BR112016017101B1 - DIARYL MACROCYCLES COMPOUNDS AS MODULATORS OF PROTEIN KINASES AND THEIR PHARMACEUTICAL COMPOSITION - Google Patents

Abstract

DIARYL MACROCYCLES AS MODULATORS OF PROTEIN KINASES The present invention relates to certain diaryl macrocyclic compounds, pharmaceutical compositions containing the same, and methods of using the same, including methods for treating cancer, pain, neurological diseases, autoimmune diseases and inflammation. .

Description

CROSS REFERENCE TO RELATED ORDERS

[1] This application claims priority under 35 U.S.C. § 119(e) for provisional applications Serial No. 61/931,506 filed January 24, 2014, Serial No. 62/049,326 filed September 11, 2014, and Serial No. 62/106,301 filed January 22, 2015, the entire contents of which are incorporated herein by reference in their entirety.

TECHNICAL FIELD

[2] The present invention relates to certain macrocyclic diaryl derivatives, pharmaceutical compositions containing the same, and methods of using the same to treat cancer, pain, neurological diseases, autoimmune diseases, and inflammation.

FUNDAMENTALS

[3] Protein kinases are essential regulators for cell growth, proliferation and survival. Genetic and epigenetic changes accumulate in cancer cells that lead to abnormal activation of signal transduction pathways that drive malignant processes. Manning, G. et al., Science 2002, 298, 1912-1934. Pharmacological inhibition of these signaling pathways presents promising intervention opportunities for targeted therapies. Sawyers, C., Nature 2004, 432, 294297.

[4] MET, together with RON, belongs to a unique subfamily of receptor tyrosine kinases, and is produced mainly in cells of epithelial or endothelial origin. Park, M. et al., Cell 1986, 45, 895-904. Hepatocyte growth factor (HGF), also known as scatter factor (SF), is the only known natural high-affinity ligand for MET, and is expressed mainly in cells of mesenchymal origin. Bottaro, D. P. et al., Science 1991, 251, 802-804. HGF/MET signaling controls proliferation, survival processes, and migration of MET-dependent cells that are critical for invasive growth during embryonic development and postnatal organ regeneration, and are fully active in adults only for wound healing. wounds and tissue regeneration processes. Trusolino, L. et al., Nature Rev. Mol. Cell. Biol. 2010, 11, 834-848. The HGF/MET axis is frequently regulated in many types of cancers through activating mutation, gene amplification, abnormal paracrine or autocrine ligand production, and is strongly linked to tumorigenesis, invasive growth and metastasis. Gherardi, E. et al., Nature Rev. Cancer 2012, 12, 89-103. Furthermore, activation of HGF/MET signaling is emerging as an important mechanism of resistance to EGFR and BRAF inhibitory treatments through MET amplification and/or upregulation of stromal HGF. Engelman, J. A. et al., Science 2007, 316, 1039-1043; Wilson, T. R. et al. , Nature 2012, 487, 505509. Due to the role of abnormal HGF/MET signaling in human oncogenesis, invasion/metastasis, and resistance, inhibition of the HGF/MET signaling pathway has great potential in cancer therapy.

[5] ALK, along with leukocyte tyrosine kinase (LTK), is grouped within the insulin receptor (IR) superfamily of receptor tyrosine kinases. ALK is primarily expressed in the central and peripheral nervous systems, suggesting a potential role in normal development and function of the nervous system. Pulford, K. et al., Cell Mol. Life Sci. 2004, 61, 2939. ALK was first discovered as a fusion protein, NPM (nucleophosmin)-ALK, encoded by a fusion gene resulting from chromosomal translocation t(2;5)(p23;q35) in anaplastic large cell lymphoma (ALCL) cell lines. Morris, S.W. et al., Science 1994, 263, 1281. More than twenty distinct ALK translocation partners have been discovered in many types of cancer, including ALCL (60-90% incidence), inflammatory myofibroblastic tumors (IMT, 5060% ), non-small cell lung carcinomas (NSCLC, 37%), colorectal cancer (CRC, 0-2.4%), breast cancers (0-2.4%), and other carcinomas. Grande, E. et al., Mol. Cancer Ther. 2011, 10, 569-579. ALK fusion proteins are localized in the cytoplasm, and ALK fusion partners play a role in dimerization or oligomerization of the fusion proteins through a coil-skin interaction to generate constitutive activation of ALK kinase function. Bischof, D. et al., Mol. Cell Biol., 1997, 17, 2312-2325. EML4-ALK, which comprises portions of the echinoderm microtubule-associated protein type 4 (EML4) and the ALK gene, was first discovered in NSCLC, is highly oncogenic, and has been shown to cause lung adenocarcinoma in transgenic mice. Soda, M. et al., Nature 2007, 448, 561566. Oncogenic point mutations of ALK in both familial and sporadic cases of neuroblastoma. Mossé, Y.P. et al., Nature 2008, 455, 930-935. ALK is an attractive molecular target for cancer therapeutic intervention due to important roles in hematopoietic, solid, and mesenchymal tumors. Big, above.

[6] Tropomyosin-related receptor tyrosine kinases (Trks) are the high-affinity receptor for neurotrophins (NTs), a family of nerve growth factor (NGF) proteins. Trk family members are highly expressed in cells of neuronal origin. Activation of Trk (TrkA, TrkB, and TrkC) by their preferred neurotrophins (NGF for TrkA, brain-derived neurotrophic factor [BDNF], and NT4/5 for TrkB and TrkC for NT3) mediates the survival and differentiation of neurons during development. The NT/Trk signaling pathway functions as an endogenous system that protects neurons after biochemical insults, transient ischemia, or physical damage. Thiele, C.J. et al., Clin. Cancer Res. 2009, 15, 5962-5967. However, Trk was originally cloned as an oncogene fused to the tropomyosin gene in the extracellular domain. Activating mutations caused by chromosomal rearrangements or mutations in NTRK1 (TrkA) have been identified in papillary and medullary thyroid carcinoma, and recently in non-small cell lung cancer. Pierotti, M.A. et al., Cancer Lett. 2006, 232, 90-98; Vaishnavi, A. et al., Nat. Med. 2013, 19, 1469-1472. Because Trk plays an important role in pain sensation as well as signaling tumor cell growth and survival, inhibitors of Trk receptor kinases may provide benefits as treatments for pain and cancer.

[7] Receptor tyrosine kinase AXL belongs to the TAM family of proteins and was originally detected in patients with chronic myeloid leukemia (CML) in the form of an unidentified transforming gene. Verma, A. et al., Mol. Cancer Ther. 2011, 10, 1763-1773. The primary ligand for TAM receptors is growth arrest-specific protein 6 (Gas6). AXL is ubiquitously expressed and has been detected in a wide variety of organs and cells, including the hippocampus and cerebellum, monocytes, macrophages, platelets, endothelial cells (EC), heart, skeletal muscle, liver, kidney, and testis. Upregulation of Gas6/AXL has been reported in many human cancers including colon, esophageal, thyroid, breast, lung, liver, and astrocytoma-glioblastoma. Id. Increased activation of AXL has been observed in in vitro and in vivo mutant EGFR lung cancer models with acquired resistance to erlotinib in the absence of EGFR T7 90M alteration or MET activation. Zhang, Z. et al, Nat. Genet. 2012, 44, 852860. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, its ligand Gas6 has been found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to tyrosine kinase inhibitors. Id. Therefore, AXL is a promising therapeutic target for patients with EGFR-mutant lung cancer who have acquired resistance to EGFR inhibitors.

[8] Crizotinib (PF-02341066) is a MET/ALK/ROS1/RON-targeted tyrosine kinase drug with moderate activity against TRKs and AXL. Cui, J. J. et al. , J. Med. Chem. 2011, 54, 6342 6363. It has been approved for the treatment of certain patients with end-stage (locally advanced or metastatic) NSCLC who express the abnormal ALK fusion gene identified by a companion diagnostic test (Vysis ALK Break Apart FISH Probe Kit). . Similar to imatinib and other kinase inhibitor drugs, resistance invariably develops after a certain time of treatment with crizotinib. Resistance mechanisms include ALK gene amplification, secondary ALK mutations, and abnormal activation of other kinases including KIT and EGFR. Katayama, R. et al., Sei. Transi. Med. 2012, 4, 120ral7. Based on the clinical success of second-generation ABL inhibitors for the treatment of imatinib resistance in CML patients, a second generation of ALK inhibitors is emerging. These drugs aim to treat NSCLC patients resistant or refractory to crizotinib with more potent inhibition against both wild-type and mutant ALK proteins. Gridelli, C. et al., Cancer Treat Rev. 2014, 40, 300-306.

[9] By modulating multiple targets among the group of tyrosine kinases structurally related to MET, ALK, AXL, and TRK, the compounds described here target resistance to crizotinib, resistance to EGFR-inhibiting drugs, and other primary indications with abnormal cell signaling due to MET, ALK, AXL, and/or TRK mutations and gene amplification. The compounds described here are inhibitors of MET, wild-type and mutant ALKs, AXL, and TRKs and will be useful in treating cancer patients with abnormal signaling of any one or more of MET, ALK, AXL, or TRKs.

[10] The Janus family of kinases (JAK) include JAK1, JAK2, JAK3 and TYK2, and are cytoplasmic tyrosine kinases required for the physiological signaling of cytokines and growth factors. Quintas-Cardama, A. et al, Nat. Rev. Drugs Discov. 2011, 10(2), 127-40; Pesu, M. et al., Immunol. Rev. 2008, 223, 132-142; Murray, P.J., J. Immunol. 2007, 178(5), 2623-2329. JAKs activate by ligand-induced oligomerization, resulting in the activation of the downstream transcription signaling pathway called STAT (signal transducers and activators of transcription). Phosphorylated STATs dimerize and translocate in the nucleus to drive the expression of specific genes involved in proliferation, apoptosis, differentiation, which are essential for hematopoiesis, inflammation and immune response. Murray, supra.

[11] Studies of knockout mice have implicated the primary roles of JAK-STAT signaling with some overlap between these. JAK1 plays a crucial role in signaling several pro-inflammatory cytokines such as IL-1, IL-4, IL-6 and tumor necrosis factor alpha (TNFot). Muller, M. et al. , Nature 1993, 366(6451), 129-135. JAK2 functions for hematopoietic growth factors such as Epo signaling, IL-3, IL-5, GM-CSF, thrombopoietin growth hormone, and prolactin-mediated signaling. Neubauer, H. et al., Cell 1998 93(3), 397-409. JAK3 plays a role in mediating immune responses, and TYK2 associates with JAK2 or JAK3 to transduce cytokine signaling, such as IL-12. Nosaka, T. et al. , Science 1995, 270 (5237), 800-802; Vainchenker, W. et al., Semin. Cell Dev. Biol. 2008, 19 (4), 385-393.

[12] Abnormal regulation of the JAK/STAT pathway has been implicated in multiple human pathological diseases, including cancer (JAK2) and rheumatoid arthritis (JAK1, JAK3). A gain-of-function mutation of JAK2 (JAK2V617F) was discovered with high frequency in MPN patients. Levine, R.L. 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, Nature 2005, 434 (7037), 1144-1148; Baxter, E. J. et al. Lancet 2005, 365 (9464), 1054-1061. Mutation in the JH2 pseudokinase domain of JAK2 constitutively leads to kinase activity. Cells containing the JAK2V617F mutation acquire the capacity for cytokine-independent growth and often become tumor-infected, providing a strong rationale for the development of JAK inhibitors as targeted therapy.

[13] Multiple JAK inhibitors in clinical trials have shown significant benefit in splenomegaly and disease-related constitutional symptoms for myelofibrosis patients, including the first JAK2 inhibitor, ruxolitinib, approved by the FDA in 2011. Quintas-Cardama, supra; Sonbol, MB et al., Ther. Adv. Hematol. 2013, 4(1), 15-35; LaFave, L.M. et al., Trends Pharmacol. Sci. 2012, 33(11), 574-582. Recently collected clinical data related to ruxolitinib treatment indicated that JAK inhibitors work in both wild-type JAK2 and mutated JAK2. Verstovsek, S. et al., N. Engl. J. Med. 2012, 366(9), 799-807; Quintas-Cardama, A. et al., Blood 2010, 115(15), 31093117. The discovery of selective inhibitors of JAK2 vs JAK1/3 remains an unresolved challenge. Furthermore, hyperactivation of JAK2/signal transducers and activators of transcription 3 (JAK2/STAT3) is responsible for abnormal differentiation of dendritic cells leading to abnormal differentiation of dendritic cells and accumulation of immunosuppressive myeloid cells in cancer (Nefedova, Y. et al., Cancer Res 2005;65(20):9525-35). In senescent Pten-null 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, 7589). Therefore, pharmacological inhibition of the JAK2/STAT3 pathway may be an important new therapeutic strategy to enhance antitumor activity through regulation of antitumor immunity.

[14] ROS1 kinase is a receptor tyrosine kinase with an unknown ligand. The normal functions of human ROS1 kinase have not been fully understood. However, it has been reported that ROS1 kinase undergoes genetic rearrangements to create constitutively active fusion proteins in a variety of 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, K.D. et al, Clin Cancer Res 2013, 19(15): 4040-4045). Targeting ROS1 fusion proteins with crizotinib has demonstrated promising clinical efficacy in patients whose NSCLC tumors are positive for ROS1 genetic abnormalities (Shaw, et al., A.T., N Engl J Med 2014, 371(21):1963-1971). Acquired resistant mutations have been observed in patients receiving crizotinib treatment (Awad, M.M. et al., N Engl J Med 2013, 368 (25): 2396-2401). It is urgent to develop the second generation of ROS1 inhibitors to overcome ROS1 resistance to crizotinib.

[15] There remains a need for small molecule inhibitors of these multiple protein or tyrosine kinase targets with desirable pharmaceutical properties. Certain macrocyclic diaryl compounds have demonstrated this advantageous activity profile in the context of the present invention.

SUMMARY

[16] In one aspect, the invention relates to a compound of the following formula (I-A):

[17] in which

[18] Ring A' and Ring B' are each independently a bicyclic or monocyclic aryl or heteroaryl; wherein one of Ring A' and Ring B1 is a monocyclic aryl or heteroaryl and the other is a bicyclic heteroaryl; and at least one of Ring A' and Ring B' comprises at least one nitrogen member of the ring;

[19] each L1 and L2 is independently -C(Rr) (R2')-, -O-, - N(Rk')“, -S-, -S(O)- or -S(O)2~ ;

[20] each R1 and R2 are independently H, deuterium, halogen, C1-galkyl, C2-6alkenyl, C2-6alkynyl, Ca-cycloalkyl, 3- to 7-membered heterocycloalkyl, Cg-io aryl, or mono- or bicyclic heteroaryl, - 0Ra', -OC(O)Ra', -OC (O) NRa' Rb' , -OS(O)Ra', -OS{O)2Ra', -SRa', -S(O)Ra', - S(O}2Ra', -S (O) NRa'Rb< , -S (0) 2NRâ'Rb', -OS (O) NRa'Rb', -OS (O) 2NRa'Rb', -NRa' Rb', -NRa'c (O) Rb', -NRa'C (O) ORb', -NRa'C (O) NRa'Rb', -NRa'S (O) Rb', -NRa'S (O) 2Rb' , -NRa' S (0) NRa'Rb' , -NRa'S (O) 2NRa'Rb', - C(O)Ra', -C(O)ORa', —C (O) NRa'Rb' , - PRa'Rb', -P(O)R3Rb', -P(O)2Ra'Rb', - P(O)NRa'Rb', -P(O)2NRa'Rb' , -P(0)ORa' , -P(O)2ORa', -CN, or -NO2, or R1' and R"' taken together with the carbon or carbons to which they are attached form a Cs-gcycloalkyl or a 4- to 6-membered heterocycloalkyl, in which each hydrogen atom in C1-galkyl, C2-6alkenyl, C2-6alkynyl, Ca-gcycloalkyl, 3- to 7-membered heterocycloalkyl, C6-aryl, mono- or bicyclic heteroaryl, 4- to 6-membered heterocycloalkyl is independently optionally substituted by deuterium , halogen, Ci-galkyl, Ci- ehaloalkyl, -OR6e', -0C(O)Re', -OC (O) NRe'Rf', -OS(O)Re', -OS(O)2Re', - OS (0) NRe'Rf', -OS (O) 2NRe'Rf', -SRe', -S(O)Re', -S(O)2Re', ~ S(O)NRe'Rf', - S (0) 2NRe'Rf', -NRe'Rf', -NRe'c (O) Rf', -NRe'C (0) 0Rf', - NRe'C (0) NRe'Rf', -NRe'S ( 0) Rf', -NRe'S (0) 2Rf', -NRe' S (0) NRe' Rf' , - NRe's (0) 2NR°'Rf', -C(O)Re' , -C(O)ORe ', -C (0) NRe'Rf', -PRe'Rf', - P(O)Re'Rf', -P (0) 2Re'Rf', -P (0) NRe'Rf', -P (0) 2NRe' Rf' , -P(O)ORe', - P(0)20Re', -CN, or -N02;

[21] each Rk is independently H, deuterium, C1-galkyl, C2-6alkenyl, C2-6alkynyl, Ca-gcycloalkyl, 3- to 7-membered heterocycloalkyl, C6-io aryl, or mono- or bicyclic heteroaryl, wherein each atom of hydrogen in C1-alkyl, C2-6alkenyl, C2-ealkynyl, C3“6cycloalkyl, 3- to 7-membered heterocycloalkyl, Cg-aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C1-galkyl, C^ - 6haloalkyl, -0Re', -OC(O)Re', -OC (0) NRe'Rf' , -OS(O)Re', -OS(O)2Re', -OS (0) NRe'Rf' , -OS (0) 2NRe'Rf' , -SRe', -S(O)Re>, -S(O)2Re', “ S(O)NRe'Rf', -S (O) 2NRe'Rf' , -NRe'Rf', -NRe'C (0) Rf', -NRe'C (0) 0Rf', - NRe'ç (O) NRe'Rf', -NRe'S(O)Rf, -NRe'S (0 ) 2Rf' , -NRe'S (0) NRe'Rf', - NRe'S (0) 2NRe'Rf', -C(O)Re', -C(O)ORe', -C (0) NRe' Rf' , -PRe'Rf', - P(0)Re'Rf', -P(O)2ReRf', -P (O) NRe' Rf' , -P (0) 2NRe'Rf', -P(O)0Re ', - P(O)2ORe', -CN, or -N02;

[22] each Ry and R4' is independently deuterium, halogen, -0Rc', -OC(O)Rc', -OC (0) NRc'Rd', -OC (=N) NRC'Rd', -0S( 0)Rc', - 0S(0)2Rc', -OS (O)NRc'Rd', -OS (O)2NRc'Rd', -SRC', -S(O)RC', -S(O) 2RC', - S(O)NRc'Rd', -S (O)2NRc'Rd', -NRc'Rd, -NRc'C (O) Rd', -NRc'c (O) 0Rd', - NRc 'C (0) NRc'Rd', -NRc'C(=N)NRc'Rd', -NRC'S (O) Rd', -NRC'S (O) 2Rd', - NRC'S (0) NRc'Rd', - NRC'S (0) 2NRc'Rd', -C(O)Rc', -C(O)ORc', -C (0) NRC' Rd' , —C (=N)NRc'Rd', -PRc'Rd ', -P (O) Rc'Rd', -P (0) 2RC' Rd', -P (0) NRC'Rd', - P (0) 2NRc'Rd', -P(0)0Rc', -P(0)20Rc', -CN, -N02, C1-6alkyl, C2-βalkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, Cg-io aryl, or mono- or bicyclic heteroaryl, or any two R3' groups or any two R4' groups taken together with the ring to which they are attached form a Cs-gcycloalkyl or a 5- to 8-membered heterocycloalkyl, in which each hydrogen atom in C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-ecycloalkyl, 3- to 7-membered heterocycloalkyl, Cε-aryl, heteroaryl C5-ecycloalkyl, mono- or bicyclic or a 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Cyl-ealkyl, C-ighaloalkyl, -0R6e', -OC(O)Re', -OC (0) NRe'Rf', -OS(O) Re', -OS(O)2Re', -OS (0) NRe'Rf', -OS (0) 2NRe'Rf' , -SRe', -S(O)Re', -S(O)2Re', - S(0)NRe'Rf', -S (O) 2NRe'Rf', -NRe 'Rf', -NRe' C (0) Rf' , -NRe'C (0) 0Rf', - NRe'θ (0) NRe'Rf', -NRe's (0) Rf', -NRe' S (0 ) 2Rf' , -NRe'S (0) NRe'Rf', - NRe's (0) 2NRe'Rf' , -C(O)Re', -0(0) ORe', -C (O) NRe'Rf' , -PRe'Rf', - P(0)Re'Rf', -P (0) 2Re'Rf', -P (0) NRe'Rf', -P (0) 2NRe'Rf', -P(O )ORe', - P(O)2ORe', -ON, or -N02;

[23] R' is H, deuterium, C1-6alkyl, C2-6alkenyl, C2_6alkynyl, Ca-βcycloalkyl, 3- to 7-membered heterocycloalkyl, Cg-io aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in Ci -βalkyl, C2-galkenyl, C2-6alkynyl, Cs-gcycloalkyl, 3- to 7-membered heterocycloalkyl, Cg-io aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, -OR1', -OC(O) R1', -0C (0) NRL'RJ ', -OSÍOJR1', - OS(O)2Ri', -OS (O)NRi'Rj', -OS (0) 2NR1'R3', -SR1', - StOJR1', -S(O)2Ri', - S (0) NR1'R.3' , -S (O)2NRi'R3', -NR^R3', -NR1'C (0) R3 ', - NR1'C (O) OR3', -NR/'c (0) NRR'R3', -NR1'S (0) R3 ', -NR1' S (O) 2R3', -NR1' S (O) NR^R3 ' , - NR1'S (0) 2NR1'R3 ', -CtOJR1', -CfOJOR1', -C (O) NR1' Rj' , -PR^R3', - P(0)Ri'R3', —P (0 ) 2Ri'Rj', -P (0) NR^R3', -P(O)2NRÍ'R3', -P(O)ORV, - PtOjzOR1', -CN, or -N02;

[24] each Ra', Rb', Rc', Rd', Re', Rf', R1' and R3' is independently selected from the group consisting of H, deuterium, Ci-θalkyl, C2-6alkenyl, C2-6alkynyl , Ca-cycloalkyl, 3- to 7-membered heterocycloalkyl, Cg-io aryl, and heteroaryl;

[25] m' is 2, 3, 4, or 5;

[26] n’ is 2, 3, or 4;

[27] p' is 0, 1, 2, 3, or 4; It is

[28] q’ is 0, 1, 2, 3, or 4;

[29] or a pharmaceutically acceptable salt thereof.

[30] In one aspect, the invention relates to a chemical entity of the following Formula (IA)

[31] in which

[32] Ring A' and Ring B' are each independently a monocyclic or bicyclic aryl or heteroaryl;

[33] wherein one of Ring A' and Ring B' is a monocyclic aryl or heteroaryl and the other is a bicyclic heteroaryl; and at least one of Ring A' and Ring B' comprises at least one nitrogen member in the ring;

[34] each R3' and R4' is independently deuterium, halogen, -0Rc', -OC(O)Rc' , -OC (0) NRc'Rd', -OC (=N) NRC'Rd', -OS (0) 0“2Rc', “ OS (O) o-2NRc'Rd', -S(0)O-2RC\ -S (0) o-2NRc'Rd', -NRc'Rd', -NRC' C (O) Rd', -NRC'C (O) NRc'Rd' , -NRC'C (=N) NRc'Rd', -NRC'S (0) 0-2Rd\ ~NRC'S (O) 0_2NRc'Rd' , -C(O)Rc', -C(O)ORc', -C (0) NRc'Rd', -C (=N) NRC' Rd', -P (0) 0_2Rc'Rd', - P (O) 0-2NRc'Rd', -P (O) Q_2ORC', -CN, -N02, C1-6alkyl, C2_6alkenyl, C2-6alkynyl, C3_6cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl, or mono heteroaryl or bicyclic; or any two R3' groups or any two R4' groups taken together with the ring to which they are attached form a 5 to 8 membered Cs-gcycloalkyl or heterocycloalkyl;

[35] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, naphthyl, and mono- or bicyclic heteroaryl is unsubstituted or substituted by one or more substituents selected from the group consisting of deuterium, halogen, Ci-6alkyl, Ci -6haloalkyl, -0Re', -OC(O)Re', -OC (0) NRe'Rf', -OS(O)0- 2Re', -OS (0) 0-2NRe'Rf', -S( O)0-2Re', -S (0) 0-2NRe'Rf', -NRe'Rf', - NRe'C(0)Rf', -NRe'C (0) NRe'Rf', -NRe'S ( 0) 0_2Rf', -NRe'S (O) 0_2NRe'Rf', - C(O)Re', -C(O)ORe', -C (0) NRe' Rf', -P (0) 0-2Re' Rf', -P (0) 0-2NRe'Rf', - P(O)0-2ORe', -CN, and -N02; It is

[36] each Rc, Rα, Re', and Rf is independently selected from the group consisting of H, deuterium, C1-galkyl, C2-6alkenyl, C2_6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl , and heteroaryl;

[37] R7' is H, deuterium, C1-galkyl, C2-salkenyl, C2-6alkynyl, Cs-gcycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl, or mono or bicyclic heteroaryl;

[38] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, naphthyl, or heteroaryl is substituted or unsubstituted by one or more substituents selected from the group consisting of deuterium, halogen, -0R1', -OCÍOJR1', - OC (0) NR1'R3 ', -OS (O) o-sR1', -OS (0) 0_2NRv R3', -S (0) o-sR1', -S (O) Q_ 2NRÍ'R3', -NR^R3', -NR1'C (0) R3', -NR^C (0) NR^R3 ', -NR^S (0) 0-2Rj', ~ NR^S (0) o-∑ NR^R3', -CtOÍR1', -CfOlOR1', -C (0) NRVR3', -P (0) O-2RÍ'R3', ~ P(0) o-pNR^R1', -P (0) o-2ORi', -CN, and -N02;

[39] wherein each R1' and R3' is independently H, deuterium, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-ecycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl, or mono- or bicyclic heteroaryl;

[40] each L1 and L2 is independently -C(Rr) (R2*)-, -0-, - N(Rk')-, or -S(0)o-2;

[41] wherein each R1' and R2' are independently H, deuterium, halogen, C1-6alkyl, C2_6alkenyl, C2_6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl, or mono- or bicyclic heteroaryl; or R1' and R2' taken together with the carbon or carbons to which they are attached form a C3-6cycloalkyl or a 4- to 6-membered heterocycloalkyl;

[42] each Rk' is independently H, deuterium, C1-6alkyl, C2-alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl, or mono- or bicyclic heteroaryl;

[43] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, naphthyl, or heteroaryl in R1', R2', or Rk' is independently unsubstituted or substituted by one or more substituents selected from the group consisting of deuterium , halogen, Ci-ealkyl, Ci-ghaloalkyl, -0Ra', -OC(O)Ra', -OC(O)NRa'Rb', -OS(O)0-2Ra', -OS(O)0_2NRa' Rb' , -S(O)0-2Ra', -S (O) 0_ 2NRa'Rb', -NRa'Rb', -NRa'c (0) Rb', -NRa'C (0) NRa'Rb ', -NRa' S (0) 0-2Rb' , ~ NRa'S (0) 0_2NRa,Rb' , -C(O)Ra', -C(O)ORa', -C (0) NRa'Rb', -P (O) 0-2Ra'Rb', -P (0) 0-2NRa'Rb', -P (0) o-zORa', -CN, and -N02;

[44] wherein each Ra' and Rb' is independently H, deuterium, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Cs-ecycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl, or heteroaryl;

[45] m' is 3, 4, or 5;

[46] n' is 2, 3, or 4;

[47] p' is 0, 1, 2, 3, or 4; It is

[48] q' is 0, 1, 2, 3, or 4;

[49] or a pharmaceutically acceptable salt thereof.

