) and methylamine (0.69 g, 22 mmol) in methanol (88 mL) were heated to 60° C. and stirred for 1 hour. The mixture was cooled to room temperature and sodium borohydride (0.33 g, 8.8 mmol) was added. The mixture was stirred for 30 minutes and then quenched by adding water (200 mL). The mixture was extracted with dichloromethane (4×100 mL) and the combined extracts were dried with brine (50 mL), sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-100% (10% methanol in ethyl acetate) in hexane) provides the target compound as a gel (2.1 g, 80%). LRESIMSm/z 299.2 [M+H]⁺ , C₁₅ H_{twenty four} F₁ N₂ O₃ The calculated value, 299.2. Step 3. 5-((2-(2-((Third-butoxycarbonyl)amino)ethoxy)-5-fluorobenzyl)(methyl)amino)pyrazolo[1,5- a] Ethyl pyrimidine-3-carboxylate (20F). The amine 20D (2.1 g, 7.0 mmol), ester 20E (1.59 g, 7.0 mmol) and Hünig base (7.0 mL, 5.2 g, 40 mmol) in butanol (17 mL) were heated at 110°C for 25 minutes. The reaction was cooled and diluted with water (250 mL). The mixture was extracted with dichloromethane (4×100 mL) and the combined extracts were dried with sodium sulfate. The mixture was concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 20-100% ethyl acetate in hexane) provided the target compound (2.1 g, 75%) as a solid. LRESIMSm/z 488.3 [M+H]⁺ , C_{twenty four} H₃₁ F₁ N₅ O₅ The calculated value, 488.2. Step 4. 5-((2-(2-((Third-butoxycarbonyl)amino)ethoxy)-5-fluorobenzyl)(methyl)amino)pyrazolo[1,5- a] Pyrimidine-3-carboxylic acid (20G). Sodium hydroxide (40 mL, 2 M in water) was added to a stirred solution of ester 20F (2.1 g, 4.3 mmol) in tetrahydrofuran:methanol (3:2, 100 mL) at room temperature. The reaction was heated to 60°C and stirred for 6.5 hours. The mixture was cooled to 0°C and acidified with hydrochloric acid (45 mL, 2 M in water), then diluted with water (100 mL). The mixture was extracted with ethyl acetate (4×150 mL) and the combined extracts were dried with brine (50 mL) and sodium sulfate. The mixture was concentrated under reduced pressure to provide the target compound (1.92 g, 97%) as a solid. LRESIMSm/z 460.2 [M+H]⁺ , C_{twenty two} H₂₇ F₁ N₅ O₅ The calculated value, 460.2. Step 5. 5-((2-(2-Aminoethoxy)-5-fluorobenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (20H) . Add hydrochloric acid (5 mL, 4M in dioxane) to a stirred solution of carboxylic acid 20G (1.92 g, 4.2 mmol) in dichloromethane (25 mL) at room temperature. The reaction was stirred for 2 hours and then concentrated under reduced pressure to provide the target compound as a solid. LRESIMSm/z 360.2 [M+H]⁺ , C₁₇ H₁₀ F₁ N₅ O₃ The calculated value, 360.2. Step 6. Under argon atmosphere, add HATU (1.67 g, 4.4 mmol) to carboxylic acid 20H (1.50 g, 4.2 mmol) and Hünig base (7.28 mL, 5.40 g, 41.8 mmol) in DMF at -78°C: Stir the solution in dichloromethane (5:1, 60 mL). The reaction was slowly warmed to room temperature and stirred for 3 hours, then quenched with water (300 mL). The mixture was extracted with ethyl acetate (3×100 mL), then dichloromethane (2×100 mL), and the combined extracts were dried with brine (50 mL) and sodium sulfate. The mixture was concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 1-4% methanol in dichloromethane) followed by recrystallization from ethyl acetate/methanol provided Example 20 as a solid (0.98 g, 68%, 2 steps). LRESIMSm/z 342.2 [M+H]⁺ , C₁₇ H₁₇ F₁ N₅ O₂ The calculated value of 342.1;¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.43 (dd,J = 6.9, 2.7 Hz, 1 H), 8.76 (d,J = 7.9 Hz, 1 H), 8.10 (s, 1 H), 7.19-7.25 (m, 1 H), 7.03-7.07 (m, 2 H), 6.72 (d,J = 7.9 Hz, 1 H), 5.64 (dd,J = 14.9, 1.5 Hz, 1 H), 4.48 (dt,J = 10.2, 4.3 Hz, 1 H), 4.04-4.10 (m, 2 H), 3.81-3.87 (m, 1 H), 3.58 (s, 3 H), 3.38-3.46 (m, 1 H).Instance 20 Alternative synthesis : Example 20 was also prepared by the following alternative route:

Step 1. 5-oxo-4H -Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (20J). At 20℃ in N₂ Downward 20I (150.00 g, 1.08 mmol) and (E )-3-ethoxyprop-2-enoic acid ethyl ester (292.16 g, 2.03 mol) in DMF (3.2 L), add Cs at one time₂ CO₃ (656.77 g, 2.02 mol). The mixture was stirred at 110°C for 6 hours. The mixture was cooled to 20°C and filtered through a pad of Celite. The filter cake was washed with ethyl acetate (3×30 mL). Add the filtrate to H₂ O (2 L) and acidified with HOAc to pH=4. The resulting precipitate was filtered to obtain 20J (173.00 g, 834.98 mmol, 86.36% yield) as a white solid.¹ H NMR (400 MHz, DMSO-d₆ ) δ 8.54 (d,J =7.91 Hz, 1H), 8.12 (s, 1H), 6.13 (d,J =7.91 Hz, 1H), 4.27 (q,J =7.11 Hz, 2H), 1.28 (t,J =7.09 Hz, 3H). Step 2. Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (20K). At 20℃ in N₂ Add POCl to a mixture of 20J (158.00 g, 762.59 mmol) in MeCN (1.6 L)₃ (584.64 g, 3.81 mol). The mixture was stirred at 100°C for 2 hours. The mixture was cooled to 20°C and poured into ice-water (5000 mL) in portions at 0°C and stirred for 20 minutes. The precipitate was filtered and dried to obtain 20K (110.00 g, 487.52 mmol, 63.93% yield) as a white solid.¹ H NMR (400 MHz, DMSO-d₆ ) δ 9.33 (d,J =7.28 Hz, 1H), 8.66 (s, 1H), 7.41 (d,J =7.15 Hz, 1H), 4.31 (q,J =7.15 Hz, 2H), 1.32 (t,J =7.09 Hz, 3H). Step 3. 4-Fluoro-2-methylaminomethyl-phenol (20M). At 25℃ in N₂ Downward 20 L (5.00 g, 35.69 mmol, 1.00eq. ) To a solution in MeOH (50.00 mL), add aqueous methylamine (8.8 mL, 71.38 mmol, 25%, 2.00eq ). The mixture was stirred at 25°C for 3 hours, then NaBH was added portion by portion₄ (2.70 g, 71.38 mmol, 2.00eq ). And the mixture was stirred for another 9 hours at 25°C. TLC showed that the reaction was complete. The mixture was concentrated under reduced pressure at 45°C. The residue was poured into water (50 mL). The aqueous phase was extracted with dichloromethane (3 x 200 mL) and the combined organic phase was washed with brine (200 mL), and subjected to anhydrous Na₂ SO₄ Dry, filter and concentrate in vacuo to obtain 20M (5.10 g, 32.87 mmol, 92.09% yield) as a colorless solid.¹ H NMR (400MHz, CDCl₃ ) δ 6.86 (dt,J =3.0, 8.7 Hz, 1H), 6.78-6.69 (m, 2H), 3.93 (s, 2H), 2.48 (s, 3H). Step 4. 5-[(5-Fluoro-2-hydroxy-benzyl)-methyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (A1). To a suspension of 20M (33.70 g, 217.17 mmol, 1.00 eq.) and 20K (49.00 g, 217.17 mmol, 1.00 eq.) in n-BuOH (740.00 mL) was added DIPEA (159.98 g, 1.24 mol, 5.70 eq.) .). The mixture was stirred at 120°C for 2 hours under nitrogen. TLC showed that the reaction was complete. The solution was cooled to 25°C, and then the solvent was removed. The residue was diluted with water (500 mL) and extracted with dichloromethane (3×500 mL). The combined organic extracts were washed with brine (300 mL) and subjected to anhydrous Na₂ SO₄ Dry and concentrate under vacuum. The residue was triturated with EtOAc (100 mL) to obtain A1 as a white solid (60.00 g, 174.25 mmol, 80.24% yield).¹ H NMR (500 MHz, chloroform-d ) δ 9.71 (s, 1H), 8.32 (d,J = 7.9 Hz, 1H), 8.30 (s, 1H), 6.98-6.87 (m, 3H), 6.37 (d,J = 7.9 Hz, 1H), 4.82 (s, 2H), 4.42 (q,J = 7.1 Hz, 2H), 3.21 (s, 3H), 1.39 (t,J = 7.1 Hz, 3H). Step 5. 5-{[2-(2-Third-butoxycarbonylamino-ethoxy)-5-fluoro-benzyl]-methyl-amino}-pyrazolo[1,5-a ] Ethyl pyrimidine-3-carboxylate (B1). To A1 (102.85g, 298.6 mmol, 1 eq.), (2-chloro-ethyl)-carbamic acid tert-butyl ester (56.33 g, 313.5 mmol, 1.05 eq.) in DMF (854 mL) Add K to the solution₂ CO₃ (206.41 g, 1493 mmol, 5.0 eq.). The mixture was heated at 80°C for 20 hours, where the conversion of starting material to product was about 85% by LC-MS. Add an additional portion of (2-chloro-ethyl)-carbamic acid tert-butyl ester (5.633 g, 31.35 mmol, 0.1 eq.) and K to the reaction flask₂ CO₃ (41.282 g, 298.6 mmol, 1 eq.). The reaction was continued to stir at 80°C for another 21 hours. The mixture was then cooled to room temperature, quenched with water (1000 ml) and extracted with EtOAc (3 x 900 mL). Then the combined organic extracts were washed with water (3 x 700mL) and brine (500 mL), and then washed with Na₂ SO₄ Dry and concentrate. The obtained residue was purified by elution with EtOAc/hexane (0-70%) through a silica gel column to obtain B1 (128.74 g, 96.7% yield) as a white solid. LC-MS (ESI)m/z 510.1 (M+Na)⁺ ；¹ H NMR (500 MHz, chloroform-d ) δ 8.30 (s, 1H), 8.26 (s, 1H), 6.92 (td,J = 8.6, 3.3 Hz, 1H), 6.83-6.76 (m, 1H), 6.31 (s, 1H), 4.93 (s, 2H), 4.51-4.44 (m, 1H), 4.36 (q,J = 7.2 Hz, 2H), 4.03 (t,J = 4.9 Hz, 2H), 3.69-3.63 (m, 1H), 3.51 (s, 2H), 3.30 (s, 2H), 1.44 (s, 9H), 1.41-1.35 (t,J = 7.2 Hz, 3H). Step 6. 11-Fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3-f][1,4,8,10]benzene And oxatriazatriazide ring-4(5H)-one (20). To B1 (128.74 g, 264.07 mmol, 1 eq.) in a solution of methanol (750 mL) and THF (250 mL) was added to H₂ LiOH in O (250 mL)^. H₂ O (55.40 g, 1320 mmol, 5.0 eq.). The clear solution was heated at 70°C for 2 hours. The reaction was neutralized to pH<5 with aqueous HCl (2M, 250 mL) at 0°C, and then with CH₂ Cl₂ (1x1000 mL, 3x500 mL) extraction. The combined organics were washed with brine (300 mL), and subjected to Na₂ SO₄ dry. After filtration, evaporation, and high-vacuum drying, a white solid (126.47 g, 275.25 mmol, 104% yield) was obtained. To acid (121.30 g, 264 mmol) in CH at 0℃₂ Cl₂ Add HCl (4 M, 204 mL) in dioxane to the solution in (996 mL). Continue stirring from 0°C to room temperature for 27 hours, until de-Boc is completed by LC-MS. The white solid was filtered, washed with DCM (400 mL), and dried under high vacuum to provide the amine 3HCl salt as a white solid (123.55 gram), which was used without further purification. To DIPEA (169.4 g, 228 mL, 1310 mmol) in DMF (3.7 L) and CH₂ Cl₂ Add acid amine HCl salt (22.92 g, 49.0 mmol, 1.00 eq.) to the solution in (1.0 L). After the solid is completely dissolved, add it to CH₂ Cl₂ Among them, pentafluorophenyl diphenylphosphinate (FDPP) (1.1 M, 19.76 g, 51.44 mmol, 1.05 eq.). By LC-MS, the coupling was completed within 30 minutes, and then the second part of salt and FDPP were added according to the same procedure as the first part. The addition of salt followed by FDPP was repeated every 30 minutes and each addition cycle was monitored by LC-MS. All salts (123.55 g, 264 mmol, 1.00 eq) and FDPP (106.44 g, 277 mmol, 1.05 eq.) were added to the reaction flask in batches. The reaction solution was concentrated to a volume of about 500 mL and a large amount of precipitate was formed. The solid product 20 was filtered and washed with DMF (50 mL×3). The filtrate was poured into water (2L) and additional product precipitated out. The solid product was filtered and washed with water (100 mL×3). The combined solid product was dried and redissolved in 10% methanol in dichloromethane (1.5 L) and then ethyl acetate (1 L) was added. The solution was concentrated to about 500 mL and a large amount of white solid formed. After filtration and drying under high vacuum, a white solid compound 20 (74.58 g, 83% yield) was obtained.Instance 20 Powder X- Ray diffraction (PXRD). The sample crystalline polymorph 1 of Example 20 was transferred to the zero background plate for PXRD analysis. The PXRD data was obtained using the Bruker D8 X-ray diffractometer according to the manufacturer’s recommended procedures. Parameters used for scanning: 2-theta range: 4.5 to 39.1 degrees; step size: 0.02 degrees; step time: 1 second; analysis time: 180 seconds. The diffraction peak is usually measured to have an error of ±0.1 degree (2θ). The results are shown in Figure 1. The data is summarized in Table 1. Table 1 2-θ (degrees) d-value Peak intensity (count) Peak intensity (%) 10.68 9.611 31.15 5.2 11.96 8.586 19.11 2.9 15.26 6.737 20.92 4.4 19.64 5.244 27.57 6.4 21.94 4.701 452.41 100 23.96 4.309 91.85 18.2 26.82 3.857 10.92 2.2 Instance 20 Differential scanning calorimetry (DSC). The DSC measurement shown in Figure 2 was performed using a Seiko Model SSC/5200 Differential Scanning Calorimeter. 7.92 mg of sample crystalline polymorph 1 of Example 20 was equilibrated at 36°C, and then ramped to 380°C at a rate of 10°C/min. The sample crystalline polymorph 1 of Example 20 showed a melting point of 298.9°C.Instance 26.

