WO2009132202A2 - Macrocyclic compounds and their use as kinase inhibitors - Google Patents

Macrocyclic compounds and their use as kinase inhibitors Download PDF

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WO2009132202A2
WO2009132202A2 PCT/US2009/041555 US2009041555W WO2009132202A2 WO 2009132202 A2 WO2009132202 A2 WO 2009132202A2 US 2009041555 W US2009041555 W US 2009041555W WO 2009132202 A2 WO2009132202 A2 WO 2009132202A2
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chloro
docosa
nonaen
tetraazatetracyclo
pentaazatetracyclo
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PCT/US2009/041555
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French (fr)
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WO2009132202A3 (en
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Andrew Paul Combs
Richard B. Sparks
Eddy W. Yue
Hao Feng
Michael Jason Bower
Wenyu Zhu
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Incyte Corporation
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Priority to EP09734200A priority Critical patent/EP2274288A2/en
Priority to JP2011506453A priority patent/JP2011518836A/en
Priority to CA2722326A priority patent/CA2722326A1/en
Publication of WO2009132202A2 publication Critical patent/WO2009132202A2/en
Publication of WO2009132202A3 publication Critical patent/WO2009132202A3/en

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Definitions

  • the present invention relates to macrocyclic compounds, and compositions thereof as well as methods of use the same for treatment of Janus Kinase and/or Anaplastic Lymphoma Kinase (J AK/ ALK)- associated diseases including, for example, inflammatory disorders, autoimmune disorders, skin disorders, myeloid proliferative disorders, as well as cancer.
  • J AK/ ALK Anaplastic Lymphoma Kinase
  • Protein kinases are a group of enzymes that regulate diverse, important biological processes including cell growth, survival and differentiation, organ formation and morphogenesis, neovascularization, tissue repair and regeneration, among others. Protein kinases exert their physiological functions through catalyzing the phosphorylation of proteins (or other substrates such as lipids) and thereby modulating the cellular activities of the substrates in various biological contexts. In addition to the functions in normal tissues/organs, many protein kinases also play a central role in a host of human diseases including cancer. A subset of protein kinases (also referred to as oncogenic protein kinases), when dysregulated, can cause tumor formation and inappropriate tumor cell survival and proliferation, and further contribute to tumor progression [See e.g. Blume -Jensen P. et al, Nature 2001, 411(6835):355- 365]. Thus far, oncogenic protein kinases represent one of the largest and most attractive groups of protein targets for cancer intervention and drug development.
  • Protein kinases can be categorized as receptor type and non-receptor type.
  • Receptor tyrosine kinases have an extracellular portion, a transmembrane domain, and an intracellular portion, while non-receptor tyrosine kinases are entirely intracellular.
  • RTK mediated signal transduction is typically initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, stimulation of the intrinsic protein tyrosine kinase activity, and receptor transphosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate cellular responses such as cell survival, proliferation, differentiation, metabolic effects, and changes in the extracellular microenvironment.
  • RTK subfamilies At present, at least nineteen (19) distinct RTK subfamilies have been identified.
  • One RTK subfamily designated the HER subfamily, includes EGFR, HER2, HER3 and HER4, and bind such ligands as epithelial growth factor (EGF), TGF-OC, amphiregulin, HB-EGF, betacellulin and heregulin.
  • a second family of RTKs designated the insulin subfamily, includes the INS-R, the IGF-IR and the IR-R.
  • a third family, the "PDGF" subfamily includes the PDGF alpha and beta receptors, CSFIR, c-kit and FLK-II.
  • FLK subfamily encompasses the Kinase insert Domain-Receptor fetal liver kinase-1 (KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fms-like tyrosine kinase 1 (flt-1).
  • FLK-1 Kinase insert Domain-Receptor fetal liver kinase-1
  • FLK-4 fetal liver kinase 4
  • flt-1 fms-like tyrosine kinase 1
  • Two other subfamilies of RTKs have been designated as the FGF receptor family (FGFRl, FGFR2, FGFR3 and FGFR4) and the Met subfamily (c-Met, Ron and Sea).
  • FGF receptor family FGFRl, FGFR2, FGFR3 and FGFR4
  • Met subfamily c-Met, Ron and Sea
  • the non-receptor type of tyrosine kinases are also composed of numerous sub-families, including Src, Btk, AbI, Fak, and Jak. Each of these subfamilies can be further subdivided into multiple members that have been frequently linked to oncogenesis.
  • Src family for example, is the largest and includes Src, Fyn, Lck and Fgr among others.
  • Bolen JB "Nonreceptor tyrosine protein kinases," Oncogene., 1993, 8(8):2025-31.
  • tyrosine kinases both receptor and nonreceptor
  • overexpression or dysregulation of tyrosine kinases may also be of prognostic value.
  • members of the HER family of RTKs have been associated with poor prognosis in breast, colorectal, head and neck and lung cancer.
  • Mutation of c-Kit tyrosine kinase has been associated with decreased survival in gastrointestinal stromal tumors. In acute myelogenous leukemia (AML), Flt-3 mutation predicts shorter disease free survival.
  • AML acute myelogenous leukemia
  • VEGFR expression which is important for tumor angiogenesis, is associated with a lower survival rate in lung cancer.
  • Tie-1 kinase expression inversely correlates with survival in gastric cancer.
  • BCR-AbI expression is an important predictor of response in chronic myelogenous leukemia (CML) and Src tyrosine kinase is an indicator of poor prognosis in all stages of colorectal cancer.
  • CML chronic myelogenous leukemia
  • Src tyrosine kinase is an indicator of poor prognosis in all stages of colorectal cancer.
  • the immune system responds to injury and threats from pathogens.
  • Cytokines are low-molecular weight polypeptides or glycoproteins that stimulate biological responses in virtually all cell types. For example, cytokines regulate many of the pathways involved in the host inflammatory response to sepsis.
  • Cytokines influence cell differentiation, proliferation and activation, and they can modulate both proinflammatory and anti-inflammatory responses to allow the host to react appropriately to pathogens. Binding of a cytokine to its cell surface receptor initiates intracellular signaling cascades that transduce the extracellular signal to the nucleus, ultimately leading to changes in gene expression.
  • the pathway involving the Janus kinase family of protein tyrosine kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs) is engaged in the signaling of a wide range of cytokines.
  • cytokine receptors do not have intrinsic tyrosine kinase activity, and thus require receptor-associated kinases to propagate a phosphorylation cascade.
  • JAKs fulfill this function. Cytokines bind to their receptors, causing receptor dimerization, and this enables JAKs to phosphorylate each other as well as specific tyrosine motifs within the cytokine receptors. STATs, and other proteins, recognize these phosphotyrosine motifs and are recruited to the receptor where they are activated by a JAK-dependent tyrosine phosphorylation events.
  • STATs Upon activation, STATs dissociate from the receptors and translocate to the nucleus to bind to specific DNA sites and alter transcription [Scott, M. J., C. J. Godshall, et al. (2002). "Jaks, STATs, Cytokines, and Sepsis.” CHn Diagn Lab Immunol 9(6): 1153-9].
  • JAK The Janus Kinase family plays a role in the cytokine-dependent regulation of proliferation and function of cells involved in immune response.
  • JAKl also known as Janus kinase-1
  • JAK2 also known as Janus kinase-2
  • JAK3 also known as Janus kinase, leukocyte; JAKL; L-JAK and Janus kinase-3
  • TYK2 also known as protein-tyrosine kinase 2).
  • JAK proteins range in size from 120 to 140 kDa and comprise seven conserved JAK homology (JH) domains; one of these is a functional catalytic kinase domain, and another is a pseudokinase domain potentially serving a regulatory function and/or serving as a docking site for STATs (Scott, Godshall et al. 2002, supra).
  • JH JAK homology
  • JAK3 is reported to be preferentially expressed in natural killer (NK) cells and activated T cells, suggesting a role in lymphoid activation (Kawamura, M., D. W. McVicar, et al. (1994). "Molecular cloning of L-JAK, a Janus family protein- tyrosine kinase expressed in natural killer cells and activated leukocytes.” Proc Natl Acad Sci U S A 91(14): 6374-8).
  • cytokine-stimulated immune and inflammatory responses contribute to normal host defense, they also play roles in the pathogenesis of diseases.
  • Pathologies such as severe combined immunodeficiency (SCID) can arise from hypoactivity, e.g. the inability of various cytokines to signal through JAK3 (Macchi, et al. Nature, 337:65-68, 1995).
  • hyperactive or inappropriate immune / inflammatory responses can contribute to the pathology of autoimmune diseases such as rheumatoid and psoriatic arthritis, asthma and systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, type I diabetes mellitus, myasthenia gravis, thyroiditis, immunoglobulin nephropathies, myocarditis as well as illnesses such as scleroderma and osteoarthritis (Ortmann, R. A., T. Cheng, et al. (2000). "Janus kinases and signal transducers and activators of transcription: their roles in cytokine signaling, development and immunoregulation.” Arthritis Res 2(1): 16-32).
  • autoimmune diseases such as rheumatoid and psoriatic arthritis, asthma and systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, type I diabetes mellitus, myasthenia gravis, thyroidit
  • Jakl-/- mice are runted at birth, fail to nurse, and die perinatally (Rodig, S. J., M. A. Meraz, et al. (1998). "Disruption of the Jakl gene demonstrates obligatory and non-redundant roles of the Jaks in cytokine -induced biologic responses.” Cell 93(3): 373-83). Jak27- mouse embryos are anemic and die around day 12.5 postcoitum due to the absence of definitive erythropoiesis.
  • JAK2 deficiency resulted in cell-type specific deficiencies in the signaling of some cytokines such as those required for definitive erythropoiesis (Neubauer, H., A. Cumano, et al. (1998). Cell 93(3): 397-409; Parganas, E., D. Wang, et al. (1998). Cell 93(3): 385-95.).
  • JAK3 appears to play a role in normal development and function of B and T lymphocytes. Mutations of JAK3 are reported to be responsible for autosomal recessive severe combined immunodeficiency (SCID) in humans (Candotti, F., S. A. Oakes, et al. (1997). "Structural and functional basis for J AK3 -deficient severe combined immunodeficiency.” Blood 90(10): 3996-4003).
  • the JAK/STAT pathway and in particular all four members of the JAK family, are believed to play a role in the pathogenesis of the asthmatic response, chronic obstructive pulmonary disease, bronchitis other related inflammatory diseases of the lower respiratory tract, inflammatory diseases or conditions of the upper respiratory tract such as those affecting the nose and sinuses (e.g. rhinitis, sinusitis) whether classically allergic reactions or not, Systemic Inflammatory Response Syndrome (SIRS), and septic shock.
  • SIRS Systemic Inflammatory Response Syndrome
  • SIRS Systemic Inflammatory Response Syndrome
  • septic shock See e.g., Pernis, A. B. and P. B. Rothman, "JAK-STAT signaling in asthma," J Clin Invest 109(10): 1279-83 (2002); and Seto, Y., H. Nakajima, et al,. "Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice.” J Immunol 170(2): 1077
  • the JAK/STAT pathway has also been implicated to play a role in inflammatory diseases/conditions of the eye including, but not limited to, dry eye disorder, crizis, uveitis, scleritis, conjunctivitis, as well as chronic allergic responses. Therefore, inhibition of JAK kinases may have a beneficial role in the therapeutic treatment of these diseases.
  • dry eye disorder is intended to encompass the disease states summarized in a recent official report of the Dry Eye Workshop (DEWS), which defined dry eye as "a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface.
  • the treatment of the dry eye disorder involves ameliorating a particular symptom of dry eye disorder, such as eye discomfort, visual disturbance, tear film instability, tear hyperosmolarity, and inflammation of the ocular surface.
  • the JAK/STAT pathway also plays a role in cancers of the immune system.
  • human CD4+ T cells acquire a transformed phenotype, an event that correlates with acquisition of constitutive phosphorylation of JAKs and STATs.
  • an association between JAK3 and STAT-I, STAT-3, and STAT-5 activation and cell-cycle progression was demonstrated by both propidium iodide staining and bromodeoxyuridine incorporation in cells of four ATLL patients tested.
  • cytokine and growth factor signal transduction at the level of the JAK kinases holds promise for the treatment of a number of human cancers.
  • cytokines of the interleukin 6 (IL- 6) family which activate the signal transducer gpl30, are major survival and growth factors for human multiple myeloma (MM) cells.
  • the signal transduction of gpl30 is believed to involve JAKl, JAK2 and Tyk2 and the downstream effectors STAT3 and the mitogen-activated protein kinase (MAPK) and AKT pathways.
  • IL-6-dependent MM cell lines treated with the JAK2 inhibitor pyridone 6 STAT3 phosphorylation and tumor cell proliferation and survival were inhibited (Pedranzini, L, et al, Cancer Research 66:9714-21, 2006.
  • Activation of JAK/STAT in cancers may occur by multiple mechanisms including cytokine stimulation (e.g. IL-6 or GM-CSF) or by a reduction in the endogenous suppressors of JAK signaling such as SOCS (suppressor of cytokine signaling) or PIAS (protein inhibitor of activated STAT) (Boudny, V., and Kovarik, J., Neoplasm. 49:349-355, 2002).
  • cytokine stimulation e.g. IL-6 or GM-CSF
  • SOCS suppressor of cytokine signaling
  • PIAS protein inhibitor of activated STAT
  • JAK3 Janus kinase 3
  • GVHD graft versus host disease
  • JAK3 was also shown to be an important molecular target for treatment of autoimmune insulin-dependent (type 1) diabetes mellitus.
  • the rationally designed JAK3 inhibitor JANEX-I exhibited potent immunomodulatory activity and delayed the onset of diabetes in the NOD mouse model of autoimmune type 1 diabetes (Cetkovic-Cvrlje, M., A. L. Dragt, et al. (2003). "Targeting JAK3 with JANEX-I for prevention of autoimmune type 1 diabetes in NOD mice.” CHn Immunol 106(3): 213-25).
  • Myeloproliferative disorders include polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis with myeloid metaplasia (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD) and the like.
  • PV polycythemia vera
  • ETD essential thrombocythemia
  • MMM myelofibrosis with myeloid metaplasia
  • CML chronic myelogenous leukemia
  • CMML chronic myelomonocytic leukemia
  • HES hypereosinophilic syndrome
  • SMCD systemic mast cell disease
  • JAK2V617F kinase has also been reported that inhibition of the JAK2V617F kinase with a small molecule inhibitor leads to inhibition of proliferation of hematopoietic cells, suggesting that the JAK2 tyrosine kinase is a potential target for pharmacologic inhibition in patients with PV, ET and MMM.
  • mutations in the receptor for thrombopoietin have also been described in MPD patients and due to the requirement of JAK2 for this receptor to signal, inhibition of JAKs may be therapeutic (Tefferi, A. Leukemia & Lymphoma, March 2008; 49(3): 388 - 397).
  • Inhibition of the JAK kinases is also envisioned to have therapeutic benefits in patients suffering from skin immune disorders such as psoriasis, and skin sensitization.
  • skin immune disorders such as psoriasis, and skin sensitization.
  • psoriasis vulgaris the most common form of psoriasis, it has been generally accepted that activated T lymphocytes are important for the maintenance of the disease and its associated psoriatic plaques (Gott Kunststoff, A.B., et al, Nat Rev Drug Disc, 4:19-34).
  • Psoriatic plaques contain a significant immune infiltrate, including leukocytes and monocytes, as well as multiple epidermal layers with increased keratinocyte proliferation.
  • blocking signal transduction at the level of JAK kinases may result in therapeutic benefits in patients suffering from psoriasis or other immune disorders of the skin (Kimbal, A.B., et al. Arch Dermatol. 2008 Feb; 144(2): 200-7).
  • Anaplastic lymphoma kinase is a receptor tyrosine kinase, believed to play an important role in the development and function of the nervous system.
  • ALK is normally expressed in the central nervous system, with peak expression during the neonatal period.
  • ALK fusion proteins are responsible for approximately 5-10% of all non-Hodgkin's lymphomas. Additional mutations/translocations and and increased expression have also been identified in lung cancer and neurological tumors (Soda, M., et al. Nature 448:561-566, 2007 and Mosse, YP, AACR 2008). Accordingly, ALK inhibitors are useful for the treatment of ALK-related tumors, including anaplastic large cell lymphomas and non-Hodgkin lymphomas in addition to skin diseases and lung cancers.
  • ALK ALK positive lymphomas
  • ALK inhibitors could be an efficient treatment for ALK positive lymphomas with few associated clinical side effects.
  • potential ALK inhibitors are highly desirable as potential treatments of ALK-related diseases/tumors.
  • certain ALK inhibitors such staurosporine derivatives are reported in WO2004079326.
  • new or improved agents which inhibit kinases such as Janus kinases and/or ALK are continually needed for developing new and more effective pharmaceuticals to treat cancer, myeloproliferative disorders, autoimmune diseases, and inflammatory diseases, to name a few.
  • the compounds, compositions and methods described herein are directed toward these needs and other ends.
  • the present invention provides, inter alia, compounds of Formula I:
  • the present invention further provides pharmaceutical compositions comprising a compound of Formula I, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present invention further provides methods of modulating an activity of one or more JAK/ ALK kinases, comprising contacting the kinases with a compound of Formula I, or pharmaceutically acceptable salt of the same.
  • the present invention further provides methods of inhibiting an activity of one or more JAK/ ALK kinases, comprising contacting the kinases with a compound of Formula I, or pharmaceutically acceptable salt of the same.
  • the present invention further provides methods of treating one or more of the various J AK/ ALK- associated diseases and disorders named herein by administering to a patient a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt of the same.
  • the present invention further provides compounds of Formula I, or pharmaceutically acceptable salts thereof, for use in therapy.
  • the present invention further provides use of the compounds of Formula I, or pharmaceutically acceptable salts thereof, for the manufacture/preparation of a medicament for use in therapy.
  • the present invention provides, inter alia, compounds of Formula I:
  • Y is O, S, S(O), S(O) 2 , CR'R", or NR 4 ;
  • 6 alkenyl, C 2 . 6 alkynyl, Q -6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 .
  • R 7 , R 8 , and R 10 are each, independently, selected from H, Cy 3 , halo, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, Ci -6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, -W 3 -Q 3 -Y 3 -Z 3 , CN, NO 2 , OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)0R al , 0C(0)R bl , 0C(0)NR cl R dl , NR cl R dl , NR cl C(0)R bl , NR cl C(0)NR cl R dl , NR cl C(0)R bl , NR cl C(0)NR cl R dl
  • 6 alkenyl, C 2 . 6 alkynyl, Q -6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 .
  • each of the Ci_ 6 alkylenyl, C 2 _ 6 alkenylenyl and C 2 _ 6 alkynylenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a , SR a , C(0)R b , C(0)NR c R d , C(0)0R a , 0C(0)R b , 0C(0)
  • Q 1 ) Q 2 ' Q 3 ' Q 4 ' an d Q 5 are each, independently, selected from aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from Ci -6 alkyl, Ci -6 haloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkylalkyl, heterocycloalkylalkyl, halo, CN, NO 2 , OR a , SR a , SF 5 , C(0)R b , C(0)NR c R d , C(0)0R a , 0
  • 6 alkenylenyl and C 2 . 6 alkynylenyl is optionally substituted by 1, 2 or 3 substituents independently selected from Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 6 alkenyl, C 2 .
  • Cy 5 and Cy 6 are each, independently, selected from aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, Ci -6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halosulfanyl, CN, NO 2 , OR a2 , SR 12 , SF 5 , C(0)R b2 , C(O)NR c2 R d2 , C(S)NR c2 R d2 , C(O)OR" 2 , 0C(0)R b2 , OC(O)NR c2 R d2 , NR
  • R al , R bl , R cl , and R dl are each, independently, selected from H, Q -6 alkyl, C 1-6 haloalkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci -6 alkyl, Ci -6 haloalkyl, C 2 .
  • each R fl is, independently, H, Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl;
  • R *2 , R b2 , R c2 , and R d2 are each, independently, selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci -6 alkyl, Ci -6 haloalkyl, C 2 _ 6 alkenyl, C 2 - 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo
  • each R b is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkylalkyl, cycloalkylalkylalkylalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkylalkylalkyl, cycloalkylalkylalkylalkylalkyl, C 2 _ 6 alkenyl, C 2 _ 6
  • R c and R d are independently selected from H, C M0 alkyl, Ci_ 6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the C M0 alkyl, Ci_ 6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,
  • R e and R f are each, independently, selected from H, C M0 alkyl, Ci_ 6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2 - ⁇ alkenyl, C 2 - ⁇ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the C M0 alkyl, Ci_ 6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylal
  • the ring containing A 1 , B 1 , D 1 , and E 1 is a benzene ring optionally substituted by one Ci -4 alkoxy
  • the ring containing A 2 , B 2 , D 2 , and E 2 is a benzene ring optionally substituted by one Ci -4 alkoxy
  • one of L 1 and L 2 is -C(O)NR 9 -
  • the other is -(CR 7 R 8 ) m -O
  • the ring containing A 1 , B 1 , D 1 , and E 1 is a benzene ring optionally substituted by one Ci -4 alkoxy
  • the ring containing A 2 , B 2 , D 2 , and E 2 is a benzene ring optionally substituted by one Ci -4 alkoxy
  • one of L 1 and L 2 is -(CR 7 R 8 ) m -C(O)-
  • the other is -(CR 7 R 8 ) m -NR 9 -
  • at least one of m is 0;
  • the ring containing A 1 , B 1 , D 1 , and E 1 is a benzene ring optionally substituted by one Ci -4 alkoxy
  • the ring containing A 1 , B 1 , D 1 , and E 1 is a benzene ring optionally substituted by one Ci -4 alkoxy
  • the ring containing A 2 , B 2 , D 2 , and E 2 is a benzene ring optionally substituted by one Ci -4 alkoxy
  • both L 1 and L 2 are selected from -(CR 7 R 8 ) m -O-, then L L is other than -O-(CR 7 R 8 ) 4 -O-;
  • the ring containing A 1 , B 1 , D 1 , and E 1 is a benzene ring optionally substituted by one Ci -4 alkoxy
  • the ring containing A 2 , B 2 , D 2 , and E 2 is a benzene ring optionally substituted by one Ci -4 alkoxy
  • L 1 is -S(O) 2 -
  • L 2 is -NH-
  • X 2 is N
  • X 1 is CH
  • X 3 is C-Br
  • Y is -NH-
  • the ring containing A 1 , B 1 , D 1 , and E 1 is a benzene ring
  • the ring containing A 2 , B 2 , D 2 , and E 2 is a benzene ring
  • the ring containing A 2 , B 2 , D 2 , and E 2 is other than a benzene ring optionally substituted by OH.
  • two adjacent R 5 on the same ring can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 .
  • 6 alkenyl, C 2 . 6 alkynyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 .
  • two adjacent R 5 on the same ring can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, Ci -6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci -6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, Cy 1 , CN, NO 2 , OR al , SR al , C(0)R bl , C(0)NR cl R dl , SF 5 , C(S)R bl , C(S)NR cl R dl , C(0)0R al , 0C(0)R bl , 0C(0)NR cl R dl , NR cl R dl , NR cl C(O)R
  • two adjacent R 5 on the same ring can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, Ci -6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci -6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halosulfanyl, Cy 1 , CN, NO 2 , OR al , SR al , C(0)R bl , C(0)NR cl R dl , SF 5 , C(S)R bl , C(S)NR cl R dl , C(O)OR al , OC(O)R bl , -W ⁇ Q ⁇ -Z 1 , OC(O)NR cl R dl ,
  • two adjacent R 5 on the same ring can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 .
  • Ci_ 6 alkenyl, C 2 . 6 alkynyl, or Ci_ 6 haloalkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 .
  • Cy 1 , Cy 2 , Cy 3 , and Cy 4 are each, independently, selected from aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 .
  • R al , R bl , R cl , and R dl are each, independently, selected from H, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C ⁇ s alkyl, halo, CN, OR a2 , SR" 2 , C(0)
  • X 2 is N
  • X 1 is CR 1
  • X 3 is CR 3
  • at least one of R 1 and R 3 is other than H.
  • both L 1 and L 2 are selected from -(CR 7 R 8 ) m -O-, then L L is other than -O-(CR 7 R 8 ) 4 -O-.
  • the compound of Formula I is other than 6-Chloro-2,4,8, 14,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-15-one.
  • the compound of Formula I is other than 6-Chloro-2,4,8, 15,23- pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaen-14-one.
  • the compound of Formula I is other than 6-Chloro-2,4,8, 15,23- pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaen-16-one.
  • the compound of Formula I is other than 6-Chloro-2,4,8, 16,23- pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaen-15-one.
  • a 1 and A 2 are each, independently, selected from CR 2 , N, NH, N(CH 3 ), O, and S. In some embodiments, one of A 1 and A 2 is selected from NH, N(CH 3 ), O, and S. In some embodiments, both A 1 and A 2 are independently selected from NH, N(CH 3 ), O, and S. In some embodiments, A 1 and A 2 are each, independently, selected from CR 2 and N.
  • the ring containing A 1 , B 1 , D 1 , and E 1 is a 6-membered aromatic ring; B 1 , D 1 , and E 1 are each, independently, CR 5 or N; and A 1 is CR 2 or N.
  • the ring containing A 1 , B 1 , D 1 , and E 1 is a 6-membered aromatic ring; B 1 , D 1 , and E 1 are each, independently, CR 5 ; and A 1 is CR 2 .
  • the ring containing A 1 , B 1 , D 1 , and E 1 is a benzene ring, and the benzene ring can be substituted or unsubstituted.
  • the ring containing A 1 , B 1 , D 1 , and E 1 is a 6-membered aromatic ring wherein at least one of A 1 , B 1 , D 1 , and E 1 is N.
  • the 6-membered aromatic ring is selected from pyridine, pyrimidine, and pyrazine rings (the 6-membered aromatic rings such as pyridine, pyrimidine, and pyrazine can be substituted or unsubstituted).
  • the 6-membered aromatic ring is selected from pyridine and pyrimidine rings.
  • the 6- membered aromatic ring is a pyridine ring.
  • D 1 is N. In some embodiments wherein the ring containing A 1 , B 1 , D 1 , and E 1 is a pyridine ring, E 1 is N. In some embodiments wherein the ring containing A 1 , B 1 , D 1 , and E 1 is a pyridine ring, B 1 is N. In some embodiments wherein the ring containing A 1 , B 1 , D 1 , and E 1 is a pyridine ring, A 1 is N. In some embodiments, the 6-membered aromatic ring is a pyrimidine ring.
  • the ring containing A 1 , B 1 , D 1 , and E 1 is a 5-membered aromatic ring (optionally substituted).
  • the 5-membered aromatic ring is selected from lH-pyrrole, furan, thiophene, lH-imidazole, lH-pyrazole, oxazole, thiazole, isoxazole, and isothiazole (the 5-membered aromatic rings can be substituted or unsubstituted).
  • the 5- membered aromatic ring is selected from lH-pyrrole, furan, and thiophene (each is optionally substituted).
  • the 5-membered aromatic ring is a thiophene ring (optionally substituted).
  • the ring containing A 2 , B 2 , D 2 , and E 2 is a 6-membered aromatic ring; B 2 ,
  • D 2 , and E 2 are each, independently, CR 5 or N; and A 2 is CR 2 or N.
  • the ring containing A 2 , B 2 , D 2 , and E 2 is a 6-membered aromatic ring; B 2 , D 2 , and E 2 are each, independently, CR 5 ; and A 2 is CR 2 .
  • the ring containing A 2 , B 2 , D 2 , and E 2 is a benzene ring, and the benzene ring can be substituted or unsubstituted.
  • the ring containing A 2 , B 2 , D 2 , and E 2 is a 6-membered aromatic ring, wherein at least one of A 2 , B 2 , D 2 , and E 2 is N.
  • the 6-membered aromatic ring is selected from pyridine, pyrimidine, and pyrazine rings (the 6-membered aromatic rings can be substituted or unsubstituted).
  • the 6-membered aromatic ring is selected from pyridine and pyrimidine rings.
  • the 6-membered aromatic ring is a pyridine ring.
  • the 6-membered aromatic ring is a pyrimidine ring.
  • the ring containing A 2 , B 2 , D 2 , and E 2 is a 5-membered aromatic ring.
  • the 5-membered aromatic ring is selected from lH-pyrrole, furan, thiophene, lH-imidazole, lH-pyrazole, oxazole, thiazole, isoxazole, and isothiazole rings(the 5-membered aromatic rings can be substituted or unsubstituted).
  • the 5-membered aromatic ring is selected from lH-pyrrole, furan, and thiophene rings.
  • the 5-membered aromatic ring is a thiophene ring.
  • X 1 is CR 1 .
  • X 1 is N. In some embodiments, X 2 is CR 2 .
  • X 2 is N.
  • X 3 is CR 3 .
  • X 3 is N.
  • Y is NR 4 .
  • Y is NH.
  • Y is N(Ci- 3 alkyl).
  • Y is N-CH 3 .
  • Y is O, S, SO, or S(O) 2 .
  • Y is O. In some embodiments, Y is S, SO, or S(O) 2 . In some embodiments, Y is S. In some embodiments, Y is SO. In some embodiments, Y is S(O) 2 .
  • Y is CR'R".
  • R' and R" are each, independently, selected from H, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
  • R' and R" are each, independently, selected from H, Ci -3 alkyl, and Ci -3 haloalkyl.
  • R' and R" are each, independently, selected from H and Ci -3 alkyl.
  • R' and R" are each, independently, selected from H and methyl. In some embodiments, R' and R" are both H.
  • the ring containing A 1 , B 1 , D 1 , and E 1 is a 6-membered aromatic ring; B 1 , D 1 , and E 1 are each, independently, CR 5 or N; A 1 is CH; the ring containing A 2 , B 2 , D 2 , and E 2 is a 6- membered aromatic ring; B 2 , D 2 , and E 2 are each, independently, CR 5 or N; A 2 is CH; X 1 is CR 1 ; X 2 is N; X 3 is CR 3 ; and Y is NR 4 .
  • one of B 1 , D 1 , and E 1 is N, and the other two are each independently CR 5 ;
  • R 1 is H;
  • R 3 is H, halo, methyl, or Ci haloalkyl; and
  • R 4 is H or Ci -3 alkyl.
  • L 1 and L 2 together form -CRV-CR 7 R 8 -.
  • L 1 and L 2 together form -(CRV) 3 -. In some embodiments, L 1 and L 2 together form -(CH 2 ) 3 -.
  • L 1 and L 2 together form -(CRV) 4 -, -(CRV) 5 -, or -(CRV) 6 -. In some embodiments, L 1 and L 2 together form -(CH 2 ) 4 -, -(CH 2 ) 5 -, or -(CH 2 ) 6 -.
  • one of L 1 and L 2 is selected from -(CRV) 1n -O-, -(CRV) 1n -S-, -(CRV) n S(O)-, and -(CRV) 1n -S(O) 2 -; and the other is selected from a bond, -(CRV) n -, -(CRV) 1n -O-, - (CRV) 1n -S-, -(CRV) 1n -S(O)-, and -(CRV) 1n -S(O) 2 -.
  • L 1 and L 2 together form -(CR 7 R 8 Xi -S-, -(CR 7 R 8 Xi-O-, -(CR 7 R 8 Xi-S(O)-,
  • L 1 and L 2 together form -(CR 7 R 8 Xi-S-, -(CR 7 R 8 Xi-O-, -(CR 7 R 8 Xi-S(O)-, -(CR 7 R 8 Xi-S(O) 2 -, -S-(CR 7 RVs-, -0-(CR 7 RVS-, -O-(CR 7 RVS(O)-, -0-(CR 7 R 8 X 2 -S(O) 2 -, or -S-S-; tl is 1, 2, or 3; and t2 is 1 or 2.
  • L 1 and L 2 together form -(CRV) 0 -O-(CR 7 R 8 X 4 -, -(CR 7 R 8 X 3 -S-(CR 7 R 8 X 4 -, -(CR 7 RVS(O)-(CR 7 R 8 X 4 -, or -(CR 7 RVS(O) 2 -(CR 7 R 8 X 4 -, t3 is 1, 2, or 3; and t4 is l or 2.
  • L 1 and L 2 together form S-S, -(CR 7 R 8 )-S-, -(CR 7 R 8 )-S(O)-, -(CRV)-S(O) 2 -, -(CR 7 R 8 XO-, -(CRV) 2 -O-, -0-(CRV) 2 -O-, -0-(CRV) 2 -S-, -O-(CRV) 2 -S(O)-, or -0-(CRV) 2 - S(O) 2 -.
  • L 1 and L 2 together form S-S, -(CH 2 )-S-, -(CH 2 )-S(0)-, -(CH 2 )-S(O) 2 -, -(CH 2 )-0-, -(CH 2 ) 2 -0-, -0-(CHz) 2 -O-, -0-(CH 2 ) 2 -S-, -O-(CH 2 ) 2 -S(O)-, or
  • L 1 and L 2 together form S-S. In some embodiments, L 1 and L 2 together form -(CH 2 )-S-, -(CH 2 )-S(0)-, -(CH 2 XS(O) 2 -, -(CH 2 )-0-, -(CHz) 2 -O-, -0-(CHz) 2 -O-, -0-(CH 2 )Z-S-, -O-(CH 2 ) 2 -S(O)-, or -0-(CH 2 ) 2 -S(O) 2 -.
  • L 1 and L 2 together form -(CRV)-O-, -(CRV)-S-, -(CRV)-S(O)-, -(CRV)-S(O) 2 -, -(CRV) 2 -O-, -(CRV) 2 -S-, -(CRV) 2 -S(O)-, -(CRV) 2 -S(O) 2 -, -0-(CRV) 3 -,
  • L 1 and L 2 together form -(CH 2 )-0-, -(CH 2 )-S-, -(CH 2 )-S(O)-, or -(CH 2 )-S(O) 2 -. In some embodiments, L 1 and L 2 together form -(CH 2 )-0- or -(CH 2 )-S-.
  • L 1 and L 2 together form -(CH 2 )-0-. In some embodiments, L 1 and L 2 together form -(CH 2 )-S-.
  • L 1 and L 2 together form -(CH 2 )-S(O)-.
  • L 1 and L 2 together form -(CH 2 XS(O) 2 -.
  • L 1 and L 2 together form -(CH 2 ) 2 -O-, -(CH 2 ) 2 -S-, -(CH 2 ) 2 -S(O)-, or -(CH 2 ⁇ -S(O) 2 -. In some embodiments, L 1 and L 2 together form -(CH 2 ) 2 -O- or -(CH 2 ) 2 -S-. In some embodiments, L 1 and L 2 together form -(CH 2 ) 2 -O.
  • L 1 and L 2 together form -(CH 2 ) 2 -S-.
  • L 1 and L 2 together form -(CH 2 ) 2 -S(O)-.
  • L 1 and L 2 together form -(CH 2 ) 2 -S(O) 2 -. In some embodiments, L 1 and L 2 together form -(CH 2 ) 3 -O-, -(CH 2 ) 3 -S-, -(CH 2 ) 3 -S(O)-, or -(CH 2 ) 3 -S(O) 2 -. In some embodiments, L 1 and L 2 together form -(CH 2 ) 3 -O- or -(CH 2 ) 3 -S-. In some embodiments, L 1 and L 2 together form -(CH 2 ) 3 -O-. In some embodiments, L 1 and L 2 together form -(CH 2 ) 3 -S-. In some embodiments, L 1 and L 2 together form -(CH 2 ) 3 -S-. In some embodiments, L 1 and L 2 together form -(CH 2 ) 3 -S(O)-.
  • L 1 and L 2 together form -(CH 2 ) 3 -S(O) 2 -. In some embodiments, L 1 and L 2 together form -(CRV)-O-(CR 7 R 8 )-, -(CR 7 R 8 )-S-( CR 7 R 8 )-,
  • L 1 and L 2 together form -(CH 2 )-O-(CH 2 )-, -(CH 2 )-S-(CH 2 )-, -(CH 2 )-S(O)-(CH 2 )-, -(CH 2 )-S(O) 2 -(CH 2 )-, -(CH 2 )-O-(CH 2 ) 2 -, -(CH 2 )-S-(CH 2 ) 2 -, -(CH 2 )-S(O)-(CH 2 ) 2 -, -(CH 2 )-S(O) 2 -(CH 2 ) 2 -, -(CH 2 ) 2 -O-(CH 2 ) 2 -, -(CH 2 ) 2 -S-(CH 2 ) 2 -, -(CH 2 ) 2 -S-(CH 2 ) 2 -, or -(CH 2 ) 2 -S(O) 2 -,
  • L 1 and L 2 together form -(CH 2 )-O-(CH 2 )-. In some embodiments, L 1 and L 2 together form -(CH 2 )-S-(CH 2 )-. In some embodiments, L 1 and L 2 together form -(CH 2 )-O-(CH 2 ) 2 - or -(CH 2 )-S-(CH 2 ) 2 -. In some embodiments, L 1 and L 2 together form -(CH 2 )-O-(CH 2 ) 2 -. In some embodiments, L 1 and L 2 together form -(CH 2 )-S-(CH 2 ) 2 -.
  • L 1 and L 2 together form -(CH 2 ) 2 -O-(CH 2 ) 2 - or -(CH 2 ) 2 -S-(CH 2 ) 2 -. In some embodiments, L 1 and L 2 together form -(CH 2 ) 2 -O-(CH 2 ) 2 - In some embodiments, L 1 and L 2 together form -(CH 2 ) 2 -S-(CH 2 ) 2 -.
  • L 1 and L 2 together form -0-(CH 2 ) 2 -0-, -0-(CH 2 ) 2 -S-, -0-(CH 2 ) 2 -S(0)-, -0-(CH 2 ) 2 -S(O) 2 -, -S-(CH 2 ) 2 -S-, -S(O)-(CH 2 ) 2 -S(0)-, or -S(O) 2 -(CH 2 ) 2 -S(O) 2 -.
  • L 1 and L 2 together form -0-(CH 2 ) 2 -0-, -0-(CH 2 ) 2 -S-, -0-(CH 2 ) 2 -S(0)-, or -0-(CH 2 ) 2 -S(O) 2 -.
  • L 1 and L 2 together form -0-(CH 2 ) 2 -0-. In some embodiments, L 1 and L 2 together form -0-(CH 2 ) 2 -S-.
  • L 1 and L 2 together form -0-(CH 2 ) 2 -S(0)-. In some embodiments, L 1 and L 2 together form -0-(CH 2 ) 2 -S(O) 2 -.
  • one of L 1 and L 2 is selected from -(CRV) 1n -NR 9 -, -(CRV) 1n -S(O) 2 -, - (CRV) 1n -C(O)-, -C(O)NR 9 -, -(CRV) 1n -S(O)NR 9 -, and -(CRV) 1n -S(O) 2 NR 9 -; and the other is selected from a bond, -(CR 7 RV, -(CR 7 R 8 ) m -NR 9 -, -(CR 7 R 8 ) m -S(O) 2 -, -(CR 7 R 8 ) m -C(O)-, -C(O)NR 9 -, -(CRV) 1n - S(O)NR 9 -, and -(CR 7 R 8 ) m -S(O) 2 NR 9 -.
  • L 1 and L 2 together form -(CR 7 R ⁇ t5 -C(O)-, -(CR 7 R 8 ) t5 -C(O)NR 9 -, -C(O)NR 9 -(CR 7 R 8 ) t5 -, -C(O)NR 9 -, -S(O) 2 NR 9 -(CR 7 R 8 ) t5 -, -(CR 7 R 8 ) t5 -S(O) 2 NR 9 -, or -S(O) 2 NR 9 -, wherein t5 is 1, 2, or 3.
  • L 1 and L 2 together form -(CRV) 15 -C(O)-, -C(O)NR 9 -, or -S(O) 2 NR 9 -, and wherein t5 is 1, 2, or 3.
  • L 1 and L 2 together form -(CR 7 R 8 )-C(O)-, -(CR 7 R 8 ) 2 -C(O)-, or -(CRV) 3 -C(O)-. In some embodiments, L 1 and L 2 together form -(CR 7 R 8 )-C(O)-. In some embodiments, L 1 and L 2 together form -(CR 7 R 8 ) 2 -C(O)-. In some embodiments, L 1 and L 2 together form -(CRV) 3 -C(O)-.
  • L 1 and L 2 together form -(CH 2 )-C(0)-, -(CH 2 ) 2 -C(O)-, or
  • L 1 and L 2 together form -(CH 2 )-C(0)-. In some embodiments, L 1 and L 2 together form -(CH 2 ) 2 -C(O)-. In some embodiments, L 1 and L 2 together form -(CH 2 ) 3 -C(O)-.
  • L 1 and L 2 together form -(CRV)-C(O)NR 9 -, -C(O)NR 9 -(CR 7 R 8 )-, or -C(O)NR 9 -. In some embodiments, L 1 and L 2 together form -(CH 2 )-C(O)NR 9 -, -C(0)NR 9 -( CH 2 )-, or -C(O)NR 9 -. In some embodiments, L 1 and L 2 together form -(CH 2 )-C(0)NH-, -C(O)NH-(CH 2 )-, or -C(O)NH-. In some embodiments, L 1 and L 2 together form -C(O)NH-(CH 2 )-, or -C(O)NH-. In some embodiments, L 1 and L 2 together form -(CH 2 )-C(0)NH-.
  • L 1 and L 2 together form -C(O)NH-(CH 2 )-.
  • L 1 and L 2 together form -C(O)NH-.
  • L 1 and L 2 together form -(CR 7 R 8 ) t7 -C(O)NR 9 -(CR 7 R 8 )t 8 , wherein t7 is 1 or 2 and t8 is 1 or 2.
  • L 1 and L 2 together form -(CRV)-C(O)NR 9 -(CRV)-.
  • L 1 and L 2 together form -(CH 2 )-C(O)NH-(CH 2 )-.
  • L 1 and L 2 together form -S(O) 2 NR 9 -(CR 7 R 8 ) t5 -, -(CR 7 R ⁇ t5 -S(O) 2 NR 9 -, or -S(O) 2 NR 9 -, wherein t5 is 1, 2, or 3.
  • L 1 and L 2 together form -S(O) 2 NR 9 -(CR 7 R 8 )-, -(CRV)-S(O) 2 NR 9 -, or -S(O) 2 NR 9 -.
  • R 9 is H or Ci -3 alkyl.
  • L 1 and L 2 together form -S(O) 2 NR 9 -(CH 2 )-, -(CH 2 )-S(O) 2 NR 9 -, or
  • L 1 and L 2 together form -S(O) 2 NH-(CH 2 )-, -(CH 2 )-S(O) 2 NH-, or -S(O) 2 NH-.
  • L 1 and L 2 together form -S(O) 2 NH-(CH 2 )-.
  • L 1 and L 2 together form -(CH 2 )-S(O) 2 NH-. In some embodiments, L 1 and L 2 together form -S(O) 2 NH-.
  • L 1 and L 2 together form -(CR 7 R 8 ) t 7-S(O) 2 NR 9 -(CR 7 R 8 )t 8 -, wherein t7 is 1 or 2 and t8 is 1 or 2. In some embodiments, L 1 and L 2 together form -(CR 7 R 8 )-S(O) 2 NR 9 -(CR 7 R 8 ).
  • L 1 and L 2 together form -(CH 2 )-S(O) 2 NR 9 -(CH 2 )-. In some embodiments, L 1 and L 2 together form -(CR 7 R 8 ) m -NR 9 -C(O)NR 9 -,
  • L 1 and L 2 together form -(CR 7 R 8 )-NR 9 -C(O)NR 9 -, -(CR 7 R 8 )-O-C(O)NR 9 -, -O-C(O)NR 9 -(CR 7 R 8 )-, -NR 9 -C(O)NR 9 -, or -0-C(O)NR 9 -.
  • L 1 and L 2 together form -(CH 2 )-NR 9 -C(O)NR 9 -. In some embodiments, L 1 and L 2 together form -(CH 2 )-NH-C(0)NH-.
  • L 1 and L 2 together form -(CR 7 R 8 )-O-C(O)NR 9 -. In some embodiments, L 1 and L 2 together form -(CH 2 )-0-C(0)NH-.
  • L 1 and L 2 together form -O-C(O)NR 9 -(CR 7 R 8 )-. In some embodiments, L 1 and L 2 together form -0-C(O)NH-(CH 2 )-. In some embodiments, L 1 and L 2 together form -NR 9 -C(O)NR 9 -, or -0-C(O)NR 9 -.
  • L 1 and L 2 together form -NH-C(O)NH-.
  • L 1 and L 2 together form -0-C(O)NH-.
  • L 1 and L 2 together form -(CR 7 R 8 ) m -NR 9 -(CR 7 R 8 ) n -.
  • L 1 and L 2 together form -NR 9 -(CR 7 R 8 ) n -. In some embodiments, L 1 and L 2 together form -NR 9 -(CR 7 R 8 )-. In some embodiments, L 1 and L 2 together form -NR 9 -(CR 7 R 8 ) 2 -. In some embodiments, L 1 and L 2 together form -NR 9 -(CR 7 R 8 ) 3 -.
  • L 1 and L 2 together form -NR 9 -(CH 2 ) n -. In some embodiments, L 1 and L 2 together form -NR 9 -(CH 2 )-. In some embodiments, L 1 and L 2 together form -NR 9 -(CH 2 ) 2 -. In some embodiments, L 1 and L 2 together form -NR 9 -(CH 2 ) 3 -. In some embodiments, L 1 and L 2 together form -(CR 7 R 8 ) m2 -NR 9 -(CR 7 R 8 ) n -, wherein m2 is 1 or 2.
  • L 1 and L 2 together form -(CR 7 R 8 )-NR 9 -(CR 7 R 8 )-, -(CR 7 R 8 )-NR 9 -(CR 7 R 8 ) 2 -, or -(CR 7 R 8 ) 2 -NR 9 -(CR 7 R 8 ) 2 -.
  • L 1 and L 2 together form -(CR 7 R 8 )-NR 9 -(CR 7 R 8 )- or -(CR 7 R 8 )-NR 9 -(CR 7 R 8 ) 2 -.
  • R 9 is H or Ci -3 alkyl.
  • L 1 and L 2 together form -(CH 2 ) m2 -NR 9 -(CH 2 ) n -, wherein m2 is 1 or 2.
  • L 1 and L 2 together form -(CH 2 )-NR 9 -(CH 2 )-, -(CH 2 )-NR 9 -(CH 2 ) 2 -, or -(CH 2 ) 2 -NR 9 -(CH 2 ) 2 -.
  • L 1 and L 2 together form -(CH 2 )-NR 9 -(CH 2 )- or -(CH 2 )-NR 9 -(CH 2 ) 2 -.
  • R 9 is H or Ci -3 alkyl.
  • L 1 and L 2 together form -(CR 7 R 8 )-NR 9 -(CR 7 R 8 )-. In some embodiments, L 1 and L 2 together form -(CH 2 )-NR 9 -(CH 2 )-. In some embodiments, L 1 and L 2 together form -NR 9 -(CR 7 R 8 ) t9 -O- wherein t9 is 1, 2, or 3. In some embodiments, L 1 and L 2 together form -NR 9 -(CR 7 R 8 )-O-. In some embodiments, L 1 and L 2 together form -NR 9 -(CR 7 R 8 ) 2 -O-. In some embodiments, L 1 and L 2 together form -NR 9 -(CR 7 R 8 ) 3 -O-.
  • L 1 and L 2 together form -NR 9 -(CH 2 )-O-. In some embodiments, L 1 and L 2 together form -NR 9 -(CH 2 ) 2 -O-.
  • L 1 and L 2 together form -NR 9 -(CH 2 ) 3 -O-.
  • one of L 1 and L 2 is selected from -(CR 7 R 8 ) m -NR 9 C(O)NR 9 -, -(CR 7 R 8 ) m - OC(O)NR 9 -, -(CR 7 R 8 ) m -NR 9 C(O)O-, and -(CR 7 R 8 ) m -NR 9 -S(O) 2 NR 9 -; and the other is selected from a bond, -(CR 7 RV, -(CR 7 R 8 ) m -NR 9 -, -(CR 7 R 8 ) m -O-, -(CR 7 R 8 ) m -S-, -(CR 7 R 8 ) m -S(O) 2 -, -(CR 7 R 8 ) m -C(O)-, - C(O)NR 9 -, -(CR 7 R 8 ) m -S(O)NR 9 -, and
  • one of L 1 and L 2 is selected from -(CR 7 R 8 ) m -NR 9 C(O)NR 9 -, -(CR 7 R 8 ) m - OC(O)NR 9 -, -(CR 7 R 8 ) m -NR 9 C(O)O-, and -(CR 7 R 8 ) m -NR 9 -S(O) 2 NR 9 -; and the other is selected from a bond, and -(CR 7 R 8 ) n .
  • L 1 and L 2 together form -(CR 7 R 8 ) m -NR 9 C(O)NR 9 -(CR 7 R 8 ) m -, -(CR 7 R 8 ) m - OC(O)NR 9 -(CR 7 R 8 ) m -, or -(CR 7 R 8 ) m -NR 9 -S(O) 2 NR 9 -(CR 7 R 8 ) m -.
  • L 1 and L 2 together form -(CR 7 R 8 ) m -NR 9 C(O)NR 9 -(CR 7 R 8 ) m -. In some embodiments, L 1 and L 2 together form -NR 9 C(O)NR 9 , -NR 9 C(O)NR 9 -(CR 7 R 8 ) m2 -, or -(CR 7 RV - NR 9 C(O)NR 9 -(CR 7 R 8 ) m2 -, wherein ml and m2 are each, independently 1 or 2.
  • L 1 and L 2 together form -NR 9 C(O)NR 9 . In some embodiments, L 1 and L 2 together form -NR 9 C(O)NR 9 -(CR 7 R 8 )-, -NR 9 C(O)NR 9 -
  • L 1 and L 2 together form -(CH 2 ) m -NR 9 C(O)NR 9 -(CH 2 ) m -. In some embodiments, L 1 and L 2 together form -NR 9 C(O)NR 9 , -NR 9 C(O)NR 9 -(CH 2 ) m2 -, or -(CH 2 ) ml - NR 9 C(O)NR 9 -(CH 2 ) m2 - wherein ml and m2 are each, independently 1 or 2.
  • L 1 and L 2 together form -NR 9 C(O)NR 9 -(CH 2 )-, -NR 9 C(O)NR 9 -(CH 2 ) 2 -, - (CH 2 )-NR 9 C(O)NR 9 -(CH 2 )-, -(CH 2 )-NR 9 C(O)NR 9 -(CH 2 ) 2 -, or -(CH 2 ) 2 -NR 9 C(O)NR 9 -(CH 2 ) 2 -.
  • L 1 and L 2 together form -(CR 7 R 8 ) m -OC(O)NR 9 -(CR 7 R 8 ) m -.
  • L 1 and L 2 together form -OC(O)NR 9 -. In some embodiments, L 1 and L 2 together form -OC(O)NR 9 -(CR 7 R 8 )-, -OC(O)NR 9 -(CR 7 R 8 ) 2 -,
  • L 1 and L 2 together form -OC(O)NR 9 -(CH 2 )-, -OC(O)NR 9 -(CH 2 ) 2 -, -(CH 2 )-OC(O)NR 9 -, -(CH 2 ) 2 -OC(O)NR 9 -, -(CH 2 )-OC(O)NR 9 -(CH 2 )-, -(CH 2 )-OC(O)NR 9 -(CH 2 ) 2 -, - (CH 2 ) 2 -OC(O)NR 9 -(CH 2 )-, or -(CH 2 ) 2 -OC(O)NR 9 -(CH 2 ) 2 -.
  • L 1 and L 2 together form -(CR 7 R 8 ) m -NR 9 S(O) 2 NR 9 -(CR 7 R 8 ) m -. In some embodiments, L 1 and L 2 together form -NR 9 S(O) 2 NR 9 -, -NR 9 S(O) 2 NR 9 -(CR 7 R 8 ) m2 -, or
  • L 1 and L 2 together form -NR 9 S(O) 2 NR 9 .
  • L 1 and L 2 together form -NR 9 S(O) 2 NR 9 -(CR 7 R 8 )-, -NR 9 S(O) 2 NR 9 - (CRV) 2 -, -(CR 7 R 8 )-NR 9 S(O) 2 NR 9 -(CR 7 R 8 )-, -(CR 7 R 8 )-NR 9 S(O) 2 NR 9 -(CR V R 8 ) 2 -, or -(CRV) 2 - NR 9 S(O) 2 NR 9 -(CR 7 R 8 ) 2 -.
  • each R 9 is independently selected from H, Ci -6 alkyl, and C(0)R bl , and wherein R bl is selected from Ci -6 alkyl, aryl, and heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci -6 alkyl, and Ci -6 haloalkyl.
  • a linkage— a moiety that links two other moieties— can be attched to the other two moieties in either direction, if the linkage is asymmetric.
  • the moiety formed by L 1 and L 2 together in compounds of Formula I can be linked to the ring containing A 1 , B 1 , D 1 , and E 1 and the containing A 2 , B 2 , D 2 , and E 2 in either direction.
  • the sulfur atom (S) can be linked to the ring containing A 1 , B 1 , D 1 , and E 1 , and oxygen atom (O) to the ring containing A 2 , B 2 , D 2 , and E 2 .
  • the oxygen atom (O) can be linked to the ring containing A 1 , B 1 , D 1 , and E 1 , and the sulfur atom (S) to the ring containing A 2 , B 2 , D 2 , and E 2 .
  • W 1 in -W'-Q'-Y'-Z 1 is 0(CR lla R llb ) q iNR f
  • W 1 can be linked to Q 1 either via the 0 or the N atom.
  • one of B 1 , D 1 , and E 1 is N, and the other two are each independently CR 5 ;
  • R 1 is H;
  • R 3 is H, halo, methyl, or Ci haloalkyl; and
  • R 4 is H or Ci -3 alkyl.
  • L 1 and L 2 together form -(CH 2 ) 2 -.
  • one of B 1 , D 1 , and E 1 is N, and the other two are each independently CR 5 ;
  • R 1 is H;
  • R 3 is H, halo, methyl, or Ci haloalkyl; and
  • R 4 is H or Ci -3 alkyl.
  • the ring containing A 1 , B 1 , D 1 , and E 1 is a 6-membered aromatic ring; B 1 , D 1 , and E 1 are each, independently, CR 5 ; A 1 is CH; the ring containing A 2 , B 2 , D 2 , and E 2 is a 6- membered aromatic ring; B 2 , D 2 , and E 2 are each, independently, CR 5 ; A 2 is CH; X 1 is CR 1 ; X 2 is N; X 3 is
  • L 1 and L 2 together form -(CH 2 ) 2 -.
  • the ring containing A 1 , B 1 , D 1 , and E 1 is a 6-membered aromatic ring; B 1 , D 1 , and E 1 are each, independently, CR 5 or N; A 1 is CH; the ring containing A 2 , B 2 , D 2 , and E 2 is a 6- membered aromatic ring; B 2 , D 2 , and E 2 are each, independently, CR 5 or N; A 2 is CH; X 1 is CR 1 ; X 2 is N; X 3 is CR 3 ; Y is NR 4 ; and L 1 and L 2 together form -(CHz)-O-, -(CHz)-S-, -(CHz)-S(O)-, -(CHz)-S(O) 2 -, - (CH 2 )-NR 9 -, -(CH 2 )Z-O-, -(CH 2 )Z-S-, -(CH 2 ) 2
  • one of B 1 , D 1 , and E 1 is N, and the other two are each independently CR 5 ;
  • R 1 is H;
  • R 3 is H, halo, methyl, or Ci haloalkyl; and
  • R 4 is H or Ci_ 3 alkyl.
  • L 1 and L 2 together form -(CH 2 ) 2 -O-.
  • the ring containing A 1 , B 1 , D 1 , and E 1 is a 6-membered aromatic ring; B 1 , D 1 , and E 1 are each, independently, CR 5 ; A 1 is CH; the ring containing A 2 , B 2 , D 2 , and E 2 is a 6- membered aromatic ring; B 2 , D 2 , and E 2 are each, independently, CR 5 ; A 2 is CH; X 1 is CR 1 ; X 2 is N; X 3 is CR 3 ; Y is NR 4 ; and L 1 and L 2 together form -(CH 2 )-0-, -(CHz)-S-, -(CHz)-S(O)-, -(CHz)-S(O) 2 -, -(CH 2 )- NR 9 -, -(CHz) 2 -O-, -(CH 2 ) Z -S-, -(CH 2 ) 2
  • one of B 1 , D 1 , and E 1 is N, and the other two are each independently CR 5 ;
  • R 1 is H;
  • R 3 is H, halo, methyl, or Ci haloalkyl;
  • R 4 is H or Ci -3 alkyl.
  • L 1 and L 2 together form -(CH 2 ) 2 -O.
  • each R 9 is, independently, H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C(0)R bl ,
  • each R 9 is, independently, H, Ci -6 alkyl, Ci -6 haloalkyl, C(0)R bl , or C(0)NR cl R dl .
  • each R 9 is independently, H or Ci -6 alkyl.
  • each R 9 is independently, H or Ci_ 4 alkyl.
  • each R 9 is independently, H or Ci -3 alkyl. In some embodiments, each R 9 is H.
  • each R 9 is, independently, H, Ci -6 alkyl, Ci -6 haloalkyl, or C(0)R bl . In some further embodiments, each R 9 is, independently, H, Ci -6 alkyl, or C(0)R bl , wherein R bl is selected from Ci -6 alkyl, C 2 . 6 alkenyl, C 2 .
  • each R 9 is, independently, H, Ci -6 alkyl, or C(0)R bl .
  • R bl is selected from aryl and heteroaryl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, and Ci -6 haloalkoxy.
  • R bl is selected from aryl and heteroaryl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci -6 alkyl, and Ci -6 haloalkyl.
  • R 7 , R 8 , and R 10 are each, independently, selected from H, halo, Ci -6 alkyl, C 2 -6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 haloalkyl, cycloalkyl, CN, NO 2 , OR al , SR al , S(O)R bl , S(O)NR cl R dl , S(O) 2 R", NR cl S(O) 2 R bl , S(O) 2 NR cl R dl , C(O)R bl , C(0)NR cl R dl , C(O)OR al , NR cl C(0)R bl , NR cl C(0)NR cl R dl , and NR cl R dl , wherein each of said Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_
  • R 7 , R 8 , and R 10 are each, independently, selected from H, halo, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C ⁇ 6 haloalkyl, CN, NO 2 , OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)0R al , and NR cl R dl .
  • R 7 , R 8 , and R 10 are each, independently, selected from H, halo, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 . 6 alkynyl, Ci -6 haloalkyl, CN, NO 2 , OR al , and SR al .
  • R 7 , R 8 , and R 10 are each, independently, selected from H, halo, Ci -6 alkyl, Ci_6 haloalkyl, CN, NO 2 , OR al , and SR al .
  • R 7 , R 8 , and R 10 are each, independently, selected from H, halo, Ci -6 alkyl, C 2 _6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 haloalkyl, CN, NO 2 , OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)0R al , or NR cl R dl .
  • R 7 , R 8 , and R 10 are each, independently, selected from H, halo, Ci -6 alkyl, CN, NO 2 , OH, Ci -6 alkoxy, Ci -6 haloalkoxy, and C 2 . 8 alkoxyalkoxy. In some embodiments, R 7 , R 8 , and R 10 are each, independently, selected from H, Ci -4 alkyl, OH, Ci -6 alkoxy, Ci -6 haloalkoxy, and C 2 . 8 alkoxyalkoxy.
  • R 7 and R 8 are each, independently, selected from H, halo, Ci -6 alkyl, CN, NO 2 , OH, Ci -6 alkoxy, Ci -6 haloalkoxy, and C 2 . 8 alkoxyalkoxy. In some further embodiments, R 7 and R 8 are each, independently, selected from H, halo, Ci_ 4 alkyl, CN, NO 2 , Ci -4 alkoxy, Ci_ 4 haloalkoxy, and C 2 . 8 alkoxyalkoxy.
  • R 7 and R 8 are each, independently, selected from H, halo, Ci_ 4 alkyl, OH, Ci -4 alkoxy, Ci_ 4 haloalkoxy, and C 2 . 8 alkoxyalkoxy. In some further embodiments, R 7 and R 8 are each, independently, selected from H, OH, Ci_ 4 alkoxy, Ci -4 haloalkoxy, and C 2 . 8 alkoxyalkoxy. In some further embodiments, R 7 and R 8 are each, independently, selected from H, OH, and C 2 . 8 alkoxyalkoxy.
  • R 7 and R 8 are each, independently, selected from H and Ci -6 alkyl. In some further embodiments, R 7 and R 8 are each, independently, selected from H and Ci -4 alkyl. In some embodiments, R 7 and R 8 are each, independently, selected from H and Ci_ 3 alkyl. In some further embodiments, R 7 and R 8 are each, independently, selected from H and methyl. In yet further embodiments, R 7 and R 8 are each H.
  • each R 10 is, independently, selected from H, halo, and Ci_ 6 alkyl. In some embodiments, each R 10 is, independently, selected from H and Ci_ 6 alkyl. In some embodiments, each R 10 is, independently, selected from H and Ci_ 4 alkyl. In some further embodiments, each R 10 is H.
  • each R 10 is, independently, selected from H and Ci -3 alkyl. In some further embodiments, each R 10 is, independently, selected from H and methyl.
  • R 1 is selected from H, halo, Ci_ 6 alkyl, Ci_ 6 haloalkyl, CN, NO 2 , OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , and NR c2 R d2 .
  • R 1 is selected from H, halo, Ci_ 6 alkyl, Ci_ 6 haloalkyl, CN, NO 2 , -O-(Ci_ 6 alkyl) and -O-(Ci_ 6 haloalkyl).
  • R 1 is selected from H, F, Cl, Br, methyl, ethyl, and Ci -2 haloalkyl.
  • R 1 is selected from H, F, Cl, and Br. In some embodiments, R 1 is selected from H, CH 3 and CF 3 . In some futher embodiments, R 1 is H or CH 3 . In yet futher embodiments, R 1 is H.
  • each R 2 is, independently, selected from H, halo, Ci_ 6 alkyl, Ci_ 6 haloalkyl, CN, NO 2 , SF 5 , OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR" 2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 NR c2 R d2 , NR c2 S(O) 2 R b2 , and NR c2 R d2 .
  • each R 2 is, independently, selected from H, halo, Ci_ 6 alkyl, Ci_ 6 haloalkyl,
  • each R 2 is, independently, selected from H, halo, Ci_ 6 alkyl, Ci_ 6 haloalkyl, CN, NO 2 , OR" 2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR" 2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 R b2 , and NR c2 R d2 .
  • each R 2 is, independently, selected from H, halo, Ci_ 6 alkyl, Ci_ 6 haloalkyl, CN, NO 2 , OR" 2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR" 2 , and NR c2 R d2 .
  • each R 2 is, independently, selected from H, halo, Ci -6 alkyl, and Ci -6 haloalkyl. In some embodiments, each R 2 is, independently, selected from H, halo, Ci_ 3 alkyl, and Ci_ 3 haloalkyl. In some embodiments, each R 2 is, independently, selected from H, F, Cl, Br, methyl, ethyl, 1- propyl, 2-propyl, and Ci -2 haloalkyl. In some embodiments, each R 2 is, independently, selected from H, F, Cl, Br, methyl, ethyl, 1-propyl, 2-propyl, and CF 3 .
  • each R 2 is, independently, selected from H, F, Cl, Br, methyl, and CF 3 . In some embodiments, each R 2 is, independently,selected from H, CH 3 , CF 3 , and halo. In some embodiments, each R 2 is, independently, selected from H, F, Cl, methyl, and CF 3 . In some futher embodiments, each R 2 is, independently, selected from H, F, and Cl.
  • each R 2 is, independently, selected from H, CH 3 and CF 3 . In some futher embodiments, each R 2 is H. In some embodiments, R 3 is selected from H, halo, Ci -6 alkyl, Ci -6 haloalkyl, CN, NO 2 , SF 5 , OR 12 ,
  • R 3 is selected from H, halo, Ci -6 alkyl, Ci -6 haloalkyl, CN, NO 2 , SF 5 , OR 12 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR 02 C(O)OR" 2 , NR c2 S(O) 2 NR c2 R d2 , NR c2 S(O) 2 R b2 , and NR c2 R d2 .
  • R 3 is selected from H, halo, Ci -6 alkyl, Ci -6 haloalkyl, CN, NO 2 , SF 5 , OR 12 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , and NR c2 R d2 .
  • R 3 is selected from H, halo, Ci -6 alkyl, Ci -6 haloalkyl, amino, Ci_ 4 alkylamino, and C 2 . 8 dialkylamino. In some embodiments, R 3 is selected from H, halo, Ci -3 alkyl, Ci -3 haloalkyl, NH 2 , NH(Ci_ 3 alkyl), and N(Ci -3 alkyl) 2 .
  • R 3 is selected from H, F, Cl, Br, methyl, ethyl, 1-propyl, 2- propyl, Ci -2 haloalkyl, NH 2 , NH(Ci_ 3 alkyl), and N(Ci -3 alkyl) 2 .
  • R 3 is selected from H, F, Cl, Br, methyl, ethyl, 1-propyl, 2-propyl, CF 3 , NH 2 , NH(Ci_ 3 alkyl), and N(Ci -3 alkyl) 2 .
  • R 3 is selected from H, Cl, Br, methyl, CF 3 , NH 2 , NH(Ci_ 3 alkyl), and N(Ci -3 alkyl) 2 . In some embodiments, R 3 is selected from H, halo, Ci -6 alkyl, and Ci -6 haloalkyl.
  • R 3 is selected from H, halo, Ci -3 alkyl, and Ci -3 haloalkyl. In some embodiments, R 3 is selected from H, F, Cl, Br, methyl, ethyl, 1-propyl, 2-propyl, and Ci -2 haloalkyl. In some embodiments, R 3 is selected from H, F, Cl, Br, methyl, ethyl, 1-propyl, 2-propyl, and CF 3 . In some embodiments, R 3 is selected from H, F, Cl, Br, methyl, and CF 3 . In some embodiments, R is selected from halo. In some embodiments, R is selected from F, Cl, Br. In some further embodiments, R 3 is Cl.
  • R 1 and R 3 are each, independently, selected from H, halo, Ci_ 6 alkyl, Ci_ 6 haloalkyl, CN, NO 2 , SF 5 , OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR" 2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 NR c2 R d2 , NR c2 S(O) 2 R b2 , and NR c2 R d2 .
  • R 1 and R 3 are each, independently, selected from H, halo, Ci_ 6 alkyl, Ci_ 6 haloalkyl, CN, NO 2 , SF 5 , OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR" 2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 R b2 , and NR c2 R d2 .
  • R 1 and R 3 are each, independently, selected from H, halo, Ci_ 6 alkyl, Ci_ 6 haloalkyl, CN, NO 2 , SF 5 , OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR" 2 , and NR c2 R d2 .
  • R 1 and R 3 are each, independently, selected from H, halo, Ci_ 6 alkyl, Ci_ 6 haloalkyl, CN, NO 2 , SF 5 , amino, Ci -4 alkylamino, C 2 .
  • R 1 and R 3 are each, independently, selected from H, halo, Ci_ 6 alkyl, and Ci_6 haloalkyl.
  • R 1 and R 3 are each, independently, selected from H, halo, Ci_ 3 alkyl, and Cu haloalkyl. In some embodiments, R 1 and R 3 are each, independently, selected from H, F, Cl, Br, methyl, ethyl, 1 -propyl, 2-propyl, and Ci_ 2 haloalkyl. In some embodiments, R 1 and R 3 are each, independently, selected from H, F, Cl, Br, methyl, ethyl, 1 -propyl, 2-propyl, and CF 3 . In some embodiments, R 1 and R 3 are each, selected from H, F, Cl, Br, methyl, and CF 3 .
  • R 1 and R 3 are SF 5 . In some embodiments, R 3 is SF 5 . In some embodiments, R 1 is H and R 3 is selected from H, halo, Ci -3 alkyl, and Ci -3 haloalkyl. In some embodiments, R 1 is H and R 3 is selected from halo, Ci alkyl, and Ci haloalkyl. In some embodiments, R 1 is H and R 3 is selected from halo. In some embodiments, R 1 is H and R 3 is Cl.
  • R 1 and R 2 are each, independently, selected from H, halo, Ci -6 alkyl, Ci -6 haloalkyl, CN, NO 2 , OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , NR c2 S(O) 2 NR c2 R d2 , NR c2 S(O) 2 R b2 , and NR c2 R d2 .
  • R 1 and R 2 are each, independently, selected from H, halo, Ci_ 6 alkyl, Ci_ 6 haloalkyl, CN, NO 2 , OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , and NR c2 R d2 .
  • R 1 and R 2 are each, independently, selected from H, halo, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
  • R 1 and R 2 are each, independently, selected from H, methyl, and ethyl.
  • R 1 and R 2 are each, independently, selected from H and methyl.
  • R 1 and R 2 are H.
  • R 1 and R 2 are each, independently, selected from H, F, Cl, Br, methyl, ethyl, and Ci -2 haloalkyl. In some further embodiments, R 1 and R 2 are each, independently, selected from H, F, Cl, methyl, and CF 3 . In yet further embodiments, R 1 and R 2 are each, independently, selected from H and methyl. In still further embodiments, R 1 and R 2 are each H.
  • R 4 is H or Ci_ 6 alkyl. In some embodiments, R 4 is H.
  • each R 5 is, independently, selected from H, halo, Ci_ 6 alkyl, Ci_ 6 haloalkyl, Cy 1 , -W'-Q'-Y'-Z 1 , CN, NO 2 , SF 5 , OR al , C(O)R bl , C(O)NR cl R dl , C(O)OR al , NR cl R dl , NR cl C(O)R bl , S(O) 2 R bl , NR cl S(O) 2 NR cl R dl , NR cl S(O) 2 R bl , and S(O) 2 NR cl R dl , wherein each of said Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, or Ci_ 6 haloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents each independently
  • each R 5 is, independently, selected from H, halo, Ci_ 6 alkyl, Ci_ 6 haloalkyl, CN, NO 2 , SF 5 , OR al , C(O)R bl , C(0)NR cl R dl , C(O)OR al , NR cl R dl , NR cl C(0)R bl , NR cl S(O) 2 NR cl R dl , S(O) 2 R bl , NR cl S(O) 2 R bl , and S(O) 2 NR cl R dl , wherein said Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, or Ci_ 6 haloalkyl, is optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci -6 alkyl, C 2 .
  • each R 5 is, independently, selected from H, halo, Ci -6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, Ci -6 haloalkyl, Cy 1 , -W'-Q'-Y'-Z 1 , CN, NO 2 , OR al , C(O)R bl , C(O)NR cl R dl , C(O)OR al , NR cl R dl , NR cl C(O)R bl , NR cl C(O)NR cl R dl , NR cl S(O) 2 NR cl R dl , S(O) 2 R bl , NR cl S(O) 2 R bl , and S(O) 2 NR cl R dl , wherein each of said Ci_6 alkyl, C 2 _6 alkenyl, C 2 _6
  • R al , R bl , R cl , and R dl are each, independently, selected from H, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci -6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_ 4 alkyl, Ci_ 4 haloalkyl, Ci -4 hydroxylalkyl, Ci
  • each R 5 is, independently, selected from H, halo, Ci -6 alkyl, Ci -6 haloalkyl, CN, NO 2 , OR al , C(0)R bl , C(0)NR cl R dl , C(0)0R al , NR cl R dl , NR cl C(O)R bl , NR cl S(0) 2 NR cl R dl , S(O) 2 R bl , NR cl S(O) 2 R bl , and S(O) 2 NR cl R dl , wherein said Ci -6 alkyl, C 2 . 6 alkenyl, C 2 .
  • Ci -6 haloalkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 _6 alkynyl, Ci_ 6 haloalkyl, halosulfanyl, CN, NO 2 , SF 5 , OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)0R al , 0C(0)R bl , 0C(0)NR cl R dl , NR cl R dl , NR cl C(O)R bl , NR cl C(0)NR cl R dl , NR cl C(0)0R al , NR cl S(0) 2 NR cl R dl , S(O)R bl , S(0)NR cl R dl , S(0)NR cl R d
  • R al , R bl , R cl , and R dl are each, independently, selected from H, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci -6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_ 4 alkyl, Ci_ 4 haloalkyl, Ci -4 hydroxylalkyl, Ci
  • R cl and R dl are each, independently, selected from H, Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 .
  • 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_ 4 alkyl, Ci_ 4 haloalkyl, Ci_ 4 hydroxylalkyl, Ci_ 4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OH, SH, O(Ci_ 4 alkyl), O(Ci_ 4 haloalkyl), O(aryl), O(arylalkyl), S(Ci_ 4 alkyl), S(Ci_ 4 haloalkyl), S(aryl), S(arylalkyl), amino, Ci -4 alkylamino, C 2 .
  • R 5 is selected C(O)NR cl R dl or NR cl R dl , wherein: R cl and R dl are each, independently, selected from H, Ci- ⁇ alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 .
  • 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -4 alkyl, Ci -4 haloalkyl, Ci -4 hydroxylalkyl, Ci -4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OH, SH, O(Ci_ 4 alkyl), O(Ci_ 4 haloalkyl), O(aryl), O(arylalkyl), S(Ci_ 4 alkyl), S(Ci_ 4 haloalkyl), S(aryl), S(arylalkyl), amino, Ci -4 alkylamino, C 2 .
  • each R 5 is, independently, selected from H, halo, Ci_ 6 alkyl, Ci_ 6 haloalkyl, CN, NO 2 , SF 5 , OR al , C(0)R bl , C(0)NR cl R dl , C(0)0R al , NR cl R dl , NR cl C(0)R bl , NR cl S(0) 2 NR cl R dl , S(O) 2 R bl , NR cl S(0) 2 R bl , and S(0) 2 NR cl R dl .
  • each R 5 is, independently, selected from H, halo, Ci_ 6 alkyl, Ci_ 6 haloalkyl, CN, NO 2 , SF 5 , OR al , C(0)R bl , C(0)NR cl R dl , C(0)0R al , NR cl R dl , NR cl C(0)R bl , S(O) 2 R bl , NR cl S(0) 2 R bl , and S(0) 2 NR cl R dl .
  • each R 5 is independently selected from H, halo, Ci -6 alkyl, Ci -6 haloalkyl,
  • each R 5 is independently selected from H, halo, Ci -6 alkyl, Ci -6 haloalkyl, ⁇ 2 , OR al , NR cl R dl , NR cl S(O) 2 R bl , S(O)R bl , S(O) 2 R bl , and S(O) 2 NR cl R dl .
  • two adjacent R 5 on the same ring can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 .
  • two adjacent R 5 on the ring containing A 1 , B 1 , D 1 , and E 1 can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 .
  • At least one R 5 is other than H. In some embodiments, at least one R 5 on the ring containing A 1 , B 1 , D 1 , and E 1 is other than H. In some embodiments, at least one R 5 on the ring containing A 2 , B 2 , D 2 , and E 2 is other than H. In some embodiments, one or two R 5 on the ring containing A 1 , B 1 , D 1 , and E 1 are other than H. In some embodiments, one R 5 on the ring containing A 1 , B 1 , D 1 , and E 1 is other than H.
  • one or two R 5 on the ring containing A 2 , B 2 , D 2 , and E 2 are other than H. In some embodiments, one R 5 on the ring containing A 2 , B 2 , D 2 , and E 2 is other than H.
  • At least one R 5 is selected fom halo, Ci_ 6 alkyl, Ci_ 6 haloalkyl, cycloalkyl, aryl, hetroaryl, heterocycloalkylalkyl, Cy 1 , CN, NO 2 , OR al , C(O)R bl , C(0)NR cl R dl ,
  • Ci_ 6 alkyl, Ci_ 6 haloalkyl, cycloalkyl, aryl, hetroaryl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C ⁇ 6 haloalkyl, halosulfanyl, CN, NO 2 , SF 5 , OR al , SR al , C(0)R
  • At least one R 5 is selected fom halo, Ci_ 6 alkyl, aryl, hetroaryl, heterocycloalkylalkyl, CN, OR al , C(0)R bl , C(0)NR cl R dl , C(0)0R al , NR cl R dl , NR cl C(O)R bl , NR cl C(0)NR cl R dl , NR cl S(0) 2 NR cl R dl , S(O) 2 R bl , NR cl S(O) 2 R bl , and S(O) 2 NR cl R dl , wherein said Ci_ 6 alkyl, aryl, hetroaryl, or heterocycloalkylalkyl, is optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci_6 alkyl, C 2 _6 alkenyl
  • At least one R 5 is Cy 1 or -W ⁇ -Q ⁇ -Y ⁇ Z 1 .
  • At least one R 5 is Cy 1 . In some embodiments, at least one R 5 on the ring containing A 1 , B 1 , D 1 , and E 1 is Cy 1 . In some other embodiments, at least one R 5 on the ring containing A 2 , B 2 , D 2 , and E 2 is Cy 1 .
  • At least one R 5 is Cy 1 that is selected from aryl and heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from Ci_ 6 alkyl, C(O)-O-(Ci_ 4 alkyl), S(O) 2 -(Ci_ 4 alkyl), and piperazinyl, wherein the piperazinyl is optionally substituted with 1 or 2 subsituents independently selected from Ci_6 alkyl, arylalkyl, aryl, heteroaryl, C(O)R bl , S(O) 2 R bl , C(0)NR cl R dl , and S(O) 2 NR cl R dl .
  • At least one R 5 is -W ⁇ -Q ⁇ Y ⁇ Z 1 . In some embodiments, at least one R 5 on the ring containing A 1 , B 1 , D 1 , and E 1 is -W ⁇ -Q ⁇ Y ⁇ Z 1 . In some other embodiments, at least one R 5 on the ring containing A 2 , B 2 , D 2 , and E 2 is -W ⁇ Q ⁇ Y ⁇ Z 1 .
  • At least one R 5 is -Q 1 ⁇ -Z 1 , -(CH ⁇ -Q ⁇ -Z 1 , -0(CR 111 R 111 XiC(O)-Q 1 - Y ⁇ Z 1 , -O(CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , -(CR lla R llb ) p iC(O)NR e (CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , - (CR lla R llb ) p iC(O)NR e - -(CR lla R llb ) p2 NR e C(O)-Q 1 -Y 1 -Z 1 , -(CR lla R llb ) p iNR e -Q 1 -Y 1 -Z 1 , - (CR lla R llb ) p
  • At least one R 5 on the ring containing A 1 , B 1 , D 1 , and E 1 is -Q 1 ⁇ -Z 1 , - (CH ⁇ -Q ⁇ -Z 1 , -O(CR lla R llb ) q iC(O)-Q 1 -Y 1 -Z 1 , -O(CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , -
  • At least one R 5 on the ring containing A 2 , B 2 , D 2 , and E 2 is -Q 1 ⁇ -Z 1 , - (CH ⁇ -Q ⁇ -Z 1 , -O(CR lla R llb ) q iC(O)-Q 1 -Y 1 -Z 1 , -O(CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , - (CR lla R llb ) p iC(O)NR e (CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , - (CR lla R llb ) p iC(O)NR e -Q 1 -Y 1 -Z 1 , -NR e (CR lla R llb ) p2 -Q 1 - Y 1 -Z 1 , -(CR lla R llb )
  • At least one R on the ring containing A , B , D , and E or on the ring containing A 2 , B 2 , D 2 , and E 2 is -W ⁇ Q ⁇ Y ⁇ Z 1 that is selected from -(CR lla R llb ) 1 P p l r " Q 1 -Y 1 -Z 1 ,
  • At least one R 5 on the ring containing A 1 , B 1 , D 1 , and E 1 or on the ring containing A 2 , B 2 , D 2 , and E 2 is -(CR lla R llb ) p iO(CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , -(CR lla R llb ) p iS(CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , -(CR lla R llb ) p iS(O)(CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , -(CR lla R llb ) p iS(O)(CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , -(CR lla R llb ) p
  • At least one R 5 is -Q 1 ⁇ -Z 1 , -(CH ⁇ -Q ⁇ -Z 1 , -0(CR 111 R 111 XiC(O)-Q 1 - Y ⁇ Z 1 , -O(CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , -(CR lla R llb ) p iC(O)NR e (CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , - (CR lla R llb ) p iC(O)NR e - Q 1 ⁇ -Z 1 , -NR'XCR ⁇ R ⁇ -Q ⁇ -Z 1 , -(CR lla R llb ) p2 NR e C(O)-Q 1 -Y 1 -Z 1 , -(CR lla R llb ) p iNR
  • At least one R 5 on the ring containing A 1 , B 1 , D 1 , and E 1 is at least one R 5 is -Q 1 ⁇ -Z 1 , -(CH ⁇ -Q ⁇ -Z 1 , -O(CR lla R llb ) q iC(O)-Q 1 -Y 1 -Z 1 , -O(CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , - (CR lla R llb ) p iC(O)NR e (CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , - (CR lla R llb ) p iC(O)NR e -Q 1 -Y 1 -Z 1 , -NR 6 CCR 111 R 11 ⁇ p2 -Q 1 - Y 1 -Z 1 , -(CR lla
  • At least one R 5 is
  • W 1 is absent, -(CH 2 )-, -0(CR lla R llb ) q iC(0)-, -O(CR lla R llb ) p2 -, -(CR lla R llb ) p iC(O)NR 6 (CR lla R llb ) p2 -, - (CR lla R llb ) p iC(0)NR 6 -, -NR 6 (CR lla R llb ) p2 -, - (CR lla R llb ) p2 NR 6 C(0)-, -(CR lla R llb ) p iNR 6 -, -(CR lla R llb ) p i0(CR lla R llb ) p2 -, -(CR lla R llb ) p iS(CR lla
  • At least one R 5 is
  • each Y 1 is independently selected from absent, Ci -6 alkylene, (CR 12a R 12b ) p3 O(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 S(CR 12a R 12b ) P 4, (CR 12a R 12b ) P 3NR e (CR 12a R 12b ) P 4, (CR 12a R 12b ) p3 C(O)(CR 12a R 12b ) P 4, (CR 12a R 12b ) p3 C(O)O(CR 12a R 12b ) P 4, C(S)NR 6 , (CR 12a R 12b ) p3 C(O)NR e (CR 12a R 12b ) P 4,
  • each Z 1 is independently selected from H, OH, CN, Ci -6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein each of the Ci -6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -6 alkyl, C 2 _ 6 alkenyl, C 2 - ⁇ alkynyl, Ci_6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,
  • each Z 1 is independently selected from aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 .
  • each Y 1 is independently selected from absent, (CH 2 ), (CR 12a R 12b ) p3 O(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 S(CR 12a R 12b ) P4 , (CR 12a R 12b ) p3 NR e (CR 12a R 12b ) P4 , (CR 12a R 12b ) p3 C(O)(CR 12a R 12b ) P4 , (CR 12a R 12b ) p3 C(O)O(CR 12a R 12b ) P4 , C(S)NR 6 , (CR 12a R 12b ) p3 C(O)NR e (CR 12a R 12b ) P4 , (CR 12a R 12b ) p3 S(O) 2 (CR 12a R 12b ) P 4, (CR 12a R 12b ) p3 S(O) 2 NR e (CR 12
  • each Z 1 is independently selected from aryl and heteroaryl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 .
  • each Z 1 is independently selected from phenyl, pyridinyl, lH-pyrazolyl, isoxazolyl, 1,3- oxazolyl, 1,3-thiazolyl, lH-imidazolyl, lH-l,2,4-triazolyl, IH-1, 2,3 -triazolyl, benzothiazolyl, [l,3]oxazolo[5,4-b]pyridinyl, 1,3,4-thiadiazolyl, furanyl, thienyl, pyrazinyl, pyrimidinyl, benzothiazolyl, furo[3,2-c]pyridinyl, 1 ,2,4-oxadiazolyl, 1,2,5-oxadiazol
  • W 1 is absent, Ci -6 alkylenyl, -O(CR lla R llb ) q iC(O)-, -
  • W 1 is absent, -(CH 2 )-, -O(CR lla R llb ) q iC(O)-, -0(CR lla R llb ) p2 -, -(CR l la R llb ) p iC(O)NR 6 (CR lla R llb ) p2 -, - (CR lla R llb ) p iC(0)NR 6 -, -NR 6 (CR lla R llb ) p2 -, - (CR l la R llb ) p2 NR 6 C(0)-, -(CR lla R llb ) p iNR 6 -, -(CR lla R llb ) p i0(CR lla R llb ) p2 -, -(CR lla R llb ) p iS(CR
  • At least one R 5 is
  • At least one R 5 is
  • each Y 1 is independently selected from absent, Ci_ 6 alkylene, (CR 12a R 12b ) p3 O(CR 12a R 12b ) p4 ,
  • each Y 1 is independently selected from absent, (CH 2 ), (CR 12a R 12b ) p3 O(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 S(CR 12a R 12b ) P 4, (CR 12a R 12b ) P 3NR e (CR 12a R 12b ) P 4, (CR 12a R 12b ) p3 C(O)(CR 12a R 12b ) P 4, (CR 12a R 12b ) p3 C(O)O(CR 12a R 12b ) P 4, C(S)NR 6 , (CR 12a R 12b ) p3 C(O)NR e (CR 12a R 12b ) P 4, (CR 12a R 12b ) p3 S(O) 2 (CR 12a R 12b ) P4 , (CR 12a R 12b ) p3 S(O) 2 (CR 12a R 12b ) P4 , (CR 12a R 12b )
  • each Z 1 is independently selected from aryl and heteroaryl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 .
  • each Z 1 is independently selected from phenyl, pyridinyl, lH-pyrazolyl, isoxazolyl, 1,3-oxazolyl, 1,3-thiazolyl, lH-imidazolyl, IH-1, 2,4- triazolyl, IH-1, 2,3 -triazolyl, benzothiazolyl, [l,3]oxazolo[5,4-b]pyridinyl, 1,3,4-thiadiazolyl, furanyl, thienyl, pyrazinyl, pyrimidinyl, benzothiazolyl, furo[3,2-c]pyridinyl, 1 ,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, l,3-benzodioxol-5-yl, and indolyl, each optionally substituted by 1, 2, 3, 4,
  • Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are each, independently, selected cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 8 alkoxyalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, C 2 . 8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0R a , C(O)NR c R d , amino, Ci -6 alkylamino and C 2 . 8 dialkylamino.
  • each Q 1 is independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Q -6 alkyl, Q -6 haloalkyl, C 2 . 8 alkoxyalkyl, C 1-6 alkoxy, Q -6 haloalkoxy, C 2 . 8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0R a , C(O)NR c R d , amino, C 1-6 alkylamino and C 2 . 8 dialkylamino.
  • each Q 1 is independently selected from cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 8 alkoxyalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, C 2 . 8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0R a , C(O)NR c R d , amino, Ci -6 alkylamino and C 2 . 8 dialkylamino.
  • each Q 1 is independently selected from such optionally substituted cycloalkyl. In other further embodiments, each Q 1 is independently selected from such optionally substituted heterocycloalkyl. In some embodiments, each Q 1 is independently selected heterocycloalkyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 8 alkoxyalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, C 2 . 8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0R a , C(0)NR c R d , amino, Ci -6 alkylamino and C 2 . 8 dialkylamino.
  • each Q 1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, (lH)-hexahydropyrrolo[l,2- a]pyrazin-2-yl, and (8H)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7-yl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 .
  • each Q 1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 .
  • each Q 1 is independently selected from azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 .
  • each Q 1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 _ 8 alkoxyalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, C 2 .
  • each Q 1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 8 alkoxyalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, C 2 .
  • each Q 1 is independently selected from azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 8 alkoxyalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, C 2 . 8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0R a , C(0)NR c R d , amino, Ci -6 alkylamino and C 2 . 8 dialkylamino.
  • each Q 1 is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 8 alkoxyalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, C 2 .
  • each Q 1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, and piperidinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 8 alkoxyalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, C 2 . 8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0R a , C(0)NR c R d , amino, Ci -6 alkylamino and C 2 . 8 dialkylamino.
  • each Q 1 is independently selected from pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Q -6 haloalkyl, C 2 . 8 alkoxyalkyl, Q -6 alkoxy, Q -6 haloalkoxy, C 2 . 8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0R a , C(0)NR c R d , amino, Q -6 alkylamino and C 2 . 8 dialkylamino.
  • each Q 1 is independently selected from pyrrolidinyl, and piperidinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 8 alkoxyalkyl, Ci -6 alkoxy, C i -6 haloalkoxy, C 2 . 8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0R a , C(0)NR c R d , amino, Ci -6 alkylamino and C 2 . 8 dialkylamino.
  • at least one R 5 is -W 6 -Q 1 -Y 1 -Z 1 .
  • At least one R 5 is -(CR lla R llb ) p iS(CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , -(CR l la R llb ) p iS(O)(CR lla R llb ) P 2-Q 1 -Y 1 -Z 1 , -(CR lla R llb ) p iS(O) 2 (CR lla R llb ) P 2-Q 1 -Y 1 -Z 1 , -(CR l la R llb ) p iS(O)NR e (CR lla R llb ) P2 -Q 1 -Y 1 -Z 1 , -(CR lla R llb ) p2 NR e S(O)(CR lla R llb ) p i-Q 1 -Y 1 -Z 1 , (CR
  • each Y 1 is independently selected from absent, Ci_ 6 alkylenyl, (CR 12a R 12b ) p3 O(CR 12a R 12b ) P4 , (CR 12a R 12b ) p3 S(CR 12a R 12b ) P4 , (CR 12a R 12b ) p3 NR e (CR 12a R 12b ) P4 , (CR 12a R 12b ) p3 C(O)(CR 12a R 12b ) P4 , (CR 12a R 12b ) p3 C(O)O(CR 12a R 12b ) P4 , C(S)NR 6 ,
  • each Y 1 is independently selected from absent, (CH 2 ), (CR 12a R 12b ) p3 O(CR 12a R 12b ) P 4, (CR 12a R 12b ) p3 S(CR 12a R 12b ) P 4, (CR 12a R 12b ) p3 NR e (CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 C(O)(CR 12a R 12b ) P4 , (CR 12a R 12b ) p3 C(O)O(CR 12a R 12b ) P4 , C(S)NR 6 ,
  • each Y 1 is independently selected from absent, Ci_ 6 alkylenyl, (CR 12a R 12b ) p3 C(O)(CR 12a R 12b ) P4 , (CR 12a R 12b ) p3 C(O)O(CR 12a R 12b ) P4 , C(S)NR 6 , (CR 12a R 12b ) p3 C(O)NR e (CR 12a R 12b ) P 4, (CR 12a R 12b ) p3 S(O) 2 (CR 12a R 12b ) p4 , and (CR 12a R 12b ) p3 NR e C(O)NR f (CR 12a R 12b ) p4 .
  • each Y 1 is independently selected from absent, (CH 2 ),
  • each Y 1 is independently selected from absent, (CR 12a R 12b ) p3 O(CR 12a R 12 V (CR 12a R 12b ) p3 S(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 NR e (CR 12a R 12b ) p4 ,
  • each Z 1 is independently selected from H, OH, CN, Ci_ 6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein each of the Ci_ 6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from halo, Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 .
  • each Z 1 is independently selected from Ci -6 alkyl, Ci -6 haloalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -6 alkyl, C 2 - ⁇ alkenyl, C 2 - ⁇ alkynyl, Ci -6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a , SR a , C(0)R b , C(0)NR c R d , C(0)0R a , 0C(0)R b , 0C(0)NR c R d , NR c R d , NR c C(0)R d , NR c C(0)0R a , NR c S(O) 2 R b , NR c S(O) 2 S(O) 2 S(
  • each Z 1 is independently selected from aryl, cycloalkyl, heteroaryl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 .
  • each R 6 is, independently, H, Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, Ci_ 6 haloalkyl, C(0)R bl , C(0)NR cl R dl , C(0)0R al , S(O)R bl , S(O) 2 R bl , or S(0) 2 NR cl R dl .
  • each R 6 is, independently, H, Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, or Ci_ 6 haloalkyl.
  • each R 6 is, independently, H or Ci_ 6 alkyl.
  • each R 6 is H or Ci -3 alkyl.
  • each R 6 is, independently, H, Ci -3 alkyl, C 2 . 3 alkenyl, C 2 . 3 alkynyl, or Ci -3 haloalkyl.
  • each R 6 is, independently, H, Ci -3 alkyl, or Ci -3 haloalkyl.
  • each R 6 is, independently, H or Ci -3 alkyl.
  • each R 6 is, independently, H or methyl. In some embodiments, each R 6 is
  • one R 6 is methyl.
  • Ci -6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, or C 1-6 haloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 .
  • R lla , R llb , R 12a , and R 12b are each, independently, selected from H, halo, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, Ci -6 haloalkyl, CN, NO 2 , OH, Ci -6 alkoxy, Ci -6 haloalkoxy, C 2 . 8 alkoxyalkyl, cycloalkyl, heterocycloalkyl, C(0)0R al , C(O)NR cl R dl , amino, Ci -6 alkylamino and C 2 - 8 dialkylamino.
  • R lla , R llb , R 12a , and R 12b are each, independently, selected from H and Ci -6 alkyl. In some further embodiments, R lla , R llb , R 12a , and R 12b are each, independently, selected from H and Ci -3 alkyl.
  • R lla , R llb , R 12a , and R 12b are each, independently, selected from H and methyl. In some further embodiments, R lla , R llb , R 12a , and R 12b are each H.
  • Ci -6 alkenyl, C 2 . 6 alkynyl, or Ci -6 haloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 .
  • each R 13 is independently selected from H, halo, Ci -6 alkyl, C 2 _ 6 alkenyl, C 2 _6 alkynyl, Ci -6 haloalkyl, CN, NO 2 , OH, Ci -6 alkoxy, Ci -6 haloalkoxy, C 2-8 alkoxyalkyl, cycloalkyl, heterocycloalkyl, C(O)OR al , C(0)NR cl R dl , amino, Ci -6 alkylamino and C 2 . 8 dialkylamino.
  • each R 13 is H or Ci -6 alkyl.
  • each R 13 is H.
  • each pi is, independently, 0 or 1. In some other embodiments, each pi is, independently, 1 or 2.
  • each p2 is, independently, 0 or 1. In some other embodiments, each p2 is, independently, 1 or 2.
  • each p3 is, independently, 0 or 1. In some other embodiments, each p3 is, independently, 1 or 2.
  • each p4 is, independently, 0 or 1. In some other embodiments, each p4 is, independently, 1 or 2. In some embodiments, each ql is 1. In some other embodiments, each ql is 2.
  • each q2 is 1. In some other embodiments, each q2 is 2.
  • each n is, independently, 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2.
  • n is 3. In some embodiments, each m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is l.
  • n is 2.
  • At least one R 5 is -W ⁇ -Q ⁇ -Y ⁇ Z 1 . In some further embodiments, at least one R 5 on the ring containing A 1 , B 1 , D 1 , and E 1 is -W ⁇ -Q ⁇ -Y ⁇ Z 1 .
  • At least one R 5 on the ring containing A 2 , B 2 , D 2 , and E 2 is -W ⁇ -Q ⁇ -Y ⁇ Z 1 .
  • each Q 1 is independently selected from cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 2 . 8 alkoxyalkyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, C 2 .
  • each Q 1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 ,
  • the ring containing A 1 , B 1 , D 1 , and E 1 is a pyridine ring, wherein said pyridine ring is optionally substituted by R 2 , if present, and optionally by 1 or 2 R 5 ; and the ring containing A 2 , B 2 , D 2 , and E 2 is a benzene ring, wherein said benzene ring optionally substituted by R 2 , if present, and optionally by 1 , 2, or 3 R 5 .
  • the ring containing A 1 , B 1 , D 1 , and E 1 is a pyridine ring, wherein said pyridine ring is optionally substituted by 1 or 2 R 5 ; and the ring containing A 2 , B 2 , D 2 , and E 2 is a benzene ring, wherein said benzene ring substituted by -W ⁇ -Q ⁇ -Y ⁇ Z 1 and optionally substituted by 1 or 2 R 5 .
  • each Q 1 is independently selected from cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 8 alkoxyalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, C 2 . 8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0R a , C(O)NR c R d , amino, C 1-6 alkylamino and C 2 . 8 dialkylamino.
  • each Q 1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 8 alkoxyalkyl, Ci -6 alkoxy, Ci-ehaloalkoxy, C 2 .
  • the compounds of Formula I of the present invention have Formula II:
  • each R 5a is, independently, selected from H, halo, Ci -6 alkyl, Ci -6 haloalkyl, CN, NO 2 , SF 5 , OR al , C(O)R bl , C(0)NR cl R dl , C(O)OR al , NR cl R dl , NR cl C(0)R bl , NR cl S(O) 2 NR cl R dl , S(O) 2 R bl , NR cl S(O) 2 R bl , and S(O) 2 NR cl R dl ; or two adjacent R 5a can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci -6 alkyl, Ci -6 haloalkyl, CN, NO 2 , SF 5 , OR al ,
  • each R 5a is, independently, selected from H halo, Ci -6 alkyl, Ci -6 haloalkyl, CN, NO 2 , SF 5 , OR al , C(0)R bl , C(0)NR cl R dl , C(0)0R al , NR cl R dl , NR cl C(0)R bl , NR cl S(0) 2 NR cl R dl , S(O) 2 R bl , NR cl S(0) 2 R bl , and S(O) 2 NR cl R dl ; and each R 5b is, independently, selected from H halo, Ci -6 alkyl, Ci -6 haloalkyl, CN, NO 2 , SF 5 , OR al , C(0)R bl , C(0)NR cl R dl , C(0)0R al ,
  • X 3 is N, and X 2 is CR 2 .
  • each R 2 is, independently, selected from H, F, Cl, Br, methyl, and CF 3 . In some futher embodiments, each R 2 is H.
  • X 2 is N, and X 3 is CR 3 .
  • R 3 is halo.
  • R 3 is F or Cl.
  • R 3 is Cl.
  • the compounds of Formula II have Formula Ha:
  • each R 5a is independently selected from H, halo, Ci -6 alkyl, Ci -6 haloalkyl, OR al , C(O)R bl , C(O)NR cl R dl , C(O)OR al , S(O) 2 R", NR cl S(O) 2 NR cl R dl , NR cl R dl , NR cl C(0)R bl , NR cl C(0)NR cl R dl , NR cl C(0)0R al , and NR cl S(O) 2 R bl .
  • each R 5a is independently selected from H, halo, Ci -6 alkyl, Ci -6 haloalkyl, OR al , C(O)R bl , NR cl R dl , NR cl C(O)R bl , NR cl C(O)NR cl R dl , NR cl C(O)OR al , NR cl S(O) 2 NR cl R dl , and NR cl S(O) 2 R bl .
  • each R 5a is H.
  • one R 5a is other than H.
  • two R 5a are other than H.
  • three R 5a are other than H. In some embodiments of the compounds of Formula Ha or pharmaceutically acceptable salts thereof, at least one R 5a is other than H.
  • At least one R 5a is selected C(O)R bl , C(O)NR cl R dl , C(O)OR al , NR cl R dl , NR cl C(O)R bl , NR cl C(0)NR cl R dl , NR cl C(O)OR al , NR cl S(O) 2 NR cl R dl , S(O) 2 R bl , NR cl S(O) 2 R bl , and S(O) 2 NR cl R dl , wherein:
  • R al , R bl , R cl , and R dl are each, independently, selected from H, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci -6 alkyl, C 2 . 6 alkenyl, C 2 .
  • 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -4 alkyl, Ci -4 haloalkyl, Ci -4 hydroxylalkyl, Ci -4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OH, SH, 0(C 1-4 alkyl), O(Ci_ 4 haloalkyl), O(aryl), O(arylalkyl), S(C 1-4 alkyl), S(Ci_ 4 haloalkyl), S(aryl), S(arylalkyl), amino, Ci -4 alkylamino, C 2 .
  • R 5a is selected NR cl R dl , and R cl and R dl together with the N atom to which they are attached form pyrrolidinyl, piperidinyl or morpholinyl, each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, Ci -4 alkyl, Ci -4 haloalkyl, Ci -4 hydroxylalkyl, Ci -4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OH, SH, O(Ci_ 4 alkyl), O(Ci_ 4 haloalkyl), O(aryl), O(arylalkyl), S(C 1-4 alkyl), S(Ci_ 4 haloalkyl), S(aryl), S(arylalkyl), amino, Ci_ 4 alkylamino,
  • each R 5b is H.
  • one of R 5b is other than H.
  • two of R 5b are other than H.
  • three of R 5b are other than H. In some embodiments of the compounds of Formula Ha or pharmaceutically acceptable salts thereof, at least one of R 5b is other than H.
  • the compounds of Formula Ha have Formula lib:
  • the compounds of Formula Ha have Formula Ha- 1 :
  • the compounds of Formula Ha have Formula IIa-2:
  • X 2 is N; and X 3 is CR 3 .
  • R 3 is halo.
  • R 3 is F or Cl.
  • R 3 is Cl.
  • the compounds of Formula II have Formula Hc:
  • each R 2 is, independently, selected from H, F, Cl, Br, methyl, and CF 3 . In some futher embodiments, each R 2 is H.
  • R 3 is halo. In some further embodiments, R 3 is F or Cl. In yet further embodiments, R 3 is Cl.
  • the compounds of Formula II have Formula Hd:
  • Y is NH or N(Ci_ 3 alkyl). In some further embodiments, Y is NH.
  • each R 2 is, independently, selected from H, F, Cl, Br, methyl, and CF 3 . In some futher embodiments, each R 2 is H.
  • X 2 is N.
  • the compounds of Formula II have Formula He:
  • each R 2 is, independently, selected from H, F, Cl, Br, methyl, and CF 3 . In some futher embodiments, each R 2 is H.
  • Y is NH
  • the compounds of Formula I of the present invention have Formula Ilia:
  • D 1 , E 1 , D 2 , and E 2 are each, independently, CR 5 or N.
  • the compounds of Formula I of the present invention have Formula IHb:
  • D 1 , E 1 , and D 2 are each, independently, CR 5 or
  • the compounds of Formula I of the present invention have Formula IHc:
  • IHd or are pharmaceutically acceptable salts thereof, wherein E 1 is CR 5 or N.
  • the compounds of Formula I of the present invention have Formula IHe:
  • IHe are pharmaceutically acceptable salts thereof, wherein D 1 is CR 5 or N.
  • the compounds of Formula I of the present invention have Formula HIf:
  • the compounds of Formula I of the present invention have Formula HIg:
  • IHg or are pharmaceutically acceptable salts thereof, wherein D 1 is CR 5 or N.
  • the compounds of Formula I of the present invention have Formula IHh:
  • IHh or are pharmaceutically acceptable salts thereof, wherein E 1 is CR 5 or N.
  • the compounds of Formula I of the present invention have Formula IVa:
  • the compounds of Formula I of the present invention have Formula IVb:
  • the compounds of Formula I of the present invention have Formula IVc:
  • the compounds of Formula I of the present invention have Formula IVd:
  • IVd or are pharmaceutically acceptable salts thereof.
  • the compounds of Formula I of the present invention have Formula V:
  • the compounds of Formula I of the present invention have Formula Va:
  • E 1 is CR 5 or N; each R Q is independently selected from selected from Ci -6 alkyl, Ci -6 haloalkyl, C 2 - ⁇ alkenyl, C 2 - ⁇ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halo, CN, NO 2 , OR a , SR a , SF 5 , C(0)R b , C(0)NR c R d , C(0)0R a , 0C(0)R b ,
  • each R 5 is, independently, H, Cy 1 , halo, Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 .
  • 6 alkenyl, C 2 . 6 alkynyl, Q -6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 .
  • each R 5 is, independently, H, Cy 1 , halo, Ci -6 alkyl, C 2 - ⁇ alkenyl, C 2 - ⁇ alkynyl, Ci -6 haloalkyl, halosulfanyl, CN, NO 2 , SF 5 , OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(S)R bl , C(S)NR cl R dl , C(0)0R al , 0C(0)R bl , 0C(0)NR cl R dl , NR cl R dl , NR cl C(O)R bl , NR cl C(0)
  • Ci_ 6 alkenyl, C 2 . 6 alkynyl, Ci_ 6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 haloalkyl, Cy 1 , CN, NO 2 , SF 5 , OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)0R al , 0C(0)R bl , 0CH 2 C(0)R bl , 0C(0)NR cl R dl , NR cl R dl , NR cl C(O)R bl , NR cl C(0)NR cl R dl ,
  • the compound of Formula IHf is a compound of Fomula IIIf-1 :
  • R 301 is selected from H, halo, Ci_6 alkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, Cy 1 , CN, NO 2 , OR al , SR al , C(0)R bl , C(0)NR cl R dl , SF 5 , C(S)R bl , C(S)NR cl R dl , C(0)0R al , 0C(0)R bl , -W ⁇ Q ⁇ -Z 1 , 0C(0)NR cl R dl , NR cl R dl , NR cl C(0)R bl , NR cl C(0)NR cl R dl , NR cl C(S)R bl , NR
  • 6 alkenyl, C 2 . 6 alkynyl, C 1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, Ci -6 haloalkyl, Cy 1 , - W 1 -Q 1 ⁇ -Z 1 , CN, NO 2 , SF 5 , OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)0R al , 0C(0)R bl , 0CH 2 C(0)R bl , 0C(0)NR cl R dl , NR cl R dl , NR cl C(O)R bl , NR cl C
  • Ci_ 6 alkynyl Ci_ 6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_ 6 alkyl, C 2 .
  • R 301 is selected from H, Ci -6 alkyl, and -W ⁇ Q ⁇ Y ⁇ Z 1 , wherein the Ci -6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci -6 haloalkyl, Cy 1 , - W 1 -Q 1 ⁇ -Z 1 , CN, NO 2 , SF 5 , OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)0R al , 0C(0)R bl , 0CH 2 C(0)R bl , 0C(0)NR cl R dl , NR cl R dl , NR cl C(O)R bl , NR cl C(0)NR cl R dl , NR cl C(O)R
  • each R 5 is, independently, H, Cy 1 , halo, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 .
  • At least one R 5 is -W ⁇ -Q ⁇ Y ⁇ Z 1 .
  • at least one R 5 on the ring containing A 2 , B 2 , D 2 , and E 2 is -W ⁇ -Q ⁇ Y ⁇ Z 1 .
  • At least one R 5 is Cy 1 .
  • At least one R 5 is Cy 1 that is selected from aryl and heteroaryl, each optionally substituted with 1 , 2, or 3 substituents independently selected from Ci_ 6 alkyl, C(O)-O-(Ci_ 4 alkyl), S(O) 2 -(Ci_ 4 alkyl), and piperazinyl, wherein the piperazinyl is optionally substituted with 1 or 2 subsituents independently selected from Ci_ 6 alkyl, arylalkyl, aryl, heteroaryl, C(O)R bl , S(O) 2 R bl , C(O)NR cl R dl , and S(O) 2 NR cl R dl .
  • At least one R 5 is -Q 1 ⁇ -Z 1 , -(CH 2 )- Q'-Y'-Z 1 , -O(CR lla R llb ) q iC(O)-Q 1 -Y 1 -Z 1 , -O(CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , -(CR lla R llb ) p iC(O)NR e (CR lla R llb ) p2 - Q'-Y'-Z 1 , - (CR lla R llb ) p iC(O)NR e -Q 1 -Y 1 -Z 1 , -
  • At least one R 5 is -(CR lla R llb ) p1 -Q 1 -Y 1 -Z 1 , -(CR lla R llb ) p iO(CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , -(CR lla R llb ) p iS(CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , -(CR lla R llb ) p1 S(O) 2 ((CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , -(CR lla R llb )
  • each Q 1 is independently selected from cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 2 . 8 alkoxyalkyl, Ci_ 6 alkoxy, Ci_ 6 haloalkoxy, C 2 .
  • each Q 1 is independently selected from cyclopentyl, cyclohexyl, pyrrolidinyl, and piperidinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 .
  • At least one R 5 is -(CR l la R llb ) p iO(CR lla R llb ) p 2-Q 1 -Y 1 -Z 1 , -(CR lla R llb ) p iS(CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 ,
  • each Q 1 is independently selected from cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 8 alkoxyalkyl, Ci -6 alkoxy, Ci_ 6 haloalkoxy, C 2 .
  • each Q 1 is independently selected from cyclopentyl, cyclohexyl, pyrrolidinyl, and piperidinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 8 alkoxyalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, C 2 .
  • At least one R 5 is -W 6 -Q 1 -Y 1 -Z 1 .
  • at least one R 5 on the ring containing A 2 , B 2 , D 2 , and E 2 is -W 6 -Q 1 -Y 1 -Z 1 .
  • At least one R 5 is -(CR l la R llb ) p iS(CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , -(CR lla R llb ) p iS(O)(CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , -(CR l la R llb ) p iS(O) -(CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 , -(CR l la R llb ) p iS(O) -(CR lla R llb ) p iS(O)NR 6 (CR lla R llb ) p2 -Q 1 -Y 1 -Z 1 ,
  • each Q 1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, (lH)-hexahydropyrrolo[l,2-a]pyrazin-2-yl, and (8H)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7-yl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 .
  • each Q 1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci- 6 alkyl, Ci -6 haloalkyl, C 2 .
  • each Q 1 is independently selected from azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Q -6 alkyl, Q -6 haloalkyl, C 2 .
  • each Q 1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Q -6 haloalkyl, C 2 . 8 alkoxyalkyl, Q -6 alkoxy, Q -6 haloalkoxy, C 2 .
  • each Q 1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 8 alkoxyalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, C 2 .
  • each Q 1 is independently selected from azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO 2 , OH, Ci -6 alkyl, Ci -6 haloalkyl, C 2 . 8 alkoxyalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, C 2 .
  • each Y 1 is independently selected from absent, Ci_ 6 alkylenyl, (CR 12a R 12b ) p3 O(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 S(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 NR e (CR 12a R 12b ) P4 , (CR 12a R 12b ) p3 C(O)(CR 12a R 12b ) P4 , (CR 12a R 12b ) p3 C(O)O(CR 12a R 12b ) P4 , C(S)NR 6 , (CR 12a R 12b ) p3 C(O)NR e (CR 12a R 12b ) P4 , (CR 12a R 12b ) p3 S(O) 2 (CR 12a R 12b ) P4 , (CR 12a R 12b ) p3 S(O) 2 (CR 12a R
  • each Y 1 is independently selected from absent, (CH 2 ), (CR 12a R 12b ) p3 O(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 S(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 NR e (CR 12a R 12b ) P 4, (CR 12a R 12b ) p3 C(O)(CR 12a R 12b ) P 4, (CR 12a R 12b ) p3 C(O)O(CR 12a R 12b ) p4 , C(S)NR 6 , (CR 12a R 12b ) P 3C(O)NR e (CR 12a R 12b ) P 4,
  • each Y 1 is independently selected from absent, Ci_ 6 alkylenyl, (CR 12a R 12b ) p3 C(O)(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 C(O)O(CR 12a R 12b ) p4 , C(S)NR 6 , (CR 12a R 12b ) p3 C(O)NR e (CR 12a R 12b ) P4 , (CR 12a R 12b ) p3 S(O) 2 (CR 12a R 12b ) p4 , and (CR 12a R 12b ) p3 NR e C(O)NR f (CR 12a R 12b ) p4 .
  • each Y 1 is independently selected from absent, (CH 2 ), (CR 12a R 12b ) p3 C(O)(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 C(O)O(CR 12a R 12b ) p4 , C(S)NR 6 , (CR 12a R 12b ) p3 C(O)NR e (CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 S(O) 2 (CR 12a R 12b ) p4 , and (CR 12a R 12b ) p3 NR e C(O)NR f (CR 12a R 12b ) p4 .
  • each Y 1 is independently selected from absent, (CR 12a R 12b ) p3 O(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 S(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 NR e (CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 C(O)(CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 C(O)NR e (CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 S(O) 2 (CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 S(O) 2 (CR 12a R 12b ) p4 , (CR 12a R 12b ) p3 S(O) 2 (CR 12a R 12b ) p4 , (CR 12a
  • each Z 1 is independently selected from H, OH, CN, Ci_ 6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein each of the Ci_ 6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a , SR a , C(O)R b , C(0)NR
  • each Z 1 is independently selected from Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, Ci_ 6 haloalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 .
  • each Z 1 is independently selected from Ci- 6 alkyl, Ci -6 haloalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -6 alkyl, C 2 - ⁇ alkenyl, C 2 - ⁇ alkynyl, Ci -6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a , SR a , C(0)R b , C(0)NR c R d , C(0)0R a , 0C(0)R b , 0C(0)NR c R d
  • each Z 1 is independently selected from aryl, cycloalkyl, heteroaryl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 .
  • the compounds of Formula I of the present invention have Formula Ia:
  • X 2 is N.
  • X 2 is CR 2 .
  • R 3 is halo.
  • R 3 is F, Cl, or Br.
  • R 3 is Cl.
  • B 1 , B 2 , D 1 , D 2 , E 1 , and E 2 are each, independently, selected from CR 5 ; and A 1 and A 2 , are each, independently, selected from CR 2 .
  • the ring containing A 1 , B 1 , D 1 , and E 1 is a benzene ring, and the benzene ring can be substituted or unsubstituted.
  • the ring containing A 1 , B 1 , D 1 , and E 1 is selected from pyridine and pyrimidine (which can be optionally substituted, for example by three R 5 and one R 2 ).
  • the ring is pyridine.
  • the ring is pyrimidine.
  • D 1 is N.
  • E 1 is N.
  • B 1 is N.
  • B 2 , D 2 , and E 2 are each, independently, selected from CR 5 ; and A 2 is CR 2 .
  • the ring containing A 2 , B 2 , D 2 , and E 2 is is selected from pyridine and pyrimidine (which can be optionally substituted, for example by three R 5 and one R 2 ).
  • the ring is pyridine.
  • the ring is pyrimidine.
  • R 1 is selected from H, halo, Ci_ 6 alkyl, and Ci_ 6 haloalkyl. In some further embodiments, R 1 is H.
  • each R 2 is, independently, selected from H, halo, Ci_ 6 alkyl, and Ci_ 6 haloalkyl. In some further embodiments, each R 2 is, independently, selected from H, halo, Ci -3 alkyl, and Ci -3 haloalkyl. In yet further embodiments, each R 2 is, independently, selected from H, F, Cl, Br, methyl, ethyl, 1 -propyl, 2- propyl, and Ci -2 haloalkyl.
  • each R 2 is, independently, selected from H, F, Cl, Br, methyl, ethyl, 1-propyl, 2-propyl, and CF 3 . In some embodiments, each R 2 is, independently, selected from H, F, Cl, Br, methyl, and CF 3 . In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, each R 2 is, independently, selected from H, CH 3 , CF 3 , and halo. In some further embodiments, each R 2 is, independently, selected from H, F, Cl, methyl, and CF 3 . In yet futher embodiments, each R 2 is, independently, selected from H, F, and Cl.
  • each R 2 is, independently, selected from H, CH 3 and CF 3 . In some further embodiments, each R 2 is H, or CH 3 . In yet futher embodiments, each R 2 is H.
  • R 3 is selected from H, halo, Ci_ 6 alkyl, and Ci_ 6 haloalkyl. In some embodiments, R 3 is selected from H, halo, Ci -3 alkyl, and Ci -3 haloalkyl. In some embodiments, R 3 is Ci_ 6 alkyl. In some embodiments, R 3 is Ci -3 alkyl. In some embodiments, R 3 is H, CH 3 or CF 3 . In some embodiments, R 3 is H. In some embodiments, R 3 is CH 3 . In some embodiments, R 3 is CF 3 . In some embodiments, R 3 is halo. In some embodiments R 3 is chloro. In some embodiments, R 3 is bromo. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
  • R 3 is SF 5 .