[50] In another aspect, the invention relates to a chemical entity with the following Formula (I):

[51] in which

[52] Ring A and Ring B are each independently a monocyclic or bicyclic aryl or heteroaryl; wherein one of Ring A and Ring B is monocyclic and the other is bicyclic; and Ring comprises at least one nitrogen member in the ring;

[53] R1 and R2 are each independently H, deuterium, C1-6alkyl, C2-6alkenyl, C2-ealkynyl, Ca-gcycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl, or mono- or bicyclic heteroaryl; or R1 and R2 taken together with the carbon to which they are attached form a 4- to 6-membered Ca-ecycloalkyl or heterocycloalkyl;

[54] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, naphthyl, or heteroaryl is unsubstituted or substituted by one or more substituents selected from the group consisting of deuterium, halogen, Ci-6alkyl, Ci-ghaloalkyl, -0Ra, -OC(O)Ra, -OC(O)NRaRb, -OS(O)0-2Ra, - OS (0) o-2NRaRb, -NRaRb, -NRaC (0) Rb, -NRaC (0) NRaRb, -NRaS (0) 0-2Rb, - NRaS (0) 0-2NRaRb, -C (0) Ra, -C(O)ORa, -C(O)NRaRb, -P (0) 0-2RaRb, -P(O)0- 2NRaRb, -P(0)o-20Ra, -CN, and -N02;

[55] wherein each Ra and Rb is independently H, deuterium, C-6alkyl, Cz-alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl, or heteroaryl;

[56] each R3 and R4 is independently deuterium, halogen, - 0Rc, -OC(O)Rc, -OC(O)NRcRd, -OC (=N) NRcRd, -OS (0) Q-2RC, -OS( O)0- 2NRcRd, -NRcRd, -NRcC(O)Rd, -NRcC (0) NRcRd, -NRcC (=N) NRcRd, -NRcS(O)0- 2Rd, -NRCS (0) o-2NRcRd, - C(O)Rc, -C(O)ORc, -C(O)NRcRd, -C(=N)NRcRd, - P (0) o..2RcRd, -P (0) 0-2NRcRd, -P( O)0-2ORc, -CN, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Cs-gcycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl, or mono- or bicyclic heteroaryl;

[57] wherein each mono- or bicyclic alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, naphthyl, and heteroaryl is unsubstituted or substituted by one or more substituents selected from the group consisting of deuterium, halogen, C]_6alkyl, Ci-ghaloalkyl, -0Re, -OC(O)Re, -OC(0)NReRf, -OS{O)0-2Re, - OS (0) o-2NReRf, -NReRf, -NReC(0)Rf, - NReC (0) NReRf, -NReS (O) o-2Rf, - NReS (0) o-2NReRf, -C(O)Re, -C(O)ORe, -C(0)NReRf, -P (0) o-2ReRf, -P(O)0- 2NReRf, -P(O)0-2θRe, -CN, and -N02; It is

[58] each Rc, Rd, Re, and Rf is independently selected from the group consisting of H, deuterium, C1-alkyl, C2-fialkenyl, C2-6alkynyl, Cs-gcycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl , and heteroaryl;

[59] R5 and Re are each independently H, deuterium, Cj-6alkyl, C2-6alkenyl, C2-5alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl, or mono- or bicyclic heteroaryl; or R5 and R° taken together with the carbon to which they are attached form a C3-6cycloalkyl or a 4- to 6-membered heterocycloalkyl;

[60] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, naphthyl, or heteroaryl is substituted or unsubstituted by one or more substituents selected from the group consisting of deuterium, halogen, Ci-ealkyl, Ci-ehaloalkyl, -0Rg, -0C(0)R9, -OC(O)NRgRh, -OS(O)0_2R9, -OS(O)0- 2NRgRh, -NRgRh, -NRgC (0) Rh, -NRgC (0) NR9Rh, -NRgS (O) 0_2Rh, -NRgS(O)0_ 2NR9Rh, -C(O)Rg, -C(O)ORg, -Ç(O)NR9Rh, -P (0) 0_2RgRh, -P (0) 0- 2NR9Rh, - P(0)o-2ORg, -CN, and -N02;

[61] wherein each Rg and Rh is independently H, deuterium, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl, or mono- or bicyclic heteroaryl;

[62] R7 is H, deuterium, C1-galkyl, Cz-βalkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl, or mono- or bicyclic heteroaryl;

[63] wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, naphthyl, or heteroaryl is substituted or unsubstituted by one or more substituents selected from the group consisting of deuterium, halogen, -OR1, -OCfOJR1, -OC (O}NR1Rj, -OSfOJo-sR1, -OS (0} 0-2NR1Rj, -NRiRj, -NRiC(O)Rj, - NRiC (O)NRiRj, -NRiS (0) 0-2Rj, -NRiS (0) 0-2NRiRj, -0(0) R1, -0(0} OR1, - C(O)NRiRj, -P (0) o-zR^, -P (0) 0-2NRiRj, -PfOJo^OR1, - CN, and -N02;

[64] wherein each R1 and Rj is independently H, deuterium, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl, or mono- or bicyclic heteroaryl;

[65] X and Y are each independently -C(Rk) (Rk) —, -0-, or -N(Rk)-;

[66] wherein each Rk is independently H, deuterium, C1-6alkyl, Cz-βalkenyl, Cz-εalkynyl, C3~6cycloalkyl, 3- to 7-membered heterocycloalkyl, phenyl, naphthyl, or mono- or bicyclic heteroaryl;

[67] m is 2, 3, or 4;

[68] n is i, 2, or 3;

[69] foot 0, 1, 2, 3, or 4; It is

[70] which is 0, 1, 2, 3, or 4;

[71] or a pharmaceutically acceptable salt thereof.

[72] In certain embodiments, the compound of Formula (I) or (IA) is a compound selected from the species described or exemplified in the detailed description below.

[73] In certain embodiments, the compound of Formula (I) or (IA) is a compound having the formula

[74] or a pharmaceutically acceptable salt thereof.

[75] In certain embodiments, the compound of Formula (I) or (IA) is a compound that has the formula

[76] or a pharmaceutically acceptable salt thereof,

[77] In certain embodiments, the compound of Formula (I) or (IA) is a compound of the formula

[78] or a pharmaceutically acceptable salt thereof.

[79] In certain embodiments, the compound of Formula (I) or (IA) is a compound that has the formula

[80] or a pharmaceutically acceptable salt thereof.

[81] In certain embodiments, the compound of Formula (I) or (IA) is a compound that has the formula

[82] or a pharmaceutically acceptable salt thereof.

[83] In certain embodiments, the compound of Formula (I) or (IA) is a compound that has the formula

[84] or a pharmaceutically acceptable salt thereof.

[85] In a further aspect, the invention relates to a free base crystalline form of the compound of formula

[86] having a powder X-ray diffraction pattern substantially the same as FIG. XX. In some embodiments, the crystalline form of polymorph 1 of the free base of the compound of formula

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

[88] in which the powder X-ray diffraction pattern has peaks at diffraction angles (20) of 21.94 and 23.96. In some embodiments, the polymorph 1 form of the free base of the compound of formula

[89] in which the powder X-ray diffraction pattern has peaks at diffraction angles (20) of 21.94, 23.96 and 19.64.

[90] In a further aspect, the invention relates to a pharmaceutical composition comprising at least one compound of Formula (I) or (IA) or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions according to the invention may further comprise a pharmaceutically acceptable excipient. The invention is also a compound of Formula (I) or (IA) or a pharmaceutically acceptable salt thereof, for use as a medicament.

[91] In another aspect, the invention is directed to a method of treating cancer, pain, neurological diseases, autoimmune diseases, or inflammation, comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I) or (IA) or a pharmaceutically acceptable salt thereof.

[92] In another aspect, the invention is directed to the use of a compound of Formula (I) or (IA) in the preparation of a medicament for the treatment of such diseases and medical conditions, and the use of such compounds and salts for treating of such illnesses and medical conditions.

[93] In yet another aspect, the invention relates to a method of inhibiting protein or tyrosine kinases, including one or more of MET, ALK, ROS1, AXL, TRKs, and JAK, comprising contacting a cell comprising a or more of such kinases 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 invention, wherein the contact is in vitro, ex vivo or in vivo.

[94] Additional embodiments, features and advantages of the invention will be apparent from the following detailed description and with the practice of the invention.

[95] For reasons of brevity, descriptions of publications cited in the present specification, including patents, are incorporated herein by reference.

DESCRIPTION OF THE DRAWINGS

[96] Fig. 1 shows a powder X-ray diffraction pattern of the crystalline polymorph form 1 of the free base 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15 -ethenopyrazolo[4,3 — f] [1,4,8,10]benzoxatriazacyclo-tridecin-4(5H)-one (Example 20).

[97] Fig. 2 shows a differential scanning calorimetry thermogram of the crystalline form of polymorph 1 of the free base of 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazole [4,3-f] [1,4,8,10]benzoxatriazacyclo-tridecin-4(5H)-one (Example 20).

DETAILED DESCRIPTION

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

[99] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one skilled in the art to which this invention belongs. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety. If a definition set forth in this section is contrary to or otherwise inconsistent with the definition set forth in a patent, application, or other publication that is incorporated herein by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.

[100] As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Note further that claims may be written to exclude any optional elements. As such, this statement is intended to serve as an antecedent basis for the use of such exclusive terminology as "the only", "only" and the like in connection with the mention of the claimed elements, or the use of a "negative" limitation.

[101] As used herein, the terms "including", "containing", and "comprising" are used in their open, non-limiting sense.

[102] To provide a more concise description, some of the quantitative expressions provided here are not qualified with the term "about." It is understood that, whether the term "about" is used explicitly or not, each quantity presented herein is intended to refer to the actual given value, and is also intended to refer to an approximation to such given value that would be reasonably inferred based on the capability common in the art, including equivalents and approximations due to experimental and/or measurement conditions for such given value. Whenever a yield is presented as a percentage, such yield refers to a mass of the entity for which the yield is presented in relation to the maximum value of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are shown as percentages refer to mass ratios unless otherwise indicated.

[103] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as normally understood by a person skilled in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein may also be used in practicing or testing the present invention, preferred methods and materials are now described. All publications referenced herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

[104] Unless otherwise indicated, the methods and techniques of the present embodiments are generally carried out in accordance with conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, for example, Loudon, Organic Chemistry, fourth edition, New York: Oxford University Press, 2002, pp 360361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth edition, Wiley-Interscience, 2001.

[105] The chemical nomenclature for the compounds described herein has generally been derived using commercially available ACD/Name 2014 (ACD/Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).

[106] It should be noted that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. On the other hand, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of embodiments belonging to the chemical groups represented by the variables are specifically encompassed by the present invention and are disclosed herein as if each and every combination were individually and explicitly described, insofar as such combinations encompass compounds that are stable compounds ( that is, compounds that can be isolated, characterized, and tested for biological activity). Furthermore, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically encompassed by the present invention and are disclosed herein as if each such subcombination of chemical groups were individually and explicitly disclosed herein.

CHEMICAL DEFINITIONS

[107] The term "alkyl" refers to a straight or branched chain alkyl group having from 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like. groups which, in the light of one skilled in the art and the teachings provided herein, would be considered equivalent to any of the preceding examples.

[108] The term "alkenyl" refers to a linear or branched-chain hydrocarbon group having from 2 to 12 carbon atoms in the chain, and having one or more double bonds. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-1-yl. Included in the scope of this term are cis and trans isomers and mixtures thereof.

[109] The term "alkynyl" refers to a straight or branched chain hydrocarbon group having from 2 to 12 carbon atoms in the chain, and having one or more triple bonds. Examples of alkynyl groups include acetylenyl (-C=CH) and propargyl (-CH2C=CH).

[110] The term "cycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic carbocycle, having from 3 to 12 ring atoms. Polycyclic carbocycles include fused, bridged, and spiro polycyclic systems. Illustrative examples of cycloalkyl groups include the following entities, in the form of correctly linked moieties:

[111] The term "halogen" represents chlorine, fluorine, bromine, or iodine. The term "halo" represents chlorine, fluorine, bromine, or iodine.

[112] The term "haloalkyl" refers to an alkyl group with one or more halo substituents, or one, two or three halo substituents. Examples of haloalkyl groups include -CF3, -(CH2)F, -CHF2, -CH2Br, -CH2CF3, and -CH2CH2F.

[113] The term "aryl" refers to monocyclic all-carbon or polycyclic groups of fused rings of 6 to 14 carbon atoms (C-6-C14), with a completely conjugated pi electron system. Aryl includes monocyclic all-carbon or polycyclic groups of fused rings of 6 to 10 carbon atoms (e.g., "Cβ-aryl"). Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted as described above by alkyl or unsubstituted. Substituent groups also include those described elsewhere in this specification in connection with aryl.

[114] The term "heterocycloalkyl" refers to a saturated or partially saturated monocyclic or polycyclic ring structure and has 3 to 12 ring atoms, with 1 to 5 of the ring atoms selected from nitrogen, oxygen and sulfur. Polycyclic ring systems include fused, bridged, and spiro systems. The ring structure may optionally contain up to two oxo groups on carbon or sulfur ring members. Illustrative examples of heterocycloalkyl groups include the following entities, in the form of correctly linked moieties:

[115] The term "heteroaryl" refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen and sulfur) having from 3 to 12 ring atoms per heterocycle. Illustrative examples of heteroaryl groups include the following entities, in the form of correctly linked moieties: A "monocyclic" heteroaryl is a five- or six-membered aromatic heterocycle. A five-membered heteroaryl contains up to four ring heteroatoms, wherein (a) one ring atom is oxygen and sulfur and zero, one, or two ring atoms is/are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. In some embodiments, a five-membered heteroaryl is furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. A six-membered heteroaryl contains one or two nitrogen atoms in the ring. In some embodiments, a six-membered heteroaryl is pyridine, pyrazine, pyrimidine, pyridazine, or triazine. A "bicyclic heteroaryl" is a fused bicyclic system comprising a heteroaryl ring fused to a phenyl or other heteroaryl ring.

[116] The term "oxo" represents a carbonyl oxygen. For example, an oxo-substituted cyclopentyl is cyclopentanone.

[117] The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group does not have any substituents. Whenever the term is used to describe a structural system, substitution is intended to occur at any position permitted by the valence in the system. In some embodiments, "substituted" means that the specified group or moiety bears one, two, or three substituents. In other embodiments, "substituted" means that the specified group or moiety bears one or two substituents. In still other embodiments, "substituted" means that the specified group or moiety bears a substituent.

[118] Any formula described herein is intended to represent a compound of that structural formula, as well as certain variants or forms. For example, a formula presented here is intended to include a racemic form, or one or more enantiomeric, diastereoisomeric, or geometric isomers, or a mixture thereof. Furthermore, any formula presented herein is intended to also refer to a hydrate, solvate or polymorph of said compound, or a mixture thereof.

[119] Any formula presented here is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures represented by the formulas given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as, H 3H, 11c 130 140,15N,180,170 31P,32P,355, 18F,3601, and 125I, respectively. Such isotopically labeled compounds are useful in metabolic studies (preferably with 14C), reaction kinetic studies (with, for example, 2H or 3H), detection or imaging techniques [such as positron emission tomography (PET) or single photon emission computed tomography (SPECT)], including drug or substrate distribution assays in tissue, or in the radioactive treatment of patients. Furthermore, substitution with heavier isotopes such as deuterium (i.e., H) may provide certain therapeutic advantages resulting from greater metabolic stability, e.g., increased half-life in vivo or reduced dosage requirements. The compounds of this invention and isotopically labeled prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and in the Examples and preparations described below, substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[120] The nomenclature "(ATOM)i-j" with j> i, when applied herein to a class of substituents, is intended to refer to embodiments of this invention for which each of the number of members of the atom, from from i to j including i and j, is performed independently. By way of example, the term C 1-3 refers independently to modalities that have one carbon member (Ci), modalities that have two carbon members (C2), and modalities that have three carbon members (C3). .

[121] Any dissubstituent referred to here is intended to cover the various bonding possibilities, when more than one of such possibilities is permitted. For example, reference to disubstituent -AB-, where A B, refers here to such disubstituents with A attached to a substituted first member and B attached to a substituted second member, and also refers to such disubstituents with A attached to the second member and substituted B attached to the first substituted member.

[122] The invention also includes pharmaceutically acceptable salts of the compounds represented by Formula (I) or (IA), preferably one of those described above and the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.

[123] A "pharmaceutically acceptable salt" is intended to mean a salt of an acid or free base of a compound represented herein, which is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S. M. Berge, et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response. A compound described herein may have a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases and inorganic and organic acids, to form a pharmaceutically acceptable salt thereof.

[124] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates , isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexine-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates , phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-l-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985.

[125] For a compound of Formula (I) or (I~A) that contains a basic nitrogen, a pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid 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, a pyranosidyl acid, such such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid such as mandelic acid, citric acid, or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic acid, 2-acetoxybenzoic acid, naphthoic, or cinnamic acid, a sulfonic acid such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid, or any compatible mixture of acids such as those set forth as examples herein, and any other acid and mixture thereof that are considered equivalent or acceptable substitutes depending on the degree of common skill in this technology.

[126] The invention also relates to pharmaceutically acceptable prodrugs of compounds of Formula (I) or (IA), and treatment methods employing such pharmaceutically acceptable prodrugs. The term "prodrug" means a precursor of a designated compound that, upon administration to a subject, gives rise to the compound in vivo through a chemical or physiological process, such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g. , a prodrug when brought to physiological pH is converted to the compound of Formula (I) or (I-A)). A "pharmaceutically acceptable prodrug" is a prodrug that is nontoxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of appropriate prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

[127] The present invention also relates to pharmaceutically active metabolites of compounds of Formula (I) or (I-A), and uses of such metabolites in the methods of the invention. A "pharmaceutically active metabolite" means a pharmacologically active product of the metabolism in the body of a compound of Formula (1} or (I-A) or a salt thereof. The prodrugs and active metabolites of a compound can be determined using routine techniques known or available in the art. See, for example, Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765- Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Designnd and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

REPRESENTATIVE MODALITIES

[128] In some embodiments of Formula (I-A), Ring A' is monocyclic aryl or heteroaryl and Ring B' is a bicyclic heteroaryl. In other embodiments, Ring A' is bicyclic heteroaryl and Ring B' is a monocyclic aryl or heteroaryl. In some embodiments, Ring A' is phenyl or a 6-membered heteroaryl. In other embodiments, Ring B' is a bicyclic heteroaryl containing 1, 2, or 3 nitrogen atoms in the ring. In other embodiments, Ring A' is phenyl or pyridyl.

[129] In still other embodiments, Ring A' is phenyl. In still other embodiments, Ring A' substituted -(R3')p, is In still other embodiments, Ring A' replaced by - (R3') p- is In some embodiments, Ring B' is where Z'-Z7 are defined as described here. In still other embodiments, ring B' is: where Z1-' are defined as described here. In still other embodiments, ring B' is: In still other embodiments, Ring B In still other embodiments, Ring B' is

[130] In other embodiments of Formula (IA), Ring A' is a bicyclic heteroaryl group, and is: where Z1-7 are defined as described here. In still other embodiments, Ring A' is: where Z1-Z7 are defined as described here. In still other embodiments, Ring A' is: In still other embodiments, Ring A' is or In still other embodiments, Ring A' is

[131] In some embodiments, Ring B' is monocyclic aryl or heteroaryl. In other embodiments, Ring B' is phenyl. In other embodiments, Ring B' is pyridyl.

[132] In some embodiments, each R3' is independently deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN, -CF3, -NH2, -NH (Ci-4alkyl) , -N (Cj-aalkyl) 2, -CO2Ci-4alkyl, -CO2H, -NHC(O)Ci_4alkyl, -SO2Ci-4alkyl, -C(O)NH2, -C (O) NH (Ci-4alkyl) , -C(O)N(Ci-4alkyl)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. In still other embodiments, each R3' is independently fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN, or -CF3. In still other embodiments, each R3' is fluorine or chlorine.

[133] In some embodiments, R'” is H, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl, thiofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, or monocyclic heteroaryl, each substituted or not replaced by pore in Formula (I-A). In other embodiments, R'" is H, or is methyl, ethyl, propyl, isopropyl, or cyclopropyl, each unsubstituted or substituted pore in Formula (I-A). In still other embodiments, R' is H or is methyl or ethyl, each unsubstituted or substituted by halogen, -OH, -OCi-4alkyl, -NH2, -NH (C1-4alkyl), -N (C1-4alkyl)2, -CO2H, -CO2Ci-4alkyl, -CONH2, cycloalkyl, or monocyclic heterocycloalkyl. In still other embodiments, R7' is H, methyl, hydroxyethyl, -CH2CONH2, or 3-pyrrolidinylmethyl. In still other embodiments, R7' is H or methyl.

[134] In some embodiments, R1' and R2' are each independently H, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl, thiofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, or heteroaryl monocyclic, each substituted or unsubstituted pore in Formula (I-A). In other embodiments, R1 is H. In still other embodiments, R"' is deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl, thiofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, or monocyclic heteroaryl , each substituted or unsubstituted pore in Formula (I-A). In still other embodiments, R2' is H or is methyl or ethyl, each unsubstituted or substituted by halogen, -OH, -OC1_4alkyl, -NH2, -NH (Ci- 4alkyl), -N(C1-4alkyl)2, -CO2H, -CO2Cx-4alkyl, -CONH2, cycloalkyl, or monocyclic heterocycloalkyl. In yet other embodiments, R2' is H, methyl, fluoromethyl, hydroxymethyl, or cyclopropyl. In yet other In still other embodiments, R2' is H. In still other embodiments, R is methyl.

[135] In some embodiments, each Rk' is independently H, methyl, ethyl, propyl, isopropyl, or cyclopropyl. In other embodiments, each Rk' is independently H or methyl.

[136] In some embodiments, each L1 and L2 is independently -CH2- or -CH(methyl)-, -CH(substituted methyl)-, -CH (C3-6cyclopropyl)-, -CH(OH)-, -0 -, -NH-, -N (C1-4alkyl)-, -N(C3- ecyclopropyl)-, -S-, -S(0)-, or -SO2-. In some embodiments, - (L1)n'*- is -CH2-O-, -CH(CI-4alkyl)-O-, or -CH(C3_6cycloalkyl)-0-. In other embodiments, -(L1)n-- is -CH(H or optionally substituted Cx-4alkyl)-N(H or optionally substituted Cx-4alkyl)-, -CH (CO2Cx-4alkyl or C(O)N(H or C1-4alkyl) 2) “N (H or optionally substituted C1-4alkyl). In still other embodiments, -(L1)n-- is CH2S (O) Q_2-. In other embodiments, -(L1)n-- is -SO2-N (H or Ci-4alkyl). In some embodiments, -(L1)^- is - (CH2) 3— • In some embodiments, -(L1)n'_ is -(CH2)2-. In some embodiments, -(L1)n'_ θ -CH (CH3) CH2-.

[137] In some embodiments, -(L2)ra» is -0-{C(Rr) (R2))2- 3-. In other embodiments, -(L )m> and -O-(CH2) 2-3-. In other embodiments, ~(L2)rar is -N(Rk J-ÍCfR1 ) (R2 ) )2-3-. In other embodiments, -(L2)m< is -N(H or Ci-^alkyl) - (CH2) 2-3-■ In other embodiments, -(L2)m« is -S- (C (R1') (R2'))2-3-. In other embodiments, ~(L2)m< is -SOs-fCtR1') (R2'))2-3“- In still other embodiments, - (L2)m- is -SO2-N (Rv ) - (C ( Rr ) (R2))2—. In still other embodiments, - (L2)ra- is -(CÍR1') (R2') )3-.

[138] 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 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 0. In other embodiments, q' is 1. In still other embodiments, q' is 2.

[139] In some embodiments of formula (I-A) they are compounds of Formula (I), or pharmaceutically acceptable salts thereof. In other embodiments, compounds of formula (I-A) are compounds of Formula (I), wherein each variable is independently defined as indicated below for Formula (I). In some embodiments, the formula (IA) variables map to Formula (I) as follows: A' is A; B' is B; R1 is R1; R2' is R2; R3’ is R3; R4' is R4; R7' is R7; Ra'-Rf' and R1' -Rk' map onto Ra-Rf and R∑-Rk, respectively; and L1 and L2 are -Y- (C(R5) (R6) )m - and -ClfR1) (R2))n-X- respectively.

[140] In some embodiments of Formula (I), ring A is phenyl or a 6-membered heteroaryl. In other embodiments, ring A is phenyl or pyridyl. In still other embodiments, it is phenyl. In still other embodiments, Ring A replaced by - (R3)p is . In still other embodiments, the Ring Replaced by -(R3)p is .

[141] In some embodiments, each R3 is independently deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN, -CF3, -NH2, -NH(CI-4 alkyl) , -N (Ci-4alkyl) 2, -CC^Ci-^alkyl, -CO2H, -NHC (0)Ci-4alkyl, -SO2C1-4 alkyl, -C(0)NH2, -C (O) NH ( Cj.-4alkyl), -C(0)N(C1-4alkyl)2z cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. In still other embodiments, each R3 is independently fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN, or -CF3. In still other embodiments, each R3 is fluorine or chlorine.

[142] In still other embodiments, Ring A replaced by -(R3)p is ' wherein R and R are each independently H, fluorine, or chlorine and M is CH or N. In some embodiments, R3a is fluorine.

[143] In some embodiments, p is 1 or 2. In other embodiments, p is zero. In still other embodiments, p is 1. In still other embodiments, p is 2.

[144] In some embodiments, Ring B is a bicyclic heteroaryl. In other embodiments, Ring B is a 9-membered bicyclic heteroaryl.

[145] In some embodiments, each R4' is independently deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN, -CF3, -NH2, -NH (Ci_4alkyl), - N (Ci-4alkyl) 2, -CO2Ci-4alkyl, -CO2H, -NHC(O)Ci-4alkyl, -SO2Ci-4alkyl, -C(O)NH2, - C (0) NH (Ci-4alkyl), - C(O)N{Ci- 4alkyl)2z cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. In still other embodiments, each R is independently fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN, or -CF3.

[146] In other embodiments, Ring B replaced by - (R4) q is:

[147] wherein Z1, Z2, Z3, and Z6 are each independently -C(RX)- or N;

[148] wherein each Rx is independently H, deuterium, halogen, Ci-4alkyl, -O-Ci-4alkyl, -OH, -NH2, -NHCi-4alkyl, -NH- phenyl, -NH-heteroaryl, CN, or -CF3;

[149] Z4 and Z5 are each independently -C- or -N-; It is

[150] Z7 is -CH-, -N-, or -NH-;

[151] In other modalities:

[152] (a) Z1, Z4 and Z7 are each -N-;

[153] (b) Z1, Z5, and Z7 are each -N-;

[154] (c) Z1 and Z3 are each -N- and Z7 is -NH-;

[155] (d) Z3 is -N- - and Z7 is -NH-;

[156] (e) Z3 and Z6 are each -N- and Z7 is -NH-;

[157] (f) z2, Z4 and Z7 are each -N-;

[158] (g) z1, Z2, Z4 and Z7 are each -N-;

[159] (h) Z1, Z3 and Z4 are each -N-;

[160] (i) z3 and Z4 are each -N-;

[161] (j) Z1, Z2, Z5, and Z7 are each -N-;

[162] (k) z 2 , z 5 ', and Z 7 are each -N-;

[163] (D z3 and Z5 are each -N-;

[164] (m) Z3, z5, and Z6 are each -N-;

[165] (n) z1, Z5, Z6, and Z7 are each -N-;

[166] (o) z2, z5, Z6, and Z7 are each -N-; or

[167] (p) z1, z3, and Z° are each -N- and Z7 is -NH-.

[168] In still other embodiments of (a)-(p), each Z of the ring atom that is not expressly defined independently is -C- or -C(RX)- (consistent with the definition of such ring atom ring) . In still other embodiments, Z3 is -N-. In another embodiment, Z7 is -N- or -NH-. In still other embodiments, Ring B replaced by -(R4)q is:

[169] where Z1'7 are otherwise defined above.

[170] In still other embodiments, Ring B replaced by -(R4)q is:

[171] In still other embodiments, Ring B replaced by - (R4) qe or In still other embodiments, Ring B replaced by -(R)q is

[172] In some embodiments, q is 0. In other embodiments, q is 1.

[173] In some embodiments, R1 and R2 are each independently H, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl, thiofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, or monocyclic heteroaryl, each substituted or unsubstituted pore in Formula (I). In other embodiments, R1 is H. In still other embodiments, R2 is deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl, thiofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, or monocyclic heteroaryl, each substituted or unsubstituted pore in Formula (I). In still other embodiments, R2 is H or is methyl or ethyl, each unsubstituted or substituted by halogen, -OH OCi_4alkyl, -NH2, -NH (Ci-4alkyl), -N (Ci-4alkyl)2, -CO2H, - CO2Ci-4alkyl, -CONH2, cycloalkyl, or monocyclic heterocycloalkyl. In still other embodiments, R2 is H, methyl, fluoromethyl, hydroxymethyl or cyclopropyl. In still other embodiments, R2 is H. In still other embodiments, Rz is methyl. In still other embodiments, R1 is H, and R2 is not H and is in the stereochemical configuration shown below:

[174] In still other embodiments, R1 and R2 are taken together to form a C3-6 cycloalkyl. In other embodiments, R1 and R" are taken together to form a 5- or 6-membered heterocycloalkyl, optionally substituted by C1-4alkyl.

[175] In some embodiments, n is 1 or 2. In still other embodiments, n is 1.