Example 26 can be prepared according to the following scheme:

Step 1. Titanium (IV) isopropoxide (1.3 equivalents) was added to a commercially available solution of methylamine in methanol (2 M, 3 equivalents), followed by the starting aldehyde 14C (1.0 equivalent). The reaction mixture was stirred at ambient temperature for 5 hours, after which sodium borohydride (1.0 equivalent) was added and the resulting mixture was further stirred for a period of 2 hours. The reaction was then quenched by adding water, and the resulting inorganic precipitate was filtered and washed with EtOAc. The organic layer was separated and the aqueous portion was further extracted with EtOAc (x2). Dry the combined extracts (K₂ CO₃ ) And concentrated in vacuo to obtain 26A. Step 2. A mixture of compound 26A (1 equivalent) and DIPEA (2 equivalent) in n-BuOH (0.2 M) was heated at 120°C overnight, cooled to ambient temperature, and then concentrated. The residue was purified using a silica gel column with EtOAc/hexane to provide the product 26B. Step 3. Add compound 26B (1 equivalent) to CH₂ Cl₂ Add 4 M HCl/dioxane (10 equivalents) to the solution in (0.2 M) and stir the mixture until all 26B is converted to 26C. After concentration, the residue was purified in reverse phase preparative HPLC to provide 26C. Step 4. Add Pd(P-t-Bu) to a solution of 26C (1 equivalent) and DIPEA (2 equivalent) in toluene (0.01 M)₃ )₂ (1 equivalent). The reaction mixture was heated at 100°C under 4 bar CO overnight, and then concentrated. The residue was purified on a silica gel column with EtOAc/hexane elution volume to provide 26.Instance 37 and 37-1.

Examples 37 and 37-1 can be prepared from racemic or spiegelmer enriched starting materials according to the following scheme:

Step 1. Compound 37B was prepared from compound 2C and compound 37A using the method described in Example 2, Synthesis A, and Step 2. Step 2. Compound 37C was prepared from compound 37B using the method described in Example 2, Synthesis A, and Step 3. Step 3. Example 37 was prepared from compound 37C using the method described in Example 2, Synthesis A, Step 4.Instance 38 and 38-1.

Examples 38 and 38-1 can be prepared from racemic or spiegelmer enriched starting materials according to the following scheme:

Step 1. Compound 38B was prepared from compounds 2C and 38A as described in Example 2, Synthesis A, Step 2. Step 2. Compound 38C was prepared from compound 38B using the method described in Example 2, Synthesis A, and Step 3. Step 3. Example 38 was prepared from compound 38C using the method described in Example 2, Synthesis B, Step 4.Instance 39

Example 39 was prepared according to the following scheme:

Step 1. 2-(3-Chloro-4-fluoro-2-methanyl-phenoxy)-ethyl]-carbamic acid tert-butyl ester (39B). To 2-chloro-3-fluoro-6-hydroxy-benzaldehyde (39A, 53 mg, 0.3 mmol) and (2-chloro-ethyl)-carbamic acid tert-butyl ester (135 mg, 0.75 mmol) in Add KI (2.0 mg, 0.012 mmol) and K to the solution in DMF (5 mL)₂ CO₃ (105 mg, 0.75 mmol). The mixture was microwaved at 100°C for 2 hours. Then the mixture was diluted with water (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layer was washed with water (3x20 mL) and brine (20 mL), and washed with Na₂ SO₄ Dry and concentrate to obtain 39B. The crude residue was used directly in the next step. LC-MS: (ESI)m/z 340.3 (M+Na)⁺ . Step 2. {[2-(3-Chloro-4-fluoro-2-methylaminomethyl-phenoxy)-ethyl]-aminocarboxylic acid tertiary butyl ester (39C). To a solution of 39B (95.4 mg, 0.3 mmol) in MeOH (3 ml) was added methylamine hydrochloride (50.7 mg, 0.75 mmol). The mixture was stirred at 60°C for 30 minutes. Then cool the solution to ambient temperature and add NaBH₄ (11.1 mg, 0.3 mmol). The mixture was stirred at ambient temperature for 2 hours. The solution was then diluted with water (50 mL) and extracted with DCM (3×20 mL). Pass the combined organic layer through Na₂ SO₄ Dry and concentrate to obtain 39C. The crude residue was used directly in the next step. LC-MS: (ESI)m/z 333.3 (M+H)⁺ . Step 3. 5-{[6-(2-Third-butoxycarbonylamino-ethoxy)-2-chloro-3-fluoro-benzyl]-methyl-amino}-pyrazolo[1 ,5-a] Ethyl pyrimidine-3-carboxylate (39D). To 20K (67.5 mg, 0.3 mmol) and 39C (99.9 mg, 0.3 mmol) inn Add DIEA (1.0 mL) to the solution in BuOH (2.0 mL). The mixture was heated in the microwave at 150°C for 2 hours. Then the mixture was diluted with water and extracted with DCM (3x20 mL). Organic layer by Na₂ SO₄ Dried, concentrated and purified by silica gel column chromatography to obtain 17 as a yellow liquid. LC-MS: (ESI)m/z 522.5 (M+H)⁺ . Step 4. 5-{[6-(2-Third-butoxycarbonylamino-ethoxy)-2-chloro-3-fluoro-benzyl]-methyl-amino}-pyrazolo[1 ,5-a]pyrimidine-3-carboxylic acid (39E). To a solution of 39D (40 mg, 0.0776 mmol) in MeOH (1mL) was added LiOH (16 mg, 0.38 mmol) and H₂ O (1 mL). The mixture was stirred at 60°C for 4 hours. The solution was cooled to ambient temperature, partially concentrated and acidified by aqueous HCl (1 N) until pH 2-3. The aqueous mixture was extracted with DCM (3x10 mL). Pass the organic layer through Na₂ SO₄ Dry and concentrate to obtain 39E. The crude residue was used directly in the next step. LC-MS: (ESI)m/z 494.3 (M+H)⁺ . Step 5. 5-{[6-(2-Amino-ethoxy)-2-chloro-3-fluoro-benzyl]-methyl-amino}-pyrazolo[1,5-a]pyrimidine -3-carboxylic acid (39F). To a solution of 39E (40 mg, 0.0776 mmol) in DCM (2 mL) was added TFA (0.4 mL). The solution was stirred for 1 hour. The solvent was removed under rotary evaporation. The residue was re-dissolved with DCM and re-concentrated (3X) to obtain 39F as a foamy solid. LC-MS: (ESI)m/z 393.5 (M+H)⁺ . Step 6. Add DIEA (0.20 mL, 1.15 mmol) to a solution of 39F (36 mg, 0.078 mmol) in 10 mL DCM. The solution was frozen with a dry ice/acetone bath and HATU (40.0 mg, 0.11 mmol) was added. The solution was slowly warmed to ambient temperature. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with water (3 × 50 mL) and brine (50 mL), and then washed with Na₂ SO₄ Dry and concentrate. The obtained residue was purified by a silica gel column (0-5% MeOH/DCM) to obtain Example 39 (6.2 mg, 23.4%) as a white solid. LC-MS (ESI)m/z 376.5 (M+H)⁺ .¹ H NMR (500 MHz, chloroform-d ) δ 9.51 (s, 1H), 8.40-8.33 (m, 2H), 7.03 (ddd, J = 8.9, 8.0, 0.7 Hz, 1H), 6.78 (dd, J = 9.3, 4.2 Hz, 1H), 6.40 ( d, J = 7.9 Hz, 1H), 5.97 (dd, J = 15.0, 2.1 Hz, 1H), 4.49-4.43(m, 1H), 4.31 (ddd, J = 10.9, 6.4, 4.5 Hz, 1H), 4.12 -4.03 (m, 1H), 3.91 (d, J = 14.9 Hz, 1H), 3.72-3.63 (m, 1H), 3.56 (s, 3H).Instance 40

Example 40 was prepared as shown in the following scheme:

Step 1. 5-[(5-Fluoro-2-hydroxy-benzyl)-methyl-amino]-2-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40B). Add LiOH (60 mg, 1.4 mmol) and H to a solution of 19A (75 mg, 0.14 mmol) in methanol (2 mL)₂ O (2 mL). The mixture was stirred at 60°C for 4 hours. The solution was cooled to ambient temperature, partially concentrated and acidified by aqueous HCl (1 N) until pH 2-3. The resulting suspension was extracted with EtOAc (3 x 20 mL). Pass the organic layer through Na₂ SO₄ Dry and concentrate to obtain 40A. LC-MS (ESI)m/z 331.6 (M+H)⁺ . Step 2. 5-[(5-Fluoro-2-hydroxy-benzyl)-methyl-amino]-2-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2-hydroxy -Ethyl)-amide (40B). To a solution of 40A (140 mg, 0.42 mmol) and 2-amino-ethanol (244 mg, 4 mmol) in DCM (5 mL) at 0°C, DIEA (0.20 mL, 1.15 mmol) and HATU (380.0 mg, 1.0 mmol). The solution was slowly warmed to ambient temperature. Then the mixture was diluted with water (25 mL) and extracted with EtOAc (3×25 mL). The combined organic layer was washed with HCl (1N, 3 x 20 mL) and brine (50 mL), and then washed with Na₂ SO₄ Dry and concentrate. The obtained residue was purified by elution with 0-5% MeOH/DCM (10 CV) through a silica gel column to obtain 40B (74 mg, 47%) as a white solid. LC-MS (ESI)m/z 374.3 (M+H)⁺ . Step 3. Add PPh to a solution of 40B (74 mg, 0.2 mmol) in THF (3 mL) and DCM (3 mL) at 0°C₃ (131 mg, 0.5 mmol) and di-tert-butyl azodicarboxylate (DTAD) (115 mg, 0.5 mmol). The mixture was warmed to ambient temperature and stirred for another 4 hours. The solvent was removed and the residue was eluted with 0-10%, MeOH/DCM (10 CV) through a silica gel column, followed by preparative TLC purification to obtain Example 40 (15 mg) as a white solid. LC-MS (ESI)m/z 356.5 (M+H)⁺ ；¹ H NMR (500 MHz, chloroform-d ) δ 8.12 (d,J = 7.7 Hz, 1H), 6.93 (ddd,J = 9.0, 3.1, 0.9 Hz, 1H), 6.78 (ddd,J = 9.0, 7.3, 3.0 Hz, 1H), 6.71 (dd,J = 9.1, 4.5 Hz, 1H), 6.28 (d,J = 7.7 Hz, 1H), 5.77 (dd,J = 15.2, 1.7 Hz, 1H), 4.38-4.33 (m, 1H), 3.98 (s, 1H), 3.91 (d,J = 1.4 Hz, 1H), 3.78 (dd,J = 15.1, 0.9 Hz, 1H), 3.45 (s, 3H), 3.43-3.36 (m, 1H), 2.45 (s, 3H).Instance 41

Example 41 was prepared using the method shown in the following scheme:

Step 1: [2-(2-Acetyl-4-fluoro-phenoxy)-ethyl]-aminocarboxylic acid tertiary butyl ester (41B). To 1-(5-fluoro-2-hydroxy- Phenyl)-ethanone (41A, 773 mg, 5.0 mmol) and (2-chloro-ethyl)-carbamic acid tert-butyl ester (1.80 g, 10.0 mmol) in a mixture of DMF (20 mL) Add KI (2.0 mg, 0.012 mmol) and Cs₂ CO₃ (3.26 g, 10.0 mmol). The mixture was stirred at 80°C overnight. The mixture was then cooled to ambient temperature, diluted with EtOAc, and washed with 1 N NaOH (5 x 10 mL) until LCMS showed no 1-(5-fluoro-2-hydroxy-phenyl)-ethanone peak. Pass the organic layer through Na₂ SO₄ Dry and concentrate. The residue was then purified by elution with EtOAc/hexane (0-30%, 10 CV) through a silica gel column to obtain the desired product 41B (1.1 g, 73.8%) as a yellow solid. MS (ESI) m/z: 320.3 (M+Na)⁺ . Step 2. Tertiary butyl (2-(4-fluoro-2-(1-hydroxyethyl)phenoxy)ethyl)aminocarboxylate (41C). To a solution of 41B (1.0 g, 3.36 mmol) in MeOH (10 mL) was added NaBH in batches₄ (640 mg, 16.8 mmol). The mixture was stirred at ambient temperature for 2 hours. Then the solution was diluted with water (50 mL) and extracted with DCM (3×20 mL). The combined DCM layer is passed through Na₂ SO₄ Dry and concentrate. The residue was purified by elution with EtOAc/hexane (0-50%, 10 CV) on a silica gel column to obtain the desired product (0.75 g, 75%) as a pale yellow solid. LC-MS (ESI)m/z 322.3 (M+Na)⁺ ；¹ H NMR (500 MHz, chloroform-d ) δ 7.11 (dd,J = 9.2, 3.4 Hz, 1H), 6.89 (ddd,J = 9.0, 7.9, 3.2 Hz, 1H), 6.77 (dd,J = 8.9, 4.4 Hz, 1H), 5.09 (q,J = 6.6 Hz, 1H), 4.92 (d,J = 4.4 Hz, 1H), 4.03 (t,J = 5.2 Hz, 2H), 3.62-3.50 (m, 2H), 1.49 (d,J = 6.4 Hz, 3H), 1.45 (s, 9H). Step 3. 6-{1-[2-(2-Third-butoxycarbonylamino-ethoxy)-5-fluoro-phenyl]-ethoxy}-imidazo[1,2-b] Ethyl pyridazine-3-carboxylate (41D). To 41C (600 mg, 2.0 mmol) and {2-[4-Fluoro-2-(1-hydroxy-ethyl)-phenoxy]-ethyl}-aminocarboxylic acid tertiary butyl group at -78℃ To a solution of the ester (450 mg, 2.0 mmol) in anhydrous THF (40.0 mL) was added NaH (60%, 80 mg, 2.0 mmol) in batches. The suspension was stirred at -78°C for 4 hours and allowed to warm to 0°C, and stirred for another 4 hours. The mixture was then placed in the refrigerator at -20°C overnight. The mixture was then quenched with a mixture of ice and 1 N HCl and extracted with EtOAc (3 x 20 mL). Organic layer by Na₂ SO₄ Dry, concentrate and purify twice to obtain the desired product (240 mg, 25%) as a yellow solid. LC-MS (ESI)m/z 511.6 (M+Na)⁺ ；¹ H NMR (500 MHz, chloroform-d ) δ 8.16 (s, 1H), 7.90 (d,J = 9.7 Hz, 1H), 7.16 (dd,J = 9.0, 3.2 Hz, 1H), 0.95 (d,J = 9.5 Hz, 1H), 6.90-6.88 (m, 1H), 6.81-6.78 (m, 1H), 6.68 (q,J = 6.2 Hz, 1H), 5.84-5.68 (m, 1H), 4.38 (q,J = 7.2 Hz, 2H), 4.15-4.09 (m, 2H), 3.60-3.52 (m, 2H), 1.65 (d,J = 6.4 Hz, 3H), 1.38 (d,J = 7.2 Hz, 3H), 1.35 (s, 9H). Step 4. Compound 41D was converted to Example 41 using methods similar to those described herein. MS: 343.2 (M+H)⁺ ；¹ H NMR (500 MHz, chloroform-d ) δ 9.82 (d,J = 7.0 Hz, 1H), 8.27 (s, 1H), 8.09 (d,J = 9.5 Hz, 1H), 7.18 (dd,J = 8.9, 3.2 Hz, 1H), 7.01-6.94 (m, 2H), 6.83 (dd,J = 9.0, 4.3 Hz, 1H), 6.60-6.53 (m, 1H), 4.63-4.52 (m, 1H), 4.27-4.16 (m, 1H), 4.16-4.04 (m, 1H), 3.70-3.56 (m , 1H), 1.70 (d,J = 6.4 Hz, 3H)Instance 42

Example 42 was prepared using the method shown in the following scheme:

Step 1. Ethyl 6-[(5-Fluoro-2-hydroxy-benzyl)-methyl-amino]-imidazo[1,2-b]pyridazine-3-carboxylate (42B). To 4-fluoro-2-methylaminomethyl-phenol (20L, 305.2 mg, 1.97 mmol) and 6-chloro-imidazo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (42A, 230 mg, 1.02 mmol) KF (180 mg, 3.01 mmol) was added to the mixture in DMSO (5 mL). The reaction mixture was stirred at 120°C under nitrogen for 18 hours. The solution was then cooled to ambient temperature, diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was further washed with water (3 × 50 mL) and brine (50 mL), and then washed with Na₂ SO₄ Dry and concentrate. The residue was then purified by elution with EtOAc/hexane (0-50%, 10 CV) through a silica gel column to obtain the desired product (240 mg, 69%) as a white solid. LC-MS (ESI)m/z 345.2 (M+H)⁺ ；¹ H NMR (500 MHz, chloroform-d ) δ 8.61 (s, 1H), 8.17 (s, 1H), 7.91 (d,J = 10.0 Hz, 1H), 7.00-6.86 (m, 4H), 4.78 (s, 2H), 4.47 (qd,J = 7.2, 0.5 Hz, 2H), 3.17 (s, 3H), 1.41 (td,J = 7.1, 0.5 Hz, 3H). Step 2. 6-{[2-(2-tert-butoxycarbonylamino-ethoxy)-5-fluoro-benzyl]-methyl-amino}-imidazo[1,2-b] Ethyl pyridazine-3-carboxylate (42C). To 6-[(5-fluoro-2-hydroxy-benzyl)-methyl-amino]-imidazo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (2B, 200 mg, 0.58 mmol) And (2-chloro-ethyl)-carbamic acid tert-butyl ester (209 mg, 1.16 mmol) in DMF (5 mL) total add K₂ CO₃ (200 mg, 1.45 mmol) and KI (2.0 mg, 0.012 mmol). The mixture was heated at 90°C for 4 hours under nitrogen. Then the mixture was diluted with water (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layer was then washed with water (3 x 5 mL) and brine (2 x 5 mL). Pass the organic layer through Na₂ SO₄ Dry and concentrate. The obtained residue was purified by elution with EtOAc/hexane (0-100%, 10 CV) through a silica gel column to obtain 42C (203 mg, 76%) as a white solid. LC-MS (ESI)m/z 510.1 (M+Na)⁺ ；¹ H NMR (500 MHz, chloroform-d ) δ (ppm) 8.16 (s, 1H), 7.85 (d,J = 9.9 Hz, 1H), 7.00 (dd,J = 8.9, 3.2 Hz, 1H), 6.95-6.87 (m, 2H), 6.80 (dd,J = 8.9, 4.3 Hz, 1H), 4.95 (s, 1H), 4.74 (s, 2H), 4.41 (q,J = 7.2 Hz, 2H), 4.04 (t,J = 5.2 Hz, 2H), 3.56-3.50 (m, 2H), 3.26 (s, 3H), 1.43 (s, 9H), 1.40 (t,J = 7.2 Hz, 3H). Step 3. Compound 42C was converted to Example 42 using methods similar to those described herein. MS: 342.5 (M+H)⁺ ；¹ H NMR (500 MHz, chloroform-d ) δ 10.01 (d,J = 6.9 Hz, 1H), 8.17 (s, 1H), 8.04 (d,J = 10.0 Hz, 1H), 7.07-7.04 (m, 1H), 7.00 (d,J = 10.0 Hz, 1H), 6.96-6.92 (m, 1H), 6.84 (dd,J = 9.1, 4.5 Hz, 1H), 5.69 (dd,J = 15.8, 1.6 Hz, 1H), 4.55 (dt,J = 9.9, 3.7 Hz, 1H), 4.20-4.09 (m, 2H), 3.98 (dd,J = 15.9, 1.0 Hz, 1H), 3.66-3.62 (m, 1H), 3.61 (s, 3H).Instance 51-1

Step 1A8 (399.4 mg, 1.16 mmol) and tert-butyl (2-chloroethyl) carbamate (260.5 mg, 1.45 mmol) in DMF (5.8 mL), add K₂ CO₃ (801.6 mg, 5.80 mmol) and heated at 80°C for 6 hours while stirring. The reaction was cooled to ambient temperature and diluted with DCM (3 mL), filtered by means of a syringe filter, and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 0-70% ethyl acetate in hexane) provided 51-1A (407.4 mg, 0.836 mmol, 72% yield). Step 2. Add LiOH aqueous solution (2M, 4.0 mL) to a solution of 51-1A (407.4 mg, 0.836 mmol) in MeOH (6 mL) and THF (4 mL) at ambient temperature. The reaction solution was heated at 70°C for 2 hours. The reaction flask was cooled to ambient temperature, diluted with water and methanol, and then quenched with aqueous HCl (2 M, 4 mL) to pH <5. The mixture was extracted with DCM (3 x 5 mL), and Na₂ SO₄ Dry, concentrate under reduced pressure, and dry under high vacuum overnight. To a solution of the acid product in DCM (6 mL) was added 4 M HCl in 1,4-dioxane (2.97 mL). The mixture was stirred at room temperature for 3 hours, and then concentrated under reduced pressure and dried under high vacuum. To a solution of de-Boc product and FDPP (352.9 mg, 0.918 mmol) in DMF (21 mL) was added Hunig base (539.5 mg, 0.327 mmol) at room temperature. The mixture was stirred for 2.5 hours, and then 2 M Na₂ CO₃ The solution (21 mL) quenched the reaction. The mixture was stirred for 15 minutes and then extracted with DCM (4×10 mL). The combined extract is Na₂ SO₄ Dry and concentrate under reduced pressure. The residue was purified by flash chromatography (ISCO system, silica (12 g), 0-11.25% methanol in dichloromethane) to provide 51-1 (164.0 mg, 0.480 mmol, 57.55% yield, three steps ).Instance 53

Example 53 was prepared using the method shown in the following scheme:

Step 1. 5-[1-(5-Fluoro-2-hydroxy-phenyl)-ethylamino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (53A). To 5-[(5-fluoro-2-hydroxy-benzyl)-methyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (20M, 300 mg, 0.87 mmol) LiOH (420 mg, 10 mmol) was added to the solution in MeOH (5 mL), followed by 5 mL of H₂ O. The mixture was stirred at 60°C for 4 hours. The solution was cooled to ambient temperature, partially concentrated and acidified with 1 N HCl until pH 2-3. The resulting suspension was extracted with EtOAc (3 x 20 mL). Via Na₂ SO₄ The combined organic layer was dried and concentrated. The residue was used directly in the next step. LCMS (ESI⁺ )m/z 317.4 (M+H)⁺ . Step 2. 3-({5-[(5-Fluoro-2-hydroxy-benzyl)-methyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carbonyl}-amino) Methyl-2-hydroxy-propionate (53B). Add DIPEA ( 1.0 mL, 5.7 mmol), followed by HATU (140.0 mg, 0.5 mmol). The solution was slowly warmed to ambient temperature. The mixture was diluted with water (25 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layer was washed with 1 N HCl (3 x 20 mL) and brine (50 mL), and washed with Na₂ SO₄ dry. The solvent was removed and the resulting white solid was used directly in the next step. LC-MS (ESI⁺ )m/z 418.4 (M+H)⁺ . Step 3. 11-fluoro-14-methyl-4- pendant oxy-4,5,6,7,13,14-hexahydro-1,15-vinylpyrazolo[4,3-f] [1,4,8,10] Methyl benzoxatriazatriazepine-7-carboxylate (53C). Add PPh to a solution of 53B (83 mg, 0.2 mmol) in DCM (5 mL)₃ (263 mg, 1.0 mmol), followed by CBr₄ (332 mg, 1.0 mmol). The mixture was stirred overnight at ambient temperature. Remove the solvent and redissolve the residue in DMF (5 mL), then add K₂ CO₃ (116.8 mg, 0.84 mmol). The mixture was then stirred at 80°C until the desired product was completely formed. The mixture was diluted with EtOAc and washed with water. Pass the organic layer through Na₂ SO₄ Dry and concentrate. The residue was purified by silica gel column (0-10%, MeOH/DCM) to obtain 53C (40 mg) as a white solid. LC-MS (ESI⁺ )m/z 400.2 (M+H)⁺ . Step 4. Add NH to 53C (20 mg, 0.05 mmol)₃ 的MeOH solution (7 N, 2 mL). The mixture was stirred at 60°C overnight. The solvent was removed and the residue was purified by silica gel column (0-10%, MeOH/DCM) to obtain Example 53 (8 mg) as an off-white solid. LC-MS (ESI⁺ )m/z 385.5 (M+H)⁺ ；¹ H NMR (300 MHz, chloroform-d ) δ 8.41 (s, 1H), 8.34 (d,J = 7.9 Hz, 1H), 8.17 (s, 1H), 6.99-6.92 (m, 2H), 6.77 (dd,J = 6.2, 3.5 Hz, 1H), 6.38 (d,J = 7.9 Hz, 1H), 5.63-5.44 (m, 2H), 5.09 (dd,J = 11.0, 8.4 Hz, 1H), 4.38 (dd,J = 14.7, 11.0 Hz, 1H), 4.28-4.17 (m, 1H), 4.17-4.07 (m, 2H), 3.22 (s, 3H).Instance 54

Example 54 was prepared using the method shown in the following scheme:

To a solution of compound 53C (20 mg, 0.05 mmol) in MeOH (2 mL) was added NaBH portion by portion₄ (19 mg, 0.5 mmol). The mixture was stirred for 4 hours. The solvent was removed and the residue was purified by silica gel column (0-10%, MeOH/DCM) to obtain the desired product (8 mg) as a white solid. LC-MS (ESI⁺ )m/z 372.5 (M+H)⁺ ；¹ H NMR (300 MHz, chloroform-d ) δ 8.39 (s, 1H), 8.32 (d,J = 7.9 Hz, 1H), 7.01-6.85 (m, 3H), 6.35 (d,J = 8.0 Hz, 1H), 5.55-5.43 (m, 1H), 4.92-4.82 (m, 1H), 4.09-3.98 (m, 2H), 3.80-3.70 (m, 3H), 3.23 (s, 3H).Instance 93