  • R 3 is selected from amino, Ci -4 alkylamino, and C 2 _ 8 dialkylamino. In some further embodiments, R 3 is selected from NH 2 , NH(Ci_ 3 alkyl), and N(Ci_ 3 alkyl) 2 . In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof:
  • R 1 is selected from H, halo, Ci_ 6 alkyl, and Ci_ 6 haloalkyl;
  • R 3 is selected from H, halo, Ci_ 6 alkyl, and Ci_ 6 haloalkyl.
  • R 1 is H; and R 3 is selected from H, halo, Ci -6 alkyl, and Ci -6 haloalkyl.
  • R 1 is H
  • R 3 is selected from H, halo, Ci -3 alkyl, and Ci -3 haloalkyl.
  • R 1 is H
  • R 3 is selected from H, F, Cl, Br, Ci -3 alkyl, and CF 3 .
  • each R 5 is independently selected from H, halo, Q -6 alkyl, Q -6 haloalkyl, Cy 1 , -W'-Q'-Y'-Z 1 , CN, NO 2 , OR al , C(O)R bl , C(O)NR cl R dl , C(O)OR al , NR cl R dl , NR cl C(O)R bl , NR cl S(O) 2 NR cl R dl , S(O) 2 R bl , NR cl S(O) 2 R bl , and S(O) 2 NR cl R dl .
  • each R 5 is independently selected from H, halo, Q -6 alkyl, Q -6 haloalkyl, CN, NO 2 , OR al , C(O)R bl , C(O)NR cl R dl , C(O)OR al , NR cl R dl , NR cl C(O)R bl , NR cl S(O) 2 NR cl R dl , S(O) 2 R bl , NR cl S(O) 2 R bl , and S(O) 2 NR cl R dl .
  • each R 5 is independently selected from H, halo, Ci -6 alkyl, Ci -6 haloalkyl, CN, NO 2 , OR al , NR cl R dl , NR cl S(O) 2 R bl , NR cl S(O) 2 NR cl R dl , S(O)R bl , S(O) 2 R bl , and S(O) 2 NR cl R dl .
  • At least one R 5 is -W'-Q'-Y'-Z 1 .
  • At least one R 5 is Cy 1 .
  • two adjacent R 5 on the same ring can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci -6 alkyl, Ci -6 haloalkyl, CN, NO 2 , OR al , C(O)R bl , C(0)NR cl R dl , C(O)OR al , NR cl R dl , NR cl C(0)R bl , NR cl S(0) 2 NR cl R dl , S(O) 2 R bl , NR cl S(O) 2 R bl , and S(O) 2 NR cl R dl .
  • two adjacent R 5 on the ring containing A 1 , B 1 , D 1 , and E 1 can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci_6 alkyl, Ci_ 6 haloalkyl, CN, NO 2 , OR al , C(0)R bl , C(0)NR cl R dl , C(0)0R al , NR cl R dl , NR cl C(0)R bl , NR cl S(0) 2 NR cl R dl , S(O) 2 R bl , NR cl S(O) 2 R bl , and S(O) 2 NR cl R dl .
  • two adjacent R 5 on the ring containing A 2 , B 2 , D 2 , and E 2 can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, Ci_6 alkyl, Ci_ 6 haloalkyl, CN, NO 2 , OR al , C(0)R bl , C(0)NR cl R dl , C(0)0R al , NR cl R dl , NR cl C(0)R bl , NR cl S(0) 2 NR cl R dl , S(O) 2 R bl , NR cl S(O) 2 R bl , and S(O) 2 NR cl R dl .
  • Y is NR 4 .
  • Y is NH or N(Ci -3 alkyl).
  • Y is NH.
  • Y is N(Ci -3 alkyl).
  • Y is N-CH 3 .
  • compounds of Formula Ia or pharmaceutically acceptable salts thereof in some embodiments,
  • L 1 and L 2 together form -(CRV) 3 -. In some further embodiments, L 1 and L 2 together form -(CH 2 ) 3 -.
  • one of L 1 and L 2 is selected from -(CRV) 1n -O-, -(CRV) 1n -S-, -(CRV) 1n -S(O)-, and -(CRV) 1n - S(O) 2 -; and the other is selected from a bond, -(CRV) n -, -(CRV) 1n -O-, -(CRV) 1n -S-, -(CRV) 1n -S(O)-, and - (CRV) 1n - S(O) 2 -.
  • compounds of Formula Ia or pharmaceutically acceptable salts thereof are selected from -(CRV) 1n -O-, -(CRV) 1n -S-, -(CRV) 1n -S(O)-, and - (CRV) 1n - S(O) 2 -.
  • L 1 and L 2 together form -(CRV) 11 -S-, -(CRV) 11 -O-, -(CRV) 11 -S(O)-, -(CRV) 11 -S(O) 2 -, -S-(CRV) 12 -S-, -0-(CRV) 12 -S-, -0-(CRV) 12 -S(O)-,
  • L 1 and L 2 together form -(CR 7 R 8 Xi -S-, -(CR 7 R 8 Xi -O-, -(CR 7 R 8 Xi-S(O)-, -(CR 7 R 8 Xi-S(O) 2 -, -S-(CR 7 RVs-, -0-(CR 7 RVS-, -0-(CR 7 R VS(O)-, -0-(CR 7 R 8 X 2 -S(O) 2 -, or -S-S-; tl is 1, 2, or 3; and t2 is l or 2.
  • L 1 and L 2 together form -(CR 7 RVO-(CR 7 R 8 X 4 -, -(CR 7 R 8 X 3 -S-(CR 7 R 8 X 4 -, -(CR 7 RV S(O)-(CR 7 R 8 X 4 -, or -(CR 7 R 8 X 3 -S(O) 2 -(CR 7 R 8 ) t4 -, t3 is 1, 2, or 3; and t4 is l or 2.
  • L 1 and L 2 together form S-S, -(CR 7 R 8 )-S-, -(CR 7 R 8 )-S(O)-, -(CR 7 R 8 XS(O) 2 -, -(CR 7 R 8 )-O-, -(CR 7 R 8 ) 2 -0-, -O-(CR 7 R 8 ) 2 -O-, -O-(CR 7 R 8 ) 2 -S-, -O-(CR 7 R 8 ) 2 -S(O)-, or -O-(CR 7 R 8 ) 2 - S(O) 2 -.
  • L 1 and L 2 together form -(CR 7 R 8 )-S-, -(CR 7 R 8 )-S(O)-, -(CR 7 R 8 XS(O) 2 -, -(CR 7 R 8 XO-, -(CR 7 RVo-, -0-(CR 7 RVo-, -O-(CR 7 R 8 ) 2 -S-, -O-(CR 7 R 8 ) 2 -S(O)-, or -O-(CR 7 R 8 ) 2 -S(O) 2 -.
  • L 1 and L 2 together form S-S, -(CH 2 )-S-, -(CH 2 )-S(0)-, -(CH 2 XS(O) 2 -, -(CH 2 )-0-, -(CH 2 ) 2 -0-, -0-(CH 2 ) 2 -0-, -0-(CH 2 ) 2 -S-, -0-(CH 2 ) 2 -S(0)-, or -0-(CH 2 ) 2 - S(O) 2 -.
  • L 1 and L 2 together form S-S.
  • L 1 and L 2 together form -(CH 2 )-S-, -(CH 2 )-S(0)-, -(CH 2 )-S(O) 2 -, -(CH 2 )-0-, -(CH 2 ) 2 -0-, -0-(CH 2 ) 2 -0-, -0-(CH 2 ) 2 -S-, -0-(CH 2 ) 2 -S(0)-, or -0-(CH 2 ) 2 - S(O) 2 -.
  • L 1 and L 2 together form -(CR 7 R 8 )-O, -(CR 7 R 8 )-S-, -(CR 7 R 8 )-S(O), -(CR 7 R 8 XS(O) 2 , -(CR 7 R 8 ) 2 -O-, -(CR 7 RVs-, -(CR 7 RVS(O)-, -(CR 7 R 8 ) 2 -S(O) 2 -, -0-(CR 7 R 8 X-, -S-(CR 7 R 8 X-, -S(O)-(CR 7 R 8 X-, or -S(O) 2 -(CR 7 R 8 ),-.
  • L 1 and L 2 together form -(CH 2 )-0-, -(CH 2 )-S-, -(CH 2 )-S(0)-, or -(CH 2 )-S(O) 2 -. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L 1 and L 2 together form -(CH 2 )-0- or -(CHz)-S-.
  • L 1 and L 2 together form -(CH 2 )-0-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
  • L 1 and L 2 together form -(CH 2 )-S-.
  • L 1 and L 2 together form -(CH 2 )-S(O)-.
  • L 1 and L 2 together form -(CH 2 )-S(O) 2 -.
  • L 1 and L 2 together form -(CH 2 ) 2 -O, -(CH 2 ) 2 -S-, -(CH 2 ) 2 -S(O)-, or -(CH 2 ) 2 -S(O) 2 -.
  • L 1 and L 2 together form - (CHz) 2 -O- or -(CHz) 2 -S-.
  • L 1 and L 2 together form -(CH 2 ) 2 -O-.
  • L 1 and L 2 together form -(CH 2 ) 2 -S-.
  • L 1 and L 2 together form -(CH 2 ) 2 -S(O)-.
  • L 1 and L 2 together form -(CH 2 ) 2 -S(O) 2 -.
  • L 1 and L 2 together form -(CH 2 ) 3 -O-, -(CH 2 ) 3 -S-, -(CH 2 ) 3 -S(O)-, or -(CH 2 ) 3 -S(O) 2 -.
  • L 1 and L 2 together form - (CHz) 3 -O- or -(CHz) 3 -S-.
  • L 1 and L 2 together form -(CH 2 ) 3 -O-.
  • L 1 and L 2 together form -(CH 2 ) 3 -S-.
  • L 1 and L 2 together form -(CH 2 ) 3 -S(O)-.
  • L 1 and L 2 together form -(CHz) 3 -S(O) 2 -. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L 1 and L 2 together form -(CRV)-O-(CR 7 R 8 )-, -(CR 7 R 8 )-S-( CR 7 R 8 )-, -(CR 7 R 8 )-S(O)-(CR 7 R 8 )-,
  • L 1 and L 2 together form -(CH 2 )-O-(CH 2 )-, -(CU 2 )S-(CU 2 )-, -(CH 2 )-S(O)-(CH 2 )-, -(CH 2 )-S(O) 2 -(CH 2 )-, -(CH 2 )-O-(CH 2 ) 2 -, -(CH 2 )-S-(CH 2 ) 2 -, -(CH 2 )-S(O)-(CH 2 ) 2 -, -(CH 2 )-S(O) 2 -(CH 2 ) 2 -, -(CH 2 ) 2 -O-(CH 2 ) 2 -, -(CH 2 ) 2 -S-(CH 2 ) 2 -, or -(CH 2 )-O-(CH 2 ) 2 -, -(CH 2 ) 2 -S-(CH 2 ) 2 -, -(CH 2
  • L 1 and L 2 together form -(CH 2 )-O-(CH 2 )- or -(CH 2 )-S-(CH 2 )-.
  • L 1 and L 2 together form -(CH 2 )-O-(CH 2 )-.
  • L 1 and L 2 together form -(CH 2 )-S-(CH 2 )-.
  • L 1 and L 2 together form -(CH 2 )-O-(CH 2 ) 2 - or -(CH 2 )-S-(CH 2 ) 2 -.
  • L 1 and L 2 together form -(CH 2 )-O-(CH 2 ) 2 -. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
  • L 1 and L 2 together form -(CH 2 )-S-(CH 2 ) 2 -.
  • L 1 and L 2 together form -(CH 2 ) 2 -O-(CH 2 ) 2 - or -(CH 2 ) 2 -S-(CH 2 ) 2 -.
  • L 1 and L 2 together form -(CH 2 ) 2 -O-(CH 2 ) 2 -
  • L 1 and L 2 together form -(CH 2 ) 2 -S-(CH 2 ) 2 -.
  • L 1 and L 2 together form -0-(CH 2 ) 2 -O-, -0-(CH 2 ) 2 -S-, -O-(CH 2 ) 2 -S(O)-, -O-(CH 2 ) 2 -S(O) 2 -, -S-(CH 2 ) 2 -S- -S(O)-(CH 2 ) 2 -S(O)-, or -S(O) 2 -(CH 2 ) 2 -S(O) 2 -.
  • L 1 and L 2 together form -0-(CH 2 ) 2 -O-, -0-(CH 2 ) 2 -S-, -0-(CH 2 ) 2 -S(O)-, or -0-(CH 2 ) 2 -S(O) 2 -.
  • L 1 and L 2 together form -0-(CH 2 ) 2 -0-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L 1 and L 2 together form -0-(CH 2 ) 2 -S-.
  • L 1 and L 2 together form -0-(CH 2 ) 2 -S(O)-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
  • L 1 and L 2 together form -0-(CH 2 ) 2 -S(O) 2 -.
  • one of L 1 and L 2 is selected from -(CR 7 R 8 ) m -NR 9 -, -(CRV) 1n -S(O) 2 -, -(CR 7 R 8 ) m -C(O)-, -C(O)NR 9 -, -(CRV) 1n -S(O)NR 9 -, and -(CRV) 1n -S(O) 2 NR 9 -; and the other is selected from a bond, -(CRV) n -, -(CRV) 1n -NR 9 -, -(CRV) 1n -S(O) 2 -, -(CRV) 1n -C(O)-, -C(O)NR 9 -, -(CRV) 1n -S(O)NR 9 -, and -(CRV) 1n -S(O) 2 NR 9 -;
  • L 1 and L 2 together form -(CR V) t5 -C(0)-, -(CR V)( S -C(O)NR 9 -, -C(O)NR 9 -(CR 7 R 8 ) t5 -, -C(O)NR 9 -, -S(O) 2 NR 9 -(CR V)( S -, -(CRV)( S -S(O) 2 NR 9 -, or -S(O) 2 NR 9 -, wherein t5 is 1, 2, or 3.
  • t5 is 1, 2, or 3.
  • L 1 and L 2 together form -(CRV) 15 -C(O)-, -C(O)NR 9 -, or -S(O) 2 NR 9 -, and wherein t5 is 1, 2, or 3.
  • L 1 and L 2 together form -(CR V)-C(O)-, -(CRV) 2 -C(O)-, or -(CRV) 3 -C(O)-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L 1 and L 2 together form -(CR 7 R 8 )- C(O)-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L 1 and L 2 together form -(CRV) 2 -C(O)-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L 1 and L 2 together form -(CRV) 3 -C(O)-.
  • L 1 and L 2 together form -(CRV)-C(O)NR 9 -, -C(O)NR 9 -(CR 7 R 8 )-, or -C(O)NR 9 -. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L 1 and L 2 together form
  • L 1 and L 2 together form -(CH 2 )-C(0)NH-, -C(O)NH-(CH 2 )-, or -C(O)NH-.
  • L 1 and L 2 together form -(CH 2 )-C(0)NH-.
  • L 1 and L 2 together form -C(O)NH-(CH 2 )-.
  • L 1 and L 2 together form -C(O)NH-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L 1 and L 2 together form -(CR 7 R 8 )t 7 -C(O)NR 9 -(CR 7 R 8 ) t8 , wherein t7 is 1 or 2 and t8 is 1 or 2. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L 1 and L 2 together form -(CR 7 R 8 )-C(O)NR 9 -(CR 7 R 8 ). In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L 1 and L 2 together form -(CH 2 )-C(O)NH-(CH 2 )-.
  • L 1 and L 2 together form -S(O) 2 NR 9 -(CR 7 R 8 ) t5 -, -(CR 7 R 8 ) t5 -S(O) 2 NR 9 -, or -S(O) 2 NR 9 -, wherein t5 is 1, 2, or 3.
  • L 1 and L 2 together form -S(O) 2 NR 9 -(CR 7 R 8 )-, -(CR 7 R 8 )-S(O) 2 NR 9 -, or -S(O) 2 NR 9 -.
  • R 9 is H or Ci -3 alkyl.
  • L 1 and L 2 together form -S(O) 2 NR 9 -(CH 2 )-, -(CH 2 )-S(O) 2 NR 9 -, or -S(O) 2 NR 9 -. In some further embodiments, L 1 and L 2 together form -S(O) 2 NH-(CH 2 )-, -(CHz)-S(O) 2 NH-, or -S(O) 2 NH-, In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
  • L 1 and L 2 together form -S(O) 2 NH-(CH 2 )-.
  • L 1 and L 2 together form -(CH 2 )-S(O) 2 NH-.
  • L 1 and L 2 together form -S(O) 2 NH-.
  • L 1 and L 2 together form -(CR 7 R 8 )t 7 -S(O) 2 NR 9 -(CR 7 R 8 ) t8 -, wherein t7 is 1 or 2 and t8 is 1 or 2.
  • L 1 and L 2 together form -(CR 7 R 8 )-S(O) 2 NR 9 -(CR 7 R 8 ).
  • compounds of Formula Ia or pharmaceutically acceptable salts thereof L 1 and L 2 together form -(CR 7 R 8 )-S(O) 2 NR 9 -(CR 7 R 8 ).
  • L 1 and L 2 together form -(CH 2 )-S(O) 2 NR 9 -(CH 2 )-.
  • L 1 and L 2 together form -(CR 7 R 8 ) m -NR 9 -C(O)NR 9 -, -(CR 7 R 8 ) m -O-C(O)NR 9 -, or -O-C(O)NR 9 -(CR 7 R 8 ) m -.
  • L 1 and L 2 together form -(CR 7 R 8 )-NR 9 -C(O)NR 9 -, -(CR 7 R 8 )-O-C(O)NR 9 -, -O-C(O)NR 9 -(CR 7 R 8 )-, -NR 9 -C(O)NR 9 -, or -0-C(O)NR 9 -.
  • L 1 and L 2 together form -(CH 2 )-NR 9 -C(O)NR 9 -. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L 1 and L 2 together form -(CH 2 )-NH-C(0)NH-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L 1 and L 2 together form -(CR 7 R 8 )-O-C(O)NR 9 -. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L 1 and L 2 together form -(CH 2 )-0-C(0)NH-.
  • L 1 and L 2 together form -O-C(O)NR 9 -(CR 7 R 8 )-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L 1 and L 2 together form -0-C(O)NH-(CH 2 )-.
  • L 1 and L 2 together form -NR 9 -C(O)NR 9 -, or -0-C(O)NR 9 -.
  • L 1 and L 2 together form -NH-C(O)NH-.
  • L 1 and L 2 together form -0-C(O)NH-.
  • L 1 and L 2 together form -(CR 7 R 8 ) m -NR 9 -(CR 7 R 8 ) n -.
  • compounds of Formula Ia or pharmaceutically acceptable salts thereof in some embodiments,
  • L 1 and L 2 together form -NR 9 -(CR 7 R 8 ) n -. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L 1 and L 2 together form -NR 9 -(CR 7 R 8 ) n -. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L 1 and L 2 together form -NR 9 -(CR 7 R 8 )-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L 1 and L 2 together form -NR 9 -(CR 7 R 8 ) 2 -. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L 1 and L 2 together form -NR 9 -(CR 7 R 8 ) 3 -.
  • L and L together form -(CR R ) m2 -NR -(CR R ) n -, wherein m2 is 1 or 2.
  • L 1 and L 2 together form -(CR 7 R 8 )- NR 9 -(CR 7 R 8 )-, -(CR 7 R 8 )-NR 9 -(CR 7 R 8 ) 2 -, or -(CR 7 R 8 ) 2 -NR 9 -(CR 7 R 8 ) 2 -.
  • L 1 and L 2 together form -(CR 7 R 8 )-NR 9 -(CR 7 R 8 )- or -(CR 7 R 8 )-NR 9 -(CR 7 R 8 ) 2 -.
  • R 9 is H or Ci_ 3 alkyl.
  • L and L together form -(CR R )-NR -(CR R )-.
  • L 1 and L 2 together form -(CH 2 )-NR 9 -(CH 2 )-.
  • L 1 and L 2 together form -NR 9 -(CR 7 R 8 ) t9 -O- wherein t9 is 1, 2, or 3.
  • L 1 and L 2 together form -NR 9 -(CR 7 R 8 )-O-.
  • L 1 and L 2 together form -NR 9 -(CR 7 R 8 ) 2 -O-.
  • L 1 and L 2 together form -NR 9 -(CR 7 R 8 ) 3 -O-.
  • L 1 and L 2 together form -NR 9 -(CH 2 )-O-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
  • L 1 and L 2 together form -NR 9 -(CH 2 ) 2 -O-.
  • L 1 and L 2 together form -NR 9 -(CH 2 ) 3 -O-.
  • one of L 1 and L 2 is selected from -(CR 7 R 8 ) m -NR 9 C(O)NR 9 -, -(CR 7 R 8 ) m -OC(O)NR 9 -, -(CR 7 R 8 ) m - NR 9 C(O)O-, and -(CR 7 R 8 ) m -NR 9 -S(O) 2 NR 9 -; and the other is selected from a bond, -(CR 7 R 8 ) n -, - (CR 7 R 8 ) m -NR 9 -, -(CR 7 R 8 ) m -O-, -(CR 7 R 8 ) m -S-, -(CR 7 R 8 ) m -S(O) 2 -, -(CR 7 R 8 ) m -C(O)-, -C(O)NR 9 -, - (CR 7 R 8 ) m -C(O)NR 9 -
  • one of L 1 and L 2 is selected from -(CR 7 R 8 ) m -NR 9 C(O)NR 9 -, -(CR 7 R 8 ) m -OC(O)NR 9 -, -(CR 7 R 8 ) m - NR 9 C(O)O-, and -(CR 7 R 8 ) m -NR 9 -S(O) 2 NR 9 -; and the other is selected from a bond, and -(CR 7 R 8 ) n .
  • L 1 and L 2 together form -(CR 7 R 8 ) m -NR 9 C(O)NR 9 -(CR 7 R 8 ) m -, -(CR 7 R 8 ) m -OC(O)NR 9 -(CR 7 R 8 ) m -, or - (CR 7 R 8 ) m -NR 9 -S(O) 2 NR 9 -(CR 7 R 8 ) m -.
  • L 1 and L 2 together form -(CR 7 R 8 ) m -NR 9 C(O)NR 9 -(CR 7 R 8 ) m -.
  • L 1 and L 2 together form -NR 9 C(O)NR 9 , -NR 9 C(O)NR 9 -(CR 7 R 8 ) m2 -, or -(CR 7 R 8 ) mr NR 9 C(O)NR 9 -(CR 7 R 8 ) m2 -, wherein ml and m2 are each, independently 1 or 2.
  • L 1 and L 2 together form -NR 9 C(O)NR 9 -.
  • L 1 and L 2 together form -NR 9 C(O)NR 9 -(CR 7 R 8 )-, -NR 9 C(O)NR 9 -(CR 7 R 8 ) 2 -, -(CR 7 R 8 )-NR 9 C(O)NR 9 - (CR 7 R 8 )-, -(CR 7 R 8 )-NR 9 C(O)NR 9 -(CR 7 R 8 ) 2 -, or -(CR 7 R 8 ) 2 -NR 9 C(O)NR 9 -(CR 7 R 8 ) 2 -.
  • L 1 and L 2 together form -(CH 2 ) m -NR 9 C(O)NR 9 -(CH 2 ) m -. In some further embodiments, L 1 and L 2 together form -NR 9 C(O)NR 9 , -NR 9 C(O)NR 9 -(CH 2 ) ⁇ , or -(CH 2 ) ml -NR 9 C(O)NR 9 -(CH 2 ) m2 - wherein ml and m2 are each, independently 1 or 2.
  • L 1 and L 2 together form -NR 9 C(O)NR 9 -(CH 2 )-, -NR 9 C(O)NR 9 -(CH 2 ) 2 -, -(CH 2 )-NR 9 C(O)NR 9 -(CH 2 )-, -(CH 2 )-NR 9 C(O)NR 9 -(CH 2 ) 2 -, or -(CH 2 ) 2 -NR 9 C(O)NR 9 -(CH 2 ) 2 -.
  • L 1 and L 2 together form -(CR 7 R 8 ) m -OC(O)NR 9 -(CR 7 R 8 ) m -.
  • L 1 and L 2 together form -OC(O)NR 9 -.
  • L 1 and L 2 together form -OC(O)NR 9 -(CR 7 R 8 )-, -OC(O)NR 9 -(CR 7 R 8 ) 2 -, -(CR 7 R 8 )-OC(O)NR 9 -, -(CR 7 R 8 ) 2 - OC(O)NR 9 -, -(CR 7 R 8 )-OC(O)NR 9 -(CR 7 R 8 )-, -(CR 7 R 8 )-OC(O)NR 9 -(CR 7 R 8 ) 2 -, -(CR 7 R 8 ) 2 -OC(O)NR 9 - (CR 7 R 8 )-, or -(CR 7 R 8 ) 2 -OC(O)NR 9 -(CR 7 R 8 ) 2 -.
  • L 1 and L 2 together form -OC(O)NR 9 -(CH 2 )-, -OC(O)NR 9 -(CH 2 ) 2 -, -(CH 2 )-OC(O)NR 9 -, -(CH 2 ) 2 -OC(O)NR 9 -, -(CH 2 )-OC(O)NR 9 -(CH 2 )-, -(CH 2 )-OC(O)NR 9 -(CH 2 ) 2 -, -(CH 2 ) 2 -OC(O)NR 9 -(CH 2 )-, or -(CH 2 ) 2 -OC(O)NR 9 -(CH 2 ) 2 -.
  • L 1 and L 2 together form -(CR 7 R 8 ) m -NR 9 S(O) 2 NR 9 -(CR 7 R 8 ) m -. In some further embodiments, L 1 and L 2 together form -NR 9 S(O) 2 NR 9 -, -NR 9 S(O) 2 NR 9 -(CR 7 R 8 ) m2 -, or -(CR 7 R 8 ) mr NR 9 S(O) 2 NR 9 -(CR 7 R 8 ) m2 -, wherein ml and m2 are each, independently 1 or 2. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
  • L 1 and L 2 together form -NR 9 S(O) 2 NR 9 .
  • L 1 and L 2 together form -NR 9 S(O) 2 NR 9 -(CR 7 R 8 )-, -NR 9 S(O) 2 NR 9 - (CR 7 R 8 ) 2 -, -(CR 7 R 8 )-NR 9 S(O) 2 NR 9 - (CR 7 R 8 )-, -(CR 7 R 8 )-NR 9 S(O) 2 NR 9 -(CR 7 R 8 ) 2 -, or -(CR 7 R 8 ) 2 -NR 9 S(O) 2 NR 9 -(CR 7 R 8 ) 2 -.
  • compounds of Formula Ia or pharmaceutically acceptable salts thereof In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
  • R 4 is H or Ci_ 6 alkyl. In some further embodiments, R 4 is H or Ci -3 alkyl. In yet further embodiments, R 4 is H or methyl. In still further embodiments, R 4 is H.
  • each R 5 is, independently, selected from H, halo, Ci -6 alkyl, Q -6 haloalkyl, CN, NO 2 , OR al , C(0)R bl , C(0)NR cl R dl , C(0)0R al , NR cl R dl , NR cl C(0)R bl , NR cl S(0) 2 NR cl R dl , S(O) 2 R bl , NR cl S(0) 2 R bl , and S(0) 2 NR cl R dl , wherein said Ci -6 alkyl, C 2 .
  • Ci -6 alkenyl, C 2 . 6 alkynyl, or Ci -6 haloalkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 _6 alkynyl, Ci_ 6 haloalkyl, halosulfanyl, CN, NO 2 , SF 5 , OR al , SR al , C(0)R bl , C(0)NR cl R dl , C(0)0R al , OC(O)R bl , OC(O)NR cl R dl , NR cl R dl , NR cl C(O)R bl , NR cl C(O)NR cl R dl , NR cl C(O)OR al , NR cl S(O) 2 NR cl R dl , S(O)
  • R al , R bl , R cl , and R dl are each, independently, selected from H, Ci -6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci -6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci -4 alkyl, Ci -4 haloalkyl, Ci -4 hydroxylalkyl, Ci
  • R cl and R dl are each, independently, selected from H, Ci -6 alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of said Ci -6 alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl is optionally substituted with with 1, 2, or 3 substituents independently selected from halo, Ci -4 alkyl, Ci -4 haloalkyl, Ci- 4 hydroxylalkyl, Ci -4 cyanoalkyl, aryl, heteroaryl, OH, O(Ci_ 4 alkyl), O(Ci_ 4 haloalkyl), piperidinyl, pyrrolidinyl, morpholinyl, and piperizinyl optionally substituted with Ci_ 4 alkyl, aryl, or arylalkyl; or R cl and R dl together with the N atom to which they are attached form pyrrolidinyl, pipe
  • each R 6 is, independently, H, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 haloalkyl, C(0)R bl , C(0)NR cl R dl , C(0)0R al , S(O)R bl , S(O) 2 R", or S(0) 2 NR cl R dl .
  • each R 6 is, independently, H, Ci_ 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, or Ci_ 6 haloalkyl.
  • each R 6 is, independently, H or Ci_ 6 alkyl. In some further embodiments, each R 6 is, independently, H or Ci -3 alkyl. In yet further embodiments, each R 6 is, independently, H or methyl. In still further embodiments, each R 6 is H. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
  • R 7 and R 8 are each, independently, selected from H, halo, Ci -6 alkyl, CN, NO 2 , OH, Ci -6 alkoxy, Ci -6 haloalkoxy, and C 2 . 8 alkoxyalkoxy. In some further embodiments, R 7 and R 8 are each, independently, selected from H, halo, Ci -4 alkyl, CN, NO 2 , Ci -4 alkoxy, Ci -4 haloalkoxy, and C 2 . 8 alkoxyalkoxy. In some further embodiments, R 7 and R 8 are each, independently, selected from H, halo, Ci -4 alkyl, OH, Ci -4 alkoxy, Ci -4 haloalkoxy, and C 2 .
  • R 7 and R 8 are each, independently, selected from H, OH, Ci -4 alkoxy, Ci -4 haloalkoxy, and C 2 . 8 alkoxyalkoxy. In some further embodiments, R 7 and R 8 are each, independently, selected from H, OH, and C 2 . 8 alkoxyalkoxy.
  • each R 10 is, independently, selected from H, halo, and Ci -6 alkyl. In some embodiments, each R 10 is, independently, selected from H and Ci -6 alkyl. In some embodiments, each R 10 is, independently, selected from H and Ci_ 4 alkyl. In some further embodiments, each R 10 is H.
  • the compounds of Formula Ia of the present invention have Formula Ia-I :
  • R 1 is H, halo, Ci -6 alkyl, Q -6 haloalkyl, NH 2 , NH(Ci -4 alkyl), N(Ci_ 4 alkyl) 2 , or CN;
  • R 3 is H, halo, Ci_ 6 alkyl, Ci_ 6 haloalkyl, NH 2 , NH(Ci_ 4 alkyl), N(Ci_ 4 alkyl) 2 , or CN; each R 5a is, independently, selected from H, halo, Q -6 alkyl, C 1-6 haloalkyl, CN, NO 2 , SF 5 , OR al , C(O)R bl , C(0)NR cl R dl , C(O)OR al , NR cl R dl , NR cl C(0)R bl , NR cl S(0) 2 NR cl R dl , S(O) 2 R bl , NR cl S(O) 2 R bl , and S(O) 2 NR cl R dl ; or two adjacent R 5a can link to form a fused cycloalkyl or fused heterocycloalkyl
  • Y is O, S, or NR 4 .
  • each R 5a is, independently, selected from H, halo, Q -6 alkyl, Q -6 haloalkyl, CN, NO 2 , SF 5 , OR al , C(0)R bl , C(0)NR cl R dl , C(0)0R al , NR cl R dl , NR cl C(0)R bl , NR cl S(0) 2 NR cl R dl , S(O) 2 R bl , NR cl S(0) 2 R bl , and S(O) 2 NR cl R dl ; and each R 5b is, independently, selected from H, halo, Ci -6 alkyl, Ci -6 haloalkyl, CN, NO 2 , SF 5 , OR al , C(O)R bl , C(0)NR cl R dl , C(
  • each R 5a is H.
  • one R 5a is other than H.
  • two R 5a are other than H. In some embodiments of the compounds of Formula Ia-I or pharmaceutically acceptable salts thereof, three R 5a are other than H.
  • At least one R 5a is other than H.
  • At least two R 5a are other than H.
  • each R 5b is H.
  • one R 5b is other than H. In some embodiments of the compounds of Formula Ia-I or pharmaceutically acceptable salts thereof, two R 5b are other than H.
  • three R 5b are other than H.
  • At least one R 5b is other than H.
  • At least two R 5b are other than H.
  • R 1 is H, halo, Q -6 alkyl, Q -6 haloalkyl, or CN; and R 3 is H, halo, Q -6 alkyl, Q -6 haloalkyl, or CN.
  • R 1 is H, halo, Q -6 alkyl, Q -6 haloalkyl, or CN.
  • R 1 is H, halo, Ci -3 alkyl, or Ci -3 haloalkyl
  • R 3 is H, halo, Ci -3 alkyl, or Ci -3 haloalkyl; each R is, independently selected from H, halo, Ci -6 alkyl, Ci -6 haloalkyl, CN, NO 2 , OR , C(O)R bl , C(O)NR cl R dl , C(O)OR al , NR cl R dl , NR cl S(O) 2 R bl , NR cl S(O) 2 NR cl R dl , S(O)R bl , S(O) 2 R bl , and
  • each R 5b is, independently selected from H, halo, Ci -6 alkyl, Ci -6 haloalkyl, CN, NO 2 , OR al , C(O)R bl , C(0)NR cl R dl , C(O)OR al , NR cl R dl , NR cl S(O) 2 R bl , NR cl S(O) 2 NR cl R dl , S(O)R bl , S(O) 2 R bl , and S(O) 2 NR cl R dl ;
  • Y is NH or N(Ci -3 alkyl); and X 2 is N.
  • the compounds of Formula Ia-I have Formula Ia-2:
  • the compounds of Formula Ia-2 have Formula Ia-2-a:
  • the compounds of Formula Ia-2 have Formula Ia-2-b:
  • the compounds of Formula Ia-2 have Formula Ia-2-c:
  • the compounds of Formula Ia-2 have Formula Ia-2-d:
  • substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • the term "Ci_ 6 alkyl” is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • each variable can be a different moiety selected from the Markush group defining the variable.
  • the two R groups can represent different moieties selected from the Markush group defined for R.
  • n-membered where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n.
  • pyridine is an example of a 6-membered heteroaryl ring
  • thiophene is an example of a 5-membered heteroaryl group.
  • alkyl is meant to refer to a saturated hydrocarbon group which is straight-chained or branched.
  • Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
  • alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
  • alkylene refers to a divalent alkyl linking group.
  • An example of alkylene is methylene (CH 2 ).
  • alkenyl refers to an alkyl group having one or more double carbon-carbon bonds.
  • Example alkenyl groups include, but are not limited to, ethenyl, propenyl, cyclohexenyl, and the like.
  • alkenylenyl refers to a divalent linking alkenyl group.
  • alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds.
  • Example alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.
  • alkynylenyl refers to a divalent linking alkynyl group.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include, but are not limited to, CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 , CH 2 CF 3 , and the like.
  • aryl refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms. In some embodiments, aryl groups have from 6 to about 10 carbon atoms.
  • cycloalkyl refers to non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups that contain up to 20 ring-forming carbon atoms.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spiro ring systems.
  • a cycloalkyl group can contain from 3 to about 15, from 3 to about 10, from 3 to about 8, from 3 to about 6, from 4 to about 6, from 3 to about 5, or from 5 to about 6 ring-forming carbon atoms.
  • Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido.
  • Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
  • cycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of pentane, pentene, hexane, and the like (e.g., 2,3-dihydro-lH-indene-l-yl, or IH- inden-2(3H)-one-l-yl).
  • heteroaryl groups refer to an aromatic heterocycle having up to 20 ring-forming atoms and having at least one heteroatom ring member (ring-forming atom) such as sulfur, oxygen, or nitrogen.
  • the heteroaryl group has at least one or more heteroatom ring-forming atoms each independently selected from sulfur, oxygen, and nitrogen.
  • Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems.
  • heteroaryl groups include without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1 ,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like.
  • the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 1 to about 5, from about 1 to about 4, from about 1 to about 3, from about 1 to about 2, carbon atoms as ring- forming atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.
  • heterocycloalkyl refers to non-aromatic heterocycles having up to 20 ring- forming atoms including cyclized alkyl, alkenyl, and alkynyl groups where one or more of the ring- forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom.
  • Hetercycloalkyl groups can be mono or polycyclic (e.g., both fused and spiro systems).
  • heterocycloalkyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-l,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, and the like.
  • a ring-forming S atom can be substituted by 1 or 2 oxo [i.e., form a S(O) or S(O) 2 ].
  • a ring-forming C atom can be substituted by oxo (i.e., form carbonyl).
  • some non-limiting examples of heterocylcoalkyl include 2-oxo-oxazolidin-yl and 2-oxo-oxazolyl.
  • heterocycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles such as indolene, isoindolene, isoindolin-l-one-3-yl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl, 5,6- dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, and 3,4-dihydroisoquinolin-l(2H)-one-3yl groups.
  • Ring- forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted by oxo or sulfido.
  • the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms.
  • the heterocycloalkyl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms.
  • the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.
  • the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.
  • halo or halogen includes fluoro, chloro, bromo, and iodo.
  • halosulfanyl refers to a sulfur group having one or more halogen substituents.
  • Example halosulfanyl groups include pentahalosulfanyl groups such as SF 5 .
  • alkoxy refers to an -O-alkyl group.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
  • haloalkoxy refers to an -O-haloalkyl group.
  • An example haloalkoxy group is OCF 3 .
  • cyanoalkyl refers to an alkyl group substituted by a cyano group (CN).
  • CN cyano group
  • One example of cyanoalkyl is -CH 2 -CN.
  • alkoxyalkoxy refers to an alkoxy group substituted by an alkoxy group.
  • alkoxyalkoxy is -OCH 2 CH 2 -OCH 3 .
  • arylalkyl refers to a Ci_ 6 alkyl substituted by aryl and "cycloalkylalkyl” refers to Ci- 6 alkyl substituted by cycloalkyl.
  • heteroarylalkyl refers to a Ci_ 6 alkyl group substituted by a heteroaryl group
  • heterocycloalkylalkyl refers to a Ci_ 6 alkyl substituted by heterocycloalkyl
  • amino refers to NH 2 .
  • alkylamino refers to an amino group substituted by an alkyl group.
  • dialkylamino refers to an amino group substituted by two alkyl groups.
  • hydroxylalkyl or “hydroxylalkyl” refers to an alkyl group substituted by a hydroxyl group.
  • An example is -CH 2 OH or - CH 2 CH 2 OH.
  • substitution means that substitution is optional and therefore includes both unsubstituted and substituted atoms and moieties.
  • a "substituted" atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced with a selection from the indicated substituent group, provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound. For example, if a methyl group (i.e., CH 3 ) is optionally substituted, then 3 hydrogen atoms on the carbon atom can be replaced with substituent groups.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. Where a compound capable of stereoisomerism or geometric isomerism is designated in its structure or name without reference to specific R/S or cis/trans configurations, it is intended that all such isomers are contemplated.
  • An example method includes fractional recrystallizaion using a chiral resolving acid which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ⁇ -camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of ⁇ -methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
  • an optically active resolving agent e.g., dinitrobenzoylphenylglycine
  • Suitable elution solvent composition can be determined by one skilled in the art.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, IH- and 3H-imidazole, IH-, 2H- and 4H- 1 ,2,4-triazole, IH- and 2H- isoindole, and IH- and 2H- pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the invention further include hydrates and solvates, as well as anhydrous and non- solvated forms.
  • compound as used herein is meant to include all stereoisomers, geometric iosomers, tautomers, and isotopes of the structures depicted.
  • All compounds and pharmaceuticaly acceptable salts thereof can be prepared or present together with other substances such as water and solvents (e.g. hydrates and solvates) or can be isolated.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
  • the compounds of the invention, or salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which is formed or detected.
  • Partial separation can include, for example, a composition enriched in the compound of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof.
  • Methods for isolating compounds and their salts are routine in the art.
  • Compounds of the invention are intended to include compounds with stable structures.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • ambient temperature and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 0 C to about 30 0 C.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (ACN) are preferred.
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (ACN) are preferred.
  • ACN acetonitrile
  • the present invention also includes quaternary ammonium salts of the compounds described herein, where the compounds are primary amines, secondary amines, or tertiary amines.
  • quaternary ammonium salts refers to derivatives of the disclosed primary amine, secondary amine, or tertiary amine compounds wherein the parent amine compounds are modified by converting the amines to quaternary ammonium cations via alkylation (and the cations are blanced by anions such as Cl " , CH 3 COO ' , or CF 3 COO ), for example methylation or ethylation.
  • the reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups.
  • protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety. Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
  • HPLC high performance liquid chromatography
  • TLC thin layer chromatography
  • the compounds of invention can be prepared according to the synthetic procedures described below in the Example section.
  • macrocycle 1-2 of the present invention can be synthesized by cyclizing precursor 1-1 [wherein Lg 1 is a leaving group such as halo (e.g., chloro)] under acidic condition, or basic condition, or in the presence of a transition metal catalysis [such as a Palladium catalyst (e.g., Pd(PPh 3 ) 4 ) or a Pd(II) catalyst] to afford the desired macrocycle 1-2.
  • a transition metal catalysis such as a Palladium catalyst (e.g., Pd(PPh 3 ) 4 ) or a Pd(II) catalyst
  • Precursors 1-1 [wherein Lg 1 is a leaving group such as halo (e.g., chloro)], 1-la [wherein Lg 1 is a leaving group such as halo (e.g., chloro)], 1-3 [wherein Lg 1 is a leaving group such as halo (e.g., chloro)], and l-3a [wherein Lg 1 is a leaving group such as halo (e.g., chloro)] can undergo similar transformations to afford products 1-2, 1-4, and 1-4 respectively.
  • Lg 1 is a leaving group such as halo (e.g., chloro)
  • 1-la wherein Lg 1 is a leaving group such as halo (e.g., chloro)
  • 1-3 wherein Lg 1 is a leaving group such as halo (e.g., chloro)
  • l-3a wherein Lg 1 is a leaving group such as halo (e.g., chloro)
  • the olefin moiety of compound 1-6 can be further reduced under suitable hydrogenation conditions [such as in the presence of a palladium catalyst (e.g., 5% Pd/C)] to afford macrocycle 1-7.
  • ruthenium such as the Grubbs catalysts or molybdenum catalysts, such as the Hoveyda catalysts
  • Acyclic precursors 1-1, 1-la, 1-3, and l-3a can be synthesized by a variety of appropriate ways that would be recognized by those skilled in organic synthesis.
  • compound 2-1 [wherein R 101 is H or an amine protecting group (such as tert-butyloxycarbonyl or BOC); Y is O, S, or NR 4 ] can be reacted with substituted heteroaromatic compound 2-2 [wherein Lg 1 and Lg 2 are each, independently, a leaving group such as halo (e.g., chloro)] in the presence of a suitable base (such as a inorganic base, for example a metal carbonate (e.g., potassium carbonate), a metal hydride (e.g., sodium hydride), a metal hydroxide (e.g., sodium hydroxide), a metal alkoxide (e.g., sodium ethoxide)] and/or in the presence of a transition metal catalyst for example a palladium catalyst [e.
  • R 101 is H or an amine protecting group protecting group
  • Precursors for the macrocycles of the present invention can be prepared by a variety of methods. For example, Mitsunobu coupling, thioether formation, amine alkylation, amide formation, sulfonamide formation, urea formation and carbamate formation can be utilized in synthesizing these compounds. Some non-limiting examples are depicted in the following schemes.
  • R 201 can be NO 2 or NHR 101 ;
  • R 101 can be H or Pg 4 ;
  • Pg 4 is an amine protecting group (such as tert-butyloxycarbonyl or BOC);
  • L la can be -(CR 7 R 8 ) m - (such as a bond or methylene) or L la is selected from -(CR 7 R 8 X 1 -, -(CR 7 R 8 ) mr NR 9 -, -(CR 7 R 8 ) mr O-,
  • Y 10 can be OH, SH, NHR 4 , or NO 2 , wherein the OH, SH, or NHR 4 can also be protected by an appropriate protecting group;
  • L 2a is selected from -(CR 7 R 8 ) n -, -(CR 7 R 8 ) mr NR 9 -, -(CR 7 R 8 ) mr O-, -(CR 7 R 8 ) ml -S-, -(CR 7 R 8 ) ml -S(O)-, -(CR 7 R 8 ) ml - S(O) 2 -, -(CR 7 R 8 ) ml -C(O)-, -(CR 7 R 8 ) ml -C
  • Compound 3-3 can undergo further chemical transformations if and when appropriate.
  • Y 10 of compound 3-3 when Y 10 of compound 3-3 is a protected OH group, it can be deprotected according to the protecting group.
  • Y 10 of compound 3-3 when Y 10 of compound 3-3 is NO 2 , it can be reduced to NH 2 under suitable conditions.
  • Compounds 3-4 and 3-5 [wherein Lg 3 is a leaving group such as halo (e.g., Br or Cl); R 201 , L la , and L 2a can be the same as those in compounds 3-1 and 3-2] can be reacted under basic conditions to afford compound 3-6.
  • compound 3-6 can be obtained by reacting compound 3-7 with compound 3-8 (wherein Lg 3 , R 201 , L la , and L 2a can be the same as those in compounds 3-4 and 3-5).
  • the NO 2 of compound 3-6 can be reduced to NH 2 under suitable conditions.
  • R 201 is NO 2 Or NHR 101 ;
  • R 101 is H or Pg 4 ; and Pg 4 is an amine protecting group (such as tert-butyloxycarbonyl or BOC)
  • Useful intermediates 3-3a and 3-6a can be made according to the methods as shown in Scheme 3a- 1 (similar to the reactions depicted in Scheme 3a, and wherein R 301 can be NO 2 or NHR 101 ; R 101 , R 201 , L la , and L 2a can be the same as those in Scheme 3a).
  • the protecting group Pg 4 of compound 3-3a and 3- 6a, when present, can be removed under suitable conditions.
  • Compounds 3-3a and 3-6a can undergo further chemical transformations when suitable reactive groups are present. For example, the NO 2 of compound 3-3a and 3-6a can be reduced to NH 2 under suitable conditions.
  • R 201 is NO 2 or NH R 101 ;
  • compounds 3-9a and 3-9b [wherein R 201 , L la , and L 2a can be the same as those in compounds 3-4 and 3-5] can be reacted under appropriate conditions to afford compound 3-10.
  • R 102 is Lg 3 (a leaving group)
  • amine alkylation can be carried out under basic conditions.
  • reductive animations can be carried out.
  • compound 3-llc can be obtained by reacting compound 3-lla with compound 3- 11b [wherein L la and L 2a can be the same as those in compounds 3-4 and 3-5] under suitable conditions.
  • the protecting group Pg 4 of compound 3-10 or 3-llc can be removed under suitable conditions.
  • Compounds 3-10 and 3-llc can undergo further chemical transformations when suitable reactive groups are present. For example, when Y 10 is NO 2 , it can be reduced to NH 2 under suitable conditions.
  • R 201 is NO 2 or NHR 101 ;
  • R 101 is H or Pg 4 ; each Pg 4 is independenly an amine protecting group (such as tert-butyloxycarbonyl or BOC) ;
  • Lg 3 is a leaving group such as halo (e.g., Br or Cl);
  • L 1 b is L 1a or L 1a -CH 2 .
  • L 2b is L 2a or L 2a -CH 2 .
  • Useful intermediates 3-10-1 and 3-llc-l can be made according to the methods outlined in Scheme 3b-l (similar to the reactions depicted in Scheme 3b, and wherein L la and L 2a can be the same as those in Scheme 3a).
  • the protecting group Pg 4 of compound 3-10-1 and 3-llc-l can be removed under suitable conditions.
  • Compounds 3-10-1 and 3-llc-l can undergo further chemical transformations when suitable reactive groups are present. For example, the NO 2 of compound 3-10-1 and 3-llc-l can be reduced to NH 2 under suitable conditions.
  • each Pg 4 is independently an amine protecting group (such as tert-butyloxycarbonyl or BOC) ;
  • Lg 3 is a leaving group such as halo (e.g., Br or Cl);
  • L 1b is L 1 a or L i3 -CH 2 .
  • L 2b is L 23 or L ⁇ -CH 2 .
  • amide compounds 3-12c, 3-13c, 3-14c, and 3-15c [wherein Pg 4 , Y 1 , L la , and L 2a can be the same as those in Scheme 3a] can be obtained from an appropriate acid such as acid 3- 12a, 3-13b, 3-14b, or 3-15a and an appropriate amine such as amine 3-12b, 3-13a, 3-14a, or 3-15b by standard coupling reactions [such as in the presence of an amide coupling reagent such as benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 2-(lH-benzotriazol-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazoll-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate
  • the acid 3- 12a, 3-13b, 3-14b, or 3- 15a can be converted to a more reactivate species such as an acid halide (e.g., acid chloride) or a mixed anhydride, and the more reactive species can be reacted with the appropriate amine 3-12b, 3-13a, 3-14a, or 3-15b respectively.
  • the protecting group Pg 4 of compound 3-12c, 3-13c, 3-14c, or 3-15c can be removed under suitable conditions.
  • Compounds 3-12c, 3-13c, 3-14c, and 3-15c can undergo further transformation when suitable reactive groups are present. For example, when Y 10 is NO 2 , it can be reduced to NH 2 under suitable conditions.
  • R 201 a is NO 2 or N HPg 4 ;
  • Pg 4 is an amine protecting group (such as tert-butyloxycarbonyl or BOC).
  • R 201 a is NO 2 or NHPg 4 ;
  • R 301 a is NO 2 or NHPg 4 ;
  • each Pg 4 is independently an amine protecting group (such as tert-butyloxycarbonyl or BOC).
  • sulfonamide compounds 3-17 and 3-19 [wherein Pg 4 , Y 1 , L la , and L 2a can be the same as those in Scheme 3a] can be obtained by reacting an appropriate sulfonyl halide (such as chloride) with an appropriate amine.
  • the protecting group Pg 4 of compounds 3-17 or 3-19 can be removed under suitable conditions.
  • Compounds 3-17 and 3-19 can undergo further chemical transformations when suitable reactive groups are present. For example, when Y 10 is NO 2 , it can be reduced to NH 2 under suitable conditions.
  • R 201a is NO 2 or NH Pg 4 ;
  • Pg 4 is an amine protecting group (such as tert-butyloxycarbonyl or BOC).
  • Useful intermediates 3-17-1 and 3-19-1 [wherein Pg 4 , Y 10 , L la , and L 2a can be the same as those in Scheme 3a] can be made according to the methods outlined in Scheme 3d-l (similar to the reactions depicted in Scheme 3d).
  • the protecting group Pg 4 of compounds 3-17-1 and 3-19-1 can be removed under suitable conditions.
  • Compounds 3-17-1 and 3-19-1 can undergo further chemical transformations when suitable reactive groups are present. For example, the NO 2 of compounds 3-17-1 and 3-19-1 can be reduced to NH 2 under suitable conditions.
  • R 201 a is NO 2 or NHPg 4 ;
  • R 30i a is N o 2 or NHPg 4 ;
  • each Pg 4 is independently an amine protecting group (such as tert-butyloxycarbonyl or BOC).
  • a phosgene equivalent e.g., triphosgene, ethyl chloroformate, trichloromethyl chloroformate, or phenyl chlorocarbonate
  • carbamates 3-23 and 3-25 can be made by reacting an appropriate amine and an appropriate alcohol with phosgene or its equivalent.
  • Sulfamide 3-25c can be made by reacting amines 3-25a and 3-25b with SO 2 Cl 2 or its equivalent (such as other thionyl halides, e.g., SO 2 Br 2 ).
  • the protecting group Pg 4 of compounds 3-21, 3-23, or 3-25 can be removed under suitable conditions.
  • Compounds 3-21, 3-23, and 3-25 can undergo further chemical transformations when suitable reactive groups are present. For example, when Y 1 (and/or R 201a ) is NO 2 , it can be reduced to NH 2 under suitable conditions.
  • R 201a is NO 2 or NHPg 4 ;
  • Pg is an amine protecting group (such as tert-butyloxycarbonyl or BOC).
  • R 201a is NO 2 or NHPg 4 ;
  • R 30ia is N o 2 or NHPg 4 ;
  • Scheme 3f A more detailed scheme (similar to Scheme 3d-l) is provided in Scheme 3f.
  • Sulfonamide 3-27 [wherein L la , and L 2a can be the same as those in Scheme 3a] can be obtained by reacting sulfonyl halide 3-26a (such as chloride) with amine 3-26b.
  • the NO 2 of compound 3-27 can be reduced to NH 2 , for example in the presence of Fe/CH 3 C00H, to afford compound 3-27a.
  • the Boc group of compound 3-27 can be removed, for example, in the presence of HCl, to afford compound 3-27b.
  • macrocycle 4-2 [wherein L la and L 2a can be the same as those in Scheme 3a] can be cyclized from acyclic precursor 4-1 by intramolecular Mitsunobu reaction/coupling.
  • one of L la and L 2a of acyclic precursor 4-1 is a bond in the intramolecular Mitsunobu reactions/couplings.
  • Lg 3 is a leaving group such as halo (e.g., Br or Cl);
  • L 1b is L 1a or L 1a -CH 2 .
  • Useful intermediates 7-4, 7-10, and 7-13 can be made according to the methods outlined in Scheme 7.
  • Aryl halide or heteroaryl halide 7-1 can be reacted with alkyne 7-2 under Sonogashira coupling reaction conditions to afford alkyne 7-3.
  • Sonogashira Y. Tohda, N. Hagihara (1975).
  • a convenient synthesis of acetylenes catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines.
  • Tetrahedron Letters 16 (50): 4467-4470. Tetrahedron Letters 16 (50): 4467-4470.
  • alkyne 7-3 can be protected with a protecting group Pg 4 , followed by the C ⁇ C bond being reduced to a saturated bond by hydrogenation to afford intermediate 7-4.
  • Aryl halide or heteroaryl halide 7-5 can be reacted with silyl substituted acetylene 7-6 [e.g. (trimethylsilyl) -acetylene] under Sonogashira coupling reaction conditions, followed by removal of the silyl group under suitable conditions [e.g., in the presence of a base (e.g., K 2 CO 3 )] to afford alkyne 7-7.
  • a base e.g., K 2 CO 3
  • Alkyne 7-7 can be reacted with aryl halide or heteroaryl halide 7-8 under Sonogashira coupling reaction condition to afford alkyne 7-9.
  • Alkyne 7-9 can be reduced via hydrogenation to produce intermediate 7- 10.
  • Aryl halide or heteroaryl halide 7-11 can be reacted with alkyne 7-12 under Sonogashira coupling reaction conditions, followed by hydrogenation to reduce the C ⁇ C bond, to afford alkyne 7-13.
  • Useful intermediates 7-4a, 7-1Oa, and 7-13a can be made according to the methods outlined in Scheme 7-1 (similar to the reactions depicted in Scheme 7).
  • Useful intermediates 7-4b, 7-1Ob, and 7-13b can be made according to the methods outlined in Scheme 7-2.
  • Aryl halide/triflate or heteroaryl halide/triflate 7-5b can be reacted with vinylboronate 7-6b (R groups can be each, independently, H (e.g., compound 7-6b is a vinylboronic acid when both R are H) or alklyl; or together with the -0-B-O- to which they are attached form an optionally substituted heterocycloalkyl) under Suzuki-Miyaura reaction condition/Suzuki coupling to form alkene 7-2b [for reviews of the Suzuki-Miyaura reaction, see e.g. Miyaura, N; Suzuki, A.
  • a vinyl stannane (such as tributyl(vinyl)stannane, equivalent to vinylboronate 7-6b in the Suzuki-Miyaura reaction described herein) can be used to react with aryl halide or heteroaryl halide 7-5b to form alkene 7-2b under Stille reaction conditions [See e.g. P. Espinet, A. M. Echavarren "The Mechanisms of the Stille Reaction"; Angewandte Chemie International Edition; 43 (36): 4704-4734
  • Aryl halide/triflate or heteroaryl halide/triflate 7-lb can be reacted with alkene 7- 2b under Heck coupling reaction conditions to afford alkene 7-3b.
  • Heck R. F.; Nolley, Jr., J. P., "Palladium- catalyzed vinylic hydrogen substitution reactions with aryl, benzyl, and styryl halides"; J. Org. Chem., 37(14): 2320-2322 (1972)].
  • an amine protecting group such as Boc group
  • Intermediate 7-1Ob can be synthesized starting from aryl halide/triflate or heteroaryl halide/triflate 7-lb (also substituted with a nitro group) through similar chemical transformations to those described in the formation of intermediate 7-4b.
  • R groups can be each, independently, H halo or OTf (i.e., compound 7-6c is a vinylboronic acid when both R are H) or alklyl; or together with the -0-B-O- to which they are attached form an optionally substituted heterocycloalkyl
  • L x is a leaving group such as
  • aryl (or heteroaryl) methyl ketone 8-1 can be reacted with aryl (or heteroaryl) aldehyde 8-2 under basic conditions [(such as in the presence of an alkali metal hydroxide (e.g. NaOH)] to afford derivative 8-3.
  • Intermediate 8-3 can be reduced via hydrogenation (such as in the presence of Pd/C, hydrogen and acetic acid) to afford compound 8-4, which further can be reduced to compound 8-5.
  • R 201a and R 301a groups of compounds 8-4 or 8-5 can undergo further chemical transformations.
  • the NO 2 group can be reduced to NH 2 ; and a protected amino group can be de-protected to NH 2 .
  • R 2013 is NO 2 or NHPg 4 ;
  • R 3013 is NO 2 or NHPg 4 ; each Pg 4 is independently an amine protecting group (such as tert-butyloxycarbonyl or BOC).
  • Useful intermediates 8-3a, 8-4a, and 8-5a can be made according to the methods outlined in Scheme 8-1 (similar to the reactions depicted in Scheme 8).
  • R 201 a is N0 2 or NHPg 4 ;
  • R 301 a is N0 2 or NHPg 4 ;
  • each Pg 4 is independently an amine protecting group (such as tert-butyloxycarbonyl or BOC).
  • Aryl (or heteroaryl) compound 9-1 can be reacted with a halogenating reagent [such as bromine (Br 2 ), N- bromoacetamide (NBA), N-bromosuccinimide ( ⁇ BS), l,3-dibromo-5,5- dimethylhydantoin (DBDMH), l,3-dichloro-5,5-dimethylhydantoin (DCDMH), N-chlorosuccinimide (NCS)] to afford halogenated compounds 9-2.
  • a halogenating reagent such as bromine (Br 2 ), N- bromoacetamide (NBA), N-bromosuccinimide ( ⁇ BS), l,3-dibromo-5,5- dimethylhydantoin (DBDMH), l,3-dichloro-5,5-dimethylhydantoin (DCDMH), N-chlorosuccinimide (NCS)
  • a fluorinated compound 9-3 can be reacted with an amine, an alcohol, or thioalcohol in the presence of a base (such as a tertiary amine, e.g., TEA) to form compound 9-4.
  • a base such as a tertiary amine, e.g., TEA
  • compound 9-4 can be oxidized to sulfinyl or sulfonyl compounds 9-5 (wherein y is 1 or 2), using an oxidizing reagent such as ra-chloroperoxybenzoic acid (raCPBA).
  • a fluorinated compound 9-6 can be reacted with an amine, an alcohol, or thioalcohol in the presence of a base (such as a tertiary amine, e.g., triethylamine or TEA) to form compound 9-7.
  • a base such as a tertiary amine, e.g., triethylamine or TEA
  • compound 9-7 can be oxidized to sulfinyl or sulfonyl compound 9-8 (wherein y is 1 or 2), using an oxidizing reagent such as ra-chloroperoxybenzoic acid (raCPBA).
  • raCPBA ra-chloroperoxybenzoic acid
  • the nitro (NO 2 ) group of compound 9-8 can be reduced, for example, in the presence of Fe (or Zn) and acetic acid, followed by introduction of an amine protecting group (such as Boc), to afford compound 9-9.

Abstract

The present invention relates to macrocyclic compounds of Formula I: or pharmaceutically acceptable salts thereof or quaternary ammonium salts thereof wherein constituent members are provided hereinwith, as well as their compositions and methods of use, which are JAK/ ALK inhibitors useful in the treatment of JAK/ALK-associated diseases including, for example, inflammatory and autoimmune disorders, as well as cancer.

Description

MACROCYCLIC COMPOUNDS AND THEIR USE AS KINASE INHIBITORS
This application claims benefit of priority to US provisional patent application serial no. 61/047,547 filed April 24, 2008, and to US provisional patent application serial no. 61/122,582 filed on December 15, 2008, each of which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to macrocyclic compounds, and compositions thereof as well as methods of use the same for treatment of Janus Kinase and/or Anaplastic Lymphoma Kinase (J AK/ ALK)- associated diseases including, for example, inflammatory disorders, autoimmune disorders, skin disorders, myeloid proliferative disorders, as well as cancer.
BACKGROUND OF THE INVENTION
Protein kinases (PKs) are a group of enzymes that regulate diverse, important biological processes including cell growth, survival and differentiation, organ formation and morphogenesis, neovascularization, tissue repair and regeneration, among others. Protein kinases exert their physiological functions through catalyzing the phosphorylation of proteins (or other substrates such as lipids) and thereby modulating the cellular activities of the substrates in various biological contexts. In addition to the functions in normal tissues/organs, many protein kinases also play a central role in a host of human diseases including cancer. A subset of protein kinases (also referred to as oncogenic protein kinases), when dysregulated, can cause tumor formation and inappropriate tumor cell survival and proliferation, and further contribute to tumor progression [See e.g. Blume -Jensen P. et al, Nature 2001, 411(6835):355- 365]. Thus far, oncogenic protein kinases represent one of the largest and most attractive groups of protein targets for cancer intervention and drug development.
Protein kinases can be categorized as receptor type and non-receptor type. Receptor tyrosine kinases (RTKs) have an extracellular portion, a transmembrane domain, and an intracellular portion, while non-receptor tyrosine kinases are entirely intracellular. RTK mediated signal transduction is typically initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, stimulation of the intrinsic protein tyrosine kinase activity, and receptor transphosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate cellular responses such as cell survival, proliferation, differentiation, metabolic effects, and changes in the extracellular microenvironment.
At present, at least nineteen (19) distinct RTK subfamilies have been identified. One RTK subfamily, designated the HER subfamily, includes EGFR, HER2, HER3 and HER4, and bind such ligands as epithelial growth factor (EGF), TGF-OC, amphiregulin, HB-EGF, betacellulin and heregulin. A second family of RTKs, designated the insulin subfamily, includes the INS-R, the IGF-IR and the IR-R. A third family, the "PDGF" subfamily, includes the PDGF alpha and beta receptors, CSFIR, c-kit and FLK-II. Another subfamily of RTKs, referred to as the FLK subfamily, encompasses the Kinase insert Domain-Receptor fetal liver kinase-1 (KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fms-like tyrosine kinase 1 (flt-1). Two other subfamilies of RTKs have been designated as the FGF receptor family (FGFRl, FGFR2, FGFR3 and FGFR4) and the Met subfamily (c-Met, Ron and Sea). For a detailed discussion of protein kinases, see for example, Blume-Jensen, P. et al., Nature. 2001, 411(6835):355-365, and Manning, G. et al., Science. 2002, 298(5600): 1912-1934.
The non-receptor type of tyrosine kinases are also composed of numerous sub-families, including Src, Btk, AbI, Fak, and Jak. Each of these subfamilies can be further subdivided into multiple members that have been frequently linked to oncogenesis. The Src family, for example, is the largest and includes Src, Fyn, Lck and Fgr among others. For a detailed discussion of these kinases, see Bolen JB, "Nonreceptor tyrosine protein kinases," Oncogene., 1993, 8(8):2025-31.
A significant number of tyrosine kinases (both receptor and nonreceptor) are associated with cancer (see Madhusudan S, Ganesan TS. Tyrosine kinase inhibitors in cancer therapy. Clin Biochem. 2004, 37(7):618-35.). Clinical studies suggest that overexpression or dysregulation of tyrosine kinases may also be of prognostic value. For example, members of the HER family of RTKs have been associated with poor prognosis in breast, colorectal, head and neck and lung cancer. Mutation of c-Kit tyrosine kinase has been associated with decreased survival in gastrointestinal stromal tumors. In acute myelogenous leukemia (AML), Flt-3 mutation predicts shorter disease free survival. VEGFR expression, which is important for tumor angiogenesis, is associated with a lower survival rate in lung cancer. Tie-1 kinase expression inversely correlates with survival in gastric cancer. BCR-AbI expression is an important predictor of response in chronic myelogenous leukemia (CML) and Src tyrosine kinase is an indicator of poor prognosis in all stages of colorectal cancer. The immune system responds to injury and threats from pathogens. Cytokines are low-molecular weight polypeptides or glycoproteins that stimulate biological responses in virtually all cell types. For example, cytokines regulate many of the pathways involved in the host inflammatory response to sepsis. Cytokines influence cell differentiation, proliferation and activation, and they can modulate both proinflammatory and anti-inflammatory responses to allow the host to react appropriately to pathogens. Binding of a cytokine to its cell surface receptor initiates intracellular signaling cascades that transduce the extracellular signal to the nucleus, ultimately leading to changes in gene expression. The pathway involving the Janus kinase family of protein tyrosine kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs) is engaged in the signaling of a wide range of cytokines. Generally, cytokine receptors do not have intrinsic tyrosine kinase activity, and thus require receptor-associated kinases to propagate a phosphorylation cascade. JAKs fulfill this function. Cytokines bind to their receptors, causing receptor dimerization, and this enables JAKs to phosphorylate each other as well as specific tyrosine motifs within the cytokine receptors. STATs, and other proteins, recognize these phosphotyrosine motifs and are recruited to the receptor where they are activated by a JAK-dependent tyrosine phosphorylation events. Upon activation, STATs dissociate from the receptors and translocate to the nucleus to bind to specific DNA sites and alter transcription [Scott, M. J., C. J. Godshall, et al. (2002). "Jaks, STATs, Cytokines, and Sepsis." CHn Diagn Lab Immunol 9(6): 1153-9].
The Janus Kinase (JAK) family plays a role in the cytokine-dependent regulation of proliferation and function of cells involved in immune response. Currently, there are four known mammalian JAK family members: JAKl (also known as Janus kinase-1), JAK2 (also known as Janus kinase-2), JAK3 (also known as Janus kinase, leukocyte; JAKL; L-JAK and Janus kinase-3) and TYK2 (also known as protein-tyrosine kinase 2). The JAK proteins range in size from 120 to 140 kDa and comprise seven conserved JAK homology (JH) domains; one of these is a functional catalytic kinase domain, and another is a pseudokinase domain potentially serving a regulatory function and/or serving as a docking site for STATs (Scott, Godshall et al. 2002, supra).
While JAKl, JAK2 and TYK2 are widely expressed, JAK3 is reported to be preferentially expressed in natural killer (NK) cells and activated T cells, suggesting a role in lymphoid activation (Kawamura, M., D. W. McVicar, et al. (1994). "Molecular cloning of L-JAK, a Janus family protein- tyrosine kinase expressed in natural killer cells and activated leukocytes." Proc Natl Acad Sci U S A 91(14): 6374-8).
Not only do the cytokine-stimulated immune and inflammatory responses contribute to normal host defense, they also play roles in the pathogenesis of diseases. Pathologies such as severe combined immunodeficiency (SCID) can arise from hypoactivity, e.g. the inability of various cytokines to signal through JAK3 (Macchi, et al. Nature, 337:65-68, 1995). In contrast, hyperactive or inappropriate immune / inflammatory responses can contribute to the pathology of autoimmune diseases such as rheumatoid and psoriatic arthritis, asthma and systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, type I diabetes mellitus, myasthenia gravis, thyroiditis, immunoglobulin nephropathies, myocarditis as well as illnesses such as scleroderma and osteoarthritis (Ortmann, R. A., T. Cheng, et al. (2000). "Janus kinases and signal transducers and activators of transcription: their roles in cytokine signaling, development and immunoregulation." Arthritis Res 2(1): 16-32). Furthermore, syndromes with a mixed presentation of autoimmune and immunodeficiency disease are quite common (Candotti, F., L. Notarangelo, et al. (2002). "Molecular aspects of primary immunodeficiencies: lessons from cytokine and other signaling pathways." / Clin Invest 109(10): 1261-9). Thus, therapeutic agents are typically aimed at augmentation or suppression of the immune and inflammatory pathways, accordingly.
Deficiencies in expression of various JAK family members have been associated with pathologies in rodents. Jakl-/- mice are runted at birth, fail to nurse, and die perinatally (Rodig, S. J., M. A. Meraz, et al. (1998). "Disruption of the Jakl gene demonstrates obligatory and non-redundant roles of the Jaks in cytokine -induced biologic responses." Cell 93(3): 373-83). Jak27- mouse embryos are anemic and die around day 12.5 postcoitum due to the absence of definitive erythropoiesis. In addition, JAK2 deficiency resulted in cell-type specific deficiencies in the signaling of some cytokines such as those required for definitive erythropoiesis (Neubauer, H., A. Cumano, et al. (1998). Cell 93(3): 397-409; Parganas, E., D. Wang, et al. (1998). Cell 93(3): 385-95.). JAK3 appears to play a role in normal development and function of B and T lymphocytes. Mutations of JAK3 are reported to be responsible for autosomal recessive severe combined immunodeficiency (SCID) in humans (Candotti, F., S. A. Oakes, et al. (1997). "Structural and functional basis for J AK3 -deficient severe combined immunodeficiency." Blood 90(10): 3996-4003).
The JAK/STAT pathway, and in particular all four members of the JAK family, are believed to play a role in the pathogenesis of the asthmatic response, chronic obstructive pulmonary disease, bronchitis other related inflammatory diseases of the lower respiratory tract, inflammatory diseases or conditions of the upper respiratory tract such as those affecting the nose and sinuses (e.g. rhinitis, sinusitis) whether classically allergic reactions or not, Systemic Inflammatory Response Syndrome (SIRS), and septic shock. See e.g., Pernis, A. B. and P. B. Rothman, "JAK-STAT signaling in asthma," J Clin Invest 109(10): 1279-83 (2002); and Seto, Y., H. Nakajima, et al,. "Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice." J Immunol 170(2): 1077-83 (2003).
The JAK/STAT pathway has also been implicated to play a role in inflammatory diseases/conditions of the eye including, but not limited to, dry eye disorder, iritis, uveitis, scleritis, conjunctivitis, as well as chronic allergic responses. Therefore, inhibition of JAK kinases may have a beneficial role in the therapeutic treatment of these diseases. As used herein, "dry eye disorder" is intended to encompass the disease states summarized in a recent official report of the Dry Eye Workshop (DEWS), which defined dry eye as "a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface." Lemp, "The Definition and Classification of Dry Eye Disease: Report of the Definition and Classification Subcommittee of the International Dry Eye Workshop", The Ocular Surface, 5(2), 75-92 April 2007, which is incorporated herein by reference in its entirety. Dry eye is also sometimes referred to as keratoconjunctivitis sicca. In some embodiments, the treatment of the dry eye disorder involves ameliorating a particular symptom of dry eye disorder, such as eye discomfort, visual disturbance, tear film instability, tear hyperosmolarity, and inflammation of the ocular surface.
The JAK/STAT pathway also plays a role in cancers of the immune system. In adult T cell leukemia/lymphoma (ATLL), human CD4+ T cells acquire a transformed phenotype, an event that correlates with acquisition of constitutive phosphorylation of JAKs and STATs. Furthermore, an association between JAK3 and STAT-I, STAT-3, and STAT-5 activation and cell-cycle progression was demonstrated by both propidium iodide staining and bromodeoxyuridine incorporation in cells of four ATLL patients tested. These results imply that JAK/STAT activation is associated with expansion of leukemic cells and that therapeutic approaches aimed at JAK/STAT inhibition may be considered to halt neoplastic growth (Takemoto, S., J. C. Mulloy, et al. (1997). "Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins." Proc Natl Acad Sci U S A 94(25): 13897-902).
Blocking cytokine and growth factor signal transduction at the level of the JAK kinases holds promise for the treatment of a number of human cancers. For example, cytokines of the interleukin 6 (IL- 6) family, which activate the signal transducer gpl30, are major survival and growth factors for human multiple myeloma (MM) cells. The signal transduction of gpl30 is believed to involve JAKl, JAK2 and Tyk2 and the downstream effectors STAT3 and the mitogen-activated protein kinase (MAPK) and AKT pathways. In IL-6-dependent MM cell lines treated with the JAK2 inhibitor pyridone 6 STAT3 phosphorylation and tumor cell proliferation and survival were inhibited (Pedranzini, L, et al, Cancer Research 66:9714-21, 2006. Activation of JAK/STAT in cancers may occur by multiple mechanisms including cytokine stimulation (e.g. IL-6 or GM-CSF) or by a reduction in the endogenous suppressors of JAK signaling such as SOCS (suppressor of cytokine signaling) or PIAS (protein inhibitor of activated STAT) (Boudny, V., and Kovarik, J., Neoplasm. 49:349-355, 2002). Importantly, activation of STAT signaling, as well as other pathways downstream of JAKs (e.g. Akt), has been correlated with poor prognosis in many cancer types (Bowman, T., et al. Oncogene 19:2474-2488, 2000). Moreover, elevated levels of circulating cytokines that signal through JAK/STAT may adversely impact patient health as they are thought to play a causal role in cachexia and/or chronic fatigue. As such, JAK inhibition may be therapeutic for the treatment of cancer patients for reasons that extend beyond potential anti-tumor activity. The cachexia indication may gain further mechanistic support with the realization that the satiety factor leptin signals through JAKs.
Pharmacological targeting of Janus kinase 3 (JAK3) has been employed successfully to control allograft rejection and graft versus host disease (GVHD). In addition to its involvement in signaling of cytokine receptors, JAK3 is also engaged in the CD40 signaling pathway of peripheral blood monocytes. During CD40-induced maturation of myeloid dendritic cells (DCs), JAK3 activity is induced, and increases in costimulatory molecule expression, IL- 12 production, and potent allogeneic stimulatory capacity are observed. A rationally designed JAK3 inhibitor WHI-P- 154 prevented these effects arresting the DCs at an immature level, suggesting that immunosuppressive therapies targeting the tyrosine kinase JAK3 may also affect the function of myeloid cells (Saemann, M. D., C. Diakos, et al. (2003).
"Prevention of CD40-triggered dendritic cell maturation and induction of T-cell hyporeactivity by targeting of Janus kinase 3." Am J Transplant 3(11): 1341-9). In the mouse model system, JAK3 was also shown to be an important molecular target for treatment of autoimmune insulin-dependent (type 1) diabetes mellitus. The rationally designed JAK3 inhibitor JANEX-I exhibited potent immunomodulatory activity and delayed the onset of diabetes in the NOD mouse model of autoimmune type 1 diabetes (Cetkovic-Cvrlje, M., A. L. Dragt, et al. (2003). "Targeting JAK3 with JANEX-I for prevention of autoimmune type 1 diabetes in NOD mice." CHn Immunol 106(3): 213-25).
It has been suggested that inhibition of JAK2 tyrosine kinase can be beneficial for patients with myeloproliferative disorders. (Levin, et al., Cancer Cell, vol. 7, 2005: 387-397) Myeloproliferative disorders (MPD) include polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis with myeloid metaplasia (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD) and the like. Although myeloproliferative disorders (such as PV, ET and MMM) are thought to be caused by acquired somatic mutation in hematopoietic progenitors, the genetic basis for these diseases has not been known. However, it has been reported that hematopoietic cells from a majority of patients with PV and a significant number of patients with ET and MMM possess a recurrent somatic activating mutation in the JAK2 tyrosine kinase. It has also been reported that inhibition of the JAK2V617F kinase with a small molecule inhibitor leads to inhibition of proliferation of hematopoietic cells, suggesting that the JAK2 tyrosine kinase is a potential target for pharmacologic inhibition in patients with PV, ET and MMM. In addition, mutations in the receptor for thrombopoietin have also been described in MPD patients and due to the requirement of JAK2 for this receptor to signal, inhibition of JAKs may be therapeutic (Tefferi, A. Leukemia & Lymphoma, March 2008; 49(3): 388 - 397).
Inhibition of the JAK kinases is also envisioned to have therapeutic benefits in patients suffering from skin immune disorders such as psoriasis, and skin sensitization. In psoriasis vulgaris, the most common form of psoriasis, it has been generally accepted that activated T lymphocytes are important for the maintenance of the disease and its associated psoriatic plaques (Gottlieb, A.B., et al, Nat Rev Drug Disc, 4:19-34). Psoriatic plaques contain a significant immune infiltrate, including leukocytes and monocytes, as well as multiple epidermal layers with increased keratinocyte proliferation. While the initial activation of immune cells in psoriasis occurs by an ill defined mechanism, the maintenance is believed to be dependent on a number of inflammatory cytokines, in addition to various chemokines and growth factors (JCI, 113:1664-1675). Many of these, including interleukins -2, -4, -6, -7, -12, -15, -18, and -23 as well as GM-CSF and IFNg, signal through the Janus (JAK) kinases (Adv Pharmacol. 2000;47: 113-74). As such, blocking signal transduction at the level of JAK kinases may result in therapeutic benefits in patients suffering from psoriasis or other immune disorders of the skin (Kimbal, A.B., et al. Arch Dermatol. 2008 Feb; 144(2): 200-7).
It has been known that certain therapeutics can cause immune reactions such as skin rash or diarrhea in some patients. For instance, administration of some of the new targeted anti-cancer agents such as Iressa, Erbitux, and Tarceva has induced acneiform rash with some patients. Another example is that some therapeutics used topically induce skin irritation, skin rash, contact dermatitis or allergic contact sensitization. For some patients, these immune reactions may be bothersome, but for others, the immune reactions such as rash or diarrhea may result in the inability to continue treatment. Although the driving force behind these immune reactions has not been elucidated completely at the present time, these immune reactions are likely linked to immune infiltrate. Inhibitors of Janus kinases or related kinases are widely sought and several publications report effective classes of compounds. For example, certain inhibitors are reported in WO 99/65909, US 2004/0198737; WO 2004/099204; WO 2004/099205; and WO 01/42246. Heteroaryl substituted pyrroles and other compounds are reported in WO 2004/72063 and WO 99/62908. For another example, certain JAK inhibitors, including pyrrolopyridine and pyrrolopyrimidines, are reported in U.S. Ser. No. 11/637,545, filed December 12, 2006.
Anaplastic lymphoma kinase (ALK), is a receptor tyrosine kinase, believed to play an important role in the development and function of the nervous system. ALK is normally expressed in the central nervous system, with peak expression during the neonatal period. However, due to chromosomal translocations, ALK is also aberrantly expressed and activated in some cancers in the form of oncogenic fusion proteins. ALK fusion proteins are responsible for approximately 5-10% of all non-Hodgkin's lymphomas. Additional mutations/translocations and and increased expression have also been identified in lung cancer and neurological tumors (Soda, M., et al. Nature 448:561-566, 2007 and Mosse, YP, AACR 2008). Accordingly, ALK inhibitors are useful for the treatment of ALK-related tumors, including anaplastic large cell lymphomas and non-Hodgkin lymphomas in addition to skin diseases and lung cancers.
The annual incidence of ALK positive lymphomas is about 100,000 worldwide. ALK is an excellent candidate for therapeutic intervention, as it plays an essential role in oncogenicity and its normal expression is mostly restricted to the central nervous system.
Hence, a specific ALK inhibitor could be an efficient treatment for ALK positive lymphomas with few associated clinical side effects. Accordingly, potential ALK inhibitors are highly desirable as potential treatments of ALK-related diseases/tumors. For example, certain ALK inhibitors such staurosporine derivatives are reported in WO2004079326. Thus, new or improved agents which inhibit kinases such as Janus kinases and/or ALK are continually needed for developing new and more effective pharmaceuticals to treat cancer, myeloproliferative disorders, autoimmune diseases, and inflammatory diseases, to name a few. The compounds, compositions and methods described herein are directed toward these needs and other ends.
SUMMARY OF THE INVENTION
The present invention provides, inter alia, compounds of Formula I:
Figure imgf000009_0001
I or pharmaceutically acceptable salts thereof or quaternary ammonium salts thereof, wherein constituent members are provided below.
The present invention further provides pharmaceutical compositions comprising a compound of Formula I, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
The present invention further provides methods of modulating an activity of one or more JAK/ ALK kinases, comprising contacting the kinases with a compound of Formula I, or pharmaceutically acceptable salt of the same. The present invention further provides methods of inhibiting an activity of one or more JAK/ ALK kinases, comprising contacting the kinases with a compound of Formula I, or pharmaceutically acceptable salt of the same.
The present invention further provides methods of treating one or more of the various J AK/ ALK- associated diseases and disorders named herein by administering to a patient a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt of the same.
The present invention further provides compounds of Formula I, or pharmaceutically acceptable salts thereof, for use in therapy.
The present invention further provides use of the compounds of Formula I, or pharmaceutically acceptable salts thereof, for the manufacture/preparation of a medicament for use in therapy.
DETAILED DESCRIPTION
The present invention provides, inter alia, compounds of Formula I:
Figure imgf000010_0001
I or pharmaceutically acceptable salts thereof or quaternary ammonium salts thereof, wherein: represents a single bond or a double bond; X1 is N or CR1; X2 is N or CR2; X3 is N or CR3;
Y is O, S, S(O), S(O)2, CR'R", or NR4;
A1 and A2 are each, independently, selected from CR2, N, NR6, O, and S; B1, B2, E1, and E2 are each, independently, selected from CR5, N, NR6, O, and S; D1 and D2 are each, independently, selected from a bond, CR5, N, NR6, O, and S; wherein the ring containing A1, B1, D1, and E1 is a 5- or 6-membered aromatic ring and wherein the ring containing A2, B2, D2, and E2 is a 5- or 6-membered aromatic ring;
L1 and L2 are each, independently selected from a bond, -(CRV)n-, -O-(CR7R8)m-CR10=, -S-(CR7R8)m-CR10=, -(CR7R8)m-CR10=, -(CR7R8)m-NR9-, -(CR7R8)m-N=, -(CR7R8)m-O-, -(CRV)1n-S-, -(CRV)1n-S(O)-, -(CRV)1n-S(O)2-, -(CRV)1n-C(O)-, -C(O)NR9-, -(CRV)1n-C(O)O-, -(CRV)1n-NR9C(O)NR9-, -(CRV)1n-OC(O)NR9-, -(CRV)1n-NR9C(O)O-, -(CRV)m-NR9-S(O)2NR9-, -(CRV)1n-S(O)NR9-, and -(CRV)1n-S(O)2NR9-; wherein at least one of L1 and L2 is other than a bond; R1 and R3 are each, independently, selected from H, halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci-
6 haloalkyl, CN, NO2, SF5, 0Ra2, SR"2, C(0)Rb2, C(O)NRc2Rd2, C(O)OR"2, 0C(0)Rb2, OC(O)NRc2Rd2, NRC 2 R d2 NR c2 C(O)R b2 NRc2C(O)NRc2Rd2, NRc2C(O)ORa2, C(=NR8)NRc2Rd2, NRc2C(=NR8)NRc2Rd2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, NRc2S(O)2Rb2, and S(O)2NRc2Rd2; each R2 is, independently, selected from H, halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, CN, NO2, SF5, 0Ra2, SR"2, C(0)Rb2, C(O)NRc2Rd2, C(O)OR"2, 0C(0)Rb2, OC(O)NRc2Rd2, NRC 2 R d2 NR c2 C(O)R b2 NRc2C(O)NRc2Rd2, NRc2C(O)ORa2, C(=NR8)NRc2Rd2, NRc2C(=NR8)NRc2Rd2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, NRc2S(O)2Rb2, and S(O)2NRc2Rd2; each R5 is, independently, H, Cy1, halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halosulfanyl, CN, NO2, SF5, 0Ral, SRal, C(0)Rbl, C(0)NRclRdl, C(S)Rbl, C(S)NRclRdl, C(0)0Ral, 0C(0)Rbl, -W^-Y^Z1, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(S)Rbl, NRclC(S)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(ORel)2, P(0)RelRfl, or P(0)0Rel0Rfl, wherein each of said Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, Cy1, halosulfanyl, CN, NO2, SF5, 0Ral, SRal, C(0)Rbl, C(0)NRclRdl, C(S)Rbl, C(S)NRclRdl, C(0)0Ral, 0C(0)Rbl, -W^-Y^Z1, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(S)Rbl, NRclC(S)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl; or two adjacent R5 on the same ring can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halosulfanyl, Cy1, oxo, CN, NO2, 0Ral, SRal, C(0)Rbl, C(0)NRclRdl, SF5, C(S)Rbl, C(S)NRclRdl, C(0)0Ral, 0C(0)Rbl, -W1^-Y1- Z1, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(S)Rbl, NRclC(S)NRclRdl,
NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(0)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(ORel)2, P(0)RelRfl, and P(0)0Rel0Rfl, wherein each of said Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Cy1, -W'-Q'-Y'-Z1, halosulfanyl, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0CH2C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl;
R4 and R6 are each, independently, selected from H, Cy2, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, -W2-X2-Y2-Z2, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, C(=NR8)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl, wherein each of said Q-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Q-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, Cy2, halosulfanyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, -W2- Q2 γ 2 Z 2 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl;
R7, R8, and R10 are each, independently, selected from H, Cy3, halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, -W3-Q3-Y3-Z3, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl, wherein each of said Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci-6 haloalkyl, halosulfanyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, Cy3, -W3-Q3-Y3-Z3, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl; each R9 is, independently, H, Cy4, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, -W4-Q4-Y4-Z4, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, C(=NR8)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, or P(0)0Rel0Rfl wherein each of said Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci-6 haloalkyl, halosulfanyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, Cy4, -W4- Q4-Y4-Z4, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)NRclRdl, NRclC(O)ORal, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, S(O)2NRclRdl, P(Rfl)2, P(ORel)2, P(O)RelRfl, and P(O)ORelORfl;
Rlla, Rllb, R12a, R12b, and R13 are each, independently, selected from H, Cy3, halo, Ci_6 alkyl, C2_6 alkenyl, C2-β alkynyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl, wherein each of said Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Q-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, halosulfanyl, CN, NO2, ORal, SRal, SF5, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, Cy3, -W3-Q3-Y3- Z3, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl;
R' and R" are each, independently, selected from H, halo, Ci-4 alkyl, C2.4 alkenyl, C2.4 alkynyl, Ci_4 haloalkyl, CN, NO2, OR"2, SRa2, C(0)Rb2, C(O)NRc2Rd2, C(0)0Ra2, 0C(0)Rb2, OC(O)NRc2Rd2, NRC 2 R d2 NR^C(0)R b2 NR c2c(O)NRc2Rd2, NRc2C(O)ORa2, C(=NR8)NRc2Rd2, NRc2C(=NR8)NRc2Rd2, NRclS(0)2NRclRdl, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, NRc2S(O)2Rb2, and S(O)2NRc2Rd2; W1, W2, W3, W4, and W5 are each, independently, selected from absent, W6, Ci-6 alkylenyl, C2.6 alkenylenyl, C2_6 alkynylenyl, (CRllaRllb)pi0(CRllaRllb)p2, (CRllaRllb)piS(CRllaRllb)p2, (CRllaRllb)piNRe(CRllaRllb)p2, (CRllaRllb)piC(O)(CRllaRllb)p2, (CRllaRllb)piC(S)(CRllaRllb)p2, (CRllaRllb)piC(0)0(CRllaRllb)p2, (CRllaRllb)piC(O)NRe(CRllaRllb)p2, (CRllaRllb)piC(S)NRe(CRllaRllb)p2, (CRllaRllb)plS(O)(CRllaRllb)p2, (CRllaRllb)plS(O) 2(CRllaRllb)p2, (CRllaRllb)plS(O)NRe(CRllaRllb)p2, (CR111R1 lb)pi S(O)2NR6CCR111R1 lb)p2, (CR111R1 lb)piNReC(O)NRf(CR111R1 lb)p2,
(CRllaRllb)piNReC(S)NRf(CRllaRllb)p2, (CRllaRllb)piNReS(O)2NRf(CRllaRllb)p2,
Figure imgf000013_0001
(CR1 laR! lb)piNReC(=NR8)NRf(CR1 laR! lb)p2, 0(CR1 laR! lb) qlC(O) , S(CRllaRllb) qlC(0), NRe(CRllaRllb) qlC(0), C(0)(CRllaRllb) qlC(0), NRe(CRllaRllb) qlNRf, 0(CRllaRllb)qiNRf, and 0(CRllaRllb) qi0, wherein each of the Ci_6 alkylenyl, C2_6 alkenylenyl and C2_6 alkynylenyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(O)Rb, NRcC(0)NRcRd, NRcC(0)0Ra, C(=NR8)NRcRd, NRcC(=NR8)NRcRd, NRcS(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, NRcS(0)2Rb, and S(0)2NRcRd; each W6 is independently selected from NRel00C(O)NRf 10° and NRe200C(O)CR13Rf 200, wherein Rel0° and Rf 10° together with the intervening NC(O)N moiety to which they are attached form a 4-7 membered heterocycloalkyl group which is optionally substituted by 1 , 2, or 3 substituents each independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(O)Rb, NRcC(0)NRcRd,
NRcC(0)0Ra, C(=NR8)NRcRd, NRcC(=NR8)NRcRd, NRcS(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, NRcS(0)2Rb, and S(0)2NRcRd, and wherein Re200 and Rf 200 together with the intervening NC(O)CR13 moiety to which they are attached form a 4-7 membered heterocycloalkyl group which is optionally substituted by 1, 2, or 3 substituents each independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2_6 alkynyl, halo, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(0)Rb, NRcC(0)NRcRd, NRcC(0)0Ra, C(=NR8)NRcRd, NRcC(=NR8)NRcRd, NRcS(0)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, NRcS(0)2Rb, and S(0)2NRcRd;
Q1) Q2' Q3' Q4' and Q5 are each, independently, selected from aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halo, CN, NO2, ORa, SRa, SF5, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(O)Rb, NRcC(0)NRcRd, NRcC(0)0Ra, C(=NR8)NRcRd, NRcC(=NR8)NRcRd, NRcS(0)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, NRcS(0)2Rb, and S(0)2NRcRd; Y1, Y2, Y3, Y4, and Y5 are each, independently, selected from absent, Ci-6 alkylenyl, C2_6 alkenylenyl, C2_6 alkynylenyl, (CR12aR12b)p3O(CR12aR12b)p4, (CR12aR12b)p3S(CR12aR12b)p4, (CR12aR12b)p3NRe(CR12aR12b)P4, (CR12aR12b)p3C(O)(CR12aR12b)P4, (CR12aR12b)p3C(S)(CR12aR12b)P4, (CR12aR12b)p3C(O)O(CR12aR12b)P4, (CR12aR12b)p3C(O)NRe(CR12aR12b)P4, (CR12aR12b)p3C(S)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O)(CR12aR12b)P4, (CR12aR12b)p3S(O) 2(CR12aR12b)P4, (CR12aR12b)p3S(O)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O)2NRe(CR12aR12b)P4, (CR12aR12b)p3NReC(O)NRf(CR12aR12b)P4,
(CR12aR12b)p3NReC(S)NRf(CR12aR12b)P4, (CR12aR12b)p3NReS(O)2NRf(CR12aR12b)P4,
(CR12aR12b)p3C(=NR8)NRe(CR12aR12b)P4, (CR12aR12b)p3NReC(=NR8)NRf(CR12R12b)P4, O(CR12aR12b)q2C(O), S(CR12aR12b)q2C(O), NRe(CR12aR12b)q2C(O), NRe(CR12aR12b)q2NRf, O(CR12aR12b)q2NRf, and O(CR12aR12b)q2O, wherein each of the Ci-6 alkylenyl, C2.6 alkenylenyl and C2.6 alkynylenyl is optionally substituted by 1, 2 or 3 substituents independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2. 6 alkynyl, halo, CN, NO2, ORa, SRa, SF5, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(0)Rb, NRcC(0)NRcRd, NRcC(0)0Ra, C(=NR8)NRcRd, NRcC(=NR8)NRcRd, NRcS(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, NRcS(0)2Rb, and S(0)2NRcRd; Z1, Z2, Z3, Z4, and Z5 are each, independently, selected from H, halo, CN, NO2, OH, Ci-6 alkoxy, Ci-βhaloalkoxy, amino, Ci-6 alkylamino, C2-8 dialkylamino, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the Ci-6 alkyl, Ci-6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, SF5, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(O)Rd, NRcC(0)0Ra, NRcS(O)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, and S(0)2NRcRd; Cy1, Cy2, Cy3, and Cy4 are each, independently, selected from aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, SF5, Cy5, -Lbl- Cy5, -W5-Q5-Y5-Z5, Ci_6 haloalkyl, halosulfanyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl;
Cy5 and Cy6 are each, independently, selected from aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halosulfanyl, CN, NO2, ORa2, SR12, SF5, C(0)Rb2, C(O)NRc2Rd2, C(S)NRc2Rd2, C(O)OR"2, 0C(0)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NR02C(O)OR"2, C(=NR8)NRc2Rd2, NRc2C(=NR8)NRc2Rd2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, NRc2S(O)2Rb2, and S(O)2NRc2Rd2;
Lbl and Lb2 are each, independently, selected from Q-4 alkylenyl, O, S, C(O), C(S), C(0)NRc2, C(S)NRc2, C(O)O, 0C(0)NRc2, NRc2, NRc2C(O)NRd2, NRc2C(S)NRd2, C(=NR8)NRc2, NRc2C(=NR8)NRd2, NRc2S(O)2NRd2, S(O), S(0)NRc2, S(O)2, and S(O)2NR'2, wherein said Q-4 alkylenyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 substituents each independently selected from halo, CN, Ci-6 alkyl, Ci-6 haloalkyl, OH, Q-6 alkoxy, Q-6 haloalkoxy, NH2, NH(Ci_4 alkyl), and N(Ci-4 alkyl)2;
Ral, Rbl, Rcl, and Rdl are each, independently, selected from H, Q-6 alkyl, C1-6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci-6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Ci_6 alkyl, halo, CN, Cy6, -Lb2-Cy6, OR"2, SRa2, SF5, C(0)Rb2, C(O)NRc2Rd2, C(S)Rb2, C(S)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NRc2C(S)Rb2,
NRc2C(S)NRc2Rd2, NR02C(O)OR"2, C(=NR8)NRc2Rd2, NRc2C(=NR8)NRc2Rd2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, NRc2S(O)2Rb2, and S(O)2NRc2Rd2; or Rcl and Rdl together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from Ci-6 alkyl, Q-6 haloalkyl, halo, CN, Cy6, -Lb2-Cy6, OR12, SRa2, SF5, C(0)Rb2, C(O)NRc2Rd2, C(S)Rb2, C(S)NRc2Rd2, C(0)0Ra2, 0C(0)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NRc2C(S)Rb2, NRc2C(S)NRc2Rd2, NR02C(O)OR"2, C(=NR8)NRc2Rd2, NRc2C(=NR8)NRc2Rd2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, NRc2S(O)2Rb2, and S(O)2NRc2Rd2; each Rel is, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, (Ci-6 alkoxy)-Ci-6 alkyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocycloalkylalkyl ; each Rfl is, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl;
R*2, Rb2, Rc2, and Rd2 are each, independently, selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci-6 alkyl, Ci-6 haloalkyl, C2_6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, and Ci-6 haloalkoxy; or Rc2 and Rd2 together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, and Ci-6 haloalkoxy; each Ra is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, wherein each of the Ci-6 alkyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from OH, CN, amino, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, Ci-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; each Rb is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the Ci-6 alkyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2-β alkenyl, C2-β alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from OH, amino, halo, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
Rc and Rd are independently selected from H, CM0 alkyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the CM0 alkyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from OH, amino, halo, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from OH, amino, halo, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; and
Re and Rf are each, independently, selected from H, CM0 alkyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2-β alkenyl, C2-β alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the CM0 alkyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by OH, amino, halo, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl ; each Rg is, independently, H, CN, or NO2; each pi is, independently, 0, 1, or 2; each p2 is, independently, 0, 1, or 2; each p3 is, independently, 0, 1, or 2; each p4 is, independently, 0, 1, or 2; each ql is, independently, 1 or 2; each q2 is, independently, 1 or 2; each n is, independently, 1, 2, or 3; and each m is, independently, 0, 1, or 2.
In some embodiments, when the ring containing A1, B1, D1, and E1 is a benzene ring optionally substituted by one Ci-4 alkoxy, the ring containing A2, B2, D2, and E2 is a benzene ring optionally substituted by one Ci-4 alkoxy, one of L1 and L2 is -C(O)NR9-, and the other is -(CR7R8)m-O, then L1=ZZZL2 is other than -C(O)-NR9-(CR7R8)2-O-.
In some embodiments, when the ring containing A1, B1, D1, and E1 is a benzene ring optionally substituted by one Ci-4 alkoxy, the ring containing A2, B2, D2, and E2 is a benzene ring optionally substituted by one Ci-4 alkoxy, one of L1 and L2 is -(CR7R8)m-C(O)-, the other is -(CR7R8)m-NR9-, and L l=zzzL 2 is .(CR7R8)m-C(O)-NR9-(CR7R8)m-, then at least one of m is 0; In some embodiments, when the ring containing A1, B1, D1, and E1 is a benzene ring optionally substituted by one Ci-4 alkoxy, the ring containing A2, B2, D2, and E2 is a benzene ring optionally substituted by one Ci-4 alkoxy, L1=ZZZL2 is -C(O)-NR9-(CR7R8)-, X2 is N, X1 is CR1, and X3 is CR3, then at least one of R1 and R3 is other than H;
In some embodiments, when the ring containing A1, B1, D1, and E1 is a benzene ring optionally substituted by one Ci-4 alkoxy, the ring containing A2, B2, D2, and E2 is a benzene ring optionally substituted by one Ci-4 alkoxy, and both L1 and L2 are selected from -(CR7R8)m-O-, then L L is other than -O-(CR7R8)4-O-;
In some embodiments, when the ring containing A1, B1, D1, and E1 is a benzene ring optionally substituted by one Ci-4 alkoxy, the ring containing A2, B2, D2, and E2 is a benzene ring optionally substituted by one Ci-4 alkoxy, and both L1 and L2 are selected from -O-(CR7R8)m-CR10=, then L1=ZZZL2 is other than -O-(CR7R8)-CR10=CR10-(CR7R8)-O-; and
In some embodiments, when L1 is -S(O) 2-, L2 is -NH-, X2 is N, X1 is CH, and X3 is C-Br, Y is -NH-, the ring containing A1, B1, D1, and E1 is a benzene ring, and the ring containing A2, B2, D2, and E2 is a benzene ring, then the ring containing A2, B2, D2, and E2 is other than a benzene ring optionally substituted by OH.
In some embodiments, each R5 is, independently, H, Cy1, halo, Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, halosulfanyl, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, S(O)2NRclRdl, P(Rfl)2, P(ORel)2, P(O)RelRfl, or P(O)ORelORfl, wherein each of said Ci_6 alkyl, C2_6 alkenyl, C2.6 alkynyl, or Ci_6 haloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, halosulfanyl, Cy1, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)NRclRdl, NRclC(O)ORal, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(O)NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, S(O)2NRclRdl, P(Rfl)2, P(ORel)2, P(O)RelRfl, and P(O)ORelORfl.
In some embodiments, two adjacent R5 on the same ring can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, Cy1, oxo, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, SF5, C(S)Rbl, C(S)NRclRdl, C(0)0Ral, 0C(0)Rbl, -W^Q^-Z1, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(S)Rbl, NRclC(S)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl, wherein each of the Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, Cy1, - W1 -Q1^-Z1, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0CH2C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl.
In some embodiments, two adjacent R5 on the same ring can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, Cy1, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, SF5, C(S)Rbl, C(S)NRclRdl, C(0)0Ral, 0C(0)Rbl,
Figure imgf000019_0001
0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(S)Rbl, NRclC(S)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl, wherein each of the Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, Cy1, -W^Q^-Z1, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0CH2C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(O)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl.
In some embodiments, two adjacent R5 on the same ring can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halosulfanyl, Cy1, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, SF5, C(S)Rbl, C(S)NRclRdl, C(O)ORal, OC(O)Rbl, -W^Q^-Z1, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)NRclRdl, NRclC(S)Rbl, NRclC(S)NRclRdl, NRclC(O)ORal, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(O)NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, S(O)2NRclRdl, P(Rfl)2, P(ORel)2, P(O)RelRfl, and P(O)ORelORfl, wherein each of said Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C^6 haloalkyl, Cy1, -W^Q^-Z1, halosulfanyl, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0CH2C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(O)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl.
In some embodiments, two adjacent R5 on the same ring can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Q-6 haloalkyl, halosulfanyl, Cy1, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(O)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(ORel)2, P(0)RelRfl, and P(0)0Rel0Rfl. In some embodiments, R4 and R6 are each, independently, selected from H, Cy2, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, C(=NR8)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(ORel)2, P(0)RelRfl, and P(O) 0Rel0Rfl, wherein each of said Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, or Ci-6 haloalkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci-6 haloalkyl, halosulfanyl, Cy2, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl.
In some embodiments, R7, R8, and R10 are each, independently, selected from H, Cy3, halo, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(ORel)2, P(0)RelRfl, and P(0)0Rel0Rfl, wherein each of said Ci_6 alkyl, C2_6 alkenyl, C2.6 alkynyl, or Ci-6 haloalkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, halosulfanyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2R", NRclS(O)2Rbl, S(O)2NRclRdl, P(Rfl)2, P(ORel)2, P(O)RelRfl, and P(O)ORelORfl.
In some embodiments, each R9 is, independently, H, Cy4, Ci_6 alkyl, C2-β alkenyl, C2-β alkynyl, Ci- 6 haloalkyl, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, C(=NR8)NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, S(O)2NRclRdl, P(Rfl)2, P(ORel)2, P(O)RelRfl, or P(O)ORelORfl wherein each of said Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, or Ci_6 haloalkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, halosulfanyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, S(O)2NRclRdl, P(Rfl)2, P(ORel)2, P(0)RelRfl, and P(0)0Rel0Rfl.
In some embodiments, Cy1, Cy2, Cy3, and Cy4 are each, independently, selected from aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, Ci_6 haloalkyl, halosulfanyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl.
In some embodiments, Ral, Rbl, Rcl, and Rdl are each, independently, selected from H, Ci_6 alkyl, C2-6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cμs alkyl, halo, CN, ORa2, SR"2, C(0)Rb2, C(O)NRc2Rd2, C(O)OR"2, 0C(0)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NRc2C(O)ORa2, C(=NR8)NRc2Rd2, NRc2C(=NR8)NRc2Rd2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, NRc2S(O)2Rb2, and S(O)2NRc2Rd2.
In some embodiments, Rcl and Rdl together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from Ci_6 alkyl, halo, CN, ORa2, SR"2, C(0)Rb2, C(O)NRc2Rd2, C(0)0Ra2, 0C(0)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NR02C(O)OR"2, C(=NR8)NRc2Rd2, NRc2C(=NR8)NRc2Rd2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, NRc2S(O)2Rb2, and S(O)2NRc2Rd2.
In some embodiments, when one of L1 and L2 is -C(O)NR9-, and the other is -(CR7R8)m-O-, then
L1=ZZZL2 is other than -C(O)-NR9-(CR7R8)2-O-. In some embodiments, when one of L1 and L2 is -(CR7R8)m-C(O)-, the other is -(CR7R8)m-NR9-, and L1=ZZZL2 is -(CR7R8)m-C(O)-NR9-(CR7R8)m-, then at least one of m is 0.
In some embodiments, when L1=ZZZL2 is -C(O)-NR9-(CR7R8)-, X2 is N, X1 is CR1, and X3 is CR3, then at least one of R1 and R3 is other than H. In some embodiments, when both L1 and L2 are selected from -(CR7R8)m-O-, then L L is other than -O-(CR7R8)4-O-.
In some embodiments, when both L1 and L2 are selected from -O-(CR7R8)m-CR10=, then LlzzzzL 2 is other than _O-(CR7R8)-CR10=CR10-(CR7R8)-O-.
In some embodiments, the compound of Formula I is other than 6-Chloro-2,4,8, 14,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-15-one.
In some embodiments, the compound of Formula I is other than 6-Chloro-2,4,8, 15,23- pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaen-14-one.
In some embodiments, the compound of Formula I is other than 6-Chloro-2,4,8, 15,23- pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaen-16-one. In some embodiments, the compound of Formula I is other than 6-Chloro-2,4,8, 16,23- pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaen-15-one.
In some embodiments, A1 and A2 are each, independently, selected from CR2, N, NH, N(CH3), O, and S. In some embodiments, one of A1 and A2 is selected from NH, N(CH3), O, and S. In some embodiments, both A1 and A2 are independently selected from NH, N(CH3), O, and S. In some embodiments, A1 and A2 are each, independently, selected from CR2 and N.
In some embodiments, the ring containing A1, B1, D1, and E1 is a 6-membered aromatic ring; B1, D1, and E1 are each, independently, CR5 or N; and A1 is CR2 or N.
In some embodiments, the ring containing A1, B1, D1, and E1 is a 6-membered aromatic ring; B1, D1, and E1 are each, independently, CR5; and A1 is CR2. In some embodiments, the ring containing A1, B1, D1, and E1 is a benzene ring, and the benzene ring can be substituted or unsubstituted.
In some embodiments, the ring containing A1, B1, D1, and E1 is a 6-membered aromatic ring wherein at least one of A1, B1, D1, and E1 is N. In some further embodiments, the 6-membered aromatic ring is selected from pyridine, pyrimidine, and pyrazine rings (the 6-membered aromatic rings such as pyridine, pyrimidine, and pyrazine can be substituted or unsubstituted). In yet further embodiments, the 6-membered aromatic ring is selected from pyridine and pyrimidine rings. In some embodiments, the 6- membered aromatic ring is a pyridine ring. In some embodiments wherein the ring containing A1, B1, D1, and E1 is a pyridine ring, D1 is N. In some embodiments wherein the ring containing A1, B1, D1, and E1 is a pyridine ring, E1 is N. In some embodiments wherein the ring containing A1, B1, D1, and E1 is a pyridine ring, B1 is N. In some embodiments wherein the ring containing A1, B1, D1, and E1 is a pyridine ring, A1 is N. In some embodiments, the 6-membered aromatic ring is a pyrimidine ring.
In some embodiments, the ring containing A1, B1, D1, and E1 is a 5-membered aromatic ring (optionally substituted). In some further embodiments, the 5-membered aromatic ring is selected from lH-pyrrole, furan, thiophene, lH-imidazole, lH-pyrazole, oxazole, thiazole, isoxazole, and isothiazole (the 5-membered aromatic rings can be substituted or unsubstituted). In yet further embodiments, the 5- membered aromatic ring is selected from lH-pyrrole, furan, and thiophene (each is optionally substituted). In still further embodiments, the 5-membered aromatic ring is a thiophene ring (optionally substituted). In some embodiments, the ring containing A2, B2, D2, and E2 is a 6-membered aromatic ring; B2,
D2, and E2 are each, independently, CR5 or N; and A2 is CR2 or N.
In some embodiments, the ring containing A2, B2, D2, and E2 is a 6-membered aromatic ring; B2, D2, and E2 are each, independently, CR5; and A2 is CR2.
In some embodiments, the ring containing A2, B2, D2, and E2 is a benzene ring, and the benzene ring can be substituted or unsubstituted.
In some embodiments, the ring containing A2, B2, D2, and E2 is a 6-membered aromatic ring, wherein at least one of A2, B2, D2, and E2 is N. In some further embodiments, the 6-membered aromatic ring is selected from pyridine, pyrimidine, and pyrazine rings (the 6-membered aromatic rings can be substituted or unsubstituted). In yet further embodiments, the 6-membered aromatic ring is selected from pyridine and pyrimidine rings. In some embodiments, the 6-membered aromatic ring is a pyridine ring. In some embodiments, the 6-membered aromatic ring is a pyrimidine ring.
In some embodiments, the ring containing A2, B2, D2, and E2 is a 5-membered aromatic ring. In some further embodiments, the 5-membered aromatic ring is selected from lH-pyrrole, furan, thiophene, lH-imidazole, lH-pyrazole, oxazole, thiazole, isoxazole, and isothiazole rings(the 5-membered aromatic rings can be substituted or unsubstituted). In yet further embodiments, the 5-membered aromatic ring is selected from lH-pyrrole, furan, and thiophene rings. In still further embodiments, the 5-membered aromatic ring is a thiophene ring.
In some embodiments, X1 is CR1.
In some embodiments, X1 is N. In some embodiments, X2 is CR2.
In some embodiments, X2 is N.
In some embodiments, X3 is CR3.
In some embodiments, X3 is N. In some embodiments, Y is NR4. In some embodiments, Y is NH. In some embodiments, Y is N(Ci-3 alkyl). In some embodiments, Y is N-CH3.
In some embodiments, Y is O, S, SO, or S(O)2.
In some embodiments, Y is O. In some embodiments, Y is S, SO, or S(O)2. In some embodiments, Y is S. In some embodiments, Y is SO. In some embodiments, Y is S(O)2.
In some embodiments, Y is CR'R". In some further embodiments, R' and R" are each, independently, selected from H, Ci_6 alkyl, and Ci_6 haloalkyl. In some yet further embodiments, R' and R" are each, independently, selected from H, Ci-3 alkyl, and Ci-3 haloalkyl. In some still further embodiments, R' and R" are each, independently, selected from H and Ci-3 alkyl. In some embodiments, R' and R" are each, independently, selected from H and methyl. In some embodiments, R' and R" are both H.
In some embodiments, the ring containing A1, B1, D1, and E1 is a 6-membered aromatic ring; B1, D1, and E1 are each, independently, CR5 or N; A1 is CH; the ring containing A2, B2, D2, and E2 is a 6- membered aromatic ring; B2, D2, and E2 are each, independently, CR5 or N; A2 is CH; X1 is CR1; X2 is N; X3 is CR3; and Y is NR4. In some further embodiments, one of B1, D1, and E1 is N, and the other two are each independently CR5; R1 is H; R3 is H, halo, methyl, or Ci haloalkyl; and R4 is H or Ci-3 alkyl.
In some embodiments, L1 and L2 are each, independently, selected from a bond, -(CR7R8)n-, -O- (CRV)1n-CR10=, -S-(CR7R8)m-CR10=, -(CR7R8)m-CR10=, -(CR7R8)m-NR9-, -(CR7R8)m-O-, -(CR7R8)m-S-, - (CR7R8)m-S(O)-, -(CR7RVS(O)2-, -(CR7R8)m-C(O)-, -C(O)NR9-, -(CR7R8)m-C(O)O-, -(CRV)1n- NR9C(O)NR9-, -(CR7R8)m-OC(O)NR9-, -(CR7R8)m-NR9C(O)O-, -(CR7R8)m-NR9-S(O)2NR9-, -(CRV)1n- S(O)NR9-, and -(CR7R8)m-S(O)2NR9-.
In some embodiments, L1 and L2 are each, independently, selected from a bond, -(CR7R8)n-, -(CR7R8)m-CR10=, -O-(CR7R8)m-CR10=, -S-(CR7R8)m-CR10=, -(CR7R8)m-NR9-, -(CR7R8)m-O-, -(CRV)1n-S-, -(CRV)1n-S(O)-, -(CRV)1n-S(O)2-, -(CRV)1n-C(O)-, -C(O)NR9-, -(CRV)1n-C(O)O-, - (CRV)1n-S(O)NR9-, and -(CRV)1n-S(O)2NR9-.
In some embodiments, L1 and L2 are each, independently, selected from a bond, -(CRV)n-, -(CRV)1n-CR10=, -(CRV)1n-NR9-, -(CRV)1n-O-, -(CRV)1n-S-, -(CRV)1n-S(O)-, -(CRV)1n- S(O)2-, - (CRV)1n-C(O)-, -C(O)NR9-, -(CRV)1n-C(O)O-, -(CRV)1n-S(O)NR9-, and -(CRV)1n-S(O)2NR9-.
As used herein, when one of L1 and L2 is selected from -O-(CR7R8)m-CR10=, -S-(CRV)1n-CR10=, -(CRV)1n-CR10=, and -(CRV)1n-N=, the other is also selected from -0-(CRV)1n-CR10=, -S-(CRV)1n- CR10=, -(CRV)1n-CR10=, and -(CRV)1n-N= (although L1 and L2 can be the same or different in such embodiments). In such embodiments, the moiety formed by L1 and L2 together can include a moiety of "-CR10=CR10-" or "-CR10=N-". In some further embodiments, the moiety formed by L1 and L2 together includes a moiety of -CR10=CR10-. In some embodiments, L1 and L2 together form -(CR7R8)m-CR10=CR10-(CR7R8)m-, -O-(CR7R8)m-CR10=CR10-(CR7R8)m-, -S-(CR7R8)m-CR10=CR10- (CRV)1n-, -O-(CR7R8)m-CR10=CR10-(CR7R8)m-O-, -O-(CR7R8)m-CR10=CR10-(CR7R8)m-S-, or -S-(CR7R8)m-CR10=CR10-(CR7R8)m-S-.
In some embodiments, L1 and L2 are each, independently, selected from a bond, -(CR7RV, and -(CR7R8)m-CR10=.
In some embodiments, L1 and L2 together form -(CR7R8)m-CR10=CR10-(CR7R8)m- or -(CRV)1n-(CR7R8X1-.
In some embodiments, L1 and L2 together form -CR10=CR10-, -(CRV)2-, or -(CRV)3-.
In some embodiments, L1 and L2 together form -CR10=CR10- or -(CRV)2-. In some embodiments, L1 and L2 together form -CH=CH- or -CH2-CH2-. In some embodiments, L1 and L2 together form -CH=CH-. In some embodiments, L1 and L2 together form -CH2-CH2-.
In some embodiments, L1 and L2 together form-CR10=CR10- or -CRV-CR7R8-. In some embodiments, L1 and L2 together form -CH=CH- or -CH2-CH2-. In some embodiments, L1 and L2 together form -CH=CH-. In some embodiments, L1 and L2 together form -CH2-CH2-. In some embodiments, L1 and L2 together form -CR10=CR10-.
In some embodiments, L1 and L2 together form -CRV-CR7R8-.
In some embodiments, L1 and L2 together form -(CRV)3-. In some embodiments, L1 and L2 together form -(CH2)3-.
In some embodiments, L1 and L2 together form -(CRV)4-, -(CRV)5-, or -(CRV)6-. In some embodiments, L1 and L2 together form -(CH2)4-, -(CH2)5-, or -(CH2)6-.
In some embodiments, one of L1 and L2 is selected from -(CRV)1n-O-, -(CRV)1n-S-, -(CRV)n S(O)-, and -(CRV)1n-S(O)2-; and the other is selected from a bond, -(CRV)n-, -(CRV)1n-O-, - (CRV)1n-S-, -(CRV)1n-S(O)-, and -(CRV)1n-S(O)2-.
In some embodiments: L1 and L2 together form -(CR7R8Xi -S-, -(CR7R8Xi-O-, -(CR7R8Xi-S(O)-,
-(CR7R8Xi-S(O) 2-, -S-(CRV)12-S-, -0-(CRV)12-S-, -0-(CRV)12-S(O)-, -0-(CR7R8X2-S(O) 2-, -S-S-, -(CR7R8X3-O-(CR7R8X4-, -(CRV)0-S-(CRVX4-, -(CRV)0- S(O)-(CR7R8X4-, or -(CR7R8X3-S(O) 2-(CR7R8)t4-; tl is 1, 2, or 3; t2 is 1 or 2; t3 is 1, 2, or 3; and t4 is 1 or 2.