[176] In some embodiments, R5 and R6 are each independently H, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl, thiofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, or monocyclic heteroaryl, each substituted or unsubstituted pore in Formula (I). In other embodiments, each R5 is H. In still other embodiments, each R6 is independently H, or is methyl, ethyl, or cyclopropyl, each substituted or unsubstituted in Formula (I). In still other embodiments, each R6 is independently H or methyl, unsubstituted or substituted by -OH. In still other embodiments, each R6 is H or methyl. In still other embodiments, R5 and R6 are taken together to form a Cs-6cycloalkyl. In other embodiments, R5 and R6 are taken together to form a 5- or 6-membered heterocycloalkyl, optionally substituted by C1-4alkyl.

[177] In some embodiments, m is 2 or 3. In other embodiments, m is 2.

[178] In some embodiments, R7 is H, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl, thiofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, or monocyclic heteroaryl, each substituted or unsubstituted pore in Formula (I). In other embodiments, R is H, or is methyl, ethyl, propyl, isopropyl, or cyclopropyl, each unsubstituted or substituted in Formula (I). In still other embodiments, R is H or is methyl or ethyl, each unsubstituted or substituted by halogen, -OH, -OCi-alkyl, -NH2, -NH (Ci-4alkyl), -N (Ci-4alkyl) 2 , -CO2H, -CO2Ci-4alkyl, -CONH2, cycloalkyl, or monocyclic heterocycloalkyl. In still other embodiments, R7 is H, methyl, hydroxyethyl, -CH2CONH2, or 3-pyrrolidinylmethyl. In still other embodiments, R7 is H or methyl.

[179] In some embodiments, each of X and Y is independently -O- or -N(Rk)-. In some embodiments, X is -0- or -N(Rk)~. In some embodiments, Y is -0-. In some embodiments, each Rk is independently H, methyl, ethyl, propyl, isopropyl, or cyclopropyl. In other embodiments, each Rk is independently H or methyl.

[180] In some embodiments, compounds of Formula (I) or (IA) are compounds of Formula (II):

[181] wherein M, R3, q, R2, X, R7, and Z1 7 are as defined in any of the various forms mentioned above;

[182] R5a, R5b, R6a and R6b are each of R5 and R6 as defined in any of the various ways recited above;

[183] or a pharmaceutically acceptable salt thereof.

[184] In some embodiments, compounds of Formula (I) or (IA) are compounds of Formula (III):

[185] in which

[186] M is CH or N;

[187] R3a and R3b are each independently H, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN, or -CF3;

[188] R2a is H or is methyl or ethyl, each unsubstituted or substituted by halogen, -OH, -OCi-4alkyl, -NH2, -NH(Ci-4alkyl), -N (Ci-4alkyl) 2, -CO2H , -CO2Ci-4alkyl, -CONH2, cycloalkyl, or monocyclic heterocycloalkyl;

[189] X1 is 0 or -N(CH3)-;

[190] R5a, R6a, R5b, and R6b are each independently H, or methyl or ethyl, each unsubstituted or substituted by halogen, -OH, -OCi-6alkyl, -NH2, -NH (Cx_4alkyl), -N( C1-4alkyl)2f -CO2H, -CON (C1-4alkyl), -CON (C1-4alkyl)2, cycloalkyl, or monocyclic heterocycloalkyl;

[191] R7a is H or is methyl or ethyl, each unsubstituted or substituted by halogen, -OH, -OCi-4alkyl, -NH2, -NH(Ci-4alkyl), -N (Ci-4alkyl) 2, -CO2H , -CO2C1-4alkyl, -CONH2, -CONH(C1-4alkyl), -CON(C1-4alkyl)2, cycloalkyl, or monocyclic heterocycloalkyl;

[192] Z1’7 are as defined in any of the various forms mentioned above;

[193] or a pharmaceutically acceptable salt thereof.

[194] In some embodiments of Formula (III), M is CH.

[195] In other embodiments, R3a and RJb are each independently H, fluorine or chlorine. In still other embodiments, R3a is H or fluorine. In still other embodiments, R3a is fluorine. In still other embodiments, R3b is H or chlorine.

[196] In some embodiments of Formula (III), R2a is H, methyl, fluoromethyl, or cyclopropyl.

[197] In some embodiments or Formula (III), X1 is 0. In other embodiments, X is -NICHa)-.

[198] In some embodiments, R7a is H, methyl, hydroxyethyl, -CH2CONH2, or 3-pyrrolidinylmethyl. In other embodiments, R7a is H or methyl.

[199] In some embodiments, compounds of Formula (I) or (IA) are compounds of Formula (IV):

[200] in which

[201] M is CH or N;

[202] X1 and

[203] each Rla and R2a is independently H, deuterium, C1-6alkyl, C3-6cycloalkyl, Cg-io aryl, -CfOIOR3', -C(O)NRaRb', -NRa'Rb', -SRa', -S (O)Ra', -S(O)NRa', -S(O)2Ra', -S(O)2NRa' or -ORa in which each hydrogen atom in Ci-ealkyl is independently optionally replaced by deuterium, halogen , -OH, ~OCi- 4alkyl, -NH2, -NH (Ci-4alkyl) , -N (Ci-4alkyl) 2, NHC (O) Ci-4alkyl, - N (Ci-4alkyl) C (O) Ci- 4alkyl, -NHC (O) NHCi-4alkyl, -N(Ci-4alkyl) C (0) NHC alkyl, NHC (O) N (Ci-4alkyl) 2, -N(CX_4alkyl)C(O)N(Ci_4alkyl) 2, -NHC (O) OCi-4alkyl, -N(CX-4alkyl) C (O) OC1_4alkyl, -CO2H, -CO2Ci-4alkyl, -CONH2, -CONH(Ci-4alkyl) , -CON (Ci-4alkyl) 2, -SCi-4alkyl, -S(O)Ci-4alkyl, -S(O)2Ci-4alkyl, -S(O)NH(Ci-4alkyl) , -S(O)2NH(Ci-4alkyl) , - S(O)N(C1-4alkyl)2, -S(O)2N(C1-4alkyl)2, C3-6cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[204] R3a and R3b are each independently H, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN, or -CF3;

[205] R7a is H, C1-galkyl or 3-7 membered heterocycloalkyl, wherein each hydrogen atom in C1-6alkyl or 3-7 membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -CN, -OH, - OCi-4alkyl, -NH2, -NH (Ci-4alkyl), -N (Ci-4alkyl) 2, -CO2H, -CO2Ci-4alkyl, -CONH2, -CONH (Ci-4alkyl), -CON (Ci-4alkyl) ) 2, cycloalkyl, or monocyclic heterocycloalkyl;

[206] each Rk' is independently H, deuterium, Cx_6alkyl, C2-6alkenyl, C2_6alkynyl, Cs-gcycloalkyl, 3- to 7-membered heterocycloalkyl, Cg-io aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom in C1-alkyl, C2-6alkenyl, Cz-alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, Cβ-aryl, or mono- or bicyclic heteroaryl in Rk' is independently optionally substituted by deuterium, halogen, Ci-ealkyl, Ci-ghaloalkyl or -ORa;

[207] wherein each Ra and Rb is independently H, deuterium, C1-6alkyl, Cz-eβlkenyl, Cz-ealkynyl, Ca-gcycloalkyl, 3- to 7-membered heterocycloalkyl, C6-io aryl, or heteroaryl;

[208] each Z1, Z2, Z3, Z4, Z5, Z6, or Z7 is independently N, NH, or C(RX), wherein each Rx when present is independently H, deuterium, halogen, Ci-4alkyl, -O- Ci-4alkyl, -OH, -NH2, -NH (Ci-4alkyl), -NH(phenyl), -NH(heteroaryl), CN, or -CF3, provided that at least one of Z1, Z2, Z3, Z4, Z5, Z6 or Z1 is N or NH; It is

[209] m' is 2 or 3;

[210] or a pharmaceutically acceptable salt thereof.

[211] In some embodiments, Z1, Z4 and Z7 are N, and Z2, Z3, Z5 and Z6 are C(RX), wherein each Rx when present is H. In some embodiments, Z1 and Z3 are N, Z7 is NH and Z2, Z4, Z5, and Z6 are C(RX), where each Rx when present is H. In some embodiments, Z1, Z3, and Z6 are N, Z7 is NH, and Z2, Z4, and Z5 are C (Rx ), wherein each Rx when present is H. In some embodiments, Z3 is N, Z1 is NH, and Z1, Z2, Z4, Z5, and Z6 are C(RX), wherein each Rx when present is H. In some In some embodiments, Z3 and Z5 are N, Z7 is NH, and Z1, Z2, Z4, and Z5 are C(RX), wherein each Rx when present is H. In some embodiments, Z2, Z4, and Z7 are N and Z1, Z3, Z5 and Z6 are C(RX), where each Rx when present is H. In some embodiments, Z1, Z5 and Z7 are N and Z2, Z3, Z4 and Z6 are C(RA), where each Rx when present is H. In some embodiments, Z1, Z2, Z4 and Z7 are N and Z3, Z5 and Z6 are C(RX), wherein each Rx when present is H. In some embodiments, Z1, Z2, Z5 and Z7 are N and Z3, Z4 and Z6 are C(RX), where each Rx when present is H. In some embodiments, Z3, Z5 and Z6 are N and Z1, Z2, Z4 and Z7 are C(RX), where each Rx when present is H. In some embodiments, Z1, Z5, Z6 and Z7 are N and Z2, Z3 and Z4 are C(RX), wherein each Rx when present is H. In some embodiments, Z1, Z2 and Z4 are N and Z3, Z5, Z6 and Z7 are C(RX), where each Rx when present is H. In some embodiments, Z1, Z3 and Z4 are N and Z2, Z5, Z6 and Z7 are C(RX), where each Rx when present is H. In some embodiments, Z3 and Z4 are N and Z1, Z2, Z5, Z6 and Z7 are C(RX), wherein each Rx when present is H. In some embodiments, Z2, Z5 and Z7 are N and Z1, Z3, Z4 and Z6 are C(Rx), where each Rx when present is H. In some embodiments, Z3 and Z5 are N and Z1, Z2, Z4, Z6 and Z7 are C(RX), in that each Rx when present is H. In some embodiments, Z2, Z5, Z6 and Z7 are N and Z1, Z3 and Z4 are C(RX), wherein each Rx when present is H.

[212] In some embodiments, Rk is selected from the group consisting of H, methyl, ethyl, propyl, iso-propyl, cyclopropyl, 2-hydroxyethyl, 2-hydroxy-2-methyl-propyl, and N-methyl-pyrrole- 3-il. In some embodiments, M is CH. In some embodiments, M is CH, Z1, Z4, and Z7 are N, and Z2, Z3, Z5, and Z6 are C(RX), wherein each Rx when present is H. In some embodiments, M is CH, Z1, Z4 and Z7 are N, Z2, Z3, Z5 and Z6 are C (Rx), where each Rx when present is H, and X1 is -N(Rk')-. In some embodiments, M is CH, Z1, Z4, and Z7 are N, Z2, Z3, Z5, and Zb are C(RX), wherein each Rx when present is H, X1 is -N(Rk')~, and X1 ' is -0-. In some embodiments, M is CH, Z1, Z4 and Z7 are N, Z2, Z3, Z5 and Z6 are C(RX), wherein each RK when present is H, X1 is -C (Rla) (R2a)-, and X1' is -0-.

[213] In some embodiments, compounds of Formula (I) or (IA) are compounds of Formula (V):

[214] in which

[215] M is CH or N;

[216] X1 and

[217] each Rla and R2a is independently H, deuterium, Cy-galkyl, Cg-gcycloalkyl, Cβ-aryl, -C(O)ORa, -C(O)NRa,Rb, -NRa'Rb', -SRa ', -S(O)Ra', -S(O)NRa' , -S(O)2Ra', -S(O)2NRa' or -0Ra wherein each hydrogen atom in Ci_6alkyl is independently optionally replaced by deuterium , halogen, -OH, -OCi- 4alkyl, -NH2, -NH (Ci-alkyl) , -N (Ci-4alkyl) 2, NHC (0) Ci-4alkyl, - N (Ci-4alkyl) Ç (O) Ci-4alkyl, -NHC (0) NHCi-4alkyl, -N(Ci-4alkyl) C (0) NHCi-4alkyl, NHC (O) N (Ci-4alkyl) 2, -N(Ci-4alkyl)C(O ), -CON (Ci-4alkyl) 2, -SCi-4alkyl, -S (0) Ci-4alkyl, -S(O)2Ci- 4alkyl, -S (O)NH(Ci-4alkyl) , -S (0} 2NH (C1-4alkyl), -S(O)N(C1-4alkyl)2f -S(O)2N (C1-4alkyl)2, Ca-cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[218] R3a and R3b are each independently H, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN, or -CF3;

[219] R7a is H, C1-alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in Cj-galkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by halogen, -OH, -OCi-4alkyl, -NH2, -NH (C1-4alkyl), -N (C1-4alkyl) 2, -CO2H, -CO2C1-4alkyl, -CONH2, - CONH (C1-4alkyl) , -CON (C1-4alkyl) 2, cycloalkyl, or monocyclic heterocycloalkyl;

[220] each Rk' is independently H, deuterium, C4-6alkyl, C2-ealkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, Cs-io aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom in C1-θalkyl, C2-βalkenyl, C2-6alkynyl, Cs-βcycloalkyl, 3- to 7-membered heterocycloalkyl, C6-io aryl, or mono- or bicyclic heteroaryl in Rk' is independently optionally substituted by deuterium, halogen, Ci-6alkyl, Ci-ghaloalkyl or -ORa;

[221] wherein each Ra and Rb is independently H, deuterium, Ci-galkyl, C2-6alkenyl, C2-εalkynyl, Ca-gcycloalkyl, 3- to 7-membered heterocycloalkyl, C6-i0 aryl, or heteroaryl;

[222] each Z1, Z2, Z3, Z4, Z5, Ze, or Z7 is independently N, NH, or C(RX), wherein each Rx when present is independently H, deuterium, halogen, Ci-4alkyl, -O- Cj.- 4alkyl, -OH, -NH2, -NH(Ci^alkyl), -NH(phenyl), -NH(heteroaryl), CN, or -CF3, provided that at least one of Z1, Z2, Z3, Z4 , Z5, Z6 or Z7 is N or NH; It is

[223] m' is 2 or 3;

[224] or a pharmaceutically acceptable salt thereof.

[225] In some embodiments, Z1, Z4 and Z7 are N, and Z2, Z3, Z5 and Z6 are C(RX), wherein each Rx when present is H. In some embodiments, Z1 and Z3 are N, Z7 is NH and Z2, Z4, Z5, and Z6 are C(RX), where each Rx when present is H. In some embodiments, Z1, Z3, and Z6 are N, Z7 is NH, and Z2, Zi, and Z5 are C(RX ), wherein each Rx when present is H. In some embodiments, Z3 is N, Z1 is NH, and Z1, Z2, Z4, Z5, and Z6 are C(RX), wherein each Rx when present is H. In some In some embodiments, Z and Z are N, Z and NH and Z, Z2, Z4 and Z5 are C(Rx), wherein each Rx when present is H. In some embodiments, Z2, Z4 and Z7 are N and Z1, Z3, Z5 and Z6 are C(RX), wherein each Rz when present is H. In some embodiments, Z1, Z5, and Z' are N and Z2, Z3, Z4, and Z6 are C(RX), wherein each Rx when present is H. In some embodiments, Z1, Z2, Z4 and Z7 are N and Z3, Z5 and Z6 are C(RX), wherein each Rx when present is H. In some embodiments, Z1, Z2, Z5 and Z7 are N and Z3, Z4 and Z6 are C(RX), where each Rx when present is H. In some embodiments, Z3, Z5 and Z6 are N and Z1, Z2, Z4 and Z7 are C(RX), where each Rx when present is H. In some embodiments, Z1, Z5, Z6 and Z7 are N and Z2, Z3 and Z4 are C(RX), wherein each Rx when present is H. In some embodiments, Z1, Z2 and Z4 are N and Z3, Z5, Z6 and Z7 are C(RX), where each Rx when present is H. In some embodiments, Z1, Z3 and Z4 are N and Z2, Z5, Z6 and Z7 are C(RX), where each Rz when present is H. In some embodiments, Z3 and Z4 are N and Z1, Z2, Z5, Z6 and Z' are C(RX), wherein each Rx when present is H. In some embodiments, Z2, Z5 and Z7 are N and Z1, Z3, Z4 and Z6 are C(RX), where each Rx when present is H. In some embodiments, Z3 and Z5 are N and Z1, Z2, Z4, Z6 and Z7 are C(RX) , wherein each Rx when present is H. In some embodiments, Z2, Z5, Z6 and Z7 are N and Z1, Z3 and Z4 are C(RX), wherein each Rx when present is H.

[226] In some embodiments, Rk' is selected from the group consisting of H, methyl, ethyl, propyl, iso-propyl, cyclopropyl, 2-hydroxyethyl, 2-hydroxy-2-methyl-propyl, and N-methyl-pyrrole -3-il. In some embodiments, M is CH. In some embodiments, M is CH, Z1, Z4, and Z7 are N, and Z2, Z3, Z5, and Z6 are C(RX), wherein each Rx when present is H. In some embodiments, M is CH, Z1, Z4 and Z7 are N, Z2, Z3, Z5 and Z6 are C(RX), where each Rx when present is H, and X1 is -N (Rk' In some embodiments, M is CH, Z1, Z4 and Z7 are N , Z2, Z3, Z5, and Z6 are C(RX), where each Rx when present is H, X1 is -N(Rk')-, and X1' is -0—. In some embodiments, M is CH, Z1, Z*3 and Z7 are N, Z2, Z3, Z5 and Zs are C(RX), where each Rx when present is H, X1 is -C(Rla) (R2a)-, and X1' is -0-.

[227] In some embodiments, compounds of Formula (I) or (IA) are compounds selected from the group consisting of

[228] in which

[229] M is CH or N;

[230] X1 and each Rla and R2a is independently H, deuterium, Ci-θalkyl, Ca-gcycloalkyl, C6-io aryl, -C(O)ORa', - C (0) NRa' Rb' , -NRa'Rb', -SRa' , -S(O)Ra', -S(O)NRa', -S(O)2Ra', -S(O)2NRa or -ORa in which each hydrogen atom in Ci-θalkyl is independently optionally replaced by deuterium , halogen, -OH, -0Ci-4alkyl, -NH2, -NH (Ci-4alkyl) , -N (Ci-4alkyl)2, NHC (0) Ci-4alkyl, -N (Ci-4alkyl) C (0) Ci-4alkyl, -NHC (O)NHCi-4alkyl, -N (Ci-4alkyl) C (O) NHCi-4alkyl, -NHC (0) N (C^4alkyl)2, -N (Ci-4alkyl) C ( 0)N (Ci-4alkyl) 2, -NHC (O) 0C1_4alkyl, - N (Ci-4alkyl) C (0) 0Ci-4alkyl, -CO2H, -CO2Ci-4alkyl, -CONH2, - CONH (Ci-4alkyl) , -CON (Ci-4alkyl) 2, -SCi-4alkyl, -S (0) Ci-4alkyl, - S(O)2C1_4alkyl, -S (0) NH (Ci-4alkyl) , -S (0) 2NH ( C1-4alkyl), -S(0)N(C1-4alkyl)2, -S(0)2N(C1-4alkyl)2, C3-6cycloalkyl, or 3- to 7-membered heterocycloalkyl;

[231] R3a and R3b are each independently H, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN, or -CF3;

[232] R7a is H, C1-alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C1-galkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by halogen, -OH, -OCi-4alkyl, - NH2, -NH (C1-4alkyl), -N (C1-4alkyl)2, -CO2H, -CO2C1-4alkyl, -CONH2, -CONH (C1-4alkyl), -CON (C1-4alkyl)2, cycloalkyl, or monocyclic heterocycloalkyl;

[233] each Rk' is independently H, deuterium, C1-6alkyl, C2-galkenyl, C2-galkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, Cg-io aryl, or mono- or bicyclic heteroaryl; wherein each hydrogen atom in C1-galkyl, C2-6alkenyl, C2-ealkynyl, Ca-gcycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or mono- or bicyclic heteroaryl in Rk/ is independently optionally substituted by deuterium, halogen, Ci-galkyl, Cj-$haloalkyl or -0Ra;

[234] wherein each Ra' and Rb' is independently H, deuterium, Ci-galkyl, C2_6alkenyl, C2-6alkynyl, Ca-ecycloalkyl, 3- to 7-membered heterocycloalkyl, Cβ-aryl, or heteroaryl;

[235] each Z1, Z2, Z3, Z4, Z5, Z6, or Z7 is independently N, NH, or C(RX), wherein each Rx when present is independently H, deuterium, halogen, Ci-4alkyl, -O- Ci-4alkyl, -OH, -NH2, -NH (C1-4alkyl), -NH (phenyl), -NH (heteroaryl), CN, or -CF3, provided that at least one of Z1, Z2, Z3, Z4, Z5, Z6 or Z7 is N or NH; It is

[236] m' is 2 or 3;

[237] or a pharmaceutically acceptable salt thereof.

[238] In some embodiments, Z1, Z4 and Z7 are N, and Z2, Z3, Z5 and Z6 are C(RX), wherein each Rx when present is H. In some embodiments, Z1 and Z3 are N, Z7 is NH and Z2, Z4, Z5, and Z6 are C(RX), where each Rx when present is H. In some embodiments, Z1, Z3, and Z6 are N, Z7 is NH, and Z2, Z4, and Z5 are C(RX ), wherein each Rx when present is H. In some embodiments, Z3 is N, Z7 is NH, and Z1, Z2, Z4, Z5, and Z6 are C(RX), wherein each Rx when present is H. In some In some embodiments, Z3 and Z6 are N, Z7 is NH, and Z1, Z2, Z4, and Z5 are C(RX), wherein each Rx when present is H. In some embodiments, Z2, Z4, and Z7 are N and Z1, Z3, Z5 and Z6 are C(RX), where each Rx when present is H. In some embodiments, Z1, Z5 and Z7 are N and Z2, Z3, Z4 and Zs are C(RX), where each Rx when present is H. In some embodiments, Z, Z, Z and Z are N and Z, Z5 and Z6 are C(RX), wherein each Rx when present is H. In some embodiments, Z1, Z2, Z5 and Z7 are N and Z3, Z4 and Z6 are C(RX), where each Rx when present is H. In some embodiments, Z3, Z5 and Z° are N and Z1, Z2, Z4 and Z7 are C(RX), where each Rx when present is H. In some embodiments, Z1, Z5, Z6 and Z' are N and Z2, Z3 and Z4 are C(RX), wherein each Rx when present is H. In some embodiments, Z1, Z2 and Z4 are N and Z1, Z5, Z6 and Z7 are C(RX), where each Rx when present is H. In some embodiments, Z1, Z2 and Z4 are N and Z5, Z5, Z6 and Z7 are C(RX), in wherein each Rx when present is H. In some embodiments, Z3 and Z4 are N and Z1, Z2, Z5, Ze and Z7 are C(RX), wherein each Rx when present is H. In some embodiments, Z2, Z5 and Z' are N and Z1, Z3, Z4 and Z6 are C(RX), where each Rx when present is H. In some embodiments, Z3 and Z5 are N and Z1, Z2, Z4, Z6 and Z7 are C(RX ), wherein each Rx when present is H. In some embodiments, Z2, Z5, Z6 and Z7 are N and Z1, Z3 and Z4 are C(RX) , wherein each Rx when present is H.

[239] In some embodiments, Rk' is selected from the group consisting of H, methyl, ethyl, propyl, iso-propyl, cyclopropyl, 2-hydroxyethyl, 2-hydroxy-2-methyl-propyl, and N-methyl-pyrrole -3-il. In some embodiments, M is CH. In some embodiments, M is CH, Z1, Z4, and Z7 are N, and Z2, Z3, Z5, and Z6 are C(RX), where each Rx when present is H. In some embodiments, M is CH, Z1, Z4 and Z7 are N, Z2, Z3, Z5 and Z6 are C(RX), where each Rx when present is H, and X1 is -N(Rk'In some embodiments, M is CH, Z1, Z4 and Z7 are N , Z2, Z3, Z5, and Z6 are C(RX), where each Rx when present is H, X1 is -N(Rk')-, and X1' is -0-. In some embodiments, M is CH, Z1 , Z4 and Z7 are N, Z2, Z3, Z5 and Z6 are C(RX), where each Rx when present is H, X1 is -C(Rla) (R2a)-, and X1' is -O-.

[240] In other embodiments, the compound of Formula (I) or (I-A) is selected from the group consisting of (13R)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazole [4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; (13R)-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1, 10,4,8]benzodioxadiazacyclotridecin-4(5H )-one; 11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; (13RJ-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazole [4,3-f] [1,10,4,8]benzodioxadiazacyclotrideein- 4(5H)-one; 12-chloro-1-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazole [4,3-f] [1,10,4, 8]benzodioxadiazacyclotridecin- 4(5H)-one; (13R)-12-chloro-1-fluoro-5-(2-hydroxyethyl}-13-methyl- 6, 7-dihydro-13H-1,15-ethenopyrazole [4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 12-chloro-1-fluoro-5-(2-hydroxyethyl)-13-methyl-6,7-di -hydro-13H-1,15-ethenopyrazole [4,3-f] [1,10,4,8]benzodioxadiazacyclotridecin- 4(5H)-one; 2-[(13R)-12-chloro-1-fluoro- 13-methyl-4-oxo-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f] [1,10,4,8]benzodioxadiazacyclotridecin-5(4H)-yl]acetamide; 2-[12-chloro-1-fluoro-13-methyl-4-oxo-6,7-dihydro-13H-1,15-ethenopyrazole [4,3-f] [1,10,4,8] benzodioxadiazacyclotridecin-5(4H)-yl]acetamide; (13R)-12-chloro-1-fluoro-13-rethyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro-13H-1,15 -ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 12-chloro-1-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6 , 7-dihydro-13H-1,15-ethenopyrazolo [4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; (13R)-12-chloro-1-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3- f][1,10 ,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazole [4,3-f] [1,10,4,8 ]benzodioxadiazacyclotridecin-4(5H)-one; (13S)-11-fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3- f][1,10,4,8]benzodioxadiazacyclotridecin -4(5H)-one; 11-fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f] [1,101 4,8]benzodioxadiazacyclotridecin-4(5H)-one ; (13R)-13-cyclopropyl-1-fluoro-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo [4, 3-f][1,10,4,8]benzodioxadiazacyclotridecin-4 (5H)-one; 13-cyclopropyl-1-fluoro-5-methyl-6,7-dihydro-13H- 1,15-ethenopyrazolo[4,3-f] [1,10,4,8] benzodioxadiazacyclotridecin- 4(5H)- onea; (13R)-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo [4,3-f][1,10,4,8]benzodioxadiazacyclotridecin- 4(5H)- onea; 11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; (13R)-12-chloro-1-fluoro-13-methyl-6,7-dihydro-13H- 1,15-ethenopyrazolo[4,3-f] [1,10,4,8]benzodioxadiazacyclotridecin- 4 (5H)-one; 12-chloro-1-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazole [4,3-f][1,10,4,8]benzodioxadiazacyclotridecin- 4(5H)- onea; 12-chloro-1-fluoro-6-methyl-6,7-dihydro-13H-1,15-ethenopyrazole [4,3-f] [1,10,4,8]benzodioxadiazacyclotridecin- 4(5H)- onea; 12-chloro-1-fluoro-7-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo [4,3-f][1,10,4,8]benzodioxadiazacyclotridecin- 4(5H)- onea; (8R)-9-chloro-10-fluoro-8-methyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1—f] [1, 10,4,7, 8]benzodioxatriazacyclotridecin - 17{14H)-one; 9-chloro-10-fluoro-8-methyl-15,1β-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7, 8]benzodioxatriazacyclotridecin- 17(14H )-one; (7R)-8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H- 3,5- (azenomethene)pyrrolo[3,4- f] [1,10,4, 8]benzodioxadiazacyclotridecin-1β(13H)-one; 8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5-(azenomethene)pyrrolo[3,4-f] [1,10,4,8]benzodioxadiazacyclotridecin- 16(13H)-one; (5R)-3-fluoro-5-methyl-14,15-dihydro-5H,10H-9,7-(azenomethene)pyrido[2,3- k]pyrrolo[3,4-d][1, 10,3,7]dioxadiazacyclotridecin-12(13H)-one; 3-fluoro-5-methyl-14,15-dihydro-5H,10H-9,7-(azenomethene)pyrido[2,3-k]pyrrolo[3,4-d] [1,10,3, 7]dioxadiazacyclotridecin-12(13H)-one; (5R)-3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H-9,7-(azenomethene)pyrido[2,3-k]pyrrolo[3,4-d ][1,3,7, 10]oxatriazacyclotridecin-12(10H)-one; 3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H-9,7-(azenomethene)pyrido[2,3- k]pyrrolo[3,4-d][1, 3,7,10]oxatriazacyclotridecin-12(10H)-one; (13R)-12-chloro-1-fluoro-5,13-dimethyl-6,7-dihydro-2H,13H-1,15-(azenomethene)pyrrolo[3,4-f][1,10, 4]benzodioxazacyclotridecin-4(5H)-one; 12-chloro-1-fluoro-5,13-dimethyl-6,7-dihydro-2H,13H- 1,15- (azenomethene)pyrrolo[3,4- f][1,10,4]benzodioxazacyclotridecin- 4(5H)-one; (7R)-8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenomethene)pyrazolo[3,4-f][1,10, 4]benzodioxazacyclotrideein-16(13H)-one; 8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H- 3,5-(azenomethene)pyrazolo[3,4- f] [1,10,4]benzodioxazacyclotridecin- 16(13H)-one; 11-fluoro-14-methyl-β,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; chloro-1-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazole [4,3-f] [1,4,8,10]benzoxatriazacyclotridecin-4(5H )- one; 12-chloro-1-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazole [4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4 (5H)- one; 12-chloro-1-fluoro-5,14-dimethyl-6,7, 13, 14-tetrahydro- 15,1-(azenomethene)pyrazolo[4,3- f][1,4,10]benzoxadiazacyclotridecin- 4(5H)-one; 12-chloro-1-fluoro-14-methyl-6,7,13,14-tetrahydro-15,1-(azenomethene)pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one; 12-chloro-1-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-(azenomethene)pyrrolo[3,2-f] [1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one; 12-chloro-1-fluoro-14-methyl-6,7,13,14-tetrahydro- 1,15- (azenomethene)pyrrolo[3,2- f][1,4,10]benzoxadiazacyclotridecin-4( 5H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,β-ethenoimidazo[5,1- f] [1,4,7,8,10]benzoxatetraazacyclotridecin-17 (14H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3- (azenomethene)imidazo[5,1- f][1,4,7,8,10] benzoxatetraazacyclotridecin-17(14H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(azenomethene)imidazo[5,1-f][1,4,7,10]benzoxatriazacyclotridecin- 17(14H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-(azenometene)pyrrolo[2,1-f][1,4,7,10]benzoxatriazacyclotrideein- 17(14H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15, 16-tetrahydro-3,6-(azenomethene)imidazo[2,1-f] [1,4,7,10]benzoxatriazacyclotridecin- 17(14H)-one; 9-chloro-1O-fluoro-7-methyl-7, 8,15,16-tetrahydro-3,6-etheno[1,2,4]triazolo[3,4—f] [1,4,7 ,8,10]benzoxatetraazacyclotridein-17(14H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(azenomethene) [1,2,4]triazolo[3,4- f] [1,4 ,7,10]benzoxatriazacyclotridecin-17(14H)-one; 8-chloro-9-fluoro-6~methyl-6,7,14,15-tetrahydro-2H-3,5-(azenomethene)pyrrolo[3,4-f] [1,4,8,10] benzoxatriazacyclotridecin-16(13H)-one; 8-chloro-9-fluoro-6-methyl-6, 7, 14,15-tetrahydro-2H- 3,5-(azenomethene)pyrazolo[3,4— f][1,4,8,10] benzoxatriazacyclotridecin-16(13H)-one; 8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5- (azenomethene)pyrazolo[3,4-f][1,4,10]benzoxadiazacyclotrideein- 16(13H)-one; 12-chloro-1-fluoro-5,14-dimethyl-6,7,13,14-tetrahydro-2H-1,15-(azenomethene)pyrrolo[3, 4- f][1,4,10] benzoxadiazacyclotridecin-4(5H)-one; (8R)-10-fluoro-8,16-dimethyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7, 8]benzodioxatriazacyclotridecin-17 {14H)-one; 10-fluoro-8,16-dimethyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7, 8]benzodioxatriazacyclotridecin-17(14H)- onea; (7R)-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenomethene)pyrrolo[3,4- f] [1,10,4,8] benzodioxadiazacyclotridecin-16(13H)-one; and 9-fluoro-7,15-dimethyl-14,15-dihydro-2H, 7H-3,5-(azenomethene)pyrrolo[3,4-f][1,10,4,8]benzodioxadiazacyclotridecin-16 (13H)-one; or a pharmaceutically acceptable salt thereof.