Step 1. To (R )-(2-Hydroxypropyl)carbamic acid tert-butyl ester (1.00 g, 5.71 mmol) and p-toluenesulfonyl chloride (1.14 g, 6.00 mmol) in DCM (29 mL) add triethyl Amine (1.44 g, 14.28 mmol) and the mixture was stirred at room temperature for 48 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by flash chromatography (ISCO system, silica (40 g), 0-20% ethyl acetate in hexane) to provide (R )-4-methylbenzenesulfonic acid 1-((tert-butoxycarbonyl)amino)propan-2-yl ester (1.12 g, 3.40 mmol, 59.54% yield). Step 2. To A8 (100.00 mg, 0.290 mmol) and (R )-4-methylbenzenesulfonic acid 1-((tert-butoxycarbonyl)amino)propan-2-yl ester (143.50 mg, 0.436 mmol) in DMF (1.45 mL), add K₂ CO₃ (200.7 mg, 1.45 mmol) and heated at 80°C for 16 hours while stirring. The reaction was cooled to ambient temperature and diluted with DCM (3 mL), filtered by means of a syringe filter, and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 0-60% ethyl acetate in hexane) provided 93A (32.90 mg, 0.0656 mmol, 22.59% yield). Step 3. Add LiOH aqueous solution (2M, 2 mL) to a solution of 93A (32.90 mg, 0.0656 mmol) in MeOH (3 mL) and THF (2 mL) at ambient temperature. The reaction solution was heated at 70°C for 2 hours. The reaction flask was cooled to ambient temperature, diluted with water and methanol, and then quenched with aqueous HCl (2 M, 2 mL) to pH <5. The mixture was extracted with DCM (3 x 5 mL), and Na₂ SO₄ Dry, concentrate under reduced pressure, and dry under high vacuum overnight. To a solution of the acid product in DCM (4 mL) was added 4 M HCl in 1,4-dioxane (2.0 mL). The mixture was stirred at room temperature for 3 hours, and then concentrated under reduced pressure and dried under high vacuum. To a solution of de-Boc product and FDPP (27.62 mg, 0.0719 mmol) in DMF (1.6 mL) was added Hunig base (42.23 mg, 0.327 mmol) at room temperature. The mixture was stirred for 2.5 hours, and then 2 M Na₂ CO₃ The solution (2 mL) quenched the reaction. The mixture was stirred for 15 minutes and then extracted with DCM (4×10 mL). The combined extract is Na₂ SO₄ Dry and concentrate under reduced pressure. The residue was purified by flash chromatography (ISCO system, silica (12 g), 0-10% methanol in dichloromethane) to provide 93 (10.1 mg, 0.0284 mmol, 43.49% yield, three steps).Instance 104 , 106 and 107