In some embodiments: L1 and L2 together form -(CR7R8Xi-S-, -(CR7R8Xi-O-, -(CR7R8Xi-S(O)-, -(CR7R8Xi-S(O) 2-, -S-(CR7RVs-, -0-(CR7RVS-, -O-(CR7RVS(O)-, -0-(CR7R8X2-S(O) 2-, or -S-S-; tl is 1, 2, or 3; and t2 is 1 or 2.
In some embodiments:
L1 and L2 together form -(CRV)0-O-(CR7R8X4-, -(CR7R8X3-S-(CR7R8X4-, -(CR7RVS(O)-(CR7R8X4-, or -(CR7RVS(O)2-(CR7R8X4-, t3 is 1, 2, or 3; and t4 is l or 2.
In some embodiments, L1 and L2 together form S-S, -(CR7R8)-S-, -(CR7R8)-S(O)-, -(CRV)-S(O)2-, -(CR7R8XO-, -(CRV)2-O-, -0-(CRV)2-O-, -0-(CRV)2-S-, -O-(CRV)2-S(O)-, or -0-(CRV)2- S(O)2-.
In some embodiments, L1 and L2 together form S-S, -(CH2)-S-, -(CH2)-S(0)-, -(CH2)-S(O)2-, -(CH2)-0-, -(CH2) 2-0-, -0-(CHz)2-O-, -0-(CH2) 2-S-, -O-(CH2)2-S(O)-, or
-0-(CH2) 2- S(O)2-. In some embodiments, L1 and L2 together form S-S. In some embodiments, L1 and L2 together form -(CH2)-S-, -(CH2)-S(0)-, -(CH2XS(O)2-, -(CH2)-0-, -(CHz)2-O-, -0-(CHz)2-O-, -0-(CH2)Z-S-, -O-(CH2)2-S(O)-, or -0-(CH2) 2-S(O)2-.
In some embodiments, L1 and L2 together form -(CRV)-O-, -(CRV)-S-, -(CRV)-S(O)-, -(CRV)-S(O)2-, -(CRV)2-O-, -(CRV)2-S-, -(CRV)2-S(O)-, -(CRV)2-S(O)2-, -0-(CRV)3-,
-S-(CRV)3-, -S(O)-(CR7R8X-, or -S(O)2-(CRV)3-.
In some embodiments, L1 and L2 together form -(CH2)-0-, -(CH2)-S-, -(CH2)-S(O)-, or -(CH2)-S(O)2-. In some embodiments, L1 and L2 together form -(CH2)-0- or -(CH2)-S-.
In some embodiments, L1 and L2 together form -(CH2)-0-. In some embodiments, L1 and L2 together form -(CH2)-S-.
In some embodiments, L1 and L2 together form -(CH2)-S(O)-.
In some embodiments, L1 and L2 together form -(CH2XS(O)2-.
In some embodiments, L1 and L2 together form -(CH2)2-O-, -(CH2)2-S-, -(CH2)2-S(O)-, or -(CH2^-S(O)2-. In some embodiments, L1 and L2 together form -(CH2)2-O- or -(CH2)2-S-. In some embodiments, L1 and L2 together form -(CH2)2-O.
In some embodiments, L1 and L2 together form -(CH2)2-S-.
In some embodiments, L1 and L2 together form -(CH2)2-S(O)-.
In some embodiments, L1 and L2 together form -(CH2)2-S(O)2-. In some embodiments, L1 and L2 together form -(CH2)3-O-, -(CH2)3-S-, -(CH2)3-S(O)-, or -(CH2)3-S(O)2-. In some embodiments, L1 and L2 together form -(CH2)3-O- or -(CH2)3-S-. In some embodiments, L1 and L2 together form -(CH2)3-O-. In some embodiments, L1 and L2 together form -(CH2)3-S-. In some embodiments, L1 and L2 together form -(CH2)3-S(O)-.
In some embodiments, L1 and L2 together form -(CH2)3-S(O)2-. In some embodiments, L1 and L2 together form -(CRV)-O-(CR7R8)-, -(CR7R8)-S-( CR7R8)-,
-(CRV)-S(O)-(CR7R8)-, -(CRV)-S(O)2-(CRV)-, -(CRV)-O-(CRV)2-, -(CRV)-S-(CRV)2-, -(CRV)-S(O)-(CRV)2-, -(CRV)-S(O)2-(CRV)2-, -(CRV)2-O-(CRV)2-, -(CRV)2-S-(CRV)2-, -(CRV)2-S(O)-(CRV)2-, or -(CRV)2-S(O)2-(CRV)2-.
In some embodiments, L1 and L2 together form -(CH2)-O-(CH2)-, -(CH2)-S-(CH2)-, -(CH2)-S(O)-(CH2)-, -(CH2)-S(O)2-(CH2)-, -(CH2)-O-(CH2)2-, -(CH2)-S-(CH2)2-, -(CH2)-S(O)-(CH2)2-, -(CH2)-S(O)2-(CH2)2-, -(CH2)2-O-(CH2)2-, -(CH2)2-S-(CH2)2-, -(CH2)2-S(O)-(CH2)2-, or -(CH2)2-S(O)2-(CH2)2-. In some embodiments, L1 and L2 together form -(CH2)-O-(CH2)- or -(CH2)-S-(CH2)-.
In some embodiments, L1 and L2 together form -(CH2)-O-(CH2)-. In some embodiments, L1 and L2 together form -(CH2)-S-(CH2)-. In some embodiments, L1 and L2 together form -(CH2)-O-(CH2)2- or -(CH2)-S-(CH2)2-. In some embodiments, L1 and L2 together form -(CH2)-O-(CH2)2-. In some embodiments, L1 and L2 together form -(CH2)-S-(CH2)2-.
In some embodiments, L1 and L2 together form -(CH2)2-O-(CH2)2- or -(CH2)2-S-(CH2)2-. In some embodiments, L1 and L2 together form -(CH2)2-O-(CH2)2- In some embodiments, L1 and L2 together form -(CH2)2-S-(CH2)2-. In some embodiments, L1 and L2 together form -0-(CH2) 2-0-, -0-(CH2) 2-S-, -0-(CH2) 2-S(0)-, -0-(CH2) 2-S(O)2-, -S-(CH2) 2-S-, -S(O)-(CH2) 2-S(0)-, or -S(O)2-(CH2) 2-S(O)2-.
In some embodiments, L1 and L2 together form -0-(CH2) 2-0-, -0-(CH2) 2-S-, -0-(CH2) 2-S(0)-, or -0-(CH2) 2-S(O)2-.
In some embodiments, L1 and L2 together form -0-(CH2) 2-0-. In some embodiments, L1 and L2 together form -0-(CH2) 2-S-.
In some embodiments, L1 and L2 together form -0-(CH2) 2-S(0)-. In some embodiments, L1 and L2 together form -0-(CH2) 2-S(O)2-.
In some embodiments, one of L1 and L2 is selected from -(CRV)1n-NR9-, -(CRV)1n-S(O)2-, - (CRV)1n-C(O)-, -C(O)NR9-, -(CRV)1n-S(O)NR9-, and -(CRV)1n-S(O)2NR9-; and the other is selected from a bond, -(CR7RV, -(CR7R8)m-NR9-, -(CR7R8)m-S(O)2-, -(CR7R8)m-C(O)-, -C(O)NR9-, -(CRV)1n- S(O)NR9-, and -(CR7R8)m-S(O)2NR9-.
In some embodiments, L1 and L2 together form -(CR7R^t5-C(O)-, -(CR7R8)t5-C(O)NR9-, -C(O)NR9-(CR7R8)t5-, -C(O)NR9-, -S(O)2NR9-(CR7R8)t5-, -(CR7R8)t5-S(O)2NR9-, or -S(O)2NR9-, wherein t5 is 1, 2, or 3.
In some embodiments, L1 and L2 together form -(CRV)15-C(O)-, -C(O)NR9-, or -S(O)2NR9-, and wherein t5 is 1, 2, or 3.
In some embodiments, L1 and L2 together form -(CR7R8)-C(O)-, -(CR7R8)2-C(O)-, or -(CRV)3-C(O)-. In some embodiments, L1 and L2 together form -(CR7R8)-C(O)-. In some embodiments, L1 and L2 together form -(CR7R8)2-C(O)-. In some embodiments, L1 and L2 together form -(CRV)3-C(O)-.
In some embodiments, L1 and L2 together form -(CH2)-C(0)-, -(CH2)2-C(O)-, or
-(CH2)3-C(O)-. In some embodiments, L1 and L2 together form -(CH2)-C(0)-. In some embodiments, L1 and L2 together form -(CH2)2-C(O)-. In some embodiments, L1 and L2 together form -(CH2)3-C(O)-.
In some embodiments, L1 and L2 together form -(CRV)-C(O)NR9-, -C(O)NR9-(CR7R8)-, or -C(O)NR9-. In some embodiments, L1 and L2 together form -(CH2)-C(O)NR9-, -C(0)NR9-( CH2)-, or -C(O)NR9-. In some embodiments, L1 and L2 together form -(CH2)-C(0)NH-, -C(O)NH-(CH2)-, or -C(O)NH-. In some embodiments, L1 and L2 together form -C(O)NH-(CH2)-, or -C(O)NH-. In some embodiments, L1 and L2 together form -(CH2)-C(0)NH-.
In some embodiments, L1 and L2 together form -C(O)NH-(CH2)-.
In some embodiments, L1 and L2 together form -C(O)NH-.
In some embodiments, L1 and L2 together form -(CR7R8)t7-C(O)NR9-(CR7R8)t8, wherein t7 is 1 or 2 and t8 is 1 or 2. In some embodiments, L1 and L2 together form -(CRV)-C(O)NR9-(CRV)-. In some embodiments, L1 and L2 together form -(CH2)-C(O)NH-(CH2)-.
In some embodiments, L1 and L2 together form -S(O)2NR9-(CR7R8)t5-, -(CR7R^t5-S(O)2NR9-, or -S(O)2NR9-, wherein t5 is 1, 2, or 3.
In some embodiments, L1 and L2 together form -S(O)2NR9-(CR7R8)-, -(CRV)-S(O)2NR9-, or -S(O)2NR9-. In some further embodiments, R9 is H or Ci-3 alkyl. In some embodiments, L1 and L2 together form -S(O)2NR9-(CH2)-, -(CH2)-S(O)2NR9-, or
-S(O)2NR9-. In some further embodiments, L1 and L2 together form -S(O)2NH-(CH2)-, -(CH2)-S(O)2NH-, or -S(O)2NH-.
In some embodiments, L1 and L2 together form -S(O)2NH-(CH2)-.
In some embodiments, L1 and L2 together form -(CH2)-S(O)2NH-. In some embodiments, L1 and L2 together form -S(O)2NH-.
In some embodiments, L1 and L2 together form -(CR7R8)t7-S(O)2NR9-(CR7R8)t8-, wherein t7 is 1 or 2 and t8 is 1 or 2. In some embodiments, L1 and L2 together form -(CR7R8)-S(O)2NR9-(CR7R8).
In some embodiments, L1 and L2 together form -(CH2)-S(O)2NR9-(CH2)-. In some embodiments, L1 and L2 together form -(CR7R8)m-NR9-C(O)NR9-,
-(CR7R8)m-O-C(O)NR9-, or -O-C(O)NR9-(CR7R8)m-.
In some embodiments, L1 and L2 together form -(CR7R8)-NR9-C(O)NR9-, -(CR7R8)-O-C(O)NR9-, -O-C(O)NR9-(CR7R8)-, -NR9-C(O)NR9-, or -0-C(O)NR9-.
In some embodiments, L1 and L2 together form -(CH2)-NR9-C(O)NR9-. In some embodiments, L1 and L2 together form -(CH2)-NH-C(0)NH-.
In some embodiments, L1 and L2 together form -(CR7R8)-O-C(O)NR9-. In some embodiments, L1 and L2 together form -(CH2)-0-C(0)NH-.
In some embodiments, L1 and L2 together form -O-C(O)NR9-(CR7R8)-. In some embodiments, L1 and L2 together form -0-C(O)NH-(CH2)-. In some embodiments, L1 and L2 together form -NR9-C(O)NR9-, or -0-C(O)NR9-.
In some embodiments, L1 and L2 together form -NH-C(O)NH-.
In some embodiments, L1 and L2 together form -0-C(O)NH-.
In some embodiments, L1 and L2 together form -(CR7R8)m-NR9-(CR7R8)n-.
In some embodiments, L1 and L2 together form -NR9-(CR7R8)n-. In some embodiments, L1 and L2 together form -NR9-(CR7R8)-. In some embodiments, L1 and L2 together form -NR9-(CR7R8)2-. In some embodiments, L1 and L2 together form -NR9-(CR7R8)3-.
In some embodiments, L1 and L2 together form -NR9-(CH2)n-. In some embodiments, L1 and L2 together form -NR9-(CH2)-. In some embodiments, L1 and L2 together form -NR9-(CH2)2-. In some embodiments, L1 and L2 together form -NR9-(CH2)3-. In some embodiments, L1 and L2 together form -(CR7R8)m2-NR9-(CR7R8)n-, wherein m2 is 1 or 2.
In some embodiments, L1 and L2 together form -(CR7R8)-NR9-(CR7R8)-, -(CR7R8)-NR9-(CR7R8)2-, or -(CR7R8)2-NR9-(CR7R8)2-. In some further embodiments, L1 and L2 together form -(CR7R8)-NR9-(CR7R8)- or -(CR7R8)-NR9-(CR7R8)2-. In some further embodiments, R9 is H or Ci-3 alkyl.
In some embodiments, L1 and L2 together form -(CH2)m2-NR9-(CH2)n-, wherein m2 is 1 or 2. In some embodiments, L1 and L2 together form -(CH2)-NR9-(CH2)-, -(CH2)-NR9-(CH2)2-, or -(CH2)2-NR9-(CH2)2-. In some further embodiments, L1 and L2 together form -(CH2)-NR9-(CH2)- or -(CH2)-NR9-(CH2)2-. In some further embodiments, R9 is H or Ci-3 alkyl.
In some embodiments, L1 and L2 together form -(CR7R8)-NR9-(CR7R8)-. In some embodiments, L1 and L2 together form -(CH2)-NR9-(CH2)-. In some embodiments, L1 and L2 together form -NR9-(CR7R8)t9-O- wherein t9 is 1, 2, or 3. In some embodiments, L1 and L2 together form -NR9-(CR7R8)-O-. In some embodiments, L1 and L2 together form -NR9-(CR7R8)2-O-. In some embodiments, L1 and L2 together form -NR9-(CR7R8)3-O-.
In some embodiments, L1 and L2 together form -NR9-(CH2)-O-. In some embodiments, L1 and L2 together form -NR9-(CH2)2-O-.
In some embodiments, L1 and L2 together form -NR9-(CH2)3-O-.
In some embodiments, one of L1 and L2 is selected from -(CR7R8)m-NR9C(O)NR9-, -(CR7R8)m- OC(O)NR9-, -(CR7R8)m-NR9C(O)O-, and -(CR7R8)m-NR9-S(O)2NR9-; and the other is selected from a bond, -(CR7RV, -(CR7R8)m-NR9-, -(CR7R8)m-O-, -(CR7R8)m-S-, -(CR7R8)m-S(O)2-, -(CR7R8)m-C(O)-, - C(O)NR9-, -(CR7R8)m-S(O)NR9-, and -(CR7R8)m-S(O)2NR9-.
In some embodiments, one of L1 and L2 is selected from -(CR7R8)m-NR9C(O)NR9-, -(CR7R8)m- OC(O)NR9-, -(CR7R8)m-NR9C(O)O-, and -(CR7R8)m-NR9-S(O)2NR9-; and the other is selected from a bond, and -(CR7R8)n.
In some embodiments, L1 and L2 together form -(CR7R8)m-NR9C(O)NR9-(CR7R8)m-, -(CR7R8)m- OC(O)NR9-(CR7R8)m-, or -(CR7R8)m-NR9-S(O)2NR9-(CR7R8)m-.
In some embodiments, L1 and L2 together form -(CR7R8)m-NR9C(O)NR9-(CR7R8)m-. In some embodiments, L1 and L2 together form -NR9C(O)NR9, -NR9C(O)NR9-(CR7R8) m2-, or -(CR7RV - NR9C(O)NR9-(CR7R8)m2-, wherein ml and m2 are each, independently 1 or 2.
In some embodiments, L1 and L2 together form -NR9C(O)NR9. In some embodiments, L1 and L2 together form -NR9C(O)NR9-(CR7R8)-, -NR9C(O)NR9-
(CRV)2-, -(CR7R8)-NR9C(O)NR9-(CR7R8)-, -(CR7R8)-NR9C(O)NR9-(CR7R8)2-, or -(CR7R8)2- NR9C(O)NR9-(CR7R8)2-.
In some embodiments, L1 and L2 together form -(CH2)m-NR9C(O)NR9-(CH2)m-. In some embodiments, L1 and L2 together form -NR9C(O)NR9, -NR9C(O)NR9-(CH2) m2-, or -(CH2)ml- NR9C(O)NR9-(CH2)m2- wherein ml and m2 are each, independently 1 or 2.
In some embodiments, L1 and L2 together form -NR9C(O)NR9-(CH2)-, -NR9C(O)NR9-(CH2)2-, - (CH2)-NR9C(O)NR9-(CH2)-, -(CH2)-NR9C(O)NR9-(CH2)2-, or -(CH2)2-NR9C(O)NR9-(CH2)2-. In some embodiments, L1 and L2 together form -(CR7R8)m-OC(O)NR9-(CR7R8)m-. In some embodiments, L1 and L2 together form -OC(O)NR9-. In some embodiments, L1 and L2 together form -OC(O)NR9-(CR7R8)-, -OC(O)NR9-(CR7R8)2-,
-(CRV)-OC(O)NR9-, -(CR7R8)2-OC(O)NR9-, -(CR7R8)-OC(O)NR9-(CR7R8)-, -(CR7R8)-OC(O)NR9- (CR7RV, -(CR7R8)2-OC(O)NR9-(CR7R8)-, or -(CR7R8)2-OC(O)NR9-(CR7R8)2-. In some embodiments, L1 and L2 together form -OC(O)NR9-(CH2)-, -OC(O)NR9-(CH2)2-, -(CH2)-OC(O)NR9-, -(CH2)2-OC(O)NR9-, -(CH2)-OC(O)NR9-(CH2)-, -(CH2)-OC(O)NR9-(CH2)2-, - (CH2)2-OC(O)NR9-(CH2)-, or -(CH2)2-OC(O)NR9-(CH2)2-.
In some embodiments, L1 and L2 together form -(CR7R8)m-NR9S(O)2NR9-(CR7R8)m-. In some embodiments, L1 and L2 together form -NR9S(O)2NR9-, -NR9S(O)2NR9-(CR7R8)m2-, or
-(CR7R8)mi-NR9S(O)2NR9-(CR7R8)m2-, wherein ml and m2 are each, independently 1 or 2.
In some embodiments, L1 and L2 together form -NR9S(O)2NR9.
In some embodiments, L1 and L2 together form -NR9S(O)2NR9-(CR7R8)-, -NR9S(O)2NR9- (CRV)2-, -(CR7R8)-NR9S(O)2NR9-(CR7R8)-, -(CR7R8)-NR9S(O)2NR9-(CRVR8)2-, or -(CRV)2- NR9S(O)2NR9-(CR7R8)2-.
In some embodiments, L1 and L2 together form -CR10=CR10-, -(CH2)2-, -(CH2)-0-, -(CH2)-S-, - (CH2)-S(O)-, -(CH2)-S(O)2-, -(CH2)-NR9-, -C(O)-NR9-, -S(O)2-NR9-, S-S-, -(CH2)2-O-, -(CH2)2-S-, - (CH2)2-S(O)-, -(CH2)2-S(O)2-, -(CH2)2-C(O)-, -(CH2)2-NR9-, -(CH2)-S(O)2-NH-, -(CH2)-NH-S(O)2-, - (CH2)-C(0)-NH-, -(CH2)-NH-C(0)-, -(CH2)-O-(CH2)-, -(CH2)-S-(CH2)-, -(CH2)-NR9-(CH2)-, -(CH2)3- NR9-, -(CH2)2-S-(CH2)-, -O-(CH2)2-O-, -O-(CH2)2-S-, -O-(CH2)2-S(O)-, -O-(CH2)2-S(O)2-, -S-(CH2)2-S-, - NR9-(CH2)2-S-, or -NR9-C(O)-(CH2)2-.
In some embodiments, L1 and L2 together form -CH=CH-, -(CH2)2-, -(CH2)-0-, -(CH2)-S-, - (CH2)-S(O)-, -(CH2)-S(O)2-, -(CHz)-NR9-, -C(O)-NH-, -S(O)2-NH-, S-S-, -(CH2)2-O-, -(CH2)2-S-, - (CH2)2-S(O)-, -(CH2)2-S(O)2-, -(CHz)2-C(O)-, -(CH2)2-NR9-, -(CH2)-S(O)2-NH-, -(CH2)-NH-S(O)2-, - (CH2)-C(0)-NH-, -(CH2)-NH-C(0)-, -(CH2)-O-(CH2)-, -(CH2)-S-(CH2)-, -(CH2)-NR9-(CH2)-, -(CHz)3-
NR9-, -(CH2)2-S-(CH2)-, -0-(CHz)2-O-, -O-(CH2)2-S-, -O-(CH2)2-S(O)-, -O-(CH2)2-S(O)2-, -S-(CH2)2-S-, - NR9-(CH2)2-S-, or -NH-C(O)-(CH2)2-, wherein each R9 is independently selected from H, Ci-6 alkyl, and C(0)Rbl, and wherein Rbl is selected from Ci-6 alkyl, aryl, and heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, and Ci-6 haloalkyl. As used herein, unless specifically indicated, a linkage— a moiety that links two other moieties— can be attched to the other two moieties in either direction, if the linkage is asymmetric. For example, the moiety formed by L1 and L2 together in compounds of Formula I can be linked to the ring containing A1, B1, D1, and E1 and the containing A2, B2, D2, and E2 in either direction. For example, when L1 and L2 together form -0-(CH2) 2-S-, the sulfur atom (S) can be linked to the ring containing A1, B1, D1, and E1, and oxygen atom (O) to the ring containing A2, B2, D2, and E2. Alternatively, when L1 and L2 together form -0-(CH2) 2-S-, the oxygen atom (O) can be linked to the ring containing A1, B1, D1, and E1, and the sulfur atom (S) to the ring containing A2, B2, D2, and E2. For another example, when W1 in -W'-Q'-Y'-Z1 is 0(CRllaRllb)qiNRf, W1 can be linked to Q1 either via the 0 or the N atom. In some embodiments, the ring containing A1, B1, D1, and E1 is a 6-membered aromatic ring; B1, D1, and E1 are each, independently, CR5 or N; A1 is CH; the ring containing A2, B2, D2, and E2 is a 6- membered aromatic ring; B2, D2, and E2 are each, independently, CR5 or N; A2 is CH; X1 is CR1; X2 is N; X3 is CR3; Y is NR4; and L1 and L2 together form -CR10=CR10-, -(CH2)2-, -(CH2)-O-, -(CH2)-S-, -(CH2)- S(O)-, -(CH2)-S(O)2-, -(CH2)-NR9-, -C(O)-NR9-, -S(O)2-NR9-, S-S-, -(CH2)2-O-, -(CH2)2-S-, -(CH2)2- S(O)-, -(CH2)2-S(O)2-, -(CH2)2-C(O)-, -(CH2)2-NR9-, -(CH2)-S(O)2-NH-, -(CH2)-NH-S(O)2-, -(CH2)- C(O)-NH-, -(CH2)-NH-C(0)-, -(CH2)-O-(CH2)-, -(CH2)-S-(CH2)-, -(CH2)-NR9-(CH2)-, -(CH2)3-NR9-, - (CH2)2-S-(CH2)-, -O-(CH2)2-O-, -O-(CH2)2-S-, -O-(CH2)2-S(O)-, -O-(CH2)2-S(O)2-, -S-(CH2)2-S-, -NR9- (CH2)2-S-, or -NR9-C(O)-(CH2)2-. In some further embodiments, one of B1, D1, and E1 is N, and the other two are each independently CR5; R1 is H; R3 is H, halo, methyl, or Ci haloalkyl; and R4 is H or Ci-3 alkyl.
In some embodiments, the ring containing A1, B1, D1, and E1 is a 6-membered aromatic ring; B1, D1, and E1 are each, independently, CR5 or N; A1 is CH; the ring containing A2, B2, D2, and E2 is a 6- membered aromatic ring; B2, D2, and E2 are each, independently, CR5 or N; A2 is CH; X1 is CR1; X2 is N; X3 is CR3; Y is NR4; and L1 and L2 together form -CH=CH-, -(CH2)2-, -(CH2)-0-, -(CH2)-S-, -(CH2)- S(O)-, -(CH2)-S(O)2-, -(CHz)-NR9-, -C(O)-NR9-, -S(O)2-NR9-, or S-S-. In some further embodiments, L1 and L2 together form -CH=CH-, -(CH2)2-, -(CH2)-0-, -(CH2)-S-, -(CH2)-S(0)-, -(CH2)-S(O)2-, or - (CH2)-NR9-. In yet further embodiments, L1 and L2 together form -(CH2)2-.
In some embodiments, the ring containing A1, B1, D1, and E1 is a 6-membered aromatic ring; B1, D1, and E1 are each, independently, CR5 or N; A1 is CH; the ring containing A2, B2, D2, and E2 is a 6- membered aromatic ring; B2, D2, and E2 are each, independently, CR5 or N; A2 is CH; X1 is CR1; X2 is N; X3 is CR3; Y is NR4; and L1 and L2 together form -CH=CH-, -(CH2)2-, -(CH2)-0-, -(CH2)-S-, -(CH2)- S(O)-, -(CH2)-S(O)2-, or -(CH2)-NR9-. In some further embodiments, one of B1, D1, and E1 is N, and the other two are each independently CR5; R1 is H; R3 is H, halo, methyl, or Ci haloalkyl; and R4 is H or Ci-3 alkyl.
In some embodiments, the ring containing A1, B1, D1, and E1 is a 6-membered aromatic ring; B1, D1, and E1 are each, independently, CR5; A1 is CH; the ring containing A2, B2, D2, and E2 is a 6- membered aromatic ring; B2, D2, and E2 are each, independently, CR5; A2 is CH; X1 is CR1; X2 is N; X3 is
CR3; Y is NR4; and L1 and L2 together form -CH=CH H--,, --((CCHHz2))2Z--,, --((CCHHzz))--OO--,, --((CCHHzz))--SS--,, --((CCHH22))--SS((CO)-, - (CH2)-S(O)2-, -(CH2)-NR9-, -C(O)-NR9-, -S(O)2-NR9-, or S-S-. In some further embodiments, L1 and L2 together form -CH=CH-, -(CH2)Z-, -(CH2)-0-, -(CHz)-S-, -(CHz)-S(O)-, -(CHz)-S(O)2-, or -(CH2)-NR9-. In yet further embodiments, L1 and L2 together form -(CH2)2-.
In some embodiments, the ring containing A1, B1, D1, and E1 is a 6-membered aromatic ring; B1, D1, and E1 are each, independently, CR5 or N; A1 is CH; the ring containing A2, B2, D2, and E2 is a 6- membered aromatic ring; B2, D2, and E2 are each, independently, CR5 or N; A2 is CH; X1 is CR1; X2 is N; X3 is CR3; Y is NR4; and L1 and L2 together form -(CHz)-O-, -(CHz)-S-, -(CHz)-S(O)-, -(CHz)-S(O)2-, - (CH2)-NR9-, -(CH2)Z-O-, -(CH2)Z-S-, -(CH2)2-S(O)-, -(CHz)2-S(O)2-, -(CHz)2-C(O)-, or -(CH2)2-NR9-. In some further embodiments, one of B1, D1, and E1 is N, and the other two are each independently CR5; R1 is H; R3 is H, halo, methyl, or Ci haloalkyl; and R4 is H or Ci_3 alkyl. In yet further embodiments, L1 and L2 together form -(CH2)2-O-.
In some embodiments, the ring containing A1, B1, D1, and E1 is a 6-membered aromatic ring; B1, D1, and E1 are each, independently, CR5; A1 is CH; the ring containing A2, B2, D2, and E2 is a 6- membered aromatic ring; B2, D2, and E2 are each, independently, CR5; A2 is CH; X1 is CR1; X2 is N; X3 is CR3; Y is NR4; and L1 and L2 together form -(CH2)-0-, -(CHz)-S-, -(CHz)-S(O)-, -(CHz)-S(O)2-, -(CH2)- NR9-, -(CHz)2-O-, -(CH2)Z-S-, -(CH2)2-S(O)-, -(CH2)2-S(O)2-, -(CH2)2-C(O)-, or -(CH2)2-NR9-. In some further embodiments, one of B1, D1, and E1 is N, and the other two are each independently CR5; R1 is H; R3 is H, halo, methyl, or Ci haloalkyl; and R4 is H or Ci-3 alkyl. In yet further embodiments, L1 and L2 together form -(CH2)2-O. In some embodiments, each R9 is, independently, H, Ci_6 alkyl, Ci_6 haloalkyl, C(0)Rbl,
C(0)NRclRdl, or C(0)0Ral. In some further embodiments, each R9 is, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C(0)Rbl, or C(0)NRclRdl.
In some embodiments, each R9 is, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C(=0)-(Ci_6 alkyl), C(=O)-(arylalkyl), C(=0)NH2, C(=0)NH(Ci_6 alkyl), C(=0)N(Ci_6 alkyl)2, C(=0)0-(C1-6 alkyl), or C(=O)O-(arylalkyl). In some embodiments, each R9 is, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C(=O)-(Ci_6 alkyl), C(=O)-(arylalkyl), C(=0)NH2, C(=0)NH(Ci_6 alkyl), or C(=0)N(Ci_4 alkyl)2. In some embodiments, each R9 is independently, H or Ci-6 alkyl. In some embodiments, each R9 is independently, H or Ci_4 alkyl. In some embodiments, each R9 is independently, H or Ci-3 alkyl. In some embodiments, each R9 is H. In some embodiments, each R9 is, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, or C(0)Rbl. In some further embodiments, each R9 is, independently, H, Ci-6 alkyl, or C(0)Rbl, wherein Rbl is selected from Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, Ci- 6 haloalkyl, Ci-6 alkoxy, and Ci-6 haloalkoxy. In some embodiments, each R9 is, independently, H, Ci-6 alkyl, or C(0)Rbl. In some further embodiments, Rbl is selected from aryl and heteroaryl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, and Ci-6 haloalkoxy. In yet further embodiments, Rbl is selected from aryl and heteroaryl, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, and Ci-6 haloalkyl. In some embodiments, R7, R8, and R10 are each, independently, selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, cycloalkyl, CN, NO2, ORal, SRal, S(O)Rbl, S(O)NRclRdl, S(O)2R", NRclS(O)2Rbl, S(O)2NRclRdl, C(O)Rbl, C(0)NRclRdl, C(O)ORal, NRclC(0)Rbl, NRclC(0)NRclRdl, and NRclRdl, wherein each of said Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl and cycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C^6 haloalkyl, cycloalkyl, CN, NO2, ORal, SRal, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclC(O)Rbl, NRclC(0)NRclRdl, and NRclRdl.
In some embodiments, R7, R8, and R10 are each, independently, selected from H, halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C^6 haloalkyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, and NRclRdl.
In some embodiments, R7, R8, and R10 are each, independently, selected from H, halo, Ci_6 alkyl, C2_6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, CN, NO2, ORal, and SRal.
In some embodiments, R7, R8, and R10 are each, independently, selected from H, halo, Ci-6 alkyl, Ci_6 haloalkyl, CN, NO2, ORal, and SRal.
In some embodiments, R7, R8, and R10 are each, independently, selected from H, halo, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, or NRclRdl.
In some embodiments, R7, R8, and R10 are each, independently, selected from H, halo, Ci-6 alkyl, CN, NO2, OH, Ci-6 alkoxy, Ci-6 haloalkoxy, and C2.8 alkoxyalkoxy. In some embodiments, R7, R8, and R10 are each, independently, selected from H, Ci-4 alkyl, OH, Ci-6 alkoxy, Ci-6 haloalkoxy, and C2.8 alkoxyalkoxy.
In some embodiments, R7 and R8 are each, independently, selected from H, halo, Ci-6 alkyl, CN, NO2, OH, Ci-6 alkoxy, Ci-6 haloalkoxy, and C2.8 alkoxyalkoxy. In some further embodiments, R7 and R8 are each, independently, selected from H, halo, Ci_4 alkyl, CN, NO2, Ci-4 alkoxy, Ci_4 haloalkoxy, and C2.8 alkoxyalkoxy. In some further embodiments, R7 and R8 are each, independently, selected from H, halo, Ci_4 alkyl, OH, Ci-4 alkoxy, Ci_4 haloalkoxy, and C2.8 alkoxyalkoxy. In some further embodiments, R7 and R8 are each, independently, selected from H, OH, Ci_4 alkoxy, Ci-4 haloalkoxy, and C2.8 alkoxyalkoxy. In some further embodiments, R7 and R8 are each, independently, selected from H, OH, and C2.8 alkoxyalkoxy.
In some embodiments, R7 and R8 are each, independently, selected from H and Ci-6 alkyl. In some further embodiments, R7 and R8 are each, independently, selected from H and Ci-4 alkyl. In some embodiments, R7 and R8 are each, independently, selected from H and Ci_3 alkyl. In some further embodiments, R7 and R8 are each, independently, selected from H and methyl. In yet further embodiments, R7 and R8 are each H.
In some embodiments, each R10 is, independently, selected from H, halo, and Ci_6 alkyl. In some embodiments, each R10 is, independently, selected from H and Ci_6 alkyl. In some embodiments, each R10 is, independently, selected from H and Ci_4 alkyl. In some further embodiments, each R10 is H.
In some embodiments, each R10 is, independently, selected from H and Ci-3 alkyl. In some further embodiments, each R10 is, independently, selected from H and methyl.
In some embodiments, R1 is selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, CN, NO2, ORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, and NRc2Rd2.
In some embodiments, R1 is selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, CN, NO2, -O-(Ci_6 alkyl) and -O-(Ci_6 haloalkyl).
In some embodiments, R1 is selected from H, F, Cl, Br, methyl, ethyl, and Ci-2 haloalkyl.
In some embodiments, R1 is selected from H, F, Cl, and Br. In some embodiments, R1 is selected from H, CH3 and CF3. In some futher embodiments, R1 is H or CH3. In yet futher embodiments, R1 is H.
In some embodiments, each R2 is, independently, selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, CN, NO2, SF5, ORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)OR"2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NRc2C(O)ORa2, NRc2S(O)2NRc2Rd2, NRc2S(O)2Rb2, and NRc2Rd2. In some embodiments, each R2 is, independently, selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl,
CN, NO2, OR"2, C(O)Rb2, C(O)NRc2Rd2, C(O)OR"2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NRc2C(O)ORa2, NRc2S(O)2NRc2Rd2, NRc2S(O)2Rb2, and NRc2Rd2.
In some embodiments, each R2 is, independently, selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, CN, NO2, OR"2, C(O)Rb2, C(O)NRc2Rd2, C(O)OR"2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NRc2C(O)ORa2, NRc2S(O)2Rb2, and NRc2Rd2.
In some embodiments, each R2 is, independently, selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, CN, NO2, OR"2, C(O)Rb2, C(O)NRc2Rd2, C(O)OR"2, and NRc2Rd2.
In some embodiments, each R2 is, independently, selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, CN, NO2, amino, Q-4 alkylamino, C2.8 dialkylamino, NHC(=0)-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)0-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)NH2, NHC(=0)NH-(Ci_4 alkyl), NHC(=0)N- (Ci_4 alkyl)2, NHC(=O)NH-(arylalkyl), NHS(=O)2-(Ci_4 alkyl), and NHS(=O)2-(arylalkyl).
In some embodiments, each R2 is, independently, selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, amino, Ci-4 alkylamino, C2.8 dialkylamino, NHC(=0)-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)0- (C1-4 alkyl), NHC(=O)O-(arylalkyl), NHC(=O)NH2, NHC(=O)NH-(Ci_4 alkyl), NHC(=O)N-(Ci_4 alkyl)2, NHC(=O)NH-(arylalkyl), NHS(=O)2-(Ci_4 alkyl), and NHS(=O)2-(arylalkyl).
In some embodiments, each R2 is, independently, selected from H, halo, Ci-6 alkyl, and Ci-6 haloalkyl. In some embodiments, each R2 is, independently, selected from H, halo, Ci_3 alkyl, and Ci_3 haloalkyl. In some embodiments, each R2 is, independently, selected from H, F, Cl, Br, methyl, ethyl, 1- propyl, 2-propyl, and Ci-2 haloalkyl. In some embodiments, each R2 is, independently, selected from H, F, Cl, Br, methyl, ethyl, 1-propyl, 2-propyl, and CF3. In some embodiments, each R2 is, independently, selected from H, F, Cl, Br, methyl, and CF3. In some embodiments, each R2 is, independently,selected from H, CH3, CF3, and halo. In some embodiments, each R2 is, independently, selected from H, F, Cl, methyl, and CF3. In some futher embodiments, each R2 is, independently, selected from H, F, and Cl.
In some embodiments, each R2 is, independently, selected from H, CH3 and CF3. In some futher embodiments, each R2 is H. In some embodiments, R3 is selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, CN, NO2, SF5, OR12,
C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NR02C(O)OR"2, NRc2S(O)2NRc2Rd2, NRc2S(O)2Rb2, and NRc2Rd2.
In some embodiments, R3 is selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, CN, NO2, SF5, OR12, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NR02C(O)OR"2, NRc2S(O)2NRc2Rd2, NRc2S(O)2Rb2, and NRc2Rd2.
In some embodiments, R3 is selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, CN, NO2, SF5, OR12, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, and NRc2Rd2.
In some embodiments, R3 is selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, amino, Ci_4 alkylamino, and C2.8 dialkylamino. In some embodiments, R3 is selected from H, halo, Ci-3 alkyl, Ci-3 haloalkyl, NH2, NH(Ci_3 alkyl), and N(Ci-3 alkyl)2. In some embodiments, R3 is selected from H, F, Cl, Br, methyl, ethyl, 1-propyl, 2- propyl, Ci-2 haloalkyl, NH2, NH(Ci_3 alkyl), and N(Ci-3 alkyl)2. In some embodiments, R3 is selected from H, F, Cl, Br, methyl, ethyl, 1-propyl, 2-propyl, CF3, NH2, NH(Ci_3 alkyl), and N(Ci-3 alkyl)2. In some embodiments, R3 is selected from H, Cl, Br, methyl, CF3, NH2, NH(Ci_3 alkyl), and N(Ci-3 alkyl)2. In some embodiments, R3 is selected from H, halo, Ci-6 alkyl, and Ci-6 haloalkyl.
In some embodiments, R3 is selected from H, halo, Ci-3 alkyl, and Ci-3 haloalkyl. In some embodiments, R3 is selected from H, F, Cl, Br, methyl, ethyl, 1-propyl, 2-propyl, and Ci-2 haloalkyl. In some embodiments, R3 is selected from H, F, Cl, Br, methyl, ethyl, 1-propyl, 2-propyl, and CF3. In some embodiments, R3 is selected from H, F, Cl, Br, methyl, and CF3. In some embodiments, R is selected from halo. In some embodiments, R is selected from F, Cl, Br. In some further embodiments, R3 is Cl.
In some embodiments, R1 and R3 are each, independently, selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, CN, NO2, SF5, ORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)OR"2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NRc2C(O)ORa2, NRc2S(O)2NRc2Rd2, NRc2S(O)2Rb2, and NRc2Rd2.
In some embodiments, R1 and R3 are each, independently, selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, CN, NO2, SF5, ORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)OR"2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NRc2C(O)ORa2, NRc2S(O)2Rb2, and NRc2Rd2.
In some embodiments, R1 and R3 are each, independently, selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, CN, NO2, SF5, ORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)OR"2, and NRc2Rd2.
In some embodiments, R1 and R3 are each, independently, selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, CN, NO2, SF5, amino, Ci-4 alkylamino, C2.8 dialkylamino, NHC(=0)-(Ci_4 alkyl), NHC(=0)0- (arylalkyl), NHC(=0)0-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)NH2, NHC(=0)NH-(Ci_4 alkyl), NHC(=0)N-(Ci_4 alkyl)2, NHC(=O)NH-(arylalkyl), NHS(=O)2-(Ci_4 alkyl), and NHS(=O)2-(arylalkyl). In some embodiments, R1 and R3 are each, independently, selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, amino, Ci-4 alkylamino, C2.8 dialkylamino, NHC(=0)-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)0-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)NH2, NHC(=O)NH-(Ci_4 alkyl), NHC(=0)N- (Ci-4 alkyl)2, NHC(=O)NH-(arylalkyl), NHS(=O)2-(Ci_4 alkyl), and NHS(=O)2-(arylalkyl).
In some embodiments, R1 and R3 are each, independently, selected from H, halo, Ci_6 alkyl, and Ci_6 haloalkyl.
In some embodiments, R1 and R3 are each, independently, selected from H, halo, Ci_3 alkyl, and Cu haloalkyl. In some embodiments, R1 and R3 are each, independently, selected from H, F, Cl, Br, methyl, ethyl, 1 -propyl, 2-propyl, and Ci_2 haloalkyl. In some embodiments, R1 and R3 are each, independently, selected from H, F, Cl, Br, methyl, ethyl, 1 -propyl, 2-propyl, and CF3. In some embodiments, R1 and R3 are each, selected from H, F, Cl, Br, methyl, and CF3.
In some embodiments, one of R1 and R3 is SF5. In some embodiments, R3 is SF5. In some embodiments, R1 is H and R3 is selected from H, halo, Ci-3 alkyl, and Ci-3 haloalkyl. In some embodiments, R1 is H and R3 is selected from halo, Ci alkyl, and Ci haloalkyl. In some embodiments, R1 is H and R3 is selected from halo. In some embodiments, R1 is H and R3 is Cl.
In some embodiments, R1 and R2 are each, independently, selected from H, halo, Ci_6 alkyl, C2.6 alkenyl, C2_6 alkynyl, Ci-6 haloalkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)OR"2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NRc2C(O)ORa2, C(=NR8)NRc2Rd2, NRc2C(=NR8)NRc2Rd2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, NRc2S(O)2Rb2, or S(O)2NRc2Rd2.
In some embodiments, R1 and R2 are each, independently, selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, CN, NO2, ORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NRc2C(O)ORa2, NRc2S(O)2NRc2Rd2, NRc2S(O)2Rb2, and NRc2Rd2.
In some embodiments, R1 and R2 are each, independently, selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, CN, NO2, ORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, and NRc2Rd2. In some further embodiments, R1 and R2 are each, independently, selected from H, halo, Ci_6 alkyl, and Ci_6 haloalkyl. In some embodiments, R1 and R2 are each, independently, selected from H, methyl, and ethyl. In some embodiments, R1 and R2 are each, independently, selected from H and methyl. In some further embodiments, R1 and R2 are H.
In some embodiments, R1 and R2 are each, independently, selected from H, F, Cl, Br, methyl, ethyl, and Ci-2 haloalkyl. In some further embodiments, R1 and R2 are each, independently, selected from H, F, Cl, methyl, and CF3. In yet further embodiments, R1 and R2 are each, independently, selected from H and methyl. In still further embodiments, R1 and R2 are each H.
In some embodiments, R4 is H or Ci_6 alkyl. In some embodiments, R4 is H.
In some embodiments, each R5 is, independently, selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, Cy1, -W'-Q'-Y'-Z1, CN, NO2, SF5, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NRclRdl, NRclC(O)Rbl, S(O)2Rbl, NRclS(O)2NRclRdl, NRclS(O)2Rbl, and S(O)2NRclRdl, wherein each of said Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, or Ci_6 haloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents each independently selected from halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, halosulfanyl, Cy1,
Figure imgf000038_0001
CN, NO2, SF5, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(O)ORal, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(O)2NRclRdl,S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, S(O)2NRclRdl, P(Rfl)2, P(ORel)2, P(O)RelRfl, and P(O)ORelORfl.
In some embodiments, each R5 is, independently, selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, CN, NO2, SF5, ORal, C(O)Rbl, C(0)NRclRdl, C(O)ORal, NRclRdl, NRclC(0)Rbl, NRclS(O)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl, wherein said Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, or Ci_6 haloalkyl, is optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Q-6 haloalkyl, halosulfanyl, CN, NO2, SF5, ORal, SRal, C(O)Rbl, C(0)NRclRdl, C(O)ORal, OC(O)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, S(O)2NRclRdl, P(Rfl)2, P(ORel)2, P(O)RelRfl, and P(O)ORelORfl. In some embodiments: each R5 is, independently, selected from H, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Cy1, -W'-Q'-Y'-Z1, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NRclRdl, NRclC(O)Rbl, NRclC(O)NRclRdl, NRclS(O)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl, wherein each of said Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, or Ci_6 haloalkyl, is optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, halosulfanyl, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, NRclS(O)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl; or each R5 is, independently, selected from H, halo, Ci_6 alkyl, C^6 haloalkyl, CN, NO2, ORal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclRdl,
NRclC(0)Rbl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl, wherein said C^6 alkyl, C2_ 6 alkenyl, C2.6 alkynyl, or Ci_6 haloalkyl, is optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, halosulfanyl, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl,
NRclS(0)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl; and
Ral, Rbl, Rcl, and Rdl are each, independently, selected from H, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_4 alkyl, Ci_4 haloalkyl, Ci-4 hydroxylalkyl, Ci-4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OH, SH, O(Ci_4 alkyl), O(Ci_4 haloalkyl), O(aryl), O(arylalkyl), S(Ci_4 alkyl), S(Ci_4 haloalkyl), S(aryl), S(arylalkyl), amino, Ci-4 alkylamino, C2.8 dialkylamino, C(=0)H, C(=0)-(Ci_4 alkyl), C(=O)-(arylalkyl), C(=0)NH2, C(=0)NH(Ci_4 alkyl), C(=0)N(Ci_4 alkyl)2, C(=0)0H, C(=0)0-(Ci_4 alkyl), C(=O)O- (arylalkyl), 0C(=0)H, 0C(=0)-(Ci_4 alkyl), OC(=O)-(arylalkyl), 0C(=0)NH2, 0C(=0)NH(Ci_4 alkyl), OC(=O)NH-(arylalkyl), 0C(=0)N(Ci_4 alkyl)2, NHC(=0)-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)0-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHS(=O)2-(Ci_4 alkyl), NHS(=O)2-(arylalkyl), NHS(=O)2-NH(Ci_4 alkyl), NHS(=O)2-N(Ci_4 alkyl)2, NHS(=O)2-NH(arylalkyl), S(=O)2-(Ci_4 alkyl), S(=O)2-(arylalkyl), S(=O)2NH(Ci_4 alkyl) and S(=O)2NH(arylalkyl); or Rcl and Rdl together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 hydroxylalkyl, Ci-4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OH, SH, O(Ci_4 alkyl), O(Ci_4 haloalkyl), O(aryl), O(arylalkyl), S(Ci_4 alkyl), S(d_4haloalkyl), S(aryl), S(arylalkyl), amino, Ci_4 alkylamino, C2_8 dialkylamino, C(=0)H, C(=O)-(Ci_4 alkyl), C(=O)-(arylalkyl), C(=0)NH2, C(=0)NH(Ci_ 4 alkyl), C(=0)N(Ci_4 alkyl)2, C(=0)0H, C(=O)O-(Ci_4 alkyl), C(=O)O-(arylalkyl), 0C(=0)H, OC(=O)- (C1-4 alkyl), OC(=O)-(arylalkyl), 0C(=0)NH2, 0C(=0)NH(Ci_4 alkyl), OC(=O)NH-(arylalkyl), 0C(=0)N(Ci_4 alkyl)2, NHC(=0)-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)0-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHS(=O)2-(Ci_4 alkyl), NHS(=O)2-(arylalkyl), NHS(=O)2-NH(Ci_4 alkyl), NHS(=O)2-N(Ci_4 alkyl)2, NHS(=O)2-NH(arylalkyl), S(=O)2-(Ci_4 alkyl), S(=O)2-(arylalkyl), S(=O)2NH(Ci_4 alkyl) and S(=O)2NH(arylalkyl). In some embodiments: each R5 is, independently, selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, CN, NO2, ORal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclRdl, NRclC(O)Rbl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl, wherein said Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, or Ci-6 haloalkyl, is optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, halosulfanyl, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, NRclS(0)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, or S(0)2NRclRdl;
Ral, Rbl, Rcl, and Rdl are each, independently, selected from H, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_4 alkyl, Ci_4 haloalkyl, Ci-4 hydroxylalkyl, Ci-4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OH, SH, 0(C1-4 alkyl), O(Ci_4 haloalkyl), O(aryl), O(arylalkyl), S(C1-4 alkyl), S(Ci_4 haloalkyl), S(aryl), S(arylalkyl), amino, Ci-4 alkylamino, C2.8 dialkylamino, C(=0)H, C(=0)-(C1-4 alkyl), C(=O)-(arylalkyl), C(=0)NH2, C(=0)NH(Ci_4 alkyl), C(=0)N(Ci_4 alkyl)2, C(=0)0H, C^O)O-(C1-4 alkyl), C(=O)O- (arylalkyl), 0C(=0)H, OC^O)-(C1-4 alkyl), OC(=O)-(arylalkyl), 0C(=0)NH2, 0C(=0)NH(Ci_4 alkyl), OC(=O)NH-(arylalkyl), 0C(=0)N(Ci_4 alkyl)2, NHC(=0)-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)0-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHS(=O)2-(Ci_4 alkyl), NHS(=O)2-(arylalkyl), NHS(=O)2-NH(Ci_4 alkyl), NHS(=O)2-N(Ci_4 alkyl)2, NHS(=O)2-NH(arylalkyl), S(=O)2-(C1-4 alkyl), S(=O)2-(arylalkyl), S(=O)2NH2, S(=O)2NH(Ci_4 alkyl) and S(=O)2NH(arylalkyl); or Rcl and Rdl together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 hydroxylalkyl, Ci-4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OH, SH, O(Ci_4 alkyl), O(Ci_4 haloalkyl), O(aryl), O(arylalkyl), S(Ci_4 alkyl), S(d_4haloalkyl), S(aryl), S(arylalkyl), amino, Ci_4 alkylamino, C2_8 dialkylamino, C(=0)H, C(=O)-(Ci_4 alkyl), C(=O)-(arylalkyl), C(=0)NH2, C(=0)NH(Ci_ 4 alkyl), C(=0)N(Ci_4 alkyl)2, C(=0)0H, C(=O)O-(Ci_4 alkyl), C(=O)O-(arylalkyl), 0C(=0)H, OC(=O)- (C1-4 alkyl), OC(=O)-(arylalkyl), 0C(=0)NH2, 0C(=0)NH(Ci_4 alkyl), OC(=O)NH-(arylalkyl), 0C(=0)N(Ci_4 alkyl)2, NHC(=0)-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)0-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHS(=O)2-(Ci_4 alkyl), NHS(=O)2-(arylalkyl), NHS(=O)2-NH(Ci_4 alkyl), NHS(=O)2-N(Ci_4 alkyl)2, NHS(=O)2-NH(arylalkyl), S(=O)2-(Ci_4 alkyl), S(=O)2-(arylalkyl), S(=O)2NH2, S(=O)2NH(Ci_4 alkyl) and S(=O)2NH(arylalkyl). In some embodiments, at least one of R5 is selected C(0)NRclRdl or NRclRdl, wherein:
Rcl and Rdl are each, independently, selected from H, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_4 alkyl, Ci_4 haloalkyl, Ci_4 hydroxylalkyl, Ci_4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OH, SH, O(Ci_4 alkyl), O(Ci_4 haloalkyl), O(aryl), O(arylalkyl), S(Ci_4 alkyl), S(Ci_4 haloalkyl), S(aryl), S(arylalkyl), amino, Ci-4 alkylamino, C2.8 dialkylamino, C(=0)H, C(=0)-(Ci_4 alkyl), C(=O)-(arylalkyl), C(=0)NH2, C(=0)NH(Ci_4 alkyl), C(=0)N(Ci_4 alkyl)2, C(=0)0H, C(=0)0-(Ci_4 alkyl), C(=O)O- (arylalkyl), 0C(=0)H, 0C(=0)-(Ci_4 alkyl), OC(=O)-(arylalkyl), 0C(=0)NH2, 0C(=0)NH(Ci_4 alkyl), OC(=O)NH-(arylalkyl), 0C(=0)N(Ci_4 alkyl)2, NHC(=0)-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)0-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHS(=O)2-(Ci_4 alkyl), NHS(=O)2-(arylalkyl), NHS(=O)2-NH(Ci_4 alkyl), NHS(=O)2-N(Ci_4 alkyl)2, NHS(=O)2-NH(arylalkyl), S(=O)2-(Ci_4 alkyl), S(=O)2-(arylalkyl), S(=O)2NH2, S(=O)2NH(Ci_4 alkyl) and S(=O)2NH(arylalkyl); or Rcl and Rdl together with the N atom to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 hydroxylalkyl, Ci-4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OH, SH, 0(Ci-4 alkyl), 0(Ci-4 haloalkyl), O(aryl), O(arylalkyl), S(Ci-4 alkyl), S(Ci-4 haloalkyl), S(aryl), S(arylalkyl), amino, Q-4 alkylamino, C2.8 dialkylamino, C(=0)H, C(=0)-(C1-4 alkyl), C(=O)-(arylalkyl), C(=0)NH2, C(=0)NH(Ci_4 alkyl), C(=0)N(Ci_4 alkyl)2, C(=0)0H, C(=O)O- (Ci_4 alkyl), C(=O)O-(arylalkyl), 0C(=0)H, OCC=O)-(C1-4 alkyl), OC(=O)-(arylalkyl), 0C(=0)NH2, 0C(=0)NH(Ci_4 alkyl), OC(=O)NH-(arylalkyl), 0C(=0)N(Ci_4 alkyl)2, NHC(=0)-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)0-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHS(=O)2-(Ci_4 alkyl), NHS(=O)2-(arylalkyl), NHS(=O)2-NH(Ci-4 alkyl), NHS(=O)2-N(d-4 alkyl)2, NHS(=O)2-NH(arylalkyl), SC=O)2-(C1-4 alkyl), S(=O)2-(arylalkyl), S(=O)2NH2, S(=O)2NH(Ci_4 alkyl) and S(=O)2NH(arylalkyl). In some embodiments, at least one of R5 is selected C(O)NRclRdl or NRclRdl, wherein: Rcl and Rdl are each, independently, selected from H, Ci-β alkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 hydroxylalkyl, Ci-4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OH, SH, O(Ci_4 alkyl), O(Ci_4 haloalkyl), O(aryl), O(arylalkyl), S(Ci_4 alkyl), S(Ci_4 haloalkyl), S(aryl), S(arylalkyl), amino, Ci-4 alkylamino, C2.8 dialkylamino, C(=0)H,
Figure imgf000042_0001
alkyl), C(=O)-(arylalkyl), C(=0)NH2, C(=0)NH(Ci_4 alkyl), C(=0)N(Ci_4 alkyl)2, C(=0)0H, CC=O)O-CC1-4 alkyl), CC=O)O- (arylalkyl), 0C(=0)H, OCC=O)-CC1-4 alkyl), OC(=O)-(arylalkyl), OCC=O)NH2, 0C(=0)NH(Ci_4 alkyl), OC(=O)NH-(arylalkyl), 0C(=0)N(Ci_4 alkyl)2, NHC(=O)-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)0-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHS(=O)2-(Ci_4 alkyl), NHS(=O)2-(arylalkyl),
NHS(=O)2-NH(Ci_4 alkyl), NHS(=O)2-N(Ci_4 alkyl)2, NHS(=O)2-NH(arylalkyl), SC=O)2-(C1-4 alkyl), S(=O)2-(arylalkyl), S(=O)2NH2, S(=O)2NH(Ci_4 alkyl) and S(=O)2NH(arylalkyl); or Rcl and Rdl together with the N atom to which they are attached form pyrrolidinyl, piperidinyl or morpholinyl, each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 hydroxylalkyl, Ci-4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OH, SH, OCC1-4 alkyl), O(Ci_4 haloalkyl), O(aryl), O(arylalkyl), SCC1-4 alkyl), S(Ci-4 haloalkyl), S(aryl), S(arylalkyl), amino, Ci-4 alkylamino, C2.8 dialkylamino, C(=0)H, C(=0)-(C1-4 alkyl), C(=O)-(arylalkyl), C(=0)NH2, C(=0)NH(Ci_4 alkyl), C(=0)N(Ci_4 alkyl)2, C(=0)0H, CC=O)O- CC1-4 alkyl), C(=O)O-(arylalkyl), 0C(=0)H, 0C(=0)-(Ci_4 alkyl), OC(=O)-(arylalkyl), 0C(=0)NH2, 0C(=0)NH(Ci_4 alkyl), OC(=O)NH-(arylalkyl), 0C(=0)N(Ci_4 alkyl)2, NHC(=0)-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)0-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHS(=O)2-(Ci_4 alkyl), NHS(=O)2-(arylalkyl), NHS(=O)2-NH(Ci_4 alkyl), NHS(=O)2-N(Ci_4 alkyl)2, NHS(=O)2-NH(arylalkyl), SC=O)2-CCW alkyl), S(=O)2-(arylalkyl), S(=O)2NH2, S(=O)2NH(Ci_4 alkyl) and S(=O)2NH(arylalkyl). In some embodiments, each R5 is, independently, selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, CN, NO2, SF5, ORal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclRdl, NRclC(0)Rbl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl.
In some embodiments, each R5 is, independently, selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, CN, NO2, SF5, ORal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclRdl, NRclC(0)Rbl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl. In some embodiments, each R5 is independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl,
I2, ORal, NRclRdl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)2Rbl, and S(O)2NRclRdl.
In some embodiments, each R5 is independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, ι2, ORal, NRclRdl, NRclS(O)2Rbl, S(O)Rbl, S(O)2Rbl, and S(O)2NRclRdl.
In some embodiments, each R5 is independently selected from H, Ci-6 alkyl, COOH, C(=O)-(Ci_4 alkyl), S(=O)2-(Ci_4 alkyl), S(=O)2NH2, S(=O)2NH(Ci_4 alkyl), NRclS(O)2NRclRdl, C(O)NRclRdl, and NRclRdl.
In some embodiments, each R5 is independently selected from H, Ci_6 alkyl, COOH, C(=O)-(Ci_4 alkyl), S(=O)2-(Ci_4 alkyl), S(=O)2NH2, S(=O)2NH(Ci_4 alkyl), C(0)NRclRdl and NRclRdl, wherein: Rcl and Rdl are each, independently, selected from H, Ci_6 alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of said Ci_6 alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl is optionally substituted with with 1, 2, or 3 substituents independently selected from halo, Ci_4 alkyl, Ci-4 haloalkyl, Ci_4 hydroxylalkyl, Ci_4 cyanoalkyl, aryl, heteroaryl, OH, O(Ci_4 alkyl), O(Ci_4 haloalkyl), piperidinyl, pyrrolidinyl, morpholinyl, and piperizinyl optionally substituted with Ci_4 alkyl, aryl, or arylalkyl; or Rcl and Rdl together with the N atom to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with 1 , 2, or 3 substituents independently selected from Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 hydroxylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, OH, O(Ci_4 alkyl), and O(Ci_4 haloalkyl).
In some embodiments, two adjacent R5 on the same ring can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, halosulfanyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl. In some embodiments, two adjacent R5 on the ring containing A1, B1, D1, and E1 can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, halosulfanyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl. In some embodiments, two adjacent R5 on the ring containing A2, B2, D2, and E2 can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci-6 haloalkyl, halosulfanyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(O)NRclRdl, NRclC(O)ORal, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(O)NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2R", NRclS(O)2Rbl, S(O)2NRclRdl, P(Rfl)2, P(ORel)2, P(O)RelRfl, and P(O)ORelORfl.
In some embodiments, at least one R5 is other than H. In some embodiments, at least one R5 on the ring containing A1, B1, D1, and E1 is other than H. In some embodiments, at least one R5 on the ring containing A2, B2, D2, and E2 is other than H. In some embodiments, one or two R5 on the ring containing A1, B1, D1, and E1 are other than H. In some embodiments, one R5 on the ring containing A1, B1, D1, and E1 is other than H. In some embodiments, one or two R5 on the ring containing A2, B2, D2, and E2 are other than H. In some embodiments, one R5 on the ring containing A2, B2, D2, and E2 is other than H.
In some embodiments, at least one R5 is selected fom halo, Ci_6 alkyl, Ci_6 haloalkyl, cycloalkyl, aryl, hetroaryl, heterocycloalkylalkyl, Cy1,
Figure imgf000044_0001
CN, NO2, ORal, C(O)Rbl, C(0)NRclRdl,
C(O)ORal, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclS(O)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl, wherein said Ci_6 alkyl, Ci_6 haloalkyl, cycloalkyl, aryl, hetroaryl, or heterocycloalkylalkyl, is optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C^6 haloalkyl, halosulfanyl, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, NRclS(0)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, or S(O)2NRclRdl.
In some embodiments, at least one R5 is selected fom halo, Ci_6 alkyl, aryl, hetroaryl, heterocycloalkylalkyl, CN, ORal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl, wherein said Ci_6 alkyl, aryl, hetroaryl, or heterocycloalkylalkyl, is optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, halosulfanyl, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, or S(O)2NRclRdl. In some embodiments, at least one R5 is selected fom C(0)NRclRdl, C(0)0Ral, NRclRdl,
NRclC(0)Rbl, NRclC(0)NRclRdl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl.
In some embodiments, at least one R5 is Cy1 or -W^-Q^-Y^Z1.
In some embodiments, at least one R5 is Cy1. In some embodiments, at least one R5 on the ring containing A1, B1, D1, and E1 is Cy1. In some other embodiments, at least one R5 on the ring containing A2, B2, D2, and E2 is Cy1.
In some embodiments, at least one R5 is Cy1 that is selected from aryl and heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from Ci_6 alkyl, C(O)-O-(Ci_4 alkyl), S(O)2-(Ci_4 alkyl), and piperazinyl, wherein the piperazinyl is optionally substituted with 1 or 2 subsituents independently selected from Ci_6 alkyl, arylalkyl, aryl, heteroaryl, C(O)Rbl, S(O)2Rbl, C(0)NRclRdl, and S(O)2NRclRdl.
In some embodiments, at least one R5 is -W^-Q^Y^Z1. In some embodiments, at least one R5 on the ring containing A1, B1, D1, and E1 is -W^-Q^Y^Z1. In some other embodiments, at least one R5 on the ring containing A2, B2, D2, and E2 is -W^Q^Y^Z1.
In some embodiments, at least one R5 is -Q1^-Z1, -(CH^-Q^-Z1, -0(CR111R111XiC(O)-Q1- Y^Z1, -O(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piC(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, - (CRllaRllb)piC(O)NRe-
Figure imgf000045_0001
-(CRllaRllb)p2NReC(O)-Q1-Y1-Z1, -(CRllaRllb)piNRe-Q1-Y1-Z1, - (CRllaRllb)piO(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piS(CRllaRllb)p2-Q1-Y1-Z1, - (CRllaRllb)piS(O)(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piS(O)2(CRllaRllb)p2-Q1-Y1-Z1, -
(CRllaRllb)piNRe(CRllaRllb)p2-Q1-Y1-Z1, -NReS(O)(CRllaRllb)pi-Q1-Y1-Z1, -S(O)NRe(CRllaRllb)p2-Q1-
Figure imgf000045_0002
Y^Z1, -C(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, or -NReC(O)NRf(CRllaRllb)p2-Q1-Y1-Z1.
In some embodiments, at least one R5 on the ring containing A1, B1, D1, and E1 is -Q1^-Z1, - (CH^-Q^-Z1, -O(CRllaRllb)qiC(O)-Q1-Y1-Z1, -O(CRllaRllb)p2-Q1-Y1-Z1, -
(CRllaRllb)piC(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, - (CRllaRllb)piC(O)NRe-Q1-Y1-Z1, -NRe(CRllaRllb)p2-Q1- Y1-Z1, -(CRllaRllb)p2NReC(O)-Q1-Y1-Z1, -(CRllaRllb)piNRe-Q1-Y1-Z1, -(CRllaRllb)piO(CRllaRllb)p2-Q1- Y^Z1, -(CRllaRllb)piS(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piS(O)(CRllaRllb)p2-Q1-Y1-Z1, - (CRllaRllb)piS(O)2(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piNRe(CRllaRllb)p2-Q1-Y1-Z1, - NReS(O)(CRllaRllb)p1-Q1-Y1-Z1,
Figure imgf000045_0003
-NReS(O)2(CRllaRllb)prQ1-Y1-Z1, - S(O)2NRe(CRllaRllb)p2-Q1-Y1-Z1, -NReC(O)(CRllaRllb)pi-Q1-Y1-Z1, -C(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, or -NR6C(O)NR^CR111R1 l\2-Ql -Y1 -Z1.
In some embodiments, at least one R5 on the ring containing A2, B2, D2, and E2 is -Q1^-Z1, - (CH^-Q^-Z1, -O(CRllaRllb)qiC(O)-Q1-Y1-Z1, -O(CRllaRllb)p2-Q1-Y1-Z1, - (CRllaRllb)piC(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, - (CRllaRllb)piC(O)NRe-Q1-Y1-Z1, -NRe(CRllaRllb)p2-Q1- Y1-Z1, -(CRllaRllb)p2NReC(O)-Q1-Y1-Z1, -(CRllaRllb)piNRe-Q1-Y1-Z1, -(CRllaRllb)piO(CRllaRllb)p2-Q1- Y^Z1, -(CRllaRllb)piS(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piS(O)(CRllaRllb)p2-Q1-Y1-Z1, - (CRllaRllb)piS(O)2(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piNRe(CRllaRllb)p2-Q1-Y1-Z1, - NReS(O)(CRllaRllb)p1-Q1-Y1-Z1, -S^NR'XCR^R^VQ^-Z1, -NReS(O)2(CRllaRllb)prQ1-Y1-Z1, - S(O)2NRe(CRllaRllb)p2-Q1-Y1-Z1, -NReC(O)(CRllaRllb)prQ1-Y1-Z1, -C(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, or -NR6C(O)NR^CR111R111^2-Q1 -Y1 -Z1.
In some embodiments, at least one R on the ring containing A , B , D , and E or on the ring containing A2, B2, D2, and E2 is -W^Q^Y^Z1 that is selected from -(CRllaRllb) 1Pplr "Q1-Y1-Z1,
-(CRllaRllb)piO(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piS(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piS(O)(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piS(O)2(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piNRe(CRllaRllb)p2-Q1-Y1-Z1, -NReS(O)(CRllaRllb)pl-Q1-Y1-Z1,
Figure imgf000046_0001
Y^Z1, -NReS(O)2(CRllaRllb)p1-Q1-Y1-Z1, -S(O)2NRe(CRllaRllb)p2-Q1-Y1-Z1, -NR6C(O)(CR111R11^pI-Q1- Y^Z1, -C(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, and -NReC(O)NRf(CRllaRllb)p2-Q1-Y1-Z1. In some embodiments, at least one R5 on the ring containing A1, B1, D1, and E1 or on the ring containing A2, B2, D2, and E2 is -(CRllaRllb)piO(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piS(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piS(O)(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piS(O)2(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piNRe(CRllaRllb)p2-Q1-Y1-Z1, -NReS(O)(CRllaRllb)p1-Q1-Y1-Z1, -S(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, -NReS(O)2(CRllaRllb)pi-Q1-Y1-Z1, -S(O)2NRe(CRllaRllb)p2-Q1-Y1-Z1, -NReC(O)(CRllaRllb)pi-Q1-Y1-Z1, -C(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, or -NR6C(O)NR^CR1 laR! 11^2-Q1 -Y1 -Z1.
In some embodiments, at least one R5 is -Q1^-Z1, -(CH^-Q^-Z1, -0(CR111R111XiC(O)-Q1- Y^Z1, -O(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piC(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, - (CRllaRllb)piC(O)NRe- Q1^-Z1, -NR'XCR^R^-Q^-Z1, -(CRllaRllb)p2NReC(O)-Q1-Y1-Z1, -(CRllaRllb)piNRe-Q1-Y1-Z1, - (CRllaRllb)pi0(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piNRe(CRllaRllb)p2-Q1-Y1-Z1, -NReS(0)2(CRllaRllb)pi-
Figure imgf000046_0002
or - NReC(O)NRf(CRllaRllb)p2-Q1-Y1-Z1.
In some embodiments, at least one R5 on the ring containing A1, B1, D1, and E1 is at least one R5 is -Q1^-Z1, -(CH^-Q^-Z1, -O(CRllaRllb)qiC(O)-Q1-Y1-Z1, -O(CRllaRllb)p2-Q1-Y1-Z1, - (CRllaRllb)piC(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, - (CRllaRllb)piC(O)NRe-Q1-Y1-Z1, -NR6CCR111R11^p2-Q1- Y1-Z1, -(CRllaRllb)p2NReC(O)-Q1-Y1-Z1, -(CRllaRllb)piNRe-Q1-Y1-Z1, -(CRllaRllb)piO(CRllaRllb)p2-Q1-
Figure imgf000046_0003
- NReC(O)(CRllaRllb)pi-Q1-Y1-Z1, -C(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, or -NReC(O)NRf(CRllaRllb)p2-Q1-Y1- Z1. In some embodiments, at least one R5 on the ring containing A2, B2, D2, and E2 is -Q1^-Z1, -
(CH^-Q^Y^Z1, -O(CRllaRllb)qiC(O)-Q1-Y1-Z1, -O(CRllaRllb)p2-Q1-Y1-Z1, -
(CRllaRllb)piC(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, - (CRllaRllb)piC(O)NRe-Q1-Y1-Z1, -NR6CCR111R11^2-Q1- Y1-Z1, -(CRllaRllb)p2NReC(O)-Q1-Y1-Z1, -(CRllaRllb)piNRe-Q1-Y1-Z1, -(CRllaRllb)piO(CRllaRllb)p2-Q1- Y^Z1, -(CRllaRllb)piNRe(CRllaRllb)p2-Q1-Y1-Z1, -NReS(O)2(CRllaRllb)pl-Q1-Y1-Z1, -
Figure imgf000046_0004
In some embodiments, at least one R5 is
1 (R5-A) wherein: each RQ is independently selected from selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halo, CN, NO2, ORa, SRa, SF5, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(0)Rb, NRcC(0)NRcRd, NRcC(0)0Ra, C(=NR8)NRcRd, NRcC(=NR8)NRcRd, NRcS(0)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, NRcS(0)2Rb, and S(0)2NRcRd; each plO is independently 0, 1, or 2; each pl l is independently 0, 1, or 2;; and each tlO is independently 0, 1, 2, 3, 4, or 5. In some embodiments of (R5-A), W1 is absent, Ci-6 alkylenyl, -O(CRllaRllb)qiC(O)-, -
0(CRllaRllb)p2-, -(CRllaRllb)plC(O)NRe(CRllaRllb)p2-, - (CRllaRllb)plC(0)NRe-, -NR6CCR1 laRllb)p2-, - (CRllaRllb)p2NReC(0)-, -(CRllaRllb)piNRe-, -(CRllaRllb)pi0(CRllaRllb)p2-, -(CRllaRllb)piS(CRllaRllb)p2-, -(CRllaRllb)plS(O)(CRllaRllb)p2-, -(CRllaRllb)plS(O)2(CRllaRllb)p2-, -(CRllaRllb)plNRe(CRllaRllb)p2-, - NReS(0)(CRllaRllb)pr, -S(O)NRe(CRllaRllb)p2-, -NReS(O)2(CRllaRllb)pr, -S(O)2NRe(CRllaRllb)p2-, - NReC(0)(CRllaRllb)pr, -C(O)NR6CCR1 laRllb)p2-, or -NR6C(O)NR^CR1 laRllb)p2-.
In some embodiments of (R5-A), W1 is absent, -(CH2)-, -0(CRllaRllb)qiC(0)-, -O(CRllaRllb)p2-, -(CRllaRllb)piC(O)NR6(CRllaRllb)p2-, - (CRllaRllb)piC(0)NR6-, -NR6(CRllaRllb)p2-, - (CRllaRllb)p2NR6C(0)-, -(CRllaRllb)piNR6-, -(CRllaRllb)pi0(CRllaRllb)p2-, -(CRllaRllb)piS(CRllaRllb)p2-, -(CRllaRllb)piS(O)(CRllaRllb)p2-, -(CRllaRllb)piS(O)2(CRllaRllb)p2-, -(CRllaRllb)piNR6(CRllaRllb)p2-, - NR6S(0)(CRllaRllb)pr, -S(O)NR6(CRllaRllb)p2-, -NR6S(0)2(CRllaRllb)pr, -S(O)2NR6(CRllaRllb)p2-, - NR6C(0)(CRllaRllb)pr, -C(O)NR^CR1 laRllb)p2-, or -NR6C(O)NR^CR1 laRllb)p2-.
In some embodiments, at least one R5 is
Figure imgf000047_0001
(R5-A3) (R5-A4)
Figure imgf000048_0001
wherein: each RQ is independently selected from selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-β alkenyl, C2-β alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halo, CN, NO2, ORa, SRa, SF5, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(O)Rb, NRcC(0)NRcRd, NRcC(0)0Ra, C(=NR8)NRcRd, NRcC(=NR8)NRcRd, NRcS(0)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd; each plO is independently 0, 1, or 2; each pl l is independently 0, 1, or 2;; and each tlO is independently 0, 1, 2, 3, 4, or 5.
In some embodiments of (R5-A), (R5-A1), (R5-A2), (R5-A3), (R5-A4), (R5-A5), (R5-A6), or (R5-A7): each Y1 is independently selected from absent, Ci-6 alkylene, (CR12aR12b)p3O(CR12aR12b)p4, (CR12aR12b)p3S(CR12aR12b)P4, (CR12aR12b)P3NRe(CR12aR12b)P4, (CR12aR12b)p3C(O)(CR12aR12b)P4, (CR12aR12b)p3C(O)O(CR12aR12b)P4, C(S)NR6, (CR12aR12b)p3C(O)NRe(CR12aR12b)P4,
(CR12aR12D)p3S(O)2(CR12aR12V, (CR12aR12D)p3S(O)2NRe(CR12aR12V, and (CR12aR12b)p3NReC(O)NRf(CR12aR12b)p4; and each Z1 is independently selected from H, OH, CN, Ci-6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein each of the Ci-6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2_6 alkenyl, C2-β alkynyl, Ci_6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(O)Rd, NRcC(0)0Ra, NRcS(0)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, and S(0)2NRcRd.
In some embodiments of (R5-A), (R5-A1), (R5-A2), (R5-A3), (R5-A4), (R5-A5), (R5-A6), or (R5-A7), each Z1 is independently selected from aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(O)Rd, NRcC(0)0Ra, NRcS(0)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, and S(0)2NRcRd. In some embodiments of (R5-A), (R5-A1), (R5-A2), (R5-A3), (R5-A4), (R5-A5), (R5-A6), or
(R5-A7): each Y1 is independently selected from absent, (CH2), (CR12aR12b)p3O(CR12aR12b)p4, (CR12aR12b)p3S(CR12aR12b)P4, (CR12aR12b)p3NRe(CR12aR12b)P4, (CR12aR12b)p3C(O)(CR12aR12b)P4, (CR12aR12b)p3C(O)O(CR12aR12b)P4, C(S)NR6, (CR12aR12b)p3C(O)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O)2(CR12aR12b)P4, (CR12aR12b)p3S(O)2NRe(CR12aR12b)p4, and (CR12aR12b)p3NReC(O)NRf(CR12aR12b)p4; and each Z1 is independently selected from H, OH, CN, Ci_6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein each of the Ci_6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(O)Rd, NRcC(0)0Ra, NRcS(0)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, and S(0)2NRcRd.
In some embodiments of (R5-A), (R5-A1), (R5-A2), (R5-A3), (R5-A4), (R5-A5), (R5-A6), or (R5-A7), each Z1 is independently selected from aryl and heteroaryl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(O)Rd, NRcC(0)0Ra, NRcS(O)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, and S(0)2NRcRd.
In some embodiments of (R5-A), (R5-A1), (R5-A2), (R5-A3), (R5-A4), (R5-A5), (R5-A6), or (R5-A7), each Z1 is independently selected from phenyl, pyridinyl, lH-pyrazolyl, isoxazolyl, 1,3- oxazolyl, 1,3-thiazolyl, lH-imidazolyl, lH-l,2,4-triazolyl, IH-1, 2,3 -triazolyl, benzothiazolyl, [l,3]oxazolo[5,4-b]pyridinyl, 1,3,4-thiadiazolyl, furanyl, thienyl, pyrazinyl, pyrimidinyl, benzothiazolyl, furo[3,2-c]pyridinyl, 1 ,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, l,3-benzodioxol-5-yl, and indolyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2_6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(O)Rd, NRcC(0)0Ra, NRcS(0)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, and S(0)2NRcRd. In some embodiments, at least one R5 is
Figure imgf000050_0001
(R5-B).
In some embodiments of (R5-B), W1 is absent, Ci-6 alkylenyl, -O(CRllaRllb)qiC(O)-, -
O(CRl laRllb)p2-, -(CRllaRllb)plC(O)NRe(CRllaRllb)p2-, - (CRl laRllb)plC(O)NRe-, -NR6CCR1 laRllb)p2-, - (CRl laRllb)p2NReC(O)-, -(CRllaRllb)piNRe-, -(CRllaRllb)piO(CRllaRllb)p2-, -(CRllaRllb)piS(CRllaRllb)p2-, -(CRl laRllb)piS(O)(CRllaRllb)p2-, -(CRllaRllb)piS(O)2(CRllaRllb)p2-, -(CRllaRllb)piNRe(CRllaRllb)p2-, - NReS(0)(CRllaRllb)pr, -S(O)NRe(CRllaRllb)p2-, -NReS(O)2(CRllaRllb)pr, -S(O)2NRe(CRllaRllb)p2-, - NReC(0)(CRllaRllb)pr, -C(O)NR6CCR1 laRllb)p2-, or -NR6C(O)NR^CR1 laRllb)p2-.
In some embodiments of (R5-B), W1 is absent, -(CH2)-, -O(CRllaRllb)qiC(O)-, -0(CRllaRllb)p2-, -(CRl laRllb)piC(O)NR6(CRllaRllb)p2-, - (CRllaRllb)piC(0)NR6-, -NR6(CRllaRllb)p2-, - (CRl laRllb)p2NR6C(0)-, -(CRllaRllb)piNR6-, -(CRllaRllb)pi0(CRllaRllb)p2-, -(CRllaRllb)piS(CRllaRllb)p2-, -(CRl laRllb)piS(O)(CRllaRllb)p2-, -(CRllaRllb)piS(O)2(CRllaRllb)p2-, -(CRllaRllb)piNR6(CRllaRllb)p2-, - NR6S(0)(CRllaRllb)pr, -S(O)NR6(CRllaRllb)p2-, -NR6S(0)2(CRllaRllb)pr, -S(O)2NR6(CRllaRllb)p2-, - NR6C(0)(CRllaRllb)pr, -C(O)NR^CR1 laRllb)p2-, or -NR6C(O)NR^CR1 laRllb)p2-.
In some embodiments, at least one R5 is
Figure imgf000050_0002
(R5-B1)
In some embodiments, at least one R5 is
Figure imgf000050_0003
(R5-B2)
In some embodiments of (R5-B), (R5-B1), or (R5-B2): each Y1 is independently selected from absent, Ci_6 alkylene, (CR12aR12b)p3O(CR12aR12b)p4,
, 12aτ> 12b , 12aτ> 12b , 12aτ> 12b-
(CRlzaR1ZD)p3S(CRlzaR1ZD)P4, (CRlzaR1ZD)p3NR6(CR12aR12D)P4, (CR12aR12D)p3C(O)(CR12aR12D)P4, (CR12aR12b)p3C(O)O(CR12aR12b)P4, C(S)NR6, (CR12aR12b)p3C(O)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O)2(CR12aR12b)P4, (CR12aR12b)P3S(O)2NRe(CR12aR12b)P4, and (CR12aR12b)p3NReC(O)NRf(CR12aR12b)p4; and each Z1 is independently selected from H, OH, CN, Ci_6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein each of the Ci_6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(O)Rd, NRcC(0)0Ra, NRcS(0)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, and S(0)2NRcRd. In some embodiments of (R5-B), (R5-B1), or (R5-B2): each Y1 is independently selected from absent, (CH2), (CR12aR12b)p3O(CR12aR12b)p4, (CR12aR12b)p3S(CR12aR12b)P4, (CR12aR12b)P3NRe(CR12aR12b)P4, (CR12aR12b)p3C(O)(CR12aR12b)P4, (CR12aR12b)p3C(O)O(CR12aR12b)P4, C(S)NR6, (CR12aR12b)p3C(O)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O)2(CR12aR12b)P4, (CR12aR12b)p3S(O)2NRe(CR12aR12b)P4, and (CR12aR12b)p3NReC(O)NRf(CR12aR12b)p4; and each Z1 is independently selected from H, OH, CN, Ci_6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein each of the Ci_6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(O)Rd, NRcC(0)0Ra, NRcS(0)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, and S(0)2NRcRd.
In some embodiments of (R5-B), (R5-B1), or (R5-B2), each Z1 is independently selected from aryl and heteroaryl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(O)Rd, NRcC(0)0Ra, NRcS(O)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, and S(0)2NRcRd.
In some embodiments of (R5-B), (R5-B1), or (R5-B2), each Z1 is independently selected from phenyl, pyridinyl, lH-pyrazolyl, isoxazolyl, 1,3-oxazolyl, 1,3-thiazolyl, lH-imidazolyl, IH-1, 2,4- triazolyl, IH-1, 2,3 -triazolyl, benzothiazolyl, [l,3]oxazolo[5,4-b]pyridinyl, 1,3,4-thiadiazolyl, furanyl, thienyl, pyrazinyl, pyrimidinyl, benzothiazolyl, furo[3,2-c]pyridinyl, 1 ,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, l,3-benzodioxol-5-yl, and indolyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, NRcS(O)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd.
In some embodiments, Q1, Q2, Q3, Q4, and Q5 are each, independently, selected cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino.
In some embodiments, each Q1 is independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Q-6 alkyl, Q-6 haloalkyl, C2.8 alkoxyalkyl, C1-6 alkoxy, Q-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, C1-6 alkylamino and C2.8 dialkylamino.
In some embodiments, each Q1 is independently selected from cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino. In some further embodiments, each Q1 is independently selected from such optionally substituted cycloalkyl. In other further embodiments, each Q1 is independently selected from such optionally substituted heterocycloalkyl. In some embodiments, each Q1 is independently selected heterocycloalkyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(0)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino.
In some embodiments, each Q1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, (lH)-hexahydropyrrolo[l,2- a]pyrazin-2-yl, and (8H)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7-yl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(0)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino. In some further embodiments, each Q1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino. In other further embodiments, each Q1 is independently selected from azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2-8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino.
In some embodiments, each Q1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2_8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(0)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino. In some further embodiments, each Q1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino. In other further embodiments, each Q1 is independently selected from azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(0)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino.
In some embodiments, each Q1 is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino.
In some embodiments, each Q1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, and piperidinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(0)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino.
In some embodiments, each Q1 is independently selected from pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Q-6 haloalkyl, C2.8 alkoxyalkyl, Q-6 alkoxy, Q-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(0)NRcRd, amino, Q-6 alkylamino and C2.8 dialkylamino.
In some embodiments, each Q1 is independently selected from pyrrolidinyl, and piperidinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, C i-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(0)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino. In some embodiments, at least one R5 is -W6-Q1-Y1-Z1.
In some embodiments, at least one R5 is -(CRllaRllb)piS(CRllaRllb)p2-Q1-Y1-Z1, -(CRl laRllb)piS(O)(CRllaRllb)P2-Q1-Y1-Z1, -(CRllaRllb)piS(O) 2(CRllaRllb)P2-Q1-Y1-Z1, -(CRl laRllb)piS(O)NRe(CRllaRllb)P2-Q1-Y1-Z1, -(CRllaRllb)p2NReS(O)(CRllaRllb)pi-Q1-Y1-Z1, (CRl laRllb)piS(O)2NRe(CRllaRllb)P2-Q1-Y1-Z1, or -(CRllaRllb)p2NReS(O)2(CRllaRllb)pi-Q1-Y1-Z1.
In some embodiments, each Y1 is independently selected from absent, Ci_6 alkylenyl, (CR12aR12b)p3O(CR12aR12b)P4, (CR12aR12b)p3S(CR12aR12b)P4, (CR12aR12b)p3NRe(CR12aR12b)P4, (CR12aR12b)p3C(O)(CR12aR12b)P4, (CR12aR12b)p3C(O)O(CR12aR12b)P4, C(S)NR6,
(CR12aR12b)p3C(O)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O)2(CR12aR12b)P4, (CR12aR12b)p3S(O)2NRe(CR12aR12b)P4, and (CR12aR12b)p3NReC(O)NRf(CR12aR12b)p4.
In some embodiments, each Y1 is independently selected from absent, (CH2), (CR12aR12b)p3O(CR12aR12b)P4, (CR12aR12b)p3S(CR12aR12b)P4, (CR12aR12b)p3NRe(CR12aR12b)p4, (CR12aR12b)p3C(O)(CR12aR12b)P4, (CR12aR12b)p3C(O)O(CR12aR12b)P4, C(S)NR6,
(CR12aR12b)p3C(O)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O)2(CR12aR12b)P4, (CR12aR12b)p3S(O)2NRe(CR12aR12b)P4, and (CR12aR12b)p3NReC(O)NRf(CR12aR12b)p4.
In some embodiments, each Y1 is independently selected from absent, Ci_6 alkylenyl, (CR12aR12b)p3C(O)(CR12aR12b)P4, (CR12aR12b)p3C(O)O(CR12aR12b)P4, C(S)NR6, (CR12aR12b)p3C(O)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O) 2(CR12aR12b)p4, and (CR12aR12b)p3NReC(O)NRf(CR12aR12b)p4. In some embodiments, each Y1 is independently selected from absent, (CH2),
(CR12aR12b)p3C(O)(CR12aR12b)P4, (CR12aR12b)p3C(O)O(CR12aR12b)P4, C(S)NR6, (CR12aR12b)p3C(O)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O) 2(CR12aR12b)p4, and (CR12aR12b)p3NReC(O)NRf(CR12aR12b)p4.
In some embodiments, each Y1 is independently selected from absent, (CR12aR12b)p3O(CR12aR12V (CR12aR12b)p3S(CR12aR12b)p4, (CR12aR12b)p3NRe(CR12aR12b)p4,
(CR12aR12b)p3C(O)(CR12aR12b)P4, (CR12aR12b)p3C(O)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O) 2(CR12aR12b)P4, (CR12aR12b)p3S(O)2NRe(CR12aR12b)P4, and (CR12aR12b)p3NReC(O)NRf(CR12aR12b)p4.
In some embodiments, each Z1 is independently selected from H, OH, CN, Ci_6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein each of the Ci_6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted by 1 , 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, NRcS(O)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd. In some embodiments, each Z1 is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2-β alkenyl, C2-β alkynyl, Ci-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(0)Rd, NRcC(0)0Ra, NRcS(O)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, and S(0)2NRcRd.
In some embodiments, each Z1 is independently selected from aryl, cycloalkyl, heteroaryl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(0)Rd, NRcC(0)0Ra, NRcS(O)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, and S(0)2NRcRd.
In some embodiments, each R6 is, independently, H, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, S(O)Rbl, S(O)2Rbl, or S(0)2NRclRdl. In some further embodiments, each R6 is, independently, H, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, or Ci_6 haloalkyl. In yet furether embodiments, each R6 is, independently, H or Ci_6 alkyl. In still furether embodiments, each R6 is H or Ci-3 alkyl.
In some embodiments, each R6 is, independently, H, Ci-3 alkyl, C2.3 alkenyl, C2.3 alkynyl, or Ci-3 haloalkyl. In some furether embodiments, each R6 is, independently, H, Ci-3 alkyl, or Ci-3 haloalkyl. In some furether embodiments, each R6 is, independently, H or Ci-3 alkyl. In some embodiments, each R6 is, independently, H or methyl. In some embodiments, each R6 is
H. In some other embodiments, one R6 is methyl.
In some embodiments, Rlla, Rllb, R12a, and R12b are each, independently, selected from H, halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(0)NRclRdl, C(O)ORal, OC(O)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl,
NRclS(O)2Rbl, and S(O)2NRclRdl, wherein each of said Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, or C1-6 haloalkyl, is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Q-6 haloalkyl, halosulfanyl, CN, NO2, ORal, SRal, SF5, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl
In some embodiments, Rlla, Rllb, R12a, and R12b are each, independently, selected from H, halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, CN, NO2, OH, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkyl, cycloalkyl, heterocycloalkyl, C(0)0Ral, C(O)NRclRdl, amino, Ci-6 alkylamino and C2-8 dialkylamino.
In some embodiments, Rlla, Rllb, R12a, and R12b are each, independently, selected from H and Ci-6 alkyl. In some further embodiments, Rlla, Rllb, R12a, and R12b are each, independently, selected from H and Ci-3 alkyl.
In some embodiments, Rlla, Rllb, R12a, and R12b are each, independently, selected from H and methyl. In some further embodiments, Rlla, Rllb, R12a, and R12b are each H.
In some embodiments, each R13 is independently selected from H, halo, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci-6 haloalkyl, CN, NO2, ORal, SRal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)NRclRdl, NRclC(O)ORal, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl, wherein each of said Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, or Ci-6 haloalkyl, is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, halosulfanyl, CN, NO2, ORal, SRal, SF5, C(O)Rbl, C(O)NRclRdl, C(O)ORal, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(O)ORal, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl, P(Rfl)2, P(ORel)2
In some embodiments, each R13 is independently selected from H, halo, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci-6 haloalkyl, CN, NO2, OH, Ci-6 alkoxy, Ci-6 haloalkoxy, C2-8 alkoxyalkyl, cycloalkyl, heterocycloalkyl, C(O)ORal, C(0)NRclRdl, amino, Ci-6 alkylamino and C2.8 dialkylamino. In some further embodiments, each R13 is H or Ci-6 alkyl. In yet further embodiments, each R13 is H.
In some embodiments, each pi is, independently, 0 or 1. In some other embodiments, each pi is, independently, 1 or 2.
In some embodiments, each p2 is, independently, 0 or 1. In some other embodiments, each p2 is, independently, 1 or 2.
In some embodiments, each p3 is, independently, 0 or 1. In some other embodiments, each p3 is, independently, 1 or 2.
In some embodiments, each p4 is, independently, 0 or 1. In some other embodiments, each p4 is, independently, 1 or 2. In some embodiments, each ql is 1. In some other embodiments, each ql is 2.
In some embodiments, each q2 is 1. In some other embodiments, each q2 is 2.
In some embodiments, each n is, independently, 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2.
In some embodiments, n is 3. In some embodiments, each m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is l.
In some embodiments, m is 2.
In some embodiments, X1 is CH; X2 is N; X3 is CR3; R3 is halo; Y is NH or N(Ci-3 alkyl); and at least one R5 is selected fom C(O)NRclRdl, C(O)ORal, NRclRdl, NRclC(O)Rbl, NRclC(O)NRclRdl,
NRclS(O)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, S(O)2NRclRdl, Cy1, and -W'-Q'-Y'-Z1. In some further embodiments, at least one R5 is -W^-Q^-Y^Z1. In some further embodiments, at least one R5 on the ring containing A1, B1, D1, and E1 is -W^-Q^-Y^Z1. In some other embodiments, at least one R5 on the ring containing A2, B2, D2, and E2 is -W^-Q^-Y^Z1. In further embodiments, each Q1 is independently selected from cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci_6 alkyl, Ci_6 haloalkyl, C2.8 alkoxyalkyl, Ci_6 alkoxy, Ci_6haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)ORa, C(O)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino. In yet further embodiments, each Q1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2,
OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino.
In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, the ring containing A1, B1, D1, and E1 is a pyridine ring, wherein said pyridine ring is optionally substituted by R2, if present, and optionally by 1 or 2 R5; and the ring containing A2, B2, D2, and E2 is a benzene ring, wherein said benzene ring optionally substituted by R2, if present, and optionally by 1 , 2, or 3 R5.
In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, the ring containing A1, B1, D1, and E1 is a pyridine ring, wherein said pyridine ring is optionally substituted by 1 or 2 R5; and the ring containing A2, B2, D2, and E2 is a benzene ring, wherein said benzene ring substituted by -W^-Q^-Y^Z1 and optionally substituted by 1 or 2 R5. In further embodiments, each Q1 is independently selected from cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, C1-6 alkylamino and C2.8 dialkylamino. In yet further embodiments, each Q1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-ehaloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2-8 dialkylamino.
In some embodiments, the compounds of Formula I of the present invention have Formula II:
Figure imgf000058_0001
wherein: each R5a is, independently, selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, CN, NO2, SF5, ORal, C(O)Rbl, C(0)NRclRdl, C(O)ORal, NRclRdl, NRclC(0)Rbl, NRclS(O)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl; or two adjacent R5a can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, CN, NO2, SF5, ORal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclRdl, NRclC(O)Rbl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl; and each R5b is, independently, selected from H, halo, Q-6 alkyl, C1-6 haloalkyl, CN, NO2, SF5, ORal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclRdl, NRclC(O)Rbl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl; or two adjacent R5b can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, CN, NO2, SF5, ORal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclRdl, NRclC(O)Rbl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl.
In some embodiments of the compounds of Formula II or pharmaceutically acceptable salts thereof: each R5a is, independently, selected from H halo, Ci-6 alkyl, Ci-6 haloalkyl, CN, NO2, SF5, ORal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclRdl, NRclC(0)Rbl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(O)2NRclRdl; and each R5b is, independently, selected from H halo, Ci-6 alkyl, Ci-6 haloalkyl, CN, NO2, SF5, ORal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclRdl, NRclC(0)Rbl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl. In some embodiments of the compounds of Formula II or pharmaceutically acceptable salts thereof, Y is O, S, or NR4. In some further embodiments, Y is NH or N(Cu alkyl). In yet further embodiments, Y is NH.
In some embodiments of the compounds of Formula II or pharmaceutically acceptable salts thereof, X3 is N, and X2 is CR2.
In some embodiments of the compounds of Formula II or pharmaceutically acceptable salts thereof, each R2 is, independently, selected from H, F, Cl, Br, methyl, and CF3. In some futher embodiments, each R2 is H.
In some embodiments of the compounds of Formula II or pharmaceutically acceptable salts thereof, X2 is N, and X3 is CR3. In some further embodiments, R3 is halo. In yet further embodiments, R3 is F or Cl. In still further embodiments, R3 is Cl.
In some embodiments, the compounds of Formula II have Formula Ha:
Figure imgf000059_0001
Ha In some embodiments of the compounds of Formula Ha or pharmaceutically acceptable salts thereof, each R5a is independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, S(O)2R", NRclS(O)2NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, and NRclS(O)2Rbl.
In some embodiments of the compounds of Formula Ha or pharmaceutically acceptable salts thereof, each R5a is independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, ORal, C(O)Rbl, NRclRdl, NRclC(O)Rbl, NRclC(O)NRclRdl, NRclC(O)ORal, NRclS(O)2NRclRdl, and NRclS(O)2Rbl.
In some embodiments of the compounds of Formula Ha or pharmaceutically acceptable salts thereof, each R5a is H.
In some embodiments of the compounds of Formula Ha or pharmaceutically acceptable salts thereof, one R5a is other than H.
In some embodiments of the compounds of Formula Ha or pharmaceutically acceptable salts thereof, two R5a are other than H.
In some embodiments of the compounds of Formula Ha or pharmaceutically acceptable salts thereof, three R5a are other than H. In some embodiments of the compounds of Formula Ha or pharmaceutically acceptable salts thereof, at least one R5a is other than H.
In some embodiments of the compounds of Formula Ha or pharmaceutically acceptable salts thereof, at least one R5a is selected C(O)Rbl, C(O)NRclRdl, C(O)ORal, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(O)ORal, NRclS(O)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl, wherein:
Ral, Rbl, Rcl, and Rdl are each, independently, selected from H, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 hydroxylalkyl, Ci-4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OH, SH, 0(C1-4 alkyl), O(Ci_4 haloalkyl), O(aryl), O(arylalkyl), S(C1-4 alkyl), S(Ci_4 haloalkyl), S(aryl), S(arylalkyl), amino, Ci-4 alkylamino, C2.8 dialkylamino, C(=0)H, C(=0)-(C1-4 alkyl), C(=O)-(arylalkyl), C(=0)NH2, C(=0)NH(Ci_4 alkyl), C(=0)N(Ci_4 alkyl)2, C(=0)0H, C(=0)0-(C1-4 alkyl), C(=O)O-
(arylalkyl), 0C(=0)H, 0C(=0)-(C1-4 alkyl), OC(=O)-(arylalkyl), 0C(=0)NH2, 0C(=0)NH(Ci_4 alkyl), OC(=O)NH-(arylalkyl), 0C(=0)N(Ci_4 alkyl)2, NHC(=0)-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)0-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHS(=O)2-(Ci_4 alkyl), NHS(=O)2-(arylalkyl), NHS(=O)2-NH(Ci_4 alkyl), NHS(=O)2-N(Ci_4 alkyl)2, NHS(=O)2-NH(arylalkyl), S^O)2-(C1-4 alkyl), S(=O)2-(arylalkyl), S(=O)2NH2, S(=O)2NH(Ci-4 alkyl) and S(=O)2NH(arylalkyl); or Rcl and Rdl together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 hydroxylalkyl, Ci-4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OH, SH, 0(Ci-4 alkyl), 0(Ci-4 haloalkyl), O(aryl), O(arylalkyl), S(Ci_4 alkyl), S(Ci_4 haloalkyl), S(aryl), S(arylalkyl), amino, Ci_4 alkylamino, C2.8 dialkylamino, C(=0)H, C(=0)-(Ci-4 alkyl), C(=O)-(arylalkyl), C(=0)NH2,
Figure imgf000060_0001
4 alkyl), C(=0)N(Ci_4 alkyl)2, C(=0)0H, Q=O)O-(C1-4 alkyl), C(=O)O-(arylalkyl), 0C(=0)H, OQ=O)- (Ci_4 alkyl), OC(=O)-(arylalkyl), 0C(=0)NH2, 0C(=0)NH(Ci_4 alkyl), OC(=O)NH-(arylalkyl), 0C(=0)N(Ci_4 alkyl)2, NHC(=0)-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)0-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHS(=O)2-(Ci_4 alkyl), NHS(=O)2-(arylalkyl), NHS(=O)2-NH(Ci_4 alkyl),
NHS(=O)2-N(Ci_4 alkyl)2, NHS(=O)2-NH(arylalkyl), S^O)2-(C1-4 alkyl), S(=O)2-(arylalkyl), S(=O)2NH2, S(=O)2NH(Ci_4 alkyl) and S(=O)2NH(arylalkyl).
In some embodiments of the compounds of Formula Ha or pharmaceutically acceptable salts thereof, at least one of R5a is selected NRclRdl, and Rcl and Rdl together with the N atom to which they are attached form pyrrolidinyl, piperidinyl or morpholinyl, each optionally substituted with 1 , 2, or 3 substituents independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 hydroxylalkyl, Ci-4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OH, SH, O(Ci_4 alkyl), O(Ci_4 haloalkyl), O(aryl), O(arylalkyl), S(C1-4 alkyl), S(Ci_4 haloalkyl), S(aryl), S(arylalkyl), amino, Ci_4 alkylamino, C2-8 dialkylamino, C(=0)H, C(=O)-(Ci-4 alkyl), C(=O)-(arylalkyl), C(=0)NH2, C(=0)NH(Ci_ 4 alkyl), C(=0)N(Ci_4 alkyl)2, C(=0)0H, C(=O)O-(C1-4 alkyl), C(=O)O-(arylalkyl), 0C(=0)H, OC(=O)- (Ci_4 alkyl), OC(=O)-(arylalkyl), 0C(=0)NH2, 0C(=0)NH(Ci_4 alkyl), OC(=O)NH-(arylalkyl), 0C(=0)N(Ci_4 alkyl)2, NHC(=0)-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)0-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHS(=O)2-(Ci_4 alkyl), NHS(=O)2-(arylalkyl), NHS(=O)2-NH(Ci_4 alkyl), NHS(=O)2-N(Ci_4 alkyl)2, NHS(=O)2-NH(arylalkyl), S(=O)2-(C1-4 alkyl), S(=O)2-(arylalkyl), S(=O)2NH2, S(=O)2NH(Ci-4 alkyl) and S(=O)2NH(arylalkyl).
In some embodiments of the compounds of Formula Ha or pharmaceutically acceptable salts thereof, each R5b is H.
In some embodiments of the compounds of Formula Ha or pharmaceutically acceptable salts thereof, one of R5b is other than H.
In some embodiments of the compounds of Formula Ha or pharmaceutically acceptable salts thereof, two of R5b are other than H.
In some embodiments of the compounds of Formula Ha or pharmaceutically acceptable salts thereof, three of R5b are other than H. In some embodiments of the compounds of Formula Ha or pharmaceutically acceptable salts thereof, at least one of R5b is other than H.
In some embodiments, the compounds of Formula Ha have Formula lib:
Figure imgf000061_0001
lib In some embodiments, the compounds of Formula Ha have Formula Ha- 1 :
Figure imgf000062_0001
Ha- 1 In some embodiments, the compounds of Formula Ha have Formula IIa-2:
Figure imgf000062_0002
In some embodiments of the compounds of Formula Ha, lib, Ha- 1, IIa-2, X2 is N; and X3 is CR3. In some further embodiments, R3 is halo. In yet further embodiments, R3 is F or Cl. In still further embodiments, R3 is Cl.
In some embodiments, the compounds of Formula II have Formula Hc:
Figure imgf000062_0003
lie
In some embodiments of the compounds of Formula Hc or pharmaceutically acceptable salts thereof, each R2 is, independently, selected from H, F, Cl, Br, methyl, and CF3. In some futher embodiments, each R2 is H.
In some embodiments of the compounds of Formula Hc or pharmaceutically acceptable salts thereof, R3 is halo. In some further embodiments, R3 is F or Cl. In yet further embodiments, R3 is Cl.
In some embodiments, the compounds of Formula II have Formula Hd:
Figure imgf000063_0001
Hd.
In some embodiments of the compounds of Formula Hd, or pharmaceutically acceptable salts thereof, Y is NH or N(Ci_3 alkyl). In some further embodiments, Y is NH.
In some embodiments of the compounds of Formula Hd or pharmaceutically acceptable salts thereof, each R2 is, independently, selected from H, F, Cl, Br, methyl, and CF3. In some futher embodiments, each R2 is H.
In some embodiments of the compounds of Formula Hd or He, X2 is N.
In some embodiments, the compounds of Formula II have Formula He:
Figure imgf000063_0002
He.
In some embodiments of the compounds of Formula He or pharmaceutically acceptable salts thereof, each R2 is, independently, selected from H, F, Cl, Br, methyl, and CF3. In some futher embodiments, each R2 is H.
In some embodiments of the compounds of Formula He or pharmaceutically acceptable salts thereof, Y is NH.
In some embodiments, the compounds of Formula I of the present invention have Formula Ilia:
Figure imgf000064_0001
or are pharmaceutically acceptable salts thereof, wherein D1, E1, D2, and E2 are each, independently, CR5 or N.
In some embodiments, the compounds of Formula I of the present invention have Formula IHb:
Figure imgf000064_0002
or are pharmaceutically acceptable salts thereof, wherein D1, E1, and D2 are each, independently, CR5 or
N.
In some embodiments, the compounds of Formula I of the present invention have Formula IHc:
Figure imgf000064_0003
IIIc or are pharmaceutically acceptable salts thereof, wherein D1 and E1 are each, independently, CR5 or N. In some embodiments, the compounds of Formula I of the present invention have Formula IHd:
Figure imgf000065_0001
IHd or are pharmaceutically acceptable salts thereof, wherein E1 is CR5 or N.
In some embodiments, the compounds of Formula I of the present invention have Formula IHe:
Figure imgf000065_0002
IHe or are pharmaceutically acceptable salts thereof, wherein D1 is CR5 or N.
In some embodiments, the compounds of Formula I of the present invention have Formula HIf:
Figure imgf000065_0003
IHf or are pharmaceutically acceptable salts thereof, wherein D1 and E1 are each, independently, CR5 or N. In some embodiments, the compounds of Formula I of the present invention have Formula HIg:
Figure imgf000066_0001
IHg or are pharmaceutically acceptable salts thereof, wherein D1 is CR5 or N.
In some embodiments, the compounds of Formula I of the present invention have Formula IHh:
Figure imgf000066_0002
IHh or are pharmaceutically acceptable salts thereof, wherein E1 is CR5 or N.
In some embodiments, the compounds of Formula I of the present invention have Formula IVa:
Figure imgf000066_0003
IVa or are pharmaceutically acceptable salts thereof.
In some embodiments, the compounds of Formula I of the present invention have Formula IVb:
Figure imgf000067_0001
IVb or are pharmaceutically acceptable salts thereof.
In some embodiments, the compounds of Formula I of the present invention have Formula IVc:
Figure imgf000067_0002
IVc or are pharmaceutically acceptable salts thereof.
In some embodiments, the compounds of Formula I of the present invention have Formula IVd:
Figure imgf000067_0003
IVd or are pharmaceutically acceptable salts thereof.
In some embodiments, the compounds of Formula I of the present invention have Formula V:
Figure imgf000068_0001
V or are pharmaceutically acceptable salts thereof, wherein:
D1 and E1, each, independently, CR5 or N; each RQ is independently selected from selected from Ci_6 alkyl, Ci_6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halo, CN, NO2, ORa, SRa, SF5, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(0)Rb, NRcC(0)NRcRd, NRcC(0)0Ra, C(=NR8)NRcRd, NRcC(=NR8)NRcRd, NRcS(0)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, NRcS(0)2Rb, and S(0)2NRcRd; plO is O or 1; pi 1 is 0 or 1; and tlO is O, 1, 2, 3, 4, or 5.
In some embodiments, the compounds of Formula I of the present invention have Formula Va:
Figure imgf000068_0002
Va or are pharmaceutically acceptable salts thereof, wherein:
E1 is CR5 or N; each RQ is independently selected from selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-β alkenyl, C2-β alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halo, CN, NO2, ORa, SRa, SF5, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb,
0C(0)NRcRd, NRcRd, NRcC(0)Rb, NRcC(0)NRcRd, NRcC(0)0Ra, C(=NR8)NRcRd, NRcC(=NR8)NRcRd, NRcS(0)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, NRcS(0)2Rb, and S(0)2NRcRd; plO is O or 1; pi 1 is 0 or 1; and tlO is O, 1, 2, 3, 4, or 5.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof: each R5 is, independently, H, Cy1, halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, halosulfanyl, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(S)Rbl, C(S)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(S)Rbl, NRclC(S)NRclRdl, NRclC(0)0Ral, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, S(O)2NRclRdl, or -W^Q^-Z1; or two adjacent R5 on the same ring can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci_6 alkyl, C2-6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, Cy1, oxo, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, SF5, C(S)Rbl, C(S)NRclRdl, C(0)0Ral, 0C(0)Rbl, -W^Q^-Z1, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(S)Rbl, NRclC(S)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl, wherein each of the Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Q-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, Cy1, - W1 -Q1^-Z1, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0CH2C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof: each R5 is, independently, H, Cy1, halo, Ci-6 alkyl, C2-β alkenyl, C2-β alkynyl, Ci-6 haloalkyl, halosulfanyl, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(S)Rbl, C(S)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(S)Rbl, NRclC(S)NRclRdl, NRclC(0)0Ral, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, S(O)2NRclRdl, or -W^Q^-Z1; or two adjacent R5 on the same ring can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci_6 alkyl, C2_6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, Cy1, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, SF5, C(S)Rbl, C(S)NRclRdl, C(0)0Ral, 0C(0)Rbl, -W^Q^-Z1, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(S)Rbl, NRclC(S)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl, wherein each of the Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, Cy1,
Figure imgf000070_0001
CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0CH2C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(O)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl.
In some embodiments, the compound of Formula IHf is a compound of Fomula IIIf-1 :
Figure imgf000070_0002
IIIf-1 wherein R301 is selected from H, halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, Cy1, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, SF5, C(S)Rbl, C(S)NRclRdl, C(0)0Ral, 0C(0)Rbl, -W^Q^-Z1, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(S)Rbl, NRclC(S)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl, wherein each of the Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Cy1, - W1 -Q1^-Z1, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0CH2C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl.
In some embodiments of compounds of Formula IHf-I, R is selected from H, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, Cy1, C(0)Rbl, C(0)NRclRdl, SF5, C(S)Rbl, C(S)NRclRdl, C(0)0Ral, 0C(0)Rbl, -W^Q^-Z1, C(=NR8)NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, and S(O)2NRclRdl, wherein each of the C^6 alkyl, C2_6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2_6 alkynyl, C^6 haloalkyl, Cy1, -W^Q^-Z1, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0CH2C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(O)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl. In some further embodiments, R301 is selected from H, Ci-6 alkyl, and -W^Q^Y^Z1, wherein the Ci-6 alkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci-6 haloalkyl, Cy1, - W1 -Q1^-Z1, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0CH2C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl. In still further embodiments, R301 is -W^Q^Y^Z1.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, HIg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof: each R5 is, independently, H, Cy1, halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, halosulfanyl, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(S)Rbl, C(S)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(S)Rbl, NRclC(S)NRclRdl, NRclC(0)0Ral, NRclS(O)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, or -W^Q^-Z1; or two adjacent R5 on the same ring link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C2_6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halosulfanyl, Cy1, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(S)Rbl, C(S)NRclRdl, C(0)0Ral, 0C(0)Rbl, -W^Q^-Z1, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl. In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, at least one R5 is -W^-Q^Y^Z1. In some further embodiments, at least one R5 on the ring containing A2, B2, D2, and E2 is -W^-Q^Y^Z1.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, at least one R5 is Cy1.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, at least one R5 is Cy1 that is selected from aryl and heteroaryl, each optionally substituted with 1 , 2, or 3 substituents independently selected from Ci_6 alkyl, C(O)-O-(Ci_4 alkyl), S(O)2-(Ci_4 alkyl), and piperazinyl, wherein the piperazinyl is optionally substituted with 1 or 2 subsituents independently selected from Ci_6 alkyl, arylalkyl, aryl, heteroaryl, C(O)Rbl, S(O)2Rbl, C(O)NRclRdl, and S(O)2NRclRdl.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, at least one R5 is -Q1^-Z1, -(CH2)- Q'-Y'-Z1, -O(CRllaRllb)qiC(O)-Q1-Y1-Z1, -O(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piC(O)NRe(CRllaRllb)p2- Q'-Y'-Z1, - (CRllaRllb)piC(O)NRe-Q1-Y1-Z1, -NRe(CRllaRllb)p2-Q1-Y1-Z1, -(CR111R11^p2NR6C(O)-Q1-
Y^Z1, -(CRllaRllb)piNRe-Q1-Y1-Z1, -(CRllaRllb)piO(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piS(CRllaRllb)p2- Q1^-Z1, -(CRllaRllb)piS(O)(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piS(O)2(CRllaRllb)p2-Q1-Y1-Z1, - (CRllaRllb)piNRe(CRllaRllb)p2-Q1-Y1-Z1, -NReS(O)(CRllaRllb)pi-Q1-Y1-Z1, -S(O)NRe(CRllaRllb)p2-Q1- Y^Z1, -NReS(O)2(CRllaRllb)p1-Q1-Y1-Z1, -S^zNR^CR11^11^^1^1^1, -NR6C(O)(CR111R11^pI-Q1- Y^Z1, -C(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, or -NReC(O)NRf(CRllaRllb)p2-Q1-Y1-Z1.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, at least one R5 is -(CRllaRllb)p1-Q1-Y1-Z1, -(CRllaRllb)piO(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piS(CRllaRllb)p2-Q1-Y1-Z1,
Figure imgf000072_0001
-(CRllaRllb)p1S(O)2((CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piNRe(CRllaRllb)p2-Q1-Y1-Z1, -NReS(O)(CRllaRllb)pl-Q1-Y1-Z1,
-S(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, -NReS(O)2(CRllaRllb)pi-Q1-Y1-Z1, -S(O)2NRe(CRllaRllb)p2-Q1-Y1-Z1, -NR6C(O)(CR111R1 lb)pi -Q1 -Y1 -Z1 , -C(O)NR^CR1 laR! 1^p2-Q1 -Y1 -Z1 , or
-NR6C(O)NR^CR111R111^2-Q1 -Y1 -Z1. In some further embodiments, each Q1 is independently selected from cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci_6 alkyl, Ci_6 haloalkyl, C2.8 alkoxyalkyl, Ci_6 alkoxy, Ci_6haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino. In yet further embodiments, each Q1 is independently selected from cyclopentyl, cyclohexyl, pyrrolidinyl, and piperidinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2-8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2-8 dialkylamino.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, at least one R5 is -(CRl laRllb)piO(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piS(CRllaRllb)p2-Q1-Y1-Z1,
-(CRl laRllb)piS(O)(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piS(O)2((CRllaRllb)p2-Q1-Y1-Z1, -(CRl laRllb)p1NRe(CRllaRllb)p2-Q1-Y1-Z1, -NReS(O)(CRllaRllb)p1-Q1-Y1-Z1,
-S(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, -NReS(O)2(CRllaRllb)prQ1-Y1-Z1, -S(O)2NRe(CRllaRllb)p2-Q1-Y1-Z1, -NR6C(O)(CR111R1 lb)pi -Q1 -Y1 -Z1 , -C(O)NR6CCR1 laR! 1^2-Q1 -Y1 -Z1 , or -NR6C(O)NR^CR111R11^p2-Q1 -Y1 -Z1. In some further embodiments, each Q1 is independently selected from cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci_6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Q-6 alkylamino and C2.8 dialkylamino. In yet further embodiments, each Q1 is independently selected from cyclopentyl, cyclohexyl, pyrrolidinyl, and piperidinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, at least one R5 is -W6-Q1-Y1-Z1. In some further embodiments, at least one R5 on the ring containing A2, B2, D2, and E2 is -W6-Q1-Y1-Z1.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, at least one R5 is -(CRl laRllb)piS(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piS(O)(CRllaRllb)p2-Q1-Y1-Z1, -(CRl laRllb)piS(O)
Figure imgf000073_0001
-(CRllaRllb)piS(O)NR6(CRllaRllb)p2-Q1-Y1-Z1,
-(CRl laRllb)p2NR6S(O)(CRllaRllb)pi-Q1-Y1-Z1, (CRllaRllb)piS(O)2NR6(CRllaRllb)p2-Q1-Y1-Z1, or -(CR111R111^p2NR6S(O)2(CR1 laR! lb)pi -Q1 -Y1 -Z1.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, each Q1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, (lH)-hexahydropyrrolo[l,2-a]pyrazin-2-yl, and (8H)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7-yl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-β haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino. In some further embodiments, each Q1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2-8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino. In other further embodiments, each Q1 is independently selected from azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Q-6 alkyl, Q-6 haloalkyl, C2.8 alkoxyalkyl, Q-6 alkoxy, C1-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino. In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa,
IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, each Q1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Q-6 haloalkyl, C2.8 alkoxyalkyl, Q-6 alkoxy, Q-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino. In some further embodiments, each Q1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(0)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino. In other further embodiments, each Q1 is independently selected from azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino. In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa,
IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, each Y1 is independently selected from absent, Ci_6 alkylenyl, (CR12aR12b)p3O(CR12aR12b)p4, (CR12aR12b)p3S(CR12aR12b)p4, (CR12aR12b)p3NRe(CR12aR12b)P4, (CR12aR12b)p3C(O)(CR12aR12b)P4, (CR12aR12b)p3C(O)O(CR12aR12b)P4, C(S)NR6, (CR12aR12b)p3C(O)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O)2(CR12aR12b)P4, (CR12aR12b)p3S(O)2NRe(CR12aR12b)P4, and (CR12aR12b)p3NReC(O)NRf(CR12aR12b)p4.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, each Y1 is independently selected from absent, (CH2), (CR12aR12b)p3O(CR12aR12b)p4, (CR12aR12b)p3S(CR12aR12b)p4, (CR12aR12b)p3NRe(CR12aR12b)P4, (CR12aR12b)p3C(O)(CR12aR12b)P4, (CR12aR12b)p3C(O)O(CR12aR12b)p4, C(S)NR6, (CR12aR12b)P3C(O)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O)2(CR12aR12b)P4, (CR12aR12b)p3S(O)2NRe(CR12aR12b)P4, and (CR12aR12b)p3NReC(O)NRf(CR12aR12b)p4.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, each Y1 is independently selected from absent, Ci_6 alkylenyl, (CR12aR12b)p3C(O)(CR12aR12b)p4, (CR12aR12b)p3C(O)O(CR12aR12b)p4, C(S)NR6, (CR12aR12b)p3C(O)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O) 2(CR12aR12b)p4, and (CR12aR12b)p3NReC(O)NRf(CR12aR12b)p4.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, each Y1 is independently selected from absent, (CH2), (CR12aR12b)p3C(O)(CR12aR12b)p4, (CR12aR12b)p3C(O)O(CR12aR12b)p4, C(S)NR6, (CR12aR12b)p3C(O)NRe(CR12aR12b)p4, (CR12aR12b)p3S(O) 2(CR12aR12b)p4, and (CR12aR12b)p3NReC(O)NRf(CR12aR12b)p4.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, each Y1 is independently selected from absent, (CR12aR12b)p3O(CR12aR12b)p4, (CR12aR12b)p3S(CR12aR12b)p4, (CR12aR12b)p3NRe(CR12aR12b)p4, (CR12aR12b)p3C(O)(CR12aR12b)p4, (CR12aR12b)p3C(O)NRe(CR12aR12b)p4, (CR12aR12b)p3S(O) 2(CR12aR12b)p4, (CR12aR12b)p3S(O)2NRe(CR12aR12b)p4, and (CR12aR12b)p3NReC(O)NRf(CR12aR12b)p4.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, each Z1 is independently selected from H, OH, CN, Ci_6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein each of the Ci_6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(0)NRcRd, C(O)ORa, OC(O)Rb, 0C(0)NRcRd, NRcRd, NRcC(0)Rd, NRcC(0)0Ra, NRcS(O)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, each Z1 is independently selected from Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(0)Rd, NRcC(0)0Ra, NRcS(O)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, each Z1 is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2-β alkenyl, C2-β alkynyl, Ci-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(O)Rd, NRcC(0)0Ra, NRcS(O)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, and S(0)2NRcRd.