[241] In other embodiments, the compound of Formula (I) or (I-A) is selected from the group consisting of 12-chloro-1-fluoro-14-methyl-6,7,13,14-tetrahydro-1 , 15-ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-3,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f] [1,4,8,10]benzoxatriazacyclotridecin-4(5H)- onea; 10-fluoro-8-methyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one; 10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-ethenoimidazo[5,1- f] [1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H)- onea; 14-ethyl-11-fluoro-6,7,13, 14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-14-propyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; ll-fluoro-14-(propan-2-i1)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f] [1,4,8,10]benzoxatriazacyclotridecin-4 (5H)-one; 14-cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-14-(2-hydroxyethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazole [4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H )- one; 11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo [4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- onea; 14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; (13R)-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f] [1,4,8,10]benzoxatriazacyclotridecin-4(5H )-one; 12-chloro-1-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f] [1,4,8,10]benzoxatriazacyclotridecin-4(5H )-one; ll-fluoro-14-methyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3—f] [1,4,8,10]benzoxatriazacyclotridecine -7-carboxamide; 11-fluoro-7-(hydroxymethyl)-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazole [4,3-f] [1,4,8,10]benzoxatriazacyclotridecin-4 (5H)- one; 11-fluoro-13-methyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazole [4,3-f] [1,4,8,10]benzoxatriazacyclotridecine -7- carboxamide; 11-fluoro-7-(hydroxymethyl)-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin-4 (5H)-one; ll-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecine-7-carboxamide ; 11-fluoro- 7-(hydroxymethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f] [1,4,8,10]benzoxatriazacyclotridecin-4(5H)- onea; methyl 11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3- f] [1,4,8,10]benzoxatriazacyclotridecine-13- carboxylate; 11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecine-13-carboxamide ; 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f]pyrido[3,2-1][1,4,8,10]oxatriazacyclotridecin -4(5H)-one; 11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f]pyrido[3,2-1][1,4,8,10]oxatriazacyclotridecin -4(5H)-one; 11-fluoro-13-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo [4,3-f]pyrido[3,2- 1] [1,4 ,8,10]oxatriazacyclotridecin-4(5H)-one; 13-cyclopropyl-1-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2- 1] [1,4,8,10]oxatriazacyclotridecin -4(5H)-one; 13-cyclopropyl-1-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; ll-fluoro-13-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecin-4 (5H}-one; 11-fluoro-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one; 11-fluoro-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one 14,14-dioxide; 6 ,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][10,1,4,8]benzoxathiadiazacyclotridecin-4(5H)-one; 14-methyl- 6, 7,13,14 -tetrahydro-1,15-ethenopyrazolo[4,3- f] [1,4,8,10]benzotiatriazacyclotridecin-4(5H)-one; 13-methyl-6,7,13,14-tetrahydro -1,15-ethenopyrazolo[4,3— f] [1,4,8,10]benzotiatriazacyclotridecin-4(5H)-one; 11-fluoro-6,7-dihydro-5H-1,15-ethenopyrazole [3,4— e][11,1,2,4,8]benzoxathiatriazacyclotridecin-4(14H)-one 13,13- dioxide; 11-fluoro-14-methyl-6,7-dihydro-5H- l,15-ethenopyrazole [3,4-e][11,1,2,4,8]benzoxathiatriazacyclotridecin-4(14H)-one 13,13-dioxide; 12-fluoro-15-methyl-5,6,7 ,8,14,15-hexahydro-4H-1,16-etheriopyrazolo [4.3-g] [1,5,9,11]benzoxatriazacyclotetradecin-4-one; 12-fluoro-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3- g] [1,5,9,11]benzoxatriazacyclotetradecin-4 -ona; (14R)-12-fluoro- 14-m.ethyl-5, 6,7,8,14,15-hexahydro-4H-1, 16-ethenopyrazole [4.3- g] [1.5, 9 ,11]benzoxatriazacyclotetradeciπ-4-one; 11-fluoro-7,14-dimethyl-4,5,6,7,13,14-hexahydro-8H-1,15-ethenopyrazolo[3,4-e] [2,4,10]benzotriazacyclotridecin-8 -ona; 11-fluoro-7,14-dimethyl- 6,7,13,14-tetrahydro-1,15-ethenopyrazolo[3,4- e] [7,2,4,10]benzoxatriazacyclotridecin-8(5H)- onea; 11-fluoro-7,14-dimethyl-4,5,6,7,13,14-hexahydro-δH-1,15-ethenopyrazolo[3,4-e] [2,4,7,10]benzotetraazacyclotridecin -8-one; ll-fluoro-4,7,14-trimethyl-4,5,6,7,13,14-hexahydro-8H-1,15-ethenopyrazolo[3,4-e] [2,4,7,10 ]benzotetraazacyclotridecin-8-one; 11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[3,4- e] [7,2,4,10]benzotiatriazacyclotridecin-θ(5H)- onea; 11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[3,4- e] [7,2,4,10]benzotiatriazacyclotridecin-8(5H)- ona 4,4-dioxide; and 12-fluoro-8,15-dimethyl-5,6,7, 8, 14,15-hexahydro-9H-1,16-ethenopyrazolo[3,4-e][7,2,4,8, 11]benzotiatetraazacyclotetradecin-9-one 4,4-dioxide; or a pharmaceutically acceptable salt thereof.

[242] In other embodiments, the compound of Formula (I) or (I-A) is selected from the group consisting of 11-chloro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazole [4,3-f] [1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 13-ethyl-1-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 13-cyclobutyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f](1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-14-methyl(6, 6, 7,7-2H4)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f] [1,4,8, 10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-13-phenyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3 - f][1,4,8, 10]benzoxatriazacyclotridecin-4(5H)-one; 13-(cyclopropylmethyl)-1-fluoro-6,7,13, 14-tetrahydro-1,15-ethenopyrazole [4,3-f] [1,4, 8,10]benzoxatriazacyclotridecin-4(5H)-one; (72?, 147?)-12-fluoro-7-hydroxy-14-methyl-5, 6,7,8,14, 15-hexahydro-4 2í-1,16-ethenopyrazolo[4,3—g] [1,5,9,11]benzoxatriazacyclotetradecin-4-one; (7S, 142?)-12-fluoro-7-hydroxy-14-methyl-5, 6,7,8,14,15-hexahydro-42í-1,16-ethenopyrazole [4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one; (72?, 132?) -11-fluoro-7,13-dimethyl-6, 7,13,14-tetrahydro-1,15-ethenopyrazole [4,3-f] [1,4,8,10]benzoxatriazacyclotridecin-4 (5H )~one; (7S, 132?) -11-fluoro-7,13-dimethyl-6,7,13, 14-tetrahydro-1,15-ethenopyrazole [4,3-f][1,4, 8,10]benzoxatriazacyclotridecin-4(5H)-one; (72?) - ll-fluoro-7,14-dimethyl-6, 7,13, 14-tetrahydro-1, 15-ethenopyrazolo [4,3-f][1,4,8,10]benzoxatriazacyclotridecin- 4(511)- one; (62?)-ll-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin- 4(5H)- one; 12-fluoro-7-hydroxy-15-methyl-5,6, 7,8, 14,15-hexahydro-42í-1,16-ethenopyrazolo[4,3-g] [1,5,9,11 ]benzoxatriazacyclotetradecin-4-one; 7S)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10]benzoxatriazacyclotridecin-4 ( 5H) - one; 11-fluoro-13-(hydroxymethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazole [4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- onea; 12-fluoro-14-(hydroxymethyl)-5,6,7,8,14,15-hexahydro-4H- 1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin - 4-one; 11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazole [4,3-f] [1,4,8,10]benzoxatriazacyclotridecin-4 (5H)- onea; 11-fluoro-14-(2-hydroxy-2-methylpropyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f] [1,4,8,10]benzoxatriazacyclotridecin -4(5H)-one; 12-fluoro-5,6,7,8,14, 15-hexahydro-4H-1,16-ethenopyrazole [4,3-g] [1,5,9]benzoxadiazacyclotetradecin-4-one; 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10]benzotiatriazacyclotridecin-4(5H)-one; ll-fluoro-14-(1-methylpyrrolidin-3-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin -4 (5H) - one; 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazole [4,3-f] [1,4,8,10]benzothiatriazacyclotridecin-4(5H)-one 8 -oxide; 11-fluoro-14-methyl-6, 7,13, 14-tetrahydro-1, 15-ethenopyrazole [4,3-f][1,4,8,10]benzotiatriazacyclotridecin-4(5H)-one 8 ,8-dioxide; (7S)-11-fluoro-7-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8]benzoxadiazacyclotridecin-4(5H)- onea; (6S, 131?)-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazole [4,3-f][1,4,8,10 ]benzoxatriazacyclotridecin-4(5H)-one; (6R,131?)-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazole [4,3-f] [1,4,8,10] benzoxatriazacyclotridecin-4(5H)-one;(7S,13S)-11-fluoro-13-(hydroxymethyl)-7-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3 - f] [1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; and 11-fluoro-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3- /] [1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one; or a pharmaceutically acceptable salt thereof,

[243] In other embodiments, the compound of Formula (I) or (I-A) is selected from the group consisting of (13R)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazole [4,3-f] [1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; <13R)—11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3- f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H )-one; (13R)-12-chloro-1-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazole [4,3-f] [1,10,4,8]benzodioxadiazacyclotridecin - 4(5H)-one; (13R)-12-chloro-1-fluoro-5-(2-hydroxyethyl)-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10 ,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 2-[(13R)-12-chloro-1-fluoro-13-methyl-4-oxo-6,7-dihydro-13H-1,15-ethenopyrazole [4,3-f] [1,10, 4,8]benzodioxadiazacyclotridecin-5(4H)-yl]acetamide; (13R)-12-chloro-1-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f] [ 1 ,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; (13R)-12-chloro-1-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H- 1,15-ethenopyrazolo[4,3-f][1, 10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; (13S)-11-fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3- f][1,10,4,8]benzodioxadiazacyclotridecin -4(5H)-one; (13R)-13-cyclopropyl-11-fluoro-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo [4,3-f][1,10,4,8]benzodioxadiazacyclotridecin- 4 (5H)-one; (13R)-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazole [4, 3-f] [1,10,4,8]benzodioxadiazacyclotridecin-4(5H)- onea; (13R)-12-chloro-1-fluoro-13-methyl-6,7-dihydro-13H- 1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin- 4 (5H)-one; (8R)-9-chloro-10-fluoro-8-methyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f] [1,10,4,7,8]benzodioxatriazacyclotridecin - 17 (14H)-one; (7R)-8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H- 3,5-(azenomethene)pyrrolo[3,4- f] [ 1,10,4, 8]benzodioxadiazacyclotridecin-16(13H)-one; (5R)-3-fluoro-5-methyl-14,15-dihydro-5H, 10H-9, 7-(azenomethene)pyrido[2,3-k]pyrrolo[3,4-d][1, 10,3,7]dioxadiazacyclotridecin-12(13H)-one; (5R)-3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H-9,7-(azenomethene)pyrido[2,3-k]pyrrolo[3, 4- d ] [1,3,7,10]oxatriazacyclotridecin-12(10H)-one; (13R)-12-chloro-1-fluoro-5,13-dimethyl-6,7-dihydro-2H, 13H-1,15-(azenometene)pyrrolo[3,4-f][1,10, 4]benzodioxazacyclotrideein-4(5H)-one; (7R)-8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5-(azenomethene)pyrazolo[3,4-f] [1/10, 4]benzodioxazacyclotridecin-16(13H)-one; (13R)-12-chloro-11-fluoro-13,14-dimethyl-6,7,13, 14-tetrahydro-1,15-ethenopyrazole [4,3-f][1,4,8,10] benzoxatriazacyclotridecin-4(5H)-one; (8R)-10-fluoro-8,16-dimethyl-15,16-dihydro-8H-3,6-ethenolmidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17 (14H)-one; (7R)-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5- (azenomethene)pyrrolo[3,4- f] [1,10,4,8] benzodioxadiazacyclotridecin-16(13H)-one; (13R)-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f] [1,4,8,10]benzoxatriazacyclotridecin-4(5H )-one; (14R)-12-fluoro-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11 ]benzoxatriazacyclotetradecin-4-one;(7R,14R)-12-fluoro-7-hydroxy-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4, 3— g] [1,5,9,11]benzoxatriazacyclotetradecin-4-one; (7S,14R)-12-fluoro-7-hydroxy-14-methyl-5,6, 7, 8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1 ,5,9,11]benzoxatriazacyclotetradecin-4-one; (7R, 13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazole [4,3-f][1,4,8,10]benzoxatriazacyclotridecin -4(5H)- one; (7S,13R)-11-fluoro-7,13-dimethyl-6, 7, 13, 14-tetrahydro-1,15-ethenopyrazole [4,3-f][1,4,8,10]benzoxatriazacyclotridecin -4(5H)- one; (7R)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazole [4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4 (5H)- one; (6R)-11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazole [4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4 (5H)- one; (7S)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazole [4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4 (5H)- one; (7S)-11-fluoro-7-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazole [4,3-f] [1,4,8]benzoxadiazacyclotridecin-4(5H)- onea; (6S,13R)-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazole [4, 3-f] [1,4,8,10]benzoxatriazacyclotridecin -4(5H)-one;(6R,13R)-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazole [4,3-f][1 ,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; and (7S,13S)-11-fluoro-13-(hydroxymethyl)-7-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4, 8,10]benzoxatriazacyclotridecin-4(5H)-one; or a pharmaceutically acceptable salt thereof.

[244] The following illustrative modalities represent compounds of Formula (I) or (IA): and pharmaceutically acceptable salts thereof.

[245] The following represent illustrative embodiments of compounds of Formula (I) or (IA):

[246] and pharmaceutically acceptable salts thereof.

[247] The following represent illustrative embodiments of compounds of Formulas (I) or (IA):

[248] and its pharmaceutically acceptable salts.

[249] Those skilled in the art will recognize that the species listed or illustrated here are not exhaustive and that other species within the scope of these defined terms may also be selected.

PHARMACEUTICAL COMPOSITIONS

[250] For treatment purposes, pharmaceutical compositions comprising the compounds described herein may further comprise one or more pharmaceutically acceptable excipients. A pharmaceutically acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate the administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, coloring agents, thickening agents, emulsifiers, or flavor modifying agents. In preferred embodiments, the pharmaceutical compositions according to the invention are sterile compositions. Pharmaceutical compositions can be prepared using formulation techniques known or becoming available to those skilled in the art.

[251] Sterile compositions are also contemplated by the invention, including compositions that are in accordance with national and local regulations governing such compositions.

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

[253] For oral administration, the compounds of the invention can be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds of the invention can be formulated to obtain a dosage of, for example, from about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 to 250 mg per day, or about 250 mg to 1 g per day. Oral tablets may include the active ingredients mixed with compatible pharmaceutically acceptable excipients, such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preserving agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Illustrative liquid oral excipients include ethanol, glycerol, water and the like. Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binders may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets 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.

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

[255] Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or another suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically acceptable excipients such as suspending agents (e.g., sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (e.g. methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

[256] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal or subcutaneous administration, the agents of the invention can be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit dose form such as ampoules or disposable injection devices, in multidose forms such as vials from which the appropriate dose can be withdrawn, or in a solid or preconcentrated form that can be used to prepare a injectable formulation. Illustrative infusion doses range from about 1 to 1000 μg/kg/minute of agent mixed with a pharmaceutical carrier for a period ranging from several minutes to several days.

[257] For nasal, inhaled, or oral administration, the pharmaceutical compositions of the invention can be administered using, for example, a spray formulation that also contains a suitable carrier. The compositions of the invention can be formulated for rectal administration as a suppository.

[258] For topical applications, the compounds of the present invention are preferably formulated as creams or ointments or similar vehicle suitable for topical administration. For topical administration, the compounds of the invention can be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% drug to carrier. Another mode of administering the agents of the present invention may utilize an adhesive formulation to perform transdermal administration.

[259] As used herein, the terms "treat" or "treatment" encompass both "preventive" and "curative" treatment. "Preventive" treatment is intended to indicate a delay in the development of a disease, a symptom of a disease, or medical condition, to suppress symptoms that may appear, or to reduce the risk of development or recurrence of a disease or symptom. "Curative" treatment includes reducing the severity of suppression or worsening of an existing disease, symptom, or condition. Thus, treatment includes improving or preventing the worsening of existing symptoms of the disease, preventing additional symptoms from occurring, improving or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., stopping the development of the disorder or disease, alleviate the disorder or disease, cause regression of the disorder or disease, alleviate a condition caused by the disease or disorder, or stop the symptoms of the disease or disorder.

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

[261] Examples of diseases include cancer, pain, neurological diseases, autoimmune diseases, and inflammation. Cancer includes, for example, lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophagogastric cancers, glioblastoma, head and neck cancers, myofibroblastic inflammatory tumors, and anaplastic large cell lymphoma. Pain includes, for example, pain of any origin or etiology, including pain associated with cancer, pain from chemotherapy treatment, nerve pain, pain from injury, or other origins. Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren's 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, allergy, and inflammation from infection or injury.

[262] In one aspect, the compounds and pharmaceutical compositions of the invention specifically target receptor tyrosine kinases, in particular, MET, ALK, AXL, TRKs and JAKs. Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, reduce or inhibit the activity of one or more of these kinases. In preferred embodiments, the treatment methods are directed to the cancer. In other embodiments, the methods are for treating lung cancer or non-small cell lung cancer.

[263] In the inhibitory methods of the invention, an "effective amount" means an amount sufficient to inhibit the target protein. Measuring such target modulation can be accomplished by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cell is preferably a cancer cell with abnormal signaling due to upregulation of MET, ALK, AXL, TRKs and/or JAKs.

[264] In methods of treatment according to the invention, an "effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects in need of such treatment. Effective amounts or doses of the compounds of the invention can be determined through routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of drug administration or release. , the pharmacokinetics of the agent, the severity and course of the infection, the subject's health status, condition and weight, and the judgment of the treating physician. An exemplary dose is in the range of about from about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 to 250 mg per day, or about 250 mg to 1 g per day. The total dosage may be administered in single or divided dosage units (e.g., BID, TID, QID).

[265] Once improvement in the patient's disease has occurred, the dose can be adjusted for preventive or maintenance treatment. For example, the dosage or frequency of administration, or both, may be reduced as a function of symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an adequate level, treatment can cease. Patients may, however, require intermittent treatment on a long-term basis following any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.

COMBINATION OF DRUGS

[266] The compounds of the invention described herein can be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein. Additionally additional active ingredients include other therapies or agents that mitigate the adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, improve other symptoms of the disease, reduce one or more side effects, or decrease the required dose of a compound of the invention. Additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present invention or may be included with a compound of the present invention in a single pharmaceutical composition. Additional active ingredients can be administered simultaneously with, before, or after administration of a compound of the present invention.

[267] Combination agents include additional active ingredients that are those known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease. For example, compositions and formulations of the invention, as well as treatment methods, may further comprise other drugs or pharmaceutical products, such as other active agents useful for treating or palliating target diseases or related symptoms or conditions. For cancer indications, such additional agents include, but are not limited to, kinase inhibitors, such as EGFR inhibitors (e.g., erlotinib, gefitinib), Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., , sunitinib), standard chemotherapy agents, such as alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormonal therapies, or corticosteroids. For pain indications, suitable combination agents include anti-inflammatories such as NSAIDs. The pharmaceutical compositions of the invention may further comprise one or more such active agents, and methods of treatment may further comprise administering an effective amount of one or more such active agents.

CHEMICAL SYNTHESIS

[268] Examples of chemical entities useful in the methods of the invention will now be described with reference to the illustrative synthetic schemes for their general preparation below and the specific examples that follow. Those skilled in the art will recognize that, to obtain the various compounds herein, the starting materials can be suitably selected so that the desired substituents will ultimately be carried through the reaction scheme with or without protection, as appropriate, to obtain the desired product. Alternatively, it may be necessary or desirable to employ, in place of the desired final substituent, a suitable group that can be carried through the reaction scheme and replaced, if appropriate, with the desired substituent. Furthermore, one skilled in the art will recognize that the transformations shown in the schemes below can be performed in any order that is compatible with the functionality of the particular pendant groups. Each of the reactions described in the general schemes is preferably carried out at a temperature from about 0°C to the reflux temperature of the organic solvent using. Unless otherwise specified, variables are as defined above with reference to Formula (I). Isotopically labeled compounds as described herein are prepared according to the methods described below using suitably labeled starting materials. Such materials are generally available from commercial suppliers of radiolabeled chemical reagents.

[269] General Method A:

[270] It will be seen that compounds of formula A or A-1 can be prepared according to General Method A, using suitably functionalized starting materials and intermediates.

[271] Step 1. To a solution of a suitably functionalized compound A-1 (-1.00 eq.), where Rs and RB are groups compatible with the reaction conditions described here and Nu is a nucleophilic group, such as an anion or a group capable of forming a nucleophile, such as a halide, in a reagent capable of promoting the composition of A-1 and A-2, such as an acid (e.g., TfOH (0.6 M)) or an alkyl halide (e.g. n-BuLi) may be added A-2, wherein Rc is a group compatible with the reaction conditions described herein and X2 is, for example, a leaving group (-1.00 eq.) at a appropriate temperature (e.g. 0°C). The mixture can be stirred at a suitable temperature (e.g. 60°C) until the reaction is complete. The reaction can then be returned to room temperature, and the reaction mixture can be quenched, neutralized, washed, extracted, dried and/or concentrated under vacuum as necessary to obtain A-3.

[272] Step 2. A mixture of A-3, wherein RA, RB and Rc are groups compatible with the reaction conditions described herein (in some exemplary embodiments described herein, A-3 may be a commercially available aldehyde or ketone, or A-3 can be prepared from step 1, -1.00 eq.) and commercially available amine A-4, wherein Rc is a group compatible with the reaction conditions described herein, (-1.50 eq. ) in a suitable solvent (e.g., methanol (0.5 M)) may be stirred at a suitable temperature (e.g., room temperature) for a suitable period of time, or until formation of the imine is complete by TLC or LC-MS. A reducing agent (e.g. NaBH4 (-2.00 eq.)) may be added to the reaction solution in portions. The mixture can be stirred at a suitable temperature (e.g. room temperature) until TLC or LC-MS shows that the reduction is complete. The reaction can be neutralized, washed, extracted, dried, and concentrated under vacuum, or as needed, to obtain A-5.

[273] Step 3. A mixture of a prepared or commercially available A-5, in which RA, RB and Rc are groups compatible with the reaction conditions described here (~1 eq.), 5-chloropyrazolo[1,5- Commercially available ethyl a]pyrimidine-3-carboxylate (A-6, ~1 eq.) and a suitable base (e.g., diisopropylethylamine (-“5 eq.)) in a suitable solvent (e.g., butanol ( 0.4 M) ) may be stirred at a suitable temperature (e.g. 110°C) for a specified period of time or until the reaction is demonstrated to be complete. The reaction can be returned to room temperature and diluted with water as needed. The mixture can be extracted, washed, dried, concentrated under reduced pressure and/or purified by chromatographic methods as necessary to provide A.

[274] In some exemplary embodiments, General Method A may be carried out as follows:

[275] Step 1. To a solution of A-1 (1.00 eq.) in TfOH (0.6 M) can be added A-2 (1.00 eq.) at 0°C. To the mixture can (0.6 M) A-2 (1.00 eq.) can be added at 0°C. The mixture can be stirred at 60°C for 4 hours or until the reaction is complete. After cooling to room temperature, the reaction mixture can be poured into ice water (w/w = 01/01), neutralized with NaHCCb to pH ~9, and extracted with EtOAc three times as needed. The combined organic layers can be washed with brine, dried over anhydrous Na2SO4 as needed, and concentrated to provide A-3.

[276] Step 2. A mixture of A-3 (commercially available aldehyde or ketone, or prepared from step 1, 1.00 eq.) and commercially available amine A-4 (1.50 eq.) in methanol ( 0.5 M) can be stirred at room temperature for 2 hours or until imine formation is demonstrated to be complete by TLC or LC-MS. NaBH4 (2.00 eq.) can be added to the reaction solution in portions. The mixture can be stirred at room temperature until TLC or LC-MS shows reduction to be complete. The reaction can be quenched with water and extracted three times with dichloromethane as needed. The combined organic phase can be washed with brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuo to obtain A-5.

[277] Step 3. Prepared or commercially available A-5 (1 eq.), ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (A-6, 1 eq.) and diisopropylethylamine (5 eq.) in butanol (0.4 M) can be heated to 110°C for 30 min or until the reaction is demonstrated to be complete. The reaction can be cooled and diluted with water. The mixture can be extracted with dichloromethane four times (as needed) and the combined extracts can be dried over anhydrous sodium sulfate. After filtration, the mixture can be concentrated under reduced pressure and the residue can be purified by flash chromatography to provide A.