Step 1. To A17^. Add K to a solution of HCl (38 mg, 0.096 mmol) and tert-butyl (2-chloroethyl) carbamate (12.9 mg, 0.072 mmol) in DMF (0.5 mL)₂ CO₃ (33.1 mg, 0.24 mmol) and stirred at 80°C for 1.5 hours while stirring. The reaction was cooled to ambient temperature and diluted with DCM (3 mL), filtered by means of a syringe filter, and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 0-60% ethyl acetate in hexane) provided 104A (20.8 mg, 0.0413 mmol, 86.3% yield). Step 2. 104 was prepared according to general method C from 104A as a white solid. Step 3. To a solution of 104 (4.6 mg, 0.0129 mmol) in DCM (0.3 mL) was added methyl 3-chloroperoxybenzoate (2.2 mg, 0.0129 mmol) and the reaction was stirred for 20 minutes, then saturated NaHCO was added₃ Aqueous solution (3 mL) and extracted with DCM (4 x 4 mL). The combined extract is Na₂ SO₄ Dry and concentrate under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 0-12.5% methanol in dichloromethane) provided 106 (0.5 mg, 10.4% yield) and 107 (1.7 mg, 33.9% yield). The following examples were prepared using methods similar to their general methods A, B, and C specifically described herein, as described herein. Instance analyze data 11-1 MS: 377.7 (M+H) ⁺ ; ¹ H NMR (500 MHz, chloroform- d ) δ 8.49 (d, J = 7.9 Hz, 1H), 8.29 (s, 1H), 7.13 (dd, J = 9.2, 7.8 Hz, 1H), 7.02 (d, J = 7.3 Hz, 1H), 6.92 (dd, J = 9.4, 3.9 Hz, 1H), 6.82 (d, J = 7.7 Hz, 1H), 4.63-4.55 (m, 1H ), 4.45 (dd, J = 10.8, 5.4 Hz, 1H), 4.31-4.23 (m, 1H), 4.00 (dd, J = 16.2, 8.7 Hz, 1H), 1.70 (d, J = 6.9 Hz, 3H) . 20 MS: 342.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) 9.43 (dd, J = 6.9, 2.7 Hz, 1 H), 8.76 (d, J = 7.9 Hz, 1 H), 8.10 (s, 1 H), 7.19-7.25 (m, 1 H), 7.03-7.07 (m, 2 H), 6.72 (d, J = 7.9 Hz, 1 H), 5.64 (dd, J = 14.9, 1.5 Hz, 1 H), 4.48 (dt, J = 10.2, 4.3 Hz, 1 H), 4.04-4.10 (m, 2 H), 3.81-3.87 (m, 1 H), 3.58 (s, 3 H), 3.38 -3.46 (m, 1 H). 39 LC-MS (ESI) m/z 376.5 (M+H) ⁺ . ¹ H NMR (500 MHz, chloroform- d ) δ 9.51 (s, 1H), 8.40-8.33 (m, 2H), 7.03 (ddd, J = 8.9, 8.0, 0.7 Hz, 1H), 6.78 (dd, J = 9.3, 4.2 Hz, 1H), 6.40 (d, J = 7.9 Hz, 1H), 5.97 (dd, J = 15.0, 2.1 Hz, 1H) , 4.49-4.43(m, 1H), 4.31 (ddd, J = 10.9, 6.4, 4.5 Hz, 1H), 4.12-4.03 (m, 1H), 3.91 (d, J = 14.9 Hz, 1H), 3.72-3.63 (m, 1H), 3.56 (s, 3H). 40 MS: 356.5 (M+H) ⁺ ; ¹ H NMR (500 MHz, chloroform- d ) δ 8.12 (d, J = 7.7 Hz, 1H), 6.93 (ddd, J = 9.0, 3.1, 0.9 Hz, 1H), 6.78 (ddd, J = 9.0, 7.3, 3.0 Hz, 1H), 6.71 (dd, J = 9.1, 4.5 Hz, 1H), 6.28 (d, J = 7.7 Hz, 1H), 5.77 (dd, J = 15.2, 1.7 Hz, 1H), 4.38-4.33 (m, 1H), 3.98 (s, 1H), 3.91 (d, J = 1.4 Hz, 1H), 3.78 (dd, J = 15.1, 0.9 Hz, 1H), 3.45 ( s, 3H), 3.43-3.36 (m, 1H), 2.45 (s, 3H). 41 MS: 343.2 (M+H) ⁺ ; ¹ H NMR (500 MHz, chloroform- d ) δ 9.82 (d, J = 7.0 Hz, 1H), 8.27 (s, 1H), 8.09 (d, J = 9.5 Hz, 1H), 7.18 (dd, J = 8.9, 3.2 Hz, 1H), 7.01-6.94 (m, 2H), 6.83 (dd, J = 9.0, 4.3 Hz, 1H), 6.60-6.53 (m, 1H), 4.63 -4.52 (m, 1H), 4.27-4.16 (m, 1H), 4.16-4.04 (m, 1H), 3.70-3.56 (m, 1H), 1.70 (d, J = 6.4 Hz, 3H). 42 MS: 342.5 (M+H) ⁺ ; ¹ H NMR (500 MHz, chloroform- d ) δ 10.01 (d, J = 6.9 Hz, 1H), 8.17 (s, 1H), 8.04 (d, J = 10.0 Hz, 1H), 7.07-7.04 (m, 1H), 7.00 (d, J = 10.0 Hz, 1H), 6.96-6.92 (m, 1H), 6.84 (dd, J = 9.1, 4.5 Hz, 1H), 5.69 (dd , J = 15.8, 1.6 Hz, 1H), 4.55 (dt, J = 9.9, 3.7 Hz, 1H), 4.20-4.09 (m, 2H), 3.98 (dd, J = 15.9, 1.0 Hz, 1H), 3.66- 3.62 (m, 1H), 3.61 (s, 3H). 43 MS: 356.6 (M+H) ⁺ ; ¹ H NMR (500 MHz, chloroform- d ) δ 8.27 (d, J = 7.9 Hz, 1H), 8.17 (s, 1H), 6.96 (ddd, J = 9.0, 3.1 , 0.9 Hz, 1H), 6.88-6.81 (m, 1H), 6.77 (dd, J = 9.0, 4.7 Hz, 1H), 6.41 (d, J = 7.9 Hz, 1H), 5.71-5.63 (m, 1H) , 4.43 (dt, J = 10.0, 4.4 Hz, 1H), 4.09 (ddd, J = 10.3, 8.4, 4.0 Hz, 1H), 3.96-3.92 (m, 1H), 3.87 (dd, J = 15.0, 0.8 Hz , 1H), 3.77 (dd, J = 15.0, 7.2 Hz, 1H), 3.55-3.51 (m, 2H), 1.33 (t, J = 7.2 Hz, 3H). 44 MS: 370.1 (M+H) ⁺ ; ¹ H NMR (500 MHz, DMSO- d ₆ ) 9.28 (dd, J = 5.8, 4.0 Hz, 1H), 8.71 (d, J = 7.9 Hz, 1 H), 8.08 (s, 1 H), 7.16 (dd, J = 9.5, 3.0 Hz, 1 H), 6.98-7.09 (m, 2 H), 6.82 (d, J = 8.0 Hz, 1 H), 5.48 (d, J = 15.0 Hz, 1 H), 4.42-4.51 (m, 1 H), 4.16-4.23 (m, 1 H), 4.04-4.14 (m, 2 H), 3.74-3.82 (m, 2 H), 3.39- 3.46 (m, 1 H), 1.58-1.81 (m, 2 H), 0.97 (t, J = 7.3 Hz, 3 H). 45 MS: 370.1 (M+H) ⁺ ; ¹ H NMR (500 MHz, DMSO- d ₆ ) 8.87-8.98 (m, 1 H), 8.69-8.79 (m, 1 H), 8.04-8.12 (m, 1 H ), 7.10-7.18 (m, 1 H), 6.92-7.04 (m, 3 H), 5.09-5.18 (m, 1 H), 4.61-4.69 (m, 1 H), 4.50-4.56 (m, 1 H) ), 4.41-4.49 (m, 1 H), 4.16 (d, J = 15.30 Hz, 1 H), 3.57-3.68 (m, 2 H), 1.23-1.27 (m, 6 H). 46 MS: 368.1 (M+H) ⁺ ; ¹ H NMR (500 MHz, DMSO- d ₆ ) 9.35 (dd, J = 7.0, 2.7 Hz, 1 H), 8.81 (d, J = 7.8 Hz, 1 H), 8.07-8.15 (m, 1 H), 7.19 (dd, J =9.2, 2.3 Hz, 1 H), 7.01-7.08 (m, 2 H), 6.98 (d, J = 7.8 Hz, 1 H), 5.53 ( dd, J = 15.1, 1.5 Hz, 1 H), 4.47 (dt, J = 10.22, 4.25 Hz, 1 H), 4.34 (t, J = 5.08 Hz, 1 H), 4.14 (d, J = 15.30 Hz, 1 H), 4.02-4.10 (m, 2 H), 3.79-3.92 (m, 1 H), 1.12-1.16 (m, 1 H), 1.03-1.08 (m, 2 H), 0.81-0.86 (m, 1 H). 47 MS: 372.1 (M+H) ⁺ ; ¹ H NMR (500 MHz, DMSO- d ₆ ) 9.25 (t, J = 4.9 Hz, 1 H), 8.71 (d, J = 7.9 Hz, 1 H), 8.07 ( s, 1 H), 7.22 (dd, J = 9.5, 3.0 Hz, 1 H), 7.05-7.11 (m, 1 H), 6.96-7.04 (m, 1 H), 6.83 (d, J = 8.0 Hz, 1 H), 5.51 (d, J = 14.6 Hz, 1 H), 4.96 (t, J = 5.4 Hz, 1 H), 4.42-4.51 (m, 1 H), 4.24 (ddd, J = 10.9, 6.8, 4.2 Hz, 1 H), 4.09-4.20 (m, 2 H), 3.91 (dt, J = 15.2, 5.5 Hz, 1 H), 3.67-3.82 (m, 3 H), 3.39-3.51 (m, 1 H ). 48 MS: 356.1 (M+H) ⁺ ; ¹ H NMR (500 MHz, DMSO- d ₆ ) 9.70 (d, J = 8.6 Hz, 1 H), 8.76 (d, J = 8.0 Hz, 1 H), 8.09 ( s, 1 H), 7.25 (dd, J = 9.5, 3.0 Hz, 1 H), 7.01-7.11 (m, 1 H), 6.94-7.00 (m, 1 H), 6.71 (d, J = 8.0 Hz, 1 H), 5.64-5.73 (m, 1 H), 4.34 (d, J = 9.6 Hz, 1 H), 4.28 (t, J = 8.9 Hz, 1 H), 4.10 (d, J = 15.0 Hz, 1 H), 3.94 (dd, J = 9.6, 3.6 Hz, 1 H), 3.58 (s, 3 H), 1.36 (d, J = 6.8 Hz, 3 H). 49 MS: 324.1 (M+H) ⁺ ; ¹ H NMR (500 MHz, DMSO- d ₆ ) 9.52 (d, J = 4.5 Hz, 1 H), 8.74 (d, J = 7.9 Hz, 1 H), 8.09 ( s, 1 H), 7.44 (d, J = 7.6 Hz, 1 H), 7.18-7.25 (m, 1 H), 7.02 (d, J = 7.9 Hz, 1 H), 6.93 (t, J = 7.4 Hz , 1 H), 6.71 (d, J = 7.9 Hz, 1 H), 5.69 (d, J = 14.8 Hz, 1 H), 4.47 (dt, J = 10.1, 4.1 Hz, 1 H), 4.01-4.13 ( m, 2 H), 3.83-3.90 (m, 1 H), 3.54-3.61 (m, 3 H), 3.38-3.46 (m, 1 H). 50 MS: 328.1 (M+H) ⁺ ; ¹ H NMR (500 MHz, DMSO- d ₆ ) 9.80 (d, J = 7.82 Hz, 1 H), 8.89 (t, J = 6.00 Hz, 1 H), 8.58 ( d, J = 7.62 Hz, 1 H), 8.03-8.08 (m, 1 H), 7.12-7.18 (m, 1 H), 6.99-7.05 (m, 2 H), 6.39 (d, J = 7.62 Hz, 1 H), 5.13-5.21 (m, 1 H), 4.46-4.53 (m, 1 H), 3.87-4.00 (m, 4 H). 51 MS: 342.3 (M+H) ⁺ ; ¹ H NMR (500 MHz, chloroform- d _{with CD 3} OD) δ 8.14 (s, 1H), 7.81-7.72 (m, 1H), 7.10 (dd, J = 9.0 , 3.0 Hz, 1H), 6.88 (ddd, J = 9.0, 7.6, 3.0 Hz, 1H), 6.80 (dd, J = 9.2, 4.4 Hz, 1H), 6.20 (d, J = 7.4 Hz, 1H), 5.75 (td, J = 7.2, 1.9 Hz, 1H), 4.52-4.46 (m, 1H), 4.09 (tdd, J = 9.6, 6.4, 3.9 Hz, 2H), 3.60-3.52 (m, 1H), 1.52 (d , J = 7.0 Hz, 3H). 51-1 MS: 342.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.71 (br d, J =5.21 Hz, 1 H), 8.77 (br d, J =6.86 Hz, 1 H ), 8.57 (d, J =7.41 Hz, 1 H), 8.04 (s, 1 H), 7.11-7.22 (m, 1 H), 6.96-7.04 (m, 2 H), 6.36 (d, J =7.68 Hz, 1 H), 5.63 (br dd, J =6.86, 5.49 Hz, 1 H), 4.50 (dt, J =10.15, 3.98 Hz, 1 H), 4.01 (td, J =9.61, 3.84 Hz, 1H) , 3.87 (dt, J =10.09, 3.74 Hz, 1 H), 3.35-3.46 (m, 1 H), 1.45 (d, J =7.14 Hz, 3 H). 52 MS: 376.5 (M+H) ⁺ ; ¹ HNMR (500 MHz, chloroform- d ) δ 9.92 (s, 1H), 8.29-8.18 (m, 2H), 7.01 (dd, J = 9.2, 8.2 Hz, 1H) , 6.77 (dd, J = 9.2, 4.2 Hz, 1H), 6.37-6.26 (m, 1H), 6.19 (d, J = 7.6 Hz, 1H), 6.12 (s, 1H), 4.53-4.45 (m, 1H) ), 4.14 (d, J = 6.3 Hz, 1H), 4.04-3.98 (m, 1H), 3.57 (s, 1H), 1.74 (d, J = 7.3 Hz, 3H). 55 MS: 385.6 (M+H) ⁺ ; ¹ H NMR (300 MHz, methanol- d ₄ ) 8.35 (d, J = 7.6 Hz, 1 H), 8.24 (s, 1 H), 7.24-6.96 (m, 1 H), 6.82 (m, 2 H), 6.41 (dd, J = 7.7, 4.8 Hz, 1 H), 5.59 (m, 1 H), 5.31—5.05 (m, 1 H), 4.39-4.21 (m, 1 H), 3.17-3.02 (m, 1 H), 1.58 (d, J = 6.9 Hz, 3H). 56 MS: 372.3 (M+H) ⁺ ; ¹ H NMR (300 MHz, methanol- d ₄ ) δ 8.35 (d, J = 7.6 Hz, 1 H), 8.18 (s, 1 H), 7.05 (d, J = 9.4 Hz, 1 H), 6.82 (dd, J = 6.5, 1.8 Hz, 1 H), 6.39 (d, J = 7.6 Hz, 1 H), 5.60 (m, 1 H), 4.92 (m, 2H), 4.08 (dd, J = 13.1, 9.9 Hz, 1 H), 3.91-3.81 (m, 2 H), 3.73 (dd, J = 12.6, 5.1 Hz, 1 H), 1.58 (d, J = 6.9 Hz, 3H ). 57 MS: 371.4 (M+H) ⁺ . ¹ H NMR (300 MHz, methanol- d ₄ ) δ 8.46 (d, J = 7.6 Hz, 1H), 8.41 (s, 1H), 7.00 (dd, J = 9.1, 2.9 Hz, 1H), 6.88-6.78 (m, 2H), 6.58 (d, J = 7.7 Hz, 1H), 5.20 (s, 1H), 4.65 (s, 2H), 3.49 (q, J = 7.3 Hz, 2H). 58 MS: 358.5 (M+H) ⁺ .) ⁺ . ¹ H NMR (300 MHz, chloroform- d ) δ 8.37 (s, 1H), 8.21 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 7.5 Hz, 3H), 6.10 (d, J = 7.6 Hz, 1H), 5.88 (s, 1H), 5.11-4.85 (m, 3H), 4.20 (dd, J = 15.1, 5.7 Hz, 1H), 4.05 ( dd, J = 14.0, 9.9 Hz, 1H), 3.83-3.68 (m, 3H), 3.44 (d, J = 7.3 Hz, 1H). 59 MS: 386.1 (M+H) ⁺ ; ¹ H NMR (500 MHz, DMSO- d ₆ ) 9.97 (s, 1 H), 8.57 (d, J = 7.6 Hz, 1 H), 8.40 (d, J = 5.9 Hz, 1 H), 8.10 (s, 1 H), 6.85 (dd, J = 8.9, 4.8 Hz, 1 H), 6.60 (d, J = 7.6 Hz, 1 H), 7.23 (dd, J = 9.3, 3.2 Hz, 1 H), 7.00 (td, J = 8.6, 3.2 Hz, 1 H), 5.90 (d, J = 6.4 Hz, 1 H), 4.27-4.34 (m, 2 H), 3.90 (t, J = 9.33 Hz, 2 H), 3.66 (s, 3 H). 60 MS: 371.1 (M+H) ⁺ ; ¹ H NMR (500 MHz, DMSO- d ₆ ) 9.98 (bs, 1H), 8.54 (d, J = 7.6 Hz, 1 H), 8.33 (d, J = 6.24 Hz , 1 H), 8.07 (s, 1 H), 7.44 (bs, 1 H), 7.28 (bs, 1 H), 7.18 (dd, J = 9.6, 3.2 Hz, 1 H), 6.94 (td, J = 8.5, 3.2 Hz, 1 H), 6.83 (dd, J = 8.9, 4.9 Hz, 1 H), 6.66 (d, J = 7.5 Hz, 1 H), 5.86 (d, J = 6.4 Hz, 1 H), 4.22-4.36 (m, 2 H), 3.84-3.97 (m, 2 H). 61 MS: 343.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.22 (dd, J =6.87, 2.86 Hz, 1 H), 8.78 (d, J =7.45 Hz, 1 H ), 8.10 (s, 1 H), 8.06 (d, J =3.44 Hz, 1 H), 7.80 (dd, J =8.59, 2.86 Hz, 1 H), 6.74 (d, J =8.02 Hz, 1 H) , 5.44 (dd, J =14.89, 1.72 Hz, 1 H), 4.69 (ddd, J =10.88, 8.59, 4.58 Hz, 1 H), 4.32-4.39 (m, 1 H), 4.21 (d, J =15.47 Hz, 1 H), 3.80-3.88 (m, 1 H), 3.58 (s, 3 H), 3.41-3.49 (m, 1 H). 62 MS: 371.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.72-8.80 (m, 2 H), 8.08 (s, 1 H), 8.01 (d, J =2.74 Hz , 1 H), 7.49 (dd, J =8.78, 2.74 Hz, 1 H), 7.00 (d, J =8.23 Hz, 1 H), 4.94-5.06 (m, 2 H), 4.57-4.68 (m, 1 H), 4.26-4.39 (m, 2 H), 3.66-3.77 (m, 1 H), 3.49-3.55 (m, 1 H), 1.56 (d, J = 6.59 Hz, 3 H), 1.22 (d, J = 6.60 Hz, 3 H). 66 MS: 368.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.56 (dd, J =6.87, 2.86 Hz, 1 H), 9.02 (d, J =6.87 Hz, 1 H ), 8.58 (d, J =8.02 Hz, 1 H), 8.03 (s, 1 H), 7.18 (dd, J =9.74, 2.86 Hz, 1 H), 6.97-7.08 (m, 2 H), 6.41 ( d, J =7.45 Hz, 1 H), 4.68-4.80 (m, 1 H), 4.48 (dt, J =10.60, 4.15 Hz, 1 H), 4.05 (ddd, J =10.45, 8.45, 4.01 Hz, 1 H), 3.75-3.84 (m, 1 H), 3.36-3.43 (m, 1 H), 1.26-1.38 (m, 1 H). 0.63 (tt, J =8.74, 4.44 Hz, 1 H), 0.37-0.49 (m, 2 H), 0.28 (dq, J =9.31, 4.53 Hz, 1 H). 67 MS: 370.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.75 (br d, J =6.30 Hz, 1 H), 8.78 (d, J =7.45 Hz, 1 H) , 8.57 (d, J =8.02 Hz, 1 H) 8.04 (s, 1 H), 7.06 (dt, J =9.16, 1.43 Hz, 1 H), 6.98-7.02 (m, 2 H), 6.39 (d, J =7.45 Hz, 1 H), 5.13 (ddd, J =10.02, 7.73, 1.72 Hz, 1 H), 4.51 (dt, J =9.88, 3.65 Hz, 1 H) 3.94 (td, J =9.88, 3.72 Hz , 1 H), 3.82-3.90 (m, 1 H), 3.39-3.43 (m, 1 H), 1.96-2.09 (m, 1 H), 1.12 (d, J =6.30 Hz, 3 H), 0.68 ( d, J =6.30 Hz, 3 H). 75 MS: 356.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.73 (d, J =8.02 Hz, 1 H), 8.25 (t, J = 4.30 Hz, 1 H), 8.10 (s, 1 H), 7.14-7.21 (m, 1 H), 7.00-7.04 (m, 2 H), 6.68 (d, J =8.02 Hz, 1 H), 5.75 (br d, J =14.32 Hz , 1 H), 4.33-4.43 (m, 1 H), 4.22 (br d, J =6.87 Hz, 1 H), 4.05 (br d, J =14.89 Hz, 1 H), 3.59-3.68 (m, 1 H), 3.59-3.68 (m, 1 H), 3.37-3.45 (m, 1 H), 1.98-2.17 (m, 2 H). 76-1 MS: 356.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.68 (d, J =7.45 Hz, 1 H), 8.53 (d, J =7.45 Hz, 1 H), 8.40 (s, 1 H), 8.03 (s, 1 H), 7.11-7.18 (m, 1 H), 6.96-7.00 (m, 2 H), 6.32 (d, J =7.45 Hz, 1 H), 5.65 -5.74 (m, 1 H), 4.29-4.36 (m, 1 H), 4.20-4.26 (m, 1 H), 3.54-3.62 (m, 1 H), 3.39-3.47 (m, 1 H), 1.98 -2.17 (m, 2 H), 1.41 (d, J =7.45 Hz, 3 H). 84 MS: 358.