In some embodiments of the compounds of Formula Ilia, HIb, IHc, IHd, IHe, IHf, IHg, IHh, IVa, IVb, IVc, IVd, V, or Va, or pharmaceutically acceptable salt thereof, each Z1 is independently selected from aryl, cycloalkyl, heteroaryl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(0)Rd, NRcC(0)0Ra, NRcS(O)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, and S(0)2NRcRd.
In some embodiments, the compounds of Formula I of the present invention have Formula Ia:
Figure imgf000076_0001
Ia or are pharmaceutically acceptable salts thereof, wherein B1, B2, D1, D2, E1, and E2 are each, independently, selected from CR5 and N; and A1 and A2, are each, independently, selected from CR2 and N.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, X2 is N.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, X2 is CR2. In some further embodiments, R3 is halo. In yet further embodiments, R3 is F, Cl, or Br. In still further embodiments, R3 is Cl.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, B1, B2, D1, D2, E1, and E2 are each, independently, selected from CR5; and A1 and A2, are each, independently, selected from CR2. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, the ring containing A1, B1, D1, and E1 is a benzene ring, and the benzene ring can be substituted or unsubstituted.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, the ring containing A1, B1, D1, and E1 is selected from pyridine and pyrimidine (which can be optionally substituted, for example by three R5 and one R2). In some embodiments, the ring is pyridine. In some embodiments, the ring is pyrimidine.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof wherein the ring containing A1, B1, D1, and E1 is a pyridine ring, D1 is N. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof wherein the ring containing A1, B1, D1, and E1 is a pyridine ring, E1 is N. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof wherein the ring containing A1, B1, D1, and E1 is a pyridine ring, B1 is N. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof wherein the ring containing A1, B1, D1, and E1 is a pyridine ring, A1 is N. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
B2, D2, and E2 are each, independently, selected from CR5; and A2 is CR2.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, the ring containing A2, B2, D2, and E2 is is selected from pyridine and pyrimidine (which can be optionally substituted, for example by three R5 and one R2). In some embodiments, the ring is pyridine. In some embodiments, the ring is pyrimidine.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, R1 is selected from H, halo, Ci_6 alkyl, and Ci_6 haloalkyl. In some further embodiments, R1 is H.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, each R2 is, independently, selected from H, halo, Ci_6 alkyl, and Ci_6 haloalkyl. In some further embodiments, each R2 is, independently, selected from H, halo, Ci-3 alkyl, and Ci-3 haloalkyl. In yet further embodiments, each R2 is, independently, selected from H, F, Cl, Br, methyl, ethyl, 1 -propyl, 2- propyl, and Ci-2 haloalkyl. In still further embodiments, each R2 is, independently, selected from H, F, Cl, Br, methyl, ethyl, 1-propyl, 2-propyl, and CF3. In some embodiments, each R2 is, independently, selected from H, F, Cl, Br, methyl, and CF3. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, each R2 is, independently, selected from H, CH3, CF3, and halo. In some further embodiments, each R2 is, independently, selected from H, F, Cl, methyl, and CF3. In yet futher embodiments, each R2 is, independently, selected from H, F, and Cl. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, each R2 is, independently, selected from H, CH3 and CF3. In some further embodiments, each R2 is H, or CH3. In yet futher embodiments, each R2 is H.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, R3 is selected from H, halo, Ci_6 alkyl, and Ci_6 haloalkyl. In some embodiments, R3 is selected from H, halo, Ci-3 alkyl, and Ci-3 haloalkyl. In some embodiments, R3 is Ci_6 alkyl. In some embodiments, R3 is Ci-3 alkyl. In some embodiments, R3 is H, CH3 or CF3. In some embodiments, R3 is H. In some embodiments, R3 is CH3. In some embodiments, R3 is CF3. In some embodiments, R3 is halo. In some embodiments R3 is chloro. In some embodiments, R3 is bromo. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
R3 is SF5.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, R3 is selected from amino, Ci-4 alkylamino, and C2_8 dialkylamino. In some further embodiments, R3 is selected from NH2, NH(Ci_3 alkyl), and N(Ci_3 alkyl)2. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof:
R1 is selected from H, halo, Ci_6 alkyl, and Ci_6 haloalkyl; and
R3 is selected from H, halo, Ci_6 alkyl, and Ci_6 haloalkyl.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof:
R1 is H; and R3 is selected from H, halo, Ci-6 alkyl, and Ci-6 haloalkyl.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof:
R1 is H; and
R3 is selected from H, halo, Ci-3 alkyl, and Ci-3 haloalkyl.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof: R1 is H; and
R3 is selected from H, F, Cl, Br, Ci-3 alkyl, and CF3.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, each R5 is independently selected from H, halo, Q-6 alkyl, Q-6 haloalkyl, Cy1, -W'-Q'-Y'-Z1, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NRclRdl, NRclC(O)Rbl, NRclS(O)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, each R5 is independently selected from H, halo, Q-6 alkyl, Q-6 haloalkyl, CN, NO2, ORal, C(O)Rbl, C(O)NRclRdl, C(O)ORal, NRclRdl, NRclC(O)Rbl, NRclS(O)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, each R5 is independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, CN, NO2, ORal, NRclRdl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)2Rbl, and S(O)2NRclRdl.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, at least one R5 is -W'-Q'-Y'-Z1.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, at least one R5 is Cy1.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, two adjacent R5 on the same ring can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, CN, NO2, ORal, C(O)Rbl, C(0)NRclRdl, C(O)ORal, NRclRdl, NRclC(0)Rbl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, two adjacent R5 on the ring containing A1, B1, D1, and E1 can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci_6 alkyl, Ci_6 haloalkyl, CN, NO2, ORal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclRdl, NRclC(0)Rbl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, two adjacent R5 on the ring containing A2, B2, D2, and E2 can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1 , 2, or 3 substituents independently selected from halo, Ci_6 alkyl, Ci_6 haloalkyl, CN, NO2, ORal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclRdl, NRclC(0)Rbl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, Y is NR4. In some embodiments, Y is NH or N(Ci-3 alkyl). In some embodiments, Y is NH. In some embodiments, Y is N(Ci-3 alkyl). In some embodiments, Y is N-CH3.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 are each, independently, selected from a bond, -(CRV)n-, -O-(CR7R8)m-CR10=, -S-(CR7R8)m-CR10=, -(CR7R8)m-CR10=, -(CR7R8)m-NR9-, -(CR7R8)m-O-, -(CR7R8)m-S-, -(CR7R8)m-S(O)-, -(CR7R8)m- S(O)2-, -(CR7R8)m-C(O)-, -C(O)NR9-, -(CR7R8)m-C(O)O-, -(CR7R8)m-NR9C(O)NR9-, -(CR7R8)m-OC(O)NR9-, -(CR7R8)m-NR9C(O)O-, -(CR7R8)m-NR9-S(O)2NR9-, -(CR7R8)m-S(O)NR9-, and -(CRV)1n-S(O)2NR9-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 are each, independently, selected from a bond, -(CRV)n-, -(CRV)1n-CR10=, -0-(CRV)1n-CR10=, -S-(CRV)1n-CR10=, -(CRV)1n-NR9-, -(CRV)1n-O-, -(CRV)1n-S-, -(CRV)1n-S(O)-, -(CRV)1n- S(O)2-, -(CRV)1n-C(O)-, -C(O)NR9-, -(CRV)1n-C(O)O-, -(CRV)1n-S(O)NR9-, and -(CRV)1n-S(O)2NR9-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CR V)m-CR10=CR10-(CR V)1n-, -0-(CR V)m-CR1O=CR1O-(CR V)1n-, -S-(CRV)m-CR10=CR10-(CRV)m-, -0-(CRV)m-CR10=CR10-(CRV)m-0-,
-0-(CR V)m-CR10=CR10-(CR V)1n-S-, or -S-(CR V)m-CR10=CR10-(CR V)1n-S-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 are each, independently, selected from a bond, -(CRV)n-, -(CRV)1n-CR10=, -(CRV)1n-NR9-, -(CRV)1n-O-, -(CRV)1n-S-, -(CRV)1n-S(O)-, -(CRV)1n- S(O)2-, -(CRV)1n-C(O)-, -C(O)NR9-, -(CRV)1n-C(O)O-, -(CRV)1n-S(O)NR9-, and -(CRV)1n-S(O)2NR9-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 are each, independently, selected from a bond, -(CRV)n-, and -(CRV)1n-CR10=.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CR V)m-CR10=CR10-(CR V)1n- or -(CRV)1n-(CRV)n-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
L1 and L2 together form -CR10=CR10-, -(CRV)2-, or -(CRV)3-. In some further embodiments, L1 and L2 together form-CR10=CR10- or -(CRV)2-. In yet further embodiments, L1 and L2 together form - CH=CH- or -CH2-CH2-. In some embodiments, L1 and L2 together form -CH=CH-. In some embodiments, L1 and L2 together form -CH2-CH2-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
L1 and L2 together form -CR10=CR10- or -CR V-CR7R8-. In some further embodiments, L1 and L2 together form -CH=CH- or -CH2-CH2-. In some embodiments, L1 and L2 together form -CH=CH-. In some embodiments, L1 and L2 together form -CH2-CH2-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CRV)3-. In some further embodiments, L1 and L2 together form -(CH2)3-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, one of L1 and L2 is selected from -(CRV)1n-O-, -(CRV)1n-S-, -(CRV)1n-S(O)-, and -(CRV)1n- S(O)2-; and the other is selected from a bond, -(CRV)n-, -(CRV)1n-O-, -(CRV)1n-S-, -(CRV)1n-S(O)-, and - (CRV)1n- S(O)2-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof:
L1 and L2 together form -(CRV)11-S-, -(CRV)11-O-, -(CRV)11-S(O)-, -(CRV)11-S(O)2-, -S-(CRV)12-S-, -0-(CRV)12-S-, -0-(CRV)12-S(O)-,
-0-(CRV)12-S(O)2-, -S-S-, -(CRV)0-O-(CRV)14-, -(CRV)13-S-(CRV)14-,
-(CRV)0- S(O)-(CRV)14-, or -(CRV)13-S(O) 2-(CRV)14-; tl is 1, 2, or 3; t2 is 1 or 2; t3 is 1, 2, or 3; and t4 is 1 or 2. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof:
L1 and L2 together form -(CR7R8Xi -S-, -(CR7R8Xi -O-, -(CR7R8Xi-S(O)-, -(CR7R8Xi-S(O) 2-, -S-(CR7RVs-, -0-(CR7RVS-, -0-(CR7R VS(O)-, -0-(CR7R8X2-S(O) 2-, or -S-S-; tl is 1, 2, or 3; and t2 is l or 2.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof:
L1 and L2 together form -(CR7RVO-(CR7R8X4-, -(CR7R8X3-S-(CR7R8X4-, -(CR7RV S(O)-(CR7R8X4-, or -(CR7R8X3-S(O) 2-(CR7R8)t4-, t3 is 1, 2, or 3; and t4 is l or 2.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form S-S, -(CR7R8)-S-, -(CR7R8)-S(O)-, -(CR7R8XS(O)2-, -(CR7R8)-O-, -(CR7R8) 2-0-, -O-(CR7R8)2-O-, -O-(CR7R8)2-S-, -O-(CR7R8)2-S(O)-, or -O-(CR7R8)2- S(O)2-. In some further embodiments, L1 and L2 together form -(CR7R8)-S-, -(CR7R8)-S(O)-, -(CR7R8XS(O)2-, -(CR7R8XO-, -(CR7RVo-, -0-(CR7RVo-, -O-(CR7R8)2-S-, -O-(CR7R8)2-S(O)-, or -O-(CR7R8)2-S(O)2-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form S-S, -(CH2)-S-, -(CH2)-S(0)-, -(CH2XS(O)2-, -(CH2)-0-, -(CH2) 2-0-, -0-(CH2) 2-0-, -0-(CH2) 2-S-, -0-(CH2) 2-S(0)-, or -0-(CH2) 2- S(O)2-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form S-S. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-S-, -(CH2)-S(0)-, -(CH2)-S(O)2-, -(CH2)-0-, -(CH2) 2-0-, -0-(CH2) 2-0-, -0-(CH2) 2-S-, -0-(CH2) 2-S(0)-, or -0-(CH2) 2- S(O)2-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CR7R8)-O, -(CR7R8)-S-, -(CR7R8)-S(O), -(CR7R8XS(O)2, -(CR7R8)2-O-, -(CR7RVs-, -(CR7RVS(O)-, -(CR7R8)2-S(O)2-, -0-(CR7R8X-, -S-(CR7R8X-, -S(O)-(CR7R8X-, or -S(O)2-(CR7R8),-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-0-, -(CH2)-S-, -(CH2)-S(0)-, or -(CH2)-S(O)2-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-0- or -(CHz)-S-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-0-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
L1 and L2 together form -(CH2)-S-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-S(O)-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-S(O)2-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)2-O, -(CH2)2-S-, -(CH2)2-S(O)-, or -(CH2)2-S(O)2-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form - (CHz)2-O- or -(CHz)2-S-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
L1 and L2 together form -(CH2)2-O-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)2-S-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)2-S(O)-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)2-S(O)2-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)3-O-, -(CH2)3-S-, -(CH2)3-S(O)-, or -(CH2)3-S(O)2-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form - (CHz)3-O- or -(CHz)3-S-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)3-O-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)3-S-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)3-S(O)-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CHz)3-S(O)2-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CRV)-O-(CR7R8)-, -(CR7R8)-S-( CR7R8)-, -(CR7R8)-S(O)-(CR7R8)-,
-(CRV)-S(O)2-(CR7R8)-, -(CRV)-O-(CRV)2-, -(CRV)-S-(CRV)2-, -(CRV)-S(O)-(CRV)2-, -(CRV)-S(O)2-(CRV)2-, -(CRV)2-O-(CRV)2-, -(CRV)2-S-(CRV)2-, -(CRV)2-S(O)-(CRV)2-, or -(CRV)2-S(O)2-(CRV)2-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-O-(CH2)-, -(CU2)S-(CU2)-, -(CH2)-S(O)-(CH2)-, -(CH2)-S(O)2-(CH2)-, -(CH2)-O-(CH2)2-, -(CH2)-S-(CH2)2-, -(CH2)-S(O)-(CH2)2-, -(CH2)-S(O)2-(CH2)2-, -(CH2)2-O-(CH2)2-, -(CH2)2-S-(CH2)2-, -(CH2)2-S(O)-(CH2)2-, or -(CH2)2-S(O)2-(CH2)2-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
L1 and L2 together form -(CH2)-O-(CH2)- or -(CH2)-S-(CH2)-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-O-(CH2)-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-S-(CH2)-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-O-(CH2)2- or -(CH2)-S-(CH2)2-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-O-(CH2)2-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
L1 and L2 together form -(CH2)-S-(CH2)2-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)2-O-(CH2)2- or -(CH2)2-S-(CH2)2-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)2-O-(CH2)2-
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)2-S-(CH2)2-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -0-(CH2) 2-O-, -0-(CH2) 2-S-, -O-(CH2) 2-S(O)-, -O-(CH2) 2-S(O)2-, -S-(CH2) 2-S- -S(O)-(CH2) 2-S(O)-, or -S(O)2-(CH2) 2-S(O)2-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -0-(CH2) 2-O-, -0-(CH2) 2-S-, -0-(CH2) 2-S(O)-, or -0-(CH2) 2-S(O)2-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -0-(CH2) 2-0-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -0-(CH2) 2-S-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -0-(CH2) 2-S(O)-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
L1 and L2 together form -0-(CH2) 2-S(O)2-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, one of L1 and L2 is selected from -(CR7R8)m-NR9-, -(CRV)1n-S(O)2-, -(CR7R8)m-C(O)-, -C(O)NR9-, -(CRV)1n-S(O)NR9-, and -(CRV)1n-S(O)2NR9-; and the other is selected from a bond, -(CRV)n-, -(CRV)1n-NR9-, -(CRV)1n-S(O)2-, -(CRV)1n-C(O)-, -C(O)NR9-, -(CRV)1n-S(O)NR9-, and -(CRV)1n-S(O)2NR9-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CR V)t5-C(0)-, -(CR V)(S-C(O)NR9-, -C(O)NR9-(CR7R8)t5-, -C(O)NR9-, -S(O)2NR9-(CR V)(S-, -(CRV)(S-S(O)2NR9-, or -S(O)2NR9-, wherein t5 is 1, 2, or 3. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
L1 and L2 together form -(CRV)15-C(O)-, -C(O)NR9-, or -S(O)2NR9-, and wherein t5 is 1, 2, or 3.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CR V)-C(O)-, -(CRV)2-C(O)-, or -(CRV)3-C(O)-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CR7R8)- C(O)-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CRV)2-C(O)-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CRV)3-C(O)-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CRV)-C(O)NR9-, -C(O)NR9-(CR7R8)-, or -C(O)NR9-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form
-(CH2)-C(O)NR9-, -C(0)NR9-( CH2)-, or -C(O)NR9-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-C(0)NH-, -C(O)NH-(CH2)-, or -C(O)NH-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-C(0)NH-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -C(O)NH-(CH2)-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -C(O)NH-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CR7R8)t7-C(O)NR9-(CR7R8)t8, wherein t7 is 1 or 2 and t8 is 1 or 2. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CR7R8)-C(O)NR9-(CR7R8). In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-C(O)NH-(CH2)-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -S(O)2NR9-(CR7R8)t5-, -(CR7R8)t5-S(O)2NR9-, or -S(O)2NR9-, wherein t5 is 1, 2, or 3.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -S(O)2NR9-(CR7R8)-, -(CR7R8)-S(O)2NR9-, or -S(O)2NR9-. In some further embodiments, R9 is H or Ci-3 alkyl.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -S(O)2NR9-(CH2)-, -(CH2)-S(O)2NR9-, or -S(O)2NR9-. In some further embodiments, L1 and L2 together form -S(O)2NH-(CH2)-, -(CHz)-S(O)2NH-, or -S(O)2NH-, In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
L1 and L2 together form -S(O)2NH-(CH2)-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-S(O)2NH-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -S(O)2NH-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CR7R8)t7-S(O)2NR9-(CR7R8)t8-, wherein t7 is 1 or 2 and t8 is 1 or 2. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CR7R8)-S(O)2NR9-(CR7R8). In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
L1 and L2 together form -(CH2)-S(O)2NR9-(CH2)-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CR7R8)m-NR9-C(O)NR9-, -(CR7R8)m-O-C(O)NR9-, or -O-C(O)NR9-(CR7R8)m-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CR7R8)-NR9-C(O)NR9-, -(CR7R8)-O-C(O)NR9-, -O-C(O)NR9-(CR7R8)-, -NR9-C(O)NR9-, or -0-C(O)NR9-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-NR9-C(O)NR9-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-NH-C(0)NH-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CR7R8)-O-C(O)NR9-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-0-C(0)NH-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -O-C(O)NR9-(CR7R8)-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -0-C(O)NH-(CH2)-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -NR9-C(O)NR9-, or -0-C(O)NR9-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -NH-C(O)NH-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -0-C(O)NH-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CR7R8)m-NR9-(CR7R8)n-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
L1 and L2 together form -NR9-(CR7R8)n-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -NR9-(CR7R8)n-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -NR9-(CR7R8)-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -NR9-(CR7R8)2-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -NR9-(CR7R8)3-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
L and L together form -(CR R )m2-NR -(CR R )n-, wherein m2 is 1 or 2. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CR7R8)- NR9-(CR7R8)-, -(CR7R8)-NR9-(CR7R8)2-, or -(CR7R8)2-NR9-(CR7R8)2-. In some further embodiments, L1 and L2 together form -(CR7R8)-NR9-(CR7R8)- or -(CR7R8)-NR9-(CR7R8)2-. In some further embodiments, R9 is H or Ci_3 alkyl.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
L and L together form -(CR R )-NR -(CR R )-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)-NR9-(CH2)-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -NR9-(CR7R8)t9-O- wherein t9 is 1, 2, or 3. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -NR9-(CR7R8)-O-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -NR9-(CR7R8)2-O-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -NR9-(CR7R8)3-O-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -NR9-(CH2)-O-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
L1 and L2 together form -NR9-(CH2)2-O-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -NR9-(CH2)3-O-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, one of L1 and L2 is selected from -(CR7R8)m-NR9C(O)NR9-, -(CR7R8)m-OC(O)NR9-, -(CR7R8)m- NR9C(O)O-, and -(CR7R8)m-NR9-S(O)2NR9-; and the other is selected from a bond, -(CR7R8)n-, - (CR7R8)m-NR9-, -(CR7R8)m-O-, -(CR7R8)m-S-, -(CR7R8)m-S(O)2-, -(CR7R8)m-C(O)-, -C(O)NR9-, - (CR7R8)m-S(O)NR9-, and -(CR7R8)m-S(O)2NR9-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, one of L1 and L2 is selected from -(CR7R8)m-NR9C(O)NR9-, -(CR7R8)m-OC(O)NR9-, -(CR7R8)m- NR9C(O)O-, and -(CR7R8)m-NR9-S(O)2NR9-; and the other is selected from a bond, and -(CR7R8)n.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CR7R8)m-NR9C(O)NR9-(CR7R8)m-, -(CR7R8)m-OC(O)NR9-(CR7R8)m-, or - (CR7R8)m-NR9-S(O)2NR9-(CR7R8)m-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
L1 and L2 together form -(CR7R8)m-NR9C(O)NR9-(CR7R8)m-. In some further embodiments, L1 and L2 together form -NR9C(O)NR9, -NR9C(O)NR9-(CR7R8) m2-, or -(CR7R8)mrNR9C(O)NR9-(CR7R8)m2-, wherein ml and m2 are each, independently 1 or 2.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -NR9C(O)NR9-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -NR9C(O)NR9-(CR7R8)-, -NR9C(O)NR9-(CR7R8)2-, -(CR7R8)-NR9C(O)NR9- (CR7R8)-, -(CR7R8)-NR9C(O)NR9-(CR7R8)2-, or -(CR7R8)2-NR9C(O)NR9-(CR7R8)2-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CH2)m-NR9C(O)NR9-(CH2)m-. In some further embodiments, L1 and L2 together form -NR9C(O)NR9, -NR9C(O)NR9-(CH2) ^, or -(CH2)ml-NR9C(O)NR9-(CH2)m2- wherein ml and m2 are each, independently 1 or 2. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -NR9C(O)NR9-(CH2)-, -NR9C(O)NR9-(CH2)2-, -(CH2)-NR9C(O)NR9-(CH2)-, -(CH2)-NR9C(O)NR9-(CH2)2-, or -(CH2)2-NR9C(O)NR9-(CH2)2-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CR7R8)m-OC(O)NR9-(CR7R8)m-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -OC(O)NR9-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -OC(O)NR9-(CR7R8)-, -OC(O)NR9-(CR7R8)2-, -(CR7R8)-OC(O)NR9-, -(CR7R8)2- OC(O)NR9-, -(CR7R8)-OC(O)NR9-(CR7R8)-, -(CR7R8)-OC(O)NR9-(CR7R8)2-, -(CR7R8)2-OC(O)NR9- (CR7R8)-, or -(CR7R8)2-OC(O)NR9-(CR7R8)2-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -OC(O)NR9-(CH2)-, -OC(O)NR9-(CH2)2-, -(CH2)-OC(O)NR9-, -(CH2)2-OC(O)NR9-, -(CH2)-OC(O)NR9-(CH2)-, -(CH2)-OC(O)NR9-(CH2)2-, -(CH2)2-OC(O)NR9-(CH2)-, or -(CH2)2-OC(O)NR9-(CH2)2-.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -(CR7R8)m-NR9S(O)2NR9-(CR7R8)m-. In some further embodiments, L1 and L2 together form -NR9S(O)2NR9-, -NR9S(O)2NR9-(CR7R8)m2-, or -(CR7R8)mrNR9S(O)2NR9-(CR7R8)m2-, wherein ml and m2 are each, independently 1 or 2. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
L1 and L2 together form -NR9S(O)2NR9.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, L1 and L2 together form -NR9S(O)2NR9-(CR7R8)-, -NR9S(O)2NR9- (CR7R8)2-, -(CR7R8)-NR9S(O)2NR9- (CR7R8)-, -(CR7R8)-NR9S(O)2NR9-(CR7R8)2-, or -(CR7R8)2-NR9S(O)2NR9-(CR7R8)2-. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
R4 is H or Ci_6 alkyl. In some further embodiments, R4 is H or Ci-3 alkyl. In yet further embodiments, R4 is H or methyl. In still further embodiments, R4 is H.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof: each R5 is, independently, selected from H, halo, Ci-6 alkyl, Q-6 haloalkyl, CN, NO2, ORal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclRdl, NRclC(0)Rbl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl, wherein said Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, or Ci-6 haloalkyl, is optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, halosulfanyl, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, OC(O)Rbl, OC(O)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(O)NRclRdl, NRclC(O)ORal, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, or S(O)2NRclRdl;
Ral, Rbl, Rcl, and Rdl are each, independently, selected from H, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 hydroxylalkyl, Ci-4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OH, SH, 0(C1-4 alkyl), O(Ci_4 haloalkyl), O(aryl), O(arylalkyl), S(C1-4 alkyl), S(Ci_4 haloalkyl), S(aryl), S(arylalkyl), amino, Ci-4 alkylamino, C2.8 dialkylamino, C(=0)H, C(=0)-(C1-4 alkyl), C(=O)-(arylalkyl), C(=0)NH2, C(=0)NH(Ci_4 alkyl), C(=0)N(Ci_4 alkyl)2, C(=0)0H, C(=0)0-(C1-4 alkyl), C(=O)O- (arylalkyl), 0C(=0)H, 0C(=0)-(Cw alkyl), OC(=O)-(arylalkyl), 0C(=0)NH2, 0C(=0)NH(Ci_4 alkyl), OC(=O)NH-(arylalkyl), 0C(=0)N(Ci_4 alkyl)2, NHC(=0)-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)0-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHS(=O)2-(Ci_4 alkyl), NHS(=O)2-(arylalkyl), NHS(=O)2-NH(Ci_4 alkyl), NHS(=O)2-N(Ci_4 alkyl)2, NHS(=O)2-NH(arylalkyl), S^O)2-(C1-4 alkyl), S(=O)2-(arylalkyl), S(=O)2NH2, S(=O)2NH(Ci-4 alkyl) and S(=O)2NH(arylalkyl); or Rcl and Rdl together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 hydroxylalkyl, Ci-4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OH, SH, O(C1-4 alkyl), O(C1-4 haloalkyl), O(aryl), O(arylalkyl), S(Ci-4 alkyl), S(Ci-4 haloalkyl), S(aryl), S(arylalkyl), amino, Ci-4 alkylamino, C2.8 dialkylamino, C(=0)H, C(=0)-(Ci_4 alkyl), C(=O)-(arylalkyl), C(=0)NH2, C(=0)NH(Ci_4 alkyl), C(=0)N(Ci_4 alkyl)2, C(=0)0H, C(=0)0-(Ci_4 alkyl), C(=O)O-(aiylalkyl), 0C(=0)H, 0C(=0)-(C1-4 alkyl), OC(=O)- (arylalkyl), 0C(=0)NH2, 0C(=0)NH(Ci_4 alkyl), OC(=O)NH-(arylalkyl), 0C(=0)N(Ci_4 alkyl)2, NHC(=0)-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)0-(Ci_4 alkyl), NHC(=O)O-(arylalkyl),
NHS(=O)2-(Ci_4 alkyl), NHS(=O)2-(arylalkyl), NHS(=O)2-NH(Ci_4 alkyl), NHS(=O)2-N(Ci_4 alkyl)2, NHS(=O)2-NH(arylalkyl), S(=O)2-(C1-4 alkyl), S(=O)2-(arylalkyl), S(=O)2NH2, S(=O)2NH(Ci_4 alkyl) and S(=O)2NH(arylalkyl).
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, each R5 is independently selected from H, Q-6 alkyl, COOH, C(=0)-(Ci-4 alkyl), St=O)2-(Q-4 alkyl), S(=O)2NH2, S(=O)2NH(Ci_4 alkyl), C(0)NRclRdl, and NRclRdl, wherein:
Rcl and Rdl are each, independently, selected from H, Ci-6 alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of said Ci-6 alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl is optionally substituted with with 1, 2, or 3 substituents independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 hydroxylalkyl, Ci-4 cyanoalkyl, aryl, heteroaryl, OH, O(Ci_4 alkyl), O(Ci_4haloalkyl), piperidinyl, pyrrolidinyl, morpholinyl, and piperizinyl optionally substituted with Ci_4 alkyl, aryl, or arylalkyl; or Rcl and Rdl together with the N atom to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionally substituted with 1 , 2, or 3 substituents independently selected from Ci-4 alkyl, Ci_4 haloalkyl, Ci-4 hydroxylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, OH, O(Ci_4 alkyl), and 0(Ci-4 haloalkyl).
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, each R6 is, independently, H, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, S(O)Rbl, S(O)2R", or S(0)2NRclRdl. In some furether embodiments, each R6 is, independently, H, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, or Ci_6 haloalkyl.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, each R6 is, independently, H or Ci_6 alkyl. In some further embodiments, each R6 is, independently, H or Ci-3 alkyl. In yet further embodiments, each R6 is, independently, H or methyl. In still further embodiments, each R6 is H. In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof,
R7 and R8 are each, independently, selected from H, halo, Ci-6 alkyl, CN, NO2, OH, Ci-6 alkoxy, Ci-6 haloalkoxy, and C2.8 alkoxyalkoxy. In some further embodiments, R7 and R8 are each, independently, selected from H, halo, Ci-4 alkyl, CN, NO2, Ci-4 alkoxy, Ci-4 haloalkoxy, and C2.8 alkoxyalkoxy. In some further embodiments, R7 and R8 are each, independently, selected from H, halo, Ci-4 alkyl, OH, Ci-4 alkoxy, Ci-4 haloalkoxy, and C2.8 alkoxyalkoxy. In some further embodiments, R7 and R8 are each, independently, selected from H, OH, Ci-4 alkoxy, Ci-4 haloalkoxy, and C2.8 alkoxyalkoxy. In some further embodiments, R7 and R8 are each, independently, selected from H, OH, and C2.8 alkoxyalkoxy.
In some embodiments of compounds of Formula Ia or pharmaceutically acceptable salts thereof, each R10 is, independently, selected from H, halo, and Ci-6 alkyl. In some embodiments, each R10 is, independently, selected from H and Ci-6 alkyl. In some embodiments, each R10 is, independently, selected from H and Ci_4 alkyl. In some further embodiments, each R10 is H.
In some embodiments, the compounds of Formula Ia of the present invention have Formula Ia-I :
Figure imgf000091_0001
Ia-I or are pharmaceutically acceptable salts thereof, wherein:
R1 is H, halo, Ci-6 alkyl, Q-6 haloalkyl, NH2, NH(Ci-4 alkyl), N(Ci_4 alkyl)2, or CN;
R3 is H, halo, Ci_6 alkyl, Ci_6 haloalkyl, NH2, NH(Ci_4 alkyl), N(Ci_4 alkyl)2, or CN; each R5a is, independently, selected from H, halo, Q-6 alkyl, C1-6 haloalkyl, CN, NO2, SF5, ORal, C(O)Rbl, C(0)NRclRdl, C(O)ORal, NRclRdl, NRclC(0)Rbl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl; or two adjacent R5a can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, CN, NO2, SF5, ORal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclRdl, NRclC(0)Rbl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl; each R5b is, independently, selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, CN, NO2, SF5, ORal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclRdl, NRclC(0)Rbl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(O)2NRclRdl; or two adjacent R5b can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, CN, NO2, SF5, ORal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclRdl, NRclC(0)Rbl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl; and
Y is O, S, or NR4.
In some embodiments of compounds of Formula Ia-I or pharmaceutically acceptable salts thereof: each R5a is, independently, selected from H, halo, Q-6 alkyl, Q-6 haloalkyl, CN, NO2, SF5, ORal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclRdl, NRclC(0)Rbl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(O)2NRclRdl; and each R5b is, independently, selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, CN, NO2, SF5, ORal, C(O)Rbl, C(0)NRclRdl, C(O)ORal, NRclRdl, NRclC(0)Rbl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl.
In some embodiments of the compounds of Formula Ia-I or pharmaceutically acceptable salts thereof, each R5a is H.
In some embodiments of the compounds of Formula Ia-I or pharmaceutically acceptable salts thereof, one R5a is other than H.
In some embodiments of the compounds of Formula Ia-I or pharmaceutically acceptable salts thereof, two R5a are other than H. In some embodiments of the compounds of Formula Ia-I or pharmaceutically acceptable salts thereof, three R5a are other than H.
In some embodiments of the compounds of Formula Ia-I or pharmaceutically acceptable salts thereof, at least one R5a is other than H.
In some embodiments of the compounds of Formula Ia-I or pharmaceutically acceptable salts thereof, at least two R5a are other than H.
In some embodiments of the compounds of Formula Ia-I or pharmaceutically acceptable salts thereof, each R5b is H.
In some embodiments of the compounds of Formula Ia-I or pharmaceutically acceptable salts thereof, one R5b is other than H. In some embodiments of the compounds of Formula Ia-I or pharmaceutically acceptable salts thereof, two R5b are other than H.
In some embodiments of the compounds of Formula Ia-I or pharmaceutically acceptable salts thereof, three R5b are other than H.
In some embodiments of the compounds of Formula Ia-I or pharmaceutically acceptable salts thereof, at least one R5b is other than H.
In some embodiments of the compounds of Formula Ia-I or pharmaceutically acceptable salts thereof, at least two R5b are other than H.
In some embodiments of compounds of Formula Ia-I or pharmaceutically acceptable salts thereof, R1 is H, halo, Q-6 alkyl, Q-6 haloalkyl, or CN; and R3 is H, halo, Q-6 alkyl, Q-6 haloalkyl, or CN. In some embodiments of compounds of Formula Ia-I or pharmaceutically acceptable salts thereof:
R1 is H, halo, Ci-3 alkyl, or Ci-3 haloalkyl;
R3 is H, halo, Ci-3 alkyl, or Ci-3 haloalkyl; each R is, independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, CN, NO2, OR , C(O)Rbl, C(O)NRclRdl, C(O)ORal, NRclRdl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)2Rbl, and
S(O)2NRclRαi; each R5b is, independently selected from H, halo, Ci-6 alkyl, Ci-6 haloalkyl, CN, NO2, ORal, C(O)Rbl, C(0)NRclRdl, C(O)ORal, NRclRdl, NRclS(O)2Rbl, NRclS(O)2NRclRdl, S(O)Rbl, S(O)2Rbl, and S(O)2NRclRdl;
Y is NH or N(Ci-3 alkyl); and X2 is N.
In some embodiments, the compounds of Formula Ia-I have Formula Ia-2:
Figure imgf000093_0001
Ia-2. In some embodiments, the compounds of Formula Ia-2 have Formula Ia-2-a:
Figure imgf000093_0002
Ia-2-a. In some embodiments, the compounds of Formula Ia-2 have Formula Ia-2-b:
Figure imgf000094_0001
Ia-2-b. In some embodiments, the compounds of Formula Ia-2 have Formula Ia-2-c:
Figure imgf000094_0002
Ia-2-c. In some embodiments, the compounds of Formula Ia-2 have Formula Ia-2-d:
Figure imgf000094_0003
Ia-2-d.
At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "Ci_6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
For compounds of the invention in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound, then the two R groups can represent different moieties selected from the Markush group defined for R. It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. The term "n-membered" where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring and thiophene is an example of a 5-membered heteroaryl group.
As used herein, the term "alkyl" is meant to refer to a saturated hydrocarbon group which is straight-chained or branched. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms. The term "alkylene" refers to a divalent alkyl linking group. An example of alkylene is methylene (CH2). As used herein, "alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds. Example alkenyl groups include, but are not limited to, ethenyl, propenyl, cyclohexenyl, and the like. The term "alkenylenyl" refers to a divalent linking alkenyl group.
As used herein, "alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds. Example alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like. The term "alkynylenyl" refers to a divalent linking alkynyl group.
As used herein, "haloalkyl" refers to an alkyl group having one or more halogen substituents. Example haloalkyl groups include, but are not limited to, CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, CH2CF3, and the like.
As used herein, "aryl" refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms. In some embodiments, aryl groups have from 6 to about 10 carbon atoms.
As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups that contain up to 20 ring-forming carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spiro ring systems. A cycloalkyl group can contain from 3 to about 15, from 3 to about 10, from 3 to about 8, from 3 to about 6, from 4 to about 6, from 3 to about 5, or from 5 to about 6 ring-forming carbon atoms. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of pentane, pentene, hexane, and the like (e.g., 2,3-dihydro-lH-indene-l-yl, or IH- inden-2(3H)-one-l-yl).
As used herein, "heteroaryl" groups refer to an aromatic heterocycle having up to 20 ring-forming atoms and having at least one heteroatom ring member (ring-forming atom) such as sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl group has at least one or more heteroatom ring-forming atoms each independently selected from sulfur, oxygen, and nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1 ,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 1 to about 5, from about 1 to about 4, from about 1 to about 3, from about 1 to about 2, carbon atoms as ring- forming atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. As used herein, "heterocycloalkyl" refers to non-aromatic heterocycles having up to 20 ring- forming atoms including cyclized alkyl, alkenyl, and alkynyl groups where one or more of the ring- forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom. Hetercycloalkyl groups can be mono or polycyclic (e.g., both fused and spiro systems). Example "heterocycloalkyl" groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-l,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, and the like. Ring- forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo (i.e. =0) or sulfide (i.e. =S). For example, a ring-forming S atom can be substituted by 1 or 2 oxo [i.e., form a S(O) or S(O)2]. For another example, a ring-forming C atom can be substituted by oxo (i.e., form carbonyl). Accordingly, some non-limiting examples of heterocylcoalkyl include 2-oxo-oxazolidin-yl and 2-oxo-oxazolyl. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles such as indolene, isoindolene, isoindolin-l-one-3-yl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl, 5,6- dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, and 3,4-dihydroisoquinolin-l(2H)-one-3yl groups. Ring- forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted by oxo or sulfido. In some embodiments, the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.
As used herein, "halo" or "halogen" includes fluoro, chloro, bromo, and iodo. As used herein, "halosulfanyl" refers to a sulfur group having one or more halogen substituents.
Example halosulfanyl groups include pentahalosulfanyl groups such as SF5.
As used herein, "alkoxy" refers to an -O-alkyl group. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
As used herein, "haloalkoxy" refers to an -O-haloalkyl group. An example haloalkoxy group is OCF3.
As used herein, "cyanoalkyl" refers to an alkyl group substituted by a cyano group (CN). One example of cyanoalkyl is -CH2-CN.
As used herein, "alkoxyalkoxy" refers to an alkoxy group substituted by an alkoxy group. One example of alkoxyalkoxy is -OCH2CH2-OCH3. As used herein, "arylalkyl" refers to a Ci_6 alkyl substituted by aryl and "cycloalkylalkyl" refers to Ci-6 alkyl substituted by cycloalkyl.
As used herein, "heteroarylalkyl" refers to a Ci_6 alkyl group substituted by a heteroaryl group, and "heterocycloalkylalkyl" refers to a Ci_6 alkyl substituted by heterocycloalkyl.
As used herein, "amino" refers to NH2. As used herein, "alkylamino" refers to an amino group substituted by an alkyl group.
As used herein, "dialkylamino" refers to an amino group substituted by two alkyl groups.
As used herein, "hydroxylalkyl" or "hydroxylalkyl" refers to an alkyl group substituted by a hydroxyl group. An example is -CH2OH or - CH2CH2OH.
As used here, C(O) refers to C(=O). As used here, C(S) refers to C(=S).
As used here, S(O) refers to S(=O).
As used here, S(O)2 refers to S(=O)2.
As used used herein, the term "optionally substituted" means that substitution is optional and therefore includes both unsubstituted and substituted atoms and moieties. A "substituted" atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced with a selection from the indicated substituent group, provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound. For example, if a methyl group (i.e., CH3) is optionally substituted, then 3 hydrogen atoms on the carbon atom can be replaced with substituent groups.
The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. Where a compound capable of stereoisomerism or geometric isomerism is designated in its structure or name without reference to specific R/S or cis/trans configurations, it is intended that all such isomers are contemplated.
Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.
Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.
Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, IH- and 3H-imidazole, IH-, 2H- and 4H- 1 ,2,4-triazole, IH- and 2H- isoindole, and IH- and 2H- pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
Compounds of the invention further include hydrates and solvates, as well as anhydrous and non- solvated forms.
The term, "compound," as used herein is meant to include all stereoisomers, geometric iosomers, tautomers, and isotopes of the structures depicted.
All compounds and pharmaceuticaly acceptable salts thereof, can be prepared or present together with other substances such as water and solvents (e.g. hydrates and solvates) or can be isolated. Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which is formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art. Compounds of the invention are intended to include compounds with stable structures. As used herein, "stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 200C to about 300C.
The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (ACN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
The present invention also includes quaternary ammonium salts of the compounds described herein, where the compounds are primary amines, secondary amines, or tertiary amines. As used herein, "quaternary ammonium salts" refers to derivatives of the disclosed primary amine, secondary amine, or tertiary amine compounds wherein the parent amine compounds are modified by converting the amines to quaternary ammonium cations via alkylation (and the cations are blanced by anions such as Cl", CH3COO', or CF3COO ), for example methylation or ethylation.
Synthesis
Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.
The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan. Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety. Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
The compounds of invention can be prepared according to the synthetic procedures described below in the Example section.
As shown in Scheme Ia, macrocycle 1-2 of the present invention can be synthesized by cyclizing precursor 1-1 [wherein Lg1 is a leaving group such as halo (e.g., chloro)] under acidic condition, or basic condition, or in the presence of a transition metal catalysis [such as a Palladium catalyst (e.g., Pd(PPh3)4) or a Pd(II) catalyst] to afford the desired macrocycle 1-2. Precursors 1-1 [wherein Lg1 is a leaving group such as halo (e.g., chloro)], 1-la [wherein Lg1 is a leaving group such as halo (e.g., chloro)], 1-3 [wherein Lg1 is a leaving group such as halo (e.g., chloro)], and l-3a [wherein Lg1 is a leaving group such as halo (e.g., chloro)] can undergo similar transformations to afford products 1-2, 1-4, and 1-4 respectively.
Scheme Ia
Figure imgf000102_0001
1 -3a
As shown in Scheme Ib, bis-olefin precusor 1-5 [wherein Llf and L2f can be independently selected from -(CR7R8)m-, -(CR7R8)m-O-, or -(CR7R8)m-S-] can be cyclized in the presence of a metathesis catalyst (ruthenium, such as the Grubbs catalysts or molybdenum catalysts, such as the Hoveyda catalysts) to afford the desired macrocycle 1-6 that contains an olefin moiety of CR10=CR10. The olefin moiety of compound 1-6 can be further reduced under suitable hydrogenation conditions [such as in the presence of a palladium catalyst (e.g., 5% Pd/C)] to afford macrocycle 1-7. Scheme Ib
olefin metathesis
Figure imgf000103_0001
Figure imgf000103_0002
Figure imgf000103_0003
As shown in Scheme Ib-I, macrocycle l-7a can be obtained similarly according to the transformations described in Scheme Ib.
Scheme Ib-I
olefin metathesis
Figure imgf000103_0004
Figure imgf000103_0005
Reduction
Figure imgf000103_0006
Acyclic precursors 1-1, 1-la, 1-3, and l-3a can be synthesized by a variety of appropriate ways that would be recognized by those skilled in organic synthesis. For example, compound 2-1 [wherein R101 is H or an amine protecting group (such as tert-butyloxycarbonyl or BOC); Y is O, S, or NR4] can be reacted with substituted heteroaromatic compound 2-2 [wherein Lg1 and Lg2 are each, independently, a leaving group such as halo (e.g., chloro)] in the presence of a suitable base (such as a inorganic base, for example a metal carbonate (e.g., potassium carbonate), a metal hydride (e.g., sodium hydride), a metal hydroxide (e.g., sodium hydroxide), a metal alkoxide (e.g., sodium ethoxide)] and/or in the presence of a transition metal catalyst for example a palladium catalyst [e.g., Pd(PPh3)4].
Scheme 2
Figure imgf000104_0001
R101 is H or an amine protecting group protecting group)
Figure imgf000104_0002
2. Nitro Reduction
2-3
Precursors for the macrocycles of the present invention (for example, precursors 1-1, 1-la, 1-3, 1- 3a, and 1-5) can be prepared by a variety of methods. For example, Mitsunobu coupling, thioether formation, amine alkylation, amide formation, sulfonamide formation, urea formation and carbamate formation can be utilized in synthesizing these compounds. Some non-limiting examples are depicted in the following schemes.
As shown in Scheme 3a, compound 3-1 [wherein R201 can be NO2 or NHR101; R101 can be H or Pg4; Pg4 is an amine protecting group (such as tert-butyloxycarbonyl or BOC); Lla can be -(CR7R8)m- (such as a bond or methylene) or Lla is selected from -(CR7R8X1-, -(CR7R8)mrNR9-, -(CR7R8)mrO-,
-(CR7RV-S-, -(CR7RXi-S(O)-, -(CR7RV-S(O)2-, -(CR7RXi-C(O)-, -(CR7RXi-C(O)O-, -(CR7RVi-
NR9C(O)NR -, -(CR7RV -OC(O)NR9-, -(CR7RV-NR9C(O)O-, -(CR7RV -NR9-S(O)2NR9-,
-(CR7RV-S(O)NR9-, and -(CR > 77τR> 8V- -S(O)2NR9-, wherein ml is 1 or 2] can be reacted with compound 3-2 [wherein Y10 can be OH, SH, NHR4, or NO2, wherein the OH, SH, or NHR4 can also be protected by an appropriate protecting group; L2a is selected from -(CR7R8)n-, -(CR7R8)mrNR9-, -(CR7R8)mrO-, -(CR7R8)ml-S-, -(CR7R8)ml-S(O)-, -(CR7R8)ml- S(O)2-, -(CR7R8)ml-C(O)-, -(CR7R8)ml-C(O)O-, -(CR7R8)mi -NR9C(O)NR9-, -(CR7R8)mi -OC(O)NR9-, -(CR7R8)mrNR9C(O)O-, -(CR7RV -NR9-S(O)2NR9- , -(CR7R8)mi -S(O)NR9-, and -(CR7R8)mi -S(O)2NR9-, wherein ml is 1 or 2; or L2a can be -(CR7R8)m- (such as a bond or methylene)] under Mitsunobu coupling reaction conditions to afford compound 3-3 [wherein Lla can be -(CR7R8)m- and L2a is selected from -(CRV)n-, -(CR7RV -NR9-, -(CR7R8)mrO-, -(CR7RV- S-, -(CR7RV-S(O)-, -(CR7RV- S(O)2-, -(CR7R V -C(O)-, -(CR7R8)ml-C(O)O-, -(CR7R8)ml- NR9C(O)NR9-, -(CR7RV -OC(O)NR9-, -(CR7RV-NR9C(O)O-, -(CR7RV -NR9-S(O)2NR9-, -(CR7RV-S(O)NR9-, and -(CR7RV-S(O)2NR9-, wherein ml is 1 or 2; or L2a can be -(CR7R8)m- and Lla is selected from -(CR7R8)n-, -(CR7RV-NR9-, -(CR7RV-O-, -(CR7R8)mrS-, -(CR7RV-S(O)-, -(CR7RV- S(O)2-, -(CR7RV-C(O)-, -(CR7R8)ml -C(O)O-, -(CR7R8)ml -NR9C(O)NR9-, -(CR7R8)ml- OC(O)NR9-, -(CR7RV -NR9C(O)O-, -(CR7R8)mrNR9-S(O)2NR9-, -(CR7R8)mi -S(O)NR9-, and -(CR7R8)mi -S(O)2NR9-, wherein ml is 1 or 2.]. Compound 3-3 can undergo further chemical transformations if and when appropriate. For example, when Y10 of compound 3-3 is a protected OH group, it can be deprotected according to the protecting group. For another example, when Y10 of compound 3-3 is NO2, it can be reduced to NH2 under suitable conditions.
Compounds 3-4 and 3-5 [wherein Lg3 is a leaving group such as halo (e.g., Br or Cl); R201, Lla, and L2a can be the same as those in compounds 3-1 and 3-2] can be reacted under basic conditions to afford compound 3-6. Alternatively compound 3-6 can be obtained by reacting compound 3-7 with compound 3-8 (wherein Lg3, R201, Lla, and L2a can be the same as those in compounds 3-4 and 3-5). The NO2 of compound 3-6 can be reduced to NH2 under suitable conditions.
Scheme 3 a
Figure imgf000106_0001
R201 is NO2 Or NHR101 ;
R101 is H or Pg4; and Pg4 is an amine protecting group (such as tert-butyloxycarbonyl or BOC)
Figure imgf000106_0002
Useful intermediates 3-3a and 3-6a can be made according to the methods as shown in Scheme 3a- 1 (similar to the reactions depicted in Scheme 3a, and wherein R301 can be NO2 or NHR101; R101, R201, Lla, and L2a can be the same as those in Scheme 3a). The protecting group Pg4 of compound 3-3a and 3- 6a, when present, can be removed under suitable conditions. Compounds 3-3a and 3-6a can undergo further chemical transformations when suitable reactive groups are present. For example, the NO2 of compound 3-3a and 3-6a can be reduced to NH2 under suitable conditions.
Scheme 3a-l
Figure imgf000107_0001
R201 is NO2 or NH R101 ;
R301 is NO2 or NH R101 ; each R1 01 is independently H or Pg4; and each Pg4 is independently an amine protecting group (such as tert-butyloxycarbonyl or BOC)
Figure imgf000107_0002
As shown in Scheme 3b, compounds 3-9a and 3-9b [wherein R201, Lla, and L2a can be the same as those in compounds 3-4 and 3-5] can be reacted under appropriate conditions to afford compound 3-10. For example, when R102 is Lg3 (a leaving group), amine alkylation can be carried out under basic conditions. When R102 is -C(=0)H (i.e., compound 3-9a is an aldehyde), reductive animations can be carried out. Similarly, compound 3-llc can be obtained by reacting compound 3-lla with compound 3- 11b [wherein Lla and L2a can be the same as those in compounds 3-4 and 3-5] under suitable conditions. The protecting group Pg4 of compound 3-10 or 3-llc can be removed under suitable conditions. Compounds 3-10 and 3-llc can undergo further chemical transformations when suitable reactive groups are present. For example, when Y10 is NO2, it can be reduced to NH2 under suitable conditions. Scheme 3b
Figure imgf000108_0001
R201 is NO2 or NHR101 ;
R101 is H or Pg4; each Pg4 is independenly an amine protecting group (such as tert-butyloxycarbonyl or BOC) ;
R102 is Lg3 or -C(=0)H;
Lg3 is a leaving group such as halo (e.g., Br or Cl); and
L1 b is L1a or L1a-CH2.
Figure imgf000108_0002
L2b is L2a or L2a-CH2.
Useful intermediates 3-10-1 and 3-llc-l can be made according to the methods outlined in Scheme 3b-l (similar to the reactions depicted in Scheme 3b, and wherein Lla and L2a can be the same as those in Scheme 3a). The protecting group Pg4 of compound 3-10-1 and 3-llc-l can be removed under suitable conditions. Compounds 3-10-1 and 3-llc-l can undergo further chemical transformations when suitable reactive groups are present. For example, the NO2 of compound 3-10-1 and 3-llc-l can be reduced to NH2 under suitable conditions.
Scheme 3b- 1
Figure imgf000109_0001
R2013 Js NO2 Or NHPg4;
R3013 Js NO2 Or NHPg4; each Pg4 is independently an amine protecting group (such as tert-butyloxycarbonyl or BOC) ;
R102 is Lg3 or -C(=0)H;
Lg3 is a leaving group such as halo (e.g., Br or Cl); and
L1b is L1 a or Li3-CH2.
Figure imgf000109_0002
3-11a-1 3-11 b-1 3-1 1C-1
L2b is L23 or L^-CH2.
As shown in Scheme 3c, amide compounds 3-12c, 3-13c, 3-14c, and 3-15c [wherein Pg4, Y1, Lla, and L2a can be the same as those in Scheme 3a] can be obtained from an appropriate acid such as acid 3- 12a, 3-13b, 3-14b, or 3-15a and an appropriate amine such as amine 3-12b, 3-13a, 3-14a, or 3-15b by standard coupling reactions [such as in the presence of an amide coupling reagent such as benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 2-(lH-benzotriazol-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazoll-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), or dicyclohexylcarbodimide (DCC), and in the presence of a suitable base such as triethylamine, diisopropylethylamine, N-methylmorpholine, or N-N-dimethylaminopyridine] . Alternatively, the acid 3- 12a, 3-13b, 3-14b, or 3- 15a can be converted to a more reactivate species such as an acid halide (e.g., acid chloride) or a mixed anhydride, and the more reactive species can be reacted with the appropriate amine 3-12b, 3-13a, 3-14a, or 3-15b respectively. The protecting group Pg4 of compound 3-12c, 3-13c, 3-14c, or 3-15c can be removed under suitable conditions. Compounds 3-12c, 3-13c, 3-14c, and 3-15c can undergo further transformation when suitable reactive groups are present. For example, when Y10 is NO2, it can be reduced to NH2 under suitable conditions.
Scheme 3c pj
Figure imgf000110_0001
or its acid halide 3-12c
R201 a is NO2 or N HPg4; and
Pg4 is an amine protecting group (such as tert-butyloxycarbonyl or BOC).
Figure imgf000110_0002
Figure imgf000110_0003
3-14c or its acid halide
Figure imgf000110_0004
or its acid halide 3-i5b 3- 15c Useful intermediates 3-12c-l, 3-13c-l, 3-14c-l, and 3-15c-l [wherein Pg4, Lla, and L2a can be the same as those in Scheme 3a] can be made according to the methods outlined in Scheme 3c- 1 (similar to the reactions depicted in Scheme 3c). The protecting group Pg4 of compounds 3-12c-l, 3-13c-l, 3-14c-l, and 3-15c-l can be removed under suitable conditions. Compounds 3-12c-l, 3-13c-l, 3-14c-l, and 3- 15c- 1 can undergo further chemical transformations when suitable reactive groups are present. For example, the NO2 of compounds 3-12c-l, 3-13c-l, 3-14c-l, and 3-15c-l can be reduced to NH2 under suitable conditions.
Scheme 3c- 1
Figure imgf000111_0001
or its acid halide 3-12c-1
R201 a is NO2 or NHPg4; R301 a is NO2 or NHPg4; each Pg4 is independently an amine protecting group (such as tert-butyloxycarbonyl or BOC).
Figure imgf000111_0002
Figure imgf000111_0003
3-14C-1 or its acid halide
Figure imgf000111_0004
As shown in Scheme 3d, sulfonamide compounds 3-17 and 3-19 [wherein Pg4, Y1, Lla, and L2a can be the same as those in Scheme 3a] can be obtained by reacting an appropriate sulfonyl halide (such as chloride) with an appropriate amine. The protecting group Pg4 of compounds 3-17 or 3-19 can be removed under suitable conditions. Compounds 3-17 and 3-19 can undergo further chemical transformations when suitable reactive groups are present. For example, when Y10 is NO2, it can be reduced to NH2 under suitable conditions.
Scheme 3d
Figure imgf000112_0001
Figure imgf000112_0002
R201a is NO2 or NH Pg4; and
Pg4 is an amine protecting group (such as tert-butyloxycarbonyl or BOC).
Useful intermediates 3-17-1 and 3-19-1 [wherein Pg4, Y10, Lla, and L2a can be the same as those in Scheme 3a] can be made according to the methods outlined in Scheme 3d-l (similar to the reactions depicted in Scheme 3d). The protecting group Pg4 of compounds 3-17-1 and 3-19-1 can be removed under suitable conditions. Compounds 3-17-1 and 3-19-1 can undergo further chemical transformations when suitable reactive groups are present. For example, the NO2 of compounds 3-17-1 and 3-19-1 can be reduced to NH2 under suitable conditions.
Il l Scheme 3d-l
Figure imgf000113_0001
Figure imgf000113_0002
R201 a is NO2 or NHPg4; R30ia is No2 or NHPg4; each Pg4 is independently an amine protecting group (such as tert-butyloxycarbonyl or BOC).
As shown in Scheme 3e, urea compound 3-21 [wherein R201a, Pg4 and Y10 can be the same as those in Scheme 3d; and Lld and L2d can be each, independently, -(CR7R8)m- (such as a bond or methylene)] can be obtained by reacting two appropriate amines with phosgene [C(=O)C12] or a phosgene equivalent [e.g., triphosgene, ethyl chloroformate, trichloromethyl chloroformate, or phenyl chlorocarbonate] . Similarly, carbamates 3-23 and 3-25 can be made by reacting an appropriate amine and an appropriate alcohol with phosgene or its equivalent. Sulfamide 3-25c can be made by reacting amines 3-25a and 3-25b with SO2Cl2 or its equivalent (such as other thionyl halides, e.g., SO2Br2). The protecting group Pg4 of compounds 3-21, 3-23, or 3-25 can be removed under suitable conditions. Compounds 3-21, 3-23, and 3-25 can undergo further chemical transformations when suitable reactive groups are present. For example, when Y1 (and/or R201a) is NO2, it can be reduced to NH2 under suitable conditions.
Scheme 3e
Figure imgf000114_0001
3-21
Figure imgf000114_0002
3-23
Figure imgf000114_0003
3-25
NHR
Figure imgf000114_0005
Figure imgf000114_0004
3- 25a 3-25b 3-25C
R201a is NO2 or NHPg4; and
Pg is an amine protecting group (such as tert-butyloxycarbonyl or BOC).
Useful intermediates 3-21-1, 3-23-1, 3-25-1, or 3-25-lc [wherein Pg4, Y10, Lla, and L2a can be the same as those in Scheme 3a] can be made according to the methods outlined in Scheme 3e-l (similar to the reactions depicted in Scheme 3e). The protecting group Pg4 of compounds 3-21, 3-23, or 3-25 can be removed under suitable conditions. Compounds 3-21, 3-23, or 3-25 can undergo further chemical transformations when suitable reactive groups are present. For example, the NO2 of compound 3-21, 3- 23, or 3-25 can be reduced to NH2 under suitable conditions. Scheme 3e-l
Figure imgf000115_0001
3-21 -1
Figure imgf000115_0002
3-25-1 a 3-25-1 b
R201a is NO2 or NHPg4;
R30ia is No2 or NHPg4; and
A more detailed scheme (similar to Scheme 3d-l) is provided in Scheme 3f. Sulfonamide 3-27 [wherein Lla, and L2a can be the same as those in Scheme 3a] can be obtained by reacting sulfonyl halide 3-26a (such as chloride) with amine 3-26b. The NO2 of compound 3-27 can be reduced to NH2, for example in the presence of Fe/CH3C00H, to afford compound 3-27a. The Boc group of compound 3-27 can be removed, for example, in the presence of HCl, to afford compound 3-27b. Scheme 3f
Figure imgf000116_0001
3-27a 3- 27b
Figure imgf000116_0002
3-29a 3-29b
As shown in Scheme 4, macrocycle 4-2 [wherein Lla and L2a can be the same as those in Scheme 3a] can be cyclized from acyclic precursor 4-1 by intramolecular Mitsunobu reaction/coupling. Preferably, one of Lla and L2a of acyclic precursor 4-1 is a bond in the intramolecular Mitsunobu reactions/couplings.
Scheme 4
Figure imgf000117_0001
4-1
4-2
In addition, many other intramolecular macrocyclizations can be useful for synthesizing the compounds of the present invention. For example, amine alkylations and reductive animations can be useful for cyclizations as shown in Scheme 5a [wherein Lla and L2a can be the same as those in Scheme 3b].
Scheme 5 a
Figure imgf000117_0002
R102 is Lg3 or -C(=0)H;
Lg3 is a leaving group such as halo (e.g., Br or Cl); and
L1b is L1a or L1a-CH2.
Figure imgf000117_0003
Amide couplings can be useful for cyclizations as shown in Scheme 5b (similar to the reactions depicted in Scheme 3c, and wherein Lla and L2a can be the same as those in Scheme 3c).
Scheme 5b
Figure imgf000118_0001
5-5a 5-5 b
Figure imgf000118_0002
Amide Coupling
Figure imgf000118_0003
Figure imgf000118_0004
5-7a 5-7b
Figure imgf000118_0005
Sulfonamide formation can be useful for cyclization as shown in Scheme 6a (similar to the reactions depicted in Scheme 3d, and wherein L ,llaa aanndd LL22aa cc;an be the same as those in Scheme 3d). Scheme 6a
Figure imgf000119_0001
6-1
Figure imgf000119_0002
6-4
6-3
Urea formation and carbamate formation can be useful for cyclizations as shown in Scheme 6b (similar to the reactions depicted in Scheme 3e, and wherein Lld and L2d are the same as those in Scheme 3e).
Scheme 6b
Urea formation
Phosgene
Figure imgf000120_0001
or its equivalent
Figure imgf000120_0002
6-5 6-6
Figure imgf000120_0003
Carbamate formation
Phosgene
Figure imgf000120_0004
or its equivalent
Figure imgf000120_0005
6-9 6-10
Useful intermediates 7-4, 7-10, and 7-13 can be made according to the methods outlined in Scheme 7. Aryl halide or heteroaryl halide 7-1 can be reacted with alkyne 7-2 under Sonogashira coupling reaction conditions to afford alkyne 7-3. [See, K. Sonogashira, Y. Tohda, N. Hagihara (1975). "A convenient synthesis of acetylenes: catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines". Tetrahedron Letters 16 (50): 4467-4470.]. The amino group of alkyne 7-3 can be protected with a protecting group Pg4, followed by the C≡C bond being reduced to a saturated bond by hydrogenation to afford intermediate 7-4. Aryl halide or heteroaryl halide 7-5 can be reacted with silyl substituted acetylene 7-6 [e.g. (trimethylsilyl) -acetylene] under Sonogashira coupling reaction conditions, followed by removal of the silyl group under suitable conditions [e.g., in the presence of a base (e.g., K2CO3)] to afford alkyne 7-7. Alkyne 7-7 can be reacted with aryl halide or heteroaryl halide 7-8 under Sonogashira coupling reaction condition to afford alkyne 7-9. Alkyne 7-9 can be reduced via hydrogenation to produce intermediate 7- 10. Aryl halide or heteroaryl halide 7-11 can be reacted with alkyne 7-12 under Sonogashira coupling reaction conditions, followed by hydrogenation to reduce the C≡C bond, to afford alkyne 7-13.
Scheme 7
Figure imgf000121_0001
1. Amine Protection
2. Reduction ine protecting group
Figure imgf000121_0002
Figure imgf000121_0003
Reduction
Pd/C, H2
Figure imgf000121_0005
Figure imgf000121_0004
Figure imgf000121_0006
Useful intermediates 7-4a, 7-1Oa, and 7-13a can be made according to the methods outlined in Scheme 7-1 (similar to the reactions depicted in Scheme 7).
Scheme 7-1
Figure imgf000122_0001
1 . Amine Protection
2. Reduction ine protecting group
Figure imgf000122_0002
Figure imgf000122_0003
Reduction
Pd/C, H2
Figure imgf000122_0005
Figure imgf000122_0004
Figure imgf000122_0006
Useful intermediates 7-4b, 7-1Ob, and 7-13b can be made according to the methods outlined in Scheme 7-2. Aryl halide/triflate or heteroaryl halide/triflate 7-5b can be reacted with vinylboronate 7-6b (R groups can be each, independently, H (e.g., compound 7-6b is a vinylboronic acid when both R are H) or alklyl; or together with the -0-B-O- to which they are attached form an optionally substituted heterocycloalkyl) under Suzuki-Miyaura reaction condition/Suzuki coupling to form alkene 7-2b [for reviews of the Suzuki-Miyaura reaction, see e.g. Miyaura, N; Suzuki, A. Chem. Rev., 1995, 95:2457- 2483]. Alternatively, a vinyl stannane (such as tributyl(vinyl)stannane, equivalent to vinylboronate 7-6b in the Suzuki-Miyaura reaction described herein) can be used to react with aryl halide or heteroaryl halide 7-5b to form alkene 7-2b under Stille reaction conditions [See e.g. P. Espinet, A. M. Echavarren "The Mechanisms of the Stille Reaction"; Angewandte Chemie International Edition; 43 (36): 4704-4734
(2004)]. Aryl halide/triflate or heteroaryl halide/triflate 7-lb can be reacted with alkene 7- 2b under Heck coupling reaction conditions to afford alkene 7-3b. [See e.g. Heck, R. F.; Nolley, Jr., J. P., "Palladium- catalyzed vinylic hydrogen substitution reactions with aryl, benzyl, and styryl halides"; J. Org. Chem., 37(14): 2320-2322 (1972)]. The amino group of alkene 7-3b can optionally be protected by an amine protecting group such as Boc group, followed by reduction of the C=C bond to a saturated bond via hydrogenation to afford intermediate 7-4b under an appropriate condition such as palladium catalyzed hydrogenation or using a hydrazine compound. [See e.g. Y. Imada, H. Iida, T. Naota, /. Am. Chem. Soc, 2005, 127, 14544-14545].
Intermediate 7-1Ob can be synthesized starting from aryl halide/triflate or heteroaryl halide/triflate 7-lb (also substituted with a nitro group) through similar chemical transformations to those described in the formation of intermediate 7-4b.
Alternatively, aryl halide/triflate or heteroaryl halide/triflate 7-llb can be reacted with alkene 7- 12b under Heck coupling reaction conditions, followed by reduction of the C=C bond, for example, via hydrogenation, to afford intermediate 7-13b.
Scheme 7-2
as
Figure imgf000124_0001
Figure imgf000124_0002
Heck Coupling
Reduction
Figure imgf000124_0003
Figure imgf000124_0004
Figure imgf000124_0005
pj302a |s |_| or an a mme protecting group such as Boc
Useful intermediates 7-4c, 7-lOc, and 7-13c can be made according to the methods outlined in Scheme 7-3 (similar to those depicted in Scheme 7-2). Scheme 7-3
Figure imgf000125_0001
1 . Amine Protection (optional)
2. Reduction is H Qr an amjne ng group such
Figure imgf000125_0002
Suzuki Coupling
Figure imgf000125_0003
Figure imgf000125_0004
7-7c group such as
R groups can be each, independently, H halo or OTf (i.e., compound 7-6c is a vinylboronic acid when both R are H) or alklyl; or together with the -0-B-O- to which they are attached form an optionally substituted heterocycloalkyl
Figure imgf000125_0005
7-8c Reduction
Heck Coupling
Figure imgf000125_0006
Figure imgf000125_0007
Lx is a leaving group such as
Figure imgf000125_0008
As shown in Scheme 8, aryl (or heteroaryl) methyl ketone 8-1 can be reacted with aryl (or heteroaryl) aldehyde 8-2 under basic conditions [(such as in the presence of an alkali metal hydroxide (e.g. NaOH)] to afford derivative 8-3. Intermediate 8-3 can be reduced via hydrogenation (such as in the presence of Pd/C, hydrogen and acetic acid) to afford compound 8-4, which further can be reduced to compound 8-5. R201a and R301a groups of compounds 8-4 or 8-5 can undergo further chemical transformations. For example, the NO2 group can be reduced to NH2; and a protected amino group can be de-protected to NH2.
Scheme 8
Figure imgf000126_0001
Reduction
Pd/C, H2
Figure imgf000126_0002
R2013 is NO2 or NHPg4;
R3013 is NO2 or NHPg4; each Pg4 is independently an amine protecting group (such as tert-butyloxycarbonyl or BOC).
Useful intermediates 8-3a, 8-4a, and 8-5a can be made according to the methods outlined in Scheme 8-1 (similar to the reactions depicted in Scheme 8).
Scheme 8-1
Figure imgf000127_0001
8-5a 8- 4a
R201 a is N02 or NHPg4; R301 a is N02 or NHPg4; each Pg4 is independently an amine protecting group (such as tert-butyloxycarbonyl or BOC).
Some additional useful intermediates can be made by the methods outlined in Scheme 9. Aryl (or heteroaryl) compound 9-1 can be reacted with a halogenating reagent [such as bromine (Br2), N- bromoacetamide (NBA), N-bromosuccinimide (ΝBS), l,3-dibromo-5,5- dimethylhydantoin (DBDMH), l,3-dichloro-5,5-dimethylhydantoin (DCDMH), N-chlorosuccinimide (NCS)] to afford halogenated compounds 9-2.
A fluorinated compound 9-3 can be reacted with an amine, an alcohol, or thioalcohol in the presence of a base (such as a tertiary amine, e.g., TEA) to form compound 9-4. Where R50 is SRal, compound 9-4 can be oxidized to sulfinyl or sulfonyl compounds 9-5 (wherein y is 1 or 2), using an oxidizing reagent such as ra-chloroperoxybenzoic acid (raCPBA).
A fluorinated compound 9-6 can be reacted with an amine, an alcohol, or thioalcohol in the presence of a base (such as a tertiary amine, e.g., triethylamine or TEA) to form compound 9-7. Where R50 is SRal, compound 9-7 can be oxidized to sulfinyl or sulfonyl compound 9-8 (wherein y is 1 or 2), using an oxidizing reagent such as ra-chloroperoxybenzoic acid (raCPBA). The nitro (NO2) group of compound 9-8 can be reduced, for example, in the presence of Fe (or Zn) and acetic acid, followed by introduction of an amine protecting group (such as Boc), to afford compound 9-9. Scheme 9
NO2
NO2 B1^A1
EWG E1' halogenation B1^A1 9-1 EWG^ E1 ^ Lx
EWG is an electron 9-2 withdrawing group, such Lx is halo as CO2Rb1 or SO3H. such as Br or Cl.
Figure imgf000128_0001
9-3 9-4 9-5
RbϋisNRclRαi, ORal,orSR 3a1
Figure imgf000128_0002
Useful intermediates 9-2a, 9-4a, 9-5a, 9-7a, 9-8a, and 9-9a can be made according to the methods outlined in Scheme 9-1 (similar to the reactions depicted in Scheme 9).
Scheme 9-1
NO2
NO2
B2^A2 EWG^ 1 E2 J halogenation B2^A2
9-1 a EWG^ A E2 -A^ Lx
EWG is an electron 9-2a withdrawing group, such Lx is halo as CO2Rb1 or SO3H. such as Br or Cl. , NO2 R50
Figure imgf000129_0002
Figure imgf000129_0001
9-3a 9-4a 9-5a
R50 is NRc1 Rd1 , ORa1 , or SRa1 ,
Figure imgf000129_0003
9-7a
9-8a y is 1 or 2 9-9a
As shown in Scheme 10, compound 10-1 [Y is O, S, or NR4; and Lg3 is a leaving group such as halo (e.g., chloro)] can be reacted with substituted heteroaromatic compound 10-2 [wherein Lg1 and Lg2 are each, independently, a leaving group such as halo (e.g., chloro)] in the presence of a suitable base (such as an inorganic base, for example a metal carbonate (e.g., potassium carbonate), a metal hydride (e.g., sodium hydride), a metal hydroxide (e.g., sodium hydroxide), a metal alkoxide (e.g., sodium ethoxide)] and/or in the presence of a transition metal catalyst for example a palladium catalyst [e.g., Pd(PPh3)4] to afford compound 10-3. Reaction of compound 10-3 and alkene 10-4 under Heck coupling reaction conditions gives alkene compound 10-5. Reduction of the C=C bond (between the two aromatic rings) of compound 10-5 to a saturated bond under an appropriate condition such as palladium catalyzed hydrogenation or using a hydrazine compound, followed by optional deprotection (when R101 is an amine protecting group) and ring closure step [in the presence of an acid (e.g. p-toluenesulfonic acid (PTSA) or HCl,) or a Pd catalyst], gives compound 10-6. Scheme 10
Figure imgf000130_0001
10-1 10-3 He* CθUpliπ9
R101 is H or an amine protecting group
1 - Reduction
2- Deprotection if R101 is an amine
Figure imgf000130_0003
Figure imgf000130_0002
protecting group
3. Acid or Pd catalyst
10-6 10-5
Similar to the chemical reactions/transformations depicted in Scheme 10, compound 11-6 can be synthesized according to the methods shown in Scheme 11 wherein alkene 11-4 is substituted with a nitro group.
Scheme 11
Figure imgf000131_0001
1. Reduction of C=C bond between the two aromatic rigns. 2. Reduction of Nitro 3. Acid or Pd catalyst
Figure imgf000131_0002
Figure imgf000131_0003
11-6 11-5
As shown in Scheme 12, arylamine 12-1 can be converted to its corresponding diazonium salt intermediate using NaNO2 under acidic condition, followed by conversion of the diazonium salt to halide 12-2 [Se e.g., "The Chemistry of Functional Groups. The Chemistry of Diazonium and Diazo Groups" Wiley: New York, 1978, the articles by Hegarty, pt. 2, pp. 511-591, and Schank, pt.2, pp. 645-657; See also, P. S. Kalsi, "Organic Reactions Stereochemistry and Mechanism: Through Solved Problems"; Chapter 6, page 362 (Sandmeyer Reaction), New Age Publishers, 4th edition, 2006]. The compound 12-2 can be converted to a carbamate compound such as the BOC-protected amine 12-3 via Curtis rearrangement [See Ende, D. J. a.; DeVries, K. M.; Clifford, P. J.; Brenek, S. /. Org. Proc. Res. Dev.
1998, 2, 382-392.]. The nitro group of compound 12-3 can be reduced to amino, followed by coupling to compound 12-5 (for example, in the presence of a base or a Pd catalyst) , to afford compound 12-6. Compound 12-6 can be reacted with alkene 12-7 under Heck Reaction conditions to afford compound 12- 8. Reduction of the C=C bond (between the two aromatic rings) of compound 12-8 to a saturated bond via hydrogenation, followed by ring closure step (for example in the presence of a Pd catalyst or an acid such as HCl or PTSA), gives compound 12-9. Optional deprotection (when R101 is an amine protecting group) of compound 12-9, followed by amide formation using an appropriation reactant such as an acid or acid halide 12-10, gives compound 12-11. The compound 12-11 (which can optionally be deprotected when R150 is an amine protecting group) can undergo further chemical modifications such as acylation (where R250 can be, e.g., -C(O)Z1), sulfonylation (where R250 can be, e.g., -S(O)2Z1), urea formation (where R250 can be, e.g., -C(O)NHZ1), carbamate formation (where R250 can be, e.g., -C(O)OZ1), or arylation/heteraylation (where R250 can be, e.g., substituted aryl or heteroaryl).
Scheme 12
Figure imgf000132_0001
R101 is H or an amine protecting group or
Figure imgf000132_0002
As shown in Scheme 13, compound 13-6 can be synthesized starting from amine 13-1, by chemical reactions similar to those for making compound 12-9 in Scheme 12. After the demethylation step (see. e.g. J. F. W. McOmie, M. L. Watts, and D. E. West, "Demethylation of aryl methyl ethers by boron tribromide"; Tetrahedron, Volume 24, Issue 5, 1968, Pages 2289-2292), the OH group of compound 13-6 can undergo further chemical modifications such as ether formation (R300 can be, e.g., Ci-6 alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl), ester formation (R can be, e.g., C(0)Rbl), or carbamate formation (R300 can be, e.g., C(0)NRclRdl).
Figure imgf000133_0001
Heck Coupling
Figure imgf000133_0002
. Reduction further modification such . ring formation as ether formation, ester- sing e.g. Pd catalyst formation , etc. . De-methylation sing e.g. BBr3
Figure imgf000133_0004
13-6
Figure imgf000133_0003
13-7
As shown in Scheme 14, compound 14-1 (with a hydroxyl group) can be reacted with an appropriation reactant such as halide 14-2, to give compound 14-3. The compound 14-3 can be deprotected (under appropriate conditions according to the amine protecting group of R150, for example, under acidic condition when R150 is Boc) followed by further chemical modifications such as acylation (where R250 can be, e.g., -C(O)Z1), sulfonylation (where R250 can be, e.g., -S(O)2Z1), urea formation (where R250 can be, e.g., -C(O)NHZ1), carbamate formation (where R250 can be, e.g., -C(O)OZ1), arylation/heteroarylation (where R250 can be, e.g., substituted aryl or heteroaryl). Scheme 14
Figure imgf000134_0001
1. Deprotection
2. Further chemical modification such as acylation, sulfonylation, urea formation, or
Figure imgf000134_0002
arylation/heteroarylation
14-4
As shown in Scheme 15, the amino group of aromatic amine 15-1 can be protected by an amine protecting group such as Boc to afford compound 15-2. The amino group of aromatic amine 15-3 can be protected by an amine protecting group such as Boc to afford compound 15-4. Alkyne 15-2 can be reacted with aryl iodide 15-4 under Sonogashira coupling reaction condition to afford alkyne 15-5. [See e.g., K. Sonogashira, Y. Tohda, N. Hagihara; "A convenient synthesis of acetylenes: catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines"; Tetrahedron Letters 16 (50): 4467-4470 (1975); see also Rafael Chinchilla and Carmen Najera, "The Sonogashira Reaction: A Booming Methodology in Synthetic Organic Chemistry"; Chem. Rev.; 2007; 107(3) pp 874 - 922.]. The reduction of the C≡C of alkyne 15-5 to carbon-carbon single bond and reduction of the nitro group to amino group can be carried out under appropriate reductive conditions, for example, by hydrogenation in the presence of a Pd catalyst (such as Pd/C) to afford compound 15-6. Amine 15-6 can be reacted with heteroaromatic compound 15-7 to give compound 15-8. Deprotection of compound 15-8 (under acid condition for Boc group, for example, in the present of an acid such as PTSA or HCl), followed by ring closure (an acid condition may also be used, for example, in the present of an acid such as PTSA or HCl), gives macrocycle 15-9. The amino group (NH2) of macrocycle 15-9 can be converted to different moieties such as NHC(0)Rbl, NHC(0)NRclRdl, NHC(S)Rbl, NHC(S)NRclRdl, NHC(0)0Ral, NHS(0)2NRclRdl, NHS(O)2R" by methods known to those skilled in the art. Scheme 15
Figure imgf000135_0001
15-8 15-9
Additional starting materials and intermediates useful for making the compounds of the present invention can be obtained from chemical vendors such as Sigma- Aldrich or can be made according to methods described in the chemical art. For example, introducing pentafluorosulfanyl (SF5) group to aromatic rings can be achieved according to the methods disclosed in US Pat. No. 6,919,484 and/or the references cited therein.
Those skilled in the art can recognize that in all of the schemes described herein, if there are functional (reactive) groups present on a substituent group such as R1, R2, R3, R4, R5, R6, R7, R8, R9, R10,
L1, L2, etc., further modification can be made if appropriate and/or desired. For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to an amide; a carboxylic acid can be converted to an ester, which in turn can be reduced to an alcohol, which in turn can be further modified. For another example, an OH group can be converted into a better leaving group such as mesylate, which in turn is suitable for nucleophilic substitution, such as by CN. For another example, an -S- can be oxidized to -S(O)- and/or -S(O)2-. For yet another example, unsaturated bond such as C=C or C≡C can be reduced to saturated bond by hydrogenation. In some embodiments, a primary amine or a secondary amine moiety (present on a substituent group such as R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, L1, L2, etc.) can be converted to amide, sulfonamide, urea, or thiourea moiety by reacting it with an appropriate reagent such as an acid chloride, a sulfonyl chloride, an isocyanate, or a thioisocyanate compound. In some embodiments, a primary amine, a secondary amine, or a tertiary amine moiety (present on a substituent group such as R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, L1, L2, etc.) can be alkylated to form a quaternary ammonium salt. One skilled in the art will recognize further such modifications. Thus, a compound of Formula I (such as compound 1-2 of Scheme 1) having a substituent which contains a functional group can be converted to another compound of Formula I having a different substituent group. As used herein, the term "reacting" refers to the bringing together of designated chemical reactants such that a chemical transformation takes place generating a compound different from any initially introduced into the system. Reacting can take place in the presence or absence of solvent.
Methods Compounds of the invention can modulate activity of one or more Janus kinases (JAKs). The term "modulate" is meant to refer to an ability to increase or decrease the activity of one or more members of the JAK family of kinases. Accordingly, compounds of the invention can be used in methods of modulating a JAK by contacting the JAK with any one or more of the compounds or compositions described herein. In some embodiments, compounds of the present invention can act as inhibitors of one or more JAKs. In further embodiments, the compounds of the invention can be used to modulate activity of a JAK in an individual in need of modulation of the enzyme by administering a modulating amount of a compound of the invention.
JAKs to which the present compounds bind and/or modulate include any member of the JAK family. In some embodiments, the JAK is JAKl, JAK2, JAK3 or TYK2. In some embodiments, the JAK is JAKl or JAK2. In some embodiments, the JAK is JAK2. In some embodiments, the JAK is JAK3. In some embodiments, the JAK is TYK2.
Another aspect of the present invention pertains to methods of treating a JAK-associated disease or disorder in an individual {e.g., patient) by administering to the individual a therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical composition thereof. In some embodiments, the individual has been diagnosed to have a JAK-associated disease or disorder and is in need of treatment for the disease or disorder. A JAK-associated disease can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the JAK, including over expression and/or abnormal activity levels. A JAK-associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating JAK activity. Examples of JAK-associated diseases include diseases involving the immune system including, for example, organ transplant rejection (e.g., allograft rejection and graft versus host disease).
Further examples of JAK-associated diseases include autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease (e.g, ulcerative colitis and Crohn's disease), ankylosing spondylitis, myasthenia gravis, immunoglobulin nephropathies, autoimmune thyroid disorders, and the like. In some embodiments, the autoimmune disease is an autoimmune bullous skin disorder such as pemphigus vulgaris (PV) or bullous pemphigoid (BP). In some embodiments, JAK-associated diseases include rheumatoid arthritis. Further examples of JAK-associated diseases include allergic conditions such as asthma, food allergies, atopic dermatitis and rhinitis. Further examples of JAK-associated diseases include viral diseases such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV).
Further examples of JAK-associated diseases or conditions include skin disorders such as psoriasis (for example, psoriasis vulgaris), atopic dermatitis, alopecia areata, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances including some pharmaceuticals when topically applied can cause skin sensitization. In some embodiments, co-administration or sequential administration of at least one JAK inhibitor of the invention together with the agent causing unwanted sensitization can be helpful in treating such unwanted sensitization or dermatitis. In some embodiments, the skin disorder is treated by topical administration of at least one JAK inhibitor of the invention.
In further embodiments, the JAK-associated disease is cancer including those characterized by solid tumors (e.g., prostate cancer, renal cancer, hepatic cancer, colorectal cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi's sarcoma,melanoma etc.), hematological cancers or malignancies [e.g., lymphoma, leukemia such as acute lymphoblastic leukemia, Chronic Lymphocytic Leukemia (CLL), myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), or multiple myeloma, and other lymphoma related diseases including Castleman's disease, Waldenstrom's macroglobulinemia and Poems syndrome], and skin cancer such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Examples of cutaneous T- cell lymphomas include Sezary syndrome and mycosis fungoides. Other kinase associated diseases may also include paraneoplastic syndromes associated with cytokine production in cancer.
JAK-associated diseases can further include those characterized by expression of a mutant JAK such as those having at least one mutation in the pseudo-kinase and/or kinase domain (e.g., JAK2V617F or JAK1R724H) or genetic or epigenetic alterations known or thought to result in dysregulated JAK activity (e.g. SOCS gene methylation or MPL mutation).
JAK-associated diseases can further include myeloproliferative disorders (MPDs) such as polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis with myeloid metaplasia (MMM), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), and the like. In some embodiments, the myeloproliferative disorder is myelofibrosis with myeloid metaplasia (MMM). In some embodiments, the myeloproliferative disorder is selected from primary myelofibrosis (PMF). PMF has been known by a variety of terms including myelofibrosis with myeloid metaplasia (MMM), agnogenic myeloid metaplasia, and chronic idiopathic myelofibrosis. Myelofibrosis (MF) can present as a de novo disorder (PMF) or evolve from previous PV or ET [post- polycythemia vera myelofibrosis
(Post-PV MF) or post- essential thrombocythemia myelofibrosis (Post-ET MF)] . Myelofibrosis develops in 10% to 20% of patients with PV (see e.g. J. L. Spivak, G. Barosi, G. Tognoni, T. Barbui, G. Finazzi, R. Marchioli, and M. Marchetti; "Chronic Myeloproliferative Disorders"; Hematology, Jan 2003; 2003: 200 - 224) and in 2% to 3% of patients with ET (See e.g. D. R. Berk and A. Ahmed; "Portal, splenic, and superior mesenteric vein thrombosis in a patient with latent essential thrombocythemia and hyperhomocysteinemia"; /. CHn. Gastroenterol, 2006; 40: 3: 227-8).
Further JAK-associated diseases include inflammation and inflammatory diseases. Examples of inflammatory diseases include inflammatory diseases of the eye {e.g., iritis, uveitis, scleritis, conjunctivitis, or related disease), inflammatory diseases of the respiratory tract {e.g., the upper respiratory tract including the nose and sinuses such as rhinitis or sinusitis or the lower respiratory tract including bronchitis, chronic obstructive pulmonary disease, and the like), inflammatory myopathy (such as myocarditis), Systemic Inflammatory Response Syndrome (SIRS), septic shock, and other inflammatory diseases.
The JAK inhibitors described herein can further be used to treat ischemia reperfusion injuries or a disease or condition related to an inflammatory ischemic event such as stroke or cardiac arrest. The JAK inhibitors described herein can further be used to treat anorexia, cachexia, or fatigue such as that resulting from or associated with cancer. The JAK inhibitors described herein can further be used to treat restenosis, sclerodermitis, or fibrosis. The JAK inhibitors described herein can further be used to treat conditions associated with hypoxia or astrogliosis such as, for example, diabetic retinopathy, cancer, or neurodegeneration. See, e.g., Dudley, A.C. et al. Biochem. J. 2005, 390(Pt 2):427-36 and Sriram, K. et al. J. Biol. Chem. 2004, 279(19): 19936-47. Epub 2004 Mar 2.
The JAK/ ALK inhibitors described herein can be used to treat any of the JAK-associated diseases, disorders or conditions and/or ALK-associated diseases, disorders or conditions, or any combination thereof. In some embodiments, the JAK inhibitors described herein can be used to treat any of the JAK-associated diseases diseases, disorders or conditions, or any combination thereof.
The JAK inhibitors described herein can further be used to treat any of the JAK-associated diseases or any combination thereof. Certain compounds of the invention (the IC50 of which with respect to ALK is less than about 10 μM) can also modulate activity of ALK kinases. The term "modulate" is meant to, in this context, refer to an ability to increase or decrease the activity of the ALK kinases. Certain compounds of the invention can be used in methods of modulating an ALK by contacting the ALK with any one or more of the compounds or compositions described herein. In some embodiments, certain compounds of the present invention (the IC50 of which with respect to ALK is less than about 10 μM) can act as inhibitors of ALK. Certain compounds of the invention (the IC50 of which with respect to ALK is less than about 10 μM) can be used to modulate activity of an ALK in an individual in need of modulation of the enzyme by administering a modulating amount of a compound of the invention.
Another aspect of the present invention pertains to methods of treating an ALK-associated disease or disorder in an individual (e.g., patient) by administering to the individual a therapeutically effective amount or dose of a compound of the present invention (the IC50 of which with respect to ALK is less than about 10 μM) or a pharmaceutical composition thereof. In some embodiments, the individual is diagnosed to have an ALK-associated disease or disorder and is in need of treatment for the disease or disorder. An ALK-associated disease can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the ALK, including over expression and/or abnormal activity levels. An ALK-associated disease can also include any disease, disorder or condition that can be prevented, ameliorated, or cured by modulating ALK activity. Examples of ALK-associated diseases include diseases involving ALK-related tumors including anaplastic large cell lymphomas and non- Hodgkin lymphomas in addition to lung cancers. Treatment of the diseases/disorders herein includes treating one or more symptoms associated with the diseases/disorders. For example, symptoms of a JAK-associated skin disorder ( such as psoriasis, atopic dermatitis, skin rash, skin irritation, or skin sensitization) include itching (prutitus).
As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a JAK/ ALK with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having a JAK/ ALK, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the JAK/ ALK. As used herein, the term "individual" or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
As used herein, the term "treating" or "treatment" refers to one or more of (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting/retarding the disease; for example, inhibiting/retarding a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder; and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease or completely eliminating/curing the disease. As used herein, treating a disease further includes treating one or more symptoms associated with the disease.
Combination Therapies
One or more additional pharmaceutical agents such as, for example, chemotherapeutics, antiinflammatory agents, steroids, immunosuppressants, as well as Bcr-Abl, Flt-3, RAF, IKK, EGFR, MET, IGFlR, and FAK, ALK kinase inhibitors such as, for example, those described in WO 2006/056399, or other agents can be used in combination with the compounds of the present invention for treatment of JAK/ALK-associated diseases, disorders or conditions. The one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.
Examples of chemotherapeutics include proteosome inhibitors (e.g., bortezomib), thalidomide, revlimid, pomalidomide, DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, tubulin targeted agents (e.g. taxanes and vincristine), topoisomerase inhibitors (e.g. irinotecan), enzymes (e.g. L-asparaginase), antimetabolites (e.g. gemcitabine and hyroxyurea), and the like.
Examples of steroids include coriticosteroids such as dexamethasone or prednisone. Examples of Bcr-Abl inhibitors include the compounds, and pharmaceutically acceptable salts thereof, of the genera and species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, EP2005/009967, EP2005/010408, and U.S. Ser. No. 60/578,491.
Examples of suitable Flt-3 inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.
Examples of suitable RAF inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO 05/028444.
Examples of suitable FAK inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 04/080980, WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO 01/014402.
Examples of suitable ALK inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 04/079326.
In some embodiments, one or more of the compounds of the invention can be used in combination with one or more other kinase inhibitors including imatinib, particularly for treating patients resistant to imatinib or other kinase inhibitors.
In some embodiments, one or more JAK/ ALK inhibitors of the invention can be used in combination with a chemotherapeutic in the treatment of cancer, such as multiple myeloma, and may improve the treatment response as compared to the response to the chemotherapeutic agent alone, without exacerbation of its toxic effects. Examples of additional pharmaceutical agents used in the treatment of multiple myeloma, for example, can include, without limitation, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, IGFlR, RAF and FAK kinase inhibitors. Additive or synergistic effects are desirable outcomes of combining a JAK/ ALK inhibitor of the present invention with an additional agent. Furthermore, resistance of multiple myeloma cells to agents such as dexamethasone may be reversible upon treatment with a JAK/ ALK inhibitor of the present invention. The agents can be combined with the present compounds in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with at least one JAK/ ALK inhibitor where the dexamethasone is administered intermittently as opposed to continuously.
In some further embodiments, combinations of one or more J AK/ ALK inhibitors of the invention with other therapeutic agents can be administered to a patient prior to, during, and/or after a bone marrow transplant or stem cell transplant. Pharmaceutical Formulations and Dosage Forms
When employed as pharmaceuticals, the compounds of the invention can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary {e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful.
This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers (excipients). In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
The compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nano particulate) preparations of the compounds of the invention can be prepared by processes known in the art, for example see International Patent Application No. WO 2002/000196. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1000 mg (1 g), more usually about 100 to about 500 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
The active compound can be effective over a wide dosage range and can be generally administered in a pharmaceutically effective amount. For example, the dosage of the active compounds of the invention as employed for the treatment of a patient in need thereof (such as an adult human) may range from 0.1 to 3000 mg per day, depending on the route and frequency of administration. Such a dosage corresponds to 0.001 to 50 mg/kg per day. In some embodiments, the dosage of the active compounds of the invention as employed for the treatment of a patient in need thereof (such as an adult human) may range from 1 to 2000 mg per day, from 1 to 1000 mg per day, from 10 to 1000 mg per day, or from 10 to 500 mg per day. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient can be mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these pre-formulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention. The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11 , more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
The therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
The compositions of the invention can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.
Labeled Compounds and Assay Methods
Another aspect of the present invention relates to labeled compounds of the invention (radio-labeled, fluorescent-labeled, etc.) that would be useful not only in radio-imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the enzyme in tissue samples, including human, and for identifying ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes enzyme assays that contain such labeled compounds.
The present invention further includes isotopically -labeled compounds of the invention. An "isotopically" or "radio-labeled" compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2H (also written as D for deuterium), 3H (also written as T for tritium), 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36Cl, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I and 131I. The radionuclide that is incorporated in the radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro receptor labeling and competition assays, compounds that incorporate 3H, 14C, 82Br, 1251 , 1311, 35S or will generally be most useful. For radio-imaging applications 11C, 18F, 125I, 123I, 124I, 1311, 75Br, 76Br or 77Br will generally be most useful.
It is understood that a "radio-labeled compound" is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from 3H, 14C, 1251 , 35S and 82Br. In some embodiments, the labeled compounds of the present invention contain a fluorescent label.
Synthetic methods for incorporating radio-isotopes and fluorescent labels into organic compounds are well known in the art.
A labeled compound of the invention (radio-labeled, fluorescent-labeled, etc.) can be used in a screening assay to identify/evaluate compounds. For example, a newly synthesized or identified compound (i.e., test compound) which is labeled can be evaluated for its ability to bind a JAK/ ALK by monitoring its concentration variation when contacting with the JAK/ALK, through tracking the labeling. For another example, a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to JAK/ALK (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the JAK/ALK directly correlates to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.
Kits
The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of JAK/ALK-associated diseases or disorders such as prostate cancer, renal cancer, hepatic cancer, breast cancer, lung cancer, and other diseases referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. In some instances where the compounds of the examples were isolated by preparative HPLC in the presence of trifluoroacetic acid (TFA) or other acid (such as HCl), the compound may have been obtained as the corresponding salt. In some instances, the corresponding salt of an exemplary compound may be described as the mono-, di-, tri-, or tetrakis- acid salt (i.e. the molar ratio of the acid to the compound is 1:1, 2:1, 3:1 or 4:1), those skilled in the art would understand that other ratios of the acid to the compound may exist or form (for example 3:1, 2:1, 2.3:1, 0.8:1, or 0.5:1). Certain compounds of the Examples were found to be inhibitors of JAK/ ALK according to one or more of the assays provided herein. In some embodiments, the IC50 value for the compound of invention with respect one or more of JAK/ ALK is less than about 100, 80, 50, 20, 10, 8, 5, 2, or 1 μM. In some embodiments, the IC50 value for the compound of invention with respect to one or more of ALK is less than about 100, 80, 50, 20, 10, 8, 5, 2, or 1 μM. In some embodiments, the IC50 value for the compound of invention with respect to one or more of JAK is less than about 100, 80, 50, 20, 10, 8, 5, 2, or 1 μM. In some embodiments, the IC50 value for the compound of invention with respect one or more of JAK/ALK is less than about 1000, 800, 500, 200, 100, 80, 50, 20, or 10 nM. Certain compounds described in Tables Al, Bl, Cl, and Dl and in the Example section were tested for inhibitory activity of JAK/ALK targets according to assays such as those described herein or those known in the art [e.g., ALK assays described in WO 04/079326; and TYK2 assays described by James E. Thompson et. al, "Photochemical preparation of a pyridone containing tetracycle: A JAK protein kinase inhibitor," Bioorganic & Medicinal Chemistry Letters, Volume 12, Issue 8, 22 April 2002, Pages 1219-1223]. For instance, Examples A1-A8, B1-B3, B5-B18, Cl, C3, C6-C10, and D1-D16 were found to have IC50 values less than 1000 nM, 800 nM, 500 nM, 200 nM, or 100 nM for at least one of JAKl, JAK2, JAK3, TYK2, and ALK. Some exemplary data of the compounds of the invention are shown in Tables Al , B 1 , Cl, and Dl in the experimental section.
In some embodiments, percentage inhibition of the compound of invention to ALK was measured at a concentration of 500 nM or 1 mM. In some embodiments, the percentage inhibition measured is about 1% to about 20%, about 20% to about 50%, about 50% to about 80%, about 80% to about 100%, about 1% to about 50%, or about 50% to about 100%.
EXAMPLES Example Al (14Z)-6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,14,16,18-decaene trifluoroacetate
Figure imgf000148_0001
Step A: 2,5-Dichloro-N-(3-vinylphenyl)pyrimidin-4-amine trifluoroacetate
Figure imgf000148_0002
3-Vinylaniline (200 mg, 2.0 mmol) [Aldrich] was stirred in N,N-dimethylformamide (10 mL) and cooled to 0 0C. Sodium hydride (96 mg, 4 mmol) was added in portions which caused significant foaming. The mixture was stirred for 5 minutes after the addition was complete. 2,4,5- Trichloropyrimidine (190 μL, 2.0 mmol) [Aldrich] was added dropwise and the mixture was stirred for 30 minutes at 0 0C and at room temperature (rt or RT) overnight. Neutralization with acetic acid and purification by preparative LCMS (pH 2) gave the desired product as a trifluoroacetate salt (400 mg, 60%). LCMS for Ci2H9Cl2N3 (M+H)+: m/z = 266.1.
Step B: 5-Chloro-N,N'-bis(3-vinylphenyl)pyrimidine-2,4-diamine trifluoroacetate
Figure imgf000148_0003
A solution of 2,5-dichloro-N-(3-vinylphenyl)pyrimidin-4-amine trifluoroacetate (150 mg, 0.56 mmol) and 3-vinylaniline (200 mg, 1.0 mmol) in 2-methoxyethanol (3.8 mL) and 3 Ν hydrogen chloride in ethanol (0.56 mL) were mixed and heated to 150 0C for 30 minutes in a microwave. Purification by preparative LCMS (pH 2) gave the desired product as a trifluoroacetate salt (150 mg, 60 %). LCMS for
C20Hi7ClN4 (M+H)+: m/z = 349.1.
Step C: (14Z)-6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,14,16,18-decaene trifluoroacetate
A solution of 5-chloro-N,N'-bis(3-vinylphenyl)pyrimidine-2,4-diamine trifluoroacetate (21 mg, 0.045 mmol) in 1 ,2-dichloroethane (20 mL) was degassed by bubbling nitrogen for 5 minutes. Benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (11 mg, 0.013 mmol) was added and the mixture was heated to 130 0C for 20 minutes in a microwave. The mixture was evaporated to give a dark mixture which was suspended in acetonitrile and filtered. The filtrate was purified by preparative LCMS (pH 2) to give the desired product as a trifluoroacetate salt (1.7 mg, 9%). LCMS for Ci8Hi4ClN4 (M+H)+: m/z = 321.1. 1H NMR (400 MHz, CD3Cl): δ 8.85 (s, 1 H), 8.75 (s, 1 H), 7.90 (s, 1 H), 7.55 (s, 1 H), 7.25 (m, 3 H), 7.02 (m, 4 H), 6.60 (s, 2 H).
Example A2.
6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene trifluoroacetate
Figure imgf000149_0001
To a solution of (14Z)-6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,14,16,18-decaene trifluoroacetate (21 mg, 0.045 mmol) in ethanol (1 mL) was added 5% palladium on carbon (5 mg) and the mixure was purged and degassed with hydrogen three times. The mixture was stirred for 1 hour with balloon pressure of hydrogen. Filtration through celite and purification by preparative LCMS (pH 2) gave the desired product as a trifluoroacetate salt (1.7 mg, 30%). LCMS for Ci8Hi6ClN4 (M+H)+: m/z = 323.1. 1H NMR (400 MHz, CD3OD): δ 7.75 (m, 2 H), 7.30 (m, 1 H), 7.22 (m, 1 H), 7.12 (m, 1 H), 7.03 (m, 2 H), 6.90 (m, 1 H), 3.00 (s, 4 H).
Example A3.
2,4,8,22-Tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
Figure imgf000149_0002
Also isolated from the reaction mixture in Example A2 was the dechlorinated product as a trifluoroacetate salt (0.7 mg, 20%). LCMS for Ci8HnN4 (M+H)+: m/z = 289.1. Example A4.
6-Chloro-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19- nonaene
Figure imgf000150_0001
Step A: (2E)-l,3-bis(3-Nitrophenyl)prop-2-en-l-one
Figure imgf000150_0002
3-Nitroacetophenone (2.23 g, 0.0135 mol) [Aldrich] and 3-nitrobenzaldehyde (2.04 g, 0.0135 mol) [Aldrich] were dissolved in methanol (20 mL), and sodium hydroxide (1.3 g, 0.032 mol) was added. The mixture was stirred for 16 hours. The solid formed was filtered and washed with water to give the desired product (3.6 g, 89%). LCMS for Ci5H11N2O5 (M+H)+: m/z = 299.1.
Step B: 3,3' -Propane-1 ,3-diyldianiline
Figure imgf000150_0003
To a solution of (2£)-l,3-bis(3-nitrophenyl)prop-2-en-l-one (2.8 g, 0.0094 mol) in NN- dimethylformamide (20 mL) was added 10% (by wt.) palladium on carbon and acetic acid (2.0 mL). The mixture was degassed with vacuum and purged with hydrogen three times before shaking on a Parr shaker for 72 hours under a hydrogen atmosphere. The mixture was filtered through celite, evaporated and purified by preparative LCMS (pH 10) to give the desired product (101 mg, 5%). LCMS for C15H19N2 (M+H)+: m/z = 227.2.
Step C: N-{3-[3-(3-Aminophenyl)propyl]phenyl}-2,5-dichloropyrimidin-4-amine
Figure imgf000151_0001
To a solution of 3,3'-propane-l,3-diyldianiline (41.0 mg, 0.181 mmol) in N,N- dimethylformamide (1.0 mL), potassium carbonate (72 mg, 0.52 mmol) was added followed by 2,4,5- trichloropyrimidine (20 μL, 0.17 mmol). The mixture was stirred for 2.5 hours and purified by preparative LCMS (pH 10) to give the desired product (21 mg, 32%). LCMS for Ci9Hi9Cl2N4 (M+H)+: τalτ = 373.1.
Step D: 6-Chloro-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene N-{3-[3-(3-Aminophenyl)propyl]phenyl}-2,5-dichloropyrimidin-4-amine (20 mg, 0.05 mmol) was stirred in 2-methoxyethanol (1.0 mL) and a solution of hydrogen chloride in ethanol (0.75 mL, 3.5 M). The mixture was heated to 150 0C for 30 minutes in a microwave. Purification by preparative LCMS gave the desired product (6.5 mg, 37%). LCMS for Ci9Hi8ClN4 (M+H)+: m/z = 337.
Example A5
6-Chloro-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19- nonaen-16-one trifluoroacetate
Figure imgf000151_0002
Step A: l,3-Bis(3-aminophenyl)propan-l-one bis( trifluoroacetate)
Figure imgf000151_0003
The desired compound was prepared according to the procedure of Example A4, step B in 8.8% yield. LCMS for Ci5Hi7N4O (M+H)+: m/z = 241.1.
Step B: 6-Chloro-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-16-one trifluoroacetate
The desired compound was prepared according to the procedure of Example A4, steps C-D, usin^ l,3-bis(3-aminophenyl)propan-l-one bis(trifluoroacetate) as a starting material (16% yield). LCMS for Ci9Hi6ClN4O (M+H)+: m/z = 351.1.
Example A6.
6-Chloro-19-methyl-17-morpholin-4-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
Figure imgf000152_0001
Step A. 4-(2-Bromo-5-methyl-4-nitrophenyl)morpholine
Figure imgf000152_0002
l-Bromo-2-fluoro-4-methyl-5-nitrobenzene (1.0 g, 4.3 mmol) [Aldrich] was stirred in N,N- dimethylformamide (10 mL) with potassium carbonate (1.5 g, 11.0 mmol), and morpholine (0.56 mL, 6.4 mmol) was added. The mixture was stirred for 3 hours and diluted with saturated sodium bicarbonate solution. Extraction with ethyl acetate gave the desired compound (1.0 g, 77%). LCMS for CnHi4BrN2O3 (M+H) +: m/z = 301.0.
Step B. 5-Bromo-2-methyl-4-morpholin-4-ylaniline
Figure imgf000153_0001
Iron powder (320 mg, 5.8 mmol) was stirred in ethanol (12 mL) with 1 N HCl solution (0.6 mL, 0.6 mmol) and heated at 60 0C for 2 hours. 5 N aqueous Ammonium chloride solution (1.0 mL, 5.0 mmol) and 4-(2-bromo-5-methyl-4-nitrophenyl)morpholine (350 mg, 1.2 mmol) were added and the mixture was heated at 60 0C for 30 minutes. The mixture was filtered through celite and the collected solids were washed with ethanol. The combined filtrates were evaporated to give the desired compound (0.24 g, 75%). LCMS for CnH16BrN2O (M+H) +: m/z = 271.0. Step C. tert-Butyl (5-bromo-2-methyl-4-morpholin-4-ylphenyl)carbamate
Figure imgf000153_0002
5-Bromo-2-methyl-4-morpholin-4-ylaniline (550 mg, 2.0 mmol) was stirred in ethanol (15 mL) and di-tørt-butyldicarbonate (440 mg, 2.0 mmol) was added. The mixture was stirred for 16 hours and evaporated. Purification by silica gel chromatography gave the desired compound (523 mg, 70%). LCMS for Ci6H24BrN2O3 (M+H) +: m/z = 371.0.
Step D. tert-Butyl {5-[(3-aminophenyl)ethynyl]-2-methyl-4-morpholin-4-ylphenyljcarbamate
Figure imgf000153_0003
tert-Butyl (5-bromo-2-methyl-4-morpholin-4-ylphenyl)carbamate (110 mg, 0.3 mmol), copper(I) iodide (4 mg, 0.02 mmol) and bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.01 mmol) were stirred in tetrahydrofuran (0.5 mL) and triethylamine (50 μL, 0.4 mmol) was added. 3-Ethynylaniline (100 μL, 1.0 mmol) was added and the mixture was heated to 80 0C for 1 hour. The mixture was filtered through celite and purified by preparative LCMS (pH 2). The product fractions were neutralized with saturated sodium bicarbonate solution, evaporated to remove acetonitrile and extracted with ethyl acetate. The extracts were evaporated to give the desired compound (25 mg, 31%). LCMS for C24H30N3O3 (M+H) +: m/z = 408.1.
Step E. tert-Butyl {5-[2-(3-aminophenyl)ethyl]-2-methyl-4-morpholin-4-ylphenyljcarbamate
Figure imgf000154_0001
tert-Butyl {5-[(3-aminophenyl)ethynyl]-2-methyl-4-morpholin-4-ylphenyl}carbamate (62 mg, 0.15 mmol) was stirred in methanol (2 mL) and 10% palladium on carbon (50 mg). The mixture was stirred under a balloon pressure of hydrogen gas for 3 hours. The mixture was filtered through celite and evaporated to give the desired compound (63 mg, 100%). LCMS for C24H34N3O3 (M+H) +: m/z = 412.1.
Step F. tert-Butyl [5-(2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethyl)-2-methyl-4-morpholin-4- ylpheny I] carbamate
Figure imgf000154_0002
tert-Butyl {5-[2-(3-aminophenyl)ethyl]-2-methyl-4-morpholin-4-ylphenyl}carbamate (31 mg,
0.08 mmol) and potassium carbonate (16 mg, 0.11 mmol) were stirred in NN-dimethylformamide (1 mL) and 2,4,5-trichloropyrimidine (9 μL, 0.08 mmol) was added. The mixture was stirred for 16 hours (or 16 h) and diluted with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate and evaporated to give the desired compound (12 mg, 14%). LCMS for C28H34NCl2N3O3 (M+H) +: m/z =
558.1.
Step H. 6-Chloro-19-methyl-17-morpholin-4-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate tørt-Butyl [5-(2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethyl)-2-methyl-4-morpholin-4- ylphenyl] carbamate (12 mg, 0.02 mmol) was stirred in 2-methoxyethanol (1 mL) and 3 N hydrogen chloride in ethanol (0.2 mL) and heated to 130 0C for 20 minutes in a microwave. Purification by preparative LCMS (pH 2) gave the desired compound as a trifluoroacetic acid salt (2.2 mg, 20%). 1H
NMR (300 MHz, CDCl3): δ 11.20 (s, 1 H), 7.95 (s, 1 H), 7.85 (s, 1 H), 7.62 (s, 1 H), 7.42 (s, 1 H), 7.04
(m, 1 H), 6.92 (m, 1 H), 6.85 (m, 1 H), 3.89 (m, 4 H), 3.10 (m, 4 H), 2.91 (m, 4 H), 2.33 (s, 3 H). LCMS for C23H25ClN5O (M+H) +: m/z = 422.0.
Example A7.
6-Chloro-19-methyl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
Figure imgf000155_0001
The desired compound was prepared according to the procedure of Example A6, steps C-H using
5-bromo-2-methylaniline [Aldrich] as the starting material in 7% yield. LCMS for Ci9Hi8ClN4 (M+H)+: m/z = 337.0. 1H NMR (300 MHz, CDCl3): δ 11.20 (s, 1 H), 7.95 (s, 1 H), 7.85 (s, 1 H), 7.62 (s, 1 H), 7.42 (s, 1 H), 7.14 (m, 1 H), 7.08 (m, 1 H), 7.00 (m, 1 H), 6.87 (m, 1 H), 2.98 (m, 4 H), 2.33 (s, 3 H).
Example A8.
6-Chloro-10-(isopropylsulfonyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
Figure imgf000156_0001
Step A. 4-Bromo-l-(isopropylthio)-2-nitrobenzene
Figure imgf000156_0002
4-Bromo-l-fluoro-2-nitrobenzene (1.0 g, 4.5 mmol) [Aldrich] and potassium carbonate (1.6 g, 11 mmol) were stirred in NN-dimethylformamide (10 mL), and 2-propanethiol (0.42 mL, 4.5 mmol) was added. The mixture was heated to 100 0C for 16 hours. The mixture was cooled to rt, diluted with water (100 mL), and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, and evaporated to give the desired compound (1.2 g, 96%). 1H ΝMR (300 MHz, CDCl3): δ 8.27 (s, 1 H), 7.62 (d, 1 H), 7.38 (d, 1 H), 3.55 (m, 1 H), 1.40 (d, 6 H).
Step B. 4-Bromo-l-(isopropylsulfonyl)-2-nitrobenzene
Figure imgf000156_0003
4-Bromo-l-(isopropylsulfonyl)-2 -nitrobenzene (750 mg, 2.7 mmol) was stirred in 1,2- dichloroethane (40 mL) with ra-chloroperbenzoic acid (1.5 g, 6.1 mmol) for 16 hours. The suspension was filtered and the collected solids were washed with 1,2-dichloroethane. The combined filtrates were evaporated and purified by silica gel chromatography to give the desired compound (600 mg, 70%). LCMS for C9H11BrNO4S (M+H) +: m/z = 307.8.
Step C. 3-{[4-(Isopropylsulfonyl)-3-nitrophenyl]ethynyl}aniline
Figure imgf000156_0004
4-Bromo-l-(isopropylsulfonyl)-2 -nitrobenzene (390 mg, 1.3 mmol), bis(triphenylphosphine)palladium(II) chloride (60 mg, 0.08 mmol) and copper(I) iodide (20 mg, 0.1 mmol) were stirred in tetrahydrofuran (5 mL) with triethylamine (250 μL, 1.8 mmol). 3-Ethynylaniline (100 μL, 1.0 mmol) was added and the mixture was stirred at rt for 1.5 hours. The mixture was evaporated, diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extracts were dried over sodium sulfate, filtered and evaporated to give the desired compound (250 mg, 60%). LCMS for Ci7H17N2O4S (M+H)+: m/z = 345.1.
Step D. tert-Butyl (3-{[isopropylsulfonyl)-3-nitrophenyl]ethynyl}phenyl)carbamate
Figure imgf000157_0001
3-{ [4-(Isopropylsulfonyl)-3-nitrophenyl]ethynyl}aniline (390 mg, 1.1 mmol) was stirred in ethanol (5 mL) and di-tert-butyldicarbonate (250 mg, 1.1 mmol) was added. The mixture was stirred for 16 hours and evaporated to give the desired compound (280 mg, 55%). 1H NMR (300 MHz, DMSOd6): δ 11.91 (s, 1 H), 10.36 (s, 1 H), 8.35 (s, 1 H), 7.92 (s, 1 H), 7.83 (m, 2 H), 7.28 (m, 2 H), 7.15 (m, 1 H), 7.07 (m, 1 H), 3.18 (m, 1 H), 3.01 (m, 4 H), 1.32 (d, 6 H).