[278] Alternative General Method A:

[279] Coupling Step 1. The mixture of suitably functionalized AA-1 (-1.00 eq.), a suitably functionalized vinyl coupling reagent (-1.00 -1.50 eq.) and a palladium catalyst (- 0.05 eq.) under appropriate reaction conditions can be heated to an appropriate temperature (e.g., ~90°C) for a suitable period of time, under an inert atmosphere until TLC indicates that the starting material has been completely consumed. The reaction mixture can be poured into H20 as needed. The mixture can be extracted and the organic phase washed, dried, concentrated, and purified by silica gel column chromatography, as necessary, to obtain AA-2.

[280] Coupling step 2. The mixture of a compound of type AA-2 (-1.00 eq.), 5-chloropyrazolo[1,5-a]pyrimidine-3-ethyl carboxylate (A-6, - 1.00 eq.) and a palladium catalyst, under appropriate reaction conditions may be heated to an appropriate temperature (e.g., 120°C) for a suitable period of time, under inert atmosphere until TLC indicates that the material match was completely consumed. The reaction mixture can be poured into H20 as needed. The mixture can be extracted and the organic phase can be washed, dried, concentrated, and purified by silica gel column chromatography, as necessary, to obtain AA-3.

[281] Step 3. To a mixture of AA-3 (~1.00 eq.) and 4-methylbenzenesulfonohydrazide (in molar excess) in a suitable solvent can be added an appropriate base (in molar excess) at an appropriate temperature under inert atmosphere. 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 concentrated under reduced pressure as needed. The concentrated reaction mixture can be diluted with water as needed and extracted. The combined organic phase can be washed, dried, filtered, concentrated in vacuo, and purified to obtain AA-4.

[282], General Method B:

[283] Step 1. An aldehyde solution BI (~1.0 eq.) in which RA and RB are groups compatible with the reaction conditions described herein, B-2 (—1.0 eq.) in which X1 is a leaving group and PG is a protecting group, a suitable base (in molar excess) and a catalyst in a suitable solvent can be heated and stirred for an appropriate amount of time until the reaction is complete. More B-2 can be added and still applied warm as needed. The mixture can be cooled to room temperature and diluted with water as needed. The mixture can be extracted, and the combined extracts can be washed, dried, and concentrated under reduced pressure as needed. The crude reaction product can be purified by flash chromatography to provide B-3.

[284] Step 2. Aldehyde B-3 (~1.0 eq.) and a suitably functionalized amine (-2.0-4.0 eq.) wherein Rc is a group compatible with the reaction conditions described herein in a suitable solvent can be heated and stirred for an appropriate amount of time. The mixture can be cooled to room temperature and a suitable reducing agent (-1.0 eq.) can be added. The mixture may be stirred for a suitable period of time, then quenched by adding water as necessary. The mixture can be extracted with a suitable organic solvent, and the combined extracts can be washed, dried and concentrated under reduced pressure as necessary. The crude reaction product can be purified by flash chromatography as necessary to provide B-4.

[285] Step 3. Compound B-4 (-1.0 eq.), ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (A-6, -1.0 eq.) and a suitable base (in molar excess) in a suitable solvent can be heated for an appropriate 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 extracts can be dried and concentrated under reduced pressure as necessary. The crude reaction product can be purified by flash chromatography to provide B1.

[286] In some exemplary embodiments, General Method B may be carried out as follows:

[287] Step 1. An aldehyde solution BI (-1.0 eq.) in which RA and RB are groups compatible with the reaction conditions described here, B-2 ('-1.0 eq.) in which X1 is a leaving group and PG is a protecting group, potassium carbonate (in molar excess) and potassium iodide (catalytic amount) in DMF can be heated to 60°C and stirred for -15 hours. More B-2 chloride can be added and still heated to 80°C can be applied as needed until the reaction is shown to be complete. The mixture can be cooled to room temperature and diluted by adding water (250 ml) as needed. The mixture can be extracted with ethyl acetate (3 x 300 mL) and the combined extracts can be washed with water (200 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure as needed. . The crude reaction product can be purified by flash chromatography to provide B-3.

[288] Step 2. Aldehyde B-3 (-1.0 eq.) and methylamine (-2.5 eq.) in methanol can be heated to 60°C and stirred for ~1 hour. The mixture can be cooled to room temperature and sodium borohydride (~1.0 eq.) can be added. The mixture can be stirred for ~30 min 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 as necessary. The crude reaction product can be purified by flash chromatography to provide B-4.

[289] Step 3. Amine B-4 (~1.0 eq.), ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (A-6, ~1.0 eq.) and base of Hünig (in molar excess) in butanol can be heated to 110°C for ~25 min. 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 over sodium sulfate as needed. The mixture can be concentrated under reduced pressure as needed. The crude reaction product can be purified by flash chromatography to provide B.

[290] General Method C

[291] Step 1. To a Cl solution (-1.0 eq.), in which RA, RB, RC, RD and RE are groups compatible with the reaction conditions described here, X1AlkNHPG (-1.5-2 ,0 eq.) wherein X1 is a leaving group, Alk is a suitably functionalized alkyl group and PG is a protecting group in a suitable solvent, a suitable base (-3.0 eq.) may be added. The mixture can be heated to an appropriate temperature for a suitable amount of time under an inert atmosphere until complete conversion of starting material to product is shown by LC-MS. The mixture can be cooled to room temperature, diluted with water and extracted with a suitable organic solvent as necessary. The combined organic extracts can be washed with water and brine, dried over NazSO^, and concentrated as needed. The resulting residue may be purified by silica gel column chromatography, as necessary, to obtain C-2.

[292] Step 2. To a solution of C-2 (1 eq.) in which RA, Rc, RD and RE are groups compatible with the reaction conditions described here, Alk is a suitably functionalized alkyl group and PG is a group protection in a suitable solvent, a suitable base (in molar excess) can be added. The solution can be heated to an appropriate temperature for an appropriate amount of time. The reaction can be neutralized with a suitable acid at pH <5, and the reaction mixture can be extracted with a suitable organic solvent. Combined organics can be washed and dried as needed. The crude reaction product mixture can be filtered, concentrated under reduced pressure, and dried under high vacuum as necessary to provide C-3.

[293] Step 3. To a solution of C-3 (--1.0 eq.) in a suitable organic solvent, a suitable acid (~4 eq.) can be added at an appropriate temperature (e.g., 0° W) . The reaction mixture can be stirred at a suitable temperature for a suitable amount of time until the reaction is demonstrated to be complete by LC-MS. The crude product may be filtered, washed, and dried under high vacuum to provide C-4.

[294] Step 4a. To a solution of C-4 ('-1.0 eq.) in a suitable solvent, a suitable base (in molar excess) may be added. The solution can be cooled in an ice-cold water bath and a suitable coupling agent (~1.5 eq.) can be added to produce an activated ester. The solution can be warmed to room temperature slowly and stirred until the starting material is shown to be converted to the desired product by LC-MS. The mixture may be diluted with water and extracted with a suitable organic solvent as necessary. The combined organic extracts can be washed, dried, and concentrated under reduced pressure as needed. The resulting residue can be purified by silica gel column chromatography to obtain C.

[295] In some exemplary embodiments, General Method C may be carried out as follows:

[296] Step 1. To a solution of Cl ( — 1.0 eq.), in which RA, RB, RC, RD and RE are groups compatible with the reaction conditions described here, X^lkNHPG (~1.5 -2.0 eq.) where X1 is a leaving group, Alk is a suitably functionalized alkyl group and PG is a protecting group in DMF (0.5M) K2CO3 (—3.0 eq.) can be added. The mixture can be heated to ~80° for ~2 hours or until complete conversion of the material can be shown by LC-MS. The mixture is brought to room temperature, diluted with water as needed and extracted three times with EtOAc as needed. The combined organic extracts can then be washed with water and brine, dried over Na2SO4, and concentrated as needed. The resulting residue can be purified by silica gel column chromatography eluting with EtOAc/Hexane (5-10%, 10 CV) to obtain C-2.

[297] Step 2. To a solution of C-2 (-1 eq.) in methanol/THF/H20 (3: 1: 1, 0.2M) LIOH.H2O (-5.0 eq.) can be added. . The solution can be heated to ~70°C for -2 hours. The reaction can be neutralized at -0°C with aq. (2M) for pH<5, and extracted four times with CH2Cl2 as needed. The combined organic extracts can be washed with brine and dried over Na2SO4 as needed. The crude product mixture may be filtered, concentrated under reduced pressure and dried under high vacuum as necessary to obtain C3.

[298] Step 3. To a solution of C-3 (-1.0 eq.) in CH2Cl2 (0.25M) can be added HCl in dioxane (4M, -4 eq.) at ~0°C. The reaction can be stirred and allowed to warm from 0°C to room temperature for about 27 hours or until reaction is complete as shown by LC-MS. The resulting reaction mixture can be filtered, washed with CH2Cl2, and dried under high vacuum to generate C-4.

[299] Step 4a. Cyclization with HATU. To a solution of C4 (-1.0 eq.) in -10 mL of DMF (~0.005M) DIPEA (-5.0 eq.) can be added. The solution can be cooled in an ice-cold water bath and HATU (-1.5 eq.) can be added. The solution can be allowed to warm to room temperature and stirred until said time at which complete conversion of the starting material to the desired product can be shown by LC-MS. The mixture can be diluted with water and extracted three times with EtOAc as needed. The combined organic extracts can be washed with water and brine, dried under Na2SO4, and concentrated under reduced pressure as needed. The resulting residue can be purified by silica gel column chromatography (0 - 5% MeOH/DCM) to obtain C.

[300] Step 4b. Cyclization with FDPP. To a solution of DIPEA (~5 eq.) in DMF/CJLCL (3:1, ~0.005M) C4 (-“1.00 eq.) can be added. After C-4 has completely dissolved, pentafluorophenyl diphenylphosphinate (FDPP, ~1.05 eq.) can be added. The coupling may be allowed to stir for 30 minutes or until such time as the reaction is shown to be complete by LC-MS. The reaction solution can be diluted with CH2CL, washed three times with water, aqueous Na,CO3 (2 M) and brine, and dried over Na,SO. as necessary. After filtration and concentration under reduced pressure, the residue can be purified by silica gel column chromatography eluting with MeOH/CH.Cl, (0-5%) to provide C.

EXAMPLES

[301] The following examples are offered to illustrate not to limit the invention. One skilled in the art will recognize that the following synthetic reactions and schemes can be modified by choosing suitable starting materials and reagents in order to access other compounds of Formula (I) or (IA). Bicyclic heteroaromatic groups with functionality suitable for use in synthetic methods are commercially available. Abbreviations: The examples described herein utilize materials including, but not limited to, those described by the following abbreviations known to those skilled in the art: Example A6

[302] Step 1. 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-methylpyrrolidin-3- amine (357.43 mg, 3.57 mmol, 1.00 eq.} in one portion at 16°C under N2. The mixture was stirred at 16°C for 10 hours under N2. Then NaBH^ (270. 00 mg, 7.14 mmol, 2.00 eq.) was added and the mixture was stirred at 16°C for 6 hours under N2. 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 x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO. j, filtered and concentrated under reduced pressure to give A6-5 (350.00 mg, 1.56 mmol, 43.71% yield) as a yellow solid. 2H NMR (300 MHz, DMSO-d6) 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) .

[303] Step 2. To a solution of A6-5 (300.00 mg, 1.34 mmol, 1.00 eq.) and ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (302 34 mg, 1.34 mmol, 1.00 eq.) in n-BuOH (40.00 mL) DIPEA (1.04 g, 8.04 mmol, 6.00 eq.) was added at 16°C under N2. The mixture was stirred at 120°C for 2 hours. TLC (PE: EtOAc=l:l) showed that the reaction was complete. The mixture was poured into water (50 ml) and extracted by DCM (50 ml X 3). The mixture was purified by prep PLC to provide formic acid salt A6 (290.00 mg, 701.43 umol, 52.35% yield) as a white solid.Example A8

[304] To a solution of ethyl 5-chloropyrazolo[1,5-a] pyrimidine-3-carboxylate HCl salt (1.25 g, 5.54 mmol) and (R)-2-(1) HCl salt -aminoethyl)-4-fluorophenol (purchased from NetChem, Inc.) in EtOH (15.83 ml) was added Hünig's base (3.58 g, 27.70 mmol) and heated at 70°C for 1.5 hours . The reaction was rotavaporized until dry, suspended in water, and extracted with DCM (5 x 50 mL). The combined extracts were dried with Na2SO4 and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (40 g), 0-5% methanol in dichloromethane) gave A8 (1.89 g, 5.49 mmol, 99% yield). Example A9

[305] Step 1. To a solution of 4-fluorophenol (2.00 g, 17.84 mmol, 1.00 eq.) in TfOH (30.00 mL) was added propanoyl chloride (1.65 g, 17 .84 mmol, 1.00 eq.) 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), neutralized with NaHCOa to make the pH ~9 and extracted with EtOAc (120 mL x 3). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na2SO4, and concentrated to provide A9-3 (1.80 g, 10.70 mmol, 59.98% yield) as a colorless oil. 1H NMR (400 MHz, CDCI3) 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).

[306] Step 2. Ammonia gas was bubbled into MeOH (20 mL) at -78°C for 10 min. A9-3 (1.00 g, 5.95 mmol, 1.00 eq.) was added to the solution and stirred at 25°C for 1 h. To the reaction mixture was added Ti(i-PrO)4 (1.63 g, 7.14 mmol, 1.20 eq.), and the mixture was stirred for an additional 1 h. Then, NaBH4 (449.93 mg, 11.89 mmol, 2.00 eq.) was added. 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 min. The mixture was filtered and the filtrate was adjusted with HCl (1 M) to pH ~1 and extracted with EtOAc (50 ml x 2). Sodium bicarbonate was added to the aqueous phase to adjust to pH -9 and extracted with DCM (50 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried with anhydrous N2SO4, filtered and concentrated in vacuo to obtain A9-5 (310.00 mg, 1.83 mmol, 30.79% yield) as a solid yellow. 1H NMR (400 MHz, CDCI3} 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).

[307] Step 3. A9-5 was coupled with ethyl 5-chloropyrazolo[1,5-a] pyrimidine-3-carboxylate in the presence of DIPEA in n-BuOH to provide A9 as described in General Method A. Example A13- 5: Preparation of 2-(1-amino-2-cyclopropylethyl)-4-fluorophenol

[308] Step 1. 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 at 25°C under N2. The mixture was stirred at 25°C for 1 h. Next, N-methoxymethanamine hydrochloride (4.79 g, 49.06 mmol, 1.10 eq.) was added. The mixture was stirred at 25°C for a further 12 hours. The reaction was quenched with 1N aqueous hydrochloric acid (50 mL), and separated into layers. The aqueous layer was extracted with DCM (30 ml x 2). The combined organic layer was washed with 50% saturated aqueous sodium carbonate (50 mL) and saturated brine (30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to obtain 2-cyclopropyl-N-methoxy-N-methylacetamide (6.00 g, 41.91 mmol, 93.96% yield) as an oil. NMR (400 MHz, CDC13) 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).

[309] Step 2. To a mixture of 2-cyclopropyl-N-methoxy-N-methylacetamide (6.00 g, 29.27 mmol, 1.00 eq.) in THE (100.00 mL) was added n- BuLi (2.5 M, 12.88 mL, 1.10 eq.) under drip, at -78°C under N2. The mixture was stirred at -78°C for 10 min. And then the mixture was treated with 2-bromo-4-fluoro-1-methoxybenzene (4.19 g, 29.27 mmol, 1.00 eq.) in THF (20 mL) over a period of 20 min. After stirring at -78°C for 1 h, the mixture was allowed to warm to 25°C and stirred for a further hour. TLC showed that the reaction was complete. The mixture was poured into 10% HCl aqueous solution (100 ml) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (300 ml x 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated 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-methoxyphenyl)ethan-1-one (2 .4 g, 39.38% yield) as a colorless oil. H NMR (400 MHz, CDCI3) 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).

[310] Step 3. To a solution of 2-cyclopropyl-l-(5-fluoro-2-methoxyphenyl)ethan-l-one (500.00 mg, 2.40 mmol, 1.00 eq.} in DCM ( 10.00 ml) BCI3 (1 M, 3.00 ml, 1.25 eq.) was added dripping at -78°C under N2. The mixture was stirred at -78°C for 2 h. TLC showed The reaction was completed. The mixture was heated to 25°C and poured into ice water (w/w = 1/1) (10 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (30 mL x 3).The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain 2-cyclopropyl-1-(5-fluoro-2-hydroxyphenyl)ethane. l-one (430.00 mg, 2.21 mmol, 92.3% yield) as an oil. 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).

[311] Step 4. To a solution of 2-cyclopropyl-l-(5-fluoro-2-hydroxyphenyl)ethan-l-one (400.00 mg, 1.92 mmol, 1.00 eq.) in MeOH ( 20.00 ml) NH2OH.HC1 (160.18 mg, 2.31 mmol, 1.20 eq.) and AcONa (189.09 mg, 2.31 mmol, 1.20 eq.) were added at 25°C under N2 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 x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the pure product 2-cyclopropyl-(5-fluoro-2-hydroxyphenyl)ethan-1-one oxime (400. 00 mg, 1.79 mmol, 93.32% yield) as a white solid. The solid was used in the next step without further purification.

[312] Step 5. To a solution of 2-cyclopropyl-l-(5-fluoro-2-hydroxyphenyl)ethan-l-one oxime (260.00 mg, 1.16 mmol, 1.00 eq.) in MeOH /HCl (10.00 ml; 4N) Pd-C (10%, 100 mg) was added under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 50°C for 12 hours. LC-MS showed that the starting material was completely consumed. The reaction mixture was filtered and the filtrate was concentrated to provide 2-(1-amino-2-cyclopropylethyl)-4-fluorophenol (200.00 mg, 955.75 umol, 82.39% yield) as a white solid . 1H NMR (400 MHz, DMSO-d6) 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). Example A14-5: Preparation of 2-(amino(phenyl)methyl)-4-fluorophenol

[313] Step 1. To a 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) was added NH2OH.HC1 (642.80 mg, 9.25 mmol, 1.00 eq.) in one portion at 25°C under N2. The mixture was stirred at 25°C for 30 min, 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 x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to provide (5-fluoro-2-hydroxyphenyl)(phenyl)methanone oxime (1.50 g, 6.49 mmol, 70 .13% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) 6.71 (dd, 5H), 7.19-7.07 (m, 2H), 6.71 (dd, J = 2.9, 8.9 Hz, 1H).

[314] Step 2. To a mixture of (5—fluoro-2-hydroxyphenyl) (phenyl)methanone 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) was added NH4CI (2.24 g, 41.82 mmol, 10.00 eq.) in one portion at 25°C under N2. The mixture was stirred at 25°C for 30 min, 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 x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SÜ4, filtered, and concentrated to provide A14-5 (630.00 mg, 2.90 mmol, 69.38% yield) as a yellow solid. XH NMR (400MHz, CDCl3) , 1H), 6.93-6.80 (m, 2H), 6.70 (dd, J = 4.9, 8.7 Hz, 1H), 5.28 (s, 1H). Example A17

[315] Step 1. To a solution of ethyl 5-((2-bromo-5-fluorobenzyl) (methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (prepared according to the 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)s (84 .72 mg, 0.147 mmol, 0.20 eq.) in dioxane (8.00 XantPhos mL) was added (127.87 mg, 0.221 mmol, 0.30 eq.) and K2CO3 (101.81 mg, 0.736 mmol, 1.00 eq. ) . The mixture was degassed and heated at 120°C for 24 hours under N2. TLC (petroleum ether/ethyl acetate=1:1) showed that the starting material was completely consumed. The reaction mixture was poured into H2O (20 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2:1 to 1:1) to give 5 Ethyl -((2-(tert-butylthio)-5-fluorobenzyl) (methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (200.00 mg, 0.48 mmol, 65.18% yield) as a yellow solid. XH NMR(400 MHz, CDC13) 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).

[316] Step 2. To a solution of ethyl 5-((2-(tert-butylthio)-5-fluorobenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (300.00 mg, 0.720 mmol, 1.00 eq.) in DCM (8.00 mL) BBr3 (902.21 mg, 3.60 mmol, 5.00 eq.) was added dripping, at 0°C under N2. The 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 x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2 SO4, filtered and concentrated 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 HCl salt of A17 (38.00 mg, 0.098 mmol, 13. 61% yield) as a white solid.Example A18

[317] Step 1. The mixture of 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.), CS2CO3 (51.18 g, 157.08 mmol, 3.00 eq.) and Pd(PPh3)2Cl2 (1.84 g, 2.62 mmol, 0.05 eq.) in THE (90.00 mL) and H20 (10.00 mL) was degassed and then heated at 90°C for 12 hours under N2. TLC (petroleum ether/ethyl acetate = 10/1) showed that the starting material was completely consumed. The reaction mixture was poured into H2 O (100 ml). The mixture was extracted with ethyl acetate (300 ml x 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (eluted by EtOAc/petroleum ether = 1/30) to obtain 4-fluoro-2- vinylphenol (3.50 g, 25.34 mmol, 48.39% yield) as a colorless oil. NMR (400 MHz, CDC13) 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).

[318] Step 2. The mixture of 4-fluoro-2-vinylphenol (1.95 g, 14.12 mmol, 1.00 eq.), TBSC1 (6.38 g, 42.35 mmol, 3.00 eq. .) and IH-imidazole (5.77 g, 84.70 mmol, 6.00 eq.) in DCM (20.00 ml) was stirred at 20°C for 5 hours under N2. TLC (petroleum ether/ethyl acetate = 10:1) showed that the starting material was completely consumed. The reaction mixture was poured into H2O (30 mL). The mixture was extracted with dichloromethane (50 ml x 3). The organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated, and purified by column chromatography on silica gel eluted with petroleum ether to obtain tri-butyl(4-fluoro-2-vinylbenzyl)silane (2 .30 g, 9.11 mmol, 64.54% yield) as a colorless oil.

[319] Step 3. The mixture of tri-butyl(4-fluoro-2-vinylbenzyl}silane (2.30 g, 9.11 mmol, 1.00 eq.), 5-chloropyrazolo[1.5-a] ethyl pyrimidine-3-carboxylate (2.06 g, 9.11 mmol, 1.00 eq.), Pd(PhCN)2C12 (118.20 mg, 0.455.63 mmol, 0.05 eq.) and tris- o-tolylphosphane (277.36 mg, 0.911 mmol, 0.10 eq.), DIPEA (7.07 g, 54.68 mmol, 6.00 eq.) in DMF (25.00 mL) was degassed and then then heated at 120°C for 24 hours under N2. TLC (petroleum ether/ethyl acetate = 1:1) showed that the starting material was completely consumed. The reaction mixture was poured into H20 (30 mL). The mixture was extracted with ethyl acetate (100 mL x 3).The organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (EtOAc:petroleum ether = 1:3) to provide ethyl (E)-5-(5-fluoro-2-hydroxystyryl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (1.00 g, 2.26 mmol, 24. 86% yield) as a white solid. XH NMR (400 MHz, CDC13) 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), 7,207.04 (m, 3H), 6.69 (d, J = 5.8 Hz, 2H), 4.20 (q, J = 6.9 Hz, 2H), 1.30-1.19 (m , 3H).

[320] Step 4. To a mixture of ethyl (E)-5-(5-fluoro-2-hydroxystyryl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (378.22 mg, 1.04 mmol , 1.00 eq.) and 4-methylbenzenesulfonohydrazide (3.29 g, 17.68 mmol, 17.00 eq.) in THE (4.00 mL) was added NaOAc (1.71 g, 20.80 mmol, 20.00 eq.) in one portion at 20°C under N2. 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 x 2). The combined organic phase was washed with saturated brine (50 mL), dried with anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by pre-HPLC (column: Phenomenex Synergi Max-RP 250*50mm*10um, 0.225% FA- ACN) to obtain A18 (120.00 mg, 0.347 mmol, 33.42% yield) as a white solid. Example A20

[321] A mixture of 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) in DMSO (5 mL) KF (180 mg, 3.01 mmol) was added. The reaction mixture was stirred at 120°C for 18 hours under nitrogen. The solution was then cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were further washed with water (3 x 50 ml) and brine (50 ml), dried over N2SO4 and concentrated. The residue was then purified by a silica gel column eluting with EtOAc/hexane (0-50%, 10 CV) to obtain the desired product as a white solid (240 mg, 69%). Example A22

[322] A21-1 was prepared according to General Method A. To a solution of A22-1 (150 mg, 0.387 mmol) in ethanol (2 mL) was added 4 M HCl in dioxane (2 mL) and the solution reaction was heated at 75°C for 2 hours. The solvents were evaporated and the residue was neutralized with Et3N and purified on a silica gel cartridge eluting with methanol/CH2Cl2 (012.5%) to obtain A22 (144 mg, 100%).Example A23

[323] Step 1. To a mixture of (5-fluoro-2-methoxyphenyl)methanethiol (496.1 mg, 2.88 mmol) and 6-chloro-imidazo[1,2-b]pyridazine-acid ethyl ester 3-carboxylic acid (650.0 mg, 2.88 mmol) in ethanol (14.4 mL) was added DIPEA (1.12 g, 8.64 mmol). The reaction mixture was stirred at 80°C for 1 hour. The solution was cooled to room temperature, diluted with water (50 mL) and extracted with DCM (3 x 50 mL). The combined extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified with flash chromatography (ISCO system, silica (120 g) eluting with EtOAc/hexane (050%), to obtain A23-2 (560 mg, 54% yield). A23-2 broke from the column during purification .

[324] Step 2. To a solution of A23-2 (498.7 mg, 1.38 mmol) in methanol (100 mL) was added 4M HCl in dioxane (10 mL) and the reaction solution was heated to 75° C for 2 hours. The solvents were evaporated and the residue was neutralized with Et3N and purified on a silica gel cartridge eluting with methanol/CH2Cl2 (0-12.5%) to provide A23 (470 mg, 98%).

[325] A1-A24 were prepared according to general method A and the methods described herein. Example B7

[326] Step 1. To a mixture of 1-(5-fluoro-2-hydroxy-phenyl)-ethanoâ (773 mg, 5.0 mmol) and acid tert-butyl ester (2-chloro-ethyl)- carbamic acid (1.80 g, 10.0 mmol) in DMF (20 mL) Kl (2.0 mg, 0.012 mmol) and CS2 CO3 (3.26 g, 10.0 mmol) were added. The mixture was stirred at 80°C overnight. The mixture was then cooled to room temperature, diluted with EtOAc, and washed with NaOHIN (5 x 10 ml) until LCMS showed no 1-(5-fluoro-2-hydroxy-phenyl)-ethanone peak. The organic layer was dried over Na2SO4 and concentrated. The residue was then purified by a silica gel column eluting with EtOAc/hexane (0-30%, 10 CV) to obtain the desired product B7-2 as a yellowish solid (1.1 g, 73.8%): LC-MS (ESI) m/z 320.3 (M+Na)+.

[327] Step 2. To a solution of B7-2 (1.0 g, 3.36 mmol) in MeOH (10 mL) was added NaBH4 (640 mg, 16.8 mmol) in portions. The mixture was stirred at room temperature for 2 h until no starting material was detected by LCMS. The solution was then diluted with water (50 ml) and extracted with DCM (3 x 20 ml). The combined DCM layers were dried over Na2SO4 and concentrated. The residue was purified through a silica gel column eluting with EtOAc/hexane (0-50%, 10 CV) to obtain the desired product B7-3 as a pale yellow solid (0.75 g, 75%). LC-MS (ESI) m/z 322.3 (M+Na)+; ÃH NMR (500 MHz, chloroform-d) 6.89 (ddd, J = 9.0, 7.9, 3.2 Hz, 7.11 (dd, J = 92, 3.4 Hz, 1H), 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).

[328] Step 3: To a solution of B7-3 (600 mg, 2.0 mmol) and {2-(4-fluoro-2-(1-hydroxy-ethyl)-phenoxy] ethyl acid tert-butyl ester }-carbamic acid (450 mg, 2.0 mmol) into dry THE (40.0 mL) at -78°C was added NaH (60%, 80 mg, 2.0 mmol) in portions. The suspension was stirred at - 78°C for 4 h and allowed to warm to 0°C and stirred for an additional 4 h. The mixture was then placed in the freezer at -20°C overnight. LC-MS showed good conversion to the desired product. The mixture was then quenched with a mixture of ice and 1N HCl and extracted with EtOAc (3 x 20 mL).The organic layer was dried over Na2SO4, concentrated and purified twice to obtain the desired product B7 as a yellow solid (240 mg, 25 %):

[329] B1-B7 were prepared according to General Method B and methods described herein. Examples 2 and 2-1.