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.78 (d, J =6.79 Hz, 1 H), 8.58 (d, J =7.62 Hz, 1 H), 8.05 (s, 1 H), 7.36 (d, J =2.61 Hz, 1 H), 7.21 (dd, J =8.85, 2.68 Hz, 1 H), 7.03 (d, J =8.85 Hz, 1 H), 6.36 (d, J =7.68 Hz, 1 H), 5.62 (quin, J =6.90 Hz, 1 H), 4.52 (dt, J =10.15, 3.98 Hz, 1 H), 3.98-4.11 (m, 1 H), 3.80-3.92 (m, 1 H), 3.35-3.47 (m, 1 H), 1.45 (d, J =7.07 Hz, 3 H). 85 MS: 356.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.73 (br d, J =5.49 Hz, 1 H), 8.74 (d, J =7.14 Hz, 1 H) , 8.57 (d, J =7.68 Hz, 1 H), 8.04 (s, 1 H), 7.06-7.14 (m, 1 H), 6.97-7.03 (m, 2 H), 6.37 (d, J =7.68 Hz , 1 H), 5.33-5.45 (m, 1 H), 4.51 (dt, J =10.15, 3.43 Hz, 1 H), 3.98 (td, J =9.88, 3.84 Hz, 1 H), 3.82-3.93 (m , 1 H), 3.39 (td, J =9.61, 2.74 Hz, 1 H), 1.85-1.99 (m, 1 H), 1.62-1.76 (m, 1 H), 0.87 (t, J =7.14 Hz, 3 H). 86 MS: 382.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.74 (dd, J =7.16, 2.00 Hz, 1 H), 8.64 (d, J =6.87 Hz, 1 H ), 8.57 (d, J =7.45 Hz, 1 H) 8.05 (s, 1 H), 6.95-7.06 (m, 3 H), 6.38 (d, J =8.02 Hz, 1 H), 5.47 (ddd, J =10.60, 7.16, 1.15 Hz, 1 H), 4.54 (dt, J =10.17, 3.79 Hz, 1 H), 4.01 (td, J =9.59, 3.72 Hz, 1 H), 3.80-3.90 (m, 1 H ), 3.39-3.48 (m, 1 H), 2.66-2.77 (m, 1 H), 2.12-2.23 (m, 1 H), 1.83 (br d, J = 2.29 Hz, 3 H), 1.55-1.73 ( m, 2 H). 87 MS: 346.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.40 (s, 1 H), 8.77 (d, J =8.23 Hz, 1 H), 8.10 (s, 1 H), 7.19-7.26 (m, 1 H), 7.01-7.08 (m, 2 H), 6.72 (d, J =8.23 Hz, 1 H), 5.64 (dd, J =15.09, 1.37 Hz, 1 H) , 4.08 (d, J =14.82 Hz, 1 H), 3.58 (s, 3 H). 88 MS: 404.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.70 (dd, J =6.87, 2.86 Hz, 1 H), 9.26 (d, J =7.45 Hz, 1 H ), 8.66 (d, J =7.45 Hz, 1 H), 8.09 (s, 1 H), 7.35-7.45 (m, 4 H), 7.28-7.34 (m, 1 H), 7.15 (dd, J =9.16 , 3.44 Hz, 1 H), 7.09-7.13 (m, 1 H), 7.04-7.09 (m, 1 H), 6.92 (d, J =6.87 Hz, 1 H), 6.52 (d, J =7.45 Hz, 1 H), 4.56 (dt, J =10.31, 4.01 Hz, 1 H), 4.08-4.14 (m, 1 H), 3.87 (ddt, J =13.75, 7.59, 3.94, 3.94 Hz, 1 H), 3.44- 3.49 (m, 1 H). 89 MS: 382.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.76 (dd, J =7.45, 2.29 Hz, 1 H), 8.77 (d, J =7.45 Hz, 1 H ), 8.58 (d, J =8.02 Hz, 1 H), 8.05 (s, 1 H), 7.09 (dt, J =9.74, 1.72 Hz, 1 H), 7.00 (dd, J =6.30, 1.72 Hz, 2 H), 6.38 (d, J =7.45 Hz, 1 H), 5.56-5.63 (m, 1 H), 4.51 (dt, J =10.17, 3.79 Hz, 1 H), 3.99 (td, J =9.59, 3.72 Hz, 1 H), 3.86 (ddt, J =13.75, 7.45, 3.72, 3.72 Hz, 1 H), 3.38-3.43 (m, 1 H), 1.94 (ddd, J =13.89, 7.88, 6.30 Hz, 1 H ) 1.44 (dt, J =14.03, 7.30 Hz, 1 H), 0.63-0.73 (m, 1 H), 0.37-0.45 (m, 1 H), 0.27-0.34 (m, 1 H), 0.18 (dq, J =9.24, 4.75 Hz, 1 H), -0.12--0.04 (m, 1 H). 90 MS: 372.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.68 (d, J =8.02 Hz, 1 H), 8.52 (d, J =7.45 Hz, 1 H), 8.36 (t, J =4.01 Hz, 1 H), 8.04 (s, 1 H), 7.16 (dd, J =9.45, 3.15 Hz, 1 H), 7.06 (dd, J =9.17, 4.58 Hz, 1 H) , 6.95-7.02 (m, 1 H), 6.30 (d, J =8.02 Hz, 1 H), 5.66-5.75 (m, 1 H), 5.45 (d, J =4.58 Hz, 1 H), 4.12-4.25 (m, 2 H), 4.05 (d, J =9.16 Hz, 1 H), 3.60-3.67 (m, 1 H), 3.28-3.31 (m, 1 H), 1.42 (d, J =6.87 Hz, 3 H). 91 MS: 372.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.70 (d, J =6.87 Hz, 1 H), 8.53 (d, J =7.45 Hz, 1 H), 8.47 (dd, J =8.31, 2.00 Hz, 1 H), 8.03 (s, 1 H), 7.07-7.13 (m, 1 H), 6.97-7.03 (m, 2 H), 6.34 (d, J =7.45 Hz, 1 H), 5.60 (quind, J =7.02, 7.02, 7.02, 7.02, 1.72 Hz, 1 H), 5.36 (d, J =4.01 Hz, 1 H), 4.42 (br d, J =10.88 Hz, 1 H), 4.01-4.14 (m, 2 H), 3.88-3.97 (m, 1 H), 3.10-3.17 (m, 1 H), 1.41 (d, J =7.45 Hz, 3 H). 92 MS: 356.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.41 (dd, J =6.01, 3.72 Hz, 1 H), 8.71 (d, J =7.45 Hz, 1 H ), 8.58 (d, J =7.45 Hz, 1 H), 8.06 (s, 1 H), 7.14 (dd, J =9.74, 3.44 Hz, 1 H), 7.07 (dd, J =9.17, 4.58 Hz, 1 H), 6.96 (ddd, J =9.17, 8.02, 3.44 Hz, 1 H), 6.35 (d, J =7.45 Hz, 1 H), 5.63-5.74 (m, 1 H), 4.77 -4.89 (m, 1 H), 3.73-3.85 (m, 1 H), 3.52-3.58 (m, 1 H), 1.43 (d, J =6.87 Hz, 3 H), 1.19 (br d, J =6.30 Hz, 3 H). 93 MS: 356.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.82 (dd, J =8.02, 2.29 Hz, 1 H), 8.81 (d, J =6.87 Hz, 1 H ), 8.58 (d, J =7.45 Hz, 1 H), 8.04 (s, 1 H), 7.12 (dd, J =9.45, 3.15 Hz, 1 H), 6.99-7.05 (m, 1 H), 6.94- 6.99 (m, 1 H), 6.36 (d, J =7.45 Hz, 1 H), 5.53 (quind, J =6.87, 6.87, 6.87, 6.87, 1.15 Hz, 1 H), 4.45-4.52 (m, 1 H ), 3.90 (ddd, J =13.46, 8.31, 4.01 Hz, 1 H), 3.10-3.17 (m, 1 H), 1.46 (d, J =6.30 Hz, 3 H), 1.44 (d, J =7.45 Hz , 3 H). 94 MS: 356.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.49 (dd, J =7.45, 2.86 Hz, 1 H), 8.77 (d, J =7.45 Hz, 1 H ), 8.09 (s, 1 H), 7.15 (dd, J =9.45, 3.15 Hz, 1 H), 7.04-7.09 (m, 1 H), 6.97-7.03 (m, 1 H), 6.73 (d, J =8.02 Hz, 1 H), 5.54 (dd, J =14.89, 1.72 Hz, 1 H), 4.55 (ddd, J =7.59, 5.87, 4.30 Hz, 1 H), 4.08 (d, J =14.89 Hz, 1 H), 3.85-3.92 (m, 1 H), 3.59 (s, 3 H), 3.16 (ddd, J =13.60, 7.88, 3.15 Hz, 1 H), 1.45 (d, J =6.30 Hz, 3 H) . 95 MS: 356.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.71 (d, J =8.59 Hz, 1 H) 8.76 (d, J =8.02 Hz, 1 H) 8.09 ( s, 1 H) 7.25 (dd, J =9.45, 3.15 Hz, 1 H) 7.02-7.09 (m, 1 H) 6.95-7.00 (m, 1 H) 6.71 (d, J =8.02 Hz, 1 H) 5.68 (dd, J =14.89, 1.15 Hz, 1 H) 4.34 (dd, J =9.45, 1.43 Hz, 1 H) 4.24-4.30 (m, 1 H) 4.10 (d, J = 14.89 Hz, 1 H) 3.94 ( dd, J =9.74, 4.01 Hz, 1 H) 3.58 (s, 3 H) 1.36 (d, J =6.87 Hz, 3 H). 96 MS: 372.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.64 (d, J = 8.23 Hz, 1 H) 8.27 (br s, 1 H) 8.08 (s, 1 H ) 7.15 (br d, J = 6.59 Hz, 1 H) 7.04-7.10 (m, 1 H) 6.96-7.02 (m, 1 H) 6.66 (d, J = 8.23 Hz, 1 H) 5.11 (br s, 1 H) 4.28 (br s, 2 H) 4.15 (br s, 1 H) 4.06 (br s, 1 H) 3.90 (br s, 2 H) 3.57 (s, 3 H) 3.29 (br s, 1 H). 97 MS: 356.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.49 (dd, J =7.45, 2.86 Hz, 1 H), 8.77 (d, J =8.02 Hz, 1 H ), 8.09 (s, 1 H), 7.15 (dd, J =9.74, 2.86 Hz, 1 H), 7.04-7.10 (m, 1 H), 6.97-7.03 (m, 1 H), 6.73 (d, J =8.02 Hz, 1 H), 5.54 (dd, J =14.89, 1.72 Hz, 1 H), 4.50-4.60 (m, 1 H), 4.08 (d, J =15.47 Hz, 1 H), 3.84-3.92 ( m, 1 H), 3.59 (s, 3 H), 3.16 (ddd, J = 13.46, 7.73, 2.86 Hz, 1 H), 1.45 (d, J = 6.30 Hz, 3 H). 98 MS: 358.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.76 (dd, J =7.45, 2.29 Hz, 1 H), 8.82 (d, J =6.87 Hz, 1 H ), 8.58 (d, J =7.45 Hz, 1 H), 8.05 (s, 1 H), 7.06-7.15 (m, 1 H), 6.99-7.04 (m, 2 H), 6.45 (d, J =8.02 Hz, 1 H), 5.57-5.66 (m, 1 H), 5.16-5.25 (m, 1 H), 4.52 (dt, J =10.17, 3.79 Hz, 1 H), 3.99 (td, J =9.74, 4.01 Hz, 1 H), 3.87 (ddt, J =13.82, 7.52, 3.94, 3.94 Hz, 1 H), 3.71 (ddd, J =11.17, 8.31, 6.30 Hz, 1 H), 3.59 (dt, J =11.17, 5.01 Hz, 1 H), 3.36-3.45 (m, 1 H). 99 MS: 372.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.72 (d, J =8.02 Hz, 1 H), 8.53 (d, J =7.45 Hz, 1 H), 8.40 (t, J =4.01 Hz, 1 H), 8.04 (s, 1 H), 7.09 (dd, J =9.16, 2.86 Hz, 1 H), 6.95-7.05 (m, 2 H), 6.42 (d, J =7.45 Hz, 1 H), 5.63-5.72 (m, 1 H), 5.16 (t, J =5.44 Hz, 1 H), 4.29-4.37 (m, 1 H), 4.19-4.27 (m, 1 H ), 3.65 (ddd, J =11.17, 8.31, 6.30 Hz, 1 H), 3.53-3.61 (m, 2 H), 3.41-3.48 (m, 1 H), 2.00-2.18 (m, 2 H). 100 MS: 356.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.46 (dd, J =7.16, 2.58 Hz, 1 H), 8.77 (d, J =8.02 Hz, 1 H ), 8.11 (s, 1 H), 7.22 (dd, J =9.74, 2.29 Hz, 1 H), 7.01-7.06 (m, 2 H), 6.74 (d, J =8.02 Hz, 1 H), 6.20- 6.30 (m, 1 H), 4.50 (dt, J =10.31, 4.01 Hz, 1 H), 4.05 (ddd, J =10.31, 9.16, 4.01 Hz, 1 H), 3.85 (ddt, J =13.68, 7.52, 3.72, 3.72 Hz, 1 H), 3.38-3.49 (m, 4 H), 1.53 (d, J =7.45 Hz, 3 H). 101 MS: 400.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.58 (dd, J =7.45, 2.86 Hz, 1 H), 8.50 (s, 1 H), 8.01 (s , 1 H), 7.36 (dd, J =9.16, 2.86 Hz, 1 H), 7.00-7.14 (m, 2 H), 5.61 (dd, J =14.61, 1.43 Hz, 1 H), 4.44-4.52 (m , 1 H), 4.14 (d, J = 12.60 Hz, 1 H), 4.00-4.09 (m, 2 H), 3.81-3.92 (m, 2 H), 3.39-3.47 (m, 1 H), 1.40 ( s, 3 H), 1.38 (s, 3 H). 102 MS: 327.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.58-9.70 (m, 1 H), 9.09 (d, J = 6.87 Hz, 1 H), 8.42 (s , 1 H), 7.22 (dd, J =9.74, 2.86 Hz, 1 H), 7.11 (d, J =7.45 Hz, 1 H), 6.84-6.97 (m, 2 H), 4.37-4.50 (m, 1 H), 3.90-4.06 (m, 3 H), 3.42-3.64 (m, 3 H), 2.54-2.62 (m, 1 H). 103 MS: 341.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.04 (d, J =6.87 Hz, 1 H), 8.56 (t, J =4.01 Hz, 1 H), 8.40 (s, 1 H), 7.19 (dd, J =9.74, 2.86 Hz, 1 H), 7.06 (d, J =6.87 Hz, 1 H), 6.81-6.96 (m, 2 H), 4.19-4.29 ( m, 2 H), 3.53-3.63 (m, 4 H), 3.24-3.31 (m, 2 H), 2.09-2.21 (m, 2 H). 104 MS: 358.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.79 (d, J =8.02 Hz, 1 H), 8.70 (dd, J =7.45, 2.86 Hz, 1 H ), 8.07 (s, 1 H), 7.59 (dd, J =8.59, 5.73 Hz, 1 H), 7.10 (td, J =8.59, 2.86 Hz, 1 H), 7.04 (dd, J =10.02, 2.58 Hz , 1 H), 6.78 (d, J =8.02 Hz, 1 H), 5.79 (dd, J =15.75, 1.43 Hz, 1 H), 4.17 (d, J =16.04 Hz, 1 H), 3.73-3.82 ( m, 1 H), 3.59 (s, 3 H), 3.52-3.58 (m, 1 H), 3.26-3.30 (m, 1 H), 3.18-3.23 (m, 1 H). 105 MS: 411.2 (M+H) ⁺ . 106 MS: 374.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.84 (d, J =8.02 Hz, 1 H), 8.09-8.19 (m, 2 H), 8.07 (s , 1 H), 7.35 (td, J =8.45, 2.58 Hz, 1 H), 7.22 (dd, J =10.31, 2.29 Hz, 1 H), 6.86 (d, J =8.02 Hz, 1 H), 5.75 ( d, J =16.61 Hz, 1 H), 4.57 (d, J =16.61 Hz, 1 H), 4.11-4.15 (m, 1 H), 3.79-3.87 (m, 2 H), 3.59 (s, 3 H) ), 3.48-3.57 (m, 1 H). 107 MS: 390.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 8.83 (d, J =8.02 Hz, 1 H), 8.12 (dd, J =9.16, 5.73 Hz, 1 H ), 8.07 (s, 1 H), 7.82 (br t, J =5.16 Hz, 1 H), 7.39 (td, J =8.59, 2.86 Hz, 1 H), 7.14-7.21 (m, 1 H), 6.84 (d, J =7.45 Hz, 1 H), 5.37-5.54 (m, 1 H), 4.61-4.76 (m, 1 H), 3.83-3.93 (m, 1 H), 3.57-3.63 (m, 5H) , 3.46-3.54 (m, 1 H). 108 MS: 371.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.73 (br d, J =6.87 Hz, 1 H) 9.09 (d, J =8.00 Hz, 1 H) 8.41 (s, 1 H) 7.20 (dd, J =9.74, 2.86 Hz, 1 H) 7.11 (d, J =6.87 Hz, 1 H) 6.94 (dd, J =9.16, 4.58 Hz, 1 H) 6.78-6.88 ( m, 1 H) 4.44 (ddd, J =8.88, 5.44, 4.01 Hz, 1 H) 3.99-4.06 (m, 1 H) 3.88-3.97 (m, 1H) 3.67-3.73 (m, 1 H) 3.47-3.53 (m, 1 H) 3.12-3.21 (m, 1 H) 2.54-2.62 (m, 1 H) 1.43 (d, J = 6.30 Hz, 3 H). 109 MS: 371.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.43 (d, J = 2.29 Hz, 1 H) 8.73 (d, J = 6.87 Hz, 1 H) 8.57 ( d, J =7.50 Hz, 1 H) 8.01 (s, 1 H) 7.16 (dd, J =9.17, 2.86 Hz, 1 H) 7.00-7.11 (m, 2 H) 6.34 (d, J =7.45 Hz, 1 H) 5.61-5.73 (m, 1 H) 4.37 (dd, J =10.31, 4.01 Hz, 1 H) 4.00 (ddt, J =8.45, 4.30, 2.22, 2.22 Hz, 1 H) 3.88-3.96 (m, 1 H) 1.48 (d, J =6.87 Hz, 3 H) 1.42 (d, J =7.45 Hz, 3 H). 110 MS: 371.2 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 9.95 (d, J =8.59 Hz, 1 H) 8.79 (d, J =6.87 Hz, 1 H) 8.58 ( d, J =7.45 Hz, 1 H) 8.04 (s, 1 H) 7.16 (dd, J =9.45, 3.15 Hz, 1 H) 6.98-7.05 (m, 1 H) 6.92-6.97 (m, 1 H) 6.34 (d, J =8.02 Hz, 1 H) 5.67 (quind, J =7.02, 7.02, 7.02, 7.02, 1.72 Hz, 1 H) 4.35 (dd, J =9.45, 1.43 Hz, 1 H) 4.20-4.30 (m , 1 H) 3.93 (dd, J =9.74, 4.01 Hz, 1 H) 1.47 (d, J =7.45 Hz, 3 H) 1.37 (d, J =6.87 Hz, 3 H) 111 MS: 371.2 (M+H) ⁺ . 