Step E. 6-Chloro-10-(isopropylsulfonyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
The desired compound was prepared according to the procedure of Example A6, steps D-G using tert-butyl (3-{ [isopropylsulfonyl)-3-nitrophenyl]ethynyl}phenyl)carbamate as the starting material.
LCMS for C2IH22ClN4O2S (M+H) +: m/z = 429.1. 1H NMR (300 MHz, CDCl3): δ 9.61 (s, 1 H), 8.39 (s, 1 H), 8.08 (s, 2 H), 7.80 (s, 1 H), 7.50 (m, 1 H), 7.38 (m, 1 H), 7.22 (m, 1 H), 3.78 (m, 1 H), 1.48 (s, 9 H), 1.25 (d, 6 H).
Example A9. 4-({[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)-iV-(4-cyanophenyl)piperazine-l- carboxamide trifluoroacetate
Figure imgf000158_0001
Step A. 2-Iodo-l -methoxy -4 -nitrobenzene
Figure imgf000158_0002
2-Methoxy-5-nitroaniline (10.0 g, 0.060 mol) was stirred in water (150 niL) and concentrated (cone.) sulfuric acid (12 niL, 0.22 mol). The solution was cooled below 5 0C with an ice-salt bath, and a solution of sodium nitrite (4.8 g, 0.070 mol) in water (40 mL) was added dropwise while maintaining the temperature below 5 0C. A solution of potassium iodide (16.8 g, 0.101 mol) was added and the mixture was heated to 90 0C for 1 hour. Cooling to 0 0C gave dark red crystals which were filtered, washed with water, and dried. Purification by silica gel chromatography using ethyl acetate/hexanes gave the desired compound (13.6 g, 75%). 1H NMR (300 MHz, DMSO-<i6): δ 8.57 (s, 1 H), 8.28 (d, 1 H), 7.19 (d, 1 H), 3.98 (s, 3 H). LCMS for C7H7INO3 (M+H) +: m/z = 280.1.
Step B. tert-Butyl{3-[(2-methoxy-5-nitrophenyl)ethynyl]phenylJcarbamate
Figure imgf000158_0003
tert-Butyl (3-ethynylphenyl)carbamate was stirred with 2-iodo-l-methoxy-4-nitrobenzene (2.60 g, 9.31 mmol) and bis(triphenylphosphine)palladium(II) chloride (163 mg, 0.23 mmol) in N,N- dimethylformamide (15 mL), and triethylamine (2.59 niL, 18.6 mmol) was added. The reaction mixture was heated at 80 0C for 15 minutes. Purification by preparative LCMS (pH 10) gave the desired compound (1.38 g, 40%). 1H NMR (300 MHz, DMSO-^6): δ 9.53 (s, 1 H), 8.25 (m, 2 H), 7.71 (s, 1 H), 7.42 (d, 1 H), 7.25 (m, 2 H), 7.18 (d, 1 H), 4.00 (s, 3 H), 1.42 (s, 9 H). LCMS for C20H21N2O5 (M+H) +: τalτ = 369.1.
Step C. tert-Butyl{3-[2-(5-amino-2-methoxyphenyl)ethyl]phenyl}carbamate
Figure imgf000159_0001
tert-Butyl{3-[(2-methoxy-5-nitrophenyl)ethynyl]phenyl}carbamate (63 mg, 0.17 mmol) and 10% palladium on carbon (122 mg, 0.10 mmol) were stirred in N,N-dimethylformamide (3.0 mL) under an atmosphere of hydrogen for 16 hours. The mixture was diluted with ethyl acetate (9.0 mL) and filtered through celite. Evaporation of the filtrate gave the desired compound (55 mg, 94%). LCMS for C20H27N2O3 (M+H) +: m/z = 343.2.
Step D. tert-Butyl[3-(2-{5-[(2,5-dichloropyrimidin-4-yl)amino]-2- methoxyphenyl}ethyl)phenyl] 'carbamate
Figure imgf000159_0002
tert-Butyl{3-[2-(5-amino-2-methoxyphenyl)ethyl]phenyl}carbamate (55 mg, 0.16 mmol), potassium carbonate (67 mg, 0.48 mmol), and 2,4,5-trichloropyrimidine (18 μL, 0.16 mmol) were stirred in NN-dimethylformamide (1.5 mL) for 30 minutes. Purification by preparative LCMS (pH 2) gave the desired compound (75 mg, 95%). 1H ΝMR (300 MHz, DMSO-<i6): δ 9.40 (s, 1 H), 9.25 (s, 1 H), 8.30 (s, 1 H), 7.40 (m, 3 H), 7.20 (m, 1 H), 7.12 (m, 1 H), 6.99 (d, 1 H) 6.80 (d, 1 H), 3.80 (s, 3 H), 2.77 (m, 4 H), 1.42 (s, 9H). LCMS for C24H27Cl2N4O3 (M+H) +: m/z = 489.1.
Step E. 6-Chloro-12-methoxy-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
Figure imgf000160_0001
tert-Butyl[3-(2-{5-[(2,5-dichloropyrimidin-4-yl)amino]-2- methoxyphenyl}ethyl)phenyl] carbamate (343 mg, 0.70 mmol) was stirred in 2-methoxyethanol (104 mL) with 3 M hydrogen chloride in ethanol (12 mL) and heated at 130 0C for 20 minutes in a microwave, (4 batches of 29 mL). Purification by preparative LCMS (pH 2) gave the desired compound (168 mg, 51%). 1H NMR (300 MHz, DMSO-<i6) δ 9.53 (s, 1 H), 9.40 (s, 1 H), 8.14 (s, 1 H), 7.91, (s, 1 H), 7.60 (s, 1 H), 7.03 (m, 2 H), 6.81 (m, 3 H), 3.79 (s, 3 H), 2.85 (s, 4 H). LCMS for Ci9Hi8ClN4O (M+H) +: m/z = 353.1.
Step F. 6- Chloro-2,4, 8, 22-tetraazatetracyclo[14.3.1.1 (3, 7).1 (9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-ol
A solution of 6-chloro-12-methoxy-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate (157 mg, 0.34 mmol) in methylene chloride (2.5 mL) was cooled to -78 0C and 1 M boron tribromide in methylene chloride (1.68 mL, 1.68 mmol) was added slowly. The mixture was allowed to warm to room temperature and stir for 16 hours. The mixture was cooled to -78 0C and saturated sodium bicarbonate solution was added. The resulting suspension was filtered and the collected solid was washed with water and ethyl acetate to give the desired compound (113 mg, 100%). 1H NMR (300 MHz, DMSOd6): δ 9.45 (s, 1 H), 9.25 (s, 1 H), 8.09 (s, 1 H), 7.92 (s, 1 H), 7.48 (s, 1 H), 7.08 (m, 1 H), 6.81 (m, 3 H), 6.71 (d, 1 H), 2.82 (s, 4 H). LCMS for Ci8Hi6ClN4O (M+H) +: m/z = 339.1.
Step G. 6-Chloro-12-(2-oxo-2-piperazin-l-ylethoxy)-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis( trifluoroacetate)
Figure imgf000161_0001
6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-ol (100 mg, 0.30 mmol), potassium carbonate (102 mg, 0.74 mmol), and tert-butyl 4-(bromoacetyl)piperazine-l-carboxylate (181 mg, 0.59 mmol) were stirred in N,N-dimethylformamide (2 mL) for 16 hours at 70 0C. Purification by preparative LCMS (pH 2) and treatment with 1 : 1 trifluoroacetic acid and methylene choride followed by evaporation gave the desired compound (33 mg, 19%). LCMS for C24H26ClN6O2 (M+H) +: m/z = 465.2.
Step H. 4-({ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaenel2-yl]oxyJacetyl)-N-(4-cyanophenyl)piperazine-l- carboxamide trifluoroacetate
6-Chloro- 12-(2-oxo-2-piperazin- 1 -ylethoxy)-2,4,8 ,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate (10.0 mg, 0.017 mmol) was stirred in NN-dimethylformamide (0.5 mL) and methylene chloride (0.5 mL) with triethylamine (12.0 μL, 0.086 mmol), and 4-isocyanatobenzonitrile (2.7 mg, 0.019 mmol) was added. Purification by preparative LCMS (pH 2) gave the desired compound (8%). LCMS for C32H30ClN8O3 (M+H) +: m/z = 609.2.
Example AlO. 4-(6-Chloropyridin-3-yl)-4-({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazine-l-carboxamide bis(trifluoroacetate)
Figure imgf000162_0001
The desired compound was prepared according to the procedure of Example A9, step H using 2- chloro-5-isocyanatopyridine as the starting material in 19% yield. LCMS for C3oH29C12N8θ3 (M+H)+: m/z = 619.2.
Example All.
4-({[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)-iV-(l-methyl-lH-indol-4-yl)piperazine-l- carboxamide trifluoroacetate
Figure imgf000162_0002
The desired compound was prepared according to the procedure of Example A9, step H using 4- isocyanato-1 -methyl- lH-indole as the starting material in 15% yield. LCMS for C34H34ClN8O3 (M+H) +: m/z = 637.2.
Example A12
12-[2-(4-Acetylpiperazin-l-yl)-2-oxoethoxy]-6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
Figure imgf000163_0001
The desired compound was prepared according to the procedure of Example A9, step H using isocyanato-ethane as the starting material in 57% yield. 1H NMR (300 MHz, DMSOd6): δ 9.42 (s, 1 H), 9.31 (s, 1 H), 8.10 (s, 1 H), 7.97 (s, 1 H), 7.60 (m, 1 H), 7.08 (m, 1 H), 6.99 (d, 1 H), 6.85 (d, 1 H), 6.80 (m, 2 H), 6.59 (m, 1 H), 4.82 (s, 2 H), 3.30 (m, 8 H), 3.03 (m, 2 H), 2.90 (m, 4 H), 1.00 (t, 3 H). LCMS for C27H31ClN7O3 (M+H) +: m/z = 536.2.
Example A13.
4-({[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)-iV-phenylpiperazine-l-carboxamide trifluoroacetate
Figure imgf000163_0002
The desired compound was prepared according to the procedure of Example A9, step H using phenyl isocyanate as the starting material in 46% yield. 1H NMR (300 MHz, DMSOd6): δ 9.38 (s, 1 H), 9.24 (s, 1 H), 8.60 (s, 1 H), 8.10 (s, 1 H), 7.99 (s, 1 H), 7.60 (s, 1 H), 7.43 (d, 2 H), 7.20 (m, 2 H), 7.08 (m, 1 H), 6.90 (m, 5 H), 4.89 (s, 2 H), 3.50 (m, 8 H), 2.89 (m, 4 H). LCMS for C3iH31ClN7O3 (M+H) +: m/z = 584.2.
Example A14 6-Chloro-12-(cyclopentyloxy)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
Figure imgf000164_0001
The desired compound was prepared according to the procedure of Example A9, step G using cyclopentyl bromide as the starting material in 32% yield. LCMS for C23H24CIN4O (M+H) +: m/z =
407.2.
Example A15.
2-{[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetamide trifluoroacetate
Figure imgf000164_0002
The desired compound was prepared according to the procedure of Example A9, step G using 2- bromoacetamide as the starting material in 56% yield. 1H NMR (300 MHz, DMS0-<i6): δ 9.40 (s, 1 H), 9.28 (s, 1 H), 8.10 (s, 1 H), 7.97 (s, 1 H), 7.63 (s, 1 H), 7.43 (s, 1 H), 7.38 (s, 1 H), 7.09 (m, 1 H), 6.99 (d, 1 H), 6.83 (d, 1 H), 6.79 (m, 2 H), 4.42 (s, 2 H), 2.89 (m, 4 H). LCMS for C20H19ClN5O2 (M+H) +: m/z = 396.1.
Example A16.
2-{[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}-iV-phenylpropanamide trifluoroacetate
Figure imgf000165_0001
The desired compound was prepared according to the procedure of Example A9, step G using 2- bromo-N-phenylpropanamide as the starting material in 69% yield. 1H ΝMR (300 MHz, DMSO-dg): δ 10.10 (s, 1 H), 9.42 (s, 1 H), 9.28 (s, 1 H), 8.10 (s, 1 H), 7.97 (s, 1 H), 7.63 (m, 3 H), 7.28 (m, 2 H), 7.04 (m, 2 H), 6.96 (d, 1 H), 6.80 (m, 3 H), 4.83 (m, 1 H), 2.95 (m, 4 H), 1.58 (d, 3 H). LCMS for C27H24ClN5O2 (M+H) +: m/z = 486.2.
Example A17. tert-Butyl 4-({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazine-l-carboxylate trifluoroacetate
Figure imgf000165_0002
The desired compound (the boc intermediate) was also prepared and isolated in Example A9, step G in 19 % yield. LCMS for C29H30ClN8O3 (M+H) +: m/z = 565.2
Example A18.
2-{[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}-iV-phenylacetamide trifluoroacetate
Figure imgf000166_0001
The desired compound was prepared according to the procedure of Example A9, step G using 2- bromo-N-phenylacetamide as the starting material in 50% yield. 1H ΝMR (300 MHz, DMSOd6): δ 10.08 (s, 1 H), 9.52 (s, 1 H), 9.40 (s, 1 H), 8.12 (s, 1 H), 7.97 (s, 1 H), 7.63 (m, 3 H), 7.33 (m, 2 H), 7.09 (m, 2 H), 6.99 (d, 1 H), 6.85 (d, 1 H), 6.83 (m, 2 H), 4.72 (s, 2 H), 2.99 (m, 4 H). LCMS for C26H23ClN5O2 (M+H) +: m/z = 472.2.
Example A19. iV-Benzyl-4-(2-{[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}- 2-oxoethyl)piperidine- 1-carboxamide bis(trifluoroacetate)
Figure imgf000166_0002
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-isocyanatO-3,5-dimethylisoxazole as starting materials in 30% yield. LCMS for C30H33ClN9O3 (M+H) +: m/z = 602.2.
Example A20. 12-[2-(4-Acetylpiperazin-l-yl)-2-oxoethoxy]-6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
Figure imgf000167_0001
6-Chloro- 12-(2-oxo-2-piperazin- 1 -ylethoxy)-2,4,8 ,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate (11.1 mg, 0.019 mmol) was stirred in NN-dimethylformamide (1.0 mL) with Ν,Ν- diisopropylethylamine (17 μL, 0.096 mmol), and acetyl chloride (1.5 μL, 0.021 mmol) was added.
Purification by preparative LCMS (pH 2) gave the desired compound (46%). LCMS for C2OH28ClN6O3 (M+H) +: m/z = 507.2.
Example A21 6-Chloro-ll-methoxy-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
Figure imgf000167_0002
Step A. 3, 5-Dinitrobromobenzene
Figure imgf000167_0003
ra-Dinitrobenzene (5.0 g, 0.030 mol) was stirred in sulfuric acid (50 mL) and heated to 85 °C. N-
Bromosuccinimide (5.0 g, 0.030 mol) was added in portions over 1.5 hours while maintaining a temperature of 85 0C. The cooled mixture was poured into ice water and the precipitate was collected, washed with water and recrystallized from methanol to give the desired compound (5.9 g, 80%). LCMS for C6H4BrN2O4 (M+H) +: m/z = 248.1.
Step B. l-Bromo-3-methoxy- 5 -nitrobenzene
Figure imgf000168_0001
3,5-Dinitrobromobenzene (1.25 g, 5.06 mmol) was stirred in methanol (12 mL) and a solution of sodium methoxide (0.5 M in methanol, 12.6 mL) was added. The mixture was heated to 60 0C for 2 hours and cooled to RT. The mixture was quenched with hydrogen chloride solution (1 N) and extracted with dichloromethane. Evaporation and purification by silica chromatography using ethyl acetate and hexanes gave the desired compound (1.0 g, 80%). LCMS for C7H7BrNO3 (M+H) +: m/z = 232.1.
Step C. tert-Butyl {3-[(E)-2-(3-methoxy-5-nitrophenyl)vinyl]phenyljcarbamate
Figure imgf000168_0002
l-Bromo-3-methoxy-5-nitrobenzene (0.50 g, 2.00 mmol), tert-butyl (3-vinylphenyl)carbamate
(0.56 g, 2.15 mmol), te?ra-N-butylammonium chloride (59.9 mg, 0.22 mmol), palladium acetate (48 mg, 0.22 mmol), and triethylamine (0.75 mL, 5.39 mmol) were stirred in NN-dimethylformamide (5.7 mL) and heated to 110 0C for 20 hours. The mixture was cooled to RT, ethyl acetate and brine were added. The ethyl acetate was separated and the aqueous layer was extracted two more times with ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate, filtered, and concentrated.
Purification by silica chromatography using ethyl acetate and hexanes gave the desired compound (0.45 g, 60%). LCMS for C20H23N2O5 (M+H) +: m/z = 371.2.
Step D. 6-Chloro-ll-methoxy-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
The desired compound was prepared according to the procedure of Example A9, steps C-E using tert-Butyl {3-[(E)-2-(3-methoxy-5-nitrophenyl)vinyl]phenyl}carbamate as the starting material in 37% yield over 3 steps. 1H NMR (300 MHz, DMSO-<i6): δ 9.41 (s, 1 H), 9.23 (s, 1 H), 8.17 (s, 1 H), 7.92 (s, 1 H), 7.40 (s, 1 H), 7.12 (m, 1 H), 6.91 (d, 1 H), 6.83 (d, 1 H), 6.71 (m, 1 H), 6.60 (m, 1 H), 3.72 (s, 3 H), 2.82 (m, 4 H). LCMS fOr Ci9H18ClN4O (M-I-H) +: m/z = 353.1.
Example A22. 6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-11-ol trifluoroacetate
Figure imgf000169_0001
The desired compound was prepared according to the procedure of Example A9, step F using 6- chloro-l l-methoxy-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate as the starting material in 94% yield. 1H NMR (300 MHz, DMSO-^6): δ 9.43 (s, 1 H), 9.23 (s, 1 H), 8.12 (s, 1 H), 7.93 (s, 1 H), 7.20 (s, 1 H), 7.12 (m, 1 H), 6.91 (d, 1 H), 6.81 (d, 1 H), 6.51 (m, 1 H), 6.40 (m, 1 H), 2.82 (m, 4 H). LCMS for Ci8Hi6ClN4O (M+H) +: m/z = 339.1.
Example A23.
2-{[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]oxy}acetyl)acetamide trifluoroacetate
Figure imgf000169_0002
The desired compound was prepared according to the procedure of Example A9, step G using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-11-ol trifluoroacetate and 2-bromoacetamide as starting materials in 40% yield. 1H NMR (300 MHz, DMSOd6): δ 9.40 (s, 1 H), 9.20 (s, 1 H), 8.10 (s, 1 H), 7.97 (s, 1 H), 7.50 (s, 1 H), 7.40 (m, 2 H), 7.09 (m, 1 H), 6.90 (d, 1 H), 6.81 (d, 1 H), 6.75 (s, 1 H), 6.60 (s, 1 H), 4.38 (s, 2 H), 2.81 (m, 4 H). LCMS for C20Hi9ClN5O2 (M+H) +: m/z = 396.1.
Example A24.
2-{[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]oxy}-iV-phenylacetamide trifluoroacetate
Figure imgf000170_0001
The desired compound was prepared according to the procedure of Example A9, step G using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-1 l-ol trifluoroacetate and 2-bromo-N-phenylacetamideas the starting material in 30% yield. 1H ΝMR (300 MHz, DMS0-<i6): δ 10.08 (s, 1 H), 9.32 (s, 1 H), 9.16 (s, 1 H), 8.12 (s, 1 H), 7.97 (s, 1 H), 7.63 (m, 2 H), 7.43 (s, 1 H), 7.30 (m, 2 H), 7.09 (m, 2 H), 6.90 (d, 1 H), 6.80 (m, 2 H), 6.68 (s, 1 H), 4.62 (s, 2 H), 2.80 (s, 4 H). LCMS for C26H23ClN5O2 (M+H) +: m/z = 472.2.
Example A25.
6-Chloro-10-methoxy-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
Figure imgf000170_0002
The desired compound was prepared according to the procedure of Example A9, steps B-E using 4-iodo-l-methoxy-2-nitrobenzene as the starting material in 38% yield over 4 steps. 1H NMR (300 MHz, DMSO-^6): δ 9.45 (s, 1 H), 8.20 (s, 1 H), 8.12 (s, 1 H), 7.87 (s, 1 H), 7.80 (s, 1 H), 7.18 (m, 1 H), 7.00 (m, 2 H), 6.91 (d, 1 H), 6.83 (d, 1 H), 3.80 (s, 3 H), 2.82 (s, 4 H). LCMS for Ci9H18ClN4O (M+H) +: m/z = 353.1.
Example A26. 6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-10-ol trifluoroacetate
Figure imgf000171_0001
The desired compound was prepared according to the procedure of Example A9, step F using 6- chloro-10-methoxy-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate as the starting material in 96% yield. 1H NMR (300 MHz, DMSO-^6): δ 9.32 (s, 1 H), 8.12 (s, 1 H), 7.88 (m, 2 H), 7.77 (s, 1 H), 7.18 (m, 1 H), 6.92 (d, 1 H), 6.81 (m, 3 H), 2.82 (m, 4 H). LCMS for Ci8Hi6ClN4O (M+H) +: m/z = 339.1.
Example A27. teιt-Butyl 4-({[6-chloro-2,4,8,22-tetraazatetracydo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)piperidine-l-carboxylate trifluoroacetate
Figure imgf000171_0002
To a solution of l-(tørt-butoxycarbonyl)piperidine-4-carboxylic acid (25.0 mg, 0.109 mmol) in NN-dimethylformamide (1.0 mL), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (124 mg, 0.33 mmol) and NN-diisopropylethylamine (48 μL, 0.27 mmol) were added, and the mixture was stirred for 15 minutes. A solution of 6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride (53.7 mg, 0.13 mmol) in N,N-dimethylformamide (1.0 mL) and NN- diisopropylethylamine (48 μL, 0.27 mmol) was added to the previous solution and stirred for 3 hours at room temperature. The precipitate was filtered, washed with water and dried under vacuum. Purification by preparative LCMS (pH 2) gave the desired compound (35 mg, 59% yield). LCMS for C29H34ClN6O3 (M+H) +: m/z = 549.2.
Example A28. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate)
Figure imgf000172_0001
terf-Butyl 4-({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)piperidine-l-carboxylate (35 mg, 0.064 mmol) was treated with trifluoroacetic acid (1.0 mL) and methylene chloride (1.0 mL) for 10 minutes and evaporated to give the desired compound (35 mg, 100% yield). 1H NMR (300 MHz, DMSOd6): δ 9.42 (s, 2 H), 9.25 (s, 1 H), 8.60 (m, 1 H), 8.28 (m, 1 H), 8.13 (s, 1 H), 8.00 (s, 1 H), 7.75 (s, 1 H), 7.20 (d, 1 H), 7.05 (m, 2 H), 6.91 (d, 1 H), 6.77 (d, 1 H), 3.38 (m, 2 H), 2.80 (m, 7 H), 2.01 (m, 2 H), 1.82 (m, 2 H). LCMS for C24H26ClN6O (M+H) +: m/z = 449.2.
Example A29. l-Acetyl-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide trifluoroacetate
Figure imgf000172_0002
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and acetyl chloride as starting materials in 16% yield. LCMS for C26H28ClN6O2 (M+H) +: m/z = 491.2.
Example A30. l-Benzoyl-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide trifluoroacetate
Figure imgf000173_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and benzoyl chloride as starting materials in 18% yield. LCMS for C3IH30ClN6O2 (M+H) +: m/z = 553.2.
Example A31. l-(l,3-Benzodioxol-5-ylcarbonyl)-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine- 4-carboxamide trifluoroacetate
Figure imgf000173_0002
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 1,3- benzodioxole-5-carbonyl chloride as starting materials in 16% yield. LCMS for C32H30ClNeO4 (M+H) " m/z = 597.2.
Example A32. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-(2-furoyl)piperidine-4-carboxamide trifluoroacetate
Figure imgf000174_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 2- furancarbonyl chloride as starting materials in 16% yield. LCMS for C29H28CIΝ6O3 (M+H) +: m/z = 543.2.
Example A33. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-(4-cyanobenzoyl)piperidine- 4-carboxamide trifluoroacetate
Figure imgf000174_0002
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20), 3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 4-cyanobenzoyl chloride as starting materials in 20% yield. LCMS for C32H29CIΝ7O2 (M+H) +: m/z
= 578.2.
Example A34. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-[(3,5-dimethylisoxazol-4-yl)carbonyl]piperidine-4- carboxamide trifluoroacetate
Figure imgf000175_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20), 3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 3,5-dimethylisoxazole-4-carbonyl chloride as starting materials in 36% yield. LCMS for C30H31CIΝ7O3 (M+H) +: m/z = 572.2.
Example A35. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-(phenylacetyl)piperidine-4- carboxamide trifluoroacetate
Figure imgf000175_0002
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and benzeneacetyl chloride as starting materials in 70% yield. 1H ΝMR (300 MHz, DMSCW6): δ 9.61 (s, 1 H), 9.44 (s, 1 H), 9.32 (s, 1 H), 8.18 (s, 1 H), 7.97 (s, 1 H), 7.72 (s, 1 H), 7.20 (m, 7 H), 7.03 (m, 2 H), 6.89 (d, 1 H), 6.79 (d, 1 H), 4.42 (d, 1 H), 4.01 (d, 1 H), 3.73 (s, 2 H), 3.02 (m, 1 H), 2.81 (m, 4 H), 2.63 (m, 2 H), 1.80 (m, 2 H), 1.41 (m, 2 H). LCMS for C32H32ClN6O2 (M+H) +: m/z = 567.2. Example A36. iV(4)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV(l)-phenylpiperidine- 1 ,4- dicarboxamide trifluor oacetate
Figure imgf000176_0001
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and phenyl isocyante as starting materials in 31% yield. LCMS for C31H31CIΝ7O2 (M+H) +: m/z = 568.2.
Example A37. iV(4)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV(l)-(4-cyanophenyl)piperidine- 1 ,4- dicarboxamide trifluor oacetate
Figure imgf000176_0002
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 4- isocyanatobenzonitrile as starting materials in 44% yield. 1H ΝMR (300 MHz, DMSCW6): δ 9.43 (s, 1 H), 9.33 (m, 2 H), 9.01 (s, 1 H), 8.12 (s, 1 H), 8.00 (s, 1 H), 7.75 (s, 1 H), 7.65 (s, 4 H), 7.20 (d, 1 H), 7.04 (m, 2 H), 6.87 (d, 1 H), 6.78 (d, 1 H), 4.20 (d, 2 H), 2.90 (m, 6 H), 2.69 (m, 1 H), 1.89 (m, 2 H), 1.61 (m, 2 H). LCMS for C32H30ClN8O2 (M+H) +: m/z = 593.2. Example A38. iV(4)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV(l)-(3-methoxyphenyl)piperidine- 1 ,4- dicarboxamide trifluor oacetate
Figure imgf000177_0001
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 1- isocyanato-3-methoxybenzene as starting materials in 66% yield. 1H ΝMR (300 MHz, DMS0-<i6): δ 9.49 (s, 1 H), 9.40 (s, 1 H), 9.33 (s, 1 H), 8.49 (s, 1 H), 8.17 (s, 1 H), 7.98 (s, 1 H), 7.72 (s, 1 H), 7.10 (m, 5 H), 6.87 (d, 1 H), 6.79 (d, 1 H), 6.48 (d, 1 H), 4.20 (d, 2 H), 3.68 (s, 3 H), 2.87 (m, 6 H), 2.66 (m, 1 H), 1.89 (m, 2 H), 1.61 (m, 2 H). LCMS for C32H33ClN7O3 (M+H) +: m/z = 598.2.
Example A39. iV(4)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV(l)-[2-(methylthio)phenyl]piperidine- 1 ,4- dicarboxamide trifluor oacetate
Figure imgf000177_0002
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 1- isocyanato-2-(methylthio)benzene as starting materials in 49% yield. LCMS for C32H32ClN7O2S (M+H) +: m/z = 614.2. Example A40. iV(l)-(6-Chloropyridin-3-yl)-iV(4)-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine- 1,4-dicarboxamide bis(trifluoroacetate)
Figure imgf000178_0001
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 2-chloro-5- isocyanatopyridine as starting materials in 23% yield. LCMS for C30H29Cl2N8O2 (M+H) +: m/z = 603.2.
Example A41. iV(4)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV(l)-(l-methyl-lH-indol- 4-yl)piperidine-l,4-dicarboxamide trifluoroacetate
Figure imgf000178_0002
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 4- isocyanato-1 -methyl- lH-indole as starting materials in 34% yield. LCMS for C34H34ClN8O2 (M+H) +: m/z = 621.2.
Example A42. N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-(phenylsulfonyl)piperidine- 4-carboxamide trifluoroacetate
Figure imgf000179_0001
N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) (10.0 mg, 0.018 mmol) was stirred in N,N-dimethylformamide (1.0 mL) with N,N-diisopropylethylamine (16 μL, 0.089 mmol), and benzenesulfonyl chloride (2.5 μL, 0.020 mmol) was added. Purification by preparative LCMS (pH 2) gave the desired compound (18%). LCMS for C30H30ClN6O3S (M+H) +: m/z = 589.2.
Example A43. l-(Anilinocarbonothioyl)-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine- 4-carboxamide trifluoroacetate
Figure imgf000179_0002
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20), 3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and isothiocyanatobenzene as starting materials in 28% yield. LCMS for C3iH30ClΝ7OS (M+H) +: m/z =
584.2.
Example A44. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate)
Figure imgf000180_0001
The desired compound was prepared according to the procedures of Examples A-27 and A-28 using l-(tert-butoxycarbonyl)piperidine-3-carboxylic acid as the starting material in 53% yield. LCMS for C24H26ClN6O (M+H) +: m/z = 449.2.
Example A45.
(3R)-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide bis(trifluoroacetate)
Figure imgf000180_0002
The desired compound was prepared according to the procedures of Examples A-27 and A-28 using (3R)-l-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid as the starting material in 37% yield. LCMS fOr C23H24ClN6O (M-I-H) +: m/z = 435.2.
Example A46. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate)
Figure imgf000181_0001
The desired compound was prepared according to the procedures of Examples A-27 and A-28 using [l-(tert-butoxycarbonyl)piperidin-4-yl] acetic acid as the starting material in 53% yield. LCMS for C25H28ClN6O (M+H) +: m/z = 463.2.
Example A47. l-Acetyl-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3-carboxamide trifluoroacetate
Figure imgf000181_0002
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate) and acetyl chloride as starting materials in 34% yield. LCMS for C26H28ClN6O2 (M+H) +: m/z = 491.2.
Example A48. l-Benzoyl-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3-carboxamide trifluoroacetate
Figure imgf000182_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate) and benzoyl chloride as starting materials in 36% yield. LCMS for C3IH30ClN6O2 (M+H) +: m/z = 553.2.
Example A49. iV(3)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV(l)-ethylpiperidine-l, 3-dicarboxamide trifluoroacetate
Figure imgf000182_0002
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate) and isocyanato- ethane as starting materials in 36% yield. LCMS for C27H3IClN7O2 (M+H) +: m/z = 520.2.
Example A50. iV(3)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV(l)-phenylpiperidine- 1,3-dicarboxamide trifluoroacetate
Figure imgf000183_0001
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate) and phenyl isocyanate as starting materials in 42% yield. 1H ΝMR (300 MHz, DMS0-<i6): δ 9.43 (s, 1 H), 9.40 (s, 1 H), 9.38 (s, 1 H), 8.59 (s, 1 H), 8.14 (s, 1 H), 8.00 (s, 1 H), 7.72 (s, 1 H), 7.44 (d, 2 H), 7.21 (m, 3 H), 7.04 (m, 2 H), 6.90 (m, 2 H), 4.22 (d, 1 H), 4.10 (d, 1 H), 2.90 (m, 6 H), 2.63 (m, 1 H), 2.03 (m, 1 H), 1.72 (m, 2 H), 1.47 (m, 1 H). LCMS for C31H31CIΝ7O2 (M+H) +: m/z = 568.2.
Example A51.
(3R)-l-Acetyl-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9, 13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine- 3-carboxamide trifluoroacetate
Figure imgf000183_0002
The desired compound was prepared according to the procedure of Example A20, using (3R)-N- [6-chloro-2,4,8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide bis(trifluoroacetate) and acetyl chloride as starting materials in 43% yield. LCMS for C25H26CIΝ6O2 (M+H) +: m/z = 477.2.
Example A52. (3R)-l-Benzoyl-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9, 13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine- 3-carboxamide trifluoroacetate
Figure imgf000184_0001
The desired compound was prepared according to the procedure of Example A20, using (3R)-N-
[6-chloro-2,4,8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide bis(trifluoroacetate) and benzoyl chloride as starting materials in 40% yield. LCMS for C30H2SClNeO2 (M+H) +: τalτ = 539.2.
Example A53.
(3R)-N(3)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N(l)-ethylpyrrolidine- 1,3-dicarboxamide trifluoroacetate
Figure imgf000184_0002
The desired compound was prepared according to the procedure of Example A9, step H using
(3R)-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide bis(trifluoroacetate) and isocyanato-ethane as starting materials in 40% yield. LCMS for C26H29C1Ν7O2 (M+H) +: τalτ = 506.2.
Example A54. (3R)-iV(3)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV(l)-phenylpyrrolidine- 1,3- dicarboxamide trifluor oacetate
Figure imgf000185_0001
The desired compound was prepared according to the procedure of Example A9, step H using
(3R)-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide bis(trifluoroacetate) and phenyl isocyanate as starting materials in 46% yield. 1H ΝMR (300 MHz, DMSO-Cf6): δ 9.53 (s, 1 H), 9.42 (s, 1 H), 9.34 (s, 1 H), 8.21 (s, 1 H), 8.14 (s, 1 H), 8.00 (s, 1 H), 7.78 (s, 1 H), 7.50 (d, 2 H), 7.20 (m, 3 H), 7.08 (m, 2 H), 6.90 (m, 2 H), 6.78 (d, 1 H), 3.70 (m, 1 H), 3.60 (m, 2 H), 3.40 (m, 1 H), 3.27 (m, 1 H), 2.87 (m, 4 H), 2.19 (m, 2 H). LCMS for C30H29ClN7O2 (M+H) +: m/z = 554.2.
Example A55. 2-(l-Acetylpiperidin-4-yl)-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide trifluoroacetate
Figure imgf000185_0002
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and acetyl chloride as starting materials in 58% yield. LCMS for C27H30ClN6O2 (M+H) +: m/z = 505.2. Example A56.
2-(l-Benzoylpiperidin-4-yl)-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide trifluoroacetate
Figure imgf000186_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and benzoyl chloride as starting materials in 58% yield. LCMS for C32H32ClN6O2 (M+H) +: m/z = 567.2.
Example A57.
4-(2-{[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-ethylpiperidine- 1-carboxamide trifluoroacetate
Figure imgf000186_0002
The desired compound was prepared according to the procedure of Example A9, step H using N-
[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and isocyanato-ethane as starting materials in 77% yield. 1H ΝMR (300 MHz, DMSCW6): δ 9.65 (s, 1 H), 9.60 (s, 1 H), 9.30 (s, 1 H), 8.20 (s, 1 H), 7.92 (s, 1 H), 7.73 (s, 1 H), 7.24 (d, 1 H), 7.12 (m, 1 H),
7.04 (d, 1 H), 6.87 (d, 1 H), 6.80 (d, 1 H), 6.40 (s, 1 H), 3.92 (d, 2 H), 3.01 (m, 2 H), 2.90 (m, 4 H), 2.62 (m, 2 H), 2.28 (d, 2 H), 1.92 (m, 1 H), 1.61 (m, 2 H), 1.12 (m, 2 H), 1.00 (t, 3 H). LCMS for C28H33ClN7O2 (M+H) +: m/z = 534.2.
Example A58.
4-(2-{[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-phenylpiperidine- 1-carboxamide trifluoroacetate
Figure imgf000187_0001
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and phenyl isocyanate as starting materials in 53% yield. 1H ΝMR (300 MHz, DMSCW6): δ 9.49 (s, 1 H), 9.38 (s, 1 H), 9.35 (s, 1 H), 8.47 (s, 1 H), 8.12 (s, 1 H), 7.99 (s, 1 H), 7.72 (s, 1 H), 7.43 (d, 2 H), 7.20 (m, 3 H), 7.04 (m, 2 H), 6.90 (m, 2 H), 6.78 (d, 1 H), 4.15 (d, 2 H), 2.82 (m, 6 H), 2.30 (d, 2 H), 2.00 (m, 1 H), 1.72 (m, 2 H), 1.20 (m, 2 H). LCMS for C32H33ClN7O2 (M+H) +: m/z = 582.2.
Example A59. iV(4)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV(l)-ethylpiperidine-l, 4-dicarboxamide trifluoroacetate
Figure imgf000187_0002
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20), 3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and isocyanato- ethane as starting materials in 25% yield. LCMS for C27H3IClN7O2 (M+H) +: m/z = 520.2.
Example A60.
Ethyl ({[4-({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)piperidin- l-yl]carbonyl}amino)acetate trifluoroacetate
Figure imgf000188_0001
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and ethyl isocyanatoacetate as starting materials in 35% yield. LCMS for C29H33ClN7O4 (M+H) +: m/z = 578.2.
Example A61. iV(4)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV(l)-cyclopentylpiperidine- 1 ,4- dicarboxamide trifluoroacetate
Figure imgf000188_0002
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and isocyanatocyclopentane as starting materials in 31% yield. LCMS for C30H35ClN7O2 (M+H) +: m/z = 560.2. Example A62. iV(3)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV(l)-cyclopentylpiperidine- 1,3-dicarboxamide trifluoroacetate
Figure imgf000189_0001
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20), 3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate) and isocyanatocyclopentane as starting materials in 58% yield. LCMS for C30H35CIN7O2 (M+H) +: m/z = 560.2.
Example A63.
(3R)-iV(3)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV(l)-cyclopentylpyrrolidine- 1,3-dicarboxamide trifluoroacetate
Figure imgf000189_0002
The desired compound was prepared according to the procedure of Example A9, step H using (3R)-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide bis(trifluoroacetate) and isocyanatocyclopentane as starting materials in 43% yield. LCMS for C29H33ClN7O2 (M+H) +: m/z = 546.2. Example A64.
4-(2-{[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-cyclopentylpiperidine-l- carboxamide trifluoroacetate
Figure imgf000190_0001
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and isocyanatocyclopentane as starting materials in 68% yield. LCMS for C3IH37ClN7O2 (M+H) +: m/z = 574.2.
Example A65. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-cyanoacetamide trifluoroacetate
Figure imgf000190_0002
The desired compound was prepared according to the procedure of Example A27 using cyanoacetic acid as the starting material in 26% yield. 1H NMR (300 MHz, DMS0-<i6): δ 9.70 (s, 1 H), 9.50 (m, 1 H), 9.48 (s, 1 H), 8.17 (s, 1 H), 7.92 (s, 1 H), 7.78 (s, 1 H), 7.25 (d, 1 H), 7.04 (m, 2 H), 6.87 (d, 1 H), 6.81 (d, 1 H), 3.92 (s, 2 H), 2.88 (m, 4 H). LCMS for C2iHi8ClN6O (M+H) +: m/z = 405.1.
Example A66. 2-[(Anilinocarbonyl)amino]-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide trifluoroacetate
Figure imgf000191_0001
The desired compound was prepared according to the procedure of Example A9, step H using 2- amino-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-
1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]acetamide bis(trifluoroacetate) and phenyl isocyanate as starting materials in 38% yield. LCMS for C27H25ClN7O2 (M+H) +: m/z = 514.2.
Example A67.
3-[(Anilinocarbonyl)amino]-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]propanamide trifluoroacetate
Figure imgf000191_0002
The desired compound was prepared according to the procedure of Example A9, step H using 3- amino-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]propanamide bis(trifluoroacetate) and phenyl isocyanate as starting materials in 35% yield. LCMS for C28H27ClN7O2 (M+H) +: m/z = 528.2.
Example A68.
(2S)-2-[(Anilinocarbonyl)amino]-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-hydroxypropanamide trifluoroacetate
Figure imgf000192_0001
The desired compound was prepared according to the procedure of Example A9, step H using (2S)-2-amino-N-[6-chloro-2,4, 8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,7).1 (9, 13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-hydroxypropanamide bis(trifluoroacetate) and phenyl isocyanate as starting materials in 36% yield. LCMS for C28H27CIΝ7O3 (M+H) +: m/z = 544.2.
Example A69.
(2S)-iV(2)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV(l)-phenylpyrrolidine- 1 ,2- dicarboxamide trifluor oacetate
Figure imgf000192_0002
The desired compound was prepared according to the procedure of Example A9, step H using (2S)-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-2-carboxamide bis(trifluoroacetate) and phenyl isocyanate as starting materials in 44% yield. 1H ΝMR (300 MHz, DMSO-^6): δ 9.43 (s, 2 H), 9.36 (s, 1 H), 8.30 (s, 1 H), 8.11 (s, 1 H), 7.98 (s, 1 H), 7.72 (s, 1 H), 7.58 (d, 2 H), 7.25 (m, 3 H), 7.04 (m, 2 H), 6.95 (m, 1 H), 6.85 (d, 1 H), 4.53 (m, 1 H), 3.68 (m, 1 H), 3.50 (m, 1 H), 2.85 (m, 4 H), 2.20 (m, 1 H), 2.01 (m, 3 H). LCMS for C30H29ClN7O2 (M+H) +: m/z = 554.2.
Example A70. tert-Butyl 4-(2-{[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)piperidine-l-carboxylate bis(trifluoroacetate)
Figure imgf000193_0001
The desired compound was prepared according to the procedure of Example A27 using 6-chloro-
2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen- 12-amine tris(trifluoroacetate) and [l-(tørt-butoxycarbonyl)piperidin-4-yl] acetic acid as the starting materials in 59% yield. LCMS for C29H35ClN7O3 (M+H) +: m/z = 564.2.
Example A71. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate)
Figure imgf000193_0002
The desired compound was prepared according to the procedure of Example A28 using tert-butyl
4-(2-{ [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)piperidine-l-carboxylate as the starting material in 100% yield. 1H NMR (300 MHz, DMSOd6): δ 9.40 (s, 1 H), 9.36 (s, 1 H), 9.25 (s, 1 H), 8.10 (s, 1 H), 8.00 (s, 1 H), 7.72 (s, 1 H), 7.22 (d, 1 H), 7.03 (m, 2 H), 6.87 (m, 1 H), 6.72 (d, 1 H), 6.69 (s, 2 H), 3.42 (d, 2 H), 2.85 (m, 4 H), 2.50 (m, 3 H), 2.30 (m, 2 H), 1.80 (d, 2 H), 1.25 (m, 2 H). LCMS for C24H27ClN7O (M+H) +: m/z = 464.2.
Example A72. l-(Aminosulfonyl)-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9, 13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4- carboxamide trifluoroacetate
Figure imgf000194_0001
To a solution of N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifiuoroacetate) (10.0 mg, 0.018 mmol) in 1,4-dioxane (1.0 mL) was added sulfamide (17.1 mg, 0.18 mmol) and the mixture was heated to 130 0C in a microwave for 10 minutes. Purification by preparative LCMS (pH 2) gave the desired compound (0.8 mg, 7% yield). LCMS for C24H27ClN7O3S (M+H) +: m/z = 528.2.
Example A73. l-(Aminosulfonyl)-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9, 13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3- carboxamide trifluoroacetate
Figure imgf000194_0002
The desired compound was prepared according to the procedure of Example A72 using N- [6 - chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate) as the starting material in 33% yield. LCMS for C24H27ClN7O3S (M+H) +: m/z = 528.2.
Example A74. (3R)-l-(Aminosulfonyl)-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine- 3-carboxamide trifluoroacetate
Figure imgf000195_0001
The desired compound was prepared according to the procedure of Example A72 using (3R)-N-
[6-chloro-2,4,8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide bis(trifluoroacetate) as the starting material in 30% yield. LCMS for C23H25ClN7O3S (M+H) +: m/z = 514.2.
Example A75.
2-[l-(Aminosulfonyl)piperidin-4-yl]-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide trifluoroacetate
Figure imgf000195_0002
The desired compound was prepared according to the procedure of Example A72 using N- [6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) as the starting material in 39% yield. LCMS for C25H29ClN7O3S (M+H) +: m/z = 542.2.
Example A76. 2-(l-Acetylpiperidin-4-yl)-iV-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide bis(trifluoroacetate)
Figure imgf000196_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and acetyl chloride as starting materials in 43% yield. 1H ΝMR (300 MHz, DMSO- d6): δ 10.02 (s, 2 H), 9.40 (s, 1 H), 9.01 (s, 1 H), 8.31 (s, 2 H), 8.20 (s, 1 H), 7.65 (s, 1 H), 7.31 (d, 1 H), 7.08 (d, 1 H), 4.38 (d, 1 H), 3.81 (d, 1 H), 3.00 (m, 6 H), 2.52 (m, 1 H), 2.32 (m, 2 H), 2.00 (s, 3 H), 1.75 (m, 2 H), 1.20 (m, 2 H). LCMS for C26H29ClN7O2 (M+H) +: m/z = 506.2.
Example A77.
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-phenylpiperidine- 1 -carboxamide bis(trifluor oacetate)
Figure imgf000196_0002
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and phenyl isocyanate as starting materials in 51% yield. LCMS for C3iH32ClΝ8O2 (M+H) +: m/z = 583.2. Example A78.
2- [ 1- (Aminosulf onyl)piperidin-4-yl] -N- [6-chloro-
2,4,8,18,22pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen- 12-yl]acetamide bis(trifluoroacetate)
Figure imgf000197_0001
The desired compound was prepared according to the procedure of Example A72 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) as the starting material in 30% yield. LCMS for C24H28ClN8O3S (M+H) +: m/z = 543.2.
Example A79. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(methylsulfonyl)piperidin- 4-yl]acetamide bis(trifluoroacetate)
Figure imgf000197_0002
The desired compound was prepared according to the procedure of Example A42, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and methanesulfonyl chloride as starting materials in 43% yield. LCMS for C25H29ClN7O3S (M+H) +: m/z = 542.2.
Example A80. 4-(2-{[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV,iV-dimethylpiperidine-l- carboxamide trifluoroacetate
Figure imgf000198_0001
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and NN- dimethylcarbamoyl chloride as starting materials in 48% yield. 1H ΝMR (300 MHz, DMSCW6): δ 9.57 (s, 1 H), 9.43 (s, 1 H), 9.32 (s, 1 H), 8.17 (s, 1 H), 7.97 (s, 1 H), 7.72 (s, 1 H), 7.21 (d, 1 H), 7.10 (m, 1 H), 7.01 (d, 1 H), 6.88 (d, 1 H), 6.80 (d, 1 H), 3.57 (d, 2 H), 2.91 (m, 2 H), 2.83 (m, 2 H), 2.71 (m, 8 H), 2.32 (d, 2 H), 1.93 (m, 1 H), 1.70 (m, 2 H), 1.20 (m, 2 H). LCMS for C28H33ClN7O2 (M+H)+: m/z = 534.2.
Example A81. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(dimethylamino)sulfonyl]piperidin- 4-yl}acetamide trifluoroacetate
Figure imgf000198_0002
The desired compound was prepared according to the procedure of Example A42, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and dimethylsulfamoyl chloride as starting materials in 38% yield. 1H ΝMR (300 MHz, DMSCW6): δ 9.42 (s, 1 H), 9.36 (s, 1 H), 9.29 (s, 1 H), 8.12 (s, 1 H), 8.00 (s, 1 H), 7.76 (s, 1 H), 7.21 (d, 1 H), 7.05 (m, 2 H), 6.89 (d, 1 H), 6.79 (d, 1 H), 3.58 (d, 2 H), 2.88 (m, 6 H), 2.76 (s, 6 H), 2.30 (d, 2 H), 1.91 (m, 1 H), 1.76 (m, 2 H), 1.21 (m, 2 H). LCMS for C27H33ClN7O3S (M+H) +: m/z = 570.2.
Example A82. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(isopropylsulfonyl)piperidin- 4-yl]acetamide trifluoroacetate
Figure imgf000199_0001
The desired compound was prepared according to the procedure of Example A42, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and propane -2- sulfonyl chloride as starting materials in 27% yield. LCMS for C28H34ClN6O3S (M+H) +: m/z = 569.2.
Example A83. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(ethylsulfonyl)piperidin- 4-yl]acetamide trifluoroacetate
Figure imgf000200_0001
The desired compound was prepared according to the procedure of Example A42, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and ethanesulfonyl chloride as starting materials in 41% yield. 1H ΝMR (300 MHz, DMS0-<i6): δ 9.40 (s, 1 H), 9.36 (s, 1 H), 9.28 (s, 1 H), 8.12 (s, 1 H), 7.98 (s, 1 H), 7.73 (s, 1 H), 7.21 (d, 1 H), 7.04 (m, 2 H), 6.87 (d, 1 H), 6.78 (d, 1 H), 3.60 (m, 2 H), 3.01 (m, 2 H), 2.83 (m, 6 H), 2.27 (m, 2 H), 1.91 (m, 1 H), 1.78 (m, 2 H), 1.22 (m, 2 H), 1.20 (m, 3 H). LCMS for C27H32ClN6O3S (M+H) +: m/z = 555.2.
Example A84.
4-(2-{[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-isopropylpiperidine-l- carboxamide trifluoroacetate
Figure imgf000200_0002
The desired compound was prepared according to the procedure of Example A9, step H using N-
[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 2- isocyanatopropane as starting materials in 41% yield. 1H ΝMR (300 MHz, DMSO-^6): δ 9.43 (s, 1 H), 9.33 (s, 1 H), 9.31 (s, 1 H), 8.12 (s, 1 H), 7.98 (s, 1 H), 7.73 (s, 1 H), 7.21 (d, 1 H), 7.04 (m, 2 H), 6.87 (d, 1 H), 6.78 (d, 1 H), 6.09 (m, 1 H), 3.95 (m, 2 H), 3.72 (m, 1 H), 2.83 (m, 4 H), 2.62 (m, 2 H), 2.27 (m, 2 H), 1.91 (m, 1 H), 1.62 (m, 2 H), 1.12 (m, 2 H), 1.00 (d, 6 H). LCMS for C29H35ClN7O3 (M+H) +: m/z = 548.2. Example A85. iV-(tert-Butyl)-4-(2-{[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9, 13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)piperidine- 1-carboxamide trifluoroacetate
Figure imgf000201_0001
O
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 2- isocyanato-2-methyl-propane as starting materials in 48% yield. 1H NMR (SOO MHz5 DMSO-Uf6): δ 9.43 (s, 1 H), 9.32 (m, 2 H), 8.13 (s, 1 H), 8.00 (s, 1 H), 7.72 (s, 1 H), 7.22 (d, 1 H), 7.09 (m, 1 H), 7.01 (d, 1 H), 6.89 (d, 1 H), 6.75 (d, 1 H), 5.71 (s, 1 H), 3.91 (d, 2 H), 2.90 (m, 2 H), 2.82 (m, 2 H), 2.61 (m, 2 H), 2.25 (d, 2 H), 1.90 (m, 1 H), 1.62 (m, 2 H), 1.23 (s, 9H), 1.10 (m, 2 H). LCMS for C30H37ClN7O2 (M+H) +: τalτ = 562.3.
Example A86. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4- yljacetamide trifluoroacetate
Figure imgf000201_0002
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 5- methoxyisoxazole-3-carbonyl chloride as starting materials in 31% yield. 1H NMR (300 MHz, DMSO- dβ): δ 9.45 (s, 1 H), 9.36 (s, 2 H), 8.12 (s, 1 H), 7.98 (s, 1 H), 7.73 (s, 1 H), 7.21 (d, 1 H), 7.04 (m, 2 H), 6.87 (d, 1 H), 6.78 (d, 1 H), 6.41 (s, 1 H), 4.42 (m, 1 H), 3.88 (m, 1 H), 3.13 (m, 2 H), 2.83 (m, 4 H), 2.45 (s, 3 H), 2.30 (m, 2 H), 2.10 (m, 1 H), 1.80 (m, 2 H), 1.20 (m, 2 H). LCMS for C30H31ClN7O3S (M+H) +: m/z = 572.2.
Example A87. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(pyrazin-2-ylcarbonyl)piperidin- 4-yl]acetamide bis(trifluoroacetate)
Figure imgf000202_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and pyrazine- 2-carbonyl chloride as starting materials in 36% yield. 1H ΝMR (300 MHz, DMS0-<i6): δ 9.42 (s, 1 H), 9.35 (s, 1 H), 9.30 (s, 1 H), 8.80 (s, 1 H), 8.72 (s, 1 H), 8.68 (s, 1 H), 8.11 (s, 1 H), 7.99 (s, 1 H), 7.73 (s, 1 H), 7.21 (d, 1 H), 7.04 (m, 2 H), 6.87 (d, 1 H), 6.78 (d, 1 H), 4.49 (m, 2 H), 3.65 (m, 1 H), 3.12 (m, 1 H), 2.81 (m, 4 H), 2.31 (m, 2 H), 2.10 (m, 1 H), 1.83 (m, 1 H), 1.68 (m, 1 H), 1.22 (m, 2 H). LCMS for C30H30ClN8O2 (M+H) +: m/z = 569.2.
Example A88. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2,2-dimethylpropanoyl)piperidin- 4-yl]acetamide trifluoroacetate
Figure imgf000203_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 2,2- dimethylpropanoyl chloride as starting materials in 31% yield. 1H ΝMR (300 MHz, DMSOd6): δ 9.50 (s, 1 H), 9.33 (s, 1 H), 9.30 (s, 1 H), 8.13 (s, 1 H), 7.98 (s, 1 H), 7.77 (s, 1 H), 7.21 (d, 1 H), 7.04 (m, 2 H), 6.87 (d, 1 H), 6.79 (d, 1 H), 4.27 (m, 2 H), 2.81 (m, 6 H), 2.25 (m, 2 H), 2.01 (m, 1 H), 1.76 (m, 2 H), 1.19 (s, 9 H), 1.04 (m, 2 H). LCMS for C30H36ClN6O2 (M+H) +: m/z = 547.2.
Example A89. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-isobutyrylpiperidin-4-yl)acetamide trifluoroacetate
Figure imgf000203_0002
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and isobutyryl chloride as starting materials in 41% yield. 1H ΝMR (300 MHz, DMSO-^6): δ 9.45 (s, 1 H), 9.38 (s, 1 H), 9.31 (s, 1 H), 8.12 (s, 1 H), 7.98 (s, 1 H), 7.73 (s, 1 H), 7.21 (d, 1 H), 7.04 (m, 2 H), 6.87 (d, 1 H), 6.78 (d, 1 H), 4.40 (m, 2 H), 3.95 (m, 2 H), 3.03 (m, 1 H), 2.83 (m, 4 H), 2.27 (m, 2 H), 2.01 (m, 1 H), 1.76 (m, 2 H), 1.10 (m, 2 H), 1.00 (m, 6 H). LCMS for C29H34ClN6O2 (M+H) +: m/z = 533.2. Example A90. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-propionylpiperidin-4-yl)acetamide trifluoroacetate
Figure imgf000204_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),
3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and propanoyl chloride as starting materials in 31% yield. LCMS for C28H32ClN6O2 (M+H) +: m/z = 519.2.
Example A91. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(methylsulfonyl)pyrrolidin- 3-yl]acetamide bis(trifluoroacetate)
Figure imgf000204_0002
The desired compound was prepared according to the procedure of Example A42, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-pyrrolidin-3-ylacetamide tris(trifluoroacetate) and methanesulfonyl chloride as starting materials in 48% yield. 1H ΝMR (300 MHz, DMSOd6): δ 10.10 (s, 1 H), 9.48 (s, 1 H), 9.41 (s, 1 H), 9.08 (s, 1 H), 8.33 (s, 2 H), 8.21 (s, 1 H), 7.69 (s, 1 H), 7.32 (d, 1 H), 7.09 (d, 1 H), 3.95 (s, 2 H), 3.44 (m, 1 H), 3.37 (m, 1 H), 3.25 (m, 1 H), 3.00 (m, 4 H), 2.90 (s, 3 H), 2.62 (m, 1 H), 2.05 (m, 1 H), 1.62 (m, 2 H). LCMS for C24H27ClN7O3S (M+H) +: m/z = 528.2. Example A92.
3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-phenylpyrrolidine- 1 -carboxamide bis(trifluor oacetate)
Figure imgf000205_0001
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-pyrrolidin-3-ylacetamide tris(trifluoroacetate) and phenyl isocyanate as starting materials in 44% yield. 1H ΝMR (300 MHz, DMSO-Cf6): δ 10.08 (s, 1 H), 9.42 (m, 2 H), 9.07 (s, 1 H), 8.32 (m, 2 H), 8.21 (s, 1 H), 8.13 (s, 1 H), 7.68 (s, 1 H), 7.50 (d, 2 H), 7.31 (d, 1 H), 7.20 (m, 2 H), 7.07 (d, 1 H), 6.89 (m, 1 H), 3.60 (m, 2 H), 3.40 (m, 1 H), 3.12 (m, 1 H), 2.99 (m, 4 H), 2.60 (m, 1 H), 2.09 (m, 2 H), 1.67 (m, 2 H). LCMS for C30H30ClN8O2 (M+H) +: τalτ = 569.2.
Example A93.
3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-methylpyrrolidine- 1 -carboxamide bis(trifluor oacetate)
Figure imgf000205_0002
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-pyrrolidin-3-ylacetamide tris(trifluoroacetate) and methyl isocyanate as starting materials in 59% yield. 1H NMR (300 MHz, DMSO-Cf6): δ 10.04 (s, 1 H), 9.40 (m, 2 H), 9.05 (s, 1 H), 8.32 (m, 2 H), 8.21 (s, 1 H), 7.68 (m, 1 H), 7.30 (m, 1 H), 7.07 (m, 1 H), 6.03 (m, 1 H), 3.40 (m, 3 H), 3.20 (m, 2 H), 2.99 (m, 4 H), 2.55 (s, 3 H), 2.00 (m, 2 H), 1.60 (m, 2 H). LCMS for C25H28ClN8O2 (M+H) +: m/z = 507.2.
Example A94.
2-(l-Acetylpyrrolidin-3-yl)-iV-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide bis(trifluoroacetate)
Figure imgf000206_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-pyrrolidin-3-ylacetamide tris(trifluoroacetate) and acetyl chloride as starting materials in 39% yield. 1H ΝMR (300 MHz, DMSO- d6): δ 10.08 (s, 1 H), 9.40 (m, 2 H), 9.07 (s, 1 H), 8.32 (m, 2 H), 8.21 (s, 1 H), 7.67 (m, 1 H), 7.30 (m, 1
H), 7.07 (m, 1 H), 3.50 (m, 4 H), 3.17 (m, 1 H), 2.99 (m, 4 H), 2.08 (m, 2 H), 1.91 (s, 3 H), 1.60 (m, 2
H). LCMS for C25H27ClN7O2 (M+H) +: m/z = 492.2.
Example A95. 4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV,iV- dimethylpiperidine-1-carboxamide bis(trifluoroacetate)
Figure imgf000206_0002
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and NN-dimethylcarbamoyl chloride as starting materials in 84% yield. LCMS for C27H32ClN8O2 (M+H) +: m/z = 535.2.
Example A96. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(dimethylamino)sulfonyl]piperidin- 4-yl}acetamide bis(trifluoroacetate)
Figure imgf000207_0001
The desired compound was prepared according to the procedure of Example A42, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and dimethylsulfamoyl chloride as starting materials in 48% yield. 1H ΝMR (300 MHz, DMSOd6): δ 10.02 (s, 1 H), 9.40 (m, 2 H), 9.02 (s, 1 H), 8.31 (m, 2 H), 8.21 (s, 1 H), 7.68 (m, 1 H), 7.30 (m, 1 H), 7.07 (m, 1 H), 3.58 (m, 2 H), 2.99 (m, 4 H), 2.85 (m, 2 H), 2.72 (s, 6 H), 2.32 (m, 2 H), 1.91 (m, 1 H), 1.77 (m, 2 H), 1.25 (m, 2 H). LCMS for C26H32ClN8O3S (M+H) +: m/z = 571.2.
Example A97. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(isopropylsulfonyl)piperidin- 4-yl]acetamide bis(trifluoroacetate)
Figure imgf000208_0001
The desired compound was prepared according to the procedure of Example A42, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and propane-2-sulfonyl chloride as starting materials in 25% yield. LCMS for C27H33ClN7O3S (M+H) +: m/z = 570.2.
Example A98. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(ethylsulfonyl)piperidin- 4-yl]acetamide bis(trifluoroacetate)
Figure imgf000208_0002
The desired compound was prepared according to the procedure of Example A42, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and ethanesulfonyl chloride as starting materials in 45% yield. 1H ΝMR (300 MHz, DMSO-Cf6): δ 10.00 (s, 1 H), 9.40 (m, 2 H), 8.98 (s, 1 H), 8.28 (m, 2 H), 8.21 (s, 1 H), 7.65 (m, 1 H), 7.30 (m, 1 H), 7.07 (m, 1 H), 3.60 (m, 2 H), 2.99 (m, 6 H), 2.81 (m, 2 H), 2.32 (m, 2 H), 1.91 (m, 1 H), 1.80 (m, 2 H), 1.25 (m, 2 H), 1.20 (t, 3 H). LCMS for C26H31ClN7O3S (M+H) +: m/z = 556.2.
Example A99. 4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-isopropylpiperidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000209_0001
The desired compound was prepared according to the procedure of Example A9, step H using N-
[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-isocyanatopropane as starting materials in 58% yield. 1H ΝMR (300 MHz, DMSO-Cf6): δ 10.08 (s, 1 H), 9.40 (m, 2 H), 9.05 (s, 1 H), 8.33 (m, 2 H), 8.20 (s, 1 H), 7.63 (m, 1 H), 7.30 (m, 1 H), 7.09 (m, 1 H), 6.09 (m, 1 H), 3.92 (m, 2 H), 3.75 (m, 1 H), 2.97 (s, 4 H), 2.62 (m, 2 H),
2.28 (m, 2 H), 1.91 (m, 1 H), 1.64 (m, 2 H), 1.09 (m, 2 H), 1.00 (d, 6 H). LCMS for C28H34ClN8O2 (M+H) +: τalτ = 549.2.
Example AlOO. 4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-methylpiperidine- 1 -carboxamide bis(trifluor oacetate)
Figure imgf000209_0002
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and methyl isocyanate as starting materials in 43% yield. 1H ΝMR (300 MHz, DMSO-^6): δ 10.08 (s, 1 H), 9.40 (m, 2 H), 9.05 (s, 1 H), 8.33 (m, 2 H), 8.20 (s, 1 H), 7.63 (m, 1 H), 7.30 (m, 1 H), 7.09 (m, 1 H), 6.38 (m, 1 H), 3.92 (m, 2 H), 2.97 (s, 4 H), 2.68 (m, 2 H), 2.55 (s, 3 H), 2.28 (m, 2 H), 1.91 (m, 1 H), 1.64 (m, 2 H), 1.09 (m, 2 H). LCMS for C26H30ClN8O2 (M+H) +: m/z = 521.2.
Example AlOl. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(5-methylisoxazol- 3-yl)carbonyl]piperidin-4-yl}acetamide bis(trifluoroacetate)
Figure imgf000210_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as starting materials in 56% yield. LCMS for C29H30ClN8O3 (M+H) +: m/z = 573.2.
Example A102. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(pyrazin-2-ylcarbonyl)piperidin- 4-yl]acetamide tris(trifluoroacetate)
Figure imgf000210_0002
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and pyrazine-2-carbonyl chloride as starting materials in 46% yield. 1H ΝMR (300 MHz, DMSOd6): δ 10.10 (s, 1 H), 9.40 (m, 2 H), 9.05 (s, 1 H), 8.80 (s, 1 H), 8.71 (s, 1 H), 8.67 (s, 1 H), 8.32 (d, 2 H), 8.20 (s, 1 H), 7.65 (s, 1 H), 7.30 (d, 1 H), 7.04 (d, 1 H), 4.52 (d, 1 H), 3.62 (d, 1 H), 3.12 (m, 1 H), 2.98 (m, 4 H), 2.88 (m, 1 H), 2.34 (m, 2 H), 2.12 (m, 1 H), 1.82 (m, 1 H), 1.70 (m, 1 H), 1.25 (m, 2 H). LCMS for C29H29ClN9O2 (M+H) +: m/z = 570.2.
Example A103. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-isobutyrylpiperidin- 4-yl)acetamide bis(trifluoroacetate)
Figure imgf000211_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and isobutyryl chloride as starting materials in 32% yield. LCMS for C28H33ClN7O2
(M+H) +: m/z = 534.2.
Example A104. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-propionylpiperidin-
4-yl)acetamide bis(trifluoroacetate)
Figure imgf000212_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and propanoyl chloride as starting materials in 20% yield. LCMS for C2VH31ClN7O2 (M+H) +: τalτ = 520.2.
Example A105. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-pyrrolidin-3-ylacetamide tris(trifluoroacetate)
Figure imgf000212_0002
The desired compound was prepared according to the procedures of Examples A-27 and A-28 using 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine bis(trifluoroacetate) and 2-(\-(tert- butoxycarbonyl)pyrrolidin-3-yl)acetic acid as the starting materials in 51% yield. 1H NMR (300 MHz, DMSO-^6): δ 10.04 (s, 1 H), 9.50 (s, 1 H), 9.40 (s, 1 H), 9.00 (s, 1 H), 8.72 (m, 2 H), 8.31 (s, 1 H), 8.29 (s, 1 H), 8.21 (s, 1 H), 7.68 (s, 1 H), 7.30 (d, 1 H), 7.08 (d, 1 H), 3.98 (s, 2 H), 3.40 (m, 1 H), 3.27 (m, 1 H), 2.97 (m, 4 H), 2.58 (m, 2 H), 2.11 (m, 1 H), 1.61 (m, 2 H). LCMS for C23H25ClN7O (M+H) +: m/z = 450.2.
Example A106. (2S)-iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-hydroxypropanamide trifluoroacetate
Figure imgf000213_0001
The desired compound was prepared according to the procedure of Example A27 using (S)-2- hydroxypropanoic acid as the starting material in 35% yield. LCMS for C21H21CIN5O2 (M+H) +: ralz - 410.1.
Example A107.
2-Amino-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide bis(trifluoroacetate)
Figure imgf000213_0002
The desired compound was prepared according to the procedures of Examples A-27 and A-28 using N-α-(tert-butoxycarbonyl) glycine as the starting material in 45% yield. LCMS for C2oH2oClΝ6θ (M+H)+: m/z = 395.1.
Example A108.
3-Amino-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]propanamide bis(trifluoroacetate)
Figure imgf000214_0001
The desired compound was prepared according to the procedures of Examples A-27 and A-28 using 3[(tert-butoxycarbonyl)amino]propionic acid as the starting material in 37% yield. LCMS for C2IH22ClN6O (M+H) +: m/z = 409.2.
Example A109.
(2S)-2-Amino-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9, 13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-hydroxypropanamide bis(trifluoroacetate)
Figure imgf000214_0002
The desired compound was prepared according to the procedures of Examples A-27 and A-28 using (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionic acid as the starting material in 29% yield. LCMS for C2i H22ClN6O2 (M+H) +: m/z = 425.1.
Example AIlO.
(2S)-iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-2-carboxamide bis(trifluoroacetate)
Figure imgf000215_0001
The desired compound was prepared according to the procedures of Examples A-27 and A-28 using (2S)-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid as the starting material in 45% yield. LCMS for C23H24ClN6O (M+H) +: m/z = 435.2.
Example AlIl.
4-(2-{[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-l,l-dimethylpiperidinium bis(trifluoroacetate)
Figure imgf000215_0002
N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) (11.6 mg, 0.020 mmol), potassium carbonate (5.6 mg, 0.040 mmol) and methyl iodide (12.5 mL, 0.020 mmol) were stirred in acetonitrile (1.0 mL) for 30 minutes. Purification by preparative LCMS (pH 2) gave the desired compound (58%). 1H ΝMR (300 MHz, DMSO-^6): δ 9.52 (s, 1 H), 9.39 (s, 1 H), 9.33 (s, 1 H), 8.18 (s, 1 H), 8.00 (s, 1 H), 7.78 (s, 1 H), 7.22 (d, 1 H), 7.05 (m, 2 H), 6.87 (d, 1 H), 6.77 (d, 1 H), 3.38 (m, 4 H), 3.07 (s, 3 H), 3.03 (s, 3 H), 2.88 (m, 4 H), 2.40 (d, 2 H), 2.03 (m, 1 H), 1.78 (m, 4 H). LCMS for C27H33ClN6O (M+H) +: m/z = 492.2.
Example Al 12. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2,2-dimethylpropanoyl)piperidin- 4-yl]acetamide bis(trifluoroacetate)
Figure imgf000216_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2,2-dimethylpropanoyl chloride as starting materials in 32% yield. LCMS for C29H35ClN7O2 (M+H) +: m/z = 548.2.
Example Al 13. iV-(tert-Butyl)-4-(2-{[6-chloro-2,4,8,18,22-pentaazatetracydo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}- 2-oxoethyl)piperidine- 1-carboxamide bis(trifluoroacetate)
Figure imgf000216_0002
O
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-isocyanato-2-methyl-propane as starting materials in 32% yield. LCMS for C29H36ClN8O2 (M+H) +: m/z = 563.3.
Example Al 14. tert-Butyl-4-(2-{[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}- 2-oxoethyl)piperazine- 1-carboxylate tris(trifluoroacetate)
Figure imgf000217_0001
The desired compound was prepared according to the procedures of Examples A-27 and A-28 using [4-(tert-butoxycarbonyl)piperazin-l-yl] acetic acid as starting material in 70% yield. LCMS for C24H27ClN7O (M+H) +: m/z = 464.2.
Example Al 15. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperazin-l-acetamide tetrakis(trifluoroacetate)
Figure imgf000217_0002
The desired compound was prepared according to the procedures of Examples A-27 and A-28 using 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine bis(trifluoroacetate) and [4-(tert- butoxycarbonyl)piperazin-l-yl] acetic acid as starting materials in 37% yield. LCMS for C23H26ClN8O (M+H) +: m/z = 465.2.
Example Al 16. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3piperidin-4-ylpropanamide bis(trifluoroacetate)
Figure imgf000218_0001
The desired compound was prepared according to the procedures of Examples A-27 and A-28 using 3-[l-(tert-butoxycarbonyl)piperidin-4-yl]propanoic acid as the starting material in 43% yield. LCMS for C26H30ClN6O (M+H) +: m/z = 477.2.
Example Al 17. iV-[6-Chloro-2,4,8,18,22-pentaaazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3piperidin-4-ylpropanamide tris(trifluoroacetate)
Figure imgf000218_0002
The desired compound was prepared according to the procedures of Examples A-27 and A-28 using 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine bis(trifluoroacetate) and 3-[l-(tert- butoxycarbonyl)piperidin-4-yl]propanoic acid as starting materials in 53% yield. LCMS for C25H29CIN7O (M+H) +: m/z = 478.2.
Example Al 18. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(4-[l,3]oxazolo[5,4-b]pyridin-2- ylpiperazin-l-yl)acetamide tris(trifluoroacetate)
Figure imgf000219_0001
N-[6-Chloro2,4,8,18,22pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperazin-l-acetamide bis(trifluoroacetate) (8.2 mg, 0.010 mmol) and [l,3]oxazolo[5,4-b]pyridine-2-thiol (3.7 mg, 0.024 mmol) were stirred in 1,4-dioxane (1 mL) and heated to 70 0C for 16 hours. The mixture was evaporated and stirred in ethanol (1 mL). Silver nitrate (7.2 mg, 0.043 mmol) and ammonium hydroxide solution (14.5 M in water) were added and the mixture was stirred at RT for 3 hours. Purification by preparative LCMS (pH 2) gave the desired compound in 17% yield. LCMS for C29H28ClNi0O2 (M+H) +: m/z = 583.2.
Example A119. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{4-[(5-methylisoxazol-3- yl)carbonyl]piperazin-l-yl}acetamide tris(trifluoroacetate)
Figure imgf000219_0002
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro2,4,8,18,22pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperazin-l-acetamide tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as starting materials in 70% yield. LCMS for C28H29ClN9O3 (M+H) +: m/z = 574.2.
Example A120. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-[(5-methylisoxazol-3-yl)carbonyl]piperidine-4- carboxamide trifluoroacetate
Figure imgf000220_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20), 3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as starting materials in 12% yield. LCMS for C29H29CIΝ7O3 (M+H) +: τalτ = 558.2.
Example A121. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-[(5-methylisoxazol-3-yl)carbonyl]piperidine-3- carboxamide trifluoroacetate
Figure imgf000220_0002
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20), 3(22),4,6,9(21), 10, 12,16, 18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as starting materials in 62% yield. LCMS for C29H29CIΝ7O3 (M+H) +: τalτ = 558.2.
Example A122. (3/?)-iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-[(5-methylisoxazol-3-yl)carbonyl]pyrrolidine-4- carboxamide trifluoroacetate
Figure imgf000221_0001
The desired compound was prepared according to the procedure of Example A20, using (3R)-N-
[6-chloro-2,4,8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide bis(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as starting materials in 60% yield. 1H ΝMR (300 MHz, DMS0-<i6): δ 9.57 (m, 1 H), 9.47 (s, 1 H), 9.38 (s, 1 H), 8.12 (s, 1 H), 7.98 (s, 1 H), 7.73 (s, 1 H), 7.21 (m, 1 H), 7.04 (m, 2 H), 6.87 (d, 2 H), 6.78 (m, 1 H), 6.50 (s, 1 H), 3.78 (m, 4 H), 3.30 (m, 1 H), 2.82 (m, 4 H), 2.46 (s, 3 H), 2.20 (m, 2 H). LCMS for C28H27ClN7O3 (M+H) +: m/z = 544.2.
Example A123.
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{4-[(5-methylisoxazol-3-yl)carbonyl]piperazin-l- yljacetamide bis(trifluoroacetate)
Figure imgf000221_0002
The desired compound was prepared according to the procedure of Example A20, using tert- butyl-4-(2-{ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-
2-oxoethyl)piperazine-l-carboxylate bis(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as starting materials in 56% yield. LCMS for C29H30ClN8O3 (M+H) +: m/z = 573.2. Example A124. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-{l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4- yljpropanamide trifluoroacetate
Figure imgf000222_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4, 8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3piperidin-4-ylpropanamide bis(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as starting materials in 54% yield. 1H ΝMR (300 MHz, DMSO-^6): δ 9.43 (s, 1 H), 9.34 (m, 2 H), 8.12 (s, 1 H), 7.98 (s, 1 H), 7.73 (s, 1 H), 7.21 (d, 1 H), 7.04 (m, 2 H), 6.87 (d, 1 H), 6.78 (d, 1 H), 6.40 (s, 1 H), 4.42 (m, 2 H), 3.88 (m, 2 H), 3.03 (m, 2 H), 2.83 (m, 4 H), 2.45 (s, 3 H), 2.27 (m, 2 H), 1.80 (m, 2 H), 1.60 (m, 2 H), 1.10 (m, 1 H). LCMS for C3IH33ClN7O3 (M+H)+: m/z = 586.2.
Example A125. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-{l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4- yljpropanamide bis(trifluoroacetate)
Figure imgf000222_0002
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro- 2,4, 8 , 18 ,22-pentaaazatetracyclo[ 14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3piperidin-4-ylpropanamide tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as starting materials in 48% yield. 1H NMR (300 MHz, DMSO-^6): δ 10.04 (s, 1 H), 9.40 (s, 2 H), 9.02 (m, 1 H), 8.30 (s, 2 H), 8.21 (s, 1 H), 7.68 (s, 1 H), 7.30 (d, 1 H), 7.04 (d, 1 H), 6.40 (s, 1 H), 4.42 (m, 2 H), 3.88 (m, 2 H), 3.03 (m, 2 H), 2.97 (m, 4 H), 2.45 (s, 3 H), 2.40 (m, 2 H), 1.80 (m, 2 H), 1.60 (m, 2 H), 1.10 (m, 1 H). LCMS for C30H32ClN8O3 (M+H) +: m/z = 587.2.
Example A126. iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-[l,3]oxazolo[5,4-b]pyridin-2-ylpiperidin-4- yl)acetamide bis(trifluoroacetate)
Figure imgf000223_0001
The desired compound was prepared according to the procedure of Example Al 18 using N- [6 - chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) as the starting material in 12% yield. LCMS for C3IH30ClN8O2 (M+H) +: m/z = 581.2.
Example A127.
2-(4-Acetylpiperazin-l-yl)-iV-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate)
Figure imgf000223_0002
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro2,4,8,18,22pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperazin-l-acetamide tris(trifluoroacetate) and acetyl chloride as starting materials in 35% yield. LCMS for C25H28ClN8O2 (M+H) +: m/z = 507.2.
Example A128. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(isoxazol-5-ylcarbonyl)piperidin- 4-yl]acetamide bis(trifluoroacetate)
Figure imgf000224_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and isoxazole-5-carbonyl chloride as starting materials in 59% yield. 1H ΝMR (300 MHz, DMSO-Cf6): δ 9.50 (d, 2 H), 9.16 (s, 1 H), 8.83 (s, 1 H), 8.40 (s, 2 H), 8.33 (s, 1 H), 7.78 (s, 1 H), 7.40 (d, 1 H), 7.19 (d, 1 H), 7.00 (s, 1 H), 4.52 (m, 1 H), 3.88 (m, 1 H), 3.32 (m, 1 H), 3.03 (s, 4 H), 2.42 (m, 2 H), 2.21 (m, 1 H), 1.93 (m, 2 H), 1.39 (m, 2 H). LCMS for C28H28ClN8O3 (M+H)+: m/z = 559.2.
Example A129. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(l-methyl-lH-pyrazol-4-yl)carbonyl]piperidin- 4-yl]acetamide bis(trifluoroacetate)
Figure imgf000224_0002
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro- 2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1 -methyl- lH-pyrazole-4-carbonyl chloride as starting materials in 42% yield. LCMS fOr C29H3IClN9O2 (M-I-H) +: m/z = 572.2.
Example A130. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(l-methyl-lH-pyrazol-3-yl)carbonyl]piperidin- 4-yl}acetamide bis(trifluoroacetate)
Figure imgf000225_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and l-methyl-lH-pyrazole-3-carbonyl chloride as starting materials in 36% yield. 1H
ΝMR (300 MHz, DMSO-^6): δ 10.08 (s, 1 H), 9.41 (s, 2 H), 9.02 (s, 1 H), 8.30 (m, 2 H), 8.20 (s, 1 H),
7.72 (s, 1 H), 7.65 (s, 1 H), 7.30 (d, 1 H), 7.05 (d, 1 H), 6.47 (s, 1 H), 4.52 (m, 2 H), 3.83 (s, 3 H), 3.12
(m, 1 H), 2.98 (m, 4 H), 2.77 (m, 1 H), 2.32 (m, 2 H), 2.12 (m, 1 H), 1.80 (m, 2 H), 1.20 (m, 2 H). LCMS for C29H3IClN9O2 (M+H) +: m/z = 572.2.
Example A131. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(5-methylisoxazol-4-yl)carbonyl]piperidin-4- yljacetamide bis(trifluoroacetate)
Figure imgf000226_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 5-methylisoxazole-4-carbonyl chloride as starting materials in 44% yield. 1H ΝMR (300 MHz, DMSO-Cf6): δ 10.05 (s, 1 H), 9.41 (s, 2 H), 9.02 (s, 1 H), 8.65 (s, 1 H), 8.33 (s, 2 H), 8.20 (s, 1 H), 7.65 (s, 1 H), 7.30 (d, 1 H), 7.05 (d, 1 H), 4.42 (m, 1 H), 3.70 (m, 1 H), 3.12 (m, 2 H), 2.98 (m, 4 H), 2.49 (s, 3 H), 2.30 (m, 2 H), 2.12 (m, 1 H), 1.80 (m, 2 H), 1.20 (m, 2 H). LCMS for C29H30ClN8O3 (M+H) +: m/z = 573.2.
Example A132. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(4-methyl-l,3-oxazol-5-yl)carbonyl]piperidin- 4-yl]acetamide bis(trifluoroacetate)
Figure imgf000226_0002
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-methyl-l,3-oxazole-5-carbonyl chloride as starting materials in 37% yield. 1H ΝMR (300 MHz, DMS0-<i6): δ 10.02 (s, 1 H), 9.41 (m, 2 H), 9.02 (s, 1 H), 8.40 (s, 1 H), 8.30 (s, 2 H), 8.20 (s, 1 H), 7.65 (s, 1 H), 7.30 (d, 1 H), 7.05 (d, 1 H), 4.52 (m, 2 H), 3.12 (m, 1 H), 2.98 (m, 4 H), 2.32 (m, 2 H), 2.21 (s, 3 H), 2.12 (m, 1 H), 1.80 (m, 2 H), 1.20 (m, 2 H). LCMS for C29H30ClN8O3 (M+H) +: m/z = 573.2.
Example A133. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3-thiazol-2-ylcarbonyl)piperidin- 4-yl]acetamide bis(trifluoroacetate)
Figure imgf000227_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and l,3-thiazole-2-carbonyl chloride as starting materials in 37% yield. 1H ΝMR (300 MHz, DMSO-Cf6): δ 10.04 (s, 1 H), 9.41 (m, 2 H), 9.02 (s, 1 H), 8.30 (m, 2 H), 8.20 (s, 1 H), 8.00 (m, 2 H), 7.65 (s, 1 H), 7.30 (d, 1 H), 7.05 (d, 1 H), 5.20 (m, 1 H), 4.48 (m, 1 H), 3.22 (m, 2 H), 2.98 (m, 4 H), 2.32 (m, 2 H), 2.12 (m, 1 H), 1.80 (m, 2 H), 1.25 (m, 2 H). LCMS for C28H28ClN8O2S (M+H) +: m/z = 575.2.
Example A134. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(l-methyl-lH-imidazol-5yl)carbonyl]piperidin- 4-yl]acetamide bis(trifluoroacetate)
Figure imgf000227_0002
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and l-methyl-lH-imidazole-5-carbonyl chloride as starting materials in 31% yield. 1H ΝMR (300 MHz, DMSO-^6): δ 9.97 (s, 1 H), 9.41 (s, 1 H), 9.38 (s, 1 H), 8.97 (s, 1 H), 8.91 (s, 1 H), 8.22 (m, 3 H), 7.85 (s, 1 H), 7.65 (s, 1 H), 7.30 (d, 1 H), 7.05 (d, 1 H), 4.00 (m, 2 H), 3.83 (s, 3 H), 2.98 (m, 6 H), 2.32 (m, 2 H), 2.12 (m, 1 H), 1.80 (m, 2 H), 1.20 (m, 2 H). LCMS for C29H31ClN9O2 (M+H) +: m/z = 572.2.
Example A135. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(isoxazol-3-ylcarbonyl)piperidin- 4-yl]acetamide bis(trifluoroacetate)
Figure imgf000228_0001
The desired compound was prepared according to the procedure of Example A27 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and isoxazole-3-carboxylic acid as starting materials in 37% yield. 1H ΝMR (300 MHz, DMSOd6): δ 10.04 (s, 1 H), 9.41 (m, 2 H), 9.02 (m, 2 H), 8.30 (m, 2 H), 8.20 (s, 1 H), 7.64 (s, 1 H), 7.30 (d, 1 H), 7.05 (d, 1 H), 6.80 (s, 1 H), 4.52 (m, 1 H), 3.83 (m, 1 H), 3.18 (m, 2 H), 2.98 (m, 4 H), 2.32 (m, 2 H), 2.12 (m, 1 H), 1.80 (m, 2 H), 1.20 (m, 2 H). LCMS for C28H28ClN8O3 (M+H) +: m/z = 559.2.
Example A136. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(lH-l,2,4-triazol-3-ylcarbonyl)piperidin-4- yl]acetamide bis(trifluoroacetate)
Figure imgf000229_0001
The desired compound was prepared according to the procedure of Example A27 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and lH-l,2,4-triazole-3-carboxylic acid as starting materials in 43% yield. LCMS for C27H28ClNi0O2 (M+H) +: m/z = 559.2.
Example A137. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(lH-l,2,3-triazol-4-ylcarbonyl)piperidin-4- yl]acetamide bis(trifluoroacetate)
Figure imgf000229_0002
The desired compound was prepared according to the procedure of Example A27 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2H-l,2,3-triazole-4-carboxylic acid as starting materials in 48% yield. 1H ΝMR (300 MHz, DMS0-<i6): δ 10.12 (s, 1 H), 9.41 (m, 2 H), 9.15 (s, 1 H), 8.32 (m, 2 H), 8.21 (m, 2 H), 7.65 (s, 1 H), 7.30 (d, 1 H), 7.05 (d, 1 H), 4.52 (m, 2 H), 3.19 (m, 2 H), 2.99 (m, 4 H), 2.32 (m, 2 H), 2.12 (m, 1 H), 1.80 (m, 2 H), 1.20 (m, 2 H). LCMS for C27H28ClNi0O2 (M+H) +: m/z = 559.2.
Example A138. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,2,5-oxadiazol-3-ylcarbonyl)piperidin-4- yl]acetamide bis(trifluoroacetate)
Figure imgf000230_0001
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and l,2,5-oxadiazole-3-carbonyl chloride as starting materials in 33% yield. 1H ΝMR (300 MHz, DMSO-^6): δ 10.08 (s, 1 H), 9.41 (s, 2 H), 9.02 (s, 1 H), 8.30 (m, 2 H), 8.20 (s, 1 H), 7.72 (s, 1 H), 7.65 (s, 1 H), 7.30 (d, 1 H), 7.05 (d, 1 H), 6.47 (s, 1 H), 4.38 (m, 1 H), 4.02 (m, 1 H), 3.19 (m, 2 H), 2.98 (m, 4 H), 2.32 (m, 2 H), 2.12 (m, 1 H), 1.80 (m, 2 H), 1.20 (m, 2 H). LCMS for C27H27ClN9O3 (M+H) +: m/z = 560.2.
Example A139. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3-oxazol-2-ylcarbonyl)piperidin- 4-yl]acetamide bis(trifluoroacetate)
Figure imgf000230_0002
The desired compound was prepared according to the procedure of Example A27 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and l,3-oxazole-2-carboxylic acid as starting materials in 31% yield. LCMS for C28H28ClN8O3 (M+H) +: m/z = 559.2.
Example A140. iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-isopropylpiperidin- 4-yl)acetamide tris(trifluoroacetate)
Figure imgf000231_0001
The desired compound was prepared according to the procedure of Example Al Il, using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-bromopropane as starting materials in 28% yield. LCMS for C27H33CIN7O
(M+H) +: m/z = 506.2.
Example A141.
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-
2-oxoethyl)-iV-(2-cyanophenyl)piperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000231_0002
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-isocyanatobenzonitrile as starting materials in 57% yield. LCMS for C32H3IClN9O2 (M+H) +: m/z = 608.2.
Example A142.
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-
2-oxoethyl)-iV-(3-cyanophenyl)piperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000232_0001
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3-isocyanatobenzonitrile as starting materials in 8% yield. LCMS for C32H31ClN9O2 (M+H) +: m/z = 608.2.
Example A143.
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-
2-oxoethyl)-iV-(4-cyanophenyl)piperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000232_0002
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-isocyanatobenzonitrile as starting materials in 35% yield. LCMS for C32H3IClN9O2 (M+H) +: m/z = 608.2.
Example A144.
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}- 2-oxoethyl)-iV-pyridin-3-ylpiperidine-l-carboxamide bis(trifluoroacetate)
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3-isocyanatopyridine as starting materials in 46% yield. 1H ΝMR (300 MHz, DMSO-Cf6): δ 10.00 (s, 1 H), 9.41 (m, 2 H), 9.24 (s, 1 H), 8.98 (s, 2 H), 8.40 (m, 1 H), 8.30 (m, 3 H), 8.20 (s, 1 H), 7.72 (m, 1 H), 7.65 (s, 1 H), 7.30 (d, 1 H), 7.05 (d, 1 H), 4.15 (m, 2 H), 2.98 (m, 6 H), 2.32 (m, 2 H), 2.12 (m, 1 H), 1.80 (m, 2 H), 1.20 (m, 2 H). LCMS for C30H31ClN9O2 (M+H) +: m/z = 584.2.
Example A145.
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}- 2-oxoethyl)-iV-(3,5-dimethylisoxazol-4-yl)piperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000233_0002
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-isocyanato-3,5-dimethylisoxazole as starting materials in 30% yield. 1H ΝMR (300 MHz, DMSO-^6): δ 10.02 (s, 1 H), 9.41 (m, 2 H), 9.00 (s, 1 H), 8.30 (m, 2 H), 8.20 (s, 1 H), 7.88 (s, 1 H), 7.67 (s, 1 H), 7.30 (d, 1 H), 7.05 (d, 1 H), 4.02 (m, 2 H), 2.98 (m, 4 H), 2.80 (m, 2 H), 2.32 (m, 2 H), 2.20 (s, 3 H), 2.12 (m, 4 H), 1.80 (m, 2 H), 1.20 (m, 2 H). LCMS for C30H33ClN9O3 (M+H) +: m/z = 602.2.
Example A146.
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-
2-oxoethyl)-iV-(2-fluorophenyl)piperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000234_0001
The desired compound was prepared according to the procedure of Example A9, step H using N-
[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and l-fluoro-2-isocyanatobenzene as starting materials in 51% yield. 1H ΝMR (300
MHz, DMSOd6): δ 10.04 (s, 1 H), 9.41 (m, 2 H), 9.02 (s, 1 H), 8.25 (m, 4 H), 7.65 (s, 1 H), 7.30 (m, 2 H), 7.05 (m, 4 H), 4.09 (m, 2 H), 2.98 (m, 4 H), 2.83 (m, 2 H), 2.32 (m, 2 H), 2.02 (m, 1 H), 1.75 (m, 2
H), 1.21 (m, 2 H). LCMS for C3iH3iClFΝ8O2 (M+H) +: m/z = 601.2.
Example A147.
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-
2-oxoethyl)-iV-(3-fluorophenyl)piperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000235_0001
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and l-fluoro-3-isocyanatobenzene as starting materials in 39% yield. LCMS for C3IH3IClFN8O2 (M+H) +: m/z = 601.2.
Example A148.
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-
2-oxoethyl)-iV-(4-fluorophenyl)piperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000235_0002
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and l-fluoro-4-isocyanatobenzene as starting materials in 32% yield. LCMS for C3IH31ClFN8O2 (M+H) +: m/z = 601.2.
Example A149. 4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}- 2-oxoethyl)-iV-(2-methylphenyl)piperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000236_0001
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and l-isocyanato-2-methylbenzene as starting materials in 31% yield. LCMS for C32H34ClN8O2 (M+H) +: m/z = 597.2.
Example A150.
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}- 2-oxoethyl)-iV-(3-methylphenyl)piperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000236_0002
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and l-isocyanato-3-methylbenzene as starting materials in 27% yield. LCMS for C32H34ClN8O2 (M+H) +: m/z = 597.2.
Example A151. 4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}- 2-oxoethyl)-iV-(4-methylphenyl)piperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000237_0001
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and l-isocyanato-4-methylbenzene as starting materials in 30% yield. LCMS for C32H34ClN8O2 (M+H) +: m/z = 597.2.
Example A152.
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}- 2-oxoethyl)-iV-(2-methoxyphenyl)piperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000237_0002
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and l-isocyanato-2-methoxybenzene as starting materials in 30% yield. LCMS for C32H34ClN8O3 (M+H) +: m/z = 613.2.
Example A153. 4-(2-{[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}- 2-oxoethyl)-iV-(3-methoxyphenyl)piperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000238_0001
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and l-isocyanato-3-methoxybenzene as starting materials in 26% yield. LCMS for C32H34ClN8O3 (M+H) +: m/z = 613.2.
Example A154.
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}- 2-oxoethyl)-iV-(4-methoxyphenyl)piperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000238_0002
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and l-isocyanato-4-methoxybenzene as starting materials in 26% yield. LCMS for C32H34ClN8O3 (M+H) +: m/z = 613.2.
Example A155. N-Benzyl-4-(2-{[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}- 2-oxoethyl)piperidine- 1-carboxamide bis(trifluoroacetate)
Figure imgf000239_0001
The desired compound was prepared according to the procedure of Example A9, step H using N- [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and benzyl isocyanate as starting materials in 35% yield. LCMS for C32H34ClN8O2 (M+H) +: τalτ = 597.2.
Example A156 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(3,5-dimethylisoxazol-4-yl)carbonyl]piperidin- 4-yl}acetamide bis(trifluoroacetate)
Figure imgf000239_0002
The desired compound was prepared according to the procedure of Example A20, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3,5-dimethylisoxazole-4-carbonyl chloride as starting materials (43% yield). LCMS for C30H32ClN8O3 (M+H) +: m/z = 587.2.
Example A157
2-[l-(l,3-Benzothiazol-2-yl)piperidin-4-yl]-y^[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide tris(trifluoroacetate)
Figure imgf000240_0001
A solution of N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) (10 mg, 0.0144 mmol), 2-chloro-benzothiazole (20.7 mg, 0.122 mmol) was heated at 80 0C for 1 hour. Then the solution was diluted with MeOH and purified on LC/MS using pH2 buffer to give the desired compound in 11% yield. LCMS for C3IH30ClN8OS (M+H) +: m/z = 597.2.
Example A158
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-[l,3]oxazolo[5,4-b]pyridin-2-ylpiperidin-4- yl)acetamide tris(trifluoroacetate)
Figure imgf000240_0002
The desired compound was prepared according to the procedure of Example Al 18, using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) as the starting material in 14% yield. LCMS for C30H29ClN9O2 (M+H) +: m/z = 582.2.
Example A159 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3-thiazol-2-yl)piperidin-4-yl]acetamide tris(trifluoroacetate)
Figure imgf000241_0001
The desired compound was prepared according to the procedure of Example A157, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-chloro-l,3-thiazole as starting materials in 12% yield. LCMS for C27H28ClN8OS (M+H) +: m/z = 547.2.
Example A160
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-methyl-3-furoyl)piperidin-4-yl]acetamide bis(trifluoroacetate)
Figure imgf000241_0002
The desired compound was prepared according to the procedure of Example A27, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 2-methyl-3-furoic acid as starting materials in 60% yield. LCMS for C30H31CIΝ7O3 (M+H) +: m/z = 572.2.
Example A161
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(3-methyl-2-furoyl)piperidin-4-yl]acetamide bis(trifluoroacetate)
Figure imgf000242_0001
The desired compound was prepared according to the procedure of Example A27, using N-[6-chloro- 2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen- 12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 3-methyl-2-furoic acid as starting materials in 51% yield. LCMS for C30H31CIΝ7O3 (M+H) +: m/z = 572.2.
Example A162
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(5-methyl-2-furoyl)piperidin-4-yl]acetamide bis(trifluoroacetate)
Figure imgf000242_0002
The desired compound was prepared according to the procedure of Example A27, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 5-methyl-2-furoic acid as starting materials in 46% yield. LCMS for C30H31 ClN7O3 (M+H) +: m/z = 572.2.
Example A163
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(5-methyl-lH-pyrazol-3-yl)carbonyl]piperidin- 4-yl}acetamide bis(trifluoroacetate)
Figure imgf000243_0001
The desired compound was prepared according to the procedure of Example A27, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen- 12-yl] -2-piperidin-4-ylacetamide bis(trifluoroacetate) and 5-methyl- 1 H-pyrazole-3 -carboxylic acid as starting materials in 29% yield. LCMS for C29H3IClN9O2 (M+H) +: m/z = 572.2.
Example A164
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(l-methyl-lH-imidazol-2- yl)carbonyl]piperidin-4-yl}acetamide bis(trifluoroacetate)
Figure imgf000243_0002
The desired compound was prepared according to the procedure of Example A27, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen- 12-yl] -2-piperidin-4-ylacetamide bis(trifluoroacetate) and 1 -methyl- 1 H-imidazole-2-carboxylic acid as starting materials in 70% yield. LCMS for C29H3iClΝ9O2 (M+H) +: m/z = 572.2.
Example A165
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(3-methylisoxazol-4-yl)carbonyl]piperidin-4- yljacetamide bis(trifluoroacetate)
Figure imgf000244_0001
The desired compound was prepared according to the procedure of Example A27, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 3-methylisoxazole-4-carboxylic acid as starting materials in 55% yield. LCMS for C29H30ClN8O3 (M+H) +: m/z = 573.2.
Example A166
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(4-methyl-l,2,5-oxadiazol-3- yl)carbonyl]piperidin-4-yl}acetamide bis(trifluoroacetate)
Figure imgf000244_0002
The desired compound was prepared according to the procedure of Example A27, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 4-methyl-l,2,5-oxadiazole-3- carboxylic acid as starting materials in 44% yield. LCMS for C28H29ClN9O3 (M+H) +: m/z = 574.2.
Example A167
2-{l-[(4-Amino-l,2,5-oxadiazol-3-yl)carbonyl]piperidin-4-yl}-/K-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide tris(trifluoroacetate)
Figure imgf000245_0001
The desired compound was prepared according to the procedure of Example A27, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen- 12-yl] -2-piperidin-4-ylacetamide bis(trifluoroacetate) and 4-amino- 1 ,2,5 -oxadiazole-3 -carboxylic acid as starting materials in 41% yield. LCMS for C27H28ClNi0O3 (M+H) +: m/z = 575.2.
Example A168
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(isothiazol-5-ylcarbonyl)piperidin-4- yl]acetamide bis(trifluoroacetate)
Figure imgf000245_0002
The desired compound was prepared according to the procedure of Example A27, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and isothiazole-5 -carboxylic acid as starting materials in 55% yield. LCMS for C28H28ClN8O2S (M+H) +: m/z = 575.2.
Example A169
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(5-fluoropyrimidin-2-yl)piperidin-4- yl]acetamide tris(trifluoroacetate)
Figure imgf000246_0001
Step A. [l-( 5 -Fluoropyrimidin-2-yl)piperidin-4-yl] 'acetic acid trifluoroacetate
TFA
Figure imgf000246_0002
Methyl piperidin-4-ylacetate (100 mg, 0.6 mmol), 2-chloro-5-fluoropyrimidine (250 mg, 1.9 mmol) and NN-diisopropylethylamine (330 μL, 1.9 mmol) were stirred in N-methylpyrrolidinone (1 mL) and heated to 150 0C for 20 minutes in a microwave. Purification by preparative LCMS (pH 2) gave the ester intermediate which was saponified by stirring in methanol (1 mL) and 2 Ν aqueous sodium hydroxide solution (1 mL) for 1 hour. Neutralization and purification by preparative LCMS gave the desired compound in 50% yield. LCMS for CnH15FN3O2 (M+H) +: m/z = 240.1.
Step B. N-[6-Chloro-2,4,8J8,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(5-fluoropyrimidin-2-yl)piperidin-4-yl]acetamide tris( trifluoroacetate)
A solution of [l-(5-fluoropyrimidin-2-yl)piperidin-4-yl]acetic acid trifluoroacetate (9.0 mg, 0.029 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafiuorophosphate (17 mg, 0.043 mmol) and N,N-diisopropylethylamine (12.6 μL, 0.0722 mmol) in NN-dimethylformamide (0.5 mL) was stirred for 15 minutes. To this reaction mixture, a solution of 6-chloro-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate) and NN-diisopropylethylamine (12.6 μL, 0.0722 mmol) in NN-dimethylformamide (0.5 mL) was added and the mixture was stirred for 1.5 hours. Purification by preparative LCMS (pH 2) gave the desired compound in 68% yield. LCMS for C28H25ClFN9O (M+H) +: m/z = 560.2.
Example A170
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-pyridin-2-ylpiperidin-4-yl)acetamide tris(trifluoroacetate)
Figure imgf000247_0001
Step A. (l-Pyridin-2-ylpiperidin-4-yl)acetic acid trifluoroacetate
TFA
Figure imgf000247_0002
The desired compound was prepared according to the procedure of Example A 169, step A using
2-fluoropyridine as starting material in 30% yield. LCMS for Ci2Hi7N2O2 (M+H) +: m/z = 221.1.
Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-pyridin-2-ylpiperidin-4-yl)acetamide tris(trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using (l-pyridin-2-ylpiperidin-4-yl)acetic acid trifluoroacetate as starting material in 50% yield. LCMS for C29H30ClN8O (M+H) +: m/z = 541.2.
Example A171
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-pyrazin-2-ylpiperidin-4-yl)acetamide tris(trifluoroacetate)
Figure imgf000247_0003
Step A. ( 1 -Pyrazin-2-ylpiperidin-4-yl)acetic acid trifluoroacetate
TFA
Figure imgf000248_0001
The desired compound was prepared according to the procedure of Example A 169, step A using 2-chloropyrazine as starting material in 50% yield. LCMS for CnHi6N3O2 (M+H) +: m/z = 222.1.
Step B. N-[6-Chloro-2,4,8J8,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-pyrazin-2-ylpiperidin-4-yl)acetamide tris( trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using (l-pyrazin-2-ylpiperidin-4-yl)acetic acid trifluoroacetate as starting material in 34% yield. LCMS for C28H29ClN9O (M+H) +: m/z = 542.2.
Example A172 y^[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-pyrimidin-2-ylpiperidin-4-yl)acetamide tris(trifluoroacetate)
Figure imgf000248_0002
Step A. (l-Pyrimidin-2-ylpiperidin-4-yl)acetic acid trifluoroacetate
TFA
Figure imgf000248_0003
The desired compound was prepared according to the procedure of Example A 169, step A usin^
2-chloropyrimidine as starting material in 40% yield. LCMS for CnHi6N3O2 (M+H) +: m/z = 222.1. Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-pyrimidin-2-ylpiperidin-4-yl)acetamide tris( trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using (l-pyrimidin-2-ylpiperidin-4-yl) acetic acid trifluoroacetate as starting material in 70% yield. 1H NMR (300 MHz, DMSO-^6): δ 10.10 (s, 1 H), 9.41 (m, 2 H), 9.10 (s, 1 H), 8.37 (m, 4 H), 8.22 (s, 1 H), 7.68 (s, 1 H), 7.31 (m, 1 H), 7.09 (m, 1 H), 6.59 (m, 1 H), 4.62 (m, 2 H), 2.92 (m, 6 H), 2.30 (m, 2 H), 2.10 (m, 1 H), 1.79 (m, 2 H), 1.10 (m, 2 H). LCMS for C28H29ClN9O (M+H) +: m/z = 542.2.
Example A173. yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(6-methylpyridazin-3-yl)piperidin-4- yl]acetamide tris(trifluoroacetate)
Figure imgf000249_0001
Step A. [ 1 -(6-Methylpyridazin-3-yl)piperidin-4-yl] 'acetic acid trifluoroacetate
TFA
Figure imgf000249_0002
The desired compound was prepared according to the procedure of Example A 169, step A using 3-chloro-6-methylpyridazine as starting material in 10% yield. LCMS for Ci2Hi8N3O2 (M+H) +: m/z = 236.1.
Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(6-methylpyridazin-3-yl)piperidin-4-yl)acetamide tris(trifluoroacetate) The desired compound was prepared according to the procedure of Example A 169, step B using [l-(6-methylpyridazin-3-yl)piperidin-4-yl)acetic acid trifluoroacetate as starting material in 62% yield. LCMS for C29H30ClN9O (M+H) +: m/z = 556.2.
Example A174 yy-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3,4-thiadiazol-2-yl)piperidin-4-yl]acetamide tris(trifluoroacetate)
Figure imgf000250_0001
Step A. [l-(l,3,4-Thiadiazol-2-yl)piperidin-4-yl]acetic acid trifluoroacetate
TFA
Figure imgf000250_0002
The desired compound was prepared according to the procedure of Example A 169, step A using 2-bromo-l,3,4-thiadiazole as starting material in 30% yield. LCMS for C9Hi4N3O2S (M+H) +: m/z = 228.1.
Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4A9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3,4-thiadiazol-2-yl)piperidin-4-yl]acetamide tris( trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using [l-(l,3,4-thiadiazol-2-yl)piperidin-4-yl]acetic acid trifluoroacetate as starting material in 79% yield. LCMS for C26H27ClN9OS (M+H) +: m/z = 548.2.
Example A175
/K-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(5-methyl-lH-pyrazol-3-yl)carbonyl]piperidin- 4-yl}acetamide bis(trifluoroacetate)
The desired compound was prepared according to the procedure of Example A27 using of N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20), 3(22),4,6,9(21), 10,12,16,18- nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 5-methyl-lH-pyrazole-3-carboxylic acid as starting materials in 27% yield. LCMS for C30H32ClN8O2 (M+H) +: m/z = 571.2.
Example A176
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(4-methylpyridin-2-yl)piperidin-4-yl]acetamide tris(trifluoroacetate)
Figure imgf000251_0002
Step A. [l-(4-Methylpyridin-2-yl)piperidin-4-yl] acetic acid trifluoroacetate
TFA
Figure imgf000251_0003
The desired compound was prepared according to the procedure of Example A 169, step A using 2-fluoro-4-methylpyridine as starting material in 8% yield. LCMS for Ci3Hi9N2O2 (M+H) +: m/z = 235.1.
Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(4-methylpyridin-2-yl)piperidin-4-yl]acetamide tris(trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using [l-(4-methylpyridin-2-yl)piperidin-4-yl] acetic acid trifluoroacetate as starting material in 38% yield. LCMS for C30H32ClN8O (M+H) +: m/z = 555.2.
Example A177 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(3-cyanopyridin-2-yl)piperidin-4-yl]acetamide tris(trifluoroacetate)
Figure imgf000252_0001
Step A. [l-(3-Cyanopyridin-2-yl)piperidin-4-yl]acetic acid trifluoroacetate
TFA
Figure imgf000252_0002
The desired compound was prepared according to the procedure of Example A 169, step A usin^ 2-chloronicotinonitrile as starting material in 33% yield. LCMS for Ci3Hi6N3O2 (M+H) +: m/z = 246.1.
Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(3-cyanopyridin-2-yl)piperidin-4-yl]acetamide tris(trifluoroacetate) The desired compound was prepared according to the procedure of Example A 169, step B using
[1 -(3 -cyanopyridin-2-yl)piperidin-4-yl] acetic acid trifluoroacetate as starting material in 38% yield. LCMS for C30H29ClN9O (M+H) +: m/z = 566.2. Example A178
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(4-cyanopyridin-2-yl)piperidin-4-yl]acetamide tris(trifluoroacetate)
Figure imgf000253_0001
Step A. [1 -(4-Cy anopyridin-2-yl)piperidin-4-yl] 'acetic acid trifluoroacetate
TFA
Figure imgf000253_0002
The desired compound was prepared according to the procedure of Example A 169, step A using 2-chloroisonicotinonitrile as starting material in 12% yield. LCMS for Ci3H16N3O2 (M+H) +: m/z = 246.1.
Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(4-cyanopyridin-2-yl)piperidin-4-yl]acetamide tris(trifluoroacetate) The desired compound was prepared according to the procedure of Example A 169, step B using
[l-(4-cyanopyridin-2-yl)piperidin-4-yl] acetic acid trifluoroacetate as starting material in 22% yield. LCMS for C30H29ClN9O (M+H) +: m/z = 566.2.
Example A179 /K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(5-cyanopyridin-2-yl)piperidin-4-yl]acetamide tris(trifluoroacetate)
Figure imgf000254_0001
Step A. [l-(5-Cyanopyridin-2-yl)piperidin-4-yl]acetic acid trifluoroacetate
TFA
Figure imgf000254_0002
The desired compound was prepared according to the procedure of Example A 169, step A using 6-chloronicotinonitrile as starting material in 19% yield. LCMS for Ci3Hi6N3O2 (M+H) +: m/z = 246.1.
Step B. N-[6-Chloro-2,4,8J8,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(5-cyanopyridin-2-yl)piperidin-4-yl]acetamide tris(trifluoroacetate) The desired compound was prepared according to the procedure of Example A 169, step B using
[1 -(5 -cyanopyridin-2-yl)piperidin-4-yl] acetic acid trifluoroacetate as starting material in 22% yield. LCMS for C30H29ClN9O (M+H) +: m/z = 566.2.
Example A180 /K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(6-chloropyridin-2-yl)piperidin-4-yl]acetamide tris(trifluoroacetate)
Figure imgf000254_0003
Step A. [l-(6-Chloropyridin-2-yl)piperidin-4-yl] acetic acid trifluoroacetate TFA
Figure imgf000255_0001
The desired compound was prepared according to the procedure of Example A 169, step A using 2,6-dichloropyridine as starting material in 100% yield. LCMS for Ci2Hi6ClN2O2 (M+H) +: m/z = 255.1.
Step B. N-[6-Chloro-2,4,8J8,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(6-chloropyridin-2-yl)piperidin-4-yl]acetamide tris(trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using [l-(6-chloropyridin-2-yl)piperidin-4-yl]acetic acid trifluoroacetate as starting material in 13% yield. LCMS for C29H29Cl2N8O (M+H) +: m/z = 575.2.
Example A181
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(6-fluoropyridin-2-yl)piperidin-4-yl]acetamide tris(trifluoroacetate)
Figure imgf000255_0002
Step A. [l-(6-Fluoropyridin-2-yl)piperidin-4-yl] acetic acid trifluoroacetate
TFA
Figure imgf000255_0003
The desired compound was prepared according to the procedure of Example A 169, step A usin^ 2,6-difluoropyridine as starting material in 39% yield. LCMS for Ci2Hi6FN2O2 (M+H) +: m/z = 239.1.
Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(6-fluoropyridin-2-yl)piperidin-4-yl]acetamide tris( trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B usin^ [l-(6-fluoropyridin-2-yl)piperidin-4-yl]acetic acid trifluoroacetate as starting material in 24% yield. LCMS for C29H29ClFN8O (M+H) +: m/z = 559.2.
Example A182
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-methylpyrimidin-4-yl)piperidin-4- yl]acetamide tris(trifluoroacetate)
Figure imgf000256_0001
Step A. [l-(2-Methylpyrimidin-2-yl)piperidin-4-y I] acetic acid trifluoroacetate
TFA
Figure imgf000256_0002
The desired compound was prepared according to the procedure of Example A 169, step A using 4-chloro-2-methylpyrimidine as starting material in 66% yield. LCMS for Ci2H18N3O2 (M+H) +: m/z = 236.1.
Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-methylpyrimidin-4-yl)piperidin-4-yl]acetamide tris(trifluoroacetate) The desired compound was prepared according to the procedure of Example A 169, step B using
[l-(2-methylpyrimidin-4-yl)piperidin-4-yl] acetic acid trifluoroacetate as starting material in 45% yield. LCMS for C29H3IClN9O (M+H) +: m/z = 556.2.
Example A183 yy-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3,4-thiadiazol-2-yl)piperidin-4-yl]acetamide bis(trifluoroacetate)
Figure imgf000257_0001
The desired compound was prepared according to the procedure of Example A 169, stepB using
6-chloro2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosal(20),3(22),4,6,9(21),10, 12,16,18 - nonaen-12-amine dihydrochloride and [1-(1, 3, 4-thiadiazol-2-yl)piperidin-4-yl] acetic acid trifluoroacetate as starting materials in 27% yield. LCMS for C27H28ClN8OS (M+H) +: m/z = 547.2.
Example A184 yy-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(pyridin-3-ylcarbonyl)piperidin-4-yl]acetamide bis(trifluoroacetate)
Figure imgf000257_0002
The desired compound was prepared according to the procedure of Example A20 using N- [6 - chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and nicotinoyl chloride as starting materials in 70% yield. LCMS for C3IH3IClN7O2 (M+H) +: m/z = 568.2.
Example A185 yy-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-isonicotinoylpiperidin-4-yl)acetamide bis(trifluoroacetate)
Figure imgf000258_0001
The desired compound was prepared according to the procedure of Example A20 using of N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and isonicotinoyl chloride as starting materials in 60% yield. LCMS for LCMS for C31H31CIΝ7O2 (M+H) +: m/z = 568.2.
Example A186 yy-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(4-cyanobenzoyl)piperidin-4-yl]acetamide trifluoroacetate
Figure imgf000258_0002
The desired compound was prepared according to the procedure of Example A20 using of N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 4-cyanobenzoyl chloride as starting materials in 53% yield. LCMS for C33H3IClN7O2 (M+H) +: m/z = 592.2.
Example A187 yy-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(3-cyanobenzoyl)piperidin-4-yl]acetamide trifluoroacetate
Figure imgf000259_0001
The desired compound was prepared according to the procedure of Example A20 using of N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 3-cyanobenzoyl chloride as starting materials in 16% yield. LCMS for C33H3IClN7O2 (M+H) +: m/z = 592.2.
Example A188 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(pyridin-3-ylcarbonyl)piperidin-4-yl]acetamide tris(trifluoroacetate)
Figure imgf000259_0002
The desired compound was prepared according to the procedure of Example A20 using of N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and nicotinoyl chloride as starting materials in 37% yield. LCMS for C30H30ClN8O2 (M+H) +: m/z = 569.2.
Example A189 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-isonicotinoylpiperidin-4-yl)acetamide tris(trifluoroacetate)
Figure imgf000260_0001
The desired compound was prepared according to the procedure of Example A20 using of N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and isonicotinoyl chloride as starting materials in 43% yield. LCMS for C30H30ClN8O2 (M+H) +: m/z = 569.2.
Example A190 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(4-cyanobenzoyl)piperidin-4-yl]acetamide bis(trifluoroacetate)
Figure imgf000260_0002
The desired compound was prepared according to the procedure of Example A20 using of N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 4-cyanobenzoyl chloride as starting materials in 49% yield. LCMS for C32H30ClN8O2 (M+H) +: m/z = 593.2.
Example A191 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(3-cyanobenzoyl)piperidin-4-yl]acetamide bis(trifluoroacetate)
Figure imgf000261_0001
The desired compound was prepared according to the procedure of Example A20 using of N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 3-cyanobenzoyl chloride as starting materials in 14% yield. LCMS for C32H30ClN8O2 (M+H) +: m/z = 593.2.
Example A192
2-(l-Benzoylpiperidin-4-yl)-/K-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide bis(trifluoroacetate)
Figure imgf000261_0002
The desired compound was prepared according to the procedure of Example A20 using of N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and benzoyl chloride as starting materials in 48% yield. LCMS for C3iH3iClΝ7O2 (M+H) +: m/z = 568.2.
Example A193. /K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(4-fluorobenzoyl)piperidin-4-yl]acetamide bis(trifluoroacetate)
Figure imgf000262_0001
The desired compound was prepared according to the procedure of Example A20 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-fluorobenzoyl chloride as starting materials in 26% yield. LCMS for C31H30CIFΝ7O2 (M+H) +: m/z = 586.2.
Example A194
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2,4-difluorobenzoyl)piperidin-4-yl]acetamide bis(trifluoroacetate)
Figure imgf000262_0002
The desired compound was prepared according to the procedure of Example A20 using N-[6-chloro- 2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen- 12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2,4-difluorobenzoyl chloride as starting materials in 42% yield. LCMS for C3IH29ClF2N7O2 (M+H) +: m/z = 604.2.
Example A195
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(phenylsulfonyl)piperidin-4-yl]acetamide bis(trifluoroacetate)
Figure imgf000263_0001
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro- 2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen- 12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and benzenesulfonyl chloride as starting materials in 44% yield. LCMS for C30H31CIΝ7O3S (M+H) +: m/z = 604.2.