Synthesis A:

[330] Example 2 can be prepared as shown in the following scheme, starting with racemic or enantiomerically enriched starting materials:

[331] Step 1. To a mixture of compounds 2A (1 equiv.) and 2B (1.2 equiv.) in anhydrous DMF (0.2 M) CS2CO3 (1.5 equiv.) is added and the reaction is heated in the form of an oil bath at 80°C under nitrogen overnight. The mixture is cooled, poured into water, and extracted with EtOAc three times. The combined organic layers are washed with water five times, washed with brine, and dried over Na2SO4. After condensation, the residue is purified on a flash column eluting with EtOAc/Hexanes to provide compound 2C.

[332] Step 2. To a solution of compound 2C (1 equiv.) in anhydrous THE (0.2 M) is added NaH (1.2 equiv.). The reaction mixture is stirred at room temperature for 0.5 hour. Compound 2D is added to the mixture and the reaction is heated at reflux under nitrogen overnight. The reaction is cooled to room temperature and diluted with a portion of water (1/3 of the volume of THF) and NaOH (3 equiv.). The mixture is stirred and heated at 70°C for 2 hours or until the ester is completely hydrolyzed to the corresponding acid. After cooling, the organic layer is separated and the aqueous layer is neutralized to pH ~5. The resulting precipitate is filtered, washed with water three times, and dried under vacuum to provide compound 2E, which is used without further purification.

[333] Step 3. To a solution of compound 2E (1 equiv.) in CH2Cl2 (0.2 M) is added 4 M HCl/dioxane (10 equiv.) and the mixture is stirred until compound 2E is completely converted to compound 2F. The mixture is concentrated, and the residue is purified by reverse phase preparative HPLC to provide compound 2F.

[334] Step 4. A solution of compound 2F (1 equiv.) and DIPEA (10 equiv.) in DMF (0.2 M) are added dropwise to a solution of HATU (1.4 equiv.) in DMF ( 0.1 M) at 0°C. After the addition is complete, the mixture is stirred at 0°C for a further 30 min. Water is added and the mixture is extracted with EtOAc three times. The combined organic layers are washed with saturated NaHCCh twice, then with brine, dried over NaSO4, and concentrated. The residue is purified on a silica gel column eluting with EtOAc/hexanes to provide Example 2.

Synthesis B:

[335] Examples 2 and 2-1 can also be prepared according to the following scheme, using racemic or enantiomerically enriched starting materials:

[336] Step 1. Compound 2C is reacted with compound 2G under the conditions described in Synthesis A, Step 2, to provide compound 2H.

[337] Step 2. Compound 2H is converted to compound 21 under the conditions described in Synthesis A, Step 3.

[338] Step 3. To a solution of compound 21 (1 equiv.) and DIPEA (2 equiv.) in toluene (0.01 M) is added Pd(P-tBu)2 (1 equiv.). The reaction mixture is heated to 100°C under 4 bar CO overnight and then concentrated. The residue is purified on a silica gel column eluting with EtOAc/hexanes to provide Example 2. Examples 10 and 10-1.

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

[340] Step 1. Compound 10C is prepared from compounds IOA and IOB, using the method described in Example 2, Synthesis A, Step 1.

[341] Step 2. Compound 10E is prepared from compounds 10C and 10D, using the method described in Example 2, Synthesis A, Step 2.

[342] Step 3. A mixture of compound IDE (1 equiv.) and NH2~NH2 (10 equiv.) in methanol (0.2 M) is heated at reflux until compound 10E is completely converted to compound 10F. The mixture is concentrated and the residue is purified on a reverse phase preparative HPLC to provide compound 10F.

[343] Step 4. Compound 10F is converted in Example 10 according to the method described for Example 2, Synthesis A, Step 4. Example 11-1

[344] Step 1: To a solution of 2-chloro-3-fluoro-6-hydroxy-benzaldehyde (175 mg, 1.0 mmol), ethylene glycol bis-tos (740 mg, 2.0 mmol) in ACN (5 mL), K2CO3 (276 mg, 2.0 mmol) and Kl (2 mg) were added. The reaction mixture was stirred at 120°C for 24 hours. The solid was removed by filtration and the filtrate was concentrated and purified by column chromatography to obtain the desired product 11-1B as a white solid. The material was used directly in the next step.

[345] Step 2: To a solution of 11-1B (373 mg, 1 mmol) in ACN (5 mL), NaN3 (650 mg, 10 mmol) was added and the mixture was stirred at 120 ° C for 24 hours. The solid was removed by filtration and the residue was concentrated and purified by column chromatography to obtain 11-1C as a white solid (200 mg, 82%). XH NMR (500 MHz, Chloroform-d) , 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).

[346] Step 3: To a solution of 11-lC (100 mg, 0.41 mmol) in anhydrous THE (5 mL) at -78°C, methyl magnesium bromide (IN in Et2O, 0.82 mL, 0 .82 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 2 hours until TLC showed no starting material present. The solution was then cooled to 0°C and quenched with saturated aqueous NH4OAC solution and extracted with EtOAc (20 mL x 3). The combined organic phase was dried over Na2SÜ4 and concentrated. The residue 11-1D was used directly in the next step. 1H 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).

[347] Step 4: To a solution of 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 THF (5.0 mL) at -78°C, NaH (60%, 17 mg, 0.44 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 8 hours until a good amount of the desired product was formed. The mixture was then diluted with water/ice and extracted with DCM (3 x 20 mL). The organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography to obtain 11-1E as a yellow liquid (20 mg, 0.045 mmol, 6%), which is used directly in the next step.

[348] Step 5: To a solution of 11-lE (20 mg, 0.045 mmol) in MeOH (ImL), LiOH (16 mg, 0.38 mmol) was added, followed by Iml of H2O. The mixture was allowed to stir at 60°C for 4 hours until LCMS and TLC showed that the reaction was complete. The solution was cooled to rt, partially concentrated and acidified by 1N HCl to pH 2-3. The aqueous mixture was extracted with DCM (3 x 10 ml). The organic layer was dried over NazSO4 and concentrated. Residue 11-1F was used directly in the next step.

[349] Step 6: To a solution of 11-1F (20 mg, 0.045 mmol) in DCM (5 mL), PPh3 was added (24 mg, 0.09 mmol). The solution was stirred for 1 h 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)+.

[350] Step 7: To a solution of 11-1G obtained from the previous step in DMF (10 mL), DIPEA (0.20 mL, 1.15 mmol) was added. The solution was cooled with a dry ice/acetone bath and HATU (40.0 mg, 0.11 mmol) was added. The solution was allowed to slowly warm to rt and LCMS shows a clear transformation of the starting material to the desired product. The mixture was then diluted with water (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layer was washed with water (3 x 50 mL) and brine (50 mL) and dried over NazSO4. The solvent was removed and the resulting residue was purified by silica column chromatography (0-5% MeOH/DCM) to obtain the desired product as a white solid (2.6 mg, 20% yield). Examples 14 and 14-1.

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

[352] Step 1. To a mixture of compounds 14A (1 equiv.) and 14B (1.2 equiv.) in anhydrous DMF (0.2 M) is added CS2CO3 (1.5 equiv.) and the reaction is heated in the form of an oil bath at 80°C under nitrogen overnight. The mixture is cooled, poured into water, and extracted with EtOAc three times. Layers with brine, and dried over Na2SOí. After condensation, the residue is purified via flash silica gel column eluting with EtOAc/hexanes to provide 14C.

[353] Step 2. To a cooled solution (-78°C) of 14C (1 equiv.) in anhydrous THE (0.2 M) is added MeMgBr (3 eq, 3 M in diethyl ether). The reaction is stirred for 2 hours at -78°C to 0°C and quenched with saturated aqueous NH4Cl, and then extracted with EtOAc (2x). The organics are dried over MgSO4, filtered and concentrated. This residue is purified by silica gel column chromatography eluting with EtOAc/Hexanes to obtain 14D.

[354] Step 3. To a solution of compound 14D (1 equiv.) in anhydrous THE (0.2 M) is added NaH (1.2 equiv.). The reaction mixture is stirred at room temperature for 0.5 hours. To the mixture is added 14E and the reaction is heated to reflux under nitrogen overnight. The reaction is cooled to room temperature and then poured into water. The product is extracted with EtOAc three times. The combined organics are washed with brine, dried over Na2SO4, and concentrated. The residue is purified with a silica gel column eluting with EtOAc/hexanes to provide product 14F.

[355] Step 4. To a solution of compound 14F (1 equiv.) in CH2Cl2 (0.2 M) is added 4 M HCl/dioxane (10 equiv.) and the mixture is stirred until all 14E is converted to 14G. After concentration, the residue is purified on a reverse phase preparative HPLC to provide 14G.

[356] Step 5. To a solution of 14G (1 equiv.) and DIPEA (2 equiv.) in toluene (0.01 M) is added Pd(Pt-BU3)2 (1 equiv.). The reaction mixture is heated to 100°C under 4 bar CO overnight and then concentrated. The residue is purified on a silica gel column eluting with 14. Examples 15 and 15-1.

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

[358] Step 1. To a suspension of 15A (1.0 equiv.) in THF (0.15 M) is added a 2.0 M aqueous NaOH solution (3 equiv.). The homogeneous reaction mixture is stirred overnight and then the organics are removed under reduced pressure. The aqueous residue is brought to pH ~4 with 1.0 M aqueous HCl. The resulting precipitate is collected by filtration and washed with H20 to obtain a solid 15B. The filtrate is extracted with EtOAc (2x), and the organic phases are concentrated under reduced pressure to provide an additional portion of 15B.

[359] Step 2. A stock solution of Jones reagent (2.β7 M) is prepared by carefully adding concentrated H2SO4 (2.3 mL) to CrO3 (2.67 g) and then diluting to 10 mL with H20 . To a suspension of 15B (1.0 equiv.) in acetone (0.067 M) Jones reagent (1.2 equiv.) is slowly added. The reaction mixture is stirred for 15 min and then quenched with i-PrOH and filtered through a pad of diatomaceous earth, washing with acetone. The filtrate is concentrated to provide 15C which is used without further purification.

[360] Step 4. To a solution of 15C (1.0 equiv.) in DMF (0.40 M) at 0°C is added NaH (60% in mineral oil, 1.5 equiv.). The reaction mixture is stirred at room temperature for 30 min and then cooled again to 0 ° C, and 2-(trimethylsilyl)ethoxymethyl chloride (4.3 mL, 1.2 equiv.) is added slowly. The reaction mixture is warmed to room temperature, stirred for 1 h, and then quenched with H20 and extracted with EtOAc (3x). The combined organics are washed with H20 (3X) and brine, then dried over MgSO$ and concentrated. The residue is purified by flash silica gel chromatography eluting with 20-30% EtOAc/hexanes to give 15D.

[361] Step 5. To a reaction mixture of 14D (1.0 equiv.), copper(I) iodide (0.05 equiv.), 8-hydroxyquinoline (0.1 equiv.), and potassium phosphate tribasic (2.0 equiv.) in DMF (0.2 M) under nitrogen atmosphere, 15D (1.2 equiv.) is added and the reaction mixture is heated to 120 ° C for 24 h. The reaction mixture is cooled to room temperature and then diluted with EtOAc. The mixture is filtered through a pad of diatomaceous earth and the filtrate is evaporated under vacuum. The crude residue is purified on a silica gel column eluting with EtOAc/Hexanes to give 15E.

[362] Step 6. A 0°C suspension of 15E (1.0 equiv.) in 1,4-dioxane (0.062 M) and water (1/3 THF) is treated with sulfamic acid (6.0 equiv. .). A solution of sodium chlorite (1.3 equiv.) and potassium dihydrogen phosphate (12 equiv.) in water (1.2 M) is added through a dropping funnel over 20 min. After the addition is complete, the ice bath is removed and the reaction mixture is stirred at room temperature for 3 h. THF is added, and the reaction mixture is stirred at room temperature for an additional 3 h. The reaction mixture is diluted with water and extracted with EtOAc (2x). The combined organic layers are washed with water and brine and then dried over Na2SO4, filtered, and concentrated. The residue is triturated with ethyl acetate/hexanes to obtain 15F.

[363] Step 7. To a solution of compound 15F (1 equiv.) in CH2Cl2 (0.2 M) is added 4 M HCl/dioxane (10 equiv.) and the mixture is stirred until all 15F is converted to 15G. After concentration, the residue is purified on a reverse phase preparative HPLC to provide 15G.

[364] Step 8. A solution of compound 15G (1 equiv.) and DIPEA (10 equiv.) in DMF (0.2 M) is added dropwise to a solution of HATU (1.4 equiv.) in DMF (0.1 M) at 0°C. After complete addition, the mixture is stirred at 0°C for a further 30 min. Water is added and the mixture is extracted with EtOAc three times. The combined organics are washed with saturated NaHCO3 twice, brine, dried over Na2SO4, and evaporated. The residue is purified with a silica gel column eluted with EtOAc/hexanes to provide 15. Examples 18 and 18-1.

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

[366] Step 1. To a reaction mixture of 14D (1.0 equiv.), ISA (1.2 equiv.), and copper(I) iodide (0.05 equiv.) in DMF (0.2 M) under a nitrogen atmosphere, NaH (3.0 equiv.) is added. The reaction mixture is heated to 120°C for 24 h and then cooled to room temperature and diluted with EtOAc. The mixture is filtered through a pad of diatomaceous earth and the filtrate is evaporated under vacuum. The crude residue is purified on a silica gel column eluted with EtOAc/Hexanes to provide 18B.

[367] Step 2. To a reaction mixture of 18B (1.0 equiv.) in DME (0.2 M) are added KOH (2 equiv.) and I2 (1.1 equiv.). The reaction mixture is stirred at room temperature for 1 h, and then quenched with NaHSOa and extracted with EtOAc. The combined organics are washed with saturated NaHCOa twice, brine, dried over Na2SO4, and evaporated. The residue is purified with a silica gel column eluted with EtOAc/hexanes to provide 18C.

[368] Step 3. To a solution of the compound 18C (1 equiv.) in CH2Cl2 (0.2 M) is added 4 M HCl/dioxane (10 equiv.) and the mixture is stirred until all the 18C is converted to 18D. After concentration, the residue is purified on a reverse phase preparative HPLC to provide 18D.

[369] Step 4. To a solution of 18D (1 equiv.) and DIPEA (2 equiv.) in toluene (0.01 M) is added Pd(Pt-Bu3)2 (1 equiv.). The reaction mixture is heated to 100°C under 4 bar CO overnight and then concentrated. The residue is purified on a silica gel column eluting with EtOAc/hexanes to provide 18.Example 20.

[370] Example 20 was prepared according to the following scheme:

[371] Step 1. tert-Butyl (2-(4-fluoro-2-formylphenoxy)ethyl)carbamate (20C). 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) was heated to 60°C and stirred for 15 hours. More 20B chloride (1.0 g, 6 mmol) and further heating at 80°C for 5 hours completed the reaction. The mixture was cooled to room temperature and diluted by adding water (250 ml). The mixture was extracted with ethyl acetate (3 x 300 mL) and the combined extracts were washed with water (200 mL) and brine (100 mL), dried with sodium sulfate, and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-20% ethyl acetate in hexane) provided 20C (3.0 g, 99%) as a viscous oil. LRESIMS m/z 306.1 [M+Na]+, calculated for C^HisFiNiNaiCh 306.1.

[372] Step 2. Tert-Butyl (2-(4-fluoro-2- ((methylamino)methyl)phenoxy)ethyl)carbamate (20D). 20C aldehyde (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, then quenched by addition of water (200 ml). The mixture was extracted with dichloromethane (4 x 100 mL) and the combined extracts 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) provided the title compound (2.1 g, 80%) as a gel. LRESIMS m/z 299.2 [M+H]+, calculated for C15H24F1N2O3 299.2.

[373] Step 3. Ethyl 5-((2-(2-((tert-butoxycarbonyl)amino)ethoxy)-5-fluorobenzyl) (methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (20F). Amine 20D (2.1 g, 7.0 mmol), ester 20E (1.59 g, 7.0 mmol) and HUnig 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 x 100 mL) and the combined extracts dried over sodium sulfate. The mixture was concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 20-100% ethyl acetate in hexane) provided the title compound (2.1 g, 75%) as a solid. LRESIMS m/z 488.3 [M+H]+, calculated for C24H31F1N5O5 4 8 8.2.

[374] Step 4. 5-( (2-(2-((tert-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 20F ester (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 x 150 mL) and the combined extracts dried with brine (50 mL) and sodium sulfate. The mixture was concentrated under reduced pressure to provide the title compound (1.92 g, 97%) as a solid. LRESIMS m/z 460.2 [M+H]+, calculated for C22H27F1N5O5 4 60.2.

[375] Step 5. 5-((2-(2-aminoethoxy)-5-fluorobenzyl) (methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (20H). Hydrochloric acid (5 mL, 4M in dioxane) was added 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 title compound as a solid. LRESIMS m/z 360.2 [M+H]+, calculated for C17H10F1N5O5 360.2.

[376] Step 6. Under an argon atmosphere, HATU (1.67 g, 4.4 mmol) was added to a stirred solution of 20H carboxylic acid (1.50 g, 4.2 mmol) and Hünig's base ( 7.28 mL, 5.40 g, 41.8 mmol) in DMF: dichloromethane (5:1, 60 mL) at -78°C. The reaction was slowly warmed to room temperature and stirred for 3 hours, then quenched in water (300 mL). The mixture was extracted with ethyl acetate (3 x 100 mL), then dichloromethane (2 x 100 mL) and the combined extracts 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 (0.98 g, 68%, 2 steps) as a solid. LRESIMS m/z 342.2 [M+H]+, calculated for C17H17FIN5O2 342.1; XH NMR (500MHz, DMSO-d6) (s, 1H), 7.19-7.25 (m, 1H), 7.03-7.07 (m, 2H), 6.72 (d, J = 7.9 Hz, 1H), 5. 64 (dd, J = 14.9, 1.5 Hz, 1H), 4.48 (dt, J = 10.2, 4.3 Hz, 1H), 4.04-4.10 (m, 2H) , 3.81-3.87 (m, 1H), 3.58 (s, 3H), 3.38-3.46 (m, 1H).

Alternative synthesis of Example 20:

[377] Example 20 was also prepared by the following alternative route:

[378] Step 1. Ethyl 5-oxo-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylate (20J). A mixture of 201 (150.00 g, 1.08 mmol) and ethyl (E)-3-ethoxyprop-2-enoate (292.16 g, 2.03 mol) in DMF (3.2 L) was added CS2CO3 (656.77 g, 2.02 mol) in one portion at 20°C under N2. The mixture was stirred at 110°C for 6 hours. The mixture was cooled to 20°C and filtered through a pad of diatomaceous earth. The filter cake was washed with ethyl acetate (3 x 30 mL). The filtrate was added to H2O (2L) 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. 1H NMR (400 MHz, DMSO-dg) 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).

[379] Step 2. 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (20K). To a mixture of 20 J (158.00 g, 762.59 mmol) in MeCN (1.6 L) was added POCl3 (584.64 g, 3.81 mol) at 20°C under N2. 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 min. The precipitate was filtered and dried to obtain 20K (110.00 g, 487.52 mmol, 63.93% yield) as a white solid. 1H NMR (400 MHz, DMSO-dg) 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).

[380] Step 3. 4-Fluorine-2-methylaminomethyl-phenol (20M). To a 20 L solution (5.00 g, 35.69 mmol, 1.00 eq.) in MeOH (50.00 ml) was added aqueous methanamine (8.8 ml, 71.38 mmol, 25%, 2 .00 eq.) in one portion at 25°C under N2. The mixture was stirred at 25°C for 3 hours, then NaBH4 (2.70 g, 71.38 mmol, 2.00 eq.) was added in portions. And the mixture was stirred at 25°C for another 9 hours. TLC showed that the reaction was completed. 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), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain 20M (5.10 g, 32.87 mmol , 92.09% yield) as a colorless solid. 1H NMR (400 MHz, CDCI3) 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).

[381] Step 4. 5-[(5-Fluoro-2-hydroxy-benzyl)-methyl-amino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (Al). 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 ), DIPEA (159.98 g, 1.24 mol, 5.70 eq.) was added. The reaction mixture was stirred at 120°C for 2 hours under nitrogen. TLC showed completion of the reaction. The solution was cooled to 25°C and then solvent was removed. The residue was diluted with water (500 ml) and extracted with dichloromethane (3 x 500 ml). The combined organic extracts were washed with brine (300 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was triturated by EtOAc (100 mL) to provide Al (60.00 g, 174.25 mmol, 80.24% yield) as a white solid. δ , 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).

[382] Step 5. 5-{[2-(2-tert-butoxycarbonylamino-ethoxy)-5-fluoro-benzyl]-methylamino}pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (Bl ). To a solution of Al (102.85g, 298.6 mmol, 1 eq.), (2-chloroethyl)-carbamic acid tert-butyl ester (56.33 g, 313.5 mmol, 1.05 eq. .) in DMF (854 mL) K2CO3 (206.41 g, 1493 mmol, 5.0 eq.) was added. The mixture was heated at 80°C for 20 hours, with ~85% conversion of starting material to product by LC-MS. Additional portions of (2-chloroethyl)-carbamic acid tert-butyl ester (5.633 g, 31.35 mmol, 0.1 eq.) and K2CO3 (41.282 g, 298.6 mmol, 1 eq.) were added to the reaction vial. The reaction was continued at 80°C for an additional 21 hours. The mixture was then cooled to room temperature, quenched with water (1000 ml) and extracted with EtOAc (3 x 900 ml). The combined organic extracts were then washed with water (3 x 700 mL) and brine (500 mL), dried over Na2SO4, and concentrated. The resulting residue was purified by a silica gel column eluting with EtOAc/hexane (0-70% to obtain Bl as a white solid (128.74 g, 96.7% yield). LC-MS (ESI) m/ z 510.1 (M+Na)+; 1H 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).

[383] Step 6. 11-Fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f] [1,4,8,10] benzoxatriazacyclotridecin-4 (5H)-one (20). To a solution of BI (128.74 g, 264.07 mmol, 1 eq.) in methanol (750 mL) and THE (250 mL) was added LiOH.H2O (55.40 g, 1320 mmol, 5.0 eq. ) in H20 (250 mL). The clear solution was heated at 70°C for 2 hours. The reaction was neutralized at 0°C with aq. (2M, 250 ml) until pH <5, and then extracted with CH2 Cl2 (1 x 1000 ml, 3 x 500 ml). The combined organics were washed with brine (300 mL), and dried over Na2SO4. After filtration, evaporation, and drying under high vacuum, a white solid was obtained (126.47 g, 275.25 mmol, 104% yield). To a solution of the acid (121.30 g, 264 mmol) in CH2 Cl2 (996 mL) was added HCl in dioxane (4 M, 204 mL) at 0°C. Maintain stirring at 0°C to room temperature for 27 hours until de-Boc was complete by LC-MS. The white solid was filtered, washed with DCM (400 mL), and dried under high vacuum to provide a white solid of the 3HC1 amine salt (123.55 grams), which was used directly without further purification. To a solution of DIPEA (169.4 g, 228 mL, 1310 mmol) in DMF (3.7 L) and CH2Cl2 (1.0 L) was added the acid amine HCl salt (22.92 g, 49.0 mmol, 1.00 eq.). After the solid salt was completely dissolved, pentafluorophenyl diphenylphosphinate (FDPP) in CH2Cl2 (1.1 M, 19.76 g, 51.44 mmol, 1.05 eq.) was added. Coupling was complete in 30 minutes by LC-MS and then the second portions of the salt and FDPP were added following the same procedure as the first portion. The salt addition followed by FDPP was repeated every 30 minutes and monitored by LC-MS for each addition cycle. A total of salt (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 portions. The reaction solution was concentrated to a volume of -500 ml and a batch of precipitate was formed. The solid product 20 was filtered and washed with DMF (50 mL x 3). The filtrate was poured into water (2L) and additional product was precipitated. The solid product was filtered and washed with water (100 ml x 3). The combined solid product was dried, and re-dissolved in 10% methanol in dichloromethane (1.5 L) and then ethyl acetate was added (1 L). The solution was condensed to -500 mL and a batch of white solid was formed. After filtration and drying under high vacuum, a white solid compound 20 was obtained (74.58 g, 83% yield).

Powder X-ray diffraction (PXRD) of Example 20.

[384] A sample of Example 20, crystalline form of polymorph 1, was transferred to a zero-bottom plate for PXRD analysis. PXRD data were obtained using a Bruker D8 X-ray diffractometer according to the manufacturer's recommended procedures. Parameters for scanning: 2-theta range: 4.5 to 39.1 degrees; step size: 0.02 degrees; step time: 1 second; analysis time: 180 seconds.

[385] Diffraction peaks are typically measured with an error of ±0.1 degrees (20).

[386] The results are shown in Fig. 1. The data are summarized in Table 1.Table 1

Differential Scanning Calorimetry (DSC) of Example 20.

[387] DSC measurements, shown in FIG. 2, were carried out using a Differential Scanning Calorimeter Model Seiko SSC/5200. A 7.92 mg sample of Example 20, the crystalline form of polymorph 1, was equilibrated at 36°C and then increased to 380°C at a rate of 10°C/min. The sample of Example 20, crystalline form of polymorph 1, showed a melting point of 298.9°C. Example 26

[388] Example 26 can be prepared according to the following scheme.

[389] Step 1. Titanium(IV) isopropoxide (1.3 equiv.) is added to a commercially available solution of methylamine in methanol (2 M, 3 equiv.) followed by the addition of the starting aldehyde 14C (1.0 equiv.). The reaction mixture is stirred at room temperature for 5 h, after which sodium borohydride (1.0 equiv.) is added and the resulting mixture is stirred for another 2 h period. The reaction is then quenched by the addition of water, the resulting inorganic precipitate is filtered and washed with EtOAc. The organic layer is separated and the aqueous part is further extracted with EtOAc (2x). The combined extracts are dried (K2CO3) and concentrated in vacuum to provide 26A.

[390] Step 2. A mixture of compound 26A (1 equiv.) and DIPEA (2 eq.) in n-BuOH (0.2 M) is heated to 120°C overnight, cooled to room temperature, and then concentrated. The residue is purified with a silica gel column eluting with EtOAc/hexanes to provide product 26B.

[391] Step 3. To a solution of compound 26B (1 equiv.) in CH2Cl2 (0.2 M) is added 4 M HCl/dioxane (10 equiv.) and the mixture is stirred until all 26B is converted to 26C. After concentration, the residue is purified on a reverse phase preparative HPLC to provide 26C.

[392] Step 4. To a solution of 26C (1 equiv.) and DIPEA (2 equiv.) in toluene (0.01 M) is added Pd(Pt-Bu3)2 (1 equiv.). The reaction mixture is heated to 100°C under 4 bar CO overnight and then concentrated. The residue is purified on a silica gel column eluting with EtOAc/hexanes to provide 26. Examples 37 and 37-1.

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

[394] Step 1. Compound 37B is prepared from compound 2C and compound 37 A using the method described for Example 2, Synthesis A, Step 2.

[395] Step 2. Compound 37C is prepared from compound 37B using the method described in Example 2, Synthesis A, Step 3.

[396] Step 3. Example 37 is prepared from compound 37C using the method described in Example 2, Synthesis A, Step 4. Examples 38 and 38-1

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

[398] Step 1. Compound 38B is prepared from compounds 2C and 38A as described in Example 2, Synthesis A, Step 2.

[399] Step 2. Compound 38C is prepared from compound 38B using the method described in Example 2, Synthesis A, Step 3.

[400] Step 3. Example 38 is prepared from compound 38C using the method described in Example 2, Synthesis B, Step 4. Example 39.

[401] Example 39 was prepared according to the following schemes:

[402] Step 1: 2-(3-Chloro-4-fluoro-2-formyl-phenoxy)-ethyl]-carbamic acid tert-butyl ester (39B). To a solution of 2-chloro-3-fluoro-6-hydroxy-benzaldehyde (39A, 53 mg, 0.3 mmol) and (2-chloro-ethyl)-carbamic acid tert-butyl ester (135 mg, 0.3 mmol) 75 mmol) in DMF (5 mL) K1 (2.0 mg, 0.012 mmol) and K2CO3 (105 mg, 0.75 mmol) were added. The mixture was microwaved at 100°C for 2 h. The mixture was then diluted with water (20 ml) and extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with water (3x20 mL) and brine (20 mL), dried over Na2SO4 and concentrated to obtain 39B. The raw residue was used directly in the next step. LC-MS: (ESI) M/Z 340.3 (M+Na)+.

[403] Step 2. {[2—(3—chloro-4-fluoro-2-methylaminomethyl-phenoxy)-ethyl]-carbamic acid tert-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 min. The solution was then cooled to room temperature and NaBH4 (11.1 mg, 0.3 mmol) was added. The mixture was stirred at room temperature for 2 h. The solution was then diluted with water (50 ml) and extracted with DCM (3 x 20 ml). The combined organic layers were dried over Na2SO4 and concentrated to 39C. The crude residue was used directly in the next step. LC-MS: (ESI) m/z 333.3 (M+H)+.