112 MS: 345.2 (M+H) ⁺ . Additional examples were prepared using methods similar to those described above.Biological examples 1 : Biochemical Kinase Analysis . MET/ALK/AXL/TRK kinase inhibition can be measured by Omnia (Invitrogen Co., Ltd.) continuous fluorescence analysis. The reaction was carried out in a 96-well plate at 30°C in a volume of 50 μL. The mixture contains 1 nM human recombinant target kinase domain, 2 μM phosphate receptor peptide, test compound (11 doses, 3-fold serial dilution, 2% DMSO final) or only DMSO, 0.2 mM DTT, and one in 20 mM Hepes 10 mM MgCl₂ , PH 7.5, and start the reaction by adding ATP (100 μM final concentration) followed by 20 min pre-incubation. The initial rate of phosphopeptide formation was measured with a Tecan Safire microplate reader within 20 minutes, where the excitation wavelength was set to 360 nm and the emission was 485 nm. K_i The value was calculated by fitting the data to the competitive inhibition equation using a nonlinear regression method (GraphPad Prism, GraphPad Software, San Diego, CA).Biological examples 2 : Cellular kinase phosphorylation ELISA analyze The experiment is based on the procedure described in the publication (Christensen, J. et al., "Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma" , Mol. Cancer Ther. 2007, 6 (12): 3314-3322.) All experiments were performed under standard conditions (37℃ and 5% CO₂ ) Under implementation. IC₅₀ The value is calculated by concentration/response curve fitting using a four-parameter method based on Microsoft Excel. The cells were seeded in a 96-well plate supplemented with 10% fetal bovine serum (FBS) and transferred to a serum-free culture [with 0.04% bovine serum albumin (BSA)] after 24 hours. In the study of ligand-dependent For RTK phosphorylation experiments, add corresponding growth factors for up to 20 minutes. After incubating the cells with inhibitors for 1 h and/or incubating with appropriate ligands for a specified period of time, the cells are supplemented with 1 mmol/L Na₃ VO₄ The HBSS is washed once, and a protein lysate is generated from the cells. Subsequently, a 96-well plate was coated with a specific capture antibody and a detection antibody specific to phosphorylated tyrosine residues was used to evaluate the phosphorylation of the selected protein kinase by a sandwich ELISA method. The antibody-coated plate was (a) overnight at 4°C in the presence of protein lysate, (b) washed seven times in 1% Tween 20 in PBS, (c) wasabi peroxidase-conjugated antibody Incubate in total phosphotyrosine (PY-20) antibody (1:500) for 30 min, (d) wash seven times, (e) in 3,3,5,5-tetramethylbenzidine peroxidase Incubate in the substrate (Bio-Rad) to initiate the color reaction. This reaction is achieved by adding 0.09 NH₂ SO₄ Stop, and (f) Use spectrophotometry to measure the absorbance at 450 nm. Cell lines for individual kinases include A549 for MET, Karpas 299 for ALK, 293-AXL for AXL, PAET RKA for TRKA, and PAE-TRKB for TRKB.Biological examples 3 : Kinase binding analysis . Kinase binding analysis system uses general KINOME at DiscoveRxscan K_d The scheme is implemented (Fabian, M. A. et al., "A small molecule-kinase interaction map for clinical kinase inhibitors", Nat. Biotechnol. 2005, 23(3): 329-36). For most analyses, in Escherichia coli derived from the BL21 strain (E. coli ) Preparation of kinase-labeled T7 phage strains in the host. Escherichia coli was grown to log phase and infected with T7 phage and incubated at 32°C with shaking until dissolved. The lysate was centrifuged and filtered to remove cell debris. The remaining kinase was produced in HEK-293 cells and then labeled with DNA for qPCR detection. The streptavidin-coated magnetic beads were treated with a biotinylated small molecule ligand at room temperature for 30 minutes to generate an affinity resin for kinase analysis. The ligandized 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. The binding reaction was pooled by combining kinase, ligandized affinity beads, and test compound in 1× binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). All reactions were performed in a 96-well polystyrene plate with a final volume of 0.135 mL. The assay plate was incubated for 1 hour with shaking at room temperature and the affinity beads were washed with washing buffer (1×PBS, 0.05% Tween 20). The beads were then resuspended in lysis buffer (1x PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature for 30 minutes with shaking. Measure the concentration of kinase in the lysate by qPCR. The results of the compounds tested in this analysis are presented in Table 2. Using this method, Example 20 also has binding affinity with PLK4 kinase (K_d 2.9 nM). Table 2. Instance TRKA K _d (nM) TRKB K _d (nM) TRKC K _d (nM) JAK1 K _d (nM) JAK2 K _d (nM) JAK3 K _d (nM) ALK K _d (nM) ROS1 K _d (nM) 11-1 1900 ＞30000 1900 20 0.031 0.18 0.30 ＞1000 4.8 120 80 twenty one 39 0.23 27 180 4.7 40 600 410 41 6.00 280 2.6 33 200 42 0.088 43 0.086 3.7 45 0.082 7.8 49 0.14 twenty four 50 0.20 0.57 51 0.065 65 0.15 4.3 51-1 0.051 37 0.048 1.8 6.8 0.73 52 6.5 270 62 75 0.015 6.5 92 0.12 8.2 93 0.082 5.7 98 0.74 14 103 1.9 28 Biological examples 4 : Ba/F3 Cell proliferation analysis . TRKA Ba/F3 cell proliferation analysis is performed by ACD (Advanced Cellular Dynamics). The Ba/F3 cell line was maintained in RPMI-1640 medium containing 10% fetal bovine serum and antibiotics. Harvest the cells grown in log phase and distribute 5,000 cells in each well of a 384-well plate in 50 µL of growth medium. Add 50 nanoliters of the diluted compound to the appropriate wells in duplicate, and place the cells in a humidified 5% CO at 37°C.₂ Incubate in an incubator for 48 hours. The viability is determined by adding 15 µL CellTiter-Glo and measuring the luminescence, which is reported as the relative light unit (RLU) measured by the technique per second. The data (RLU) for each compound was normalized to the average maximum response obtained in the presence of vehicle only (DMSO). These data are used to derive the% inhibition (100-% of maximum response) and the average of the two data points/concentrations is used to calculate the IC via non-linear regression analysis using GraphPad Prism software (GraphPad Co., Ltd., San Diego, CA)₅₀ Value (the concentration that causes half of the maximum inhibition of cell survival). Using this method, Example 20 uses 3.0 nM IC₅₀ Inhibit cell proliferation of TRKA Ba/F3 cells. The data of the compounds tested in this analysis are presented in Table 3.Biological examples 5 : EML4-ALK Ba/F3 Stable cell line generation and cell proliferation analysis . The EML4-ALK wild-type gene (variant 1) was synthesized at GenScript and cloned in pCDH-CMV-MCS-EF1-Puro plasmid (System Biosciences Co., Ltd.). The Ba/F3-EML4-ALK wild-type cell line is produced by transfecting Ba/F3 cells with a lentivirus containing EML4-ALK wild-type. Stable cell lines were selected by puromycin treatment followed by IL-3 withdrawal. 5000 cells were seeded in a 384-well white plate overnight, and then treated with the compound. Cell proliferation was measured using CellTiter-Glo luciferase-based ATP detection assay (Promega) after 48 hours of incubation with various concentrations of compounds according to the manufacturer's protocol. IC₅₀ The measurement was performed using GraphPad Prism software (GraphPad Co., Ltd., San Diego, CA.). The data of the compounds tested in this analysis are presented in Table 3.Biological examples 6 : Cell proliferation analysis . The colorectal cell line KM 12 (with endogenous TPM3-TRKA fusion gene) cells were cultured in DMEM medium supplemented with 10% fetal bovine serum and 100 U/mL penicillin/streptomycin. 5000 cells were seeded in a 384-well white plate for 24 hours, and then treated with the compound. The cell proliferation line was measured using CellTiter-Glo luciferase-based ATP detection analysis (Promega) according to the manufacturer's protocol after 72 hours of incubation. IC₅₀ The measurement was performed using GraphPad Prism software (GraphPad Co., Ltd., San Diego, CA.). Another option is to culture the colorectal cell line KM 12 (with endogenous TPM3-TRKA fusion gene) cells in DMEM medium supplemented with 10% fetal bovine serum and 100 U/mL penicillin/streptomycin. The primary thrombocytosis cell line SET-2 cells (with endogenous JAK2 V618F point mutation) or T-cell lymphoma Karpas-299 cell line (with endogenous NPM-ALK fusion gene) were supplemented with 10% fetus Cultured in bovine serum and 100 U/mL penicillin/streptomycin RPMI medium. 5000 cells were seeded in a 384-well white plate for 24 hours, and then treated with the compound. The cell proliferation line was measured using CellTiter-Glo luciferase-based ATP detection analysis (Promega) according to the manufacturer's protocol after 72 hours of incubation. IC₅₀ The measurement was performed using GraphPad Prism software (GraphPad Co., Ltd., San Diego, CA.). The data of the compounds tested in these analyses are presented in Table 3. table 3 Instance KM 12 cell proliferation IC ₅₀ (nM) SET2 cell proliferation IC ₅₀ (nM) Karpas 299 cell proliferation IC ₅₀ (nM) EML4-ALK Ba/F3 cell proliferation IC ₅₀ (nM) 11-1 ＞10000 ＞10000 ＞10000 20 0.86 2000 1000 39 3.8 8800 3800 40 204 ＞10000 ＞10000 41 118 1500 3900 42 4.0 2000 3400 43 2.6 1700 2800 44 9.9 2030 4100 45 0.35 8000 ＞10000 46 1.5 7000 7100 47 31 ＞10000 ＞10000 48 62 6000 6000 49 6.7 7000 3900 50 74 6000 4100 51 3.2 425 832 51-1 1.3 234 289 248 52 52 3600 7800 59 ＞1000 60 ＞1000 61 0.6 3747 3900 62 0.9 4000 66 17.5 1543 1900 67 2.8 1231 1200 75 0.6 4436 3900 76-1 5.8 1003 3800 84 0.8 3146 4200 85 0.9 928 1080 86 1998 1000 87 0.3 2734 1591 88 50.4 1900 3129 89 0.2 859 1398 90 1.8 5911 1653 91 1.8 1536 961 92 0.3 142 88.7 78.6 93 0.5 242 23.7 21.1 94 0.2 ＞10000 ＞10000 95 0.4 2673 4107 96 0.6 6000 5000 97 0.3 6500 1419 98 7.4 808 281 99 6.3 6848 506 100 0.6 5834 5364 101 ＞1000 6000 ＞10000 102 1.2 2450 2304 103 15 ＞10000 1956 104 0.3 2353 5747 105 500 ＞10000 ＞5000 106 176 ＞10000 ＞10000 107 75.6 3000 ＞10000 108 3.6 870 619 109 0.86 398 225 110 0.7 219 163 111 76 1996 329 Biological examples 7 ：Research on cell mechanism -TRKA And downstream signal target phosphorylation analysis . The colorectal cell line KM 12 (with endogenous TPM3-TRKA fusion gene) cells were cultured in DMEM medium supplemented with 10% fetal bovine serum and 100 U/mL penicillin/streptomycin. One million cells were seeded in a 6-well plate for 24 hours and then treated with the compound. The cells were washed with 1xPBS and collected after 5 hours of treatment, and in RIPA buffer (50 mM Tris, pH 7.4, 150 mM NaCl, 1%) supplemented with 10 mM EDTA, Halt protease and phosphatase inhibitor (Thermo Scientific) NP-40, 0.5% deoxycholate, 0.1% SDS). The protein lysate (20 µg) was analyzed on a 4-12% Bolt Bis-Tris precast gel, analyzed with MES operating buffer (Life Technologies), and transferred to nitrocellulose using the Trans-Blot Turbo transfer system (Bio-Rad) Membrane and use targeted phosphorylated TRK A (Cell Signaling Technology, Y496, Y680, Y681, pure line C50F3; dilution 1:1000), total TRK A (Santa Cruz Biotechnology, sc-11; pure line C-14, dilution 1:2000 ), phosphorylated AKT (Cell signaling, S473, D9E, #9271; dilution 1:5000), total AKT (Cell Signaling Technology, 40D4; dilution 1:2000), phosphorylated ERK (Cell Signaling Technology, Thr 202/204, D13.14.4E, #4370; dilution 1:2000), total ERK (Cell Signaling Technology; dilution 1:1000) and tubulin (Sigma, T4026, dilution 1:5000) antibody detection. The antibody is usually incubated overnight at 4°C with gentle shaking, then washed and incubated with the appropriate HRP-conjugated secondary antibody. Expose the film to a chemiluminescent substrate at room temperature for 5 min (SuperSignal West Femto, Thermo Scientific). Images were obtained using the C-Digit imaging system (LI-COR Biosciences). Obtain the relative density of the band directly through Image Studio Digits of LICOR. With the help of GraphPad Prism software (GraphPad Co., Ltd., San Diego, CA), the semi-inhibitory concentration (IC₅₀ )value. Using this method, Example 20 inhibited the autophosphorylation of TPM3-TRKA in KM12 cells, and its IC₅₀ It is 1.07 nM, and inhibits the phosphorylation of its downstream signal targets AKT and ERK, its IC₅₀ They are 2.80 nM and 2.00 nM, respectively.Biological examples 8 ：Analysis of Caspase Activity . Maintain KM12 cells in DMEM medium containing 10% fetal bovine serum and antibiotics. 500,000 cells were seeded in a 12-well plate and various concentrations of compounds were introduced for 72 hours. For the staurosporine treatment, 500 nM STS was added at 60 hours and incubated for 12 hours as a positive control. Collect all cells and wash twice with 1xPBS, and then in lysis buffer (20mM HEPES, 150 mM NaCl, 10 mM KCl, 5 mM EDTA, 1% NP40) supplemented with Halt protease and phosphatase inhibitor (Thermo Scientific) In lysis. For caspase analysis, approximately 20 μL (20 μg) of cell lysate is incubated with 20 μL caspase 3 glo reagent (Promega), incubated at 37°C for 20 minutes, and then released by luminescence Measure enzyme activity. For western blotting, the cell lysates are boiled and analyzed by SDS-PAGE/immunoblotting using PARP or actin antibodies. Using this method, Example 20 induced apoptosis in KM 12 cells.