Example A196
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(3-methoxyphenyl)sulfonyl]piperidin-4- yljacetamide bis(trifluoroacetate)
Figure imgf000263_0002
The desired compound was prepared according to the procedure of Example A42 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3-methoxybenzenesulfonyl chloride as starting materials in 28% yield. LCMS for C3IH33ClN7O4S (M+H) +: m/z = 634.2.
Example A197
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(4-methoxyphenyl)sulfonyl]piperidin-4- yljacetamide bis(trifluoroacetate)
Figure imgf000264_0001
The desired compound was prepared according to the procedure of Example A42 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-methoxybenzenesulfonyl chloride as starting materials in 41% yield. LCMS for C3IH33ClN7O4S (M+H) +: m/z = 634.2.
Example A198 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(2-cyanophenyl)sulfonyl]piperidin-4- yljacetamide bis(trifluoroacetate)
The desired compound was prepared according to the procedure of Example A42 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-cyanobenzenesulfonyl chloride as starting materials in 20% yield. LCMS for C3iH30ClΝ8O3S (M+H) +: m/z = 629.2.
Example A199 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(4-cyanophenyl)sulfonyl]piperidin-4- yljacetamide bis(trifluoroacetate)
Figure imgf000265_0001
The desired compound was prepared according to the procedure of Example A42 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-cyanobenzenesulfonyl chloride as starting materials in 22% yield. LCMS for C3IH30ClN8O3S (M+H) +: m/z = 629.2.
Example A200 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(5-methylisoxazol-4-yl)sulfonyl]piperidin-4- yljacetamide bis(trifluoroacetate)
Figure imgf000265_0002
The desired compound was prepared according to the procedure of Example A42 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 5-methylisoxazole-4-sulfonyl chloride as starting materials in 12% yield. LCMS for C28H30ClN8O4S (M+H) +: m/z = 609.2. Example A201 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-furylsulfonyl)piperidin-4-yl]acetamide bis(trifluoroacetate)
Figure imgf000266_0001
The desired compound was prepared according to the procedure of Example A42 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and furan-2-sulfonyl chloride as starting materials in 8% yield. LCMS for C28H29ClN7O4S (M+H) +: m/z = 594.2.
Example A202 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(pyridin-3-ylsulfonyl)piperidin-4-yl]acetamide tris(trifluoroacetate)
Figure imgf000266_0002
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro- 2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen- 12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and pyridine-3-sulfonyl chloride hydrochloride as starting materials in 31% yield. LCMS for C29H30ClN8O3S (M+H) +: m/z = 605.2. Example A203 yy-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(4-fluorobenzoyl)piperidin-4-yl]acetamide trifluoroacetate
Figure imgf000267_0001
The desired compound was prepared according to the procedure of Example A20 using N- [6 - chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 4-fluorobenzoyl chloride as starting materials in 20% yield. LCMS for C32H3IClFN6O2 (M+H) +: m/z = 585.2.
Example A204 yy-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2,4-difluorobenzoyl)piperidin-4-yl]acetamide trifluoroacetate
Figure imgf000267_0002
The desired compound was prepared according to the procedure of Example A20 using N- [6 - chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 2,4-difluorobenzoyl chloride as starting materials in 12% yield. LCMS for C32H30ClF2N6O2 (M+H) +: m/z = 603.2.
Example A205 yy-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(phenylsulfonyl)piperidin-4-yl]acetamide trifluoroacetate
Figure imgf000268_0001
The desired compound was prepared according to the procedure of Example A42 using N- [6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and benzenesulfonyl chloride as starting materials in 26% yield. LCMS for C3IH32ClN6O3S (M+H) +: m/z = 603.2.
Example A206 yy-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(3-methoxyphenyl)sulfonyl]piperidin-4- yljacetamide trifluoroacetate
Figure imgf000268_0002
The desired compound was prepared according to the procedure of Example A42 using N- [6 - chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 3-methoxybenzenesulfonyl chloride as starting materials in 19% yield. LCMS for C32H34ClN6O4S (M+H) +: m/z = 633.2.
Example A207 yy-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(4-methoxyphenyl)sulfonyl]piperidin-4- yljacetamide trifluoroacetate
Figure imgf000269_0001
The desired compound was prepared according to the procedure of Example A42 using N- [6 - chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 4-methoxybenzenesulfonyl chloride as starting materials in 20% yield. LCMS for C32H34ClN6O4S (M+H) +: m/z = 633.2.
Example A208
/K-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(2-cyanophenyl)sulfonyl]piperidin-4- yljacetamide trifluoroacetate
Figure imgf000269_0002
The desired compound was prepared according to the procedure of Example A42 using N- [6 - chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 2-cyanobenzenesulfonyl chloride as starting materials in 26% yield. LCMS for C32H31ClN7O3S (M+H) +: m/z = 628.2. Example A209
/K-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(4-cyanophenyl)sulfonyl]piperidin-4- yljacetamide trifluoroacetate
Figure imgf000270_0001
The desired compound was prepared according to the procedure of Example A42 using N- [6 - chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 4-cyanobenzenesulfonyl chloride as starting materials in 21% yield. LCMS for C32H31ClN7O3S (M+H) +: m/z = 628.2.
Example A210
/K-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(5-methylisoxazol-4-yl)sulfonyl]piperidin-4- yljacetamide trifluoroacetate
Figure imgf000270_0002
The desired compound was prepared according to the procedure of Example A42 using N- [6 - chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 5-methylisoxazole-4-sulfonyl chloride as starting materials in 21% yield. LCMS for C29H3IClN7O4S (M+H) +: m/z = 608.2.
Example A211 yy-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-furylsulfonyl)piperidin-4-yl]acetamide trifluoroacetate
Figure imgf000271_0001
The desired compound was prepared according to the procedure of Example A42 using N- [6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and furan-2-sulfonyl chloride as starting materials in 24% yield. LCMS for C29H30ClN6O4S (M+H) +: m/z = 593.2.
Example A212 yy-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(pyridin-3-ylsulfonyl)piperidin-4-yl]acetamide bis(trifluoroacetate)
Figure imgf000271_0002
The desired compound was prepared according to the procedure of Example A42 using N- [6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and pyridine-3-sulfonyl chloride hydrochloride as starting materials in 28% yield. LCMS for C30H31CIN7O3S (M+H) +: m/z = 604.2.
Example A213 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(5-cyclopropylisoxazol-4- yl)carbonyl]piperidin-4-yl}acetamide bis(trifluoroacetate)
Figure imgf000272_0001
The desired compound was prepared according to the procedure of Example A27 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 5-cyclopropylisoxazole-4-carboxylic acid as starting materials in 18% yield. LCMS for C3iH32ClΝ8O3 (M+H) +: m/z = 599.2.
Example A214 /K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(5-isopropylisoxazol-3-yl)carbonyl]piperidin-4- yljacetamide bis(trifluoroacetate)
Figure imgf000272_0002
The desired compound was prepared according to the procedure of Example A27 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and S-isopropylisoxazole-S-carboxylic acid as starting materials in 18% yield. LCMS for C3iH34ClΝ8O3 (M+H) +: m/z = 601.2. Example A215 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(3-methoxyisoxazol-5-yl)carbonyl]piperidin-4- yljacetamide bis(trifluoroacetate)
Figure imgf000273_0001
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro- 2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen- 12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3-methoxyisoxazole-5-carboxylic acid as starting materials in 24% yield. LCMS for C29H30ClN8O4 (M+H) +: m/z = 589.2.
Example A216 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(4-methyl-l,3-thiazol-5-yl)carbonyl]piperidin- 4-yl}acetamide bis(trifluoroacetate)
Figure imgf000273_0002
The desired compound was prepared according to the procedure of Example A27 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-methyl-l,3-thiazole-5-carboxylic acid as starting materials in 62% yield. LCMS for C29H30ClN8O2S (M+H) +: m/z = 589.2.
Example A217 2-{l-[(2-Amino-l,3-thiazol-4-yl)carbonyl]piperidin-4-yl}-/K-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide tris(trifluoroacetate)
Figure imgf000274_0001
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-
2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen- 12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-amino-l,3-thiazole-4-carboxylic acid hydrobromide as starting materials in 36% yield. LCMS for C28H29ClN9O2S (M+H) +: m/z = 590.2.
Example A218 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(5-isopropylisoxazol-4-yl)carbonyl]piperidin-4- yljacetamide bis(trifluoroacetate)
Figure imgf000274_0002
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-
2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen- 12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 5-isopropylisoxazole-4-carboxylic acid as starting materials in 18% yield. LCMS for C3IH34ClN8O3 (M+H) +: m/z = 601.2.
Example A219 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-phenylpiperidin-4-yl)acetamide tris(trifluoroacetate)
Figure imgf000275_0001
Step A. ( 1 -Phenylpiperidin-4-yl)acetic acid trifluoroacetate
TFA
Figure imgf000275_0002
Methyl piperidin-4-ylacetate (100 mg, 0.60 mmol) and phenylboronic acid (120 mg, 0.95 mmol) were stirred in dimethyl sulfoxide (1 mL) with copper diacetate (230 mg, 1.3 mmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (190 μL, 1.3 mmol). The mixture was heated at 130 0C for 30 minutes in a microwave. Purification by preparative LCMS gave the desired ester. The ester intermediate (22 mg) was stirred with a IN solution of sodium hydroxide in water (1 mL) and methanol (1 mL) at rt for 1 hour. Acetic acid was added and the mixture was purified by preparative LCMS to give the desired compound in 5% yield. LCMS for Ci3H18NO2 (M+H) +: m/z = 220.1.
Step B. N-[6-Chloro-2,4,8J8,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-phenylpiperidin-4-yl)acetamide tris( trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using (l-phenylpiperidin-4-yl)acetic acid trifluoroacetate as starting material in 17% yield. LCMS for C30H31CIN7O (M+H) +: m/z = 540.2.
Example A220
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-cyanophenyl)piperidin-4-yl]acetamide tris(trifluoroacetate)
Figure imgf000276_0001
Step A. [1 -(2-Cy anophenyl)piperidin-4-yl] acetic acid trifluoroacetate
TFA
Figure imgf000276_0002
The desired compound was prepared according to the procedure of Example A 169, step A usin^ 2-chlorobenzonitrile as starting material in 39% yield. LCMS for Ci4Hi7N2O2 (M+H) +: m/z = 245.1.
Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-cyanophenyl)piperidin-4-yl]acetamide tris(trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using [1 -(2 -cyanophenyl)piperidin-4-yl] acetic acid trifluoroacetate as starting material in 40% yield. LCMS for C3IH30ClN8O (M+H) +: m/z = 565.2.
Example A221 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(4-cyanophenyl)piperidin-4-yl]acetamide tris(trifluoroacetate)
Figure imgf000276_0003
Step A. [l-(4-Cyanophenyl)piperidin-4-yl] acetic acid trifluoroacetate
TFA
Figure imgf000277_0001
The desired compound was prepared according to the procedure of Example A 169, step A using 4-chlorobenzonitrile as starting material in 38% yield. LCMS for Ci4Hi7N2O2 (M+H) +: m/z = 245.1.
Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(4-cyanophenyl)piperidin-4-yl]acetamide tris(trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using [l-(4-cyanophenyl)piperidin-4-yl] acetic acid trifluoroacetate as starting material in 57% yield. LCMS for C3IH30ClN8O (M+H) +: m/z = 565.2.
Example A222
2-[l-(3-Chloro-2-cyanophenyl)piperidin-4-yl]-y^-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide tris(trifluoroacetate)
Figure imgf000277_0002
Step A. [l-(3-Chloro-2-cyanophenyl)piperidin-4-yl]-acetic acid trifluoroacetate
Figure imgf000277_0003
The desired compound was prepared according to the procedure of Example A 169, step A using
2,6-dichlorobenzonitrile as starting material in 27% yield. LCMS for Ci4Hi6ClN2O2 (M+H) +: m/z = 279.1. Step B. 2-[l-(3-Chloro-2-cyanophenyl)piperidin-4-yl]-N-[6-chloro-2,4,8, 18,22- pentaazatetracydo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yljacetamide tris(trifluoroacetate) The desired compound was prepared according to the procedure of Example A 169, step B using
[1 -(3 -Chloro-2-cyanophenyl)piperidin-4-yl] acetic acid trifluoroacetate as starting material in 18% yield. LCMS for C3IH29Cl2N8O (M+H) +: m/z = 599.2.
Example A223 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(2-chlorophenyl)sulfonyl]piperidin-4- yljacetamide bis(trifluoroacetate)
Figure imgf000278_0001
The desired compound was prepared according to the procedure of Example A42 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-chlorobenzenesulfonyl chloride as starting materials in 22% yield. LCMS for C30H30Cl2N7O3S (M+H) +: m/z = 638.2.
Example A224 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-{[2-(trifluoromethyl)phenyl]sulfonyl}piperidin- 4-yl)acetamide bis(trifluoroacetate)
Figure imgf000279_0001
The desired compound was prepared according to the procedure of Example A42 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen- 12-yl] -2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-(trifluoromethyl)benzenesulfonyl chloride as starting materials in 14% yield. LCMS for C31H30CIF3Ν7O3S (M+H) +: m/z = 672.2.
Example A225
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(2-methylphenyl)sulfonyl]piperidin-4- yljacetamide bis(trifluoroacetate)
Figure imgf000279_0002
The desired compound was prepared according to the procedure of Example A42 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen- 12-yl] -2 -piperidin-4-ylacetamide tris(trifluoroacetate) and 2-methylbenzenesulfonyl chloride as starting materials in 18% yield. LCMS for C3IH33ClN7O3S (M+H) +: m/z = 618.2.
Example A226.
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(2-fluorophenyl)sulfonyl]piperidin-4- yljacetamide bis(trifluoroacetate)
Figure imgf000280_0001
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro- 2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen- 12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-fluorobenzenesulfonyl chloride as starting materials in 16% yield. LCMS for C30H30CIFΝ7O3S (M+H) +: m/z = 622.2.
Example A227
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-{[2- (trifluoromethoxy)phenyl]sulfonyl}piperidin-4-yl)acetamide bis(trifluoroacetate)
Figure imgf000280_0002
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro- 2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen- 12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-(trifluoromethoxy)benzenesulfonyl chloride as starting materials in 16% yield. LCMS for C31H30CIF3Ν7O4S (M+H) +: m/z = 688.2.
Example A228
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(3-cyanophenyl)sulfonyl]piperidin-4- yljacetamide bis(trifluoroacetate)
Figure imgf000281_0001
The desired compound was prepared according to the procedure of Example A42 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3-cyanobenzenesulfonyl chloride as starting materials in 25% yield. LCMS for C3IH30ClN8O3S (M+H) +: m/z = 629.2.
Example A229
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(l-methyl-lH-imidazol-4-yl)sulfonyl]piperidin- 4-yl}acetamide bis(trifluoroacetate)
Figure imgf000281_0002
The desired compound was prepared according to the procedure of Example A42 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen- 12-yl] -2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1 -methyl- 1 H-imidazole-4-sulfonyl chloride as starting materials in 17% yield. LCMS for C28H31ClN9O3S (M+H) +: m/z = 608.2.
Example A230 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(l,2-dimethyl-lH-imidazol-4- yl)sulfonyl]piperidin-4-yl}acetamide bis(trifluoroacetate)
Figure imgf000282_0001
The desired compound was prepared according to the procedure of Example A42 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen- 12-yl] -2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1 ,2-dimethyl- 1 H-imidazole-4-sulfonyl chloride as starting materials in 24% yield. LCMS for C29H33ClN9O3S (M+H) +: m/z = 622.2.
Example A231 y^[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(3,5-dimethylisoxazol-4-yl)sulfonyl]piperidin- 4-yl}acetamide bis(trifluoroacetate)
Figure imgf000282_0002
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro- 2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen- 12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3,5-dimethylisoxazole-4-sulfonyl chloride as starting materials in 17% yield. LCMS for C29H32ClN8O4S (M+H) +: m/z = 623.2.
Example A232 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(2,4-dimethyl-l,3-thiazol-5- yl)sulfonyl]piperidin-4-yl}acetamide bis(trifluoroacetate)
Figure imgf000283_0001
The desired compound was prepared according to the procedure of Example A42 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2,4-dimethyl-l ,3-thiazole-5-sulfonyl chloride as starting materials in 22% yield. LCMS for C29H32ClN8O3S2 (M+H) +: m/z = 639.2.
Example A233 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-cyano-3-methoxyphenyl)piperidin-4- yl]acetamide tris(trifluoroacetate)
Figure imgf000283_0002
Step A. [l-(2-Cyano-3-methoxyphenyl)piperidin-4-yl]acetic acid trifluoroacetate
Figure imgf000283_0003
The desired compound was prepared according to the procedure of Example A 169, step A using 2-fluoro-6-methoxybenzonitrile as starting material in 4% yield. LCMS for Ci5Hi9N2O3 (M+H) +: m/z = 275.1.
Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-cyano-3-methoxyphenyl)piperidin-4- yl] acetamide tris(trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using [l-(2-cyano-3-methoxyphenyl)piperidin-4-yl]acetic acid trifluoroacetate as starting material in 27% yield. LCMS for C32H32ClN8O2 (M+H) +: m/z = 595.2.
Example A234
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-cyano-3-fluorophenyl)piperidin-4- yl]acetamide tris(trifluoroacetate)
Figure imgf000284_0001
Step A. [l-(2-Cyano-3-fluorophenyl)piperidin-4-yl]acetic acid trifluoroacetate
Figure imgf000284_0002
The desired compound was prepared according to the procedure of Example A 169, step A using 2,6-difluorobenzonitrile as starting material in 43% yield. LCMS for Ci4Hi6FN2O2 (M+H) +: m/z = 263.1.
Step B. N-[6-Chloro-2,4,8J8,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-cyano-3-fluorophenyl)piperidin-4-yl]acetamide tris( trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using [l-(2-cyano-3-fluorophenyl)piperidin-4-yl]acetic acid trifluoroacetate as starting material in 8% yield. LCMS for C3IH29ClFN8O (M+H) +: m/z = 583.2.
Example A235
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[2-cyano-3-(trifluoromethyl)phenyl]piperidin- 4-yl}acetamide tris(trifluoroacetate)
Figure imgf000285_0001
Step A. {l-[2-Cyano-3-(trifluoromethyl)phenyl]piperidin-4-yljacetic acid trifluoroacetate
Figure imgf000285_0002
The desired compound was prepared according to the procedure of Example A 169, step A usin^
2-fluoro-6-(trifluoromethyl)benzonitrile as starting material in 42% yield. LCMS for CiSHi6F3N2O2 (M+H) +: m/z = 313.1.
Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[2-cyano-3-(trifluoromethyl)phenyl]piperidin-4- yljacetamide tris(trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using { l-[2-cyano-3-(trifluoromethyl)phenyl]piperidin-4-yl}acetic acid trifluoroacetate as starting material in 23% yield. LCMS for C32H29ClF3N8O (M+H) +: m/z = 633.2.
Example A236. yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-cyano-3-methylphenyl)piperidin-4- yl]acetamide tris(trifluoroacetate)
Figure imgf000286_0001
Step A. [l-(2-Cyano-3-methylphenyl)piperidin-4-yl]acetic acid trifluoroacetate
Figure imgf000286_0002
The desired compound was prepared according to the procedure of Example A 169, step A using 2-chloro-6-methylbenzonitrile as starting material in 4% yield. LCMS for Ci5H19N2O2 (M+H) +: m/z = 259.1.
Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-cyano-3-methylphenyl)piperidin-4-yl]acetamide tris(trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using [l-(2-cyano-3-methylphenyl)piperidin-4-yl]acetic acid trifluoroacetate as starting material in 35% yield. LCMS for C32H32ClN8O (M+H) +: m/z = 579.2.
Example A237
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[2-cyano-5-(trifluoromethyl)phenyl]piperidin- 4-yl}acetamide tris(trifluoroacetate)
Figure imgf000287_0001
Step A. (l-[2-Cyano-5-(trifluoromethyl)phenyl]piperidin-4-ylJacetic acid trifluoroacetate
Figure imgf000287_0002
The desired compound was prepared according to the procedure of Example A 169, step A using 2-fluoro-4-(trifluoromethyl)benzonitrile as starting material in 9% yield. LCMS for Ci5H16F3N2O2 (M+H) +: τalτ = 313.1.
Step B. N-[6-Chloro-2,4,8J8,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22)AA9(21)J0J2,16,18-nonaen-12-yl]-2-{l-[2-cyano-5-(trifluoromethyl)phenyl]piperidin-4- yljacetamide tris( trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using { l-[2-cyano-5-(trifluoromethyl)phenyl]piperidin-4-yl}acetic acid trifluoroacetate as starting material in 32% yield. LCMS for C32H29ClF3N8O (M+H) +: m/z = 633.2.
Example A238
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(3-cyano-6-methylpyridin-2-yl)piperidin-4- yl]acetamide tris(trifluoroacetate)
Figure imgf000288_0001
Step A. [l-(3-Cyano-6-methylpyridin-2-yl)piperidin-4-yl]acetic acid trifluoroacetate
Figure imgf000288_0002
The desired compound was prepared according to the procedure of Example A 169, step A using 2-chloro-6-methylnicotinonitrile as starting material in 4% yield. LCMS for Ci4Hi8N3O2 (M+H) +: m/z = 260.1.
Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(3-cyano-6-methylpyridin-2-yl)piperidin-4- yljacetamide tris(trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using [1 -(3 -cyano-6-methylpyridin-2-yl)piperidin-4-yl] acetic acid trifluoroacetate as starting material in 23% yield. LCMS for C31 H31 ClN9O (M+H) +: m/z = 580.2.
Example A239 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(3-cyano-4,6-dimethylpyridin-2-yl)piperidin-4- yl]acetamide tris(trifluoroacetate)
Figure imgf000289_0001
Step A. [l-(3-Cyano-4,6-dimethylpyridin-2-yl)piperidin-4-yl]acetic acid trifluoroacetate
Figure imgf000289_0002
The desired compound was prepared according to the procedure of Example A 169, step A using 2-chloro-3-cyano-4,6-dimethylpyridine as starting material in 59% yield. LCMS for Ci5H20N3O2 (M+H) +: m/z = 274.1.
Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracydo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4A9(21),10,12,16,18-nonaen-12-yl]-2-[l-(3-cyano-4,6-dimethylpyridin-2-yl)piperidin-4- yl] acetamide tris( trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using [l-(3-cyano-4,6-dimethylpyridin-2-yl)piperidin-4-yl]acetic acid trifluoroacetate as starting material in 25% yield. LCMS for C32H33ClN9O2 (M+H) +: m/z = 594.2.
Example A240
2-[l-(5-Chloro-4-cyanopyridin-3-yl)piperidin-4-yl]-/K-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide tris(trifluoroacetate)
Figure imgf000290_0001
Step A. [l-(5-Chloro-4-cyanopyridin-3-yl)piperidin-4-yl]acetic acid trifluoroacetate
Figure imgf000290_0002
The desired compound was prepared according to the procedure of Example A 169, step A using 3,5-dichloroisonicotinonitrile as starting material in 50% yield. LCMS for Ci3Hi5ClN3O2 (M+H) +: m/z = 280.1.
Step B. 2-[l-(5-Chloro-4-cyanopyridin-3-yl)piperidin-4-yl]-N-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl] acetamide tris( trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using . [l-(5-chloro-4-cyanopyridin-3-yl)piperidin-4-yl]acetic acid trifluoroacetate as starting material in 17% yield. LCMS for C30H28Cl2N9O (M+H) +: m/z = 600.2.
Example A241
2-[l-(6-Chloro-3-cyano-5-fluoropyridin-2-yl)piperidin-4-yl]-y^-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide tris(trifluoroacetate)
Figure imgf000291_0001
Step A. [l-(6-Chloro-3-cyano-5-fluoropyridin-2-yl)piperidin-4-yl]acetic acid trifluoroacetate
Figure imgf000291_0002
The desired compound was prepared according to the procedure of Example A 169, step A using 2,6-dichloro-5-fluoronicotinonitrile as starting material in 8% yield. LCMS for Ci3Hi4ClFN3O2 (M+H) +: τalτ = 298.1.
Step B. 2-[l-(6-Chloro-3-cyano-5-fluoropyridin-2-yl)piperiώn-4-yl]-N-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yljacetamide tris(trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using . [l-(6-chloro-3-cyano-5-fluoropyridin-2-yl)piperidin-4-yl]acetic acid trifluoroacetate as starting material in 9% yield. LCMS for C30H27Cl2FN9O (M+H) +: m/z = 618.2.
Example A242 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-pyridin-4-ylpiperidin-4-yl)acetamide tris(trifluoroacetate)
Figure imgf000292_0001
Step A. (l-Pyridin-4-ylpiperidin-4-yl)acetic acid trifluoroacetate
TFA
Figure imgf000292_0002
The desired compound was prepared according to the procedure of Example A 169, step A using 4- bromopyridine hydrochloride as starting material in 99% yield. LCMS for Ci2Hi7N2O2 (M+H) +: m/z = 221.1.
Step B. N-[6-Chloro-2,4,8J8,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-pyridin-4-ylpiperidin-4-yl)acetamide tris( trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using (l-pyridin-4-ylpiperidin-4-yl)acetic acid trifluoroacetate as starting material in 8% yield. LCMS for C29H30ClN8O (M+H) +: m/z = 541.2.
Example A243
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(3-fluoropyridin-4-yl)piperidin-4-yl]acetamide tris(trifluoroacetate)
Figure imgf000292_0003
Step A. [l-(3-Fluoropyridin-4-yl)piperidin-4-yl]acetic acid trifluoroacetate TFA
Figure imgf000293_0001
The desired compound was prepared according to the procedure of Example A 169, step A using 4-bromo-3-fluoropyridine hydrochloride as starting material in 82% yield. LCMS for Ci2H16FN2O2 (M+H) +: m/z = 239.1.
Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(3-fluoropyridin-4-yl)piperidin-4-yl]acetamide tris(trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using [1 -(3 -fluoropyridin-4-yl)piperidin-4-yl] acetic acid trifluoroacetate as starting material in 24% yield. LCMS for C29H29FN8O (M+H) +: m/z = 559.2.
Example A244 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-fluoropyridin-4-yl)piperidin-4-yl]acetamide tris(trifluoroacetate)
Figure imgf000293_0002
Step A. [l-(2-Fluoropyridin-4-yl)piperidin-4-yl] acetic acid trifluoroacetate
TFA
Figure imgf000293_0003
The desired compound was prepared according to the procedure of Example A 169, step A using
4-bromo-2-fluoropyridine as starting material in 13% yield. LCMS for Ci2Hi6FN2O2 (M+H) +: m/z = 239.1. Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-fluoropyridin-4-yl)piperidin-4-yl]acetamide tris(trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B usin^ [1 -(2 -fluoropyridin-4-yl)piperidin-4-yl] acetic acid trifluoroacetate as starting material in 23% yield. LCMS for C29H29ClFN8O (M+H) +: m/z = 559.2.
Example A245
/K-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(cyanoacetyl)piperidin-4-yl]acetamide bis(trifluoroacetate)
Figure imgf000294_0001
The desired compound was prepared according to the procedure of Example A27 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and cyanoacetic acid as starting materials in 41% yield. LCMS for C27H28ClN8O2 (M+H) +: m/z = 531.2.
Example A246 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3-oxazol-2-yl)piperidin- 4-yl]acetamide tris(trifluoroacetate)
Figure imgf000295_0001
Step A. [ 1 -( 1 ,3-Oxazol-2-yl)piperidin-4-yl] 'acetic acid trifluoroacetate
TFA
Figure imgf000295_0002
The desired compound was prepared according to the procedure of Example A 169, step A using 2-chloro-l,3-oxazole as starting material in 20% yield. LCMS for Ci0Hi5N2O3 (M+H) +: m/z = 211.1.
Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3-oxazol-2-yl)piperidin-4-yl]acetamide tris(trifluoroacetate) The desired compound was prepared according to the procedure of Example A 169, step B using
[l-(l,3-oxazol-2-yl)piperidin-4-yl]acetic acid trifluoroacetate as starting material in 8% yield. LCMS for C27H28ClN8O2 (M+H) +: m/z = 531.2.
Example A247 yy-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(5-methylisoxazol- 3-yl)piperidin-4-yl]acetamide bis(trifluoroacetate)
Figure imgf000295_0003
Step A. [l-( 5 -Methylisoxazol-3-yl)piperidin-4-yl] acetic acid trifluoroacetate TFA
Figure imgf000296_0001
The desired compound was prepared according to the procedure of Example A 169, step A using 3-chloro-2,5-dimethyl-isoxazolium chloride as starting material in 10% yield. LCMS for CHHI7N2O3 (M+H) +: τalτ = 225.1.
Step B. N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(5-methylisoxazol-3-yl)piperidin-4-yl]acetamide tris(trifluoroacetate)
The desired compound was prepared according to the procedure of Example A 169, step B using [l-(5-methylisoxazol-3-yl)piperidin-4-yl]acetic acid trifluoroacetate as starting material in 14% yield. LCMS for C28H30ClN8O2 (M+H) +: m/z = 545.2.
Example A248 yy-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(5-methylisoxazol-3-yl)piperidin-4-yl]acetamide trifluoroacetate
Figure imgf000296_0002
The desired compound was prepared according to the procedure of Example A 169, stepB usin^ 6-chloro2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosal(20),3(22),4,6,9(21),10, 12,16,18 - nonaen-12-amine dihydrochloride and [1 -(5 -methylisoxazol-3-yl)piperidin-4-yl] acetic acid trifluoroacetate as starting materials in 8% yield. LCMS for C29H3iClN7O2 (M+H) +: m/z = 544.2.
Example A249 6-Chloro-12-{2-oxo-2-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl]ethoxy}-2,4,8,18,22pentaazatetracyclo[14.3.1.1(3,7).l(9,13)] docosal(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000297_0001
Step A. 7-(Chloroacetyl)-3-(trifluoromethyl)-5, 6, 7, 8-tetrahydro[l, 2,4]triazolo[4, 3-a]pyrazine
Figure imgf000297_0002
Bromoacetic acid (300 mg, 2.2 mmol) and 3-(trifluoromethyl)-5,6,7,8- tetrahydro[l,2,4]triazolo[4,3-a]pyrazine hydrochloride (490 mg, 2.2 mmol) were stirred in dichloromethane (5 mL) with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (412 mg, 2.2 mmol) and N,N-diisopropylethylamine (560 mL, 3.2 μmol) for 3 hours at rt. The mixture was washed with water, dried over sodium sulfate and evaporated to give the desired compound in 33% yield. LCMS for C8H8ClF3N4O (M+H) +: m/z = 269.0.
Step B. 6-Chloro-12-{2-oxo-2-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl]ethoxy}-2, 4, 8,18, 22-pentaazatetracyclo[14.3.1.1 (3, 7).1 (9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
The desired compound was prepared according to the procedure of Example A9, step G using 6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-ol and 7-(chloroacetyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyrazine as starting materials in 30% yield. LCMS for C25H22ClF3N9O2 (M+H) +: m/z = 572.2.
Example Bl
(14Z)-6-Methyl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,14,16,18-decaene trifluoroacetate
Figure imgf000298_0001
Step A: 2-Chloro-5-methyl-N-(3-vinylphenyl)pyrimidin-4-amine
Figure imgf000298_0002
This compound was prepared according to the procedure of Example Al, step A, using 2,4- dichloro-5-methylpyrimidine and 3-vinylaniline as the starting materials in 39% yield. LCMS calculated for Ci3Hi3ClN3 (M+H)+: m/z = 246.1.
Step B: 5-Methyl-N,N'-bis(3-vinylphenyl)pyrimidine-2,4-diamine trifluoroacetate
Figure imgf000298_0003
This compound was prepared according to the procedure of Example Al, step B, using 2-chloro-
5-methyl-N-(3-vinylphenyl)pyrimidin-4-amine and 3-vinylaniline as the starting materials in 64% yield. LCMS calculated for C2iH2iN4 (M+H)+: m/z = 329.3.
Step C: {14Z)-6-Methyl-2,4,8,22-tetraazatetracyclo[143AA{3,7)A{9,13)]docosa- l(20),3(22),4,6,9(21),10,12,14,16,18-decaene trifluoroacetate
This compound was prepared according to the procedure of Example Al, step C using 5-methyl-
N,N-bis(3-vinylphenyl)pyrimidine-2,4-diamine trifluoroacetate as the starting materials in 17% yield.
LCMS calculated for Ci9HnN4 (M-I-H)+: m/z = 301.1. 1H NMR (400 MHz, DMS0-<i6): δlθ.02 (brs, 1 H),
9.62 (brs, 1 H), 8.67 (s, 1 H), 8.50 (s, 1 H), 7.91 (s, 1 H), 7.32-7.14 (m, 3 H), 7.05-6.95 (m, 3 H), 6.74- 6.66 (m, 2 H), 2.14 (s, 3 H).
Example B2 6-Methyl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene trifluoroacetate
Figure imgf000299_0001
This compound was prepared according to the procedure of Example A2, using (14Z)-6-methyl- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,14,16,18-decaene trifluoroacetate as the starting material in 65% yield. LCMS calculated for Ci9H19N4(M+H)+: m/z = 303.2. 1H NMR (400 MHz, DMS0-<i6): δ 10.15 (s, 1 H), 9.87 (s, 1 H), 7.89 (s, 1 H), 7.79 (s, 1 H), 7.73 (s, 1 H), 7.25 (t, 1 H), 7.17 (t, 1 H), 7.02 (m, 2 H), 6.95 (d, 1 H), 6.87 (dd, 1 H), 2.95 (s, 4 H), 2.14 (s, 3 H).
Example B3
6-Bromo-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene trifluoroacetate
Figure imgf000299_0002
Step A: tert-Butyl (3-[(3-aminophenyl)ethynyl]phenyl}carbamate
Figure imgf000299_0003
A solution of 3-ethynylaniline (1.16 g, 9.87 mmol) and tert-butyl (3-iodophenyl)carbamate (3.0 g, 9.4 mmol) in THF (28 mL) was treated with bis(triphenylphosphine)palladium(II) chloride (330 mg, 0.47 mmol), copper(I) iodide (140 mg, 0.75 mmol) and NN-diisopropylethylamine (3.27 ml, 18.8 mmol), and stirred at 25 0C overnight. The reaction was diluted with water and extracted with ethyl acetate three times. The combined organic solutions were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.42 g, 49%). LCMS for Ci9H2IN2O2 (M+H)+: m/z = 309.1.
Step B: tert-Butyl (3-[2-(3-aminophenyl)ethyl]phenyl}carbamate
Figure imgf000300_0001
To a solution of tert-butyl {3-[(3-aminophenyl)ethynyl]phenyl}carbamate (0.5 g, 2.0 mmol) in methanol (10 mL) was added 10% palladium on carbon (0.50 g, 0.43 mmol) and the mixture was stirred under an atmosphere of hydrogen for 24 h. The reaction mixture was filtered through a pad of celite, rinsed with methanol and dichloromethane. The solvents were evaporated to give a crude oil. This material was purified by flash column chromatography to yield the desired product (430 mg, 85%). LCMS for Ci9H25N2O2(M+H)+: m/z = 313.2.
Step C: tert-Butyl [3-(2-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]phenyl}ethyl)phenyl]carbamate
Figure imgf000300_0002
This compound was prepared according to the procedure of Example B5, step G using 5-bromo-
2,4-dichloropyrimidine and tert-butyl {3-[2-(3-aminophenyl)ethyl]phenyl}carbamate as the starting materials in 70 % yield. LCMS calculated for C23H25BrClN4O2 (M+H)+: m/z = 503.1, 505.1.
Step D: 6-Bromo-2,4,8,22-tetraazatetracyclo[14.3AA{3,7)A{9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
This compound was prepared according to the procedure of Example B5, step H using tert-butyl
[3-(2-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]phenyl}ethyl)phenyl]carbamate as the starting material in 43% yield. LCMS calculated for Ci8H16BrN4 (M+H)+: m/z = 367.2, 369.2. 1H NMR (400
MHz, CD3OD): δ 8.16 (s, 1 H), 7.73 (s, 1 H), 7.69 (s, 1 H), 7.29 (m, 1 H), 7.21 (t, 1 H), 7.13 (d, 1 H),
7.00-7.08 (m, 2 H), 6.90 (d, 1 H), 2.99 (m, 4 H). Example B5
Methyl 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-ll-carboxylate trifluoroacetate
Step A: 3-Bromo-5-nitrobenzoic acid
Figure imgf000301_0001
ra-Nitrobenzoic acid (11.2 g, 67.0 mmol) was taken up in sulfuric acid (30 mL) and heated to 60 0C. To this solution was added N-bromosuccinimide (14.3 g, 80.4 mmol) in three portions each over a 15 minute period. After stirring for 2 h, the mixture was poured into crushed ice (100 g) to precipitate a solid. The solid was filtered, washed with water followed by hexanes to give the desired product (16 g, 97%). LCMS for C7H3BrNO4 (M-H)+: m/z = 244.0, 246.0.
Step B: Methyl 3-bromo-5-nitrobenzoate
Figure imgf000301_0002
A solution of 3-bromo-5-nitrobenzoic acid (15.4 g, 62.6 mmol) in methanol (120 mL) and sulfuric acid (1.7 mL, 31 mmol) was heated to reflux overnight. After cooling to 0 0C for 0.5 h, the precipitated solid was filtered to give the desired product as a white solid (15.5 g, 95%). LCMS for C8H7BrNO4 (M+H)+: m/z = 260.0, 262.0.
Step C: Methyl 3-nitro-5-[(trimethylsilyl)ethynyl]benzoate
Figure imgf000302_0001
A solution of methyl 3-bromo-5-nitrobenzoate (0.331 g, 1.27 mmol), (trimethylsilyl) acetylene (0.27 mL, 1.9 mmol), bis(triphenylphosphine)palladium(II) chloride (45 mg, 0.064 mmol), copper(I) iodide (19 mg, 0.10 mmol) and triethylamine (0.26 mL, 1.9 mol) in DMF (5 mL) was stirred at room temperature overnight. The solution was diluted with ethyl acetate and 1 N HCl. The aqueous layer was extracted with ethyl acetate once, and the combined organic solutions were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (10% ethyl acetate in hexanes) to give the desired product (310 mg, 88%). LCMS for Ci3Hi6NO4Si (M+H)+: m/z = 278.1.
Step D: Methyl 3-ethynyl-5-nitrobenzoate
Figure imgf000302_0002
Methyl 3-nitro-5-[(trimethylsilyl)ethynyl]benzoate (7.9 g, 28 mmol) was dissolved in THF (90 mL) and methanol (90 mL) and then potassium carbonate (2.0 g, 14 mmol) was added. The resulting solution was stirred at room temperature for 1 hour. The reaction was quenched with 1 N HCl, and the solvent was removed in vacuo. The aqueous residue was extracted with ethyl acetate twice. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated to give a solid. The solid was washed with ether to give the desired product (4 g, 68%). LCMS for Ci0H8NO4 (M+H)+: m/z = 206.0.
Step E: Methyl 3-({3-[(tert-butoxycarbonyl)amino]phenyljethynyl)-5-nitrobenzoate
Figure imgf000303_0001
A solution of methyl 3-ethynyl-5-nitrobenzoate (1.45 g, 7.08 mmol), tert-butyl (3- iodophenyl)carbamate (2.26 g, 7.08 mmol) in THF (28 mL) was treated with bis(triphenylphosphine)palladium(II) chloride (248 mg, 0.354 mmol), copper(I) iodide (108 mg, 0.566 mmol) and N,N-diisopropylethylamine (2.47 mL, 14.2 mmol) and stirred at 25 0C overnight. The reaction was diluted with water and extracted with ethyl acetate three times. The combined organic solutions were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.85 g, 66%). LCMS for C2IH20N2O6Na (M+Na)+: m/z = 419.3.
Step F: Methyl 3-amino-5-(2-{3-[(tert-butoxycarbonyl)amino]phenyljethyl)benzoate
Figure imgf000303_0002
To a solution of methyl 3-({3-[(tert-butoxycarbonyl)amino]phenyl}ethynyl)-5-nitrobenzoate (1.85 g, 4.67 mmol) in methanol (50 mL) was added 10% palladium on carbon (1.85 g, 1.58 mmol), and the mixture was hydrogenated under 55 psi of H2 for 72 hours with shaking. The solution was filtered through a pad of celite, and filtrate was concentrated. The residue was purified by flash column chromatography to give the desired product as a yellow oil (1.70 g, 98%). LCMS for C2iH27N2O4 (M+H)+: m/z = 371.1.
Step G: Methyl 3-(2-{3-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-5-[(2,5-dichloropyrimidin-4- yl)amino]benzoate
Figure imgf000304_0001
A solution of 2,4,5-trichloropyrimidine (0.371 mL, 3.24 mmol) and methyl 3-amino-5-(2-{3- [(tert-butoxycarbonyl)amino]phenyl}ethyl)benzoate (1.20 g, 3.24 mmol) in DMF (20 mL) and potassium carbonate (895 mg, 6.48 mmol) were stirred at 60 0C overnight. The reaction mixture was diluted with 1 N HCl and extracted with ethyl acetate three times. The combined organic solutions were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.20 g, 72%). LCMS for C25H26Cl2N4O4Na (M+Na)+: m/z = 539.3, 541.3.
Step H: Methyl 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-ll-carboxylate trifluoroacetate
A solution of methyl 3-(2-{3-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-5-[(2,5- dichloropyrimidin-4-yl)amino]benzoate (124 mg, 0.240 mmol), 4.0 M of hydrogen chloride in 1,4- dioxane (0.21 mL, 0.84 mmol) in 2-methoxyethanol (16 mL) was microwaved at 130 0C for 5 minutes. Purification by preparative LCMS gave the desired product as a white solid (51 mg, 43%). LCMS for C20H18ClN4O2 (M+H)+: m/z = 381.3. 1H NMR (400 MHz, DMSO-^6): δ 9.44 (m, 2 H), 8.16 (s, 1 H), 8.04 (m, 1 H), 7.83 (m, 1 H), 7.74 (m, 1 H), 7.61 (m, 1 H), 7.12 (t, / = 7.5 Hz, 1 H), 6.88 (m, 1 H), 6.82 (m, 1 H), 3.83 (s, 3 H), 2.94 (m, 2 H), 2.87 (m, 2 H).
Example B6
6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene-11-carboxylic acid trifluoroacetate
Figure imgf000304_0002
A solution of methyl 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l 1 -carboxylate trifluoroacetate (45 mg, 90.9 μmol) in acetonitrile (5 mL) and 2.0 M of sodium hydroxide in water (227 μL, 0.455 mmol) were stirred at 25 0C overnight. Purification by preparative LCMS gave the desired product as a white solid (16 mg, 48%). LCMS for Ci9Hi6ClN4O2 (M+H)+: m/z = 367.1. 1H NMR (400 MHz, DMSO-^6): δ 9.33 (s, 1 H), 9.28 (s, 1 H), 8.12 (s, 1 H), 8.01 (m, 1 H), 7.86 (m, 1 H), 7.71 (m, 1 H), 7.58 (m, 1 H), 7.11 (t, 1 H), 6.91 (m, 1 H), 6.82 (m, 1 H), 2.93 (m, 2 H), 2.87 (m, 2 H).
Example B7
6-Chloro-iV-(3-chloro-4-fluorophenyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-ll-carboxamide trifluoroacetate
Figure imgf000305_0001
To a solution of methyl 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxylate (13.5 mg, 0.0354 mmol) in methylene chloride (0.4 mL) was added 3-chloro-4-fluoroaniline (10.3 mg, 0.0709 mmol). The resulting solution was cooled down to 0 0C and treated with 2.0 M of trimethylaluminum in toluene (35.4 μL, 0.0709 mmol) under an atmosphere of nitrogen. After stirring at 25 0C for 2 h, the reaction mixture was quenched with 1 M potassium sodium tartrate solution dropwise at 0 0C. The aqueous layer was extracted with ethyl acetate once, and the combined organic solutions were dried over Na2SO4, filtered, and concentrated. Purification by preparative LCMS gave the desired product as a white solid (13.2 mg, 75%). LCMS for C25Hi9Cl2FN5O (M+H)+: m/z = 494.2. 1H NMR (400 MHz DMSO-^6): δ 10.35 (s, 1 H), 9.40 (s, 1 H), 9.38 (s, 1 H), 8.11 (s, 1 H), 8.00 (dd, 1 H), 7.93 (m, 1 H), 7.83 (m, 1 H), 7.65 (m, 1 H), 7.60 (m, 1 H), 7.55 (m, 1 H), 7.36 (t, 1 H), 7.07 (t, 1 H), 6.85 (m, 1 H), 6.79 (m, 1 H), 2.92 (m, 2 H), 2.89 (m, 2 H).
Example B8
6-Chloro-ll-[(4-methylpiperazin-l-yl)carbonyl]-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
Figure imgf000306_0001
The desired compound was prepared according to the procedure of Example B7, using methyl 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene-11-carboxylate and 4-(aminomethyl)pyridine as the starting materials in 55% yield. LCMS for C24H26ClN6O (M+H)+: m/z = 449.4. 1H NMR (400 MHz, DMSOd6 ): δ 10.01 (br s, 1 H), 9.40 (s, 1 H), 9.23 (s, 1 H), 8.15 (s, 1 H), 7.92 (m, 2 H), 7.14 (m, 3 H), 6.92 (m, 1 H), 6.83 (m, 1 H), 3.43 (bs, 4 H), 3.08 (br s, 4 H), 2.86 (m, 4 H), 2.82 (s, 3 H).
Example B9 6-Chloro-iV-(4-morpholin-4-ylphenyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene-ll-carboxamide trifluoroacetate
Figure imgf000306_0002
The desired compound was prepared according to the procedure of Example B7, using methyl 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene-11-carboxylate and 4-morpholin-4-ylaniline as the starting materials in 45% yield. LCMS for
C29H28ClN6O2 (M+H)+: m/z = 527.4. 1H NMR (400 MHz, DMS0-<i6 ): δ 10.04 (s, 1 H), 9.37 (s, 1 H), 9.32 (s, 1 H), 8.14 (s, 1 H), 7.92 (m, 2 H), 7.61 (m, 4 H), 7.12 (t, 1 H), 6.92 (m, 3 H), 6.82 (d, 1 H), 3.73 (m, 4 H), 3.06 (m, 4 H), 2.94 (m, 4 H).
Example BlO
6-Chloro-iV-[4-(2-hydroxyethyl)phenyl]-2,4,8,22-tetraazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene-ll-carboxamide trifluoroacetate
Figure imgf000307_0001
The desired compound was prepared according to the procedure of Example B7, using methyl 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene-11-carboxylate and p-aminophenylethanol as the starting materials in 41% yield. LCMS for
C27H25ClN5O2 (M+H)+: m/z = 486.3. 1H NMR (400 MHz, DMSO-^6): δ 10.15 (s, 1 H), 9.42 (m, 2 H), 8.15 (s, 1 H), 7.94 (m, 1 H), 7.89 (m, 1 H), 7.64 (m, 4 H), 7.17 (m, 3 H), 6.92 (m, 1 H), 6.84 (m, 1 H), 3.56 (t, 2 H), 2.93 (m, 4 H), 2.85 (s, 1 H), 2.67 (t, 2 H).
Example BIl
6-Chloro-iV-(pyridin-4-ylmethyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene-ll-carboxamide bis(trifluoroacetate)
Figure imgf000307_0002
The desired compound was prepared according to the procedure of Example B7, using methyl 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene-11-carboxylate and 4-(aminomethyl)pyridine as the starting materials in 53% yield. LCMS for
C25H22ClN6O (M+H)+: m/z = 457.3. 1H NMR (400 MHz, DMSO-^6 ): δ 9.45 (s, 1 H), 9.39 (s, 1 H), 9.27 (t, 1 H), 8.78 (s, 1 H), 8.76 (s, 1 H), 8.15 (s, 1 H), 7.94 (m, 1 H), 7.88 (m, 1 H), 7.83 (d, 1 H), 7.63 (m, 1 H), 7.59 (m, 1 H), 7.12 (t, 1 H), 6.91 (m, 1 H), 6.84 (m, 1 H), 4.67 (d, 2 H), 2.94 (m, 4 H).
Example B 12 l-{[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]carbonyl}piperidin-3-ol trifluoroacetate
Figure imgf000308_0001
The desired compound was prepared according to the procedure of Example B7, using methyl 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene-11-carboxylate and piperidin-3-ol as the starting materials in 33% yield. LCMS for
C24H25CIN5O2 (MH-H)+: m/z = 450.4. 1H NMR (400 MHz, DMS0-<i6): δ 9.38 (s, 1 H), 9.24 (s, 1 H), 8.13 (s, 1 H), 7.91 (m, 1 H), 7.86 (m, 1 H), 7.12 (m, 2 H), 6.92 (m, 3 H), 6.82 (m, 1 H), 4.14 (m, 0.5 H), 3.84 (m, 0.5 H), 3.10 (m, 1 H), 2.87 (m, 4 H), 1.84 (m, 1 H), 1.64 (m, 1 H), 1.38 (m, 2 H).
Example B 13
6-Chloro-iV-(3-chlorophenyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,
13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene-ll-carboxamide trifluoroacetate
Figure imgf000308_0002
The desired compound was prepared according to the procedure of Example B7, using methyl 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene-11-carboxylate and ra-chloroaniline as the starting materials in 55% yield. LCMS for
C25H20Cl2N5O (M+H)+: m/z = 476.2. 1H NMR (400 MHz, DMSO-^6 ): δ 10.33 (s, 1 H), 9.31 (s, 1 H), 9.27 (s, 1 H), 8.09 (s, 1 H), 7.93 (m, 1 H), 7.89 (m, 1 H), 7.86 (m, 1 H), 7.63 (m, 2 H), 7.55 (m, 1 H), 7.32 (t, 1 H), 7.09 (m, 2 H), 6.87 (m, 1 H), 6.79 (m, 1 H), 2.91 (m, 4 H).
Example B 14
6-Chloro-iV-(2-chlorophenyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9, 13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene-ll-carboxamide trifluoroacetate
Figure imgf000309_0001
The desired compound was prepared according to the procedure of Example B7, using methyl 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene-11-carboxylate and o-chloroaniline as the starting materials in 46% yield. LCMS for
C25H20Cl2N5O (M+H)+: m/z = 476.2. 1H NMR (400 MHz, DMS0-<i6 ): δ 10.02 (s, 1 H), 9.39 (s, 1 H), 9.38 (s, 1 H), 8.14 (s, 1 H), 7.97 (m, 1 H), 7.90 (m, 1 H), 7.70 (m, 1 H), 7.65 (m, 1 H), 7.55 (m, 2 H), 7.37 (m, 1 H), 7.27 (m, 1 H), 7.12 (t, 1 H), 6.92 (m, 1 H), 6.83 (m, 1 H), 2.94 (m, 4 H).
Example B 15
6-Chloro-iV-(4-chlorophenyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,
13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene-ll-carboxamide trifluoroacetate
Figure imgf000309_0002
The desired compound was prepared according to the procedure of Example B7, using methyl 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene-11-carboxylate and p-chloroaniline as the starting materials in 48% yield. LCMS for
C25H20Cl2N5O (M+H)+: m/z = 476.2. 1H NMR (400 MHz, DMSO-^6 ): δ 10.35 (s, 1 H), 9.38 (s, 1 H), 9.34 (s, 1 H), 8.14 (s, 1 H), 7.97 (m, 1 H), 7.89 (m, 1 H), 7.80 (m, 1 H), 7.78 (m, 1 H), 7.65 (m, 1 H), 7.59 (m, 1 H), 7.41 (m, 1 H), 7.39 (m, 1 H), 7.12 (t, 1 H), 6.92 (m, 1 H), 6.84 (m, 1 H), 2.93 (m, 4 H).
Example B 16 iV-(tert-Butyl)-6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-ll-sulfonamide trifluoroacetate
Figure imgf000310_0001
Step A. 3-Bromo-5-nitrobenzenesulfonic acid
Figure imgf000310_0002
The desired compound was prepared according to the procedure of Example B5, step A using 3- nitrobenzenesulfonic acid as the starting material in 61% yield. LCMS for C6H3BrNO5S (M-H)+: m/z =
280.1, 282.1.
Step B. 3-Bromo-N-(tert-butyl)-5-nitrobenzenesulfonamide
Figure imgf000310_0003
A solution of 3-bromo-5-nitrobenzenesulfonic acid (1.86 g, 6.59 mmol) in toluene (37 mL) and phosphorus pentachloride (2.75 g, 13.2 mmol) were heated at 100 0C overnight. The reaction mixture was cooled to 0 0C and treated with tørt-butylamine (1.03 mL, 9.89 mmol) and NN-diisopropylethylamine (5.74 mL, 33.0 mmol). After stirring at 25 0C for 30 min, the reaction mixture was diluted with 1 Ν HCl and extracted with ethyl acetate three times. The combined organic layers were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (2.2 g, 98%). 1H ΝMR (400 MHz, (400 MHz, DMSO-^6 ): δ 8.62 (m, 1 H), 8.56 (m, 1 H), 8.37 (m, 1 H), 8.03 (s, 1 H), 1.32 (s, 9 H).
Step C. 3-[(3-Aminophenyl)ethynyl]-N-(tert-butyl)-5-nitrobenzenesulfonamide
Figure imgf000311_0001
The desired compound was prepared according to the procedure of Example B5, step E using 3- bromo-N-(tert-butyl)-5-nitrobenzenesulfonamide and 3-ethynylaniline as the starting materials in 32% yield. LCMS for Ci8H20N3O4S (M+H)+: m/z = 374.2.
Step D. tert-Butyl [3-({3-[(tert-butylamino)sulfonyl]-5-nitrophenyl}ethynyl)phenyl]carbamate
Figure imgf000311_0002
A solution of 3-[(3-aminophenyl)ethynyl]-N-(tert-butyl)-5-nitrobenzenesulfonamide (180 mg, 0.482 mmol), di-tert-butyldicarbonate (116 mg, 0.53 mmol), ethanol (5 mL) and NN- diisopropylethylamine (84.0 mL, 0.482 mmol) was stirred at 25 0C overnight. The reaction mixture was concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (186 mg, 81%). LCMS calculated for C23H27N3O6SNa (M+Na)+: m/z = 496.1.
Step E. tert-Butyl [3-(2-{3-amino-5-[(tert-butylamino)sulfonyl]phenyl}ethyl)phenyl]carbamate
Figure imgf000311_0003
The desired compound was prepared according to the procedure of Example B5, step F using tert- butyl [3-({3-[(tert-butylamino)sulfonyl]-5-nitrophenyl}ethynyl)phenyl]carbamate as a starting material in 58% yield. LCMS for C23H33N3O4SNa (M+Na)+: m/z = 470.4.
Step F. tert-Butyl [3-(2-{3-[(tert-butylamino)sulfonyl]-5-[(2,5-dichloropyrimidin-4- yl)amino]phenyljethyl)phenyl] carbamate
Figure imgf000312_0001
The desired compound was prepared according to the procedure of Example B5, step G using tert-butyl [3-(2-{3-amino-5-[(tert-butylamino)sulfonyl]phenyl}ethyl)phenyl]carbamate and 2,4,5- trichloropyrimidine as the starting materials in 35% yield. LCMS for C27H33Cl2N5O4SNa (M+Na)+: m/z = 616.2, 618.2.
Step G. N-(tert-Butyl)-6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-ll-sulfonamide trifluoroacetate The desired compound was prepared according to the procedure of Example B5, step H using tert-butyl [3-(2-{3-[(tert-butylamino)sulfonyl]-5-[(2,5-dichloropyrimidin-4- yl)amino]phenyl}ethyl)phenyl]carbamate as a starting material in 53% yield. LCMS for C22H25ClN5O2S
(M+H)+: m/z = 458.3. 1H NMR (400 MHz, DMSO-^6): δ 9.51 (s, 1 H), 9.43 (s, 1 H), 8.16 (s, 1 H), 7.94 (m, 1 H), 7.82 (s, 1 H), 7.58 (m, 1 H), 7.46 (m, 1 H), 7.44 (s, 1 H), 7.11 (t, 1 H), 6.91 (m, 1 H), 6.81 (m, 1 H), 2.95 (m, 2 H), 2.86 (m, 2 H), 1.08 (s, 9 H).
Example B 17
6-Bromo-iV-(^rt-butyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-ll-sulfonamide trifluoroacetate
Figure imgf000312_0002
Example B 18
6-Bromo-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaene-ll-sulfonamide trifluoroacetate
Figure imgf000313_0001
Step A. tert-Butyl [3-(2-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-5-[(tert- butylamino)sulfonyl]phenyl}ethyl)phenyl]carbamate
Figure imgf000313_0002
The desired compound was prepared according to the procedure of Example B5, step G using tert-bvXy\ [3-(2-{3-amino-5-[(tert-butylamino)sulfonyl]phenyl}ethyl)phenyl]carbamate and 5-bromo-2,4- dichloropyrimidine as the starting materials in 44% yield. LCMS for C2VH33BrClN5O4SNa (M+Na)+: m/z
= 660.3, 662.3.
Step B. 6-Bromo-N-(tert-butyl)-2,4,8,22-tetraazatetracyclo[ 14.3.1.1(3,7).1(9,13 )]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-ll-sulfonamide trifluoroacetate
6-Bromo-2, 4, 8, 22-tetraazatetracyclo[14.3.1.1 (3, 7).1 (9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaene-ll-sulfonamide trifluoroacetate The desired compounds were prepared according to the procedure of Example B5, step H using tert-buiyl [3-(2-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-5-[(tert- butylamino)sulfonyl]phenyl}ethyl)phenyl]carbamate as the starting material in 31% (Example B17) and
23% (Example B 18) yield respectively.
Example B 17: LCMS for C22H25BrN5O2S (M+H)+: m/z = 502.2, 504.2. 1H NMR (400 MHz, DMSO-^6): δ 9.45 (s, 1 H), 9.34 (s, 1 H), 8.23 (s, 1 H), 7.89 (s, 1 H), 7.79 (s, 1 H), 7.58 (m, 1 H), 7.46 (s, 1 H), 7.43 (s, 1 H), 7.11 (t, 1 H), 6.89 (m, 1 H), 6.81 (m, 1 H), 2.97 (m, 2 H), 2.89 (m, 2 H), 1.07 (s, 9 H).
Example B18: LCMS for Ci8Hi7BrN5O2S (M+H)+: m/z = 446.2, 448.2. 1H NMR (400 MHz, DMS0-<i6): δ 9.43 (s, 1 H), 9.30 (s, 1 H), 8.22 (s, 1 H), 7.93 (m, 1 H), 7.84 (m, 1 H), 7.60 (m, 1 H), 7.47 (m, 1 H), 7.29 (s, 2 H), 7.11 (t, 1 H), 6.89 (m, 1 H), 6.83 (m, 1 H), 2.96(m, 2 H), 2.91 (m, 2 H). Example B19
6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride
Figure imgf000314_0001
Step A: tert-Butyl (2-iodo-4-nitrophenyl)carbamate
Figure imgf000314_0002
To a solution of 2-iodo-4-nitroaniline (20.0 g, 75.8 mmol) in THF (150 niL) at 0 0C was added sodium hydride (2.18 g, 90.9 mmol). After stirring for 0.5 h, di-tørt-butyldicarbonate (17.4 g, 79.5 mmol) was added to the reaction flask and the reaction mixture was warmed to rt and stirred overnight. LCMS showed 50% conversion of the starting materials (SM). The reaction solution was cooled down to 0 0C and another 0.7 eq NaH was added. After stirring overnight, the reaction solution was diluted with water and ethyl acetate. The organic solution was separated and washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified with silica gel chromatography (20% ethyl acetate/hexanes) to give the desired product as white solid (17.2 g, 62%). LCMS calculated for CiiHi4IN2O4(M+H)+: m/z = 365.0.
Step B: tert-Butyl (3-ethynylphenyl)carbamate
Figure imgf000314_0003
A solution of 3-ethynylaniline (20.2 g, 172 mmol) and di-tørt-butyldicarbonate (41.4 g, 190 mmol) in ethanol (310 ml) was stirred at 25 0C overnight. Then the reaction solution was concentrated. The crude residue was purified by flash column chromatography to yield the desired product (37.5 g, 100%). LCMS calculated for Ci3Hi6NO2(M+H)+: m/z = 218.1. Step C: tert-Butyl [3-({2-[(tert-butoxycarbonyl)amino]-5-nitrophenyl}ethynyl)phenyl]carbamate
Figure imgf000315_0001
A solution of tert-butyl (3-ethynylphenyl)carbamate (12.7 g, 58.5 mmol), tert-butyl (2-iodo-4- nitrophenyl)carbamate (14.2 g, 39.0 mmol), bis(triphenylphosphine)palladium(II) chloride (1.37 g, 1.95 mmol), and copper(I) iodide (371 mg, 1.95 mmol) in THF (200 mL) was treated with NN- diisopropylethylamine (7.47 mL, 42.9 mmol) dropwise and stirred at 20 0C overnight. The reaction mixture was concentrated and diluted with water (200 mL) and ethyl acetate (200 mL). The organic layer was separated, washed with brine, dried with sodium sulfate, filtered, and concentrated to give a yellow/brown solid which was washed with ethyl acetate to give the desired product as light yellow solid (15 g, 85%). LCMS calculated for C24H27N3O6Na(IVLi-Na)+: m/z = 476.2.
Step D: tert-Butyl [3-(2-{5-amino-2-[(tert-butoxycarbonyl)amino]phenyljethyl)phenyl]carbamate
Figure imgf000315_0002
To a solution of tert-butyl [3-({2-[(tert-butoxycarbonyl)amino]-5- nitrophenyl}ethynyl)phenyl]carbamate (15.0 g, 33.1 mmol) in DMF (234 mL) was added 10% Palladium on carbon(13.1 g, 11.2 mmol). The solution was shaked under 55 psi H2 atmosphere for 72 h. The solution was filtered through a pad of celite. The filtrate was concentrated and purified with silica gel chromatography (45% ethyl acetate/hexanes) to give an intermediate as yellow oil. To a solution of the intermediate in methanol (200 mL) was added 10% Palladium on carbon (12 g). The resulting solution was shaked under 55 psi H2 atmosphere overnight. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. The crude product was purified with a short pad of silica gel to give the desire product (11.5 g, 81%). LCMS calculated for C24H33N3O4Na(M-I-Na)+: m/z = 450.2. Step E: tert-Butyl [3-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2,5-dichloropyrimidin-4- yl)amino]phenyl}ethyl)phenyl]carbamate
Figure imgf000316_0001
A solution of tert-butyl [3-(2-{5-amino-2-[(tert- butoxycarbonyl)amino]phenyl}ethyl)phenyl] carbamate (8.15 g, 19.1 mmol) in DMF (19 mL) was treated with potassium carbonate (3.42 g, 24.8 mol) and stirred at 25 0C for 5 minutes. The reaction mixture was treated with 2,4,5-trichloropyrimidine (2.40 mL, 21.0 mmol) dropwise and stirred at 20 0C overnight. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (300 mL). The organic layer was separated and washed with brine (50 mL), dried with sodium sulfate, filtered, and concentrated to give a crude orange oil. The residue was purified with silica gel chromatography to give the desired product (10.9 g, 99.5%). LCMS calculated for C28H33Cl2N5O4Na(M+^)+: m/z = 596.0, 598.0.
Step F: 6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4A9(21),10,12,16,18-nonaen-12-amine dihydrochloride
A solution of tert-butyl [3-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2,5-dichloropyrimidin-4- yl)amino]phenyl}ethyl)phenyl]carbamate (4.70 g, 8.18 mmol) in acetonitrile (750 mL), water (75 mL) and 2-butanol (1.0 mL) was treated with 4.0 M of hydrogen chloride in 1,4-dioxane (7.2 mL, 28.6 mmol) and refluxed for 20 hours. The reaction mixture was concentrated and the tan solid was triturated with dichloromethane and methanol to give the desired product (2.83 g, 84%). LCMS calculated for
Ci8H17ClN5(M+H)+: m/z = 338.1. 1H NMR (400 MHz, DMSO-^6 ): δ 8.37 (s, 1 H), 7.89 (s, 1 H), 7.79 (s, 1 H), 7.59 (m, 1 H), 7.43 (m, 3 H), 7.36 (d, 1 H), 7.17 (m, 2 H), 6.91 (dd, 2 H), 3.08 (d, 4 H).
Example B20 6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate)
Figure imgf000317_0001
Step A: tert-Butyl {5-[(trimethylsilyl)ethynyl]pyridin-3-yl}carbamate
Figure imgf000317_0002
To a solution of tert-butyl (5-bromopyridin-3-yl)carbamate (3.00 g, 11.0 mmol) and THF (30 niL) was added (trimethylsilyl) acetylene (1.60 g, 16.3 mmol), (triphenylphosphine)palladium(II) chloride (0.31 g, 0.44 mmol), copper(I) iodide (84 mg, 0.44 mmol) and triethylamine (1.7 mL, 12 mmol) under nitrogen atmosphere. The mixture was heated at 50 0C overnight. The solvent removed in vacuo. The residue was diluted with EtOAc and water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (2.0 g, 63%). LCMS calculated for Ci5H23N2O2Si(MH-H)+: m/z = 291.1.
Step B: tert-Butyl (5-ethynylpyridin-3-yl)carbamate
Figure imgf000317_0003
This compound was prepared according to the procedure of Example B 5 step D, using tert-butyl {5-[(trimethylsilyl)ethynyl]pyridin-3-yl}carbamate as the starting material in 66% yield. LCMS calculated for CI2HI5N2O2(MH-H)+: m/z = 219.1.
Step C: tert-Butyl [5-({2-[(tert-butoxycarbonyl)amino]-5-nitrophenyl}ethynyl)pyridin-3-yl]carbamate
Figure imgf000317_0004
This compound was prepared according to the procedure of Example B 19 step C, using tert-butyl (5-ethynylpyridin-3-yl)carbamate and tert-butyl (2-iodo-4-nitrophenyl)carbamate as the starting material in 85% yield. LCMS calculated for C23H27N4O6(IVLi-H)+: m/z = 455.1.
Step D: tert-Butyl [5-({5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethynyl)pyridin-3-yl]carbamate
Figure imgf000318_0001
A mixture of tert-butyl [5-({2-[(tert-butoxycarbonyl)armno]-5-nitrophenyl}ethynyl)pyridin-3- yl]carbamate (1.60 g, 3.52 mmol), methanol (37 mL), acetic acid (7.3 mL), water (3.7 mL) and iron (905 mg, 16.2 mmol) was stirred at 60 0C for 3 h. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate and extracted with ethyl acetate once. The combined organic solutions were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.40 g, 94%). LCMS calculated for C23H29N4O4(M-I-H)+: m/z = 425.1.
Step E: tert-Butyl [5 -(2-{5-amino-2-[(tert-butoxycarbonyl)amino]phenyljethyl)pyridin-3-y I] carbamate
Figure imgf000318_0002
To a solution of tert-butyl [5-({5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethynyl)pyridin- 3-yl]carbamate (1.50 g, 3.53 mmol) in methanol (30 mL) was added 10% palladium on carbon (150 mg, 0.141 mmol), and the mixture was hydrogenated under 25 psi of H2 for 2 hours with shaking. The solution was filtered through a pad of celite, and filtrate was concentrated. The residue was purified by flash column chromatography to give the desired product (1.40 g, 92%). LCMS calculated for C23H33N4O4(M+H)+: m/z = 429.1.
Step F: tert-Butyl [5-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2,5-dichloropyrimidin-4- yl)amino]phenyljethyl)pyridin-3-yl] carbamate
Figure imgf000319_0001
This compound was prepared according to the procedure of Example B 19 step E, using tert-butyl [5-(2-{5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)pyridin-3-yl]carbamate and 2,4,5- trichloropyrimidine as the starting materials in 43% yield. LCMS calculated for C2VH33Cl2N6O4(M+!!)"1": m/z = 575.1, 577.1.
Step G: 2-[2-(5-Aminopyridin-3-yl)ethyl]-N(4)-(2,5-dichloropyrimidin-4-yl)benzene-l,4-diamine trihydrochloride
Figure imgf000319_0002
A solution of 4.0 M of hydrogen chloride in 1,4-dioxane (30 mL, 120 mmol), tert-butyl [5-(2-{2- [(tert-butoxycarbonyl)amino]-5-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (860 mg, 1.49 mmol) and methanol (15 mL) was stirred at 25 0C for 1 hour. The solvent was removed in vacuo. The crude residue was dissolved in DCM and triturated with ether to give the desired product (0.57 g, 73%). LCMS calculated for Ci7Hi7Cl2N6(M+H)+: m/z = 375.0, 377.0.
Step H: 6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate)
To a solution of 2-[2-(5-aminopyridin-3-yl)ethyl]-N(4)-(2,5-dichloropyrimidin-4-yl)benzene-l,4- diamine trihydrochloride (450 mg, 0.928 mmol) in 1,4-dioxane (9.0 mL) and DMF (3.0 mL) and N,N- diisopropylethylamine (647 μL, 3.71 mmol). The mixture was stirred at room temperature for 5 minutes. The reaction mixture was treated with tris(dibenzylideneacetone)dipalladium (128 mg, 0.139 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (161 mg, 0.278 mmol) and cesium carbonate (605 mg, 1.86 mmol). The mixture was degassed with N2 and heated in microwave at 160 0C for 30 minutes. The reaction solution was concentrated in vacuo. The residue was dissolved in DMSO, filtered and purified on preparative LCMS to give the desired product (120 mg, 23%). LCMS calculated for
CivHi6ClN6(M+H)+: m/z = 339.1. 1H NMR (400 MHz, DMSO-Cf6 ): δ 9.99 (s, 1 H), 9.29 (s, 1 H), 8.96 (s, 1 H), 8.33 (d, 1 H), 8.30 (d, 1 H), 8.18 (s, 1 H), 7.53 (s, 1 H), 6.91-6.99 (m, 2 H), 2.71-3.02 (m, 4 H).
Example B21 6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen- 11 -amine bis(trifluoroacetate)
Figure imgf000320_0001
Step A: tert-Butyl [6-chloro-2,4,8,22-tetraazatetracydo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]carbamate
Figure imgf000320_0002
To a solution of 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxylic acid (9.2 mg, 25.1 μmol) in tert-butyl alcohol (0.16 niL) was added triethylamine (3.5 μL, 25.1 μmol) and diphenylphosphonic azide (5.4 μL, 25.1 μmol). The resulting mixture was heated at 85 0C overnight. The reaction mixture was diluted with DMSO and purified with preparative LCMS to give the desired product (6 mg, 55%). H NMR (400
MHz, DMSO-<i6 ): δ 9.33 (s, 1 H), 9.22 (s, 1 H), 8.09 (s, 1 H), 7.92 (s, 1 H), 7.31 (m, 2 H), 7.08 (t, 1 H), 7.03 (s, 1 H), 6.88 (dd, 1 H), 6.80 (dd, 1 H), 2.80 (d, 4 H), 1.46 (s, 9 H). LCMS calculated for C23H25ClN5O2(M-FH)+: m/z = 438.2.
Step B: 6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-amine bis(trifluoroacetate)
A solution of tert-butyl [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]carbamate (134 mg, 0.306 mmol), 4.0 M of hydrogen chloride in 1,4-dioxane (229 μL, 918 μmol) and methylene chloride (11 mL) was stirred at 25 0C overnight. The reaction solution was concentrated and the residue was dissolved in methanol and purified with preparative LCMS to yield the desired product (102 mg, 74%). 1H NMR (400 MHz, DMS0-<i6 ): δ 9.40 (s, 1 H), 9.32 (s, 1 H), 8.14 (s, 1 H), 7.89 (m, 1 H), 7.64 (s, 1 H), 7.10 (dd, 1 H), 6.87 (m, 2 H), 6.81 (m, 2 H), 2.87 (m, 4 H). LCMS calculated for Ci8Hi7ClN5(M+H)+: m/z = 338.1.
Example B22
Methyl 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-12-carboxylate trifluoroacetate
Figure imgf000321_0001
Step A: 2-Iodo-4-nitrobenzoic acid
Figure imgf000321_0002
To a solution of 2-amino-4-nitrobenzoic acid (14.5 g, 79.6 mmol) in 2.0 M of sulfuric acid aqueous solution (398 mL, 796 mmol) was added a solution of sodium nitrite (8.24 g, 0.119 mol) in water dropwise at 0 0C. After the addition, the resulting solution was stirred at same temperature for 1 hour, then a solution of potassium iodide (19.8 g, 0.119 mol) in water was added dropwise at 0 0C. The resulting mixture was stirred at rt for 72 hours. The precipitate was filtered and washed by water to give the desired product (19.5 g, 83%). LCMS calculated for C7H5INθ4(M+H)+: m/z = 294.0.
Step B: Methyl 2-iodo-4-nitrobenzoate
Figure imgf000321_0003
A solution of 2-iodo-4-nitrobenzoic acid (9 g, 30.7 mmol), methanol (88 mL) and sulfuric acid (0.82 mL, 15.4 mmol) was heated to reflux overnight. The reaction solution was cooled down to 0 0C for 30 minutes. The solid was filtered to give the desired product (5.90 g, 62%). LCMS calculated for C8H7INO4(M+H)+: m/z = 308.0.
Step C: Methyl 2-({3-[(tert-butoxycarbonyl)amino]phenyl}ethynyl)-4-nitrobenzoate
Figure imgf000322_0001
This compound was prepared according to the procedure of Example B 19 step C, using tert-butyl (3-ethynylphenyl)carbamate and methyl 2-iodo-4-nitrobenzoate as the starting materials in 87% yield. LCMS calculated for C2iH21N2O6(M+H)+: m/z = 397.1.
Step D: Methyl 4-amino-2-(2-{3-[(tert-butoxycarbonyl)amino]phenyljethyl)benzoate
Figure imgf000322_0002
This compound was prepared according to the procedure of Example B 19 step D, using methyl 2- ({3-[(tert-butoxycarbonyl)amino]phenyl}ethynyl)-4-nitrobenzoate as the starting material in 83% yield. LCMS calculated for C2iH27N2O4(M+H)+: m/z = 371.1.
Step E: Methyl 2-(2-{3-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-4-[(2, 5-dichloropyrimidin-4- yl)amino]benzoate
Figure imgf000322_0003
This compound was prepared according to the procedure of Example B 19 step E, using methyl 4- amino-2-(2-{3-[(tert-butoxycarbonyl)amino]phenyl}ethyl)benzoate as the starting material in 29% yield. LCMS calculated for C25H27Cl2N4O4(IVLHr)+: m/z = 517.1.
Step F: Methyl 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-12-carboxylate trifluoroacetate
This compound was prepared according to the procedure of Example B 19 step F, using methyl 2- (2-{3-[(ter^butoxycarbonyl)amino]phenyl}ethyl)-4-[(2,5-dichloropyrimidin-4-yl)amino]benzoate as the starting material in 62% yield. LCMS calculated for C20Hi8ClN4O2(M+H)+: m/z = 381.1. 1H NMR (400 MHz, DMSOd6 ): δ 9.49 (m, 2 H), 8.18 (s, 1 H), 8.03 (m, 1 H), 7.90 (m, 1 H), 7.83 (d, 1 H),, 7.17 (dd, 1 H), 7.08 (dd, 1 H), 6.97 (m, 1 H), 6.77 (m, 1 H), 3.82 (s, 3 H), 3.22 (m, 2 H), 2.93 (m, 2 H).
Example B23
[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]methanol trifluoroacetate
Figure imgf000323_0001
To a solution of methyl 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-12-carboxylate (1.06 g, 2.78 mmol) in dichloromethane (DCM, 44 mL) was added 1.0 M of diisobutylaluminum hydride in methylene chloride (12.5 mL, 12.5 mmol) at 0 0C. The resulting solution was allowed to warm up to rt for 2 hours. The reaction was quenched with 1 N HCl and diluted with ethyl acetate. The organic solution was dried over sodium sulfate and concentrated; and the residue was dissolve in DMSO/methanol and purified with preparative
LCMS to give the desired product (629 mg, 48%). 1H NMR (400 MHz, DMSO-^6 ): δ 9.63 (s, 1 H), 9.49 (s, 1 H), 8.17 (s, 1 H), 7.97 (m, 1 H), 7.69 (d, 1 H), 7.30 (d, 1 H), 7.10 (dd, 1 H), 7.04 (dd, 1 H), 6.87 (m, 1 H), 6.84 (m, 1 H), 4.54 (s, 2 H), 2.90 (m, 4 H). LCMS calculated for Ci9Hi8ClN4O(M+H)+: m/z = 353.2.
Example B24
[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-ll-yl]methanol trifluoroacetate
Figure imgf000324_0001
The desired compound was prepared according to the procedure of Example B23, using methyl 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene-11 -carboxylate as the starting material in 60% yield. H NMR (400 MHz, DMSO-^6 ): δ 9.50 (s, 1 H), 9.40 (s, 1 H), 8.14 (s, 1 H), 7.88 (m, 1 H), 7.60 (m, 1 H), 7.10 (dd, 1 H), 7.04 (m, 1 H), 6.95 (m, 1 H), 6.87 (m, 2 H), 4.44 (s, 2 H), 2.87 (m, 4 H). LCMS calculated for Ci9Hi8ClN4O(M+H)+: m/z = 353.2.
Example B25 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[(3S)-pyrrolidin-3- yl]urea trihydrochloride
Figure imgf000324_0002
Step A: tert-Butyl {iSyi-liilβ-chloro-lAA^ll-pentaazatetracyclolU.i.l.lii, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]aminojcarbonyl)amino]pyrrolidine- 1 -carboxylate
Figure imgf000325_0001
To a solution of 20% phosgene in toluene(0.49 niL, 0.93 mmol) was added a solution of tert- butyl (3S)-3-aminopyrrolidine-l-carboxylate (38 mg, 0.20 mmol) and triethylamine (102 μL, 0.734 mmol) in THF (0.5 mL). The resulting solution was stirred for 2 hours then concentrated. To the isolated solids was added DCM (0.75 mL) followed by 6-chloro-2 ,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine bis(trifluoroacetate) (70 mg, 0.1 mmol) and triethylamine (73 μL, 0.52 mmol). The resulting mixture was stirred at room temperature overnight and concentrated. The residue was purified by flash column chromatography to yield the desired product (34 mg, 50%). LCMS calculated for C27H32C1N8O3(M+H)+: m/z = 551.1.
Step B: N-[6-Chloro-2,4,8,18,22-pentaazatetracydo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-pyrrolidin-3- yljurea dihydrochloride To the product from the previous step was added a solution of hydrogen chloride in 1,4-dioxane
(4.0 M, 0.8 mL, 3 mmol). The mixture was stirred for 2 hours then the solvent evaporated and the solids dried under vacuum to give the desired product (33 mg, 46%). LCMS calculated for C22H24C1N8O(M+H)+: m/z = 451.0.
Example B26 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide trifluoroacetate
Figure imgf000326_0001
6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride (20 mg, 0.06 mmol) in DCM (0.3 niL) was treated with triethylamine (24.8 μL, 0.178 mmol) and acetyl chloride (5.1 μL, 0.071 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the crude residue was dissolved in a mixture of acetonitrile and methanol and purified by preparative LCMS to give the desired product (10.4 mg, 35%). LCMS calculated for C20H19ClN5O (M+H)+: m/z = 380.2.
Example B27 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]cyclopropanecarboxamide trifluoroacetate
Figure imgf000326_0002
The desired compound was prepared according to the procedure of Example B26 , using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and cyclopropanecarbonyl chloride as the starting materials in 30% yield. LCMS for C22H2IClN5O (M+H)+: m/z = 406.3.
Example B28 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-methoxyacetamide trifluoroacetate
Figure imgf000327_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and methoxyacetyl chloride as the starting materials in 40% yield. LCMS for C2IH21ClN5O2 (M+H)+: m/z = 410.3. 1H NMR (400 MHz, CDCl3): δ 11.84 (s, 1 H), 8.42 (s, 1 H), 8.08 (d, 1 H), 7.85 (m, 3 H), 7.27 (m, 2 H), 7.11 (d, 1 H), 7.01 (m, 2 H), 4.10 (s, 2 H), 3.79 (s, 3 H), 2.92 (t, 4 H).
Example B29 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzamide trifluoroacetate
Figure imgf000327_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and benzoyl chloride as the starting materials in 45% yield. LCMS for C25H2IClN5O (M+H)+: m/z = 442.0. 1H NMR (400 MHz, DMSO-^6 ): δ 9.91 (s, 1 H), 9.38 (s, 1 H), 9.25 (s, 1 H), 8.12 (s, 1 H), 8.08 (s, 1 H), 7.98 (d, 2 H), 7.83 (s, 1 H), 7.57 (m, 3 H), 7.21 (d, 1 H), 7.09 (m, 2 H), 6.86 (d, 1 H), 6.75 (d, 1 H), 2.86 (dd, 4 H).
Example B30 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]nicotinamide bis(trifluoroacetate)
Figure imgf000328_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and nicotinoyl chloride hydrochloride as the starting materials in 40% yield.
LCMS for C24H20ClN6O (M+H)+: m/z = 443.0. 1H NMR (400 MHz, DMS0-<i6 ): δ 10.18 (s, 1 H), 9.76 (s, 1 H), 9.69 (s, 1 H), 9.19 (s, 1 H), 8.81 (d, 1 H), 8.41 (d, 1 H), 8.21 (s, 1 H), 7.97 (s, 1 H), 7.85 (s, 1 H), 7.66 (m, 1 H), 7.25 (d, 1 H), 7.10 (m, 2 H), 6.88 (d, 1 H), 6.81 (d, 1 H), 2.92 (dd, 4 H).
Example B31 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-methyl-lH-pyrazole-3-carboxamide trifluoroacetate
Figure imgf000328_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-methyl-lH-pyrazole-3-carbonyl chloride as the starting materials in 27% yield. LCMS for C23H2iClN7O (M+H)+: m/z = 446.3. 1H NMR (400 MHz, DMSOd6 ): δ 9.59 (m, 3 H), 8.19 (s, 1 H), 7.99 (s, 1 H), 7.83 (s, 1 H), 7.79 (s, 1 H), 7.36 (d, 1 H), 7.08 (m, 2 H), 6.87 (d, 1 H), 6.79 (d, 1 H), 6.75 (s, 1 H), 3.97 (s, 3 H), 2.90 (dd, 4 H). Example B32 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-phenylacetamide trifluoroacetate
Figure imgf000329_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and benzeneacetyl chloride as the starting materials in 11% yield. LCMS for C26H23ClN5O (M+H)+: m/z = 456.3.
Example B33 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-furamide trifluoroacetate
Figure imgf000329_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 2-furancarbonyl chloride as the starting materials in 41% yield. LCMS for C23H19ClN5O2 (M+H)+: m/z = 432.0.
Example B34 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]thiophene-2-carboxamide trifluoroacetate
Figure imgf000330_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 2-thiophenecarbonyl chloride as the starting materials in 41% yield. LCMS for C23H19ClN5OS (M+H)+: m/z = 448.0.
Example B35 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-methylbenzamide trifluoroacetate
Figure imgf000330_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 2-methylbenzoyl chloride as the starting materials in 36% yield. LCMS for C26H23C1N5O(M+H)+: m/z = 456.1.
Example B36 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-methoxybenzamide trifluoroacetate
Figure imgf000331_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 2-methoxybenzoyl chloride as the starting materials in 38% yield. LCMS for C26H23ClN5O2(IVLHr)+ : m/z = 472.3.
Example B37 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyridine-2-carboxamide bis(trifluoroacetate)
Figure imgf000331_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and pyridine -2-carbonyl chloride hydrochloride as the starting materials in 24% yield. LCMS for C24H20ClN6O(M+H)+: m/z = 443.3.
Example B38 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-fluorobenzamide trifluoroacetate
Figure imgf000332_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 2-fluorobenzoyl chloride as the starting materials in 24% yield. LCMS for C25H20ClFN5O(IVLHr)+: m/z = 460.0.
Example B39
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]isonicotinamide bis(trifluoroacetate)
Figure imgf000332_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and isonicotinoyl chloride hydrochloride as the starting materials in 37% yield. LCMS for C24H2oClN60(M+H)+: m/z = 443.3.
Example B40 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3,5-dimethylisoxazole-4-carboxamide trifluoroacetate
Figure imgf000333_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 3,5-dimethylisoxazole-4-carbonyl chloride as the starting materials in 34% yield. LCMS for C24H22ClN6O2(IVLHr)+: m/z = 461.3.
Example B41
2-Chloro-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzamide hydrochloride
Figure imgf000333_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 2-chlorobenzoyl chloride as the starting materials in 24% yield. LCMS for C25H2oCl2N50(M+H)+: m/z = 476.2.
Example B42
3-Chloro-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzamide hydrochloride
Figure imgf000334_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 3-chlorobenzoyl chloride as the starting materials in 60% yield. LCMS for C25H20Cl2N5O(IVLHr)+: m/z = 476.3.
Example B43
4-Chloro-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzamide hydrochloride
Figure imgf000334_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 4-chlorobenzoyl chloride as the starting materials in 66% yield. LCMS for C25H20Cl2N5O(M+H)+: m/z = 476.2.
Example B44 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrazine-2-carboxamide bis(trifluoroacetate)
Figure imgf000335_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and pyrazine-2-carbonyl chloride as the starting materials in 23% yield. LCMS for C23Hi9CiN7CK]VLi-H)+: m/z = 444.3.
Example B45
4-(Acetylamino)-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,
13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzamide trifluoroacetate
Figure imgf000335_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 4-acetamidobenzoyl chloride as the starting materials in 25% yield. LCMS for C27H24ClN6O2(M-FH)+: m/z = 499.3.
Example B46 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-methylbenzamide trifluoroacetate
Figure imgf000336_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 3-methylbenzoyl chloride as the starting materials in 38% yield. LCMS for C26H23ClN5O(IVLHr)+: m/z = 456.0.
Example B47 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-methylbenzamide trifluoroacetate
Figure imgf000336_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 4-methylbenzoyl chloride as the starting materials in 39% yield. LCMS for C26H23C1N5O(M+H)+: m/z = 456.2.
Example B48 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-fluorobenzamide trifluoroacetate
Figure imgf000337_0001
The desired compound was prepared according to the procedure of Example B26 7, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 3-fluorolbenzoyl chloride as the starting materials in 32% yield. LCMS for C25H20ClFN5O(IVLHr)+: m/z = 460.3.
Example B49 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-fluorobenzamide trifluoroacetate
Figure imgf000337_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 4-fluorolbenzoyl chloride as the starting materials in 36% yield. LCMS for
C25H20ClFN5O(M+H)+: m/z = 460.3. 1H NMR (400 MHz, DMSO-^6 ): δ 9.95 (s, 1 H), 9.49 (s, 1 H), 9.40 (s, 1 H), 8.17 (s, 1 H), 8.06 (m, 3 H), 7.83 (s, 1 H), 7.38 (t, 2 H), 7.21 (d, 1 H), 7.09 (m, 2 H), 6.86 (d, 1 H), 6.78 (d, 1 H), 2.86 (dd, 4 H).
Example B50 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-methyl-lH-pyrrole-2-carboxamide trifluoroacetate
Figure imgf000338_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 1 -methyl- lH-pyrrole-2-carbonyl chloride as the starting materials in 29% yield. LCMS for C24H22ClN6O(M-I-H)+: m/z = 445.1.
Example B51 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-methyl-lH-imidazole-5-carboxamide bis(trifluoroacetate)
Figure imgf000338_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-methyl-lH-imidazole-5-carbonyl chloride as the starting materials in 26% yield. LCMS for C23H21C1N7O(M+H)+: m/z = 446.3.
Example B52 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l,3-thiazole-2-carboxamide trifluoroacetate
Figure imgf000339_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l,3-thiazole-2-carbonyl chloride as the starting materials in 31% yield. LCMS for C22Hi8CrN6OS(IVLi-H)+: m/z = 449.0. 1H NMR (400 MHz, DMS0-<i6 ): δ 10.30 (s, 1 H), 9.45 (s, 1 H), 9.36 (s, 1 H), 8.14 (m, 3 H), 8.02 (s, 1 H), 7.83 (s, 1 H), 7.37 (d, 1 H), 7.09 (m, 2 H), 6.86 (d, 1 H), 6.77 (d, 1 H), 2.86 (dd, 4 H).
Example B53 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]isoxazole-5-carboxamide trifluoroacetate
Figure imgf000339_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and isoxazole-5-carbonyl chloride as the starting materials in 40% yield. LCMS for C22Hi8ClN6O2(M-FH)+: m/z = 433.0.
Example B54 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]propanamide trifluoroacetate
Figure imgf000340_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and propanoyl chloride as the starting materials in 24% yield. LCMS for C2iH21ClN5O(M+H)+: m/z = 394.3.
Example B55 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-methylpropanamide trifluoroacetate
Figure imgf000340_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and isobutyryl chloride as the starting materials in 24% yield. LCMS for C22H23C1N5O(M+H)+: m/z = 408.3.
Example B56 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]butanamide trifluoroacetate
Figure imgf000341_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and butylryl chloride as the starting materials in 26% yield. LCMS for C22H23ClN5O(IVLHr)+: m/z = 408.3.
Example B57 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]cyclobutanecarboxamide hydrochloride
Figure imgf000341_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and cyclobutanecarboxylic acid chloride as the starting materials in 40% yield. LCMS for C23H23C1N5O(M+H)+: m/z = 420.3.
Example B58 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2,2-dimethylpropanamide trifluoroacetate
Figure imgf000342_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 2,2-dimethylpropanoyl chloride as the starting materials in 14% yield. LCMS for C23H25CiN5O(IVLi-H)+: m/z = 422.3.
Example B59 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-furamide trifluoroacetate
Figure imgf000342_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 3-furoyl chloride as the starting materials in 22% yield. LCMS for C23H19C1N5O2(M+H)+: m/z = 432.3.
Example B60 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]cyclopentanecarboxamide trifluoroacetate
Figure imgf000343_0001
The desired compound was prepared according to the procedure of Example B26 , using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and cyclopentanecarbonyl chloride as the starting materials in 22% yield. LCMS for C24H25C1N5O(M+H)+: m/z = 434.3.
Example B61 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-methylbutanamide trifluoroacetate
Figure imgf000343_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and DL-2-methylbutrylchloride as the starting materials in 27% yield. LCMS for
C23H25C1N5O(M+H)+: m/z = 422.3. 1H NMR (400 MHz, DMSOd6 ): δ 9.37 (s, 1 H), 9.29 (s, 1 H), 9.22 (s, 1 H), 8.10 (s, 1 H), 8.01 (s, 1 H), 7.75 (s, 1 H), 7.19 (d, 1 H), 7.05 (m, 2 H), 6.86 (d, 1 H), 6.75 (d, 1 H), 2.82 (dd, 4 H), 2.16 (s, 1 H), 1.61 (m, 1 H), 1.40 (m, 1 H), 1.12 (d, 3 H), 0.91 (t, 3 H).
Example B62 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]thiophene-3-carboxamide trifluoroacetate
Figure imgf000344_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and thiophene-3-carbonyl chloride as the starting materials in 21% yield. LCMS for C23Hi9CrN5OS(IVLi-H)+: m/z = 448.3.
Example B63 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]cyclohexanecarboxamide trifluoroacetate
Figure imgf000344_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and cyclohexanecarbonyl chloride as the starting materials in 20% yield. LCMS for C25H27C1N5O(M+H)+: m/z = 448.3.
Example B64 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-cyanobenzamide trifluoroacetate
Figure imgf000345_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 4-cyanobenzoyl chloride as the starting materials in 7% yield. LCMS for C26H20ClN6O(IVLHr)+: m/z = 467.3.
Example B65 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-cyanobenzamide trifluoroacetate
Figure imgf000345_0002
The desired compound was prepared according to the procedure of Example B26 7, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 3-cyanobenzoyl chloride as the starting materials in 8% yield. LCMS for C26H20ClN6O(M+H)+: m/z = 467.4.
Example B66 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-methoxybenzamide trifluoroacetate
Figure imgf000346_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 3-methoxybenzoyl chloride as the starting materials in 14% yield. LCMS for C26H23CIN5O2(MH-H)+: m/z = 472.2.
Example B67 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-methoxybenzamide trifluoroacetate
Figure imgf000346_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 4-methoxybenzoyl chloride as the starting materials in 10% yield. LCMS for
C26H23CIN5O2(MH-H)+: m/z = 472.3.
Example B68 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-5-methylisoxazole-3-carboxamide trifluoroacetate
Figure imgf000347_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 21% yield. LCMS for C23H20ClN6O2(IVLHr)+: m/z = 447.0.
Example B69
6-Chloro-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]nicotinamide bis(trifluoroacetate)
Figure imgf000347_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 6-chloronicotinoyl chloride as the starting materials in 19% yield. LCMS for C24H19C12N6O(M+H)+: m/z = 476.9, 478.9.
Example B70
2-Chloro-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]nicotinamide bis(trifluoroacetate)
Figure imgf000348_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 2-chloronicotinoyl chloride as the starting materials in 12% yield. LCMS for C24HI9CI2N6CK]VLI-H)+: m/z = 477.2, 479.2.
Example B71 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l,3-benzodioxole-5-carboxamide trifluoroacetate
Figure imgf000348_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l,3-benzodioxole-5-carbonyl chloride as the starting materials in 7% yield. LCMS for C26H21ClN5O3(M-I-H)+: m/z = 486.2.
Example B72 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]quinoxaline-2-carboxamide bis(trifluoroacetate)
Figure imgf000349_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and quinoxaline-2-carbonyl chloride as the starting materials in 14% yield. LCMS for C27H21C1N7O(M+H)+: m/z = 494.3.
Example B73
4-tert-Butyl-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,
13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzamide trifluoroacetate
Figure imgf000349_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 4-(l,l-dimethylethyl)-benzoyl chloride as the starting materials in 30% yield. LCMS for C29H29C1N5O(M+H)+: m/z = 498.4.
Example B74 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l,3-benzothiazole-2-carboxamide trifluoroacetate
Figure imgf000350_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l,3-benzothiazole-2-carbonyl chloride as the starting materials in 20% yield. LCMS for C26H2oClN6OS(M+H)+: m/z = 499.2.
Example B75 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(trifluoromethyl)benzamide trifluoroacetate
Figure imgf000350_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 4-(trifluoromethyl)benzoyl chloride as the starting materials in 22% yield. LCMS for C26H2oClF3N5θ(M+H)+: m/z = 510.0. Example B76 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-(trifluoromethyl)benzamide trifluoroacetate
Figure imgf000351_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 3-(trifluoromethyl)benzoyl chloride as the starting materials in 24% yield. LCMS for C26H20ClF3N5O(IVLHr)+: m/z = 510.0.
Example B77 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-6-(trifluoromethyl)nicotinamide bis(trifluoroacetate)
Figure imgf000351_0002
The desired compound was prepared according to the procedure of Example B26 , using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 6-(trifluoromethyl)nicotinoyl chloride as the starting materials in 18% yield. LCMS for C25Hi9ClF3N6θ(M+H)+: m/z = 511.0. Example B78 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-methyl-l,3-oxazole-5-carboxamide trifluoroacetate
Figure imgf000352_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 4-methyl-l,3-oxazole-5-carbonyl chloride as the starting materials in 24% yield. LCMS for C23H20ClN6O2(IVLHr)+: m/z = 447.0.
Example B79 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-benzofuran-5-carboxamide trifluoroacetate
Figure imgf000352_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-benzofuran-5-carbonyl chloride as the starting materials in 13% yield. LCMS for C27H21C1N5O2(M+H)+: m/z = 482.2.
Example B80 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrazolo[l,5-a]pyridine-3-carboxamide bis(trifluoroacetate)
Figure imgf000353_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and pyrazolo[l,5-a]pyridine-3-carbonyl chloride as the starting materials in 17% yield. LCMS for C26H2ICiN7CK]VLi-H)+: m/z = 482.0.
Example B81 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-l-carboxamide trifluoroacetate
Figure imgf000353_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 1-pyrrolidinecarbonyl chloride as the starting materials in 20% yield. LCMS for C23H24C1N6O(M+H)+: m/z = 435.0.
Example B82 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(dimethylamino)benzamide bis(trifluoroacetate)
Figure imgf000354_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 4-(dimethylamino)benzoyl chloride as the starting materials in 8% yield. LCMS for C27H26C1N6O(M+H)+: m/z = 485.0.
Example B83 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-phenylurea trifluoroacetate
Figure imgf000354_0002
A solution of 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride (20 mg, 0.049 mmol) in DCM (0.3 mL) was treated with triethylamine (20.4 μL, 0.146 mmol) and phenyl isocyanate (7.9 μL, 0.073 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the crude residue was dissolved in a mixture of acetonitrile/methanol and purified by preparative LCMS to give the desired product (6.0 mg, 21%). LCMS calculated for C25H22ClN6O (M+H)+: m/z = 457.3. 1H NMR (400 MHz, DMS0-<i6 ): δ 9.54 (s, 1 H), 9.44 (s, 1 H), 9.04 (s, 1 H), 8.17 (s, 1 H), 8.00 (d, 2 H), 7.69 (m, 2 H), 7.45 (t, 2 H), 7.25 (t, 2 H), 7.09 (t, 1 H), 7.00 (d, 1 H), 6.95 (t, 1 H), 6.84 (m, 2 H), 2.92 (m, 4 H). Example B84 iV-(2-Chlorophenyl)-iV'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea trifluoroacetate
Figure imgf000355_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-chloro-2-isocyanatobenzene as the starting materials in 11% yield. LCMS for C25H2ICl2N6O(IVLHr)+: m/z = 491.2.
Example B85 iV-(3-Chlorophenyl)-iV'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea trifluoroacetate
Figure imgf000355_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-chloro-3-isocyanatobenzene as the starting materials in 22% yield. LCMS for C25H21C12N6O(M+H)+: m/z = 491.0.
Example B86 iV-(4-Chlorophenyl)-iV'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea trifluoroacetate
Figure imgf000356_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-chloro-4-isocyanatobenzene as the starting materials in 29% yield. LCMS for C25H21Cl2N6O(IVLHr)+: m/z = 491.0.
Example B87 iV-(tert-Butyl)-iV'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,
13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea trifluoroacetate
Figure imgf000356_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 2-methyl-2-isocyanatopropane as the starting materials in 7% yield. LCMS for C23H26C1N6O(M+H)+: m/z = 437.3.
Example B88 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-cyclopentylurea trifluoroacetate
Figure imgf000357_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and isocyanatocyclopentane as the starting materials in 31 % yield. LCMS for C24H26C1N6O(M+H)+: m/z = 449.2.
Example B89 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-3-thienylurea trifluoroacetate
Figure imgf000357_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 3-isocyanatothiophene as the starting materials in 7% yield. LCMS for C23H2oClN6OS(M+H)+: m/z = 463.4.
Example B90 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(3-methylphenyl)urea trifluoroacetate
Figure imgf000358_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 3-methyl-l-isocyanatobenzene as the starting materials in 17% yield. LCMS for C26H24ClN6O(IVLHr)+: m/z = 471.3.
Example B91 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-methylphenyl)urea trifluoroacetate
Figure imgf000358_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 2-methyl-l-isocyanatobenzene as the starting materials in 14% yield. LCMS for C26H24C1N6O(M+H)+: m/z = 471.3.
Example B92 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(4-methylphenyl)urea trifluoroacetate
Figure imgf000359_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 4-methyl-l-isocyanatobenzene as the starting materials in 21% yield. LCMS for C26H24ClN6O(IVLHr)+: m/z = 471.3.
Example B93 iV-benzyl-iV'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea trifluoroacetate
Figure imgf000359_0002
The desired compound was prepared according to the procedure of Example B83 3, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and benzyl isocyanate as the starting materials in 17% yield. LCMS for C26H24C1N6O(M+H)+: m/z = 471.3.
Example B94 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(3,5-dimethylisoxazol-4-yl)urea trifluoroacetate
Figure imgf000360_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 4-isocyanato-3,5-dimethylisoxazole as the starting materials in 18% yield. LCMS for C24H23ClN7O2(IVLHr)+: m/z = 476.4.
Example B95 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(3-cyanophenyl)urea trifluoroacetate
Figure imgf000360_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 3-isocyanatobenzonitrile as the starting materials in 20% yield. LCMS for C26H21C1N7O(M+H)+: m/z = 482.3.
Example B96 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(4-cyanophenyl)urea trifluoroacetate
Figure imgf000361_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 4-isocyanatobenzonitrile as the starting materials in 19% yield. LCMS for C26H21C1N7O(M+H)+: m/z = 482.3.
Example B97 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-ethylphenyl)urea trifluoroacetate
Figure imgf000361_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-ethyl-2-isocyanatobenzene as the starting materials in 22% yield. LCMS for C27H26C1N6O(M+H)+: m/z = 485.3.
Example B98 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(4-ethylphenyl)urea trifluoroacetate
Figure imgf000362_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 4-ethylphenyl isocyanate as the starting materials in 20% yield. LCMS for C27H26ClN6O(IVLHr)+: m/z = 485.3.
Example B99 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(3-ethylphenyl)urea trifluoroacetate
Figure imgf000362_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 3-ethylphenyl isocyanate as the starting materials in 22% yield. LCMS for C27H26C1N6O(M+H)+: m/z = 485.3.
Example BlOO iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(3-methoxyphenyl)urea trifluoroacetate
Figure imgf000363_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-isocyanato-3-methoxybenzene as the starting materials in 17% yield. LCMS for C26H24ClN6O2(IVLHr)+: m/z = 487.3.
Example BlOl iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(4-methoxyphenyl)urea trifluoroacetate
Figure imgf000363_0002
The desired compound was prepared according to the procedure of Example B83 3, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and l-isocyanato-4-methoxybenzene as the starting materials in 18% yield. LCMS for C26H24C1N6O2(M+H)+: m/z = 487.3.
Example B 102 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-methoxyphenyl)urea trifluoroacetate
Figure imgf000364_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-isocyanato-2-methoxybenzene as the starting materials in 19% yield. LCMS for C26H24ClN6O2(IVLHr)+: m/z = 487.0.
Example B 103 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2,3-dihydro-lH-inden-5-yl)urea trifluoroacetate
Figure imgf000364_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 5-isocyanatoindane as the starting materials in 16% yield. LCMS for C28H26C1N6O(M+H)+: m/z = 497.1.
Example B 104 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-isopropylphenyl)urea trifluoroacetate
Figure imgf000365_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-isocyanato-2-isopropylbenzene as the starting materials in 22% yield. LCMS for C28H28C1N6O(M+H)+: m/z = 499.1.
Example B 105 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-propylphenyl)urea trifluoroacetate
Figure imgf000365_0002
The desired compound was prepared according to the procedure of Example B83 I, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and l-isocyanato-2-propylbenzene as the starting materials in 27% yield. LCMS for C28H28C1N6O(M+H)+: m/z = 499.0.
Example B 106 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-ethoxyphenyl)urea trifluoroacetate
Figure imgf000366_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-ethoxy-2-isocyanatobenzene as the starting materials in 22% yield. LCMS for C27H26CiN6O2(IVLi-H)+: m/z = 501.0.
Example B 107 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[2-(methylthio)phenyl]urea trifluoroacetate
Figure imgf000366_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-isocyanato-2-(methythio)benzene as the starting materials in 20% yield. LCMS for C26H24C1N6OS(M+H)+: m/z = 503.0.
Example B 108 iV-[2-(Chloromethyl)phenyl]-iV'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea trifluoroacetate
Figure imgf000367_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-(chloromethyl)-2-isocyanatobenzene as the starting materials in 6% yield. LCMS for C26H23Cl2N6O(IVLHr)+: m/z = 505.3, 507.3.
Example B 109 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(5,6,7,8-tetrahydronaphthalen-l-yl)urea trifluoroacetate
Figure imgf000367_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 5-isocyanato-l,2,3,4-tetrahydronaphthalene as the starting materials in 4% yield. LCMS for C29H28C1N6O(M+H)+: m/z = 511.3.
Example BIlO iV-(2-tert-Butylphenyl)-iV'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea trifluoroacetate
Figure imgf000368_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-tert-butyl-2-isocyanatobenzene as the starting materials in 28% yield. LCMS for C29H30ClN6O(IVLHr)+: m/z = 513.3.
Example Bill iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[2-(trifluoromethyl)phenyl]urea trifluoroacetate
Figure imgf000368_0002
The desired compound was prepared according to the procedure of Example B83 I, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and l-isocyanato-2-(trifluoromethyl)benzene as the starting materials in 16% yield. LCMS for C26H2iClF3N6O(M+H)+: m/z = 525.3.
Example B 112 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[3-(trifluoromethyl)phenyl]urea trifluoroacetate
Figure imgf000369_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-isocyanato-3-(trifluoromethyl)benzene as the starting materials in 21% yield. LCMS for C26H21CIF3N6O(IVLI-H)+: m/z = 525.0.
Example B 113 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2,6-dichlorophenyl)urea trifluoroacetate
Figure imgf000369_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l,3-dichloro-2-isocyanatobenzene as the starting materials in 21% yield.
LCMS for C25H20Cl3N6O(M-FH)+: m/z = 525.0, 527.0.
Example B 114 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-methylurea trifluoroacetate
Figure imgf000370_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and methyl isocyanate as the starting materials in 29% yield. LCMS for C2oH2oClN60(M+H)+: m/z = 395.0.
Example B 115 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-ethylurea trifluoroacetate
Figure imgf000370_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and ethyl isocyanate as the starting materials in 23% yield. LCMS for C2iH22ClN6O(M+H)+: m/z = 409.0.
Example B 116 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-isopropylurea trifluoroacetate
Figure imgf000371_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 2-isocyanatopropane as the starting materials in 24% yield. LCMS for C22H24CiN6O(IVLi-H)+: m/z = 423.4.
Example B 117 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-furylmethyl)urea trifluoroacetate
Figure imgf000371_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 2-(isocyanatomethyl)furan as the starting materials in 33% yield. LCMS for
C24H22C1N6O2(M+H)+: m/z = 461.2. 1H NMR (400 MHz, DMSO-^6 ): δ 9.50 (s, 1 H), 9.38 (s, 1 H), 8.12 (s, 1 H), 7.99 (s, 1 H), 7.79 (s, 1 H), 7.65 (m, 3 H), 7.09 (t, 1 H), 6.96 (m, 2 H), 6.88 (d, 1 H), 6.79 (d, 1 H), 6.40 (d, 1 H), 6.27 (d, 1 H), 4.29 (d, 2 H), 2.86 (m, 4 H).
Example B 118 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-methyl-3-furyl)urea trifluoroacetate
Figure imgf000372_0001
The desired compound was prepared according to the procedure of Example B83, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 3-isocyanato-2-methylfuran as the starting materials in 24% yield. LCMS for C24H22CIN6O2(IVLI-H)+: m/z = 461.3.
Example B119 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-cyclohexylurea trifluoroacetate
Figure imgf000372_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and cyclohexylisocyanate as the starting materials in 35% yield. LCMS for C25H28C1N6O(M+H)+: m/z = 463.4.
Example B 120 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(4-methyl-2-thienyl)urea trifluoroacetate
Figure imgf000373_0001
The desired compound was prepared according to the procedure of Example B83 3, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 2-isocyanato-4-methylthiophene as the starting materials in 30% yield. LCMS for C24H22ClN6OS(IVLHr)+: m/z = 477.3.
Example B 121 iV-(6-Chloropyridin-3-yl)-iV'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea bis(trifluoroacetate)
Figure imgf000373_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 2-chloro-5-isocyanatopyridine as the starting materials in 15% yield. LCMS for C24H20Cl2N7O(M+H)+: m/z = 492.3, 494.3.
Example B 122 iV-(2-Chloro-6-methylphenyl)-iV'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea trifluoroacetate
Figure imgf000374_0001
The desired compound was prepared according to the procedure of Example B83 using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-chloro-2-isocyanato-3-methylbenzene as the starting materials in 24% yield. LCMS for C26H23Cl2N6O(IVLHr)+: m/z = 505.3, 507.3.
Example B 123 iV-(5-Chloro-2-methylphenyl)-iV'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea trifluoroacetate
Figure imgf000374_0002
The desired compound was prepared according to the procedure of Example B83 using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 4-chloro-2-isocyanato-l-methylbenzene as the starting materials in 9% yield. LCMS for C26H23C12N6O(M+H)+: m/z = 505.2, 507.2.
Example B 124 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-l-naphthylurea trifluoroacetate
Figure imgf000375_0001
The desired compound was prepared according to the procedure of Example B83 using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 1-isocyanato-naphthalene as the starting materials in 14% yield. LCMS for C29H24CIN6O(MH-H)+: m/z = 507.2.
Example B 125 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(l-methyl-lH-indol-4-yl)urea trifluoroacetate
Figure imgf000375_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 4-isocyanato-l -methyl- lH-indole as the starting materials in 14% yield. LCMS for C28H25ClN7O(M-I-H)+: m/z = 510.2.
Example B 126 iV-(2-sec-Butylphenyl)-iV'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea trifluoroacetate
Figure imgf000376_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-seobutyl-2-isocyanatobenzene as the starting materials in 11% yield. LCMS for C29H30CIN6CK]VLI-H)+: m/z = 513.3.
Example B 127 iV-l-Adamantyl-iV'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,
13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea trifluoroacetate
Figure imgf000376_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 1-isocyanatoadamantane as the starting materials in 16% yield. LCMS for C29H32ClN6O(M-FH)+: m/z = 515.3.
Example B 128 2 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[2-(difluoromethoxy)phenyl]urea trifluoroacetate
Figure imgf000377_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-(difluoromethoxy)-2-isocyanatobenzene as the starting materials in 25% yield. LCMS for C26H22ClF2N6O2(IV^H)+: m/z = 523.3.
Example B 129 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2,2-dimethyl-2,3-dihydro- l-benzofuran-7-yl)urea trifluoroacetate
Figure imgf000377_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 7-isocyanato-2,2-dimethyl-2,3-dihydro-l-benzofuran as the starting materials in 10% yield. LCMS for C29H28C1N6O2(M+H)+: m/z = 527.3.
Example B 130 iV-Biphenyl-2-yl-iV'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9, 13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea trifluoroacetate
Figure imgf000378_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 2-isocyanatobiphenyl as the starting materials in 27% yield. LCMS for C3iH26ClN6O(M+H)+: m/z = 533.3.
Example B131 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[2-(trifluoromethoxy)phenyl]urea trifluoroacetate
Figure imgf000378_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-isocyanato-2-(trifluoromethoxy)benzene as the starting materials in 29% yield. LCMS for C26H21ClF3N6O2(Mi-H)+: m/z = 541.3. 1H NMR (400 MHz, DMSO-^6 ): δ 9.44 (s, 1 H), 9.31 (s, 1 H), 8.78 (s, 1 H), 8.55 (s, 1 H), 8.19 (d, 1 H), 8.12 (s, 1 H), 8.01 (s, 1 H), 7.74 (s, 1 H), 7.58 (d, 1 H), 7.37 (m, 2 H), 7.09 (m, 3 H), 6.88 (d, 1 H), 6.80 (d, 1 H), 2.92 (dd, 4 H). Example B 132 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[4-(trifluoromethoxy)phenyl]urea trifluoroacetate
Figure imgf000379_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-isocyanato-4-(trifluoromethoxy)benzene as the starting materials in 24% yield. LCMS for C26H2IClF3N6O2(IVLHr)+: m/z = 541.3.
Example B 133 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(6-morpholin-4-ylpyridin-2-yl)urea bis(trifluoroacetate)
Figure imgf000379_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 4-(6-isocyanatopyridin-2-yl)morpholine as the starting materials in 11% yield. LCMS for C28H28C1N8O2(M+H)+: m/z = 543.3. Example B 134 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-furylmethyl)urea bis(trifluoroacetate)
Figure imgf000380_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen- 12-amine bis(trifluoroacetate) and 2-(isocyanatomethyl)furan as the starting materials in 34% yield.
LCMS for C23H21C1N7O2(M+H)+: m/z = 462.1. 1H NMR (400 MHz, DMSO-^6 ): δ 9.96 (s, 1 H), 9.31 (s, 1 H), 8.97 (m, 1 H), 8.30 (m, 2 H), 8.18 (s, 1 H), 7.89 (m, 1 H), 7.71 (d, 1 H), 7.60 (d, 1 H), 7.56 (d, 1 H), 6.95-7.02 (m, 2 H), 6.41 (dd, 1 H), 6.28 (dd, 1 H), 4.29 (d, 2 H), 2.96 (m, 4 H).
Example B 135 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-methylurea bis(trifluoroacetate)
Figure imgf000380_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen- 12-amine bis(trifluoroacetate) and methyl isocyanate as the starting materials in 52% yield. LCMS for Ci9H19ClN7O(M-I-H)+: m/z = 396.1. 1H NMR (400 MHz, DMSOd6 ): δ 9.97 (s, 1 H), 9.31 (s, 1 H), 8.99 (m, 1 H), 8.30 (m, 2 H), 8.18 (s, 1 H), 7.84 (m, 1 H), 7.65 (d, 1 H), 7.56 (d, 1 H), 6.98 (dd, 1 H), 6.40 (bs, 1 H), 2.96 (m, 4 H), 2.64 (d, 3 H).
Example B 136 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzenesulfonamide trifluoroacetate
Figure imgf000381_0001
A solution of 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride (20 mg, 0.049 mmol) in DCM (0.3 mL) was treated with triethylamine (20.4 μL, 0.146 mmol) and benzenesulfonyl chloride (9.3 μL, 0.073 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the crude residue was dissolved in a mixture of acetonitrile and methanol and purified by preparative LCMS to give the desired product (15 mg, 52%). LCMS calculated for C24H21ClN5O2S (M+H)+: m/z =
478.2. 1H NMR (400 MHz, DMS0-<i6 ): δ 9.60 (s, 1 H), 9.47 (s, 1 H), 9.26 (s, 1 H), 8.13 (s, 1 H), 7.79 (d, 2 H), 7.70 (d, 2 H), 7.63 (m, 1 H), 7.57 (t, 2 H), 7.05 (t, 1 H), 6.92 (d, 1 H), 6.84 (d, 1 H), 6.71 (m, 2 H), 2.81 (d, 2 H), 2.65 (d, 2 H).
Example B 137
2-Chloro-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzenesulfonamide trifluoroacetate
Figure imgf000381_0002
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 2-chlorobenzenesulfonyl chloride as the starting materials in 17% yield. LCMS for C24H20CI2N5O2S(MH-H)+: m/z = 512.0, 514.0.
Example B 138
3-Chloro-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzenesulfonamide trifluoroacetate
Figure imgf000382_0001
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 3-chlorobenzenesulfonyl chloride as the starting materials in 28% yield. LCMS for C24H20CI2N5O2S(MH-H)+: m/z = 511.9, 513.9. 1H NMR (400 MHz, DMS0-<i6 ): δ 9.77 (s, 1 H), 9.47 (s, 1 H), 9.26 (s, 1 H), 8.13 (s, 1 H), 7.81 (d, 2 H), 7.77-7.60 (m, 4 H), 7.05 (t, 1 H), 6.92 (d, 1 H), 6.84 (d, 1 H), 6.71 (m, 2 H), 2.81 (d, 2 H), 2.65 (d, 2 H).
Example B 139
4-Chloro-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzenesulfonamide trifluoroacetate
Figure imgf000382_0002
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 4-chlorobenzenesulfonyl chloride as the starting materials in 26% yield. LCMS for C24H20CI2N5O2S(MH-H)+: m/z = 511.9, 513.9.
Example B 140 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methanesulfonamide trifluoroacetate
Figure imgf000383_0001
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and methanesulfonyl chloride as the starting materials in 12% yield. LCMS for CI9H19CIN5O2S(MH-H)+: m/z = 416.2.