[404] Step 3. 5-{[6-(2-tert-Butoxycarbonylamino-ethoxy)-2-chloro-3-fluoro-benzyl]methyl-amino}-pyrazolo[1,5-a]pyrimidine acid ethyl ester -3-carboxylic (39D) . To a solution of 20K (67.5 mg, 0.3 mmol) and 39C (99.9 mg, 0.3 mmol) in n-BuOH (2.0 mL) was added DIEA (1.0 mL). The mixture was heated under microwave at 150°C for 2 hours. The mixture was then diluted with water and extracted with DCM (3 x 20 ml). The organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography to obtain 17 as a yellow liquid. LC-MS: (ESI) m/z 522.5 (M+H)+.

[405] Step 4. 5-{[6-(2-tert-butoxycarbonylamino-ethoxy)-2-chloro-3-fluoro-benzyl]methyl-amino}-pyrazolo[1,5- a] pyrimidine-3- acid carboxylic acid (39E). To a solution of 39D (40 mg, 0.0776 mmol) in MeOH (1 mL) were added LiOH (16 mg, 0.38 mmol) and H2O (1 mL). The mixture was stirred at 60°C for 4 h. The solution was cooled to room temperature, partially concentrated and acidified by aqueous HCl (IN) to pH 2-3. The aqueous mixture was extracted with DCM (3 x 10 ml). The organic layer was dried over Na2SO4 and concentrated to obtain 39E. The raw residue was used directly in the next step. LC-MS: (ESI) m/z 494.3 (M+H)+.

[406] 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), TFA (0.4 mL) was added. The solution was stirred for 1 h. The solvent was removed under rotavapor. The residue was re-dissolved with DCM and re-concentrated (3X) to obtain 39F as a foam-like solid. LC-MS: (ESI) m/z 393.5 (M+H)+.

[407] Step 6. To a solution of 39F (36 mg, 0.078 mmol) in 10 mL of DCM was added DIEA (0.20 mL, 1.15 mmol). The solution was cooled with a dry ice/acetone bath and HATU (40.0 mg, 0.11 mmol) was added. The solution was allowed to warm to room temperature slowly. 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 x 50 mL) and brine (50 mL), dried over Na2SO4, and concentrated. The resulting residue was purified by a silica column (0-5% MeOH/DCM) to obtain Example 39 as a white solid (6.2 mg, 23.4%). LC-MS (ESI) m/z 376.5 (M+H)+. Xh 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) .Example 40.

[408] Example 40 was prepared as shown in the following scheme:

[409] Step 1. 5-[(5-Fluoro-2-hydroxy-benzyl)-methyl-amino]-2-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40B). To a solution of 19A (75 mg, 0.14 mmol) in MeOH (2 mL) were added LiOH (60 mg, 1.4 mmol) and H2O (2 mL). The mixture was stirred at 60°C for 4 h. The solution was cooled to room temperature, partially concentrated and acidified by aqueous HCl (IN) to pH 2-3. The resulting suspension was extracted with EtOAc (3 x 20 mL). The organic layer was dried over Na2SO4 and concentrated to obtain 40A. LC-MS (ESI) m/z 331.6 (M+H)+.

[410] Step 2. 5-[(5-Fluoro-2-hydroxy-benzyl)-methyl-amino]-2-methyl-pyrazolo[1,5-a]pyrimidine acid (2-Hydroxy-ethyl)-amide -3-carboxylic acid (40B). To a solution of 40A (140 mg, 0.42 mmol) and 2-aminoethanol (244 mg, 4 mmol) in DCM (5 mL) at 0°C was added DIEA (0.20 mL, 1.15 mmol ) and HATU (380.0 mg, 1.0 mmol). The solution was allowed to warm to room temperature slowly. The mixture was then diluted with water (25 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with HCl (1N, 3 x 20 mL) and brine (50 mL), dried over Na2SO4 and concentrated. . The resulting residue was purified by a silica gel column eluting with 0-5% MeOH/DCM (10 CV) to obtain 40B as a white solid (74 mg, 47%). LC-MS (ESI) m/z 374.3 (M+H)+.

[411] Step 3. To a solution of 40B (74 mg, 0.2 mmol) in THF (3 mL) and DCM (3 mL) at 0°C were added PPha (131 mg, 0.5 mmol) and azodicarboxylate of di-tert-butyl (DTAD) (115 mg, 0.5 mmol). The mixture was allowed to warm to room temperature and stirred for an additional 4 h. The solvent was removed and the residue was purified by a silica gel column eluting with 0-10% MeOH/DCM (10 CV), followed by preparative TLC to obtain Example 40 as a white solid (15 mg). LC-MS (ESI) m/z 356.5 (M+H)+; lH 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, 7 = 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). Example 41.

[412] Example 41 was prepared using the method presented in the following scheme:

[413] Step 1. [2-(2-Acetyl-4-fluoro-phenoxy)-ethyl]-carbamic acid tert-butyl ester (41B). 1-(5-fluoro-2-hydroxy-phenyl)-ethanone (41A, 773 (2-chloroethyl) acid tert-butyl ester (1.80 g, 10.0 mmol) in DMF (20 mL) was Kl (2.0 mg, 0.012 mmol) and Cs2CO3 (3.26 g, 10.0 mmol) were added. The mixture was stirred at 80°C overnight. The mixture was then cooled to room temperature, diluted with EtOAc , and washed with 1N NaOH (5 x 10 ml) until LCMS showed no 1-(5-fluoro-2-hydroxy-phenyl)-ethanone peak. The organic layer was dried over Na2SO4 and concentrated. The residue was then purified by a silica gel column eluting with EtOAc/hexane (0-30%, 10 CV) to obtain the desired product 41B as a yellow solid (1.1 g, 73.8%). LC-MS (ESI) m/z 320.3 (M+Na)+.

[414] Step 2. Tert-butyl (2-(4-fluoro-2-(1-hydroxyethyl)phenoxy) ethyl)carbamate (41C). To a solution of 41B (1.0 g, 3.36 mmol) in MeOH (10 mL) was added NaBH4 (640 mg, 16.8 mmol) in portions. The mixture was stirred at room temperature for 2 h. The solution was then diluted with water (50 ml) and extracted with DCM (3 x 20 ml). The combined DCM layers were dried over Na2SO4 and concentrated. The residue was purified by a silica gel column eluting with EtOAc/hexane (0-50%, 10 CV) to obtain the desired product as a pale yellow solid (0.75 g, 75%). LC-MS (ESI) m/z 322.3 (M+Na)+; 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).

[415] Step 3. 6-{l-[2-(2-tert-butoxycarbonylamino-ethoxy)-5-fluoro-phenyl]-ethoxy}imidazo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (41D). To a solution of 41C (600 mg, 2.0 mmol) and {2-[4-fluoro-2-(1-hydroxy-ethyl)-phenoxy]-ethyl}-carbamic acid tert-butyl ester (450 mg, 2.0 mmol) in dry THF (40.0 mL) at -78°C was added NaH (60%, 80 mg, 2.0 mmol) in portions. The suspension was stirred at -78°C for 4 h and allowed to warm to 0°C and stirred for an additional 4 h. The mixture was then placed in the freezer at -20°C overnight. The mixture was then quenched with a mixture of ice and 1N HCl and extracted with EtOAc (3 x 20 mL). The organic layer was dried over Na2SO4, concentrated and purified twice to obtain the desired product as a yellow solid (240 mg, 25%). LC-MS (ESI) m/z 511.6 (M+Na)+; XH NMR (500 MHz, Chloroform-d) δ 8.16 (s, 1H) 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).

[416] Step 4. Compound 41D was converted in Example 41, using methods analogous to those described here. MS: 343.2 (M+H)+; ÃH 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, 3Hz, 1H), 6.60-6.53 (m, 1H), 4.63-4.52 (m, 1H), 4.27-4.16 (m, 1H), 4.164.04 (m , 1H), 3.70-3.56 (m, 1H), 1.70 (d, J = 6.4 Hz, 3H). Example 42.

[417] Example 42 was prepared using the methods shown in the following scheme:

[418] Step 1. 6-[(5-Fluoro-2-hydroxy-benzyl)-methyl-amino]imidazo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (42B). To a mixture of 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) in DMSO (5 mL) was added KF (180 mg, 3.01 mmol). The reaction mixture was stirred at 120°C for 18 hours under nitrogen. The solution was then cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were further washed with water (3 x 50 mL) and brine (50 mL), dried over Na2SO4 and concentrated. The residue was then purified by a silica gel column eluting with EtOAc/hexane (0-50%, 10 CV) to obtain the desired product as a white solid (240 mg, 69%). LC-MS (ESI) m/z 345.2 (M+H)+; TH 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).

[419] Step 2. 6-{[2-(2-tert-Butoxycarbonylamino-ethoxy}-5-fluoro-benzyl]-methyl-amino}imidazo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (42C) To a solution of 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-chloroethyl)-carbamic acid tert-butyl ester (209 mg, 1.16 mmol) in DMF (5 mL) were added K2CO3 (200 mg, 1.45 mmol) and Kl (2.0 mg, 0.012 mmol). The mixture was heated at 90°C for 4 h under nitrogen. The mixture was then diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined layers were then washed with water (3x5 mL) and brine (2x5 mL). The organic layer was dried over Na2SO4 and concentrated. The resulting residue was purified by a silica gel column eluting with EtOAc/hexane (0-100%, 10 CV), to obtain 42C as a white solid (203 mg, 76%). LC-MS (ESI) m/z 510.1 (M+Na) +; XH 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 = 1.2 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).

[420] Step 3. Compound 42C was converted to Example 42, using methods analogous to those described here. MS: 342.5 (M+H)+; Xh 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), 420.66- 62 (m, 1H), 3.61 ( s, 3H). Example 51-1

[421] Step 1. To a solution of A8 (399.4 mg, 1.16 mmol) and tert-butyl (2-chloroethyl)carbamate (260.5 mg, 1.45 mmol) in DMF (5. 8 mL) K2CO3 (801.6 mg, 5.80 mmol) was added and heated to 80°C with stirring for 6 hours. The reaction was cooled to room temperature and diluted with DCM (3 mL), filtered through 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).

[422] Step 2. To a solution of 51-1A (407.4 mg, 0.836 mmol) in MeOH (6 mL) and THF (4 mL) was added aqueous LiOH solution (2 M, 4.0 mL) in the room temperature. The reaction solution was heated at 70°C for 2 hours. The reaction vial was cooled to room temperature, diluted with water and methanol, and then quenched with aqueous HCl solution (2 M, 4 mL) until pH <5. The mixture was extracted with DCM (3x5 mL), dried with concentrated Na2SO4 under reduced pressure, and dried 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 the product de-Boc and FDPP (352.9 mg, 0.918 mmol) in DMF (21 mL) was added Hünig's base (539.5 mg, 0.327 mmol) at room temperature. The mixture was stirred for 2.5 hours, and then quenched with 2M Na2CO3 solution (21 mL). The mixture was stirred for 15 min and then extracted with DCM (4 x 10 mL). The combined extracts were dried with NazSO4 and concentrated under reduced pressure. The residue was purified with 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 for three phases). Example 53.

[423] Example 53 was prepared using the methods shown in the following scheme:

[424] Step 1. 5-[1-(5-Fluoro-2-hydroxy-phenyl)-ethylamino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (53A). To a solution of 5-[(5-fluoro-2-hydroxy-benzyl)-methyl-amino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (20M, 300 mg, 0.87 mmol ) in MeOH (5 mL), LiOH (420 mg, 10 mmol) was added, followed by 5 mL of H2O. The mixture was allowed to stir at 60°C for 4 h. The solution was cooled to room temperature, partially concentrated and acidified with 1N HCl to pH 2-3. The resulting suspension was extracted with EtOAc (3 x 20 ml). The combined organic layers were dried over Na2SÜ4 and concentrated. The residue was used directly in the next step. LCMS (ÈSI + ) m/z 317.4 (M+H)+.

[425] Step 2. 3-({5-[(5-fluoro-2-hydroxy-benzyl)-methyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carbonyl}-amine acid methyl ester )-2-hydroxy-propionic (53B). A solution of 53A (80 mg, 0.25 mmol) and 3-amino-2-hydroxy-propionic acid methyl ester hydrochloride (70 mg, 0.5 mmol) in DCM (5 mL) at 0°C was DIPEA (1.0 mL, 5.7 mmol) was added, followed by HATU (140.0 mg, 0.5 mmol). The solution was allowed to warm to room temperature slowly. The mixture was diluted with water (25 ml) and extracted with EtOAc (3 x 25 ml). The combined organic layers were washed with 1N HCl (3 x 20 mL) and brine (50 mL), and dried over Na2SO4. 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)+.

[426] Step 3. Methyl 11-fluoro-14-methyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1, 4,8,10]benzoxatriazacyclotridecine-7-carboxylate (53C). To a solution of 53B (83 mg, 0.2 mmol) in DCM (5 mL) was added PPh3 (263 mg, 1.0 mmol), followed by CBr4 (332 mg, 1.0 mmol). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was re-dissolved in DMF (5 mL), followed by the addition of K2CO3 (116.8 mg, 0.84 mmol). The mixture was then stirred at 80°C until the desired product was completely formed. The mixture was then diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica column (010% MeOH/DCM) to obtain 53C as a white solid (40 mg). LCMS (ESI+) m/z 400.2 (M+H)+.

[427] Step 4. At 53C (20 mg, 0.05 mmol) NH3 in MeOH solution (7N, 2 mL) was added. The mixture was stirred at 60°C overnight. The solvent was removed and the residue was purified by column of silica (0-10% MeOH/DCM) to obtain Example 53 as an off-white solid (8 mg). LC-MS (ESI+) m/z 385.5 (M+H)+; NMR (300 MHz, Chloroform-d) δ 8.41 (s, 1H), 8.34 (d, J = 1.9 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). Example 54.

[428] Example 54 was prepared using the method presented in the following scheme:

[429] To a solution of Compound 53C (20 mg, 0.05 mmol) in MeOH (2 mL) was added NaBH4 (19 mg, 0.5 mmol) in portions. The mixture was stirred for 4 h. The solvent was removed and the residue was purified by silica column (0-10% MeOH/DCM) to obtain the desired product as a white solid (8 mg). LC-MS (ESI+) m/z 372.5 (M+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). Example 93.

[430] Step 1. To a solution of tert-butyl (R)—(2—hydroxypropyl) carbamate (1.00 g, 5.71 mmol) and tosyl chloride (1.14 g, 6.00 mmol) in DCM (29 mL) triethylamine (1.44 g, 14.28 mmol) was added and the mixture was stirred at room temperature for 48 hours. The reaction solution was concentrated under reduced pressure and the residue was purified with flash chromatography (ISCO system, silica (40 g), 0-20% ethyl acetate in hexane) to provide (R)-1-((tert-butoxycarbonyl )amino)propan-2-yl 4-methylbenzenesulfonate (1.12 g, 3.40 mmol, 59.54% yield).

[431] Step 2. To a solution of A8 (100.00 mg, 0.290 mmol) and (R)-1-((tert-butoxycarbonyl)amino)propan-2-yl 4-methylbenzenesulfonate (143.50 mg, 0.436 mmol) in DMF (1.45 mL) K2CO3 (200.7 mg, 1.45 mmol) was added and heated at 80°C with stirring for 16 hours. The reaction was cooled to room temperature and diluted with DCM (3 mL), filtered through a syringe filter, and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 060% ethyl acetate in hexane) gave 93A (32.90 mg, 0.0656 mmol, 22.59% yield).

[432] Step 3. To a solution of 93A (32.90 mg, 0.0656 mmol) in MeOH (3 mL) and THE (2 mL) was added aqueous LiOH solution (2 M, 2 mL) at room temperature . The reaction solution was heated at 70°C for 2 hours. The reaction vial was cooled to room temperature, diluted with water and methanol, and then quenched with aqueous HCl solution (2 M, 2 mL) until pH <5. The mixture was extracted with DCM (3x5 mL), dried with NazSO4, concentrated under reduced pressure and dried 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 the product de-Boc and FDPP (27.62 mg, 0.0719 mmol) in DMF (1.6 mL) was added Hünig's base (42.23 mg, 0.327 mmol) at room temperature. The mixture was stirred for 2.5 hours, and then quenched with 2M Na2CO3 solution (2 ml). The mixture was stirred for 15 min then extracted with DCM (4 x 10 mL). The combined extracts were dried with Na2SO4 and concentrated under reduced pressure. The residue was purified with flash chromatography (ISCO system, silica (12 g), 0-10% methanol in dichloromethane) to provide 93 (10.1 mg, 0.0284 mmol, 43.49% yield for three steps) . Examples 104, 106 and 107

[433] Step 1. To a solution of A17 HCl (38 mg, 0.096 mmol) and tert-butyl (2-chloroethyl) carbamate (12.9 mg, 0.072 mmol) in DMF (0.5 mL) was added K2CO3 ( 33.1 mg, 0.24 mmol) and heated to 80°C with stirring for 1.5 hours. The reaction was cooled to room temperature and diluted with DCM (3 mL), filtered through 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).

[434] Step 2. 104 was prepared according to General Method C from 104A as a white solid.

[435] Step 3. To a solution of 104 (4.6 mg, 0.0129 mmol) in DCM (0.3 mL) was added methyl 3-chlorobenzoperoxoate (2.2 mg, 0.0129 mmol) and to The reaction was stirred for 20 minutes followed by the addition of saturated NaHCOa solution (3 mL) and extracted with DCM (4x4 mL). The combined extracts were dried with Na2SO4 and concentrated under reduced pressure. Flash chromatography (ISCO system, silica (12 g), 0-12.5% methanol in dichloromethane) gave 106 (0.5 mg, 10.4% yield) and 107 (1.7 mg, 33.9 % yield).

[436] The following examples were prepared using methods analogous to those described herein especially General Methods A, B and C, as described herein.

[437] Additional examples are prepared using methods analogous to those described above.

Biological Example 1: Biochemical Kinase Assays.

[438] MET/ALK/AXL/TRKs enzyme inhibition can be measured by Omnia continuous fluorimetric assay (Invitrogen Inc.). Reactions are conducted in 50 μL volumes in 96-well plates at 30°C. Mixtures contain 1 nM recombinant human target kinase domain, 2 μM peptide phosphoacceptor, test compound (11 doses, 3-fold serial dilutions, 2% final DMSO) or DMSO alone, 0.2 mM DTT, and 10 mM MgC12 in 20 mM Hepes, pH 7.5, and reactions are initiated by the addition of ATP (final concentration 100 μM) after a 20 min pre-incubation. Initial rates of phosphopeptide formation are measured over 20 min using a Tecan Safire microplate reader with wavelength settings of 360 nm for excitation and 485 nm for emission. Ki values are calculated by fitting the data to the equation for competitive inhibition using the nonlinear regression method (GraphPad Prism, GraphPad Software, San Diego, CA).

Biological Example 2: Cellular Kinase Phosphorylation ELISA Assays

[439] The experiments are performed based on the procedures 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 are performed under standard conditions (37 ° C and 5% CO2). IC5o values are calculated by fitting the concentration/response curve using a four-parameter method based on Microsoft Excel. Cells are seeded in 96-well plates in medium supplemented with 10% fetal bovine serum (FBS) and transferred to serum-free medium [with 0.04% bovine serum albumin (BSA)] after 24 h. In experiments investigating ligand-dependent RTK phosphorylation, corresponding growth factors are added for up to 20 min. After incubating the cells with an inhibitor for 1 h and/or appropriate ligands for the designated times, the cells are washed once with HBSS supplemented with 1 mmol/L NaaVOo and protein lysates are generated from the cells. Subsequently, phosphorylation of selected -protein kinases is assessed by a sandwich ELISA method using specific capture antibodies to coat the 96-well plates and a detection antibody specific for the phosphorylated tyrosine residues. Antibody-coated plates are (a) incubated in the presence of protein lysates at 4°C overnight, (b) washed seven times in 1% Tween 20 in PBS, (c) incubated in an anti-total phosphotyrosine-conjugated antibody to horseradish peroxidase (PY-20)(1:500) for 30 min, (d) washed seven times again, (e) incubated in 3,3,5,5-tetramethylbenzidine peroxidase substrate (Bio-Rad) to initiate a colorimetric reaction that is stopped by adding 0.09N H2SO4 and (f) measurements for absorbance at 450 nm using a spectrophotometer. Cell lines that are used 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 Example 3: Kinase Binding Assays.

[440] Kinase binding assays were performed in DiscoveRx using the general KINOMEscan Kd protocol (Fabian, MA et al., "A small molecule-kinase interaction map by clinical kinase inhibitors", Nat. Biotechnol. 2005, 23(3 ):329-36). For most assays, kinase-targeting T7 phage strains were prepared in an E. coli host derived from strain BL21. E. coli were grown to log phase and infected with T7 phage and incubated with shaking at 32°C until lysis. Lysates were centrifuged and filtered to remove cellular debris. The remaining kinases were produced in HEK-293 cells and subsequently labeled with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 min at room temperature to generate affinity resins for kinase assays. Ligand 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 to reduce binding. does not specify. Binding reactions were set up by combining kinases, ligand affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). All reactions were performed in 96-well polystyrene plates in a final volume of 0.135 ml. Assay plates were incubated at room temperature with shaking for 1 hour and affinity beads were washed with wash buffer (1x PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (lx PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. Kinase concentration in eluates was measured by qPCR. The results for the compounds tested in this assay are presented in Table 2. With this method, Example 20 also had a binding affinity for PLK4 kinase (Kd 2.9 nM). Table 2.

Biological Example 4: Ba/F3 Cell Proliferation Assay.

[441] TRKA Ba/F3 cell proliferation assays were performed by ACD (Advanced Cellular Dynamics). Ba/F3 cell lines were maintained in RPMI-1640 culture medium containing 10% fetal bovine serum and antibiotics. Cells growing in logarithmic phase were collected, and 5,000 cells were distributed into each well of a 384-well plate in 50 μL of growth medium. Compounds diluted in fifty nanoliters were added to the appropriate wells, in duplicate, and cells were cultured for 48 hours at 37°C in a humidified 5% CO2 incubator. Viability was determined by adding 15 μL of CellTiter-Glo and measuring luminescence, which is reported as relative light units (RLÜ) measured in counts per second. The data (RLU) for each compound were normalized to the maximum mean response obtained in the presence of vehicle (DMSO) alone. These data were used to derive the percentage of inhibition (100 - % maximal response) and the average of the two data points/concentration was used to calculate IC50 values (concentration that causes half-maximal inhibition of cell survival) across of nonlinear regression analysis using GraphPad Prism software (GraphPad, Inc., San Diego, CA). With this method, Example 20 inhibited cell proliferation of TRKA Ba/F3 cells with an IC50 of 3.0 nM. Data for the compounds tested in this assay are presented in Table 3.

Biological Example 5: Creation of Stable Cell Line and EML4 ALK-Ba/F3 Cell Proliferation Assay.

[442] The EML4-ALK wild-type gene (variant 1) was synthesized in GenScript and cloned into plasmid pCDH-CMV-MCS-EFl-Puro (System Biosciences, Inc). Ba/F3-EML4-ALK wild-type cell line was generated by infecting Ba/F3 cells with lentivirus containing wild-type EML4-ALK. Stable cell lines were selected by treatment with puromycin, followed by withdrawal of IL-3. 5,000 cells were seeded in white 384-well plates overnight before compound treatment. Cell proliferation was measured using a CellTiter-Glo luciferase-based ATP detection assay (Promega) following the manufacturer's protocol after 48 hours of various concentrations of compound incubation. IC5o determinations were performed using GraphPad Prism software (GraphPad, Inc., San Diego, CA.). Data for the compounds tested in this assay are presented in Table 3

Biological Example 6: Cell Proliferation Assays.

[443] KM 12 cells from colorectal cell lines (harboring endogenous TPM3-TRKA fusion gene) were cultured in DMEM medium, supplemented with 10% fetal bovine serum and 100 U/mL penicillin/streptomycin. 5,000 cells were seeded in a 384-well white plate for 24 hours before treatment with the compounds. Cell proliferation was measured using a CellTiter-Glo luciferase-based ATP detection assay (Promega) following the manufacturer's protocol after 72 hours of incubation. IC50 determinations were performed using GraphPad Prism software (GraphPad, Inc., San Diego, CA).

[444] Alternatively: Colorectal cell line KM 12 cells (harboring endogenous TPM3-TRKA fusion gene) were cultured in DMEM medium, supplemented with 10% fetal bovine serum and 100 U/mL penicillin/streptomycin. SET-2 cells from essential thrombocythemia cell line (harboring endogenous JAK2 V618F point mutation) or Karpas-299 T-cell lymphoma cell line (harboring endogenous NPM-ALK fusion gene) were cultured in RPMI medium, supplemented with de 10% fetal bovine serum and 100 U/mL of penicillin/streptomycin. 5,000 cells were seeded in a 384-well white plate for 24 hours before treatment with the compounds. Cell proliferation was measured using a CellTiter-Glo luciferase-based ATP detection assay (Promega) following the manufacturer's protocol after 72 hours of incubation. IC50 determinations were performed using GraphPad Prism software (GraphPad, Inc., San Diego, CA).

[445] Data for the compounds tested in these assays are presented in Table 3.Table 3

Biological Example 7: Cellular Mechanism of TRKA Action Studies and Assay Downstream Signal Target Phosphorylation Assays.

[446] KM 12 cells from colorectal cell lines (harboring endogenous TPM3-TRKA fusion gene) 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 before treatment with the compounds. Cells were washed with 1x PBS and collected after 5 hours of treatment and lysed in RIPA buffer (50 mM Tris, pH 7.4, 150 mM NaCl, 1% NP-40, 0.5% deoxycholate, SDS 0.1%), supplemented with 10 mM EDTA, Halt protease and phosphatase inhibitors (Thermo Scientific). Protein lysates (20 μg) were resolved on 4-12% Bolt BisTris precast gels with MES running buffer (Life Technologies), transferred to nitrocellulose membranes using Trans-Blot Turbo Transfer System (Bio-Rad) and detected with antibodies directed to phosphorylated TRK A (Cell Signaling Technology, Y496, Y680, Y681, clone C50F3; 1:1000 dilution), total TRK A (Santa Cruz Biotechnology, SC-11; clone C-14, 1:2000 dilution ), 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). Antibodies were typically incubated overnight at 4°C with gentle shaking, followed by washing and incubation with the appropriate HRP-conjugated secondary antibodies. Membranes were exposed to chemiluminescent substrate for 5 min at room temperature (SuperSignal West Femto, Thermo Scientific). Images were obtained with a C-Digit imaging system (LI-COR Biosciences). The relative density of the bands was obtained directly using Image Studio Digits from LICOR. Semi-inhibitory concentration (IC50) values were calculated using nonlinear regression analysis using GraphPad Prism software (GraphPad, Inc., San Diego, CA). With this method, Example 20 inhibited the autophosphorylation of TPM3-TRKA with an IC50 of 1.07 nM and the phosphorylation of its downstream signaling targets AKT and ERK with an IC50 of 2.80 nM and 2.00 nM, respectively, in KM 12 cells.

Biological Example 8: Caspase Activity Assays.

[447] KM 12 cells were maintained in DMEM medium supplemented with 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 staurosporine treatment, 500 nM STS was added at 60 hours and 12 hours incubation, as a positive control. All cells were collected and washed with 1x PBS twice and then lysed in a lysis buffer (20 mM HEPES, 150 mM NaCl, 10 mM KCl, 5 mM EDTA, 1% NP40) supplemented with Halt protease and phosphatase inhibitors. (Thermo Scientific) . For caspase assays, approximately 20 μL (20 μg) of cell lysate was incubated with 20 μL of caspase3 glo reagent (Promega), measuring enzyme activity through the release of luminescence after 20 min of incubation at 37°C. For Western blotting, cell lysates were boiled and analyzed by SDS-PAGE/immunoblotting using PARP, or actin antibodies. With this method, Example 20 induced apoptosis of KM 12 cells.