Figure 1 shows 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzene The powder X-ray diffraction pattern of the crystalline polymorph 1 of the free base of cyclo-tridecin-4(5H)-one (Example 20). Figure 2 shows 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-vinyl pyrazolo[4,3-f][1,4,8,10]benzene Differential scanning calorimetry thermogram of the crystalline polymorph 1 of the free base of oxatriazatriazepine-4(5H)-one (Example 20).

Claims (27)

A compound of the following formula (IA),

Of which ring A'system

or

Ring B'system:

Each of L ¹ and L ^{2 is} independently -C(R ^1' )(R ^2' )-, -O-, -N(R ^k' )-, -S-, -S(O)- or -S (O) ₂ -; each of R ^{1 'and} R ^2' are independently lines H, deuterium, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl alkyl, 3-7 heterocycloalkyl, C ₆ - ₁₀ aryl or mono- or bicyclic heteroaryl ^{group, -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 ^1' and R ^{2 'together} with one or more carbon attached together form C _3-6 cycloalkyl or 4-6 heterocycloalkyl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-7 heterocycloalkyl, C ₆ - ₁₀ aryl group, a mono- or bicyclic heteroaryl Each hydrogen atom in an aryl group and a 4- to 6-membered heterocycloalkyl group is independently substituted with the following as appropriate: deuterium, halogen, C _1-6 alkyl, C _1-6 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 R ^k'is independently H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C ₆ - ₁₀ aryl or mono- or bicyclic heteroaryl, wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-7 heterocyclyl alkyl, C ₆ - ₁₀ aryl or mono- or bicyclic heteroaryl group of each hydrogen atom is independently optionally substituted by the following: deuterium, halo, C _1-6 alkyl, C _1-6 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 R ^{3 'and} R ^4' independently based deuterium, halogen , -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', -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 , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 7 heterocycloalkyl, C ₆ - ₁₀ aryl or heteroaryl mono- or bicyclic aryl group, or any two of R ^{3 'group,} or any two of R ^4' groups which form a C ₅ together with the ring attached _-8 cycloalkyl or 5- to 8-membered heterocycloalkyl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3 to 7-membered hetero cycloalkyl, C ₆ - ₁₀ aryl group, a mono- or bicyclic heteroaryl group or a C _5-8 cycloalkyl group each a hydrogen atom view 5-8 heterocycloalkyl independently substituted with the case where the following substitutions: deuterium, halo , C _1-6 alkyl, C _1-6 ^{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; R ^{7 'based} H, deuterium, C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-7 heterocycloalkyl, C ₆ - ₁₀ aryl or mono- or bicyclic heteroaryl, wherein the C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-7 heterocycloalkyl, C ₆ - ₁₀ aryl or mono- or bicyclic heteroaryl group of each of the hydrogen atom is optionally independently substituted with the following substituents: deuterium, ^{halo, -OR i ', -OC (O} ) R i', -OC (O) NR i 'R j', -OS (O) R i ', -OS ^{_{(O) 2 R i ',}} -OS (O) NR i' R j ', -OS (O) 2 NR i' R j ', -SR i', -S (O) R i ', -S ( ^{_{O) 2 R i ', -S}} (O) NR i' R j ', -S (O) 2 NR i' R j ', -NR i' R j ', -NR i' C (O) R j ^{', -NR i' C (O} ) OR j ', -NR i' C (O) NR i 'R j', -NR i 'S (O) R j', -NR i 'S (O) 2 ^{R j ', -NR i' S} (O) NR i 'R j', -NR i 'S (O) 2 NR i' R j ', -C (O) R i', -C (O) OR ^{i ', -C (O) NR} i' R j ', -PR i' R j ', -P (O) R i' R j ', -P (O) 2 R i' R j ', -P ^{(O) NR i 'R j} ', -P (O) 2 NR i 'R j', -P (O) oR i ', -P (O) 2 oR i', -CN or -NO _2; each ^-Ra' , R ^b' , R ^c' , R ^d' , Re ^' , R ^f' , R ^i'and R ^j'are independently selected from the group consisting of H, deuterium, C _1-6 alkane Group, C _2-6 alkenyl group, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-7 heterocycloalkyl, C ₆ - ₁₀ aryl group and a heteroaryl group; m 'lines 3, 4 or 5; n' lines 2, 3 or 4; p'is 0, 1, 2, 3, or 4; and q'is 1 or 2; or a pharmaceutically acceptable salt thereof. Such as the compound of claim 1, wherein ring A'is

, Or its pharmaceutically acceptable salt. Such as the compound of claim 1, wherein ring A'is

, Or its pharmaceutically acceptable salt. Such as the compound of claim 1, wherein ring B'is

or

, Or its pharmaceutically acceptable salt. The compound of any one of claims 1 to 4, wherein each R ^3'is independently deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy , Isopropoxy, -CN, -CF ₃ , -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CO ₂ C _1-4 alkyl, -CO ₂ H, -NHC(O)C _1-4 alkyl, -SO ₂ C _1-4 alkyl, -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C(O)N(C _1-4 alkyl) ₂ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, hexahydropyridinyl, hexahydropyrazinyl, morpholinyl or Thiomorpholinyl, or a pharmaceutically acceptable salt thereof. Such as the compound of any one of claims 1 to 4, wherein each R ^3'is independently fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, iso Propoxy, -CN or -CF ₃ , or a pharmaceutically acceptable salt thereof. The compound according to any one of the request 1-4, wherein each of R ^{3 'based} fluorine or chlorine, or a pharmaceutically acceptable salt thereof. A compound according to any one of items 1 to 4, such as a request, wherein R ^{7 'based} H, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl , Furanyl, thiofuranyl, hexahydropyridinyl, hexahydropyrazinyl, morpholinyl, phenyl or monocyclic heteroaryl, or a pharmaceutically acceptable salt thereof. A compound according to any one of items 1 to 4, request, wherein R ^{7 'based} H, methyl, or based acceptable salts of ethyl, propyl, isopropyl or cyclopropyl, or a pharmaceutically. A compound according to any one of items 1 to 4, request, wherein R ^{7 'is} H or system-based methyl or ethyl, each of which is unsubstituted or substituted by the following: halo, -OH, -OC _1-4 alkyl, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CO ₂ H, -CO ₂ C _1-4 alkyl, -CONH ₂ , cycloalkyl or Monocyclic heterocycloalkyl, or a pharmaceutically acceptable salt thereof. A compound according to any one of items 1 to 4, request, wherein R ^{7 'based} H, methyl, hydroxyethyl, -CH ₂ CONH ₂ or 3-pyrrolidinyl group, or a pharmaceutically acceptable salt thereof. The compound according requested item of 1 to 4, wherein R ^{7 'based} H or methyl, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 4, wherein R ^1'and R ^2'are each independently H, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, Cyclopentyl, pyrrolidinyl, furyl, thiofuranyl, hexahydropyridyl, hexahydropyrazinyl, morpholinyl, phenyl or monocyclic heteroaryl, or a pharmaceutically acceptable salt thereof. A compound according to any one of items 1 to 4, such as a request, wherein R ^{1 'system} H, or a pharmaceutically acceptable salt thereof. A compound according to any one of items 1 to 4, such as a request, wherein R ^{2 'based} deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl Group, thiofuranyl, hexahydropyridyl, hexahydropyrazinyl, morpholinyl, phenyl or monocyclic heteroaryl, or a pharmaceutically acceptable salt thereof. A compound according to any one of items 1 to 4, request, wherein R ^{2 'or} H system based methyl or ethyl, each of which is unsubstituted or substituted by the following: halo, -OH, -OC _1-4 alkyl, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CO ₂ H, -CO ₂ C _1-4 alkyl, -CONH ₂ , cycloalkyl or Monocyclic heterocycloalkyl, or a pharmaceutically acceptable salt thereof. The requested item compound of any one of to 4, wherein R ^{2 'based} H, methyl, fluoromethyl, hydroxymethyl or cyclopropyl, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 4, wherein each R ^k'is independently H, methyl, ethyl, propyl, isopropyl, or cyclopropyl, or a pharmaceutically acceptable salt thereof. Such as the compound of any one of claims 1 to 4, wherein each of L ¹ and L ^{2 is} independently -CH ₂ -, -CH (methyl) -, -CH (substituted methyl) -, -CH ( C _3-6 cycloalkyl)-, -O-, -NH-, -N (C _1-4 alkyl), -N (C _3-6 cycloalkyl), -S-, -S(O) -Or -SO ₂ -, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 4, wherein -(L ¹ ) _n' -is -CH ₂ -O-, -CH(C _1-4 alkyl)-O-, -CH(C _{3- 6} cycloalkyl) -O-; or -CH (H or optionally substituted C _1-4 alkyl) -N (H or optionally substituted C _1-4 alkyl) -, -CH (CO ₂ C _1-4 alkyl or C (O) N (H or C _1-4 alkyl) ₂ )-N (H or optionally substituted C _1-4 alkyl), or pharmaceutically acceptable Salt. A compound according to any one of items 1 to 4, request, wherein - (L ²⁾ _{m 'based} ^{-O- (C (R 1')} (R 2 ')) 2-3 -, - O- (CH 2) _2-3 -, -N(R ^k' )-(C(R ^1' )(R ^2' )) _2-3 -, -N(H or C _1-4 alkyl)-(CH ₂ ) _{2- 3} -, -S-(C(R ^1' )(R ^2' )) _2-3 -, -SO ₂ -(C(R ^1' )(R ^2' )) _2-3 -, -SO _2- N(R ^k' )-(C(R ^1' )(R ^2' )) ₂ -or -(C(R ^1' )(R ^2' )) ₃ -, or a pharmaceutically acceptable salt thereof. A compound according to any one of claims 1 to 4, wherein m'is 3, 4 or 5, or a pharmaceutically acceptable salt thereof. A compound according to any one of claims 1 to 4, wherein n'is 2, 3 or 4, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 4, wherein p'is 0, 1, or 2, or a pharmaceutically acceptable salt thereof. A compound according to any one of claims 1 to 4, wherein q'is 1, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising (a) at least one compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable excipient. A use of a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cancer, pain, neurological disease, autoimmune disease and inflammation.

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