Example B 141 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]ethanesulfonamide trifluoroacetate
Figure imgf000383_0002
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and ethanesulfonyl chloride as the starting materials in 8% yield. LCMS for C20H21CIN5O2S(MH-H)+: m/z = 430.3.
Example B 142 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]propane-l-sulfonamide trifluoroacetate
Figure imgf000384_0001
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 1-propanesulfonyl chloride as the starting materials in 7% yield. LCMS for C2IH23ClN5O2S(IVLHr)+: m/z = 444.3.
Example B 143 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]propane-2-sulfonamide trifluoroacetate
Figure imgf000384_0002
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and propane -2-sulfonyl chloride as the starting materials in 7% yield. LCMS for C2iH23ClN5O2S(M+H)+: m/z = 444.2.
Example B 144 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-methyl-lH-imidazole-4-sulfonamide bis(trifluoroacetate)
Figure imgf000385_0001
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 1 -methyl- lH-imidazole-4-sulfonyl chloride as the starting materials in 8% yield. LCMS for C22H21C1N7O2S(M+H)+: m/z = 482.2.
Example B 145 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-5-methylisoxazole-4-sulfonamide trifluoroacetate
Figure imgf000385_0002
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 5-methylisoxazole-4-sulfonyl chloride as the starting materials in 7% yield. LCMS for C22H20ClN6O3S(M+H)+: m/z = 483.3.
Example B 146 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]thiophene-2-sulfonamide trifluoroacetate
Figure imgf000386_0001
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 2-thiophenesulfonyl chloride as the starting materials in 25% yield. LCMS for C22Hi9ClN5O2S2(IVLHr)+: m/z = 484.2.
Example B 147 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-phenylmethanesulfonamide trifluoroacetate
Figure imgf000386_0002
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and phenylmethanesulfonyl chloride as the starting materials in 25% yield. LCMS for C25H23C1N5O2S(M+H)+: m/z = 492.3.
Example B 148 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-methylbenzenesulfonamide trifluoroacetate
Figure imgf000387_0001
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 3-methylbenzenesulfonyl chloride as the starting materials in 17% yield. LCMS for C25H23CIN5O2S(IVLI-H)+: m/z = 492.3.
Example B 149 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-methylbenzenesulfonamide trifluoroacetate
Figure imgf000387_0002
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 2-methylbenzenesulfonyl chloride as the starting materials in 22% yield. LCMS for C25H23ClN5O2S(M-I-H)+: m/z = 492.3. 1H NMR (400 MHz, DMS0-<i6 ): δ 9.58 (s, 1 H), 9.37 (s, 1 H), 9.13 (s, 1 H), 8.10 (s, 1 H), 7.82 (s, 1 H), 7.78 (s, 1 H), 7.65 (d, 1 H), 7.51 (t, 1 H), 7.42 (d, 1 H), 7.30 (t, 1 H), 7.06 (t, 1 H), 6.92 (d, 1 H), 6.85 (d, 1 H), 6.69 (t, 2 H), 2.83 (d, 2 H), 2.65 (d, 2 H), 2.60 (s, 3 H).
Example B 150 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-methylbenzenesulfonamide trifluoroacetate
Figure imgf000388_0001
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 4-methylbenzenesulfonyl chloride as the starting materials inl9% yield. LCMS for C25H23ClN5O2S(IVLHr)+: m/z = 492.3.
Example B151 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l,2-dimethyl-lH-imidazole-4-sulfonamide bis(trifluoroacetate)
Figure imgf000388_0002
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and l,2-dimethyl-lH-imidazole-4-sulfonyl chloride as the starting materials in 21% yield. LCMS for C23H23C1N7O2S(M+H)+: m/z = 496.3.
Example B 152 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3,5-dimethylisoxazole-4-sulfonamide trifluoroacetate
Figure imgf000389_0001
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 3,5-dimethylisoxazole-4-sulfonyl chloride as the starting materials in 14% yield. LCMS for C23H22CIN6O3S(MH-H)+: m/z = 497.2.
Example B 153 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-cyanobenzenesulfonamide trifluoroacetate
Figure imgf000389_0002
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 3-cyanobenzenesulfonyl chloride as the starting materials in 8% yield. LCMS for C25H20CIN6O2S(MH-H)+: m/z = 503.3.
Example B 154 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-cyanobenzenesulfonamide trifluoroacetate
Figure imgf000390_0001
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 4-cyanobenzenesulfonyl chloride as the starting materials in 7% yield. LCMS for C25H20ClN6O2S(IVLHr)+: m/z = 503.3.
Example B 155 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-cyanobenzenesulfonamide trifluoroacetate
Figure imgf000390_0002
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 2-cyanobenzenesulfonyl chloride as the starting materials in 10% yield. LCMS for C25H2oClN602S(M+H)+: m/z = 503.1.
Example B 156 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-methoxybenzenesulfonamide trifluoroacetate
Figure imgf000391_0001
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 4-methoxybenzenesulfonyl chloride as the starting materials in 16% yield. LCMS for C25H23ClN5O3S(IVLHr)+: m/z = 508.0.
Example B 157 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-methoxybenzenesulfonamide trifluoroacetate
Figure imgf000391_0002
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 3-methoxybenzenesulfonyl chloride as the starting materials in 16% yield. LCMS for C25H23C1N5O3S(M+H)+: m/z = 508.0.
Example B 158 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]cyclopropanesulfonamide trifluoroacetate
Figure imgf000392_0001
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and cyclopropanesulfonyl chloride as the starting materials in 17% yield. LCMS for C2IH2ICIN5O2S(IVLI-H)+: m/z = 442.0.
Example B 159
3-({[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}sulfonyl)benzoic acid trifluoroacetate
Figure imgf000392_0002
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 3-(chlorosulfonyl)benzoic acid as the starting materials in 22% yield. LCMS for C25H21ClN5O4S(M-I-H)+: m/z = 522.0.
Example B 160 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]quinoline-8-sulfonamide bis(trifluoroacetate)
Figure imgf000393_0001
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and quinolin-8-sulfonyl chloride as the starting materials in 18% yield. LCMS for C27H22CiN6O2S(IVLi-H)+: m/z = 529.0.
Example B161 iV-[4-({[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}sulfonyl)phenyl]acetamide trifluoroacetate
Figure imgf000393_0002
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and p-acetaminobenzenesulfonyl chloride as the starting materials in 19% yield. LCMS for C26H24ClN6O3S(M-I-H)+: m/z = 535.0.
Example B 162 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(trifluoromethyl)benzenesulfonamide trifluoroacetate
Figure imgf000394_0001
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 4-(trifluoromethyl)benzenesulfonyl chloride as the starting materials in 17% yield. LCMS for C25H20ClF3N5O2S(IVLHr)+: m/z = 546.3.
Example B 163 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-(trifluoromethyl)benzenesulfonamide trifluoroacetate
Figure imgf000394_0002
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 3-(trifluoromethyl)benzenesulfonyl chloride as the starting materials in 24% yield. LCMS for C25H20ClF3N5O2S(M+H)+: m/z = 546.3.
Example B 164 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(trifluoromethyl)benzenesulfonamide trifluoroacetate
Figure imgf000395_0001
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 2-(trifluoromethyl)benzenesulfonyl chloride as the starting materials in 18% yield. LCMS for C25H20CrF3N5O2S(IVLi-H)+: m/z = 546.3.
Example B 165 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-methyl-3,4-dihydro-2H-l,4- benzoxazine-7-sulfonamide trifluoroacetate
Figure imgf000395_0002
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 4-methyl-3,4-dihydro-2H-l,4-benzoxazine-7-sulfonyl chloride as the starting materials in 27% yield. LCMS for C27H26ClN6O3S(M-I-H)+: m/z = 549.3.
Example B 166 tert-Butyl (3S)-3-[({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,
13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]pyrrolidine-
1-carboxylate
Figure imgf000396_0001
The desired compound was prepared according to the procedure of Example B25 step A, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and tert-buiyl (3S)-3-aminopyrrolidine-l-carboxylate as the starting materials in 47% yield. LCMS for C28H33CiN7O3(IVLi-H)+: m/z = 550.3.
Example B 167 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[(3S)-pyrrolidin-3-yl]urea bis(trifluoroacetate)
Figure imgf000396_0002
The desired compound was prepared according to the procedure of Example B25 step B, using tert-butyl (3S)-3-[({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino}carbonyl)amino]pyrrolidine-l-carboxylate as the starting material in 46% yield. LCMS for C23H25C1N7O(M+H)+: m/z = 450.4.
Example B 168 iV-[(3S)-l-Acetylpyrrolidin-3-yl]-iV'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea trifluoroacetate
Figure imgf000397_0001
The desired compound was prepared according to the procedure of Example B26, using N- [6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea dihydrochloride and acetyl chloride as the starting materials in 36% yield. LCMS for C25H27C1Ν7O2(M+H)+: m/z = 492.3.
Example B 169
(3S)-3-[({[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]-N- methylpyrrolidine-1-carboxamide trifluoracetate
Figure imgf000397_0002
The desired compound was prepared according to the procedure of Example B 83, using N- [6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea dihydrochloride and methyl isocyanate as the starting materials in 50% yield. LCMS for C25H28C1Ν8O2(M+H)+: m/z = 507.2.
Example B 170
N-[(3S)-l-Benzoylpyrrolidin-3-yl]-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea trifluoroacetate
Figure imgf000398_0001
The desired compound was prepared according to the procedure of Example B26, using N- [6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea dihydrochloride and benzoyl chloride as the starting materials in 39% yield. LCMS for C30H29ClN7O2(IVLHr)+: m/z = 554.3. 1H NMR (400 MHz, DMSO- dβ ): δ 9.55 (s, 1 H), 9.40 (s, 1 H), 8.15 (s, 1 H), 7.98 (m, 1 H), 7.71-7.41 (m, 8 H), 7.09 (m, 1 H), 6.99- 6.78 (m, 4 H), 4.18 (d, 1 H), 3.76-3.48 (m, 3 H), 3.42-3.25 (m, 1 H), 2.86 (d, 4 H), 2.17 (m, 1 H), 1.85 (m, I H).
Example B 171
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-l-(pyridin-3-ylcarbonyl)pyrrolidin- 3-yl]urea bis(trifluoroacetate)
Figure imgf000398_0002
The desired compound was prepared according to the procedure of Example B26, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea dihydrochloride and nicotinoyl chloride hydrochloride as the starting materials in 42% yield. LCMS for C29H28C1N8O2(M+H)+: m/z = 555.3. 1H NMR (400 MHz, DMSO-Cf6 ): δ 9.77 (s, 1 H), 9.62 (s, 1 H), 8.79 (s, 1 H), 8.69 (s, 1 H), 8.19 (s, 1 H), 8.07 (m, 1 H), 7.95 (d, 1 H), 7.75-7.52 (m, 4 H), 7.09 (m, 1 H), 6.99-6.78 (m, 4 H), 4.20 (d, 1 H), 3.77-3.50 (m, 3 H), 3.41-3.20 (m, 1 H), 2.86 (d, 4 H), 2.17 (m, 1 H), 1.85 (m, 1 H).
Example B 172 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[(3S)-l-(methylsulfonyl)pyrrolidin- 3-yl]urea trifluoroacetate
Figure imgf000399_0001
The desired compound was prepared according to the procedure of Example B 136, using N- [6 - chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea dihydrochloride as the starting material in 16% yield. LCMS for C24H27ClN7O3S(M-FH)+: m/z = 528.1.
Example B 173
N-[(3S)-l-Benzylpyrrolidin-3-yl]-iV'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea bis(trifluoroacetate)
Figure imgf000400_0001
The desired compound was prepared according to the procedure of Example B 192, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea dihydrochloride and benzaldehyde as the starting materials in 9% yield. LCMS for C3oH31ClΝ70(M+H)+: m/z = 540.1.
Example B 174 tert-Butyl (3R)-3-[({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]pyrrolidine-l-carboxylate
Figure imgf000400_0002
The desired compound was prepared according to the procedure of Example B25 step A, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and tert-butyl (3R)-3-aminopyrrolidine-l-carboxylate as the starting materials in 27% yield. LCMS for C28H33ClN7O3(M+!^: m/z = 550.3.
Example B 175 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[(3R)-pyrrolidin-3-yl]urea dihydrochloride
Figure imgf000401_0001
The desired compound was prepared according to the procedure of Example B25 step B, using tert-butyl (3R)-3-[({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-
1(20), 3(22),4,6,9(21), 10,12,16, 18 -nonaen-12-yl] amino Jcarbonyl) amino] pyrrolidine- 1-carboxylate as the starting material in 25% yield. LCMS for C23H25ClN7O(M-FH)+: m/z = 450.0. 1H NMR (400 MHz, DMSO-^6 ): δ 10.20 (s, 1 H), 10.05 (s, 1 H), 9.38-9.15 (br , 2 H), 8.28 (s, 1 H), 8.20 (s, 1 H), 7.89 (s, 1 H), 7.75 (d, 1 H), 7.64 (m, 1 H), 7.15 (t, 1 H), 6.96 (d, 1 H), 6.87 (m, 1 H), 4.20 (m, 1 H), 3.68 (d, 1 H), 3.45 (d, 1 H), 3.39-3.10 (m, 2 H), 2.99 (m, 4 H), 2.17 (m, 1 H), 1.80 (m, 1 H).
Example B 176 iV-[(3R)-l-Benzoylpyrrolidin-3-yl]-iV'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea trifluoroacetate
Figure imgf000401_0002
The desired compound was prepared according to the procedure of Example B26, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3R)-pyrrolidin-3-yl]urea dihydrochloride and benzoyl chloride as the starting materials in 18% yield. LCMS for C30H29ClΝ7O2(M+H)+: m/z = 554.1. Example B 177 iV-[(3R)-l-Acetylpyrrolidin-3-yl]-iV'-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea trifluoroacetate
Figure imgf000402_0001
The desired compound was prepare according to the procedure of Example B26, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3R)-pyrrolidin-3-yl]urea dihydrochloride and acetyl chloride as the starting materials in 18% yield. LCMS for C25H27C1Ν7O2(M+H)+: m/z = 492.1.
Example B 178 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[(3R)-l-(methylsulfonyl)pyrrolidin-3-yl]urea trifluoroacetate
Figure imgf000402_0002
The desired compound was prepared according to the procedure of Example B 136, using N- [6 - chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3R)-pyrrolidin-3-yl]urea dihydrochloride as the starting material in 18% yield. LCMS for C24H27ClN7O3S(IVLi-H)+: m/z = 528.1.
Example B 179
(3R)-3-[({[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]pyrrolidine- 1 -sulfonamide trifluoroacetate
Figure imgf000403_0001
A suspension of N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3R)-pyrrolidin-3-yl]urea dihydrochloride (15 mg, 0.029 mmol) and sulfamide (13.8 mg, 0.143 mmol) in pyridine (0.4 mL, 5 mmol) was heated to 130 0C for 3 minutes in a microwave reactor. The crude mixture was dissolved in methanol and purified by preparative LCMS to give the desired product (2.4 mg, 13%). LCMS for C23H26ClN8O2S(M-I-H)+: m/z = 529.3.
Example B 180 tert-Butyl 4-[({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]piperidine-l-carboxylate
Figure imgf000403_0002
The desired compound was prepared according to the procedure of Example B25 step A, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and tert-butyl 4-aminopiperidine-l-carboxylate as the starting materials in 33% yield. LCMS for C29H35ClN7O3(IVLHr)+: m/z = 564.4.
Example B181 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-piperidin-4-ylurea dihydrochloride
Figure imgf000404_0001
The desired compound was prepared according to the procedure of Example B25 step B, using tert-butyl 4-[({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18 -nonaen-12-yl] amino Jcarbonyl) amino] piperidine-1-carboxylate as the starting material in 30% yield. LCMS for C24H27C1N7O(M+H)+: m/z = 464.0.
Example B 182 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[l-(methylsulfonyl)piperidin-4-yl]urea trifluoroacetate
Figure imgf000404_0002
The desired compound was prepared according to the procedure of Example B 136, using N- [6 - Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-piperidin-4-ylurea dihydrochloride as the starting material in 11% yield. LCMS for C25H29ClN7O3S(IVLHr)+: m/z = 542.0.
Example B 183
4-[({[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]piperidine-l-sulfonamide trifluoroacetate
Figure imgf000405_0001
The desired compound was prepared according to the procedure of Example B 179, using 4-[({ [6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]amino}carbonyl)amino]piperidine-l-sulfonamide trifluoroacetate as the starting material in 7% yield. LCMS for C24H28C1N8O3S(M+H)+: m/z = 543.2.
Example B 184 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]sulfamide trifluoroacetate
Figure imgf000405_0002
The desired compound was prepared according to the procedure of Example B 179, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride as the starting material in 25% yield. LCMS for Ci8Hi8ClN6θ2S(M+H)+: m/z = 417.2.
Example B 185 tert-Butyl {2-[({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}carbamate
Figure imgf000406_0001
To a solution of 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride (314 mg, 0.764 mmol) in DCM (3.4 mL) were added N,N-diisopropylethylamine (0.53 mL, 3.1 mmol) and 20% phosgene in toluene (0.53 mL, 0.99 mmol). After stirring for 2 hours, N-(2-aminoethyl)(tert-butoxy)carboxamide (0.182 mL, 1.15 mmol) was added to reaction flask and stirred overnight. The resulting precipitate was filtered and washed with DCM to yield the desired product (326 mg, 81%). LCMS calculated for C26H3iClΝ7θ3(M+H)+: m/z = 524.3.
Example B 186 iV-{2-[({[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}acetamide trifluoroacetate
Figure imgf000407_0001
Step A: N-(2-Aminoethyl)-N'-[6-chloro-2, 4, 8, 22-tetraazatetracyclo[14.3.1.1 (3, 7).1 (9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea dihydrochloride
Figure imgf000407_0002
To a solution of tert-butyl {2-[({ [6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]amino}carbonyl)amino]ethyl}carbamate (326 mg, 0.622 mmol) in DCM (12 niL) was added 4.0 M of hydrogen chloride in l,4-dioxane(0.544 mL, 2.18 mmol). After stirring overnight, the reaction solution was diluted with ether. The resulting precipitate was filtered and dried under vacuum to give the desired product (245 mg, 79%). LCMS calculated for C2iH23ClN7O(M+H)+: m/z = 424.2.
Step B: N-{2-[({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}acetamide trifluoroacetate
The desired compound was prepared according to the procedure of Example B26, using N-(2- aminoethyl)-Ν'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-
1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]urea dihydrochloride and acetyl chloride as the starting materials in 48% yield. LCMS for C23H25C1N7O2(M+H)+: m/z = 466.2. Example B 187 iV-{2-[({[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}methanesulfonamide trifluoroacetate
Figure imgf000408_0001
The desired compound was prepared according to the procedure of Example B 136, using N-(2- aminoethyl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea dihydrochloride as the starting material in 38% yield. LCMS for C22H25ClN7O3S(IVLHr)+: m/z = 502.2.
Example B 188 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-{[(isopropylamino)carbonyl]amino}ethyl)urea trifluoroacetate
Figure imgf000409_0001
The desired compound was prepared according to the procedure of Example B83, using N-(2- aminoethyl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]urea dihydrochloride and 2-isocyanatopropane as the starting materials in 24% yield. LCMS for C25H30ClN8O2(IV^H)+: m/z = 509.5.
Example B 189 iV-{2-[({[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}benzamide trifluoroacetate
Figure imgf000409_0002
The desired compound was prepared according to the procedure of Example B26, using N-(2- aminoethyl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]urea dihydrochloride and benzoyl chloride as the starting materials in 18% yield. LCMS for C28H27ClN7O2(IVLi-H)+: m/z = 528.5.
Example B190 iV-{2-[({[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}pyridine-2- carboxamide trifluoroacetate
Figure imgf000410_0001
The desired compound was prepared according to the procedure of Example B26, using N-(2- aminoethyl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea dihydrochloride and pyridine-2-carbonyl chloride as the starting materials in 12% yield. LCMS for C27H26ClN8O2(M-I-H)+: m/z = 529.3.
Example B191
6-Chloro-ll-(piperazin-l-ylmethyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene dihydrochloride
Figure imgf000410_0002
Step A: tert-Butyl 4-{[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]methyljpiperazine-l-carboxylate
Figure imgf000411_0001
To a solution of [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]methanol trifluoroacetate (0.731 g, 1.56 mmol) in THF (15 niL) was added methanesulfonyl chloride (151 μL, 1.95 mmol) and NN-diisopropylethylamine (0.93 mL, 5.32 mmol) at 0 0C. The resulting reaction solution was stirred at same temperature for 2 hours. The reaction solution was diluted with DMF (8 mL) and N-tert-butoxycarbonylpiperazine (396 mg, 2.13 mmol) was added, followed by NN-diisopropylethylamine (0.818 mL, 4.70 mmol). The reaction solution was stirred at 40 0C overnight. The reaction solution was diluted with 1 Ν HCl solution and ethyl acetate and the aqueous layer was extracted with ethyl acetate once. The aqueous layer was neutralized with 50% NaOH solution to pH 10, and then extracted with EtOAc twice. The combined organic solutions were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography to yield the desired product (410 mg, 50%). LCMS calculated for C28H34CIN6O2(MH-H)+: m/z = 521.2.
Step B: 6-Chloro-ll-(piperazin-l-ylmethyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene dihydrochloride
The desired compound was prepared according to the procedure of Example B 186 step A, using tert-butyl 4-{ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-l l-yl]methyl}piperazine-l-carboxylate as the starting materials in 98% yield. LCMS for C23H26CIN6(MH-H)+: m/z = 421.2.
Example B192
6-Chloro-ll-{[4-(4-fluorobenzyl)piperazin-l-yl]methyl}-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000411_0002
To a mixture of 6-chloro-l l-(piperazin-l-ylmethyl)-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene dihydrochloride (37.1 mg, 75.1 μmol) and 4-fluorobenzaldehyde (12 μL, 110 μmol) in DMF (0.5 mL) was added sodium triacetoxyborohydride (32 mg, 0.15 mmol). The reaction was stirred at room temperature overnight. The reaction solution was diluted with methanol and purified by preparative LCMS to give the desired product as white solid (15.3 mg, 23%). LCMS calculated for
C3oH3iClFN6(M+H)+: m/z = 529.3. 1H NMR (400 MHz, DMSO-<i6 ): δ 9.65 (s, 1 H), 9.44 (s, 1 H), 8.19 (s, 1 H), 7.85 (m, 2 H), 7.46 (m, 2 H), 7.25 (m, 2 H), 7.13 (m, 3 H), 6.91 (m, 1 H), 6.86 (m, 1 H), 4.11 (bd, 4 H), 3.13 (bs, 8 H), 2.87 (m, 4 H).
Example B193
6-Chloro-ll-({4-[4-(pyrimidin-2-yloxy)benzyl]piperazin-l-yl}methyl)-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000412_0001
The desired compound was prepared according to the procedure of Example B 192, using 6- chloro-l l-(piperazin-l-ylmethyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene dihydrochloride and 4-(pyrimidin-2-yloxy)benzaldehyde as the starting materials in 50% yield. LCMS for C34H34CiN8O(M+H)+: m/z = 605.3.
Example B194
6-Chloro-ll-{[4-(4-nitrobenzyl)piperazin-l-yl]methyl}-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000412_0002
The desired compound was prepared according to the procedure of Example B 192, using 6- chloro-l l-(piperazin-l-ylmethyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene dihydrochloride and p-nitrobenzaldehyde as the starting materials in 41% yield. LCMS for C30H3IClN7O2(IVLHr)+: m/z = 556.3.
Example B195
6-Chloro-ll-[(4-{4-[(4-chlorophenyl)sulfonyl]benzyl}piperazin-l-yl)methyl]-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000413_0001
The desired compound was prepared according to the procedure of Example B 192, using 6- chloro-l l-(piperazin-l-ylmethyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene dihydrochloride and 4-[(4- chlorophenyl)sulfonyl]benzaldehyde as the starting materials in 28% yield. LCMS for C36H35C12N6O2S(M+H)+: m/z = 685.3, 687.3.
Example B196
H-({4-[(4-Bromo-2-thienyl)methyl]piperazin-l-yl}methyl)-6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000413_0002
The desired compound was prepared according to the procedure of Example B 192, using 6- chloro-l l-(piperazin-l-ylmethyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9, 13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene dihydrochloride and 4-bromothiophene-2-carbaldehyde as the starting materials in 29% yield. LCMS for C28H29BrClN6S(M+H)+: m/z = 595.2. 1H NMR (400 MHz, DMSO-^6 ): δ 9.46 (s, 1 H), 9.30 (s, 1 H), 8.15 (s, 1 H), 7.87 (m, 2 H), 7.64 (s, 1 H), 7.14 (m, 4 H), 6.92 (m, 1 H), 6.84 (m, 1 H), 4.20 (bs, 2 H), 3.89 (bs, 2 H), 3.30 (bs, 2 H), 3.01 (bs, 4 H), 2.87 (m, 6 H).
Example B197 6-Chloro-ll-{[4-(4-methoxybenzyl)piperazin-l-yl]methyl}-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000414_0001
The desired compound was prepared according to the procedure of Example B 192, using 6- chloro-l l-(piperazin-l-ylmethyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-
1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene dihydrochloride and 4-methoxybenzaldehyde as the starting materials in 32% yield. LCMS for C3iH34ClN6O(M+H)+: m/z = 541.3.
Example B198 6-Chloro-ll-{[4-(3-methoxybenzyl)piperazin-l-yl]methyl}-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000414_0002
The desired compound was prepared according to the procedure of Example B 192, using 6- chloro-l l-(piperazin-l-ylmethyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-
1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene dihydrochloride and 3-methoxybenzaldehyde as the starting materials in 41% yield. LCMS for C3iH34ClN6O(M+H)+: m/z = 541.3.
Example B199 6-Chloro-ll-{[4-(4-chlorobenzyl)piperazin-l-yl]methyl}-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000415_0001
The desired compound was prepared according to the procedure of Example B 192, using 6- chloro-l l-(piperazin-l-ylmethyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene dihydrochloride and 4-chlorobenzaldehyde as the starting materials in 30% yield. LCMS for C30H3ICl2N6(IVLHr)+: m/z = 545.3, 547.3.
Example B200
6-Chloro-iV-phenyl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-12-carboxamide trifluoroacetate
Figure imgf000415_0002
The desired compound was prepared according to the procedure of Example B7, using methyl 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene-12-carboxylate and aniline as the starting materials in 51% yield. LCMS for C25H21CIN5O
(M+H)+: m/z = 442.1. 1H NMR (400 MHz, DMS0-<i6 ): δ 10.32 (s, 1 H), 9.38 (s, 1 H), 9.32 (s, 1 H), 8.14 (s, 1 H), 8.05 (m, 1 H), 7.90 (m, 1 H), 7.74 (m, 2 H), 7.41 (d, 1 H), 7.32 (m, 2 H), 7.17 (dd, 1 H), 7.08 (m, 2 H), 6.88 (m, 1 H), 6.76 (m, 1 H), 3.05 (m, 2 H), 2.93 (m, 2 H).
Example B201 1 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]pyridine-2-carboxamide trifluoroacetate
Figure imgf000416_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l- amine bis(trifluoroacetate) and pyridine -2 -carbonyl chloride as the starting materials in 35% yield.
LCMS for C24H20CIN6CK]VLI-H)+: m/z = 443.2. 1H NMR (400 MHz, DMSOd6 ): δ 10.54 (s, 1 H), 9.51 (s, 2 H), 8.72 (m, 1 H), 8.16 (s, 1 H), 8.13 (m, 1 H), 8.05 (m, 1 H), 7.92 (m, 1 H), 7.75 (m, 1 H), 7.66 (m, 1 H), 7.49 (m, 1 H), 7.45 (m, 1 H), 7.11 (dd, 1 H), 6.89 (m, 1 H), 6.84 (m, 1 H), 2.89 (m, 4 H).
Example B202 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]-iV'-phenylurea trifluoroacetate
Figure imgf000416_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l- amine bis(trifluoroacetate) and phenyl isocyanate as the starting materials in 28% yield. LCMS for
C25H22ClN6O(M-I-H)+: m/z = 457.2. 1H NMR (400 MHz, DMSOd6 ): δ 9.39 (s, 1 H), 9.28 (s, 1 H), 8.69 (s, 1 H), 8.64 (s, 1 H), 8.08 (s, 1 H), 7.90 (m, 1 H), 7.40 (m, 2 H), 7.31 (m, 1 H), 7.22 (m, 3 H), 7.06 (dd, 1 H), 7.01 (m, 1 H), 6.89 (m, 2 H), 6.78 (m, 1 H), 2.80 (m, 4 H).
Example B203 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]benzenesulfonamide trifluoroacetate
Figure imgf000417_0001
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-11 -amine bis(trifluoroacetate) and benzenesulfonyl chloride as the starting materials in 42% yield.
LCMS for C24H21CIN5O2S(MH-H)+: m/z = 478.1. 1H NMR (400 MHz, DMS0-<i6 ): δ 10.24 (s, 1 H), 9.55 (s, 1 H), 9.50 (s, 1 H), 8.15 (s, 1 H), 7.76 (m, 3 H), 7.50 (m, 3 H), 7.40 (m, 1 H), 7.10 (dd, 1 H),6.94 (m, 1 H), 6.88 (m, 1 H), 6.80 (m, 1 H), 6.69 (m, 1 H), 2.74 (m, 4 H).
Example B204 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]-l,3-benzothiazole-2-carboxamide trifluoroacetate
Figure imgf000417_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l- amine bis(trifluoroacetate) and l,3-benzothiazole-2-carbonyl chloride as the starting materials in 43% yield. LCMS for C26H2OCIN6OS(MH-H)+: m/z = 499.2. 1H NMR (400 MHz, DMS0-<i6 ): δ 11.06 (s, 1 H), 9.38 (s, 2 H), 8.25 (m, 2 H), 8.13 (s, 1 H), 7.94 (m, 1 H), 7.62 (m, 5 H), 7.11 (dd, 1 H), 6.89 (m, 1 H), 6.83 (m, 1 H), 2.88 (m, 4 H).
Example B205 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]-5-methylisoxazole-3-carboxamide trifluoroacetate
Figure imgf000418_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l- amine bis(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 42% yield. LCMS for C23H20CrN6O2(IVLi-H)+: m/z = 447.2. 1H NMR (400 MHz, DMS0-<i6 ): δ 10.59 (s, 1 H), 9.59 (s, 2 H), 8.17 (s, 1 H), 7.88 (m, 1 H), 7.59 (m, 1 H), 7.49 (m, 1 H), 7.35 (m, 1 H), 7.11 (dd, 1 H), 6.89 (m, 1 H), 6.84 (m, 1 H), 6.64 (m, 1 H), 2.88 (m, 4 H), 2.48 (s, 3 H).
Example B206 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]isoxazole-5-carboxamide trifluoroacetate
Figure imgf000418_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l- amine bis(trifluoroacetate) and isoxazole-5-carbonyl chloride as the starting materials in 45% yield.
LCMS for C22H18C1N6O2(M+H)+: m/z = 433.1. 1H NMR (400 MHz, DMSO-^6 ): δ 10.65 (s, 1 H), 9.52 (s, 1 H), 9.49 (s, 1 H), 8.75 (d, 1 H), 8.12 (s, 1 H), 7.84 (m, 1 H), 7.56 (m, 1 H), 7.48 (m, 1 H), 7.27 (m, 1 H), 7.20 (d, 1 H), 7.06 (dd, 1 H), 6.85 (m, 1 H), 6.82 (m, 1 H), 2.84 (m, 4 H).
Example B207 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]-l-methyl-lH-pyrazole-3-carboxamide trifluoroacetate
Figure imgf000419_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l- amine bis(trifluoroacetate) and l-methyl-lH-pyrazole-3-carbonyl chloride as the starting materials in 47% yield. LCMS for C23H2ICiN7CK]VLi-H)+: m/z = 446.2. 1H NMR (400 MHz, DMSOd6 ): δ 9.93 (s, 1 H), 9.76 (s, 1 H), 9.70 (s, 1 H), 8.20 (s, 1 H), 7.88 (m, 1 H), 7.82 (d, 1 H), 7.64 (m, 1 H), 7.42 (m, 1 H), 7.36 (m, 1 H), 7.11 (dd, 1 H), 6.87 (m, 2 H), 6.73 (d, 1 H), 3.94 (s, 3 H), 2.86 (m, 4 H).
Example B208 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]-l-methyl-lH-imidazole-5-carboxamide trifluoroacetate
Figure imgf000419_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l- amine bis(trifluoroacetate) and l-methyl-lH-imidazole-5-carbonyl chloride hydrochloride as the starting materials in 29% yield. LCMS for C23H2iClN7O(M-ι-H)+: m/z = 446.2.
Example B209 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]-l,3-thiazole-2-carboxamide trifluoroacetate
Figure imgf000419_0003
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l- amine bis(trifluoroacetate) and l,3-thiazole-2-carbonyl chloride as the starting materials in 37% yield.
LCMS for C22H18C1N6OS(M+H)+: m/z = 449.2. 1H NMR (400 MHz, DMSO-^6 ): δ 10.67 (s, 1 H), 9.57 (m, 2 H), 8.13 (s, 1 H), 8.07 (m, 2 H), 7.84 (m, 1 H), 7.60 (m, 1 H), 7.45 (m, 1 H), 7.40 (m, 1 H), 7.07 (dd, 1 H), 6.85 (m, 2 H), 2.84 (m, 4 H).
Example B210 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]-4-methyl-l,3-oxazole-5-carboxamide trifluoroacetate
Figure imgf000420_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l- amine bis(trifluoroacetate) and 4-methyl-l,3-oxazole-5-carbonyl chloride as the starting materials in 55% yield. LCMS for C23H20ClN6O2(M+^+: m/z = 447.2. 1H NMR (400 MHz, DMSO-^6 ): δ 10.20 (s, 1 H), 9.69 (s, 1 H), 9.63 (s, 1 H), 8.48 (d, 1 H), 8.15 (s, 1 H), 7.82 (m, 1 H), 7.55 (m, 1 H), 7.43 (m, 1 H), 7.29 (m, 1 H), 7.07 (dd, 1 H), 6.84 (m, 2 H), 2.84 (m, 4 H), 2.36 (s, 3 H).
Example B211 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]cyclobutanecarboxamide trifluoroacetate
Figure imgf000420_0002
The desired compound was prepared according to the procedure of Example B26, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l- amine bis(trifluoroacetate) and cyclobutanecarboxylic acid chloride as the starting materials in 51 % yield. LCMS for C23H23C1N5O(M+H)+: m/z = 420.2. Example B212 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]-iV'-(4-cyanophenyl)urea trifluoroacetate
Figure imgf000421_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l- amine bis(trifluoroacetate) and 4-isocyanatobenzonitrile as the starting materials in 52% yield. LCMS for
C26H21C1N7O(M+H)+: m/z = 482.2. 1H NMR (400 MHz, DMSOd6 ): δ 9.55 (s, 1 H), 9.49 (s, 1 H), 9.35 (s, 1 H), 8.97 (s, 1 H), 8.12 (s, 1 H), 7.86 (m, 1 H), 7.67 (m, 2 H), 7.59 (m, 2 H), 7.33 (m, 1 H), 7.23 (m, 1 H), 7.05 (m, 2 H), 6.83 (m, 2 H), 2.82 (m, 4 H).
Example B213 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]-iV'-(2-fluorophenyl)urea trifluoroacetate
Figure imgf000421_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l- amine bis(trifluoroacetate) and l-fluoro-2-isocyanatobenzene as the starting materials in 43% yield. LCMS for C25H2iClFN6O(M+H)+: m/z = 475.2.
Example B214 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]-iV'-(3-fluorophenyl)urea trifluoroacetate
Figure imgf000422_0001
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l- amine bis(trifluoroacetate) and l-fluoro-3-isocyanatobenzene as the starting materials in 49% yield.
LCMS for C25H2iClFN6O(M+H)+: m/z = 475.2. 1H NMR (400 MHz, DMS0-<i6 ): δ 9.56 (s, 1 H), 9.47 (s, 1 H), 9.03 (m, 1 H), 8.81 (m, 1 H), 8.12 (s, 1 H), 7.86 (m, 1 H), 7.40 (m, 1 H), 7.31 (m, 1 H), 7.24 (m, 2 H), 7.05 (m, 3 H), 6.84 (m, 2 H), 6.68 (m, 1 H), 2.82 (m, 4 H).
Example B215 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]-iV'-cyclopentylurea trifluoroacetate
Figure imgf000422_0002
The desired compound was prepared according to the procedure of Example B83, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l- amine bis(trifluoroacetate) and isocyanatocyclopentane as the starting materials in 39% yield. LCMS for C24H26C1N6O(M+H)+: m/z = 449.2.
Example B216 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-ll-yl]-2-cyanobenzenesulfonamide trifluoroacetate
Figure imgf000422_0003
The desired compound was prepared according to the procedure of Example B 136, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen- 11 -amine bis(trifluoroacetate) and -cyanobenzenesulfonyl chloride as the starting materials in 27% yield. LCMS for C25H2OClN6O2S(IVLi-H)+: m/z = 503.1.
Example B217
6-Chloro-ll-{[4-(6-chloropyridin-2-yl)piperazin-l-yl]methyl}-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000423_0001
To a solution of 6-chloro-l l-(piperazin-l-ylmethyl)-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene dihydrochloride (31.5 mg, 0.064 mmol) in DMF (0.30 mL) were added 2,6-dichloro- pyridine (20.0 mg 0.135 mmol) and N,N-diisopropylethylamine (44.4 μL, 0.255 mmol). The reaction was microwaved at 180 0C for 15 minutes. The reaction solution was diluted with methanol and purified with preparative LCMS to give the desired product as white solid (8.5 mg, 21 %). LCMS for C28H28Cl2N7(M-I-H)+: m/z : 532.2.
Example B218
6-Chloro-ll-{[4-(2-chloropyrimidin-4-yl)piperazin-l-yl]methyl}-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000423_0002
To a solution of 6-chloro-l l-(piperazin-l-ylmethyl)-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene dihydrochloride (21.0 mg, 0.0425 mmol) in DMF (0.6 mL) were added 2,4-dichloropyrimidine (6.6 mg, 0.045 mmol) and N,N-diisopropylethylamine (29.6 μL, 0.170 mmol). the resulting mixture was stirred at 70 0C for 2 h. The reaction solution was diluted with methanol and purified by preparative LCMS to give the desired product (8.2 mg 31%). LCMS for C27H27C12N8(M+H)+: m/z = 533.2.
Example B219 tert-Butyl (3R)-3-({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}amino)pyrrolidine-l-carboxylate bis(trifluoroacetate)
Figure imgf000424_0001
The desired compound was prepared according to the procedure of Example B 191 step A, using [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl] methanol trifluoroacetate and tert-butyl (3R)-3-aminopyrrolidine-l-carboxylate as the starting materials in 52% yield. LCMS for C28H34ClN6O2(M+^+: m/z = 521.3.
Example B220 tert-Butyl (3S)-3-({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}amino)pyrrolidine-l-carboxylate bis(trifluoroacetate)
Figure imgf000424_0002
The desired compound was prepared according to the procedure of Example B 191 step A, using [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl] methanol trifluoroacetate and tert-butyl (3S)-3-aminopyrrolidine-l-carboxylate as the starting materials in 47% yield. LCMS for C28H34CIN6O2(MH-H)+: m/z = 521.3.
Example B221 tert-Butyl 4-{[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}piperazine-l-carboxylate bis(trifluoroacetate)
Figure imgf000425_0001
The desired compound was prepared according to the procedure of Example B 191 step A, using
[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl] methanol trifluoroacetate and tert-butyl piperazine-1-carboxylate as the starting materials in 63% yield. LCMS for C28H34CIN6O2(MH-H)+: m/z = 521.3.
Example B222
(3R)-iV-{[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}pyrrolidin-3-amine tris(trifluoroacetate)
Figure imgf000425_0002
The desired compound was prepared according to the procedure of Example B 191 step B, usin^ tert-butyl (3R)-3-({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}amino)pyrrolidine-l-carboxylate bis(trifluoroacetate) as the starting material in 67% yield. LCMS for C23H26C1N6(M+H)+: m/z = 421.3.
Example B223
(3S)-iV-{[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}pyrrolidin-3-amine tris(trifluoroacetate)
Figure imgf000426_0001
The desired compound was prepared according to the procedure of Example B 191 step B, using tert-butyl (3S)-3-({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}amino)pyrrolidine-l-carboxylate bis(trifluoroacetate) as the starting material in 72% yield. LCMS for C23H26C1N6(M+H)+: m/z = 421.3.
Example B224
6-Chloro-12-(piperazin-l-ylmethyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000426_0002
The desired compound was prepared according to the procedure of Example B 191 step B, using tert-butyl 4-{ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}piperazine-l-carboxylate trifluoroacetate as the starting materials in 47% yield. LCMS for C23H26C1N6(M+H)+: m/z = 421.3.
Example B225 12-[(4-Acetylpiperazin-l-yl)methyl]-6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000427_0001
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-
12-(piperazin- 1 -ylmethyl)-2,4, 8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and acetyl chloride as the starting materials in 52% yield. LCMS for C25H28C1N6O(M+H)+: m/z = 463.2.
Example B226 iV-[(3S)-l-Acetylpyrrolidin-3-yl]-iV'-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea bis(trifluoroacetate)
Figure imgf000427_0002
The desired compound was prepared according to the procedure of Example B26, using N- [6- Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea dihydrochloride and acetyl chloride as the starting materials in 18% yield. LCMS for C24H26C1Ν8O2(M+H)+: m/z = 493.2.
Example B227 iV-[(3S)-l-benzoylpyrrolidin-3-yl]-iV'-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea bis(trifluoroacetate)
Figure imgf000428_0001
The desired compound was prepared according to the procedure of Example B26, using N-[6- Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea dihydrochloride and benzoyl chloride as the starting materials in 23% yield. LCMS for C29H28CIN8O2(IVLI-H)+: m/z = 555.3.
Example B228 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[(3S)-l-(cyclopropylcarbonyl)pyrrolidin-3- yl]urea trifluoroacetate
Figure imgf000428_0002
The desired compound was prepared according to the procedure of Example B26, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea dihydrochloride and cyclopropanecarbonyl chloride as the starting materials in 10% yield. LCMS for C27H29ClN7O2(M-I-H)+: m/z = 518.2. Example B229 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[(3S)-l-isobutyrylpyrrolidin-3-yl]urea trifluoroacetate
Figure imgf000429_0001
The desired compound was prepared according to the procedure of Example B26, using N- [6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea dihydrochloride and isobutyryl chloride as the starting materials in 9% yield. LCMS for C27H3IClN7O2(IVLHr)+: m/z = 520.2.
Example B230
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-l-(isoxazol-5-ylcarbonyl)pyrrolidin-3- yl]urea trifluoroacetate
Figure imgf000429_0002
The desired compound was prepared according to the procedure of Example B26, using N- [6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea dihydrochloride and isoxazole-5-carbonyl chloride as the starting materials in 8% yield. LCMS for C27H26ClN8O3(IVLi-H)+: m/z = 545.3.
Example B231 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[(3S)-l-(l,3-thiazol-2-ylcarbonyl)pyrrolidin-3- yl]urea trifluoroacetate
Figure imgf000430_0001
The desired compound was prepared according to the procedure of Example B26, using N- [6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea dihydrochloride and l,3-thiazole-2-carbonyl chloride as the starting materials in 8% yield. LCMS for C27H26ClN8O2S(M-I-H)+: m/z = 561.3.
Example B232
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-{(3S)-l-[(l-methyl-lH-pyrazol-3- yl)carbonyl]pyrrolidin-3-yl}urea bis(trifluoroacetate)
Figure imgf000431_0001
The desired compound was prepared according to the procedure of Example B26, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea dihydrochloride and 1 -methyl- lH-pyrazole-3-carbonyl chloride as the starting materials in 9% yield. LCMS for C28H29ClN9O2(M-I-H)+: m/z = 558.3.
Example B233 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[(3S)-l-(pyridin-2-ylcarbonyl)pyrrolidin-3- yl]urea bis(trifluoroacetate)
Figure imgf000431_0002
The desired compound was prepared according to the procedure of Example B26, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea dihydrochloride and pyridine-2-carbonyl chloride hydrochloride as the starting materials in 6% yield. LCMS for C29H28ClN8O2(M-I-H)+: m/z = 555.2. Example B234 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[(3S)-l-isonicotinoylpyrrolidin-3-yl]urea bis(trifluoroacetate)
Figure imgf000432_0001
The desired compound was prepared according to the procedure of Example B26, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea dihydrochloride and isonicotinoyl chloride hydrochloride as the starting materials in 6% yield. LCMS for C29H28C1Ν8O2(M+H)+: m/z = 555.0.
Example B235 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[(3S)-l-(4-cyanobenzoyl)pyrrolidin-3-yl]urea trifluoroacetate
Figure imgf000432_0002
The desired compound was prepared according to the procedure of Example B267, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea dihydrochloride and 4-cyanobenzoyl chloride as the starting materials in 9% yield. LCMS for C3iH28ClΝ8O2(M+H)+: m/z = 579.3.
Example B236 tert-Butyl [(3R)-l-({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)pyrrolidin-3-yl]carbamate
Figure imgf000433_0001
To a mixture of 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride (30 mg, 0.07 mmol) and pyridine (18.9 μL, 0.234 mmol) in methylene chloride (0.4 mL) was added 20% phosgene in toluene(l:4, phosgene:toluene, 50.2 μL, 0.0950 mmol). The resulting mixture was stirred for 1 hour before adding tert-butyl (3R)-pyrrolidin-3-ylcarbamate (14.3 mg, 0.0767 mmol) and pyridine (13.0 μL, 0.161 mmol). The mixture was allowed to stir overnight. It was diluted with methanol and purified by preparative
LCMS (pH 10) to give the desired product. LCMS calculated for C28H33ClN7O3 (M+H)+: m/z = 550.2.
Example B237 tert-Butyl 3-[({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]piperidine-l-carboxylate
Figure imgf000434_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and tert-butyl 3-aminopiperidine-l-carboxylate as the starting materials in 20% yield. LCMS for C29H35ClN7O3 (M+H)+: m/z = 564.2.
Example B238 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-piperidin-3-ylurea bis(trifluoroacetate)
Figure imgf000434_0002
The desired compound was prepared according to the procedure of Example B21, step B, using tert-butyl 3-[({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18 -nonaen-12-yl] amino Jcarbonyl) amino] piperidine-1-carboxylate as the starting material in 80% yield. LCMS for C24H27ClN7O (M+H)+: m/z = 464.4.
Example B239 iV'-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV,iV-dimethylurea trifluoroacetate
Figure imgf000435_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and dimethylamine hydrochloride as the starting materials in 14% yield. LCMS for C2IH22ClN6O (M+H)+: m/z = 409.1.
Example B240 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-cyclopropylurea trifluoroacetate
Figure imgf000435_0002
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and cyclopopylamine as the starting materials in 10% yield. LCMS for C22H22ClN6O (M+H)+: m/z = 421.1.
Example B241 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-hydroxyethyl)urea trifluoroacetate
Figure imgf000436_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and ethanolamine as the starting materials in 9% yield. LCMS for C2IH22ClN6O2 (M+H)+: m/z = 425.1.
Example B242 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-hydroxy-l-methylethyl)urea trifluoroacetate
Figure imgf000436_0002
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 2-amino-l-propanol as the starting materials in 12% yield. LCMS for C22H24ClN6O2 (M+H)+: m/z = 439.1.
Example B243 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-methoxyethyl)urea trifluoroacetate
Figure imgf000437_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 2-methoxyethylamine as the starting materials in 8% yield. LCMS for C22H24ClN6O2 (M+H)+: m/z = 439.1.
Example B244 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-lH-l,2,4-triazol-3-ylurea trifluoroacetate
Figure imgf000437_0002
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 3-amino-l,2,4-triazole as the starting materials in 8% yield. LCMS for C2IHi9ClN9O (M+H)+: m/z = 448.0.
Example B245 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-l,3-thiazol-2-ylurea trifluoroacetate
Figure imgf000438_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 2-aminothiazole as the starting materials in 10% yield. LCMS for C22H19ClN7OS (M+H)+: m/z = 464.0. 1HNMR (400 MHz, DMSO) δ9.49 (s, 1 H), 9.41 (s, 1 H), 8.48 (s, 1 H), 8.14 (s, 1 H), 8.00 (s, 1 H), 7.75-7.71 (m, 2 H), 7.39 (d, 2 H), 7.12-7.03 (m, 3 H), 6.87 (d, 1 H), 6.82 (d, 1 H), 2.92 (m, 4 H).
Example B246 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(pyridin-4-ylmethyl)ureabis(trifluoroacetate)
Figure imgf000438_0002
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 4-(aminomethyl)pyridine as the starting materials in 11% yield. LCMS for C25H23ClN7O (M+H)+: m/z = 472.1.
Example B247 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-methoxy-l-methylethyl)ureatrifluoroacetate
Figure imgf000439_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and l-methoxypropan-2-amine as the starting materials in 20% yield. LCMS for C23H26CIN6O2 (MH-H)+: m/z = 453.5. 1HNMR (400 MHz, DMSO) δ9.58 (s, 1 H), 9.45 (s, 1 H), 8.13 (s, 1 H), 7.98 (s, 1 H), 7.74-7.70 (m, 2 H), 7.62 (d, 1 H), 7.09 (t, 1 H), 6.94 (d, 1 H), 6.87 (d, 1 H), 6.81 (d, 1 H), 6.55 (d, 1 H), 3.83 (m, 1 H), 3.38-3.25 (m, 5 H), 2.88 (m, 4 H), 1.09 (d, 3 H).
Example B248 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(5-methyl-l,3-thiazol-2-yl)urea trifluoroacetate
Figure imgf000439_0002
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 5-methyl-l,3-thiazol-2-amine as the starting materials in 11% yield. LCMS calculated for C23H21ClN7OS (M+H)+: m/z = 478.0. Example B249 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(4-methyl-l,3-thiazol-2-yl)ureatrifluoroacetate
Figure imgf000440_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 4-methyl-l,3-thiazole-2-amine as the starting materials in 11% yield. LCMS for C23H2IClN7OS (M+H)+: m/z = 478.0.
Example B250
2-[({[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]-l,3-thiazole-4-carboxylic acid trifluoroacetate
Figure imgf000440_0002
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 2-amino-l,3-thiazole-4-carboxylic acid hydrobromide as the starting materials in 7% yield. LCMS for C23Hi9ClN7O3S (M+H)+: m/z = 508.0.
Example B251 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-lH-tetrazol-5-ylurea trifluoroacetate
Figure imgf000441_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and lH-tetrazol-5 -amine as the starting materials in 5% yield. LCMS for C20H18ClNioO (M+H)+: m/z = 449.1.
Example B252 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(5-chloro-l,3-thiazol-2-yl)urea trifluoroacetate
Figure imgf000441_0002
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 5-chloro-l,3-thiazol-2-amine hydrochloride as the starting materials in 4% yield. LCMS for C22H18Cl2N7OS (M+H)+: m/z = 498.0.
Example B253 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-pyridin-2-ylurea bis(trifluoroacetate)
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 2-pyridinamine as the starting materials in 4% yield. LCMS for C24H21ClN7O (M+H)+: m/z = 458.1.
Example B254 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-morpholin-4-ylethyl)urea bis(trifluoroacetate)
Figure imgf000442_0002
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and N-(2-aminoethyl)morpholine as the starting materials in 31% yield. LCMS for C25H29ClN7O2 (M+H)+: m/z = 494.3. 1HNMR (300 MHz, CD30D) δ 8.10 (s, 1 H), 7.83 (s, 1 H), 7.76 (s, 1 H), 7.57 (d, 1 H), 7.21 (t, 1 H), 7.06 (d, 1 H), 7.00 (d, 1 H), 6.91 (d, 1 H), 4.09 (m, 2 H), 3.79 (m, 2 H), 3.64 (m, 4 H), 3.35 (m, 2 H), 3.20 (m, 2 H), 3.05 (m, 4 H).
Example B255 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-pyrrolidin-l-ylethyl)urea bis(trifluoroacetate)
Figure imgf000443_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 1-pyrrolidineethanamine as the starting materials in 33% yield. LCMS for C25H29ClN7O (M+H)+: m/z = 478.2.
Example B256 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[2-(l-methylpyrrolidin-2-yl)ethyl]urea bis(trifluoroacetate)
Figure imgf000443_0002
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 2-(l-methyllpyrrolidin-2-yl)ethanamine as the starting materials in 37% yield. LCMS for C26H3IClN7O (M+H)+: m/z = 492.2. 1HNMR (300 MHz, CD30D) δ 8.11 (s, 1 H), 7.83 (s, 1 H), 7.76 (s, 1 H), 7.55 (d, 1 H), 7.21 (t, 1 H), 7.06 (d, 1 H), 6.99 (d, 1 H), 6.91 (d, 1 H), 3.68 (m, 1 H), 3.32 (m, 2 H), 3.19 (m, 2 H), 3.02 (m, 4 H), 2.95 (m, 2 H), 2.45 (m, 1 H), 2.25-1.92 (m, 4 H), 1.80 (m, 2 H).
Example B257 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[2-(2-oxopyrrolidin-l-yl)ethyl]urea trifluoroacetate
Figure imgf000444_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and l-(2-aminoethyl)pyrrolidin-2-one hydrochloride as the starting materials in 34% yield. LCMS for C25H27ClN7O2 (M+H)+: m/z = 492.1.
Example B258 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-piperidin-l-ylethyl)urea bis(trifluoroacetate)
Figure imgf000444_0002
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 1-piperidineethanamine as the starting materials in 42% yield. LCMS for C26H3IClN7O (M+H)+: m/z = 492.2.
Example B259 tert-Butyl 4-{2-[({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}piperazine-l- carboxylate
Figure imgf000445_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and tert-butyl 4-(2-aminoethyl)piperazine-l-carboxylate as the starting materials in 10% yield. LCMS for C30H38ClN8O3 (M+H)+: m/z = 593.2.
Example B260 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-piperazin-l-ylethyl)urea trihydrochloride
Figure imgf000446_0001
The desired compound was prepared according to the procedure of Example B25, step B, using terf-butyl 4-{2-[({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino}carbonyl)amino]ethyl}piperazine-l-carboxylate as the starting material in 90% yield. LCMS for C25H30ClN8O (M+H)+: m/z = 493.2.
Example B261 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV-[(3S)-l-methylpyrrolidin-3-yl]urea bis(trifluoroacetate)
Figure imgf000446_0002
The desired compound was prepared according to the procedure of Example B 192, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea dihydrochloride and formaldehyde as the starting materials in 20% yield. LCMS for C24H27C1Ν7O(M+H)+: m/z = 464.1.
Example B262 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[(3S)-l-pyrimidin-2-ylpyrrolidin-3-yl]urea bis(trifluoroacetate)
Figure imgf000447_0001
A mixture of N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea (18 mg, 0.040 mmol), 2- chloropyrimidine (8.5 mg, 0.074 mmol), and NN-diisopropylethylamine (14 μL, 0.080 mmol) in isopropyl alcohol (0.4 mL) was heated in a microwave at 100 0C for 10 minutes. The mixture was diluted with methanol and purified by preparative LCMS (pH 2) to give of the desired product as a white solid (12.5 mg, 36%). LCMS for C27H27C1Ν9O(M+H)+: m/z = 528.3.
Example B263 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV-{l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4- yljurea trifluoroacetate
Figure imgf000447_0002
The desired compound was prepared according to the procedure of Example B26, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-piperidin-4-ylurea trihydrochloride and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 10% yield. LCMS for C29H30CIN8O3(IVLI-H)+: m/z = 573.0.
Example B264 iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-{l-[(5-methylisoxazol-4-yl)carbonyl]piperidin-4- yljurea trifluoroacetate
Figure imgf000448_0001
The desired compound was prepared according to the procedure of Example B26, using N-[6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-piperidin-4-ylurea trihydrochloride and 5-methylisoxazole-4-carbonyl chloride as the starting materials in 10% yield. LCMS for C29H30ClN8O3(M-I-H)+: m/z = 573.0.
Example B265 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-{(3S)-l-[(5-methylisoxazol-3- yl)carbonyl]pyrrolidin-3-yl}urea bis(trifluoroacetate)
Figure imgf000449_0001
The desired compound was prepared according to the procedure of Example B26, using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(35)-pyrrolidin-3-yl]urea trihydrochloride and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 28% yield. LCMS for C27H27CIN9O3(MH-H)+: m/z = 560.1.
Example B266
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-{(3S)-l-[(5-methylisoxazol-4- yl)carbonyl]pyrrolidin-3-yl}urea bis(trifluoroacetate)
Figure imgf000449_0002
The desired compound was prepared according to the procedure of Example B26, using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea trihydrochloride and 5-methylisoxazole-4-carbonyl chloride as the starting materials in 17% yield. LCMS for C27H27C1Ν9O3(M+H)+: m/z = 560.0. Example B267 iV-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[(3S)-l-(lH-pyrazol-4-ylcarbonyl)pyrrolidin-3- yl]urea bis(trifluoroacetate)
Figure imgf000450_0001
To a mixture of N-[6-chloro-2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea trihydrochloride (10 mg, 0.02 mmol), lH-pyrazole-4-carboxylic acid (3.2 mg, 0.029 mmol) and triethylamine (10.6 μL, 0.076 mmol) in DMF (0.2 mL) was added benzotiazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (15.2 mg, 0.034 mmol). The resulting solution was stirred overnight at room temperature. The reaction solution was diluted with methanol and purified with preparative LCMS to give the desired product (1.1 mg, 6%). LCMS for C26H26ClNiOO2(M+!!)+: m/z = 545.4.
Example B268 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[(3S)-l-(lH-pyrazol-5-ylcarbonyl)pyrrolidin-3- yl]urea bis(trifluoroacetate)
Figure imgf000451_0001
The desired compound was prepared according to the procedure of Example B267, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea trihydrochloride and lH-pyrazole-5-carboxylic acid as the starting materials in 11% yield. LCMS for C26H26CrNiOO2(IVLi-H)+: m/z = 545.3.
Example B269 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-{(3S)-l-[(l-methyl-lH-pyrazol-4- yl)carbonyl]pyrrolidin-3-yl}urea bis(trifluoroacetate)
Figure imgf000451_0002
The desired compound was prepared according to the procedure of Example B267, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea trihydrochloride and 1 -methyl- lH-pyrazole-4-carboxylic acid as the starting materials in 22% yield. LCMS for C27H28ClNi0O2(M-I-H)+: m/z = 559.3. Example B270 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-{(3S)-l-[(5-cyclopropylisoxazol-3- yl)carbonyl]pyrrolidin-3-yl}urea bis(trifluoroacetate)
Figure imgf000452_0001
The desired compound was prepared according to the procedure of Example B267, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea trihydrochloride and 5-cyclopropylisoxzole-3-carboxylic acid as the starting materials in 18% yield. LCMS for C29H29CIN9O3(MH-H)+: m/z = 586.3.
Example B271 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[(3S)-l-(isoxazol-5-ylcarbonyl)pyrrolidin-3- yl]urea bis(trifluoroacetate)
Figure imgf000452_0002
The desired compound was prepared according to the procedure of Example B26, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea trihydrochloride and isoxazole-5-carbonyl chloride as the starting materials in 7% yield. LCMS for C26H25CiN9O3(M-I-H)+: m/z = 546.2.
Example B272 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-{(3S)-l-[(l-methyl-lH-pyrazol-3- yl)carbonyl]pyrrolidin-3-yl}urea bis(trifluoroacetate)
Figure imgf000453_0001
The desired compound was prepared according to the procedure of Example B26, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea trihydrochloride and 1 -methyl- lH-pyrazole-3-carbonyl chloride as the starting materials in 9% yield. LCMS for C27H28ClNi0O2(M-I-H)+: m/z = 559.2.
Example B273 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-{(3S)-l-[(4-methyl-l,3-oxazol-5- yl)carbonyl]pyrrolidin-3-yl}urea bis(trifluoroacetate)
Figure imgf000454_0001
The desired compound was prepared according to the procedure of Example B26, using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea trihydrochloride and 4-methyl-l,3-oxazole-5-carbonyl chloride as the starting materials in 7% yield. LCMS for C27H27C1Ν9O3(M+H)+: m/z = 560.2.
Example B274
N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-{(3S)-l-[(3,5-dimethylisoxazol-4- yl)carbonyl]pyrrolidin-3-yl}urea bis(trifluoroacetate)
Figure imgf000454_0002
The desired compound was prepared according to the procedure of Example B26, using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea trihydrochloride and 3,5-dimethylisoxazole -4-carbonyl chloride as the starting materials in 19% yield. LCMS for C28H29ClN9O3 (M+H)+: m/z = 574.3.
Example B275 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-[(3S)-l-[l,3]oxazolo[5,4-b]pyridin-2-ylpyrrolidin- 3-yl]urea tris(trifluoroacetate)
Figure imgf000455_0001
A mixture of N-[6-chloro-2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea trihydrochloride (15 mg, 0.027 mmol), [l,3]oxazole[5,4-b]pyridine-2-thiol (4.9 mg, 0.032 mmol) and triethylamine (14.9 μL, 0.107 mol) in 1,4-dioxane (0.1 mL) was stirred at 70 0C for 3 hours. The solvent was removed in vacuo. To the residue was added ethanol (0.2 mL), silver nitrate (9 mg, 0.05 mmol) and 29% ammonium hydroxide in water (30 μL, 0.2 mmol). The resulting solution was stirred overnight at room temperature. The reaction solution was diluted with methanol and purified with preparative LCMS to give the desired product (1.7 mg, 7%). LCMS for C28H26ClΝio02(M+H)+: m/z = 569.0.
Example B276 6-Chloro-iV-(4-methylpyrimidin-2-yl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine bis(trifluoroacetate)
Figure imgf000455_0002
A mixture of 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride (15 mg, 0.036 mmol), 2-chloro-4- methylpyrimidine (5.8 mg, 0.045 mmol) and N,N-diisopropylethylamine (22 μL, 0.13 mmol) in isopropyl alcohol (0.2 mL) was heated at 180 0C for 40 min in the microwave reactor. The reaction solution was diluted with methanol and purified with preparative LCMS to give the desired product (2.4 mg, 8%). LCMS for C23H21C1Ν7(M+H)+: m/z = 430.3.
Example B277
2-{[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}pyrimidin-4-ol bis(trifluoroacetate)
Figure imgf000456_0001
The desired compound was prepared according to the procedure of Example B276, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 2-chloro-4-methoxypyrimidine as the starting materials in 16% yield. LCMS for C22H19C1N7O(M+H)+: m/z = 432.3.
Example B278
Ethyl 2-{[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-l,3-oxazole-4-carboxylate bis(trifluoroacetate)
Figure imgf000457_0001
The desired compound was prepared according to the procedure of Example B276, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and ethyl-2-chloro-l,3-oxazole-4-carboxylate as the starting materials in 5% yield. LCMS for C24H22CIN6O3(IVLI-H)+: m/z = 477.2.
Example B279
6-Chloro-iV-(4-phenylpyrimidin-2-yl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate)
Figure imgf000457_0002
The desired compound was prepared according to the procedure of Example B276, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and 2-chloro-4-phenylpyrimidine as the starting materials in 8% yield. LCMS for C28H23C1N7(M+H)+: m/z = 492.4.
Example B280
2-Chloro-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-6-methylpyrimidine-4-carboxamide bis(trifluoroacetate)
Figure imgf000458_0001
The desired compound was prepared according to the procedure of Example B276, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and methyl-2-chloro-6-methylpyrimidine-4-carboxylate as the starting materials in 8% yield. LCMS for C24H20Cl2N7O(M+H)+: m/z = 492.3.
Example B281 iV-[4-(4-Aminopiperidin-l-yl)pyrimidin-2-yl]-6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate)
Figure imgf000458_0002
To a solution of 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride (10 mg, 0.02 mmol) in 2- methoxyethanol (0.2 mL) was added tert-butyl [l-(2-chloropyrimidin-4-yl)piperidin-4-yl] carbamate (9.1 mg, 0.029 mmol) and 4.0 M hydrogen chloride in 1,4-dioxane (9.1 μL, 0.036 mmol). The solution was heated at 130 0C for 15 min. The reaction solution was diluted with methanol and purified with preparative LCMS to give the desired product (7.0 mg, 30%). LCMS for C27H29CiN9(M+H)+: m/z = 514.1. Example B282 iV-[4-(4-Aminopiperidin-l-yl)pyrimidin-2-yl]-6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tetrakis(trifluoroacetate)
Figure imgf000459_0001
The desired compound was prepared according to the procedure of Example B281, using 6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine trihydrochloride and tert-butyl [l-(2-chloropyrimidin-4-yl)piperidin-4-yl]carbamate as the starting materials in 31% yield. LCMS for C26H28CINIO(IVLI-H)+: m/z = 515.1.
Example B283 iV-[(3S)-l-Benzylpyrrolidin-3-yl]-iV'-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV- methylurea
Figure imgf000460_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and (3S)-l-benzyl-N-methylpyrrolidin-3-amine as the starting materials in 32% yield. LCMS for C3IH33ClN7O (M+H)+: m/z = 554.3.
Example B284 iV-[(3S)-l-Benzylpyrrolidin-3-yl]-iV'-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV- methylurea
Figure imgf000460_0002
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine and (3S)-l-benzyl-N-methylpyrrolidin-3-amine as the starting materials in 33% yield. LCMS for C30H32ClN8O (M+H)+: m/z = 555.3. Example B285 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperazine-l-carboxamidetrihydrochloride
Figure imgf000461_0001
Step A: tert-Butyl 4-({[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-
1(20), 3(22), 4,6, 9(21), 10, 12,16, 18-nonaen-12-yl]amino}carbonyl)piperazine-l-carboxy late
Figure imgf000461_0002
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine and tert-buiyl piperidine-1-carboxylate as the starting materials in 54% yield. LCMS for C27H32ClN8O3 (M+H)+: m/z = 551.3.
Step B: N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperazine-l-carboxamidetrihydrochloride
The desired compound was prepared according to the procedure of Example B21, step B, using tert-butyl 4-({ [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino}carbonyl)piperazine-l-carboxylate as the starting material in 96% yield. LCMS for C22H24ClN8O (M+H)+: m/z = 451.4.
Example B286
4-Benzoyl-iV-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperazine-l-carboxamide bis(trifluoroacetate)
Figure imgf000462_0001
The desired compound was prepared according to the procedure of Example B26, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]piperazine-l-carboxamide trihydrochloride and benzoyl chloride as the starting materials in 45% yield. LCMS for C29H28C1Ν8O2(M+H)+: m/z = 555.3.
Example B287
4-Benzyl-iV-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperazine-l-carboxamidetris(trifluoroacetate)
Figure imgf000462_0002
The desired compound was prepared according to the procedure of Example B 192, using N-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]piperazine-l-carboxamide trihydrochloride and benzaldehyde as the starting materials in 22% yield. LCMS for C29H30ClN8O(IVLHr)+: m/z = 541.3.
Example B288 iV'-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV-methyl-iV-[(3S)-pyrrolidin-3-yl]urea tris(trifluoroacetate)
Figure imgf000463_0001
Step A: N-[(3S)-l-Benzylpyrrolidin-3-yl] N'-[6-chloro-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N- methylurea
Figure imgf000463_0002
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine and (3S)-l-benzyl-N-methylpyrrolidin-3-amine as the starting materials in 33% yield. LCMS for C30H32ClN8O (M+H)+: m/z = 555.3.
Step B: N'-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N-methyl-N-[(3S)-pyrrolidin-3-yl]urea tris(trifluoroacetate)
To a mixture of N-[(3S)-l-benzylpyrrolidin-3-yl] N'-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N- methylurea (45 mg, 0.037 mmol) and 10% palladium on carbon (50 mg, 0.05 mmol) in methanol (0.5 mL) was added ammonium formate (32 mg, 0.51 mmol). The reaction solution was stirred at 65 0C overnight. The reaction solution was cooled to room temperature and diluted with methanol and purified with preparative LCMS to give the desired product (1.2 mg, 2%). LCMS for C23H26ClN8O (M+H)+: m/z = 465.2.
Example B289 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-pyridin-2-ylpiperazine-l-carboxamide tris(trifluoroacetate)
Figure imgf000464_0001
The desired compound was prepared according to the procedure of Example B236, using 6-chloro-
2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen- 12-amine and N-(2-pyridyl)piperazine as the starting materials in 27% yield. LCMS for C27H27ClN9O (M+H)+: m/z = 528.3.
Example B290 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-pyridin-2-ylpiperazine-l-carboxamide bis(trifluoroacetate)
Figure imgf000465_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and N-(2-pyridyl)piperazine as the starting materials in 18% yield. LCMS for C28H28ClN8O (M+H)+: m/z = 527.3.
Example B291 iV-[(3S)-l-Benzoylpyrrolidin-3-yl]-iV'-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV- methylurea bis(trifluoroacetate)
Figure imgf000465_0002
The desired compound was prepared according to the procedure of Example B26, using N'-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N-methyl-N-[(3S)-pyrrolidin-3-yl]urea trihydrochloride and benzoyl chloride as the starting materials in 14% yield. LCMS for C3oH3oClΝ802(M+H)+: m/z = 569.3.
Example B292 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-phenylpiperazine-l-carboxamide tris(trifluoroacetate)
Figure imgf000466_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine trihydrochloride and 1-phenylpiperazine as the starting materials in 28% yield. LCMS for C28H28ClN8O (M+H)+: m/z = 527.2. 1HNMR (300 MHz, CD3OD) δ 9.29 (s, 1 H), 8.30 (d, 2 H), 8.16 (s, 1 H), 7.72 (s, 1 H), 7.33 (t, 2 H), 7.24 (d, 1 H), 7.13 (d, 3 H), 6.99 (t, 1 H), 3.79 (t, 4 H), 3.35 (m, 4 H), 3.11 (q, 4 H).
Example B293 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-pyridin-4-ylpiperazine-l-carboxamide tetrakis(trifluoroacetate)
Figure imgf000467_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine trihydrochloride and l-pyridin-4-ylpiperazine as the starting materials in 19% yield. LCMS for C27H27ClN9O (M+H)+: m/z = 528.3.
Example B294 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-pyrazin-2-ylpiperazine-l-carboxamide tetrakis(trifluoroacetate)
Figure imgf000467_0002
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine trihydrochloride and 2-piperazin-l-ylpyrazine as the starting materials in 19% yield. LCMS for C26H26ClNi0O (M+H)+: m/z = 529.3. Example B295 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(2-fluorophenyl)piperazine-l-carboxamide tris(trifluoroacetate)
Figure imgf000468_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine trihydrochloride and l-(2-fluorophenyl)piperazine as the starting materials in 23% yield. LCMS for C28H27ClFN8O (M+H)+: m/z = 545.3.
Example B296
6-Chloro-iV-[4-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-ylcarbonyl)-l,3-oxazol-2-yl]-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine bis(trifluoroacetate)
Figure imgf000468_0002
The desired compound was prepared according to the procedure of Example B7, using methyl ethyl 2- { [6-chloro-2,4,8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-l,3-oxazole-4-carboxylate bis(trifluoroacetate) and octahydropyrrolo[l,2-a]pyrazine as the starting materials in 25% yield. LCMS for C2QH30ClN8O2 (M+H)+: m/z = 557.3.
Example B297 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(4-fluorophenyl)piperazine-l-carboxamide tris(trifluoroacetate)
Figure imgf000469_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine trihydrochloride and N-(4-fluorophenyl)piperazine as the starting materials in 17% yield. LCMS for C28H27ClFN8O (M+H)+: m/z = 545.3.
Example B298 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(2-methoxyphenyl)piperazine-l-carboxamide tis(trifluoroacetate)
Figure imgf000470_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine trihydrochloride and l-(2-methoxyphenyl)piperazine as the starting materials in 25% yield. LCMS for C29H30ClN8O2 (M+H)+: m/z = 557.4.
Example B299 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(4-methoxyphenyl)piperazine-l-carboxamide tris(trifluoroacetate)
Figure imgf000470_0002
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine trihydrochloride and l-(4-methoxyphenyl)piperazine as the starting materials in 12% yield. LCMS for C29H30ClN8O2 (M+H)+: m/z = 557.3. Example B300 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(2-cyanophenyl)piperazine-l-carboxamide tris(trifluoroacetate)
Figure imgf000471_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine trihydrochloride and 2-piperazin-l-yl-benzonitrile as the starting materials in 18% yield. LCMS for C29H27ClN9O (M+H)+: m/z = 552.2.
Example B301 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-[5-(trifluoromethyl)pyridin-2-yl]piperazine-l- carboxamide tris(trifluoroacetate)
Figure imgf000472_0001
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine trihydrochloride and l-[5-(trifluoromethyl)pyridine-2-yl]piperazine as the starting materials in 18% yield. LCMS for C28H26ClF3N9O (M+H)+: m/z = 596.3.
Example B302 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-[3-chloro-5-(trifluoromethyl)pyridin-2- yl]piperazine-l-carboxamide tris(trifluoroacetate)
Figure imgf000472_0002
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine trihydrochloride and l-[3-chloro-5-(trifluoromethyl)pyridine-2-yl]piperazine as the starting materials in 19% yield. LCMS for C28H25Cl2F3N9O (M+H)+: m/z = 630.3.
Example B303 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(4-cyanophenyl)piperazine-l-carboxamide tris(trifluoroacetate)
Figure imgf000473_0001
Step A: Phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]carbamate
Figure imgf000473_0002
To a solution of 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine trihydrochloride (100.0 mg, 0.223 mmol) in pyridine (1 mL) was added carbonochloridic acid, phenyl ester (42.0 μL, 0.335 mmol). The reaction solution was stirred at room temperature overnight. The reaction solution was concentrated and diluted with water. The resulting precipitate was filtered and dried under vacuum to give the desired product (100 mg, 88%). LCMS for C24H20ClN6O2 (M+H)+: m/z = 459.2.
Step B: N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(4-cyanophenyl)piperazine-l-carboxamide tris(trifluoroacetate)
A mixture of phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]carbamate (12 mg, 0.026 mmol), 4-piperazin-l- ylbenzonitrile hydrochloride (9.0 mg, 0.040 mmol) and triethylamin (11 mL, 0.078 mmol) and chloroform (0.2 mL) was stirred at 70 0C overnight. The solvent was removed in vacuo and the residue was dissolved in methanol and purified with preparative LCMS to give the desired product (6.1 mg, 30%). LCMS for C29H27ClN9O (M+H)+: m/z = 552.3.
Example B304 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(3-methoxyphenyl)piperazine-l-carboxamide tris(trifluoroacetate)
Figure imgf000474_0001
The desired compound was prepared according to the procedure of Example B303, using phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]carbamate and l-(3-methoxyphenyl)piperazine dihydrochloride as the starting materials in 45% yield. LCMS for C29H30ClN8O2 (M+H)+: m/z = 557.4.
Example B305 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(2-chlorophenyl)piperazine-l-carboxamide bis(trifluoroacetate)
Figure imgf000475_0001
The desired compound was prepared according to the procedure of Example B303, using phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]carbamate and l-(2-chlorophenyl)piperazine hydrochloride as the starting materials in 40% yield. LCMS for C28H27Cl2N8O (M+H)+: m/z = 561.3.
Example B306 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(3-chlorophenyl)piperazine-l-carboxamide tris(trifluoroacetate)
Figure imgf000475_0002
The desired compound was prepared according to the procedure of Example B303, using phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]carbamate and l-(3-chlorophenyl)piperazine hydrochloride as the starting materials in 45% yield. LCMS for C28H27Cl2N8O (M+H)+: m/z = 561.3.
Example B307 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(4-chlorophenyl)piperazine-l-carboxamide tris(trifluoroacetate)
Figure imgf000476_0001
The desired compound was prepared according to the procedure of Example B303, using phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21), 10,12,16,18- nonaen-12-yl]carbamate and l-(4-chlorophenyl)piperazine hydrochloride as the starting materials in 47% yield. LCMS for C28H27Cl2N8O (M+H)+: m/z = 561.3.
Example B308 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(6-methylpyrazin-2-yl)piperazine-l-carboxamide tris(trifluoroacetate)
Figure imgf000477_0001
The desired compound was prepared according to the procedure of Example B303, using phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21), 10,12,16,18- nonaen-12-yl]carbamate and 2-methyl-6-piperazin-l-ylpyrazine as the starting materials in 32% yield. LCMS for C27H28ClNi0O (M+H)+: m/z = 543.3.
Example B309 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-pyrimidin-2-ylpiperazine-l-carboxamide tris(trifluoroacetate)
Figure imgf000477_0002
The desired compound was prepared according to the procedure of Example B303, using phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21), 10,12,16,18- nonaen-12-yl]carbamate and 2-piperazin-l-ylpyrimidine as the starting materials in 39% yield. LCMS for C26H26ClNi0O (M+H)+: m/z = 529.3. 1HNMR (400 MHz, CD30D) δ 9.30 (s, 1 H), 8.40 (m, 2 H), 8.29 (d, 2 H), 8.15 (s, 1 H), 7.71 (s, 2 H), 7.23 (d, 1 H), 7.13 (d, 1 H), 6.68 (t, 1 H), 3.93 (t, 4 H), 3.68 (m, 4 H), 3.10 (m, 4 H).
Example B310 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(5-cyanopyridin-2-yl)piperazine-l-carboxamide tris(trifluoroacetate)
Figure imgf000478_0001
The desired compound was prepared according to the procedure of Example B303, using phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21), 10,12,16,18- nonaen-12-yl]carbamate and 6-piperazin-l-ylnicotinonitrile as the starting materials in 44% yield. LCMS for C28H26ClNi0O (M+H)+: m/z = 553.3.
Example B311 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(3-cyanopyridin-2-yl)piperazine-l-carboxamide tris(trifluoroacetate)
Figure imgf000479_0001
The desired compound was prepared according to the procedure of Example B303, using phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]carbamate and 2-piperazin-l-ylnicotinonitrile as the starting materials in 32% yield. LCMS for C28H26ClNi0O (M+H)+: m/z = 553.3.
Example B312 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-phenylpyrrolidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000479_0002
The desired compound was prepared according to the procedure of Example B303, using phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]carbamate and 3-phenylpyrrolidine as the starting materials in 38% yield. LCMS for C28H27ClN7O (M+H)+: m/z = 512.3. 1HNMR (400 MHz, CD30D) δ 9.29 (s, 1 H), 8.28 (d, 2 H), 8.13 (s, 1 H), 7.70 (s, 1 H), 7.35 (d, 4 H), 7.26 (m, 2 H), 7.12 (d, 1 H), 3.98 (t, 1 H), 3.77 (t, 1 H), 3.62 - 3.49 (m, 4 H), 3.11 (m, 5 H).
Example B313 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-pyrazin-2-ylpyrrolidine-l-carboxamide tetrakis(trifluoroacetate)
Figure imgf000480_0001
The desired compound was prepared according to the procedure of Example B303, using phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]carbamate and 2-pyrrolidin-3-ylpyrazine trihydrochloride as the starting materials in 33% yield. LCMS for C26H25ClN9O (M+H)+: m/z = 514.2.
Example B314 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-phenylpiperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000481_0001
The desired compound was prepared according to the procedure of Example B303, using phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]carbamate and 4-phenylpiperidine as the starting materials in 32% yield. LCMS for C29H29ClN7O (M+H)+: m/z = 526.3.
Example B315 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]hexahydropyrrolo[l,2-a]pyrazine-2(lH)- carboxamide tris(trifluoroacetate)
Figure imgf000481_0002
The desired compound was prepared according to the procedure of Example B303, using phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]carbamate and octahydropyrrolo[l,2-a]pyrazine as the starting materials in 29% yield. LCMS for C25H28ClN8O (M+H)+: m/z = 491.1.
Example B316 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- a]pyrazine-7(8H)-carboxamide tris(trifluoroacetate)
Figure imgf000482_0001
The desired compound was prepared according to the procedure of Example B303, using phenyl
[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]carbamate and 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3,-a]pyrazine hydrochloride as the starting materials in 13% yield. LCMS for C24H2ICIF3NI0O (M+H)+: m/z = 557.1.
Example B317
4-Acetyl-iV-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperazine-l-carboxamide bis(trifluoroacetate)
Figure imgf000482_0002
The desired compound was prepared according to the procedure of Example B303, using phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21), 10,12,16,18- nonaen-12-yl]carbamate and 1-acetylpiperazine as the starting materials in 42% yield. LCMS for C24H26ClN8O2 (M+H)+: m/z = 493.4. Example B318 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(methylsulfonyl)piperazine-l-carboxamide bis(trifluoroacetate)
Figure imgf000483_0001
The desired compound was prepared according to the procedure of Example B303, using phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]carbamate and l-(methylsulfonyl)piperazine as the starting materials in 37% yield. LCMS for C23H26ClN8O3S (M+H)+: m/z = 529.3.
Example B319 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(phenylsulfonyl)piperazine-l-carboxamide bis(trifluoroacetate)
Figure imgf000483_0002
The desired compound was prepared according to the procedure of Example B303, using phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]carbamate and l-(phenylsulfonyl)piperazine as the starting materials in 29% yield. LCMS for C28H28ClN8O3S (M+H)+: m/z = 591.3.
Example B320 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-methyl-4-phenylpiperazine-l-carboxamide tris(trifluoroacetate)
Figure imgf000484_0001
The desired compound was prepared according to the procedure of Example B303, using phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21), 10,12,16,18- nonaen-12-yl]carbamate and 2-methyl-l-phenylpiperazine as the starting materials in 54% yield. LCMS for C29H30ClN8O (M+H)+: m/z = 541.4.
Example B321 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-(phenylsulfonyl)pyrrolidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000485_0001
The desired compound was prepared according to the procedure of Example B303, using phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21), 10,12,16,18- nonaen-12-yl]carbamate and 3-(phenylsulfonyl)pyrrolidine as the starting materials in 32% yield. LCMS for C28H27ClN7O3S (M+H)+: m/z = 576.2. 1HNMR (400 MHz, DMSO) δ 10.01 (s, 1 H), 9.37 (s, 1 H), 9.02 (s, 1 H), 8.29 (s, 2 H), 8.20 (s, 1 H), 7.91 (m, 3 H), 7.80 (t, 1 H), 7.69 (t, 2 H), 7.62 (s, 1 H), 7.14 (d, 1 H), 7.02 (d, 1 H), 4.21 (m, 1 H), 3.80 (d, 1 H), 3.60 (t, 1 H), 3.43 (m, 2 H), 2.98 (m, 4 H), 2.23 (m, 2 H).
Example B322 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-cyano-4-phenylpiperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000485_0002
The desired compound was prepared according to the procedure of Example B303, using phenyl [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21), 10,12,16,18- nonaen-12-yl]carbamate and 4-phenylpiperidine-4-carbonitrile as the starting materials in 50% yield. LCMS for C30H28ClN8O (M+H)+: m/z = 551.2. 1HNMR (400 MHz, DMSO) δ 9.98 (s, 1 H), 9.36 (s, 1 H), 8.99 (s, 1 H), 8.29 (m, 3 H), 8.20 (s, 1 H), 7.63 (s, 1 H), 7.58 (d, 2 H), 7.47 (t, 2 H), 7.39 (t, 1 H), 7.15 (d, 1 H), 7.03 (t, 1 H), 4.30 (d, 2 H), 3.13 (t, 2 H), 2.98 (m, 4 H), 2.21 (d, 2 H), 1.99 (t, 2 H).
Example B323 iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-cyanourea trifluoroacetate
Figure imgf000486_0001
The desired compound was prepared according to the procedure of Example B236, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and cyanamide as the starting materials in 14% yield. LCMS for C20H17CIN7O (M+H)+: m/z = 406.1.
Example B324 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-hydroxyurea trifluoroacetate
Figure imgf000486_0002
The desired compound was prepared according to the procedure of Example B236, using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride and hydroxylamine as the starting materials in 11% yield. LCMS for Ci9Hi8ClN6O2 (M+H)+: m/z = 397.1. Example B325 iV-{2-[({[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}ethanesulfonamide trifluoroacetate
Figure imgf000487_0001
The desired compound was prepared according to the procedure of Example B 136, using N-(2- aminoethyl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea dihydrochloride and ethanesulfonyl chloride as the starting materials in 27% yield. LCMS for C23H27ClN7O3S(IVLHr)+: m/z = 516.3.
Example B326 iV-{2-[({[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}propane-l-sulfonamide trifluoroacetate
Figure imgf000487_0002
The desired compound was prepared according to the procedure of Example B 136, using N-(2- aminoethyl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea dihydrochloride and 1-propanesulfonyl chloride as the starting materials in 32% yield. LCMS for C24H29CIN7O3S(MH-H)+: m/z = 530.3.
Example B327 iV-{2-[({[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]amino}carbonyl)amino]ethyl}cyclopropanesulfonamide trifluoroacetate
Figure imgf000488_0001
O V
The desired compound was prepared according to the procedure of Example B 136, using N-(2- aminoethyl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-
1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]urea dihydrochloride and cyclopropanesulfonyl chloride as the starting materials in 23% yield. LCMS for C24H27CIN7O3S(MH-H)+: m/z = 528.3.
Example B328 iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV'-(2-{[(dimethylamino)sulfonyl]amino}ethyl)urea trifluoroacetate
Figure imgf000489_0001
The desired compound was prepared according to the procedure of Example B 136, using N-(2- aminoethyl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]urea dihydrochloride and dimethylsulfamoyl chloride as the starting materials in 18% yield. LCMS for C23H28CIN8O3S(IVLI-H)+: m/z = 531.3.
Example B329 iV-{2-[({[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}benzenesulfonamide trifluoroacetate
Figure imgf000489_0002
The desired compound was prepared according to the procedure of Example B 136, using N-(2- aminoethyl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-
1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]urea dihydrochloride and benzenesulfonyl chloride as the starting materials in 22% yield. LCMS for C27H27ClN7O3S(M-I-H)+: m/z = 564.3. Example B330
5-Chloro-iV-{2-[({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}thiophene-2- sulfonamide trifluoroacetate
Figure imgf000490_0001
The desired compound was prepared according to the procedure of Example B 136, using N-(2- aminoethyl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea dihydrochloride and 5-chlorothiophene-2-sulfonyl chloride as the starting materials in 11% yield. LCMS for C25H24Cl2N7O3S2(IVLi-H)+: m/z = 604.2, 606.3.
Example B331
6-Chloro-iV-{2-[({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}pyridine-3-sulfonamide trifluoroacetate
Figure imgf000490_0002
The desired compound was prepared according to the procedure of Example B 136, using N-(2- aminoethyl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea dihydrochloride and 6-chloropyridien-3-sulfonyl chloride as the starting materials in 9% yield. LCMS for C26H25CI2N8O3S(MH-H)+: m/z = 599.2, 601.3.
Example B332 iV-{2-[({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}-l-methyl-lH-pyrazole- 3-sulfonamide trifluoroacetate
Figure imgf000491_0001
The desired compound was prepared according to the procedure of Example B 136, using N-(2- aminoethyl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea dihydrochloride and l-methyl-lH-pyrazole-3- sulfonyl chloride as the starting materials in 17% yield. LCMS for C25H27CIN9O3S(MH-H)+: m/z = 568.3.
Example B333
6-Chloro-iV-[l,3]oxazolo[5,4-b]pyridin-2-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate)
Figure imgf000491_0002
A microwave tube was charged with palladium acetate (1.09 mg, 0.00487 mmol) and dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (6.9 mg, 0.015 mmol). The vessel was evacuated and backfilled with nitrogen (this process was repeated a total of 3 times) and tert-butyl alcohol (1.0 niL) and water (0.351 μL, 0.0195 mmol) were added via syringe. After addition of the water, the solution was heated to 80 0C for 1 min. A second microwave tube was charged with 6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride (20.0 mg, 0.0487 mmol), 2-chloro[l,3]oxazolo[5,4-b]pyridine (7.5 mg, 0.049 mmol) and potassium carbonate (33.6 mg, 0.243 mmol). The vessel was evacuated and backfilled with nitrogen and the activated catalyst solution was transferred from the first reaction vessel into the second via cannula. The reaction was microwaved on 200 watts , 120 0C for 30 minutes. The reaction solution was diluted with DMSO, filtered and purified with preparative LCMS to give the desired product as off-wihte solid (4.2 mg, 11%). LCMS for C24Hi9ClN7O(M+H)+: m/z = 456.3.
Example B334 l-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV-methylmethanamine trihydrochloride
Figure imgf000492_0001
Step A: (2-Iodo-4-nitrophenyl)methanol
Figure imgf000492_0002
To a solution of methyl 2-iodo-4-nitrobenzoate (25.6 g, 83.4 mmol) in THF (400 mL) was added lithium tetrahydroborate (2.2 g, 92 mmol). The reaction solution was stirred at rt for 2 h and cooled down to 0 0C, and water was added dropwise. After stirring for 10 min, ethyl acetate was added. The organic solution was separated and washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified with flash chromatography (30% ethyl acetate/hexs) to give the desired product as yellow solid (15.6 g, 67%). LCMS calculated for C7H7INO3(M+H)+: m/z = 280.0.
Step B: 2-Iodo-4-nitrobenzyl methanesulfonate
Figure imgf000493_0001
To a solution of (2-iodo-4-nitrophenyl)methanol (6.01 g, 21.5 mmol) in methylene chloride (50 mL) was added N,N-diisopropylethylamine (7.50 mL, 43.1 mmol) and methanesulfonyl chloride (1.83 mL, 23.7 mmol) at 0 0C. The reaction solution was stirred at same temperature for 2 hours. The reaction was quenched with water, and aqueous layer was extracted with DCM once. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated The crude product was purified by flash column chromatography to give the desired product (6.15 g, 80%). LCMS calculated for C8H9INO5S(M+H)+: m/z = 358.0.
Step C: l-(2-Iodo-4-nitrophenyl)-N-methylmethanamine hydrochloride
Figure imgf000493_0002
A solution of 2-iodo-4-nitrobenzyl methanesulfonate (6.00 g, 0.0168 mol) in DMF (50 mL) was treated with N,N-diisopropylethylamine (8.78 mL, 0.0504 mol) and 33% methylamine in ethanol(6.79 mL, 0.0504 mol) and stirred at 20 0C overnight. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (300 mL). The organic layer was separated and washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated to a crude orange oil. The crude material was dissolve in 10 mL methanol and treated 4 Ν HCl in dioxane and diluted with ethyl ether. The precipitate was filtered and dried under vaccum to give the desired product (5 g, 90.58%). LCMS calculated for C8H10IΝ2O2(M+H)+: m/z = 293.1.
Step D: tert-Butyl (2-iodo-4-nitrobenzyl)methylcarbamate
Figure imgf000493_0003
To a solution of l-(2-iodo-4-nitrophenyl)-N-methylmethanamine hydrochloride (5.00 g, 15.2 mmol) in ethanol (36 mL) was added di-tert-butyldicarbonate (3.49 g, 16.0 mmol). The resulting solution was stirred at room temperature overnight. Solvent was evaporated in vacuo, the residue was purified by flash column chromatography to yield the desired product (4.90 g, 82%). LCMS calculated for Ci3Hi7IΝ2O4Νa(M+Νa)+: m/z = 415.0. Step E: tert-Butyl (4-amino-2-iodobenzyl)methylcarbamate
Figure imgf000494_0001
Into the reaction was added tert-buiyl (2-iodo-4-nitrobenzyl)methylcarbamate (4.90 g, 12.5 mmol), methanol (85 mL) , acetic acid (14.2 mL) and iron (4.19 g, 75.0 mmol) powder. The reaction solution was heated at 50 0C for 1.5 h. After cooling to room temperature, the reaction solution was diluted with ethyl acetate and a saturated sodium carbonate solution. The reaction mixture was filtered through a pad of celite and washed with EtOAc. The aqueous layer was extracted with ethyl acetate once. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography to yield the desired product (4.10 g, 91%). LCMS calculated for Ci3H19IN2O2Na(IVLi-H)+: m/z = 385.1.
Step F: tert-Butyl {4-[(2,5-dichloropyrimidin-4-yl)amino]-2-iodobenzyl}methylcarbamate
Figure imgf000494_0002
The desired compound was prepared according to the procedure of Example B5, step G using tert-buiyl (4-amino-2-iodobenzyl)methylcarbamate and 2,4,5-trichloropyrimidine as the starting materials in 57% yield. LCMS for Ci7H20Cl2IN4O2 (M+H)+: m/z = 509.1, 511.1.
Step G: tert-Butyl (2-[(E)-2-(5-aminopyridin-3-yl)vinyl]-4-[(2,5-dichloropyrimidin-4- yl)amino]phenyljcarbamate
Figure imgf000494_0003
To a solution of tert-butyl {4-[(2,5-dichloropyrimidin-4-yl)amino]-2- iodobenzyljmethylcarbamate (3.30 g, 6.48 mmol) in acetonitrile (40 mL), THF (30 mL) and water (30 mL) was added 5-vinylpyridin-3-amine (1.56 g, 13.0 mmol), sodium carbonate (1.37 g, 13.0 mmol), palladium acetate (43.6 mg, 0.194 mmol) and trisodium 3,3',3"-phosphinetriyltris(4,6- dimethylbenzenesulfonate) (381 mg, 0.583 mmol). The reaction flask was evacuated and backfilled with nitrogen (this process was repeated a total of 3 times). The reaction solution was heated at 80 0C for 16 hours. The aqueous layer was separated and extracted with ethyl acetate once. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography to yield the desired product (2.40 g, 78%). LCMS for C24H27Cl2N6O2 (M+H)+: m/z = 501.3, 503.3.
Step H: tert-Butyl (2-[2-(5-aminopyridin-3-yl)ethyl]-4-[(2,5-dichloropyrimidin-4- yl)amino]benzyl}carbamate
Figure imgf000495_0001
To a solution of tert-butyl {2-[(E)-2-(5-aminopyridin-3-yl)vinyl]-4-[(2,5-dichloropyrimidin-4- yl)amino]benzyl}carbamate (90.0 mg, 0.185 mmol) in THF (4 mL) was added p- toluenesulfonylhydrazide (0.515 g, 2.76 mmol). The reaction solution was heated to reflux at 90 0C, then a solution of sodium acetate (0.363 g, 4.42 mmol) in water (3.7 mL, 20 mmol) was added dropwise over 4 h period. Another portion of p-toluenesulfonylhydrazide (0.343 g, 1.84 mmol) was added to reaction flask, then a solution of sodium acetate (0.242 g, 2.95 mmol) in water was added dropwise overnight under reflux. The reaction solution was diluted with ethyl acetate. Aqueous layer was extracted with ethyl acetate twice. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography to yield the desired product (56 mg, 62%). LCMS for C24H29Cl2N6O2 (M+H)+: m/z = 503.3, 505.3.
Step I: tert-Butyl {[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}methylcarbamate
Figure imgf000496_0001
This compound was prepared according to the procedure of Example B20 step H, using tert-butyl {2-[2-(5-aminopyridin-3-yl)ethyl]-4-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}carbamate as the starting materials in 99% yield. LCMS calculated for C24H28C1N6O2(M+H)+: m/z = 467.3.
Step J: l-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N-methylmethanamine trihydrochloride
The desired compound was prepared according to the procedure of Example B21, step B, using tert-butyl { [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}methylcarbamate as the starting material in 73% yield. LCMS for Ci9H20ClN6 (M+H)+: m/z = 367.2.
Example B335 iV-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}-iV-methyl-l-[(5-methylisoxazol-3- yl)carbonyl]piperidine-4-carboxamide bis(trifluoroacetate)
Figure imgf000496_0002
Step A: tert-Butyl 4-{[{[6-chloro-2, 4, 8,18, 22-pentaazatetracyclo[14.3.1.1 (3, 7).1 (9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}(methyl)amino]carbonyl}piperidine-l- carboxylate bis(trifluoroacetate)
Figure imgf000497_0001
The desired compound was prepared according to the procedure of Example B267, using l-[6- Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N-methylmethanamine trihydrochloride and l-(tert-butoxycarbonyl)piperidine-4- carboxylic acid as the starting materials in 49% yield. LCMS for C30H37CiΝ7O3(M+H)+: m/z = 578.4.
Step B: N-f[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}-N-methylpiperidine-4-carboxamide trihydrochloride
Figure imgf000497_0002
The desired compound was prepared according to the procedure of Example B21, step B, using tert-butyl 4-{ [{ [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}(methyl)amino]carbonyl}piperidine-l- carboxylate bis(trifluoroacetate) as the starting material in 84% yield. LCMS for C2SH29ClN7O (M+H)+: m/z = 478.3.
Step C: N-{[6-Chloro-2,4,8J8,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}-N-methyl-l-[(5-methylisoxazol-3- yl)carbonyl]piperidine-4-carboxamide bis(trifluoroacetate) The desired compound was prepared according to the procedure of Example B267, using N- { [6- Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl] methyl }-N-methylpiperidine-4-carboxamide trihydrochloride and 5-methylisoxazole-3- carboxylic acid as the starting materials in 64% yield. LCMS for C30H32ClN8O3(IV^H)+: m/z = 587.3.
Example B336
N-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}-l-(isoxazol-5-ylcarbonyl)-N- methylpiperidine-4-carboxamide bis(trifluoroacetate)
Figure imgf000498_0001
The desired compound was prepared according to the procedure of Example B267, using N- { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen- 12-yl] methyl } -N-methylpiperidine-4-carboxamide trihydrochloride and isoxazole-5 -carboxylic acid as the starting materials in 62% yield. LCMS for C29H3oClΝ803(M+H)+: m/z = 573.3.
Example B337
N(4)-{[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}-N(4)-methyl-N(l)-phenylpiperidine-l,4- dicarboxamide bis(trifluoroacetate)
Figure imgf000499_0001
The desired compound was prepared according to the procedure of Example B 83, using N- { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl] methyl }-N-methylpiperidine-4-carboxamide trihydrochloride and phenyl isocyanate as the starting materials in 53% yield. LCMS for C32H34CIN8O2(MH-H)+: m/z = 597.3.
Example B338 iV-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}-iV-methyl-l-pyrimidin-2-ylpiperidine-4- carboxamide tris(trifluoroacetate)
Figure imgf000499_0002
The desired compound was prepared according to the procedure of Example B276, using N- { [6- Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl] methyl }-N-methylpiperidine-4-carboxamide trihydrochloride and 2-chloropyrimidine as the starting materials in 34% yield. LCMS for C29H3IClN9O(M-I-H)+: m/z = 556.3.
Example B339 l-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV-methyl-iV-(piperidin-4-ylmethyl)methanamine tetrahydrochloride
Figure imgf000500_0001
Step A: tert-Butyl 4-{[{[6-chloro-2, 4, 8,18, 22-pentaazatetracyclo[14.3.1.1 (3, 7).1 (9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methylj(methyl)amino]methyljpiperidine-l-carboxylate tris(trifluoroacetate)
Figure imgf000500_0002
The desired compound was prepared according to the procedure of Example B 192, using l-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N-methylmethanamine trihydrochloride and tert-butyl 4-formylpiperidine-l-carboxylate as the starting materials in 46% yield. LCMS for C30H39CIN7O2(IVLI-H)+: m/z = 564.5.
Step B: 1 -[6- Chloro-2,4, 8, 18, 22-pentaazatetracyclo[14.3.1.1 (3, 7).1 (9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N-methyl-N-(piperidin-4-ylmethyl)methanamine tetrahydrochloride
The desired compound was prepared according to the procedure of Example B21, step B, using tert-butyl 4-{ [{ [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}(methyl)amino]methyl}piperidine-l-carboxylate tris(trifluoroacetate) as the starting material in 91% yield. LCMS for C25H3IClN7 (M+H)+: m/z = 464.3.
Example B340
2-[(4-{[{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}(methyl)amino]methyl}piperidin-l- yl)sulfonyl]benzonitrile tris(trifluoroacetate)
Figure imgf000501_0001
The desired compound was prepared according to the procedure of Example B 136, using l-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N-methyl-N-(piperidin-4-ylmethyl)methanamine tetrahydrochloride and 2- cyanobenzenesulfonyl chloride as the starting materials in 55% yield. LCMS for C32H34ClN8O2S(M+!!)"1": m/z = 629.2.
Example B341 l-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV-methyl-iV-{[l-(phenylsulfonyl)piperidin-4- yl]methyl}methanamine tris(trifluoroacetate)
Figure imgf000502_0001
The desired compound was prepared according to the procedure of Example B 136, using l-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen- 12-yl] -N-methyl-N-(piperidin-4-ylmethyl)methanamine tetrahydrochloride and benzenesulfonyl chloride as the starting materials in 42% yield. LCMS for C3IH35CIN7O2S(MH-H)+: m/z = 604.3.
Example B342 l-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV-methyl-iV-({l-[(5-methylisoxazol-4- yl)sulfonyl]piperidin-4-yl}methyl)methanamine tris(trifluoroacetate)
Figure imgf000502_0002
The desired compound was prepared according to the procedure of Example B 136, using l-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N-methyl-N-(piperidin-4-ylmethyl)methanamine tetrahydrochloride and 5- methylisoxazole-4-sulfonyl chloride as the starting materials in 32% yield. LCMS for C29H34C1Ν8O3S(M+H)+: m/z = 609.4.
Example B343 l-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV-({l-[(l,2-dimethyl-lH-imidazol-4- yl)sulfonyl]piperidin-4-yl}methyl)-iV-methylmethanamine tris(trifluoroacetate)
Figure imgf000503_0001
The desired compound was prepared according to the procedure of Example B 136, using l-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen- 12-yl] -N-methyl-N-(piperidin-4-ylmethyl)methanamine tetrahydrochloride and 1 ,2-dimethyl- 1 H- imidazole-4-sulfonyl chloride as the starting materials in 28% yield. LCMS for C30H37CiN9O2S(M-I-H)+: m/z = 622.3.
Example B344 l-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV-methyl-iV-({l-[(5-methylisoxazol-3- yl)carbonyl]piperidin-4-yl}methyl)methanamine tris(trifluoroacetate)
Figure imgf000503_0002
The desired compound was prepared according to the procedure of Example B267, using l-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen- 12-yl] -N-methyl-N-(piperidin-4-ylmethyl)methanamine tetrahydrochloride and 5- methylisoxazole-3-carboxylic acid as the starting materials in 48% yield. LCMS for C30H34ClN8O2(IVLHr)+: m/z = 573.4.
Example B345 l-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV-{[l-(isoxazol-5-ylcarbonyl)piperidin-4-yl]methyl}- iV-methylmethanamine tris(trifluoroacetate)
Figure imgf000504_0001
The desired compound was prepared according to the procedure of Example B267, using l-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N-methyl-N-(piperidin-4-ylmethyl)methanamine tetrahydrochloride and isoxazole-5- carboxylic acid as the starting materials in 36% yield. LCMS for C29H32ClN8O2(M+!!)"1": m/z = 559.4.
Example B346 l-(l-Acetylpiperidin-4-yl)-iV-{[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}-iV-methylmethanamine tris(trifluoroacetate)
Figure imgf000504_0002
The desired compound was prepared according to the procedure of Example B26, using l-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N-methyl-N-(piperidin-4-ylmethyl)methanamine tetrahydrochloride and acetyl chloride as the starting materials in 22% yield. LCMS for C27H33CiΝ7O(M+H)+: m/z = 506.4.
Example B347 l-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV-methyl-N-({l-[(4-methyl-l,3-oxazol-5- yl)carbonyl]piperidin-4-yl}methyl)methanamine tris(trifluoroacetate)
Figure imgf000505_0001
The desired compound was prepared according to the procedure of Example B26, using l-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N-methyl-N-(piperidin-4-ylmethyl)methanamine tetrahydrochloride and 4-methyl-l,3- oxazole-5-carbonyl chloride as the starting materials in 16% yield. LCMS for C30H34CiN8O2(M+^"1": m/z = 573.4.
Example B348
4-{[{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}(methyl)amino]methyl}-iV-pyridin-3- ylpiperidine-1-carboxamide tetrakis(trifluoroacetate)
Figure imgf000506_0001
The desired compound was prepared according to the procedure of Example B83, using l-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N-methyl-N-(piperidin-4-ylmethyl)methanamine tetrahydrochloride and 3- isocyanatopyridine as the starting materials in 19% yield. LCMS for C3IH35CiN9O(M+!!)"1": m/z = 584.4.
Example B349
4-{[{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}(methyl)amino]methyl}-iV-(2-methyl-3- furyl)piperidine- 1-carboxamide tris(trifluoroacetate)
Figure imgf000506_0002
The desired compound was prepared according to the procedure of Example B83, using l-[6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-N-methyl-N-(piperidin-4-ylmethyl)methanamine tetrahydrochloride and 3-isocyanato-2- methylfuran as the starting materials in 14% yield. LCMS for C3iH36ClΝ8O2(M+H)+: m/z = 587.4.
Example B350 6-Chloro-12-(lH-pyrazol-4-yl)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000507_0001
Step A: 6-Chloro-12-iodo-2,4, 8,18, 22-pentaazatetracyclo[14.3.1.1(3, 7).1(9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
Figure imgf000507_0002
To a solution of 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine trihydrochloride (161 mg, 0.359 mmol) in 2.0 M of sulfuric acid in water (1.8 mL, 3.59 mmol) was added a solution of sodium nitrite (37.2 mg, 0.539 mmol) in water dropwise at 0 0C. The reaction solution was stirred at same temperature for 1 h, then a solution of potassium iodide (89.4 mg, 0.539 mmol) in water was added at 0 0C. The reaction solution was stirred at room temperature for 48 h. The precipitate was filtered and washed by water and dried under vacuum to give the desired product (103 mg, 64%). LCMS for Ci7H14ClIN5(M+H)+: m/z = 450.1.
Step B: 6-Chloro-12-(lH-pyrazol-4-yl)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
A mixture of 6-chloro-12-iodo-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene (14.1 mg, 0.0314 mmol), l-(l-ethoxyethyl)-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (10.0 mg, 0.0376 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (1.5 mg, 0.0019 mmol) and potassium phosphate (20 mg, 0.094 mmol) in 1,4-dioxane (0.8 mL) and water (0.2 mL) was degassed and heated at 120 0C for 2 h. The reaction solution was concentrated and diluted with methanol and purified with preparative LCMS. The resulting intermediate was treated with TFA (0.3 mL) and stirred at room temperature for 2 h. The reaction solution was diluted with methanol and purified with preparative LCMS to give the desired product (8.4 mg, 37%). LCMS for C2oHi7ClN7(M+H)+: m/z : 390.3.
Example Cl 6-Chloro-2,4,8,15,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-14-one hydrochloride
Figure imgf000508_0001
Step A: tert-Butyl (3-[(3-nitrobenzoyl)amino]phenyl}carbamate
Figure imgf000508_0002
To a stirring solution of tert-butyl (3-aminophenyl)carbamate (2.00 g, 9.6 mmol) and triethylamine (1.40 rnL, 10 mol) in dry tetrahydrofuran (27.3 rnL) at 0 0C was slowly added a solution of 3-nitrobenzoyl chloride (1.87 g, 10.1 mmol) in tetrahydrofuran (7.8 rnL). The resulting mixture was slowly warmed up to rt and stirred for one additional hour at rt. The reaction mixture was treated with Na2CO3 (aq). The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as a white powder (3.4 g, 99%). LCMS for Ci8H19N3O5 (M-?Bu+H)+: m/z = 302.0. 1H NMR (400 MHz, CD3OD): δ 8.79 (t, /= 2.0 Hz, IH), 8.43 (ddd, J = 8.0, 2.0, 1.2 Hz, IH), 8.31 (ddd, / = 6.4, 2.4, 1.2 Hz, IH), 7.87 (t, / = 2.1 Hz, IH), 7.77 (t, / = 8.0 Hz, IH), 7.60 (ddd, /= 8.0, 4.0, 2.4, IH), 7.25 (t, / = 8.0 Hz, IH), 7.19 (d, /= 1.2 Hz, IH), 1.52 (s, 9H).
Step B: tert-Butyl {3-[(3-aminobenzoyl)amino]phenyljcarbamate
Figure imgf000509_0001
To a solution of tert-butyl {3-[(3-nitrobenzoyl)amino]phenyl}carbamate (2.00 g, 5.6 mmol) in water (4 mL), methanol (22 mL) and acetic acid (8.6 mL) was added iron (0.782 g, 14.0 mmol) powder in small quantities. When the addition was completed, the mixture was stirred in water bath for 3 h. The mixture was filtered, and the cake was washed with MeOH/EtOAc. The brown filtrate was concentrated and diluted with H2O, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as an off-white powder
(1.6 g, 87%). LCMS for Ci8H2IN3O3 (M+H)+: m/z = 328.1.
Step C: tert-Butyl [3-({3-[(2,5-dichloropyrimidin-4-yl)amino]benzoyl}amino)phenyl]carbamate
Figure imgf000509_0002
To a solution of tert-butyl {3-[(3-aminobenzoyl)amino]phenyl}carbamate (0.500 g, 1.53 mol) and 2,4,5-trichloropyrimidine (0.25 g, 1.4 mmol) in DMF (3.7 mL) was added potassium carbonate (0.29 g, 2.1 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with saturated (sat'd) NH4Cl and water. EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc twice and the combined organics were washed with water, dried, filtered and concentrated to give 800 mg of crude product, which was purified by Combi-Flash column chromatography (12 g column, 0 to 30% EtOAc in hexane) to give the desired product (66 mg, 10%).
LCMS for C22H2ICl2N5O3 (M-?Bu+H)+: m/z = 420.0, 418.1. 1H NMR (400 MHz, CD3OD): δ 8.26 (s, IH), 8.11 (t, / = 2.0 Hz, IH), 7.89 (ddd, / = 8.0, 2.0, 1.2 Hz, IH), 7.85 (t, /= 2.0 Hz, IH), 7.74 (ddd, / = 7.6, 2.0, 0.8 Hz, IH), 7.53 (t, /= 8.0 Hz, IH), 7.32 (dd, /= 8.0, 1.2 Hz, IH), 7.24 (t, / = 8.0 Hz, IH), 7.19 (m, IH), 1.52 (s, 9H). Step D: 6-Chloro-2,4,8,15,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-14-one hydrochloride
To a solution of tert-butyl [3-({3-[(2,5-dichloropyrimidin-4- yl)amino]benzoyl}amino)phenyl]carbamate (20.0 mg, 0.042 mmol) in 2-methoxyethanol (0.2 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (63 μL). The resulting mixture was heated at 150 0C in the microwave for 15 min. After filtration of the reaction mixture, the crude was triturated with MeOH/EtOAc to give the desired product as an off-white powder (2 mg, 14%). LCMS for Ci7Hi2ClN5O
(M+H)+: m/z = 338.0. 1H NMR (400 MHz, CD3OD): δ 9.57 (s, IH), 9.42 (s, IH), 8.33 (s, IH), 8.16 (s, IH), 7.91 (s, IH), 7.29 (dd, / = 7.9, 7.6 Hz, IH), 7.15 (d, / = 7.9 Hz, IH), 7.10 - 7.05 (m, 2H), 6.90 (dd, / = 8.2, 0.9 Hz, IH), 6.84 - 6.81 (m, IH), 4.11 (s, 2H).
Example C2
6-Chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-15-one hydrochloride
Figure imgf000510_0001
Step A: N-(3-Aminophenyl)-3-nitrobenzamide hydrochloride
Figure imgf000510_0002
tert-Butyl {3-[(3-nitrobenzoyl)amino]phenyl}carbamate (0.60 g, 1.7 mmol) was mixed with 4 M of hydrogen chloride in 1 ,4-dioxane (7 mL) and stirred at rt for 2 h. After concentration, the desired white powder solid product (0.49 g, 99%) as a HCl salt was used in the next step. MF = Ci3HnN3O3;
LCMS calculated for Ci3HnN3O3 (M+H)+: m/z = 258.0. 1H NMR (400 MHz, CD3OD): δ 8.82 (t, /= 2.0 Hz, IH), 8.46 (ddd, /= 8.4, 2.4, 1.2 Hz, IH), 8.36 (ddd, / = 8.4, 2.4, 1.2 Hz, IH), 8.21 (t, / = 2.0 Hz, IH), 7.80 (t, / = 8.0 Hz, IH), 7.68 (ddd, / = 8.0, 4.0, 2.4, IH), 7.54 (t, / = 8.4 Hz, IH), 7.19 (ddd, / = 8.0, 2.0, 1.2 Hz, IH). Step B: N-{3-[(2, 5-Dichloropyrimidin-4-yl)amino]phenylj-3-nitrobenzamide
Figure imgf000511_0001
To a solution of N-(3-aminophenyl)-3-nitrobenzamide hydrochloride (0.200 g, 0.681 mmol) and 2,4,5-trichloropyrimidine (0.071 mL, 0.619 mmol) in DMF (1.6 mL) was added potassium carbonate (0.30 g, 2.2 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc twice. The combined organics were washed with water, dried, filtered and concentrated to give the desired product as a light brown powder (330 mg). LCMS for Ci7H11Cl2N5O3
(M+H)+: m/z = 403.9, 405.9, 407.9. 1H NMR (400 MHz, CD3OD): δ 8.82 (t, /= 2.0 Hz, IH), 8.45 (ddd, /= 8.0, 2.0, 1.2 Hz, IH), 8.34 (ddd, / = 7.6, 2.0, 1.2 Hz, IH), 8.24 (s, IH), 7.97 (br, 2H), 7.76 (t, / = 8.0 Hz, IH), 7.56 (m, IH), 7.43 (ddd, / = 8.0, 2.0, 1.2, IH).
Step C: 3-Amino-N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}benzamide
Figure imgf000511_0002
To a solution N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}-3-nitrobenzamide (50.0 mg,
0.124 mmol) in water (0.09 mL), methanol (0.48 mL) and acetic acid (0.19 mL) was added iron (17 mg, 0.31 mmol) powder in small quantities. When the addition was completed, the mixture was stirred at 0 0C for 3 h, 3 eq additional iron powder was added. The mixture was filtered, and the cake was washed with MeOH/EtOAc. The brown filtrate was concentrated and diluted with H2O, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as a light brown powder (32 mg, 69%). LCMS for C17H13Cl2N5O (M+H)+: m/z = 374.0, 376.0. 1H NMR (400 MHz, CD3OD): δ 9.57 (s, IH), 9.42 (s, IH), 8.33 (s, IH), 8.16 (s, IH), 7.91 (s, IH), 7.29 (dd, / = 7.9, 7.6 Hz, IH), 7.15 (d, / = 7.9 Hz, IH), 7.10 - 7.05 (m, 2H), 6.90 (dd, / = 8.2, 0.9 Hz, IH), 6.84 - 6.81 (m, IH), 4.11 (s, 2H). Step D: 6- Chloro-2,4, 8, 14, 22-pentaazatetracyclo[14.3.1.1 (3, 7).1 (9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-15-one hydrochloride
To a solution of 3-amino-N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}benzamide (20.0 mg, 0.053 mmol) in 2-methoxyethanol (0.295 niL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (67 μL). The resulting mixture was heated at 150 0C in a microwave for 15 min. After filtration of the reaction mixture, the crude was triturated with MeOH/EtOAc to give the desired product as an off-white powder (12 mg, 66%). LCMS for Ci7H12ClN5O (M+H)+: m/z = 337.9. 1H NMR (400 MHz, DMSO- d6): δ 10.32 (s, IH), 10.16 (ddd, / = 8.0, 2.0, 1.2 Hz, IH), 9.66 (ddd, /= 7.6, 2.0, 1.2 Hz, IH), 9.38 (s, IH), 6.30 (br, IH), 8.24 (m, IH), 7.38 (ddd, / = 8.0, 2.0, 1.2, IH), 7.50 (t, /= 8.0 Hz, IH), 7.25 (m, 2H), 7.16 (m, IH), 6.95 (t, / = 2.0 Hz, IH).