Claims (27)

1. Compound characterized by the fact that it has the following formula (IV): where: M is CH or N; X1 and ', -NRa'Rb', - SRa', -S(O)Ra', -S(O)NRa', -S(O)2Ra', -S(O)2NRa' or -ORa' where each hydrogen atom in C1-6 alkyl is independently optionally substituted by halogen, -OH, -OC1-4alkyl, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, NHC(O)C1-4alkyl , -N(C1-4alkyl)C(O)C1-4alkyl, -NHC(O)NHC1-4alkyl, -N(C1-4alkyl)C(O)NHC1-4alkyl, -NHC(O)N(C1-4alkyl )2, -N(C1-4alkyl)C(O)N(C1-4alkyl)2, -NHC(O)OC1-4alkyl, -N(C1-4alkyl)C(O)OC1-4alkyl, -CO2H, - CO2C1-4alkyl, -CONH2, -CONH(C1-4alkyl), -CON(C1-4alkyl)2, -SC1-4alkyl, -S(O)C1-4alkyl, -S(O)2C1-4alkyl, -S( O)NH(C1-4alkyl), -S(O)2NH(CI-4alkyl), -S(O)N(C1-4alkyl)2, -S(O)2N(C1-4alkyl)2, C3-6cycloalkyl , or 3- to 7-membered heterocycloalkyl; R3a and R3b are each independently H, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN, or -CF3; R7a is H, C1-6alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C1-6alkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by halogen, -CN, -OH, -OC1-4alkyl, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, -CO2H, -CO2C1-4alkyl, -CONH2, -CONH(C1-4alkyl), -CON(C1-4alkyl)2, C3- 6 cycloalkyl, or 3- to 7-membered heterocycloalkyl; each Rk' is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl; wherein each hydrogen atom in C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl in Rk' is independently optionally substituted by halogen, C1-6 alkyl, C1-6 halolkyl or -ORa'; wherein each Ra' and Rb' is independently H, C1-6alkyl, C2-6alkenyl, Cealkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each heterocycloalkyl or heteroaryl comprising from 1 to 4 ring atoms selected from nitrogen, oxygen, and sulfur; each Z1, Z2, Z3, Z4, Z5, Z6, or Z7 is independently N, NH, or C(Rx), wherein each Rx when present is H, provided that at least one of Z1, Z2, Z3, Z4, Z5 , Z6 or Z7 is N or NH; and m' is 2 or 3; X1 and X1' are independently -C(R1a)(R2a)-, -S-, -S(O)- , -S(O)2-, —O— or -N(Rk')-; each R1a and R2a is independently H, C1-6alkyl, C3-6cycloalkyl, C6-10 aryl, -C(O)ORa', -C(O)NRa'Rb', -NRa'Rb', - SRa', - S(O)Ra', -S(O)NRa', -S(O)2Ra', -S(OhNRa' or -ORa' in which each hydrogen atom in C1-6alkyl is independently optionally substituted by halogen, - OH, -OC1- 4alkyl, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, NHC(O)C1-4alkyl, -N(C1-4alkyl)C(O)C1-4alkyl, -NHC(O)NHC1-4alkyl, - N(C1-4alkyl)C(O)NHC1-4alkyl, NHC(O)N(C1-4alkyl)2, -N(C1-4alkyl)C(O)N(C1 -4alkyl)2, -NHC(O)OC1-4alkyl, -N(C1-4alkyl)C(O)OC1-4alkyl, -CO2H, -CO2C1-4alkyl, -CONH2, - CONH(C1-4alkyl), -CON (C1-4alkyl)2, -SC1-4alkyl, -S(O)C1- 4alkyl, -S(O)2C1-4alkyl, -S(O)NH(C1-4alkyl), -S(O)2NH(C1 -4alkyl), -S(O)N(C1-4alkyl)2, -S(O)2N(C1-4alkyl)2, C3-6cycloalkyl, or 3- to 7-membered heterocycloalkyl; R3a and R3b are each independently H , fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN, or -CF3; R7a is H, C1-6alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C1-6alkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by halogen, -OH, -OC1-4alkyl, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, -CO2H, -CO2C1 -4alkyl, -CONH2, -CONH(C1-4alkyl), -CON(C1-4alkyl)2, C3-6 cycloalkyl, or 3- to 7-membered heterocycloalkyl; each Rk' is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl; wherein each hydrogen atom in C1-6alkyl, Coalkenyl, C2-alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl in Rk' is independently optionally substituted by halogen, C1-6alkyl, C1-6halolkyl or -ORa'; wherein each Ra' and Rb' is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each heterocycloalkyl or heteroaryl comprising from 1 to 4 ring atoms selected from nitrogen, oxygen and sulfur; each Z1, Z2, Z3, Z4, Z5, Z6, or Z7 is independently N, NH, or C(Rx), wherein each Rx when present is H, provided that at least one of Z1, Z2, Z3, Z4, Z5 , Z6 or Z7 is N or NH; and m' is 2 or 3; or a pharmaceutically acceptable salt thereof. 2. Compound, according to claim 1, characterized by the fact that it is of Formula (V): where M is CH or N; X1 and X1' are independently -C(R1a)(R2a)-, -S-, -S(O)- , -S(O)2-, -O- or -N(Rk')-; each R1a and R2a is independently H, C1-6alkyl, C3-6cycloalkyl, C6-10 aryl, -C(O)ORa', -C(O)NRa'Rb', -NRa'Rb', - SRa', - S(O)Ra', -S(O)NRa', -S(O)2Ra', -S(O)2NRa' or -ORa' wherein each hydrogen atom in C1-6alkyl is independently optionally substituted by halogen , -OH, -OC1- 4alkyl, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, NHC(O)C1- 4alkyl, -N(C1-4alkyl)C(O)C1- 4alkyl, -NHC(O)NHC1-4alkyl, - N(C1-4alkyl)C(O)NHC1-4alkyl, NHC(O)N(C1-4alkyl)2, -N(C1-4alkyl)C(O)N (C1-4alkyl)2, -NHC(O)OC1-4alkyl, -N(C1-4alkyl)C(O)OC1-4alkyl, -CO2H, -CO2C1-4alkyl, -CONH2, - CONH(C1-4alkyl), -CON(C1-4alkyl)2, -SC1-4alkyl, -S(O)C1-4alkyl, -S(O)2C1-4alkyl, -S(O)NH(C1-4alkyl), -S(O)2NH (C1-4alkyl), -S(O)N(C1-4alkyl)2, -S(O)2N(C1-4alkyl)2, C3-6cycloalkyl, or 3- to 7-membered heterocycloalkyl; R3a and R3b are each independently H, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN, or -CF3; R7a is H, C1-6alkyl or 3-7 membered heterocycloalkyl, wherein each hydrogen atom in C1-6alkyl or 3-7 membered heterocycloalkyl is independently optionally substituted by halogen, -OH, -OC1-4alkyl, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, -CO2H, -CO2C1-4alkyl, - CONH2, -CONH(C1-4alkyl), -CON(C1-4alkyl)2, C3-6 cycloalkyl, or 3- to 7-membered heterocycloalkyl; each Rk' is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl; wherein each hydrogen atom in C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl in Rk' is independently optionally substituted by halogen, C1-6alkyl, C1-6halolkyl or -ORa'; wherein each Ra' and Rb' is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each heterocycloalkyl or heteroaryl comprising from 1 to 4 ring atoms selected from nitrogen, oxygen and sulfur; each Z1, Z2, Z3, Z4, Z5, Z6, or Z7 is independently N, NH, or C(Rx), wherein each Rx when present is H, provided that at least one of Z1, Z2, Z3, Z4, Z5 , Z6 or Z7 is N or NH; and m' is 2 or 3; or a pharmaceutically acceptable salt thereof. 3. Compound according to claim 1 or 2, characterized in that it is selected from the group consisting of where M is CH or N; X1 and X1' are independently -C(R1a)(R2a)-, -S-, -S(O)- , -S(O)2-, -O- or -N(Rk')-; each R1a and R2a is independently H, C1-6alkyl, C3-6cycloalkyl, C6-10 aryl, -C(O)ORa', -C(O)NRa'Rb', -NRa'Rb', - SRa', - S(O)Ra', -S(O)NRa', -S(O)2Ra', -S(OhNRa' or -ORa' in which each hydrogen atom in C1-6alkyl is independently optionally substituted by halogen, - OH, -OC1- 4alkyl, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, NHC(O)C1-4alkyl, -N(C1-4alkyl)C(O)C1-4alkyl, -NHC(O)NHC1-4alkyl, -N(C1-4alkyl)C(O)NHC1-4alkyl, -NHC(O)N(C1-4alkyl)2, -N(C1-4alkyl)C(O)N( C1-4alkyl)2, -NHC(O)OC1-4alkyl, -N(C1-4alkyl)C(O)OC1-4alkyl, -CO2H, -CO2C1-4alkyl, -CONH2, - CONH(C1-4alkyl), - CON(C1-4alkyl)2, -SC1-4alkyl, -S(O)C1- 4alkyl, -S(O)2C1-4alkyl, -S(O)NH(C1-4alkyl), -S(OhNH(C1- 4alkyl), -S(O)N(C1-4alkyl)2, -S(O)2N(C1-4alkyl)2, C3-6cycloalkyl, or 3- to 7-membered heterocycloalkyl; R3a and R3b are each independently H, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN, or -CF3; R7a is H, C1-6alkyl, or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C1-6alkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by halogen, -OH, -OC1-4alkyl, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, -CO2H, -CO2C1 -4alkyl, -CONH2, -CONH(C1-4alkyl), -CON(C1-4alkyl)2, C3-6 cycloalkyl, or 3- to 7-membered heterocycloalkyl; each Rk' is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl; wherein each hydrogen atom in C1-6alkyl, Cealkenyl, C2-ealkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl in Rk' is independently optionally substituted by halogen, C1-6alkyl, C1-6haloalkyl or-ORa'; wherein each Ra' and Rb' is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl; each heterocycloalkyl or heteroaryl comprising from 1 to 4 ring atoms selected from nitrogen, oxygen and sulfur; and each Z1, Z2, Z3, Z4, Z5, Z6, or Z7 is independently N, NH, or C(Rx), wherein each Rx when present is H, provided that at least one of Z1, Z2, Z3, Z4, Z5, Z6 or Z7 is N or NH; and or a pharmaceutically acceptable salt thereof. 4. Compound according to any one of claims 1 to 3, characterized in that each R3a and R3b are independently fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, -CN, or - CF3, or a pharmaceutically acceptable salt thereof. 5. Compound according to any one of claims 1 to 4, characterized in that each R3a and R3b are independently fluorine or chlorine, or a pharmaceutically acceptable salt thereof. 6. Compound according to any one of claims 1 to 5, characterized by the fact that R7a is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl, thiofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, or 5- to 10-membered heteroaryl, or a pharmaceutically acceptable salt thereof. 7. Compound according to any one of claims 1 to 6, characterized in that R7a is H, or is methyl, ethyl, propyl, isopropyl, or cyclopropyl, or a pharmaceutically acceptable salt thereof. 8. Compound according to any one of claims 1 to 5, characterized in that R7a is H or is methyl or ethyl, each unsubstituted or substituted by halogen, -OH, -OC1-4alkyl, -NH2, - NH(C1-4alkyl), -N(C1-4alkyl)2, -CO2H, -CO2C1-4alkyl, -CONH2, C3-6 cycloalkyl, or 3- to 7-membered heterocycloalkyl, or a pharmaceutically acceptable salt thereof. 9. Compound according to any one of claims 1 to 5, characterized in that R7a is H, methyl, hydroxyethyl, -CH2CONH2, or 3-pyrrolidinylmethyl, or a pharmaceutically acceptable salt thereof. 10. Compound according to any one of claims 1 to 9, characterized in that R7a is H or methyl, or a pharmaceutically acceptable salt thereof. 11. Compound according to any one of claims 1 to 10, characterized in that R1a and R2a are each independently H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl, thiofuranyl, piperidinyl , piperazinyl, morpholinyl, phenyl, or 5- to 6-membered heteroaryl, or a pharmaceutically acceptable salt thereof. 12. Compound according to any one of claims 1 to 11, characterized by the fact that R1a is H, or a pharmaceutically acceptable salt thereof. 13. Compound according to any one of claims 1 to 12, characterized in that R2a is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, furanyl, thiofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, or 5- to 6-membered heteroaryl, or a pharmaceutically acceptable salt thereof. 14. Compound according to any one of claims 1 to 12, characterized in that R2a is H or is methyl or ethyl, each unsubstituted or substituted by halogen, -OH, -OC1-4alkyl, -NH2, - NH(C1-4alkyl), -N(CI-4alkyl)2, -CO2H, -CO2C1-4alkyl, -CONH2, C3-6 cycloalkyl, or 3- to 7-membered heterocycloalkyl, or a pharmaceutically acceptable salt thereof. 15. Compound according to any one of claims 1 to 12, characterized in that R2a is H, methyl, fluoromethyl, hydroxymethyl or cyclopropyl, or a pharmaceutically acceptable salt thereof. 16. Compound according to any one of claims 1 to 15, characterized by the fact that Z1, Z4 and Z7 are N, and Z2, Z3, Z5 and Z6 are C(Rx), wherein each Rx when present is H , or a pharmaceutically acceptable salt thereof. 17. Compound according to any one of claims 1 to 15, characterized by the fact that M is CH, Z1, Z4 and Z7 are N, and Z2, Z3, Z5 and Z6 are C(Rx), wherein each Rx when present it is H, or a pharmaceutically acceptable salt thereof. 18. Compound according to any one of claims 1 to 15, characterized by the fact that M is CH, Z1, Z4 and Z7 are N, Z2, Z3, Z5 and Z6 are C(Rx), wherein each Rx when present is H, and X1 is -N(Rk')-, or a pharmaceutically acceptable salt thereof. 19. Compound according to any one of claims 1 to 15, characterized by the fact that M is CH, Z1, Z4 and Z7 are N, Z2, Z3, Z5 and Z6 are C(Rx), wherein each Rx when present is H, X1 is -N(Rk')-, and X1' is -O-, or a pharmaceutically acceptable salt thereof. 20. Compound according to any one of claims 1 to 15, characterized by the fact that M is CH, Z1, Z4 and Z7 are N, Z2, Z3, Z5 and Z6 are C(Rx), wherein each Rx when present is H, X1 is -C(R1a)(R2a)-, and X1' is -O-, or a pharmaceutically acceptable salt thereof. 21. Compound according to any one of claims 1 to 20, characterized in that Rk' is selected from the group consisting of H, methyl, ethyl, propyl, iso-propyl, cyclopropyl, 2-hydroxyethyl, 2-hydroxy -2-methyl-propyl and N-methyl-pyrrol-3-yl, or a pharmaceutically acceptable salt thereof. 22. Compound according to claims 1 to 21, characterized in that Rk' is H or methyl, or a pharmaceutically acceptable salt thereof. 23. Compound according to claim 1, characterized in that it is selected from the group consisting of (13R)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4 ,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; (13R)-11-fluoro-5,13-dimethyl-6,7-dihydro-13H- 1,15-ethenopyrazolo[4,3- f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H )-one; 11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; (13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3- f][1,10,4,8]benzodioxadiazacyclotridecin -4(5H)-one; 12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H )-one; (13R)-12-chloro-11-fluoro-5-(2-hydroxyethyl)-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3- f][1,10 ,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-5-(2-hydroxyethyl)-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3- f][1,10,4,8 ]benzodioxadiazacyclotridecin-4(5H)-one; 2- [(13R)-12-chloro-11-fluoro-13-methyl-4-oxo-6,7-dihydro-13H- 1,15-ethenopyrazolo[4,3- f][1,10, 4.8]benzodioxadiazacyclotridecin-5(4H)-yl]acetamide; 2-[12-chloro-11-fluoro-13-methyl-4-oxo-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3- f][1,10,4,8] benzodioxadiazacyclotridecin-5(4H)-yl]acetamide; (13R)-12-chloro-11-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1 ,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-13-methyl-5-(pyrrolidin-2-ylmethyl)-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3- f][1,10,4 ,8]benzodioxadiazacyclotridecin-4(5H)-one; (13R)-12-chloro-11-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3- f][1,10 ,4,8]benzodioxadiazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-7-(hydroxymethyl)-5,13-dimethyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3- f][1,10,4,8 ]benzodioxadiazacyclotridecin-4(5H)-one; (13S)-11-fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin - 4(5H)-one; 11-fluoro-13-(fluoromethyl)-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3- f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H )-one; (13R)- 13-cyclopropyl-11-fluoro-5-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin- 4 (5H)-one; 13-cyclopropyl-11-fluoro-5-methyl-6,7-dihydro- 13H-1,15-ethenopyrazolo[4,3- f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)- onea; (13R)- 11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3- f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)- onea; 11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)-one; (13R)- 12-chloro-11-fluoro-13-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin- 4 (5H)-one; 12-chloro-11-fluoro-13-methyl-6,7-dihydro-13H- 1,15-ethenopyrazolo[4,3- f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)- onea; 12-chloro-11-fluoro-6-methyl-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzodioxadiazacyclotridecin- 4(5H)- onea; 12-chloro-11-fluoro-7-methyl-6,7-dihydro-13H- 1,15-ethenopyrazolo[4,3- f][1,10,4,8]benzodioxadiazacyclotridecin-4(5H)- onea; (8R)-9-chloro-10-fluoro-8-methyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1- f][1,10,4,7,8]benzodioxatriazacyclotridecin -17(14H)-one; 9-chloro-10-fluoro-8-methyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H )-one; (7R)-8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5- (azenomethene)pyrrolo[3,4- f][1,10,4, 8]benzodioxadiazacyclotridecin-16(13H)-one; 8-chloro-9-fluoro-7-methyl-14,15-dihydro-2H,7H-3,5- (azenomethene)pyrrolo[3,4- f][1,10,4,8]benzodioxadiazacyclotridecin- 16(13H)-one; (5R)- 3-fluoro-5-methyl-14,15-dihydro-5H,10H-9,7- (azenomethene)pyrido[2,3-k]pyrrolo[3,4-d][1, 10,3,7]dioxadiazacyclotridecin-12(13H)-one; 3-fluoro-5-methyl-14,15-dihydro-5H,10H-9,7-(azenomethene)pyrido[2,3- k]pyrrolo[3,4-d][1,10,3, 7]dioxadiazacyclotridecin-12(13H)-one; (5R)-3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H- 9,7-(azenomethene)pyrido[2,3-k]pyrrolo[3,4- d ][1,3,7,10]oxatriazacyclotridecin-12(10H)-one; 3-fluoro-5,16-dimethyl-13,14,15,16-tetrahydro-5H-9,7-(azenomethene)pyrido[2,3-k]pyrrolo[3,4-d][1, 3,7,10]oxatriazacyclotridecin-12(10H)-one; (13R)-12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-2H,13H-1,15- (azenomethene)pyrrolo[3,4- f][1,10, 4]benzodioxazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-5,13-dimethyl-6,7-dihydro-2H,13H-1,15- (azenomethene)pyrrolo[3,4- f][1,10,4]benzodioxazacyclotridecin- 4(5H)-one; (7R)-8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5- (azenomethene)pyrazolo[3,4- f][1,10, 4]benzodioxazacyclotridecin-16(13H)-one; 8-chloro-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5- (azenomethene)pyrazolo[3,4- f][1,10,4]benzodioxazacyclotridecin- 16(13H)-one; 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; (13R)-12-chloro-11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10 ]benzoxatriazacyclotridecin-4(5H)-one; 12-chloro-11-fluoro-13,14-dimethyl-6,7,13,14- tetrahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecin-4 (5H)-one; 12-chloro-11-fluoro-5,14-dimethyl-6,7,13,14-tetrahydro-15,1-(azenomethene)pyrazolo[4,3-f][1,4,10]benzoxadiazacyclotridecin- 4(5H)-one; 12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-15,1- (azenomethene)pyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one; 12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15- (azenomethene)pyrrolo[3,2- f][1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one; 12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15- (azenomethene)pyrrolo[3,2- f][1,4,10]benzoxadiazacyclotridecin-4( 5H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-ethenoimidazo[5,1- f][1,4,7,8,10]benzoxatetra-azacyclotridecin -17(14H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-6,3-(azenomethene)imidazo[5,1-f][1,4,7,8,10] benzoxatetra-azacyclotridecin-17(14H)-one; 9-chloro-10-fluoro-7-methyl- 7,8,15,16-tetrahydro-6,3-(azenomethene)imidazo[5,1- f][1,4,7,10]benzoxatriazacyclotridecin- 17(14H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6- (azenomethene)pyrrolo[2,1- f][1,4,7,10]benzoxatriazacyclotridecin- 17(14H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-(azenomethene)imidazo[2,1- f][1,4,7,10]benzoxatriazacyclotridecin- 17(14H)-one; 9-chloro-10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-etheno[1,2,4]triazolo[3,4-f][1,4,7 ,8,10]benzoxatetraazacyclotridecin-17(14H)-one; 9-chloro-10-fluoro-7-methyl- 7,8,15,16-tetrahydro-6,3-(azenomethene)[1,2,4]triazolo[3,4- f][1,4 ,7,10]benzoxatriazacyclotridecin-17(14H)-one; 8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5- (azenomethene)pyrrolo[3,4- f][1,4,8,10] benzoxatriazacyclotridecin-16(13H)-one; 8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5- (azenomethene)pyrazolo[3,4- f][1,4,8,10] benzoxatriazacyclotridecin-16(13H)-one; 8-chloro-9-fluoro-6-methyl-6,7,14,15-tetrahydro-2H-3,5- (azenomethene)pyrazolo[3,4- f][1,4,10]benzoxadiazacyclotridecin- 16(13H)-one; 12-chloro-11-fluoro-5,14-dimethyl-6,7,13,14-tetrahydro-2H-1,15- (azenomethene)pyrrolo[3,4- f][1,4,10] benzoxadiazacyclotridecin-4(5H)-one; (8R)-10-fluoro-8,16-dimethyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1- f][1,10,4,7,8]benzodioxatriazacyclotridecin-17 (14H)-one; 10-fluoro-8,16-dimethyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1- f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)- onea; (7R)-9-fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5- (azenomethene)pyrrolo[3,4- f][1,10,4,8] benzodioxadiazacyclotridecin-16(13H)-one; 9- fluoro-7,15-dimethyl-14,15-dihydro-2H,7H-3,5- (azenomethene)pyrrolo[3,4- f][1,10,4,8]benzodioxadiazacyclotridecin-16( 13H)-one; 12-chloro-11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin- 4(5H )-one; 10-fluoro-8-methyl-15,16-dihydro-8H-3,6-ethenoimidazo[5,1-f][1,10,4,7,8]benzodioxatriazacyclotridecin-17(14H)-one; 10-fluoro-7-methyl-7,8,15,16-tetrahydro-3,6-ethenoimidazo[5,1-f][1,4,7,8,10]benzoxatetraazacyclotridecin-17(14H )-one; 14-ethyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-14-propyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-14-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecin-4 (5H)-one; 14-cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-14-(2-hydroxyethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecin-4(5H )-one; 11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin- 4(5H)- onea; 14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; (13R)-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecin-4(5 H )-one; 12-chloro-11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin- 4(5H )-one; 11-fluoro-14-methyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecin-7 -carboxamide; 11-fluoro-7-(hydroxymethyl)-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecin-4 (5H)-one; 11-fluoro-13-methyl-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin- 7 -carboxamide; 11-fluoro-7-(hydroxymethyl)-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecin-4 (5H)-one; 11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-7-carboxamide; 11-fluoro-7-(hydroxymethyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- onea; methyl 11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-13-carboxylate; 11-fluoro-4-oxo-4,5,6,7,13,14-hexahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecine-13-carboxamide; 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-1][1,4,8,10]oxatriazacyclotridecin -4(5H)-one; 11-fluoro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f]pyrido[3,2-l][1,4,8,10]oxatriazacyclotridecin -4(5H)-one; 11-fluoro-13-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-1][1,4 ,8,10]oxatriazacyclotridecin-4(5H)-one; 13-cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f]pyrido[3,2-1][1,4,8,10]oxatriazacyclotridecin -4(5H)-one; 13-cyclopropyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-13-(propan-2-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecin-4 (5H)-one; 11-fluoro-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one; 11-fluoro-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one 14,14-dioxide; 6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][10,1,4,8]benzoxathiadiazacyclotridecin-4(5H)-one; 14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzotiatriazacyclotridecin-4(5H)-one; 13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzotiatriazacyclotridecin-4(5H)-one; 11-fluoro-6,7-dihydro-5H-1,15-ethenopyrazolo[3,4- e][11,1,2,4,8]benzoxathiatriazacyclotridecin-4(14H)-one 13,13-dioxide ; 11-fluoro-14-methyl-6,7-dihydro-5H-1,15-ethenopyrazolo[3,4- e][11,1,2,4,8]benzoxathiatriazacyclotridecin-4(14H)-one 13 ,13-dioxide; 12-fluoro-15-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one ; 12-fluoro-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-4-one ; (14R)-12-fluoro-14-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin - 4-one; 11-fluoro-7,14-dimethyl-4,5,6,7,13,14-hexahydro-8H- 1,15-ethenopyrazolo[3,4-e][2,4,10]benzotriazacyclotridecin-8-one ; 11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[3,4-e][7,2,4,10]benzoxatriazacyclotridecin- 8(5H)- onea; 11-fluoro-7,14-dimethyl-4,5,6,7,13,14-hexahydro-8H-1,15-ethenopyrazolo[3,4-e][2,4,7,10]benzotetraazacyclotridecin -8-one; 11-fluoro-4,7,14-trimethyl-4,5,6,7,13,14-hexahydro-8H-1,15-ethenopyrazolo[3,4- e][2,4,7,10]benzotetra -azacyclotridecin-8-one; 11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[3,4- e][7,2,4,10]benzotiatriazacyclotridecin-8(5H)- onea; 11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[3,4-e][7,2,4,10]benzotiatriazacyclotridecin- 8(5H)- ona 4,4-dioxide; 12-fluoro-8,15-dimethyl-5,6,7,8,14,15-hexahydro-9H-1,16-ethenopyrazolo[3,4- e][7,2,4,8,11]benzotiatetra -zacyclotetradecin-9-one 4,4-dioxide; 11-chloro-13-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 13-ethyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 13-cyclobutyl-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one ; 11-fluoro-14-methyl(6,6,7,7-2H4)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f ][1,4,8, 10]benzoxatriazacyclotridecin-4(5H)-one; 11-fluoro-13-phenyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one; 13-(cyclopropylmethyl)-11-fluoro-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f ][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- onea; (7R,14R)- 12-fluoro-7-hydroxy-14-methyl-5,6,7,8,14,15-hexahydro-4H- 1,16-ethenopyrazolo[4.3- g ][1.5 ,9,11]benzoxatriazacyclotetradecin-4-one; (7S,14R)- 12-fluoro-7-hydroxy-14-methyl-5,6,7,8,14,15-hexahydro-4H- 1,16-ethenopyrazolo[4.3- g ][1.5 ,9,11]benzoxatriazacyclotetradecin-4-one; (7R,13R)- 11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f ][1,4,8,10]benzoxatriazacyclotridecin - 4(5H)-one; (7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecin -4(5H)-one; (7R)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4 (5H)-one; (6R)-11-fluoro-6,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f ][1,4,8,10]benzoxatriazacyclotridecin-4 (5H)-one; 12-fluoro-7-hydroxy-15-methyl-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin - 4-one; (7S)-11-fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecin-4 (5H)-one; 11-fluoro-13-(hydroxymethyl)-6,7,13,14-tetrahydro-1,15- ethenopyrazolo[4,3- f ][1,4,8,10]benzoxatriazacyclotridecin- 4(5H)- onea; 12-fluoro-14-(hydroxymethyl)-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3- g ][1,5,9,11]benzoxatriazacyclotetradecin-4 -ona; 11-fluoro-13,14-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f ][1,4,8,10]benzoxatriazacyclotridecin-4(5H)- onea; 11-fluoro-14-(2-hydroxy-2-methylpropyl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecin -4(5H)-one; 12-fluoro-5,6,7,8,14,15-hexahydro-4H-1,16-ethenopyrazolo[4,3-g][1,5,9]benzoxadiazacyclotetradecin-4-one; 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzotiatriazacyclotridecin-4(5H)-one; 11-fluoro-14-(1-methylpyrrolidin-3-yl)-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecin -4(5H)-one; 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzotiatriazacyclotridecin-4(5H)-one 8 -oxide; 11-fluoro-14-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzotiatriazacyclotridecin-4(5H)-one 8 ,8- dioxide; (7S)-11-fluoro-7-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f ][1,4,8]benzoxadiazacyclotridecin-4(5H)- onea; (6S,13R)-11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f ][1,4,8,10]benzoxatriazacyclotridecin -4(5H)-one; (6R,13R)- 11-fluoro-6,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f ][1,4,8,10]benzoxatriazacyclotridecin - 4(5H)-one; (7S,13S)-11-fluoro-13-(hydroxymethyl)-7-methyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f ][1,4,8 ,10]benzoxatriazacyclotridecin-4(5H)-one; and 11-fluoro-6,7-dihydro-13H-1,15-ethenopyrazolo[4,3-f][1,10,4,8]benzoxathiadiazacyclotridecin-4(5H)-one; or a pharmaceutically acceptable salt thereof. 24. Compound, according to claim 1, characterized by the fact that it has the formula or a pharmaceutically acceptable salt thereof. 25. Compound, according to claim 1, characterized by the fact that it has the formula or a pharmaceutically acceptable salt thereof. 26. Compound, according to claim 25, characterized by the fact that it has the formula 27. Pharmaceutical composition, characterized by the fact that it comprises (a) a compound, as defined in any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable excipient.