Example C3
6-Chloro-16-thia-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- I(21),3(23),4,6,9(22),10,12,17,19-nonaene l6,16-dioxide
Figure imgf000512_0001
Step A: tert-Butyl [3-({[(3-nitrophenyl)sulfonyl]amino}methyl)phenyl] 'carbamate
Figure imgf000512_0002
To a stirring solution of tert-butyl [3-(aminomethyl)phenyl]carbamate (2.00 g, 9.0 mmol) and triethylamine (1.32 mL, 9.45 mmol) in dry tetrahydrofuran (25.5 mL) at 0 0C was slowly added a solution of ra-nitrobenzenesulfonyl chloride (2.09 g, 9.45 mmol) in tetrahydrofuran (7.3 mL). The resulting mixture was slowly warmed up to rt and stirred for one additional hour at rt. The reaction mixture was treated with Na2CO3 (aq) and layers separated. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as an off- white powder (4.0 g, 100%). LCMS for Ci8H21N3O6S (M-Boc+H)+: m/z = 308.0. 1H NMR (400 MHz, CD3OD): δ 8.43 (t, / = 2.0 Hz, IH), 8.31 (ddd, / = 8.0, 2.0, 1.2 Hz, IH), 8.04 (dt, / = 8.0, 2.8 Hz, IH), 7.64 (t, / = 8.0 Hz, IH), 7.19 (br, IH), 7.04 (m, 2H), 6.77 (dt, / = 7.2, 1.2 Hz, IH), 4.13 (s, 2H).
Step B: N-(3-Aminobenzyl)-3-nitrobenzenesulfonamide hydrochloride
Figure imgf000513_0001
tert-Butyl [3-({ [(3-nitrophenyl)sulfonyl]amino}methyl)phenyl]carbamate (1.00 g, 2.45 mmol) was mixed with 4 M of hydrogen chloride in 1,4-dioxane (10 mL) and stirred at rt for 2 h. After concentration, the crude off-white powder product (0.97 g) was used in the next step. (Molecular
Formula (MF) = Ci3Hi3N3O4S; LCMS calculated for Ci3Hi3N3O4S (M+H)+: m/z = 308.0. 1H NMR (400 MHz, CD3OD): δ 8.55 (t, /= 2.0 Hz, IH), 8.44 (ddd, / = 8.4, 2.4, 1.2 Hz, IH), 8.20 (ddd, / = 7.6, 2.4, 1.2 Hz, IH), 7.81 (t, /= 8.0 Hz, IH), 7.40 (m, 2H), 7.36 (dd, / = 7.6, 1.2 Hz, IH), 7.23 (ddd, / = 8.0, 2.4, 1.2, IH), 4.21 (s, 2H).
Step C: N-{3-[(2, 5-Dichloropyrimidin-4-yl)amino]benzylj-3-nitrobenzenesulfonamide
Figure imgf000513_0002
To a solution of N-(3-aminobenzyl)-3-nitrobenzenesulfonamide hydrochloride (0.400 g, 1.16 mmol) and 2,4,5-trichloropyrimidine (0.12 mL, 1.06 mmol) in DMF (2.8 mL) was added potassium carbonate (0.51 g, 3.7 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with saturated (sat'd) NH4Cl and water. EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc twice. The combined organics were washed with water, dried, filtered and concentrated to give 660 mg of crude residue, which was purified by Combi-Flash column chromatography (12 g column, 0 to 30% EtOAc in hexane) to give the desired product (135 mg, 28%). LCMS for Ci7Hi3Cl2N5O4S (M+H)+: m/z = 453.9, 455.9, 457.9. 1H NMR (400 MHz, CD3OD): δ 8.85 (s, IH), 8.48 (t, / = 2.0 Hz, IH), 8.29 (ddd, / = 8.0, 2.0, 1.2 Hz, IH), 8.21 (s, IH), 8.08 (ddd, / = 8.0, 1.6, 0.8 Hz, IH), 7.64 (t, / = 8.0 Hz, IH), 7.41 (m, 2H), 7.17 (t, / = 8.0 Hz, IH), 4.21 (s, 2H).
Step D: 3-Amino-N-{3-[(2, 5-dichloropyrimidin-4-yl)amino]benzyljbenzenesulfonamide
Figure imgf000514_0001
To a solution N-{3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}-3-nitrobenzenesulfonamide (50.0 mg, 0.11 mmol) in water (0.08 mL), methanol (0.42 mL) and acetic acid (0.17 mL) was added iron (15 mg, 0.28 mmol) powder in small quantities. When the addition was completed, the mixture was stirred in water bath for 3 h and the reaction was complete. The mixture was filtered and the cake was washed with MeOH/EtOAc. The brown filtrate was concentrated and diluted with H2O, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as a light brown powder (42 mg, 90%). LCMS for Ci7Hi5Cl2N5O2S (M+H)+: m/z = 424.0, 426.0, 428.0. 1H NMR (400 MHz, CD3OD): δ 8.22 (t, /= 2.0 Hz, IH), 8.52 (ddd, / = 8.0, 2.0, 1.2 Hz, IH), 7.48 (m, IH), 7.40 (t, / = 8.0 Hz, IH), 7.28 (m, IH), 7.20 (t, / = 8.0 Hz, IH), 7.08 (ddd, / = 8.4, 2.0, 1.2, IH), 6.84 (ddd, / = 8.0, 1.6, 1.2, IH), 4.21 (s, 2H).
Step E: 6-Chloro-16-thia-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- I(21),3(23),4,6,9(22),10,12,17,19-nonaene l6,16-dioxide To a solution of 3-amino-N-{3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}benzenesulfonamide
(38.0 mg, 0.089 mmol) in 2-methoxyethanol (0.49 mL) was added 4.0 M of hydrogen chloride in 1,4- dioxane (45 μL). The resulting mixture was heated at 150 0C in the microwave for 15 min. The mixture was diluted with Na2CO3 (aq), extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the crude, which was purified by Combi-Flash column chromatography (4 g column, 0 to 50% EtOAc in Hex) to the desired product as a white powder (7 mg,
20%). LCMS for Ci7Hi4ClN5O2S (M+H)+: m/z = 388.0, 390.0. 1H NMR (400 MHz, CD3OD): δ 7.62 (m, IH), 7.54 (s, IH), 7.28 (t, /= 2.0 Hz, IH), 7.08 (ddd, / = 8.0, 2.0, 1.2 Hz, IH), 6.78 (t, J = 8.0 Hz, IH), 6.35 (m, IH), 6.18 (ddd, / = 8.0, 1.6, 1.0 Hz, IH), 5.98 (m, IH), 5.82 (ddd, /= 7.6, 2.0, 1.0, IH), 4.20 (s, 2H).
Example C4 6-Chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-14-one
Figure imgf000515_0001
Step A: tert-Butyl (3-{[(3-nitrobenzoyl)amino]methyl}phenyl)carbamate
Figure imgf000515_0002
To a stirring solution of tert-butyl [3-(aminomethyl)phenyl]carbamate (2.0 g, 9.0 mmol) and triethylamine (1.3 mL, 9.4 mmol) in dry tetrahydrofuran (25 mL) at 0 0C slowly added a solution of 3- nitrobenzoyl chloride (1.75 g, 9.45 mmol) in tetrahydrofuran (7.3 mL). The resulting mixture was slowly warmed up to rt and stirred for one additional hour at rt. The reaction mixture was treated with Na2CO3 (aq), separated. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as an off-white powder (3.5 g, 100%).
LCMS for Ci9H21N3O5 (M-?Bu+H)+: m/z = 316.0. 1H NMR (400 MHz, CD3OD): δ 8.71 (t, / = 2.0 Hz, IH), 8.38 (ddd, / = 8.4, 1.6, 1.2 Hz, IH), 8.23 (ddd, / = 8.0, 1.6, 0.8 Hz, IH), 7.70 (t, /= 8.0 Hz, IH), 7.44 (s, IH), 7.28 (m, IH), 7.20 (t, / = 7.6, IH), 7.00 (d / = 7.6 Hz, IH), 4.90 (s, 2H), 1.49 (s, 9H).
Step B: tert-Butyl (3-{[(3-aminobenzoyl)amino]methyl}phenyl)carbamate
Figure imgf000516_0001
To a solution tert-butyl (3-{ [(3-nitrobenzoyl)amino]methyl}phenyl)carbamate (1.50 g, 4.04 mmol) in water (2.91 mL), methanol (16 mL) and acetic acid (6.2 mL) was added iron (0.564 g, 10.1 mmol) powder in small quantities. When the addition was completed, the mixture was stirred in water bath for 4 h, and the reaction was complete. The mixture was filtered, and the cake was washed with MeOH/EtOAc. The brown filtrate was concentrated and diluted with H2O, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as a brown solid (1.8 g). LCMS fOr Ci9H23N3O3 (MH-H)+: m/z = 342.1. 1H NMR (400 MHz, CD3OD): δ 7.38 (t, / = 2.0 Hz, IH), 7.28 (ddd, / = 8.0, 2.0, 1.2 Hz, IH), 7.22 (t, / = 8.0 Hz, IH), 7.16 (s, IH), 7.14 (t, /= 8.0 Hz, IH), 7.08 (m, IH), 6.96 (ddd, / = 8.0, 2.4, 1.2 Hz, IH), 6.85 (ddd, / = 8.0, 2.0, 1.2, IH), 4.50 (s, 2H), 1.50 (s, 9H).
Step C: tert-Butyl (3-[({3-[(2, 5-dichloropyrimidin-4-yl)amino]benzoyljamino)methyl]phenyljcarbamate
Figure imgf000516_0002
To a solution of tert-butyl (3-{ [(3-aminobenzoyl)amino]methyl}phenyl)carbamate (0.60 g, 1.8 mmol) and 2,4,5-trichloropyrimidine (0.183 mL, 1.6 mmol) in DMF (4.3 mL) was added potassium carbonate (0.331 g, 2.4 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc twice. The combined organics were washed with water, dried, filtered and concentrated to give the crude, which was purified by silica gel column chromatography to give the desired product (138 mg, 18%). LCMS for C23H23Cl2N5O3 (M-?Bu+H)+: m/z = 432.0, 434.0, 436.0. 1H NMR (400 MHz, CD3OD): δ 8.23 (s, IH), 8.04 (t, / = 2.0 Hz, IH), 7.96 (s, IH), 7.83 (ddd, / = 8.0, 2.0, 1.2 Hz, IH), 7.67 (ddd, / = 7.6, 2.4, 1.2 Hz, IH), 7.48 (m, 2H), 7.21 (t, / = 8.0 Hz, IH), 7.00 (d, /= 7.6 Hz, IH), 4.54 (s, 2H), 1.49 (s, 9H). Step D: 6-Chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-14-one
To a solution of tert-butyl {3-[({3-[(2,5-dichloropyrimidin-4- yl)amino]benzoyl}amino)methyl]phenyl}carbamate (40.0 mg, 0.0819 mmol) in 2-methoxyethanol (0.452 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (100 μL). The resulting mixture was heated at 150 0C in the microwave for 15 min. The cloudy mixture was diluted with Na2CO3 (aq), filtered, washed with water. The crude cake was triturated with MeOH to give the desired product as an off-white powder
(18 mg, 62%). LCMS for Ci8Hi4ClN5O (M+H)+: m/z = 352.0. 1H NMR (400 MHz, DMS0-<i6): δ 10.24 (s, IH), 10.05 (t, / = 2.0 Hz, IH), 9.66 (s, IH), 9.05 (ddd, /= 8.0, 2.0, 1.2 Hz, IH), 8.62 (t, / = 2.0 Hz, IH), 8.25 (t, / = 8.0 Hz, IH), 8.00 (m, IH), 7.76 (ddd, / = 7.6, 2.0, 1.2, IH), 7.52 (m, IH), 7.36 (t, / = 7.6 Hz, IH), 7.02 (m, IH), 6.90 (m, IH), 4.32 (s, 2H).
Example C5 6-Chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-16-one hydrochloride
Figure imgf000517_0001
Step A: N-(3-Aminobenzyl)-3-nitrobenzamide hydrochloride
Figure imgf000517_0002
tert-butyl (3-{ [(3-nitrobenzoyl)amino]methyl}phenyl)carbamate (1.00 g, 2.69 mmol) was mixed with 4 M of hydrogen chloride in 1,4-dioxane (10 mL) and stirred at rt for 2 h. After concentration, the desired product was isolated as a white powder (0.82 grams, 99% yield) and used in the next step without further purification. MF = Ci4Hi3N3O3; LCMS calculated for Ci4Hi3N3O3 (M+H)+: m/z = 272.0. 1H NMR (400 MHz, CD3OD): δ 8.73 (t, / = 2.0 Hz, IH), 8.42 (ddd, / = 8.4, 2.4, 1.2 Hz, IH), 8.28 (ddd, / = 8.0, 2.4, 1.2 Hz, IH), 7.76 (t, J = 8.4 Hz, IH), 7.52 (m, 2H), 7.45 (s, IH), 7.31 (ddd, / = 8.4, 2.0, 1.2, IH), 4.66 (s, 2H).
Step B: N-{3-[(2, 5-Dichloropyrimidin-4-yl)amino]benzylj-3-nitrobenzamide
Figure imgf000518_0001
To a solution of N-(3-aminobenzyl)-3-nitrobenzamide hydrochloride (0.70 g, 2.3 mmol) and 2,4,5-trichloropyrimidine (0.237 mL, 2.07 mmol) in DMF (5.5 mL) was added potassium carbonate (1.0 g, 7.2 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc twice. The combined organics were washed with water, dried, filtered and concentrated to give 1.25 grams of crude material, which was triturated with MeOH/EtOAc to give the desired product as an off-white powder (665 mg, 77%). LCMS for Ci8H13Cl2N5O3 (M+H)+: m/z =
418.0, 420.0, 422.0. 1H NMR (400 MHz, DMS0-<i6): δ 9.53 (s, IH), 9.49 (t, /= 2.0 Hz, IH), 8.74 (t, / = 2.0 Hz, IH), 8.36 (m, 3H), 7.78 (t, /= 8.0 Hz, IH), 7.52 (s, IH), 7.47 (d, / = 8.0 Hz, IH), 7.34 (t, / = 7.6 Hz, IH), 7.15 (d, / = 8.0, IH), 4.52 (d, /= 6.0 Hz, 2H).
Step C: 3-Amino-N-{3-[(2,5-dichloropyrimidin-4-yl)amino]benzyljbenzamide
Figure imgf000518_0002
To a solution N-{3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}-3-nitrobenzamide (400.0 mg, 0.956 mmol) in water (0.7 mL), methanol (3.7 mL) and acetic acid (1.5 mL) was added iron (130 mg, 2.4 mmol) powder in small quantities. When the addition was completed, the very cloudy mixture was stirred at 0 0C for 1 h and then heat at 40 0C for 3 h. The mixture was filtered, and the cake was washed with MeOH/EtOAc. The filtrate was concentrated and the residue was diluted with H2O, then the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as an off-white powder (435 mg). LCMS for CI8HI5CI2NSO
(M+H)+: m/z = 388.0, 390.0, 392.0. 1H NMR (400 MHz, CD3OD): δ 8.20 (s, IH), 7.59 (t, / = 2.0 Hz, IH), 7.52 (d, / = 8.0 Hz, IH), 7.36 (t, / = 8.0 Hz, IH), 7.24 (m, 2H), 7.20 (m, 2H), 6.93 (m, IH), 4.60 (s, 2H).
Step D: 6-Chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- 1(21 ),3(23),4,6,9(22),10,12,17,19-nonaen-16-one hydrochloride
To a solution of 3-amino-N-{3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}benzamide (80.0 mg, 0.206 mmol) in 2-methoxyethanol (1.1 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (154 μL). The resulting mixture was heated at 150 0C in a microwave for 15 min. The cloudy mixture was filtered. The crude cake was recrystallized from MeOH to give the desired product as an off-white powder (25 mg, 34%). LCMS for Ci8H14ClN5O (M+H)+: m/z = 352.0. 1H NMR (400 MHz, DMSO- d6): δ 10.06 (s, IH), 9.50 (t, / = 2.0 Hz, IH), 9.05 (t, /= 2.0 Hz, IH), 8.24 (m, IH), 7.86 (s, IH), 7.75 (d, / = 8.0 Hz, IH), 7.50 (t, / = 8.0 Hz, IH), 7.42 (d, /= 8.0 Hz, IH), 7.28 (m, 2H), 7.10 (t, / = 7.6 Hz, IH), 6.96 (d, / = 8.0 Hz, IH), 4.42 (d, / = 6.0 Hz, 2H).
Example C6
6-Chloro-15-thia-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-
I(20),3(22),4,6,9(21),10,12,16,18-nonaene l5,15-dioxide trifluoroacetate
Figure imgf000519_0001
Step A: N-(3-Aminophenyl)-3-nitrobenzenesulfonamide
Figure imgf000519_0002
Into a 1-neck round-bottom flask were added ra-phenylenediamine (1.6 g, 14 mmol) and tetrahydrofuran (30 mL) and triethylamine (2.0 mL, 14 mmol). The mixture was cooled in ice bath and then ra-nitrobenzenesulfonyl chloride (2.1 g, 9.6 mmol) was slowly added. The resultant mixture was warmed up to rt. after 1 h and EtOAc and water were then added. Aqueous layer was extracted again with EtOAc. The organics layers were combined, dried over Na2SO4 and the solvent was removed under vacuum. The crude was purified by silica gel column chromatography to give the desired product (2.5 g,
89%). LCMS for Ci2H11N3O4S (M+H)+: m/z = 294.0. 1H NMR (SOO MHZ5 CD3OD): δ 8.56 (t, /= 2.0 Hz, IH), 8.40 (ddd, / = 8.2, 2.3, 1.2 Hz, IH), 8.09 (ddd, / = 7.8, 1.7, 1.0 HZ, IH), 7.73 (t, / = 8.1 Hz, IH), 6.91 (t, / = 8.1 Hz, IH), 6.51 (t, / = 2.2 Hz, IH), 6.42 (ddd, / = 8.1, 2.2, 1.0 Hz, IH), 6.36 (ddd, / = 7.9, 2.1, 1.0 Hz, IH).
Step B: N-{3-[(2, 5-Dichloropyrimidin-4-yl)amino]phenyl}-3-nitrobenzenesulfonamide
Figure imgf000520_0001
To a solution of N-(3-aminophenyl)-3-nitrobenzenesulfonamide (1.00 g, 3.41 mmol) and 2,4,5- trichloropyrimidine (0.57 g, 3.1 mmol) in DMF (10 mL) was added potassium carbonate (0.52 g, 3.7 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous was extracted with EtOAc. The combined organics were washed with water and brine then dried (MgSO4), filtered, and concentrated. The crude was purified by combi-flash column chromatography to give the desired product (1.2 g, 88%). LCMS for C16H11Cl2N5O4S (M+H)+: m/z = 439.9, 441.9. 1H NMR (400 MHz, DMSO- d6): δ 10.65 (s, IH), 9.51 (s, IH), 8.54 (t, / = 2.1 Hz, IH), 8.43 (ddd, / = 8.2, 2.0, 1.0 Hz, IH), 8.37 (s, IH), 8.18 (ddd, / = 8.0, 2.0, 1.0 Hz, IH), 7.84 (t, /= 8.0 Hz, IH), 7.50 (t, /= 2.0 Hz, IH), 7.29 (ddd, / = 8.2, 2.0, 1.2 Hz, IH), 7.24 (m, IH), 6.88 (ddd, / = 8.0, 2.0, 1.2 Hz, IH).
Step C: 3-Amino-N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}benzenesulfonamide
Figure imgf000520_0002
To a solution N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}-3-nitrobenzenesulfonamide (0.5 g, 1.0 mmol) in water (0.9 mL), methanol (4.4 mL) and acetic acid (1.7 mL) was added iron (250 mg, 4.5 mmol) powder in one portion. The mixture was stirred at 0 0C for 1 h and then mixed with celite and filtered. The crude cake was washed with EtOAc. The brown filtrate was concentrated and mixed with EtOAc and NaHCO3/water. The aqueous phase was extracted once with EtOAc. The organic phases were combined and dried over Na2SO4. The volatiles were removed under vacuum to give the desired product (0.45 g, 100%). LCMS for Ci6H13Cl2N5O2S (M+H)+: m/z = 410.0, 411.9. 1H NMR (400 MHz, DMSO-Cf6): δ 9.57 (s, IH), 9.42 (s, IH), 8.33 (s, IH), 8.16 (s, IH), 7.91 (s, IH), 7.29 (dd, / = 7.9, 7.6 Hz, IH), 7.15 (d, / = 7.9 Hz, IH), 7.10 - 7.05 (m, 2H), 6.90 (dd, / = 8.2, 0.9 Hz, IH), 6.84 - 6.81 (m, IH), 4.11 (s, 2H).
Step D: 6-Chloro-15-thia-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene 15,15-dioxide trifluoroacetate
To a solution of 3-amino-N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}benzenesulfonamide (80 mg, 0.2 mmol) and in 2-methoxyethanol (1 mL) was added 4.0 M of hydrogen chloride in 1,4- dioxane (49 μL). The resulting mixture was heated at 150 0C in a microwave for 15 min. The mixture was condensed and diluted with MeOH to 5 mL and purified using preparative LCMS (pH 2). Pure fraction was freeze dried to give the desired product (25 mg, 34%). LCMS for Ci6Hi2ClN5O2S (M+H)+: m/z = 374.0. 1H NMR (400 MHz, DMS0-<i6): δ 10.22 (s, IH), 9.69 (s, IH), 9.11 (s, IH), 8.27 (t, /= 2,0 Hz, IH), 8.14 (s, IH), 7.79 (t, /= 2.0 Hz, IH), 7.45 (m, IH), 7.22 (ddd, / = 7.8, 2.0, 1.2 Hz, IH), 7.15 (t, / = 8.0 Hz, IH), 7.06 (s, IH), 6.94 (s, IH), 6.70 (ddd, / = 8.0, 2.2, 1.0 Hz, IH).
Example C7
6-Chloro-14-thia-2,4,8,15,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- I(20),3(22),4,6,9(21),10,12,16,18-nonaene l4,14-dioxide trifluoroacetate
Figure imgf000521_0001
Step A: tert-Butyl (3-{[(3-nitrophenyl)sulfonyl]amino}phenyl)carbamate
Figure imgf000521_0002
Into a 1-neck round-bottom flask were added tert-butyl (3-aminophenyl)carbamate (2.0 g, 9.6 mmol) and tetrahydrofuran (30 mL) and triethylamine (2.0 mL, 14 mmol). The mixture was stirred at 0 0C and ra-nitrobenzenesulfonyl chloride (2.1 g, 9.6 mmol) was slowly added. The reaction was warmed to rt and stirred for 1 h. The solvent was removed under vacuum and EtOAc and water were added. The aqueous phase was extracted again with EtOAc. The organics were combined, dried over Na2SO4 and the solvents were removed under vacuum. The crude was purified by combi-flash column chromatography to give the desired product (1.5 g, 39%). IXMS for C17H19N3O6S (M-fBu+H)+: m/z = 338.0. 1H NMR (400 MHz, DMSO-^6): δ 10.47 (s, IH), 9.35 (s, IH), 8.51 (t, /= 2.0 Hz, IH), 8.43 (ddd, / = 8.2, 2.2, 1.0 Hz, IH), 8.12 (ddd, /= 7.8, 1.8, 1.0 Hz, IH), 7.84 (t, /= 8.0 Hz, IH), 7.35 (br, IH), 7.07 (m, IH), 7.06 (s, IH), 6.68 (dt, / = 7.0, 2.0 Hz, IH), 1.42 (s, 9H).
Step B: tert-Butyl (3-{[(3-aminophenyl)sulfonyl]aminojphenyl)carbamate
Figure imgf000522_0001
To a solution tert-butyl (3-{ [(3-nitrophenyl)sulfonyl]amino}phenyl)carbamate (0.51 g, 0.0013 mol) in water (1 mL), methanol (5 mL) and acetic acid (2 mL) was added iron (290 mg, 5.2 mmol) powder in one batch. The mixture was stirred at 0 0C for 0.5 h. The reaction mixture was mixed with celite, filtered, and the cake was washed with EtOAc. The brown filtrate was concentrated, followed by the addition of EtOAc and NaHCO3/water. The aqueous phase was extracted with EtOAc. The organics were combined, dried over Na2SO4 and concentrated to give the desired product as a yellow powder (0.46 g, 98%). LCMS for CnH2IN3O4S (M-?Bu+H)+: m/z = 308.0. 1H NMR (400 MHz, DMS0-<i6): δ 10.02 (s, IH), 9.31 (s, IH), 7.33 (br, IH), 7.10 (t, / = 8.0 Hz, IH), 7.02 (m, IH), 6.93 (t, / = 2.0 Hz, IH), 6.85 (ddd, / = 7.6, 1.8, 1.0 Hz, IH), 6.67 (m, IH), 5.53 (s, IH), 1.43 (s, 9H).
Step C: tert-Butyl (3-[({3-[(2, 5-dichloropyrimidin-4-yl)amino]phenyl}sulfonyl)amino]phenyl}carbamate
Figure imgf000523_0001
To a solution of tert-butyl (3-{ [(3-aminophenyl)sulfonyl]amino}phenyl)carbamate (0.30 g, 0.82 mmol) and 2,4,5-trichloropyrimidine (0.14 g, 0.75 mmol) in DMF (2 mL) was added potassium carbonate (0.12 g, 0.90 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous phase was extracted with EtOAc. The combined organics were washed with water and brine then dried (MgSO4), filtered, and concentrated. The resulted crude mixture was purified by column chromatography to give the desired product (70 mg, 18%). LCMS for C2IH21Cl2N5O4S (M-?Bu+H)+: m/z = 454.0, 455.9.
1H NMR (500 MHz, DMSO-<i6): δ 9.28 (s, IH), 8.41 (s, IH), 8.12 (br, IH), 7.85 (dt, / = 7.4, 1.8 Hz, IH), 7.55 (br, IH), 7.57 (dt, / = 7.9, 1.8 Hz, IH), 7.39 (s, IH), 7.04 (m, IH), 7.02 (dt, /= 8.2, 2.0 Hz, IH), 6.71 (dt, / = 7.5, 1.8 Hz, IH), 1.43 (s, 9H).
Step D: 6-Chloro-14-thia-2,4,8,15,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene 14,14-dioxide trifluoroacetate To a solution of tert-butyl {3-[({3-[(2,5-dichloropyrimidin-4- yl)amino]phenyl}sulfonyl)amino]phenyl}carbamate (20 mg, 0.04 mmol) and in 2-methoxyethanol (1 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (60 μL). The resulting mixture was heated at 150 0C in a microwave for 15 min. The mixture was condensed and diluted with MeOH to 5 mL and purified using preparative LCMS (pH 2) to give the desired product (10 mg, 68%). LCMS for Ci6Hi2ClN5O2S (M+H)+: m/z = 374.0. 1H NMR (400 MHz, DMS0-<i6): δ 10.24 (s, IH), 9.61 (s, IH), 9.53 (s, IH), 8.29 (br, IH), 8.17 (s, IH), 7.94 (t, /= 2.2 Hz, IH), 7.55 (m, IH), 7.44 (m, IH), 7.06 (m, IH), 6.94 (s, IH), 6.71 (ddd, / = 7.8, 2.0, 0.9 Hz, IH), 6.52 (ddd, /= 8.0, 2.2, 0.9 Hz, IH).
Example C8 6-Chloro-15-thia-2,4,8,16,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- I(21),3(23),4,6,9(22),10,12,17,19-nonaene l5,15-dioxide trifluoroacetate
Figure imgf000524_0001
Step A: tert-Butyl (3-{[(3-nitrobenzyl)sulfonyl]amino}phenyl)carbamate
Figure imgf000524_0002
Into a 1-neck round-bottom flask was added tert-butyl (3-aminophenyl)carbamate (1.0 g, 4.8 mmol) and tetrahydrofuran (20 mL) and triethylamine (1.0 mL, 7.2 mmol). The mixture was cooled in an ice bath and (3-nitrophenyl)methanesulfonyl chloride (1.1 g, 4.8 mmol) was slowly added. The resultant mixture was warmed to rt. The solvent was removed under vacuum and EtOAc and water added. The aqueous phase was extracted again with EtOAc. The organic layers were combined, dried over Na2SO4 and the solvent removed under vacuum to give the desired product (1.94 g, 99%). LCMS for Ci8H21N3O6S (M-Boc+H)+: m/z = 308.0. 1H NMR (400 MHz, DMSO-^6): δ 9.84 (s, IH), 9.37 (s, IH), 8.98 (s, IH), 8.19 (ddd, / = 8.1, 2.3, 1.1 Hz, IH), 8.11 (t, / = 1.9 Hz, IH), 7.71 (dt, /= 7.7, 1.3 Hz, IH), 7.63 (t, / = 7.9 Hz, IH), 7.44 (t, / = 2.0 Hz, IH), 7.15 (t, /= 8.0 Hz, IH), 7.10 (m, IH), 6.81 (t, / = 8.0 Hz, IH), 6.78 (br, IH), 6.75 (ddd, / = 7.4, 2.2, 1.6 Hz, IH), 1.46 (s, 9H).
Step B: tert-Butyl (3-{[(3-aminobenzyl)sulfonyl]amino}phenyl)carbamate
Figure imgf000524_0003
To a solution tert-butyl (3-{ [(3-nitrobenzyl)sulfonyl]amino}phenyl)carbamate (1.1 g, 2.7 mmol) in water (2 mL), methanol (100 mL) and acetic acid (4.1 mL) was added iron (0.60 g, 11.0 mmol) powder in one batch. The mixture was stirred at 0 0C for 2 h. The mixture was mixed with celite, filtered, and the cake was washed with EtOAc. The brown filtrate was concentrated and EtOAc and NaHCO3/water were added. The water layer was extracted with EtOAc once more. The organic layers were combined, dried over Na2SO4 and concentrated to give the desired product as a yellow powder (0.9 g, 90%). LCMS for Ci8H23N3O4S (M-?Bu+H)+: m/z = 322.0. 1H NMR (400 MHz, DMS0-<i6): δ 9.72 (s, IH), 9.39 (s, IH), 7.44 (br, IH), 7.16 (t, / = 8.2 Hz, IH), 7.12 (m, IH), 6.94 QL, J = 1.1 Hz, IH), 7.79 (dt, /= 7.2, 2.1 Hz, IH), 6.50 (m, IH), 6.49 (s, IH), 6.35 (m, IH).
Step C: tert-Butyl (3-[({3-[(2, 5-dichloropyrimidin-4-yl)amino]benzyljsulfonyl)amino]phenyljcarbamate
Figure imgf000525_0001
To a solution of tert-butyl (3-{ [(3-aminobenzyl)sulfonyl]amino}phenyl)carbamate (0.64 g, 1.7 mmol) and 2,4,5-trichloropyrimidine (0.28 g, 1.5 mmol) in DMF (5 mL) was added potassium carbonate (0.26 g, 1.8 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat'd NH4Cl and water. EtOAc was then added and the layers separated. The aqueous phase was extracted with EtOAc. The combined organics were washed with water and brine then dried (MgSO4), filtered, and concentrated to give the desired product (0.75 g, 92%). LCMS for C22H23Cl2N5O4S
(M-tBu+H)+: m/z = 467.9, 469.9.
Step D: 6-Chloro-15-thia-2,4,8,16,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene 15,15 -dioxide trifluoroacetate To a solution of tert-butyl {3-[({3-[(2,5-dichloropyrimidin-4- yl)amino]benzyl}sulfonyl)amino]phenyl}carbamate (40 mg, 0.08 mmol) and in 2-methoxyethanol (1 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (60 μL). The resulting mixture was heated at 150 0C in the microwave for 15 min. The mixture was condensed and diluted with MeOH to 5 mL and purified using preparative LCMS (pH 2) to give the desired product (25 mg, 84%). LCMS for
CnH14ClN5O2S (M+H)+: m/z = 388.0, 390.0. 1H NMR (400 MHz, DMS0-<i6): δ 9.63 (s, IH), 9.34 (s, IH), 8.97 (s, IH), 8.23 (t, / = 1.8 Hz, IH), 8.19 (s, IH), 8.00 (t, / = 2.0 Hz, IH), 7.40 (dt, / = 8.4, 1.8 Hz, IH), 7.35 (t, / = 8.0 Hz, IH), 7.23 (t, / = 8.0 Hz, IH), 7.20 (dt, / = 7.4, 1.5 Hz, IH), 6.99 (ddd, / = 8.0, 2.0, 1.0 Hz, IH), 6.95 (ddd, / = 8.0, 2.1, 1.0 Hz, IH), 4.17 (s, 2H).
Example C9
6-Chloro-15-thia-2,4,8,14,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- I(21),3(23),4,6,9(22),10,12,17,19-nonaene l5,15-dioxide trifluoroacetate
Figure imgf000526_0001
Step A: N-(3-Aminophenyl)-l-(3-nitrophenyl)methanesulfonamide hydrochloride
Figure imgf000526_0002
tert-Butyl (3-{ [(3-nitrobenzyl)sulfonyl]amino}phenyl)carbamate (0.50 g, 1.2 mmol) and 4.0 M of hydrogen chloride were dissolved in 1 ,4-dioxane (3 mL) and stirred at rt for 2 h. The solvent was removed under vacuum and the white powder product (0.37 g, 98%) as a HCl salt was used in the next step without further purification. LCMS for Ci3Hi3N3O4S (M+H)+: m/z = 308.0.
Step B: N-{3-[(2,5-Dichloropyrimidin-4-yl)amino]phenyl}-l-(3-nitrophenyl)methanesulfonamide
Figure imgf000526_0003
To a solution of N-(3-aminophenyl)-l-(3-nitrophenyl)methanesulfonamide-hydrogen chloride
(0.10 g, 0.29 mmol) and 2,4,5-trichloropyrimidine (0.065 g, 0.35 mmol) in DMF (1 mL) was added potassium carbonate (0.20 g, 1.4 mmol). The resulting mixture was stirred overnight at room temperature. Additional triethylamine (0.099 mL, 0.71 mmol) was added and stirred again overnight. The reaction was then quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous phase was extracted with EtOAc. The combined organics were washed with water and brine then dried (MgSO4), filtered, and concentrated. The crude was purified by column chromatography to give the desired product (0.080 g, 60%). LCMS for Ci7Hi3Cl2N5O4S (M+H)+: m/z = 453.9, 455.9.
Step C: l-(3-Aminophenyl)-N-{3-[(2, 5-dichloropyrimidin-4-yl)amino]phenyl}methanesulfonamide
Figure imgf000527_0001
To a solution of N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}-l-(3- nitrophenyl)methanesulfonamide (0.060 g, 0.13 mmol) in water (0.1 mL), methanol (0.5 mL) and acetic acid (0.20 mL) was added iron (0.030 g, 0.53 mmol) powder in one batch. The mixture was stirred at 0 0C for 0.5 h. The reactoin was mixed with celite, filtered, and the cake was washed with EtOAc. The brown filtrate was concentrated and EtOAc and ΝaHCO3/water added. Water phase was extracted with EtOAc twice. The organics were combined, dried over Na2SO4 and concentrated to give the desired product as a yellow powder (0.050 g, 89%. LCMS for Ci7Hi5Cl2N5O2S (M+H)+: m/z = 423.9, 426.0.
Step D: 6-Chloro-15-thia-2,4,8,14,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene 15,15 -dioxide trifluoroacetate
To a solution of l-(3-aminophenyl)-N-{3-[(2,5-dichloropyrimidin-4- yl) amino] phenyl Jmethanesulfonamide (20 mg, 0.05 mmol) and in 2-methoxyethanol (1 mL) was added
4.0 M of hydrogen chloride in 1,4-dioxane (24 μL). The resulting mixture was heated at 150 0C in a microwave for 15 min. The mixture was concentrated, then diluted with MeOH to 5 mL and purified using preparative LCMS (pH 2) to give the desired product (10 mg, 55%). LCMS for Ci7Hi4ClN5O2S
(M+H)+: m/z = 388.0, 390.0. 1H NMR (400 MHz, DMS0-<i6): δ 9.61 (s, IH), 9.53 (s, IH), 9.21 (s, IH), 8.21 (t, / = 1.9 Hz, IH), 8.18 (s, IH), 7.91 (t, / = 2.0 Hz, IH), 7.33 (t, / = 8.0 Hz, IH), 7.25 (t, / = 7.8 Hz, IH), 7.20 (ddd, / = 8.0, 2.1, 1.0 Hz, IH), 7.13 (m, 2H), 6.99 (dt, / = 7.8, 1.2 Hz, IH), 4.13 (s, 2H).
Example ClO
6-Chloro-2,4,8,14,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-15-one trifluoroacetate
Figure imgf000528_0001
Step A: tert-Butyl (3-{[(3-nitrophenyl)acetyl]amino}phenyl)carbamate
Figure imgf000528_0002
tert-Butyl (3-aminophenyl)carbamate (1.0 g, 4.8 mmol) was dissolved in methylene chloride (4 mL) and then thionyl chloride (2.0 mL, 27 mmol) was added. The mixture was heated at 80 0C for 1 h. The solvent was removed under vacuum. Tetrahydrofuran (20 mL), triethylamine (2.3 mL, 17 mmol) and (3-nitrophenyl)acetic acid (0.87 g, 4.8 mmol) were then added and the mixture was stirred at rt for 1 h. The solvent was removed under vacuum and then EtOAc and water were added. The aqueous phase was extracted again with EtOAc. The organics were combined, dried over Na2SO4 and concentrated to give the desired product as a white powder (1.70 g, 95%). LCMS for Ci9H2IN3O5 (M-?Bu+H)+: m/z = 316.0.
Step B: N-(3-Aminophenyl)-2-(3-nitrophenyl)acetamide hydrochloride
Figure imgf000528_0003
Into the reaction was added tert-butyl (3-{ [(3-nitrophenyl)acetyl]amino}phenyl)carbamate (0.46 g, 1-2 mmol) and 4.0 M of hydrogen chloride in 1,4-dioxane (3 mL). The mixture was stirred at rt for 2 h. The solvent was removed under vacuum to give the desired product (0.34 g, 100%) as a white powder.
LCMS for Ci4H13N3O3 (M+H)+: m/z = 272.0.
Step C: N-{3-[(2, 5-Dichloropyrimidin-4-yl)amino]phenyl}-2-(3-nitrophenyl)acetamide
Figure imgf000529_0001
To a solution of N-(3-aminophenyl)-2-(3-nitrophenyl)acetamide-hydrogen chloride(0.11 g, 0.35 mmol) and 2,4,5-trichloropyrimidine (0.065 g, 0.35 mmol) in DMF (1 mL) was added potassium carbonate (0.20 g, 1.4 mmol). The resulting mixture was stirred overnight at room temperature. Additional triethylamine (0.099 mL, 0.71 mmol) was then added an stirred overnight again. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous was extracted with EtOAc. The combined organics were washed with water and brine then dried (MgSO4), filtered, and concentrated. The resulted mixture was purified by column chromatography to give the desired product (0.080 g, 53%). LCMS for Ci8H13Cl2N5O3 (M+H)+: m/z = 418.0, 419.9. 1H NMR (400 MHz, DMSO-^6): δ 10.33 (s, IH), 9.53 (s, IH), 8.35 (s, IH), 8.23 (t, / = 2.0 Hz, IH), 8.12 (ddd, / = 8.2, 2.4, 1.0 Hz, IH), 7.82 (t, /= 2.0 Hz, IH), 7.78 (dt, / = 7.8, 1.4 Hz, IH), 7.62 (t, / = 7.9 Hz, IH), 7.36 (dt, / = 8.0, 1.7 Hz, IH), 7.30 (t, /= 7.8 Hz, IH), 7.25 (dt, / = 8.0, 1.7 Hz, IH).
Step D: 2-(3-Aminophenyl)-N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}acetamide
Figure imgf000529_0002
To a solution N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}-2-(3-nitrophenyl)acetamide (0.055 g, 0.13 mmol) in water (0.1 mL), methanol (0.5 mL) and acetic acid (0.20 mL) was added iron (0.030 g, 0.53 mmol) powder in one batch. The mixture was stirred at 0 0C for 0.5 h. The reaction was mixed with celite, filtered, and the cake was washed with EtOAc. The brown filtrate was concentrated and EtOAc and ΝaHCO3/water added. The aqueous phase was extracted with EtOAc. The organics were combined, died over Na2SO4 and concentrated to give the desired product as a yellow powder (30 mg,
58%). LCMS for Ci8H15Cl2N5O (M+H)+: m/z = 388.0, 390.0. Step E: 6-Chloro-2,4,8,14,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-15-one trifluoroacetate
To a solution of 2-(3-aminophenyl)-N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}acetamide (20 mg, 0.05 mmol) and in 2-methoxyethanol (1 mL) was added 4.0 M of hydrogen chloride in 1,4- dioxane (24 μL). The resulting mixture was heated at 150 0C in the microwave for 15 min. The mixture was concentrated, diluted with MeOH to 5 mL and purified using preparative LCMS (pH 2) to give the desired product (4.0 mg, 22%). LCMS for Ci8Hi4ClN5O (M+H)+: m/z = 351.9.
Example CIl 6-Chloro-2,4,8,16,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-15-one trifluoroacetate
Figure imgf000530_0001
Step A: tert-Butyl (3-{[(3-aminophenyl)acetyl]aminojphenyl)carbamate
To a solution of tert-butyl (3-{ [(3-nitrophenyl)acetyl]amino}phenyl)carbamate (0.35 g, 0.94 mmol) in methanol (100 mL) was added 10% palladium on carbon (1:10, Palladium:carbon black, 0.15 g, 0.13 mmol). The reaction was shaken under 60 psi hydrogen gas overnight. The crude mixture was filtered through celite and concentrated under vacuum to give the desired product (0.30 g, 94%). LCMS for Ci9H23N3O3 (M-^Bu-I-H)+: m/z = 286.0.
Step B: tert-Butyl (3-[({3-[(2, S-dichloropyrimidin^-yljaminoJphenyljacetyljaminoJphenyljcarbamate
Figure imgf000531_0001
To a solution of tert-butyl (3-{ [(3-aminophenyl)acetyl]amino}phenyl)carbamate (0.31 g, 0.91 mmol) and 2,4,5-trichloropyrimidine (0.15 g, 0.82 mmol) in DMF (3 mL) was added potassium carbonate (0.14 g, 0.99 mmol). The resulting mixture was stirred overnight at rt. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous was extracted with EtOAc and the combined organics were washed with water and brine then dried (MgSO4), filtered, and concentrated. The crude mixture was purified by column chromatography to give the desired product
(0.25 g, 62%). LCMS for C23H23Cl2N5O3 (M-?Bu+H)+: m/z = 432.0, 434.0. 1H NMR (400 MHz, DMSO-^6): δ 10.12 (s, IH), 9.54 (s, IH), 9.32 (s, IH), 8.35 (s, IH), 7.93 (s, IH), 7.78 (t, /= 2.1 Hz, IH), 7.47 (s, IH), 7.46 (m, IH), 7.33 (dd, /= 8.7, 7.5 Hz, IH), 7.31 (m, IH), 7.15 (m, IH), 7.11 (t, / = 8.0 Hz, IH), 6.98 (m, IH).
Step C: 6-Chloro-2,4,8,16,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-15-one trifluoroacetate To a solution of tert-butyl {3-[({3-[(2,5-dichloropyrimidin-4- yl)amino]phenyl}acetyl)amino]phenyl}carbamate (20 mg, 0.04 mmol) and in 2-methoxyethanol (1 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (50 μL). The resulting mixture was heated at 150 0C in a microwave for 15 min. The mixture was condensed and diluted with DMSO to 5 mL and purified using preparative LCMS (pH 2) to give the desired product (5.0 mg, 35%). LCMS for Ci8Hi4ClN5O (M+H)+: m/z = 352.2.
Example C12
6-Chloro-2,4,8,17,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
Figure imgf000532_0001
Step A: tert-Butyl {2-[(3-aminophenyl)ethynyl]pyridin-4-yl}carbamate
Figure imgf000532_0002
tert-Butyl (2-iodopyridin-4-yl)carbamate (2.41 g, 7.5 mmol), copper(I) iodide (50 mg, 0.3 mmol) and bis(triphenylphosphine)palladium(II) chloride (200 mg, 0.3 mmol) were stirred in tetrahydrofuran (22 mL) with triethylamine (1.1 mL, 8.1 mmol) under N2 at rt. 3-Ethynylaniline (0.75 mL, 7.2 mmol) was added and the mixture was stirred at rt for 40 hours. The reaction mixture was diluted with water. After removal of the solvent, the aqueous residue was extracted with EtOAc three times, followed by drying, filtration, and concentration to give the desired product as a brown solid (1.97 g, 89%). LCMS for Ci8H20N3O2 (M+H)+: m/z = 310.1. Step B: tert-Butyl [2-({3-[(2, 5 -dichloropyrimidin-4-yl)amino]phenyljethynyl)pyridin-4-yl] carbamate
Figure imgf000532_0003
To a solution of tert-bvXy\ {2-[(3-aminophenyl)ethynyl]pyridin-4-yl}carbamate (0.50 g, 1.6 mmol) and 2,4,5-trichloropyrimidine (0.19 mL, 1.7 mmol) in NN-dimethylformamide (5.0 mL) was added potassium carbonate (0.670 g, 4.85 mmol). The resultant mixture was stirred for 40 hours at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine then dried (Na2SO4), filtered and concentrated to give the desired product as a light brown gum (0.665 g, 90%). LCMS for C22H20Cl2N5O2 (M+H) +: m/z = 456.0, 458.0.
Step C: tert-Butyl [2-(2-{3-[(2, 5-dichloropyrimidin-4-yl)amino]phenyljethyl)pyridin-4-yl] carbamate
Figure imgf000533_0001
To a mixture of tert-butyl [2-({3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethynyl)pyridin-4- yl]carbamate (740 mg, 1.6 mmol) in methanol (15 mL) and tetrahydrofuran (15 mL) was added 10% palladium on carbon (148 mg, 0.139 mmol). The resultant mixture was hydrogenated at 55 psi for 20 hours. The crude mixture was filtered and concentrated to give the desired product as a light yellow solid (0.65 g, 87%). LCMS for C22H24Cl2N5O2 (M+H) +: m/z = 460.0, 462.0.
Step D: N-{3-[2-(4-Aminopyridin-2-yl)ethyl]phenyl}-2,5-dichloropyrimidin-4-amine dihydrochloride
Figure imgf000533_0002
To a mixture of tert-butyl [2-(2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-4- yl]carbamate (0.75 g, 1.6 mmol) in 1,4-dioxane (3.0 mL) was added 4 M hydrogen chloride in 1,4- dioxane (7.1 mL). The resultant reaction mixture was stirred at rt for 2 hours. The reaction mixture was concentrated under vacuum to give the desired product as a light yellow powder (0.67 g, 95%). LCMS for Ci7Hi6Cl2N5 (M+H) +: m/z = 360.2, 362.0.
Step E: 6- Chloro-2,4, 8, 17, 22-pentaazatetracyclo[14.3.1.1 (3, 7).1 (9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
To a mixture of N-{3-[2-(4-aminopyridin-2-yl)ethyl]phenyl}-2,5-dichloropyrimidin-4-amine dihydrochloride (90.0 mg, 0.21 mmol) and triethylamine (0.087 mL, 0.62 mmol) in dry 1,4-dioxane (1.8 niL) was added (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (7.2 mg, 0.013 mmol), palladium acetate (1.9 mg, 0.008 mmol) and cesium carbonate (135 mg, 0.42 mmol). The mixture was degassed by bubbling N2 through the solution. The sealed tube was then microwaved at 150 0C for 30 min. The reaction mixture was diluted with TΗF/MeOΗ, filtered, and concentrated to give the residue, which was purified by silica gel column chromatography to provide the desired product (24 mg, 36%) as a white powder. LCMS for Ci7Hi5ClN5 (M+Η) +: m/z = 324.0. 1H NMR (400 MHz, DMSO-<i6): δ 9.69 (s, IH), 9.28 (s, IH), 8.15 (m, 3H), 7.74 (d, / = 1.6 Hz, IH), 7.27 (dd, / = 16.0, 8.0 Hz, IH), 7.07 (dd, / = 12.4, 3.2 Hz, 2H), 6.84 (dd, / = 5.6, 2.0 Hz, IH), 2.93 (m, 4H).
Example C13
6-Fluoro-2,4,8,17,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
Figure imgf000534_0001
Step A: tert-Butyl {2-[2-(3-aminophenyl)ethyl]pyridin-4-yl}carbamate
Figure imgf000534_0002
To a mixture of tert-butyl {2-[(3-aminophenyl)ethynyl]pyridin-4-yl}carbamate (250 mg, 1.62 mmol) (prepared in Example C 12, step A) in methanol (10 mL) was added 10% palladium on carbon (0.30 g, 0.24 mmol). The reaction mixture was hydrogenated at 50 psi overnight. The resultant mixture was filtered and concentrated to provide the desired product (240 mg, 95%) as a white solid. LCMS for Ci8H24N3O2 (M+H)+: m/z = 314.0.
Step B: tert-Butyl [2-(2-{3-[(2-chloro-5-fluoropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-4-yl]carbamate
Figure imgf000535_0001
To a solution of tert-butyl {2-[2-(3-aminophenyl)ethyl]pyridin-4-yl}carbamate (240 mg, 0.76 mmol) and 2,4-dichloro-5-fluoropyrimidine (134 mg, 0.80 mmol) in N,N-dimethylformamide (3.5 mL) was added potassium carbonate (318 mg, 0.23 mmol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was filtered first to remove K2CO3, followed by quenching with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine, then dried (Na2SO4), filtered and concentrated to give the residue, which was purified by silica gel column chromatography to give the desired product as an off-white solid (123 mg, 36%). LCMS for C22H24ClFN5O2 (M+H) +: m/z = 444.1.
Step C: N-{3-[2-(4-Aminopyridin-2-yl)ethyl]phenylj-2-chloro-5-fluoropyrimidin-4-amine dihydrochloride
Figure imgf000535_0002
To a mixture of tert-butyl [2-(2-{3-[(2-chloro-5-fluoropyrimidin-4- yl)amino]phenyl}ethyl)pyridin-4-yl]carbamate (123 mg, 0.28 mmol) in 1,4-dioxane (0.51 mL) was added 4 M hydrogen chloride in 1,4-dioxane (1.21 mL). The resultant reaction mixture was stirred at rt for 1 hour. The reaction mixture was concentrated under vacuum to provide the desired product as an off- white powder (113 mg, 98%). LCMS fOr Ci7Hi6ClFN5 (M-FH) +: m/z = 344.0.
Step D: 6-fluoro-2,4, 8, 17, 22-pentaazatetracyclo[14.3.1.1 (3, 7).1 (9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
To a mixture of N-{3-[2-(4-aminopyridin-2-yl)ethyl]phenyl}-2-chloro-5-fluoropyrimidin-4-amine dihydrochloride (50.0 mg, 0.12 mmol) and triethylamine (0.05 mL, 0.36 mmol) in dry 1,4-dioxane (1.0 mL) was added (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.16 mg, 0.007 mmol), palladium acetate (1.1 mg, 0.0048 mmol) and cesium carbonate (78.2 mg, 0.24 mmol). The cloudy mixture was degassed by bubbling N2 through the solution. The sealed tube was then microwaved at 150 0C for 30 min. The reaction mixture was diluted with THF, filtered and concentrated to give the residue, which was then triturated with MeOH/THF/EtOAc to provide the desired product as a white powder (15 mg, 41%). LCMS for Ci7Hi5FN5 (M+H) +: m/z = 308.0. 1H NMR (400 MHz, DMSO-^6): δ 9.68 (s, IH), 9.58 (s, IH), 8.14 (m, 3H), 7.84 (s, IH), 7.26 (dd, /= 15.2, 7.2 Hz, IH), 7.04 (dd, / = 7.2, 2.0 Hz, 2H), 6.84 (dd, / = 5.6, 2.0 Hz, IH), 2.90 (m, 4H).
Example C14 (14Z)-6-Chloro-2,4,8,17,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,14,16,18-decaene
Figure imgf000536_0001
Step A: tert-Butyl {2-[(Z)-2-(3-aminophenyl)vinyl]pyridin-4-yljcarbamate
Figure imgf000536_0002
To a mixture of tert-butyl {2-[(3-aminophenyl)ethynyl]pyridin-4-yl}carbamate (430 mg, 1.4 mmol) in methanol (15 mL) was added 10% palladium on carbon (150 mg, 0.14 mmol) and hydrogenated at 60 psi for 20 hours. After filtration and concentration, the crude residue was purified by silica gel column chromatography to give the desired product (160 mg, 37%). LCMS for Ci8H22N3O2 (M+H)+: m/z = 312.1
Step B: tert-Butyl [2-((Z)-2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}vinyl)pyridin-4-yl]carbamate
Figure imgf000537_0001
To a solution of tert-butyl {2-[(Z)-2-(3-aminophenyl)vinyl]pyridin-4-yl}carbamate (50.0 mg, 0.16 mmol) and 2,4,5-trichloropyrimidine (0.019 mL, 0.17 mmol) in NN-dimethylformamide (0.50 mL) was added potassium carbonate (66.6 mg, 0.48 mmol). The resultant mixture was stirred for 16 hours at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine then dried (Na2SO4), filtered and concentrated to give the desired product as a light brown gum (66 mg, 90%). LCMS for C22H22Cl2N5O2 (M+H)+: m/z = 458.0, 460.0.
Step C: N-{3-[(Z)-2-(4-Aminopyridin-2-yl)vinyl]phenylj-2,5-dichloropyrimidin-4-amine dihydrochloride
Figure imgf000537_0002
To a mixture of tert-butyl [2-((Z)-2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}vinyl)pyridin- 4-yl] carbamate (73.6 mg, 0.16 mmol) in 1,4-dioxane (0.50 mL) was added 4 M of hydrogen chloride in 1,4-dioxane (0.70 mL). The resultant reaction mixture was stirred at rt for 1 hour. The reaction mixture was concentrated under vacuum to give the desired product as a light yellow powder (66 mg, 95%). LCMS for Ci7Hi4Cl2N5 (M+H) +: m/z = 358.0.
Step D: (14Z)-6- Chloro-2,4, 8, 17, 22-pentaazatetracyclo[14.3.1.1 (3, 7).1 (9,13)]docosa- l(20),3(22),4,6,9(21),10,12,14,16,18-decaene
To a mixture of N-{3-[(Z)-2-(4-aminopyridin-2-yl)vinyl]phenyl}-2,5-dichloropyrimidin-4-amine dihydrochloride (34.6 mg, 0.08 mmol) and triethylamine (0.034 mL, 0.24 mmol) in dry 1,4-dioxane (0.70 mL) was added (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.8 mg, 0.0048 mmol), palladium acetate (0.7 mg, 0.003 mmol) and cesium carbonate (52.3 mg, 0.16 mmol). The mixture was degassed by bubbling N2 through the solution. The sealed tube was then microwaved at 150 0C for 30 min. The reaction mixture was diluted with THF/MeOH, filtered and concentrated to give the residue, which was then triturated with MeOH/EtOAc/THF to provide the desired product as a light yellow powder (9 mg, 35%). LCMS for Ci7Hi3ClN5 (M+H) +: m/z = 322.0. 1H NMR (300 MHz, DMS0-<i6): δ 9.81 (s, IH), 9.33 (s, IH), 9.15 (s, IH), 8.49 (s, IH), 8.26 (m, IH), 8.19 (s, IH), 7.33 (m, IH), 7.24 (m, IH), 7.08 (d, /= 5.7 Hz, IH), 6.93 (dd, /= 5.7, 2.1 Hz, IH), 6.83 (m, IH), 6.58 (d, / = 13.5 Hz, IH).
Example C15
6-Chloro-2,4,8,19,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
Figure imgf000538_0001
Step A: tert-Butyl (4-bromopyridin-2-yl)carbamate
Figure imgf000538_0002
A solution of 4-bromopyridin-2-amine (1.60 g, 9.25 mmol) in tetrahydrofuran (16 mL) was slowly added to a stirring solution of 1 M sodium bis(trimethylsilyl)amide in tetrahydrofuran (17.8 mL, 19.4 mmol) at rt. After the mixture was stirred at rt for 1 hour, a solution of di-tørt-butyldicarbonate (2.2 g, 10.0 mmol) in tetrahydrofuran (16 mL) was slowly added. The mixture was stirred at rt for 1 hour. The reaction mixture was quenched with NH4Cl (aq) and THF was removed under vacuum. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product (2.32 g, 92%) as a light brown powder. LCMS for CeH6BrN2O2 ([M-(fBu)+H]+H) +: m/z = 216.9, 218.9.
Step B: tert-Butyl {4-[(3-aminophenyl)ethynyl]pyridin-2-yl}carbamate
Figure imgf000539_0001
tert-Butyl (4-bromopyridin-2-yl)carbamate (1.935 g, 7.09 mmol), copper(I) iodide (0.67 g, 3.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.20 g, 0.28 mmol) were stirred in tetrahydrofuran (22 mL) with triethylamine (1.09 mL, 7.82 mmol) under N2 at rt. 3-Ethynylaniline (0.815 mL, 7.79 mmol) was added and the mixture was heated at 70 0C for 2 hours and only very little product was observed. Thus more 3-ethynylaniline (0.41 mL, 3.9 mmol) was added and the mixture was heated at 70 C over the weekend. The reaction mixture was filtered and concentrated to give a brown residue, which was purified by silica gel column chromatography to give the desired product (340 mg, 16%).
LCMS for Ci8H20N3O2 (M+H)+: m/z = 310.1
Step C: tert-Butyl {4-[2-(3-aminophenyl)ethyl]pyridin-2-yl}carbamate
Figure imgf000539_0002
To a mixture of tert-butyl {4-[(3-aminophenyl)ethynyl]pyridin-2-yl}carbamate (328 mg, 1.06 mmol) in methanol (8 mL) and methylene chloride (8 mL) was added 10% palladium on carbon (100 mg, 0.09 mmol). The resultant mixture was hydrogenated at 30 psi for 18 hours. The reaction mixture was filtered, washed with MeOH/DCM and concentrated to give the desired product (326 mg, 98%) as a light brown powder. LCMS for Ci8H24N3O2 (M+H)+: m/z = 314.1.
Step D: tert-Butyl [4-(2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-2-yl]carbamate
Figure imgf000539_0003
To a solution of tert-butyl {4-[2-(3-aminophenyl)ethyl]pyridin-2-yl}carbamate (160 mg, 0.51 mmol) and 2,4,5-trichloropyrimidine (98.3 mg, 0.54 mol) in NN-dimethylformamide (2.3 mL) was added potassium carbonate (212 mg, 1.53 mmol). The resultant mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered first to remove K2CO3, followed by quenching with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then dried (Na2SO4), filtered and concentrated to give the residue, which was purified by trituration with cold EtOAc to give the desired product (123 mg, 36%) as an off-white powder. LCMS for C22H24Cl2N5O2 (M+H) +: m/z = 460.1, 462.0.
Step E: N-{3-[2-(2-Aminopyridin-4-yl)ethyl]phenyl}-2,5-dichloropyrimidin-4-amine dihydrochloride
Figure imgf000540_0001
To a mixture of tert-butyl [4-(2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-2- yl]carbamate (128 mg, 0.28 mmol) in 1,4-dioxane (0.64 mL) was added 4 M of hydrogen chloride in 1,4- dioxane (3.0 mL). The resultant reaction mixture was stirred at rt for 2 hours. The reaction mixture was concentrated under vacuum to give the desired product (120 mg, 100%) as a very hygroscopic off-white powder. LCMS for Ci7H16Cl2N5 (M+H)+: m/z = 360.0
Step F: 6-Chloro-2,4,8,19,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene To a mixture of N-{3-[2-(2-aminopyridin-4-yl)ethyl]phenyl}-2,5-dichloropyrimidin-4-amine dihydrochloride (35.0 mg, 0.08 mmol) and triethylamine (0.034 mL, 0.24 mmol) in a mixed solvent of 1,4-dioxane (0.70 mL) and NN-dimethylformamide (0.70 mL) at rt were added (9,9-dimethyl-9H- xanthene-4,5-diyl)bis(diphenylphosphine) (5.6 mg, 0.010 mmol), palladium acetate (2.2 mg, 0.010 mmol) and cesium carbonate (52.6 mg, 0.16 mmol). The mixture was degassed by bubbling N2 through the solution. The sealed tube was then microwaved at 160 0C for 20 min. The reaction mixture was diluted with TΗF/MeOΗ, filtered and concentrated to give a residue, which was triturated with MeOΗ/EtOAc (1:1) to provide the desired product (16 mg, 61%) as a light brown powder. LCMS for CI7HI5CIN5 (M+H) +: m/z = 324.0. 1H NMR (400 MHz, DMSO-^6): δ 9.44 (s, IH), 9.22 (s, IH), 8.18 (m, IH), 8.06 (m, IH), 7.86 (m, IH), 7.68 (m, IH), 7.40 (m, IH), 7.28 (m, IH), 7.05 (m, IH), 6.28 (m, IH), 3.05 (m, 4H).
Example C16
6-Fluoro-2,4,8,19,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
Figure imgf000541_0001
Step A: tert-Butyl [4-(2-{3-[(2-chloro-5-fluoropyrimidin-4-yl)amino]phenyljethyl)pyridin-2-yl] carbamate
Figure imgf000541_0002
To a solution of tert-butyl {4-[2-(3-aminophenyl)ethyl]pyridin-2-yl}carbamate (160 mg, 0.51 mmol) (prepared in Example C15, step C) and 2,4-dichloro-5-fluoropyrimidine (89.5 mg, 0.54 mmol) in NN-dimethylformamide (2.3 mL) was added potassium carbonate (212 mg, 1.53 mmol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was filtered first to remove K2CO3, followed by quenching with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then dried (Na2SO4), filtered and concentrated to give the residue, which was purified by silica gel column chromatography to give the desired product as an off-white solid (93 mg, 41%). LCMS for C22H24ClFN5O2 (M+H)+: m/z = 444.1.
Step B: N-{3-[2-(2-Aminopyridin-4-yl)ethyl]phenyl}-2-chloro-5-fluoropyrimidin-4-amine dihydrochloride
Figure imgf000541_0003
To a mixture of tert-butyl [4-(2-{3-[(2-chloro-5-fluoropyrimidin-4- yl)amino]phenyl}ethyl)pyridin-2-yl]carbamate (88 mg, 0.20 mmol) in 1,4-dioxane (0.50 mL) was added 4 M hydrogen chloride in 1,4-dioxane (2.0 mL). The resultant reaction mixture was stirred at 40 0C for 1 hour. The reaction mixture was concentrated under vacuum to give the desired product as a very hygroscopic white powder (83 mg, 100%). LCMS for Ci7H16ClFN5 (M+H)+: m/z = 344.1.
Step C: 6-Fluoro-2,4,8,19,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
To a mixture of N-{3-[2-(2-aminopyridin-4-yl)ethyl]phenyl}-2-chloro-5-fluoropyrimidin-4-amine dihydrochloride (35.0 mg, 0.084 mmol) and triethylamine (0.035 mL, 0.25 mmol) in a mixed solvent of 1,4-dioxane (0.70 mL) and NN-dimethylformamide (0.70 mL) were added (9,9-dimethyl-9H-xanthene- 4,5-diyl)bis(diphenylphosphine) (5.8 mg, 0.01 mmol), palladium acetate (2.3 mg, 0.01 mmol) and cesium carbonate (54.7 mg, 0.17 mmol). The mixture was degassed by bubbling N2 through the solution. The sealed tube was then microwaved at 160 0C for 30 min. The reaction mixture was diluted with TΗF/MeOΗ, filtered and concentrated to give the residue, which was purified by silica gel column chromatography to provide the desired product as a white powder (7.8 mg, 30%). LCMS for C17Η15FN5
(M+H)+: m/z = 308.1. 1H NMR (400 MHz, CD3OD): δ 8.09 (d, / = 5.2 Hz, IH), 8.00 (s, IH), 7.96 (d, / = 4.0 Hz, IH), 7.81 (d, /= 1.6 Hz, IH), 7.31 (m, IH), 7.04 (m, 2H), 6.91 (m, IH).
Example C17
6-Chloro-2,4,8,20,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
Figure imgf000542_0001
Step A: tert-Butyl {6-[(3-aminophenyl)ethynyl]pyridin-2-yl}carbamate
Figure imgf000543_0001
tert-Butyl (6-iodopyridin-2-yl)carbamate (1.50 g, 4.68 mmol), copper(I) iodide (68.0 mg, 0.36 mmol) and bis(triphenylphosphine)palladium(II) chloride (100 mg, 0.2 mmol) were stirred in tetrahydrofuran (14 mL) with triethylamine (0.70 mL, 5.0 mmol) under N2 at rt. 3-Ethynylaniline (0.47 mL, 4.5 mmol) was added and the mixture was heated at 60 0C overnight. The mixture was filtered, washed with EtOAc and concentrated under vacuum to give the desired product as a brown solid (1.23 g,
89%). LCMS for Ci4H12N3O2 ([M-(?Bu)+H]+H)+: m/z = 254.1.
Step B: tert-Butyl {6-[2-(3-aminophenyl)ethyl]pyridin-2-yljcarbamate
Figure imgf000543_0002
To a mixture of tert-butyl {6-[(3-aminophenyl)ethynyl]pyridin-2-yl}carbamate (70.0 mg, 2.3 mmol) in methanol (25 mL) and was added 10% palladium on carbon (700 mg, 0.60 mmol). The resultant mixture was hydrogenated at 60 psi for 3 hours. The reaction mixture was filtered, washed with
MeOH and concentrated to give the desired product (680 mg, 96%). LCMS for Ci8H24N3O2 (M+H)+: m/z = 314.1.
Step C: tert-Butyl [6-(2-{3-[(2, 5 >-dichloropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-2-yl] 'carbamate
Figure imgf000543_0003
To a solution of tert-butyl {6-[2-(3-aminophenyl)ethyl]pyridin-2-yl}carbamate (200 mg, 0.64 mmol) and 2,4,5-trichloropyrimidine (123 mg, 0.67 mmol) in N,N-dimethylformamide (2.9 mL) was added potassium carbonate (264 mg, 1.91 mmol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was filtered first to remove K2CO3, followed by quenching with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then dried (Na2SO4), filtered and concentrated to give the residue, which was purified by silica gel column chromatography to give the desired product as a light brown gel (231 mg, 79%). LCMS for Ci7H16Cl2N5 [(M-Boc+H)+H]+: m/z = 360.0, 362.0.
Step D: N-{3-[2-(6-Aminopyridin-2-yl)ethyl]phenyl}-2,5-dichloropyrimidin-4-amine dihydrochloride
Figure imgf000544_0001
To a mixture of tert-buiyl [6-(2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-2- yl]carbamate (230 mg, 0.50 mmol) in 1,4-dioxane (1.0 mL) was added 4 M hydrogen chloride in 1,4- dioxane (5.0 mL). The resultant reaction mixture was stirred at rt for 2 hours. The reaction mixture was concentrated under vacuum to give the desired product (212 mg, 98%) as a very hydroscopic light yellow powder. LCMS for Ci7H16Cl2N5 (M+H)+: m/z = 360.0.
Step E: 6-Chloro-2,4,8,20,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
To a mixture of N-{3-[2-(6-aminopyridin-2-yl)ethyl]phenyl}-2,5-dichloropyrimidin-4-amine dihydrochloride (50 mg, 0.12 mmol) and triethylamine (0.048 mL, 0.35 mmol) in a mixed solvent of 1,4- dioxane (0.80 mL) and NN-dimethylformamide (0.80 mL) were added (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphine) (8.0 mg, 0.014 mmol), palladium acetate (3.1 mg, 0.014 mmol) and cesium carbonate (75.2 mg, 0.23 mmol). The mixture was degassed by bubbling N2 through the solution. The sealed tube was then microwaved at 160 0C for 30 min. The reaction mixture was diluted with TΗF/MeOΗ, filtered and concentrated to give the residue, which was purified by silica gel column chromatography to provide the desired product as a white powder (14 mg, 37%). LCMS for Ci7Hi5ClN5 (M+H)+: m/z = 324.0. 1H NMR (400 MHz, CD3OD): δ 8.70 (s, IH), 8.02 (s, IH), 7.63 (d, /= 7.6 Hz, IH), 7.07 (m, 2H), 6.90 (dd, /= 8.0, 1.6 Hz, IH), 6.84 (d, /= 8.0 Hz, IH), 6.79 (d, / = 8.0 Hz, IH), 3.22 (s, 4H).
Example C18 6-Fluoro-2,4,8,20,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
Figure imgf000545_0001
Step A: tert-Butyl [6-(2-{3-[(2-chloro-5-fluoropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-2-yl]carbamate
Figure imgf000545_0002
To a solution of tert-butyl {6-[2-(3-aminophenyl)ethyl]pyridin-2-yl}carbamate (200 mg, 0.64 mmol) (prepared in Example C17, step B) and 2,4-dichloro-5-fluoropyrimidine (112 mg, 0.67 mmol) in NN-dimethylformamide (2.9 mL) was added potassium carbonate (264 mg, 1.91 mmol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was filtered first to remove K2CO3 The filtrate was concentrated to give the residue, which was purified by silica gel column chromatography to give the desired product as a light yellow gum (216 mg, 76%). LCMS for
C22H24ClFN5O2 (M+H)+: m/z = 444.0.
Step B: N-{3-[2-(6-Aminopyridin-2-yl)ethyl]phenyl}-2-chloro-5-fluoropyrimidin-4-amine dihydrochloride
Figure imgf000545_0003
To a mixture of tert-butyl [6-(2-{3-[(2-chloro-5-fluoropyrimidin-4- yl)amino]phenyl}ethyl)pyridin-2-yl]carbamate (215 mg, 0.48 mmol) in 1,4-dioxane (0.90 mL) was added 4 M of hydrogen chloride in 1,4-dioxane (4.5 mL). The resultant reaction mixture was stirred at 35 0C for 3 hours. The reaction mixture was concentrated under vacuum to give the desired product as a very hydroscopic light yellow powder (194 mg, 96%). LCMS for Ci7H16ClFN5 (M+H)+: m/z = 344.1. Step C: 6-Fluoro-2,4,8,20,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
To a mixture of N-{3-[2-(6-ariiinopyridin-2-yl)ethyl]phenyl}-2-chloro-5-fluoropyrimidin-4-amine dihydrochloride (35.0 mg, 0.084 mmol) and triethylamine (0.035 mL, 0.25 mmol) in a mixed solvent of 1,4-dioxane (0.70 mL) and N,N-dimethylformamide (0.70 mL) was added (9,9-dimethyl-9H-xanthene- 4,5-diyl)bis(diphenylphosphine) (5.8 mg, 0.01 mmol), palladium acetate (2.3 mg, 0.01 mmol) and cesium carbonate (54.7 mg, 0.17 mmol). The mixture was degassed by bubbling N2 through the solution. The sealed tube was then microwaved at 160 0C for 1 hour. The reaction mixture was diluted with TΗF/MeOΗ, filtered and concentrated to give a residue, which was purified by silica gel column chromatography to provide the desired product as a white powder (6.4 mg, 25%). LCMS for Ci7H15FN5
(M+H)+: m/z = 308.1.
Example C19
6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000546_0001
Step A: tert-Butyl {5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbamate
Figure imgf000546_0002
Into the reaction flask were added tert-butyl (5-bromopyridin-3-yl)carbamate (2.00 g, 7.32 mmol), copper(I) iodide (56 mg, 0.29 mmol), bis(triphenylphosphine)palladium(II) chloride (0.20 g, 0.29 mmol), tetrahydrofuran (20 mL) and triethylamine (1.1 mL, 8.0 mmol). The reaction mixture was stirred under N2 bubbling for 5 min. 3-Ethynylaniline (0.849 g, 7.3 mmol) was then added. The reaction mixture was heated at 50 0C overnight. After removal of the solvent, the residue was treated with EtOAc and water. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude was purified by silica gel column chromatography to give the desired product as a yellow gel (0.60 g, 49%). LCMS for Ci4H12N3O2 ([M-(?Bu)+H]+H)+: m/z = 254.0.
Step B: tert-Butyl {5-[2-(3-aminophenyl)ethyl]pyridin-3-yljcarbamate
Figure imgf000547_0001
Into the reaction flask was added tert-butyl {5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbamate (0.50 g, 1.6 mmol), 50 mL of methanol and 10% palladium on carbon (100 mg, 0.094 mmol). The mixture was hydrogenated at 50 psi for 3 h. The reaction mixture was filtered to remove the catalyst and then concentrated under vacuum to give the desired product as an off-white powder (0.50 g, 99%).
LCMS for Ci8H24N3O2 (M+H)+: m/z = 314.1.
Step C: tert-Butyl [5-(2-{3-[(2, 5-dichloropyrimidin-4-yl)amino]phenyljethyl)pyridin-3-yl] carbamate
Figure imgf000547_0002
To a solution of tert-butyl {5-[2-(3-aminophenyl)ethyl]pyridin-3-yl}carbamate (0.50 g, 1.6 mmol) and 2,4,5-trichloropyrimidine (0.30 g, 1.6 mmol) in N,N-dimethylformamide (4 mL) was added potassium carbonate (0.43 g, 3.11 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc once. The combined organic layers were washed with water and brine then dried (Na2SO4), filtered, and concentrated. The crude mixture was purified by silica gel column chromatography to give the desired product as a white powder (0.60 g, 82%). LCMS for
C22H24Cl2N5O2 (M+H)+: m/z = 460.1, 462.1.
Step D: N-{3-[2-(5-Aminopyridin-3-yl)ethyl]phenyl}-2,5-dichloropyrimidin-4-amine dihydrochloride
Figure imgf000548_0001
Into the reaction vessel were added tert-bvXy\ [5-(2-{3-[(2,5-dichloropyrimidin-4- yl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (0.20 g, 0.43 mmol) and methanol (2.0 mL) and 4.0 M hydrogen chloride in 1,4-dioxane (2.0 mL). The reaction mixture was stirred at rt for 2 h and then concentrated under vacuum to give the desired product as an off-white powder (140 mg, 96%). LCMS for Ci7H16Cl2N5 (M+H)+: m/z = 360.0, 362.0.
Step E: 6-Chloro-2,4,8,18,22-pentaazatetracydo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) Into a reaction vial were added N-{3-[2-(5-aminopyridin-3-yl)ethyl]phenyl}-2,5- dichloropyrimidin-4-amine (100 mg, 0.28 mmol) and 1,4-dioxane (2 mL) and triethylamine (0.116 mL, 0.83 mmol). The mixture was stirred at rt for 5 min, followed by the addition of palladium acetate (1.2 mg, 0.006 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.8 mg, 0.008 mmol) and cesium carbonate (0.181 g, 0.56 mmol). The reaction mixture was degassed with N2 bubbling. The vial was sealed and heated in a 150 0C oil bath for 1 hour. After filtration and concentration, the crude was purified by prep-ΗPLC to give the desired product as an off-white powder (25 mg, 28%). LCMS for
CnH15ClN5 (M+H)+: m/z = 324.0. 1H NMR (400 MHz, DMSO-<i6): δ 10.02 (s, IH), 9.39 (s, IH), 8.92 (d, / = 2.0 Hz, IH), 8.36 (d, / = 1.5 Hz, IH), 8.33 (d, / = 2.3 Hz, IH), 8.22 (s, IH), 7.64 (d, / = 1.8 Hz, IH), 7.30 (d, /= 7.8 Hz, IH), 7.09 (m, 2H), 2.99 (m, 4H).
Example C20
(14Z)-6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,14,16,18-decaene bis(trifluoroacetate)
Figure imgf000548_0002
Step A: tert-Butyl {5-[(Z)-2-(3-aminophenyl)vinyl]pyridin-3-yl}carbamate
Figure imgf000549_0001
Into a reaction flask were added tert-butyl {5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbamate (0.45 g, 1.4 mmol) (prepared in Example C19, step A), methanol (15 mL) and 100 mg of Lindlar's catalyst. The reaction mixture was hydrogenated at 35 psi for 2 h. After removal of the solvent, the crude was purified by silica gel column chromatography to give the desired product as a white powder (0.19 g,
42%). LCMS for Ci8H22N3O2 (M+H)+: m/z = 312.0.
Step B: tert-Butyl [5 -((Z)-2-{3- [(2,5 -dichloropyrimidin-4-yl)amino]phenyljvinyl)pyridin-3-yl] carbamate
Figure imgf000549_0002
Into a reaction flask were added tert-butyl {5-[(Z)-2-(3-aminophenyl)vinyl]pyridin-3- yljcarbamate (80 mg, 0.26 mmol) and 2,4,5-trichloropyrimidine (57 mg, 0.31 mmol) and potassium carbonate (71 mg, 0.51 mmol) and NN-dimethylformamide (2 mL). The resultant mixture was stirred over the weekend at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine, and then dried (Na2SO4), filtered, and concentrated. The crude mixture was purified by silica gel column chromatography to give the desired product as a brown oil (55 mg, 47%). LCMS for C22H22Cl2N5O2 (M+H)+: m/z = 458.0, 460.0.
Step C: N-{3-(Z)-[2-(5-Aminopyridin-3-yl)ethyl]phenyl}-2, 5-dichloropyrimidin-4-amine dihydrochloride
Figure imgf000549_0003
Into a reaction flask were added tert-butyl [5-((Z)-2-{3-[(2,5-dichloropyrimidin-4- yl)amino]phenyl}vinyl)pyridin-3-yl]carbamate (55 mg, 0.12 mmol), methanol (1.0 mL) and 4.0 M of hydrogen chloride in 1,4-dioxane (1.0 mL). The reaction mixture was stirred at rt for 2 h and then concentrated under vacuum to give the desired product as a white powder (39 mg, 98%). LCMS for
Ci7H14Cl2N5 (M+H)+: m/z = 358.0, 360.0.
Step D: (14Z)-6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,14,16,18-decaene bis(trifluoroacetate)
Into a reaction vial were added N-{3-[(Z)-2-(5-aminopyridin-3-yl)vinyl]phenyl}-2,5- dichloropyrimidin-4-amine (50 mg, 0.14 mmol), 1,4-dioxane (2 mL) and triethylamine (0.058 mL, 0.42 mmol). The mixture was stirred at rt for 5 min, followed by the addition of palladium acetate (0.6 mg, 0.003 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.4 mg, 0.004 mmol) and cesium carbonate (91 mg, 0.28 mmol). The reaction mixture was degassed with N2 bubbling. The vial was sealed and heated in a 150 0C oil bath for 1 h. The solvent was removed under vacuum and the crude was purified by prep-ΗPLC to give the desired product as a white powder (15 mg, 30%). LCMS for
CnH13ClN5 (M+H)+: m/z = 322.0. 1H NMR (400 MHz, DMSO-<i6): δ 9.89 (s, IH), 9.48 (d, /= 2.0 Hz, IH), 9.35 (s, IH), 8.40 (s, IH), 8.31 (s, 2H), 8.22 (s, IH), 7.33 (d, /= 7.9 Hz, IH), 7.24 (ddd, /= 7.9, 2.0, 1.2 Hz, IH), 7.08 (d, / = 7.7 Hz, IH), 6.91 (d, /= 13.0 Hz, IH), 6.67 (d, / = 13.2 Hz, IH).
Example C21
6-Fluoro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000550_0001
Step A: tert-Butyl [5-(2-{3-[(2-chloro-5-fluoropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-3-yl]carbamate
Figure imgf000550_0002
To a solution of tert-butyl {5-[2-(3-aminophenyl)ethyl]pyridin-3-yl}carbamate (0.20 g, 0.64 mmol) (prepared in Example C19, step B) and 2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2 mmol) in NN-dimethylformamide (4 mL) was added potassium carbonate (0.430 g, 3.1 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc once. The combined organic layers were washed with water and brine, and then dried (Na2SO4), filtered, and concentrated. The crude was purified by silica gel column chromatography to give the desired product as a light yellow oil (60 mg, 20%). LCMS for C22H24ClFN5O2 (M+H)+: m/z = 444.0.
Step B: N-{3-[2-(5-Aminopyridin-3-yl)ethyl]phenyl}-2-chloro-5-fluoropyrimidin-4-amine dihydrochloride
Figure imgf000551_0001
Into a reaction flask were added tert-buiyl [5-(2-{3-[(2-chloro-5-fluoropyrimidin-4- yl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (48 mg, 0.11 mmol), methanol (0.50 mL) and 4.0 M of hydrogen chloride in 1,4-dioxane (0.50 mL). The reaction mixture was stirred at rt for 2 h and then concentrated under vacuum to give the desired product as an off-white powder (35 mg, 97%). LCMS for
Ci7H16ClFN5 (M+H)+: m/z = 344.0.
Step C: 6-Fluoro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Into a reaction vial were added N-{3-[2-(5-aminopyridin-3-yl)ethyl]phenyl}-2-chloro-5- fluoropyrimidin-4-amine dihydrochloride (30 mg, 0.087 mmol), 1,4-dioxane (1 mL) and triethylamine (0.037 mL, 0.26 mmol). The mixture was stirred at rt for 5 min, followed by the addition of palladium acetate (0.4 mg, 0.0017 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.5 mg,
0.0026 mmol) and cesium carbonate (56.9 mg, 0.17 mmol). The reaction mixture was degassed with N2 bubbling. The vial was sealed and heated in a 150 0C oil bath for 2 h. After concentration, the crude was purified by prep-ΗPLC to give the desired product as an off-white powder (10 mg, 37%). LCMS for
CnHi5FN5 (M+H)+: m/z = 308.1. 1 H NMR (400 MHz, DMSO-^6): δ 9.99 (s, IH), 9.84 (s, IH), 8.97 (d, / = 2.0 Hz, IH), 8.40 (d, / = 1.5 Hz, IH), 8.36 (d, / = 2.3 Hz, IH), 8.20 (d, / = 4.1 Hz, IH), 7.71 (d, / = 1.8 Hz, IH), 7.30 (d, / = 7.9 Hz, IH), 7.07 (m, 2H), 3.01 (m, 2H), 2.94 (m, 2H).
Example C22 14-Benzoyl-6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
Figure imgf000552_0001
Step A: tert-Butyl {3-[(3-nitrobenzyl)amino]phenyl}carbamate
Figure imgf000552_0002
To a solution of l-(bromomethyl)-3-nitro- benzene (4.50 g, 0.021 mol) and tert-butyl (3- aminophenyl)carbamate (4.34 g, 0.021 mol) in NN-dimethylformamide (50 mL) was added potassium carbonate (4.32 g, 0.03 mol). The resultant mixture was stirred at room temperature overnight and the reaction was complete. The reaction mixture was filtered first to remove K2CO3, and then quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then (jrie(j (Νa $Q ) filtered and concentrated to give the desired product as a light brown gel (6.94 g, 97%). LCMS for Ci8H22N3O4 (M+H)+: m/z = 344.1.
Step B: N-(3-Nitrobenzyl)benzene-l,3-diamine dihydrochloride
Figure imgf000552_0003
tert-Butyl {3-[(3-nitrobenzyl)amino]phenyl}carbamate (7.15 g, 0.021 mol) was mixed with 4 M of hydrogen chloride in 1,4-dioxane (68.3 mL) and stirred at rt for 1 hour and concentrated to give the desired product (6.32 g, 96%) as an off-white powder. LCMS for Ci3Hi4N3O2 (M+H)+: m/z = 244.1.
Step C: N-(2,5-Dichloropyrimidin-4-yl)-N'-(3-nitrobenzyl)benzene-l,3-diamine
Figure imgf000553_0001
To a solution of N-(3-nitrobenzyl)benzene-l,3-diamine dihydrochloride (6.58 g, 0.021 mol) and 2,4,5-trichloropyrimidine (2.38 mL, 0.021 mol) in NN-dimethylformamide (70 mL) was added potassium carbonate (10.1 g, 0.073 mol). The resultant mixture was stirred for 60 h at room temperature. The reaction mixture was filtered first to remove K2CO3, and then quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then dried (Na2SO4), filtered and concentrated to give the residue (10.5 g), which was purified by silica gel column chromatography to give the desired product as a light yellow powder (6.19 g, 76%). LCMS for Ci7Hi4Cl2N5O2 (M+H)+: m/z = 389.9.
Step D: N-(3-Aminobenzyl)-N'-(2,5-dichloropyrimidin-4-yl)benzene-l,3-diamine
Figure imgf000553_0002
To a solution of N-(2,5-dichloropyrimidin-4-yl)-N'-(3-nitrobenzyl)benzene-l,3-diamine (2.00 g,
5.12 mmol) in methanol (30 mL) was added 10% palladium on carbon (200 mg, 0.2 mmol). The resultant mixture was hydrogenated at 25 psi for 18 h. The reaction mixture was filtered, washed with MeOH and concentrated to give the desired product (1.72 g, 93%) as a light yellow powder. LCMS for Ci7Hi6Cl2Ν5 (M+H)+: m/z = 360.2.
Step E: 6- Chloro-2,4, 8, 14, 22-pentaazatetracydo[14.3.1.1 (3, 7).1 (9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
Figure imgf000554_0001
To a solution of N-(3-aminobenzyl)-N'-(2,5-dichloropyrimidin-4-yl)benzene-l,3-diamine (900 mg, 2.0 mmol) in 2-methoxyethanol (18 mL) was added 4.00 M of hydrogen chloride in 1,4-dioxane (1.88 mL). The resultant mixture was heated at 150 0C in the microwave for 5 min. After cooling, water and NaOH (12 Ν) were added to neutralize the mixture to pH = 7. The aqueous layer was extracted with EtOAc four times. The combined organic layers were dried, filtered and concentrated. The residue was purified by silica gel column chromatography to give the desired product as an off-white powder (66 mg, 8%). LCMS for Ci7Hi5ClN5 (M+H)+: m/z = 324.0.
Step F: 14-Benzoyl-6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
To a stirring solution of 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).1(9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene (20.0 mg, 0.0618 mmol) in N,N-dimethylformamide (0.24 mL) was added triethylamine (17.2 μL), followed by the addition of benzoyl chloride (17.4 mg, 0.12 mmol). The resultant solution was stirred at rt for 30 min. The mixture was quenched with H2O and concentrated. The residue was purified by silica gel column chromatography to give the desired product as an off-white powder (l l mg, 42%). LCMS for C24Hi9ClN5O (M+H)+: m/z = 428.1. 1H NMR (SOO MHz, DMSO-^6): δ 9.42 (s, IH), 9.11 (s, IH), 8.12 (s, 2H), 7.82 (s, IH), 7.25 (m, 4H), 7.15 (m, 4H), 7.03 (m, 3H), 4.86 (m, 2H).
Example C23
6-Chloro-14-(pyridin-2-ylcarbonyl)-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
Figure imgf000555_0001
The desired compound was prepared as a white powder according to the procedure of Example C22, step F, using 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene and pyridine-2-carbonyl chloride hydrochloride as the starting materials in 29% yield. LCMS for C23Hi8ClN6O (M+H)+: m/z = 429.0.
Example C24
6-Chloro-14-(4-methylbenzoyl)-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
Figure imgf000555_0002
The desired compound was prepared as a white powder according to the procedure of Example
C22, step F, using 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-
1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene and 4-methylbenzoic acid chloride as the starting materials in
48% yield. LCMS for C25H21ClN5O (M+H)+: m/z = 442.0.
Example C25
6-Chloro-14-(2-thienylcarbonyl)-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
Figure imgf000556_0001
The desired compound was prepared as a white powder according to the procedure of Example
C22, step F, using 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-
1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene and 2-thiophenecarbonyl chloride as the starting materials in
34% yield. LCMS for C22Hi7ClN5OS (M+H)+: m/z = 434.0.
Example C26
14-Butyryl-6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
Figure imgf000556_0002
The desired compound was prepared as a white powder according to the procedure of Example C22, step F, using 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene and butyryl chloride as the starting materials in 50% yield. LCMS for C2IH21ClN5O (M+H)+: m/z = 394.1.
Example C27
6-Chloro-14-(pyridin-3-ylcarbonyl)-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
Figure imgf000557_0001
The desired compound was prepared as a white powder according to the procedure of Example C22, step F, using 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene and nicotinoyl chloride hydrochloride as the starting materials in 60% yield. LCMS for C23H18ClN6O (M+H)+: m/z = 429.0. 1H NMR (300 MHz, DMSO-^6): δ 9.43 (s, IH), 9.15 (s, IH), 8.40 (s, IH), 8.14 (s, 2H), 7.89 (s, IH), 7.62 (s, IH), 7.23 (m, 4H), 7.10 (m, 4H), 4.85 (m, 2H).
Example C28
Methyl 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-12-carboxylate
Figure imgf000557_0002
Step A: 6-Chloro-12-iodo-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
Figure imgf000557_0003
To a suspension of 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine trihydrochloride (30.0 mg, 0.067 mmol) (prepared in Example B 19, step F) in 2.0 M of sulfuric acid in water (0.502 mL) was added a solution of sodium nitrite (6.93 mg, 0.10 mmol) in water dropwise at 0 0C. After addition, the resultant cloudy solution was stirred at same temperature for 1 h. Then this cold solution was added dropwise to a solution of potassium iodide (16.7 mg, 0.10 mmol) and copper cyanide (0.90 mg, 0.01 mmol) in water at 0 0C. The resultant mixture was stirred at rt overnight. The precipite was filtered and washed by water and dried to give the desired product as a light brown powder (28 mg, 93%). LCMS for Ci7H14ClIN5 (M+H)+: m/z = 449.9.
Step B: Methyl 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-12-carboxylate
The mixture of 6-chloro-12-iodo-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene (20.0 mg, 0.0445 mmol) in methanol (2.0 mL) was added triethylamine (0.0248 mL, 0.178 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (20.0 mg, 0.025 mmol). The mixture was refluxed under a CO balloon overnight. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography to give the desired product as an off-white powder (7 mg, 41%). LCMS for Ci9Hi7ClN5O2 (M+H)+: m/z = 382.0.
Example C29 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(lH-indol-3-yl)acetamide bis(trifluoroacetate)
Figure imgf000558_0001
A solution of indole-3-acetic acid (6.5 mg, 0.037 mmol), NNN',N-tetramethyl-0-(7- azabenzotriazol-l-yl)uronium hexafluorophosphate (38 mg, 0.10 mmol) in N,N-dimethylformamide (0.5 mL) and NN-diisopropylethylamine (15 μL, 0.086 mmol) was stirred for 15 minutes. A solution of 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine dihydrochloride (15 mg, 0.036 mmol) (prepared in Example C20, step H) in NN- dimethylformamide (0.2 mL) and NN-diisopropylethylamine (15 μL, 0.086 mmol) was added to the previous solution and the reaction mixture was stirred overnight . The reaction mixture was concentrated and purified by preparative LCMS (pH 2) to afford the desired product as a tristrifluoroacetic acid salt (10 mg, 55%). LCMS for C28H24ClN6O (M+H)+: m/z = 495.1. 1H NMR (300 MHz, DMS0-<i6): δ 10.96 (s, IH), 9.36 (s, IH), 9.25 (s, IH), 8.10 (s, IH), 7.93 (s, IH), 7.66 (m, 2H), 7.38 (d, / = 8.1 Hz, IH), 7.30 (m, 2H), 7.10 (m, 2H), 7.01 (m, 3H), 6.82 (m, IH), 6.53 (m, IH), 3.76 (s, 2H), 2.76 (m, 4H).
Example C30 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(3-methylisoxazol-5-yl)acetamide trifluoroacetate
Figure imgf000559_0001
The desired compound was prepared according to the procedure of Example C29, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and (3-methylisoxazol-5-yl)acetic acid as the starting materials in 36% yield (6 mg). LCMS for C24H22ClN6O2 (M+H)+: m/z = 461.0. 1H NMR (300 MHz, DMSO-^6): δ 9.67 (s, IH), 9.37 (s, IH), 9.26 (s, IH), 8.11 (s, IH), 7.98 (s, IH), 7.76 (d, / = 2.7 Hz, IH), 7.25 (m, IH), 7.06 (m, 2H), 6.86 (m, IH), 6.75 (m, IH), 6.27 (s, IH), 3.91 (s, 2H), 2.84 (m, 4H), 2.21 (s, 3H).
Example C31 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(lH-tetrazol-5-yl)acetamide trifluoroacetate
Figure imgf000560_0001
The desired compound was prepared according to the procedure of Example C29, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and lH-tetrazol-5-ylacetic acid as the starting materials in 50% yield. LCMS for C2IHi9ClN9O (M+H)+: m/z = 448.0. 1H NMR (300 MHz, DMSOd6): δ 9.81 (s, IH), 9.31 (s, IH), 9.15 (s, IH), 8.09 (s, IH), 8.00 (m, IH), 7.78 (m, IH), 7.28 (m, IH), 7.07 (m, 2H), 6.87 (m, IH), 6.76 (m, IH), 4.17 (s, 2H), 2.86 (s, 4H).
Example C32 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(3-thienyl)acetamide trifluoroacetate
Figure imgf000560_0002
The desired compound was prepared according to the procedure of Example C29, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 3-thienylacetic acid as the starting materials in 25% yield. LCMS for
C24H2IClN5OS (M+H)+: m/z = 462.0. 1H NMR (300 MHz, DMSOd6): δ 9.46 (s, IH), 9.40 (s, IH), 9.30 (s, IH), 8.11 (s, IH), 7.96 (s, IH), 7.72 (d, / = 2.4 Hz, IH), 7.52 (dd, / = 4.9, 3.0 Hz, IH), 7.36 (m, IH), 7.26 (d, / = 8.4 Hz, IH), 7.13 (dd, / = 5.0, 1.2 Hz, IH), 7.06 (t, /= 7.9 Hz, IH), 7.02 (dd, / = 8.6, 2.2 Hz, IH), 6.85 (d, /= 8.5 Hz, IH), 6.70 (d, / = 7.7 Hz, IH), 3.68 (s, 2H), 2.75 (m, 4H).
Example C33 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(lH-imidazol-4-yl)acetamide bis(trifluoroacetate)
Figure imgf000561_0001
The desired compound was prepared according to the procedure of Example C29, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and lH-imidazol-4-ylacetic acid hydrochloride as the starting materials in 31% yield. LCMS for C23H21ClN7O (M+Η)+: m/z = 446.1.
Example C34 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(2-methyl-lH-indol-3-yl)acetamide trifluoroacetate
Figure imgf000562_0001
The desired compound was prepared according to the procedure of Example C29, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and (2-methyl-lH-indol-3-yl)acetic acid as the starting materials in 54% yield. LCMS for C29H26ClN6O (M+Η)+: m/z = 509.1. 1H NMR (300 MHz, DMSO-^6): δ 10.87 (s, IH), 9.32 (s, IH), 9.20 (s, IH), 9.10 (s, IH), 8.08 (s, IH), 7.94 (s, IH), 7.67 (m, IH), 7.59 (m, IH), 7.32 (m, IH), 7.26 (m, 2H), 7.00 (m, 5H), 6.82 (m, 2H), 6.54 (m, IH), 3.70 (s, 2H), 2.70 (s, 4H).
Example C35
2-(l-Benzothien-3-yl)-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide trifluoroacetate
Figure imgf000562_0002
The desired compound was prepared according to the procedure of Example C29, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and benzo[&]thiophene-3-acetic acid as the starting materials in 64% yield. LCMS for C28H23ClN5OS (M+H)+: m/z = 512.0.
Example C36 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(2-furyl)acetamide trifluoroacetate
Figure imgf000563_0001
The desired compound was prepared according to the procedure of Example C29, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 2-furylacetic acid as the starting materials in 61% yield. LCMS for
C24H2IClN5O2 (M+H)+: m/z = 446.1. 1H NMR (300 MHz, DMSO-^6): δ 9.51 (s, IH), 9.36 (s, IH), 9.24 (s, IH), 8.11 (s, IH), 7.99 (s, IH), 7.74 (d, / = 2.3 Hz, IH), 7.61 (m, IH), 7.25 (d, / = 8.5 Hz, IH), 7.06 (m, 2H), 6.86 (m,lH), 6.74 (m,lH), 6.42 (dd, / = 3.2, 2.0 Hz, IH), 6.29 (m, IH), 3.75 (s, 2H), 2.82 (m, 4H).
Example C37 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-methyl-lH-indol-3-yl)acetamide trifluoroacetate
Figure imgf000564_0001
The desired compound was prepared according to the procedure of Example C29, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-methyl-3-indoleacetic acid as the starting materials in 54% yield. LCMS for C29H26ClN6O (M+H)+: m/z = 509.2.
Example C38 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(2-methyl-l,3-thiazol-4-yl)acetamide trifluoroacetate
Figure imgf000564_0002
The desired compound was prepared according to the procedure of Example C29, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and (2-methyl-l,3-thiazol-4-yl)acetic acid as the starting materials in 57% yield. LCMS for C24H22ClN6OS (M+H)+: m/z = 477.0.
Example C39 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-pyridin-3-ylacetamide bis(trifluoroacetate)
Figure imgf000565_0001
The desired compound was prepared according to the procedure of Example C29, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and pyridin-3-ylacetic acid as the starting materials in 48% yield. LCMS for C25H22ClN6O (M+H)+: m/z = 457.1.
Example C40 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-pyridin-4-ylacetamide bis(trifluoroacetate)
Figure imgf000565_0002
The desired compound was prepared according to the procedure of Example C29, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and pyridin-4-ylacetic acid as the starting materials in 45% yield. LCMS for C25H22ClN6O (M+H)+: m/z = 457.0. Example C41 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-pyridin-2-ylacetamide bis(trifluoroacetate)
Figure imgf000566_0001
The desired compound was prepared according to the procedure of Example C29, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and pyridin-2-ylacetic acid as the starting materials in 45% yield. LCMS for C25H22ClN6O (M+H)+: m/z = 457.2.
Example C42 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(2-thienyl)acetamide trifluoroacetate
Figure imgf000566_0002
The desired compound was prepared according to the procedure of Example C29, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 2-thienylacetic acid as the starting materials in 20% yield. LCMS for C24H2IClN5OS (M+H)+: m/z = 462.0.
Example C43 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(2,4-dimethyl-l,3-thiazol-5-yl)acetamide trifluoroacetate
Figure imgf000567_0001
The desired compound was prepared according to the procedure of Example C29, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and (2,4-dimethyl-l,3-thiazol-5-yl)acetic acid as the starting materials in 42% yield. LCMS for C25H24ClN6OS (M+H)+: m/z = 491.0.
Example C44 2-(lH-Benzimidazol-2-yl)-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide bis(trifluoroacetate) FA
Figure imgf000567_0002
The desired compound was prepared according to the procedure of Example C29, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and lH-benzimidazol-2-ylacetic acid as the starting materials in 23% yield. LCMS for C27H23ClN7O (M+H)+: m/z = 496.0.
Example C45
2-(l,2-Benzisoxazol-3-yl)-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide trifluoroacetate
Figure imgf000568_0001
The desired compound was prepared according to the procedure of Example C29, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l,2-benzisoxazol-3-ylacetic acid as the starting materials in 10% yield. LCMS for C27H22ClN6O2 (M+H)+: m/z = 497.1.
Example C46 iV-/6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(2,5-dimethyl-l,3-thiazol-4-yl)acetamide trifluoroacetate
Figure imgf000569_0001
The desired compound was prepared according to the procedure of Example C29, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and (2,5-dimethyl-l,3-thiazol-4-yl)acetic acid as the starting materials in 42% yield. LCMS TOrC25H24ClN6OS (M+H)+: m/z = 491.0.
Example C47
2-(l-Benzofuran-3-yl)-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide trifluoroacetate
Figure imgf000569_0002
The desired compound was prepared according to the procedure of Example C29, using 6-chloro- 2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and l-benzofuran-3-ylacetic acid as the starting materials in 28% yield. LCMS for C28H23ClN5O2 (M+H)+: m/z = 496.0.
Example C48 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-(4-methyl-l,3-thiazol-5-yl)propanamide trifluoroacetate
Figure imgf000570_0001
The desired compound was prepared according to the procedure of Example C29, using 6-chloro-
2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- amine dihydrochloride and 3-(4-methyl-l,3-thiazol-5-yl)propanoic acid as the starting materials in 42% yield. LCMS for C25H24ClN6OS (M+H)+: m/z = 491.0. 1H NMR (300 MHz, DMSO-^6): δ 9.52 (s, IH), 9.45 (s, IH), 9.35 (s, IH), 8.88 (s, IH), 8.81 (dd, /= 4.5, 1.5 Hz, IH), 8.14 (s, IH), 8.67 (dd, / = 8.4, 1.3 Hz, IH), 7.92 (s, IH), 7.71 (d, / = 2.4 Hz, IH), 7.61 (dd, / = 8.5, 4.4 Hz, IH), 7.20 (d, / = 8.6 Hz, IH), 7.08 (d, / = 7.6 Hz, IH), 7.00 (dd, / = 8.5, 2.3 Hz, IH), 6.85 (d, / = 7.6 Hz, IH), 6.75 (d, / = 7.6 Hz, IH), 3.08 (t, /= 7.1 Hz, 2H), 3.23 (s, 3H), 3.00 (s, IH), 2.64 (m, 2H).
Example C49 iV-[6-Fluoro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4- yljacetamide trifluoroacetate
Figure imgf000571_0001
Step A: tert-Butyl (2-iodo-4-nitrophenyl)carbamate
Figure imgf000571_0002
oc
Into the reaction flask was added 2-iodo-4-nitroaniline (2.0 g, 7.6 mmol) and NN- dimethylformamide (30 mL). Sodium hydride (0.22 g, 9.1 mmol) was added at 0 0C, followed by the addition of di-tert-butyldicarbonate (1.8 g, 8.3 mmol). The mixture was warmed up to rt and stirred over the weekend. To it was added water and EtOAc. The aqueous layer was extracted again with EtOAc. The organic layers were combined and dried over Na2SO4. After filtration and concentration, the crude was purified by silica gel column chromatography to give the desired product (1.5 g, 55%). LCMS for
CnHi4IN2O4 (M+H)+: m/z = 364.9.
Step B: tert-Butyl [5-({2-[(tert-butoxycarbonyl)amino]-5-nitrophenyl}ethynyl)pyridin-3-yl]carbamate
Figure imgf000571_0003
Into the reaction flask was added tert-butyl (2-iodo-4-nitrophenyl)carbamate (1.5 g, 4.1 mmol) and copper(I) iodide (0.031 g, 0.16 mmol), bis(triphenylphosphine)palladium(II) chloride (0.12 g, 0.16 mmol), tetrahydrofuran (10 mL), and triethylamine (0.63 mL). The mixture was stirred under bubbling N2 for 5 min, and tert-butyl (5-ethynylpyridin-3-yl)carbamate (0.90 g, 4.1 mmol) was then added. The reaction mixture was stirred at 65 0C for 1 h. After concentration, the residue was diluted with EtOAc and water. The aqueous layer was extracted again with EtOAc. The organic layers were combined and dried over Na2SO4. After filtration and concentration, the crude was purified by silica gel column chromatography to give the desired product (1.6 g, 85%). LCMS for C23H27N4O6 (M+H)+: m/z = 455.1.
Step C: tert-Butyl [5-({5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethynyl)pyridin-3-yl]carbamate
Figure imgf000572_0001
Into the reaction flask was added tert-butyl [5-({2-[(tert-butoxycarbonyl)amino]-5- nitrophenyl}ethynyl)pyridin-3-yl]carbamate (1.6 g, 3.5 mmol), methanol (40 mL), acetic acid (7 mL), and water (4 mL). Then iron (0.90 g, 0.016 mol) powder was added. The reaction mixture was heated at 60 0C for 3 h. After filtration, the cake was rinsed with EtOAc. The filtrate was concentrated and the resideue was diluted with NaHCO3 and EtOAc. After layer separation, the organic layer was dried, filtered and concentrated to give the desired product (1.4 g, 94%). LCMS for C23H29N4O4 (M+H)+: m/z = 425.1.
Step D: tert-Butyl [5-(2-{5-amino-2-[(tert-butoxycarbonyl)amino]phenyljethyl)pyridin-3-yl]carbamate
Figure imgf000572_0002
Into the reaction flask was added tert-butyl [5-({5-amino-2-[(tert- butoxycarbonyl)amino]phenyl}ethynyl)pyridin-3-yl] carbamate (1.5 g, 3.5 mmol) and methanol (30 mL) and 10% palladium on carbon (0.15 g, 0.14 mmol) . The reaction mixture was hydrogenated at 25 psi for 2 h. The mixture was filtered and concentrated to give the desired product (1.4 g, 92%). LCMS for C23H33N4O4 (M+H)+: m/z = 429.1.
Step E: tert-Butyl [5-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2-chloro-5-fluoropyrimidin-4- yl)amino]phenyl}ethyl)pyridin-3-yl]carbamate
Figure imgf000573_0001
To a solution of tert-butyl [5-(2-{5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)pyridin- 3-yl]carbamate (0.27 g, 0.63 mmol) and 2,4-dichloro-5-fluoropyrimidine (0.105 g, 0.63 mmol) in N,N- dimethylformamide (4 mL) was added potassium carbonate (0.446 g, 3.23 mmol). The resultant mixture was stirred overnight at rt. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography to give the desired product (50 mg, 14%). LCMS for C27H33ClFN6O4 (M+H)+: m/z = 559.2.
Step F: 2-[2-(5-Aminopyridin-3-yl)ethyl]-N(4)-(2-chloro-5-fluoropyrimidin-4-yl)benzene-l,4-diamine trihydrochloride
Figure imgf000573_0002
Into the reaction flask was added tert-butyl [5-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2-chloro-5- fluoropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (0.050 g, 0.089 mmol), methanol (0.6 mL), and 4.0 M of hydrogen chloride in 1,4-dioxane (1 mL). The mixture was stirred at rt overnight and concentrated under vacuum to give the desired product (10 mg, 95%). LCMS for Ci7Hi7ClFN6 (M+H)+: m/z = 359.0. Step G: 6-Fluoro-2, 4, 8,18, 22-pentaazatetracyclo[14.3.1.1 (3, 7).1 (9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate)
Figure imgf000574_0001
Into the reaction flask was added 2-[2-(5-aminopyridin-3-yl)ethyl]-N(4)-(2-chloro-5- fluoropyrimidin-4-yl)benzene-l,4-diamine trihydrochloride (0.034 g, 0.095 mmol), 1,4-dioxane (0.6 mL), and triethylamine (0.04 mL). The mixture was stirred at rt for 5 min. To it was then added palladium acetate (1 mg, 0.004 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2 mg, 0.003 mmol) and cesium carbonate (60 mg, 0.2 mmol). The mixture was degassed with N2 bubbling. The tube was sealed and heated at 160 0C for 20 min under microwave irradiation. After filtration and concentration, the crude was purified by preparative ΗPLC (pΗ 2) to give the desired product (2.5 mg, 8%), LCMS for CnH16FN6 (M+H)+: m/z = 323.1.
Step H: Methyl {l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl}acetate
Figure imgf000574_0002
Into the reaction flask was added methyl piperidin-4-ylacetate (2.2 g, 14 mmol), tetrahydrofuran
(50 mL), and triethylamine (1.7 mL) and 5-methylisoxazole-3-carbonyl chloride (2.0 g, 14 mmol). The mixture was stirred at rt for 5 min. To it was added water and EtOAc. The water phase was extracted again with EtOAc. The organic layers were combined and dried over Na2SO4. After filtration and concentration, the desired product (2.8 g, 75%) was used without further purification. LCMS for Ci3H19N2O4 (M+H)+: m/z = 267.0
Step I: {1 -[(5 -MethyHsoxazol-3-yl)carbonyl]piperidin-4-yl) 'acetic acid
Figure imgf000575_0001
Into the reaction flask was added methyl { l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4- yljacetate (2.8 g, 10.0 mmol) and methanol (10 mL) and 3 M of sodium hydroxide in water (10 mL). The mixture was stirred at rt for 2 h. After concentration, the residue was neutralized to pH = 7. The mixture was extraced with EtOAc twice. The combined organic layers were dried and concentrated to give the desired product (0.30 g, 11%). LCMS for Ci2H17N2O4 (M+H)+: m/z = 253.1
Step J: N-[6-Fluoro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4A9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4- yljacetamide bis(trifluoroacetate)
A solution of { l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl} acetic acid (2.0 mg, 0.0079 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (8.1 mg, 0.021 mmol) in NN-dimethylformamide (0.1 mL) and N,N-diisopropylethylamine (3.2 uL) was stirred for 15 minutes. A solution of 6-fluoro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate) (2.5 mg, 0.0078 mmol) in NN- dimethylformamide (0.04 mL) and was added to the previous solution and stirred overnight. The reaction mixture was purified by preparative HPLC (pH 2) to give the desired product (0.5 mg, 14%). LCMS for C29H30FN8O3 (M+H)+: m/z = 557.1.
Example C50
6-Methyl-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate)
Figure imgf000575_0002
Step A: tert-Butyl [5-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2-chloro-5-methylpyrimidin-4- yl)amino]phenyl}ethyl)pyridin-3-yl]carbamate
Figure imgf000576_0001
To a solution of tert-butyl [5-(2-{5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethyl)pyridin- 3-yl]carbamate (0.27 g, 0.63 mmol) (prepared in Example C49, step D) and 2,4-dichloro-5- methylpyrimidine (0.103 g, 0.63 mmol) in NN-dimethylformamide (4 mL) was added potassium carbonate (0.446 g, 3.23 mmol). The resultant mixture was stirred overnight at rt overnight. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude was purified by silica gel column chromatography to give the desired product (30 mg, 9%). LCMS for C28H34ClN6O4 (M+H)+: m/z = 555.2.
Step B: 2-[2-(5-Aminopyridin-3-yl)ethyl]-N(4)-(2-chloro-5-methylpyrimidin-4-yl)benzene-l,4-diamine trihydrochloride
Figure imgf000576_0002
Into the reaction flask was added tert-butyl [5-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2-chloro-5- methylpyrimidin-4-yl)amino]phenyl}ethyl)pyridin-3-yl]carbamate (0.030 g, 0.054 mmol), methanol (0.6 mL), and 4.0 M of hydrogen chloride in 1,4-dioxane (1 mL). The mixture was stirred at rt overnight and concentrated to give the desired product (21 mg, 95%). LCMS for Ci8H20ClN6
(M+H)+: m/z = 355.1.
Step C: 6-Methyl-2,4,8,18,22-pentaazatetracyclo[143AA(3,7)A(9,n)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate)
Into the reaction flask was added 2-[2-(5-aminopyridin-3-yl)ethyl]-N(4)-(2-chloro-5- methylpyrimidin-4-yl)benzene-l,4-diamine trihydrochloride (0.019 g, 0.054 mmol), 1,4-dioxane (0.4 mL), and triethylamine (0.02 mL). The mixture was stirred at rt for 5 min. To it was added palladium acetate (0.6 mg, 0.002 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1 mg, 0.002 mmol), and cesium carbonate (40 mg, 0.1 mmol). The mixture was degassed with N2 bubbling. The tube was sealed and heated at 160 0C for 20 min in a microwave. The mixture was filtered and purified by preparative ΗPLC (pΗ T) to give the desired product (8.5 mg, 50%). LCMS for Ci8Hi9N6 (M+H)+: m/z = 319.2.
Example C51
2-{l-[(5-Methylisoxazol-3-yl)carbonyl]piperidin-4-yl}-iV-[6-methyl-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide bis(trifluoroacetate)
Figure imgf000577_0001
A solution of { l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl} acetic acid (4.8 mg, 0.019 mmol) (prepared in Example C49, step I), NNN',N'-tetramethyl-0-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (19 mg, 0.050 mmol) in NN-dimethylformamide (0.2 mL) and NN- diisopropylethylamine (7.6 uL) was stirred for 15 minutes. A solution of 6-methyl-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate) (6.0 mg, 0.019 mmol) (prepared in Example C29, step C) in NN-dimethylformamide (0.1 mL) and was added to the previous solution and was stirred overnight . The reaction mixture was purified by preparative HPLC (pH 2) to give the desired product (0.5 mg, 19%). LCMS for C30H33N8O3 (M+H)+: m/z = 553.2. 1H NMR (300 MHz, DMSO-^6): δ 9.83 (s, IH), 9.38 (s, IH), 9.34 (s, IH), 8.52 (s, IH), 8.19 (s, IH), 8.12 (s, IH), 7.90 (s, IH), 7.62 (d, / = 2.4 Hz, IH), 7.28 (d, /= 8.7 Hz, IH), 7.00 (dd, / = 8.3, 2.2 Hz, IH), 6.41 (dd, / = 8.1, 0.8 Hz, IH), 4.42 (m, 4H), 3.86 (m, 4H), 2.90-3.10 (m, 6H), 2.10-2.30 (m, 4H), 2.66 (s, 3H). Example C52 iV-[6-Fluoro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4- yljacetamide trifluoroacetate
Figure imgf000578_0001
Step A: tert-Butyl [3-({2-[(tert-butoxycarbonyl)amino]-5-nitrophenylJethynyl)phenyl]carbamate
Figure imgf000578_0002
NHBoc
Into the reaction flask was added tert-butyl (2-iodo-4-nitrophenyl)carbamate (2.71 g, 7.44 mmol), copper(I) iodide (0.057 g, 0.30 mmol), bis(triphenylphosphine)palladium(II) chloride (0.21 g, 0.30 mmol), tetrahydrofuran (20 mL), and triethylamine (1.1 mL). It was stirred under N2 bubbling for 5 min. tert-Butyl (3-ethynylphenyl)carbamate (1.62 g, 7.44 mmol) was then added. The reaction mixture was stirred at 65 0C for 3 h. After concentration, the residue was diluted with EtOAc and water. The aqueous layer was extracted again with fresh EtOAc. The organic layers were combined and dried over Na2SO4. After filtration and concentration, the crude was purified by silica gel column chromatography to give the desired product (2.7 g, 80%). LCMS for C24H28N3O6 (M+H)+: m/z = 454.1.
Step B: tert-Butyl [^-({S-amino^-Ktert-butoxycarbonyljaminojphenyljethynyljphenyljcarbamate
Figure imgf000579_0001
Into the reaction flask was added tert-bvXy\ [3-({2-[(tørt-butoxycarbonyl)amino]-5- nitrophenyl}ethynyl)phenyl]carbamate (2.7 g, 6.0 mmol), methanol (70 mL), acetic acid (10 mL), and water (7 mL) . Then iron powder (1.8 g, 30 mmol) was added. The reaction mixture was heated at 60 0C for 3 h. After filtration, the cake was rinsed with EtOAc. The filtrate was concentrated and the residue was diluted with NaHCO3 (aq) and EtOAc. After the layers were separated, the organic layer was dried, filtered and concentrated to give the desired product (2.3 g, 91%). LCMS for C24H30N3O4 (M+H)+: m/z = 424.2.
Step C: tert-Butyl [3-(2-{ 5 -amino-2-[(tert-butoxycarbonyl)amino]phenyljethyl)phenyl] carbamate
Figure imgf000579_0002
NHBoc
Into the reaction falsk was added tert-butyl [3-({5-amino-2-[(tert- butoxycarbonyl)amino]phenyl}ethynyl)phenyl]carbamate (1.0 g, 2.4 mmol), 50 mL of methanol, and 10% palladium on carbon (0.10 g, 0.097 mmol). The reaction mixture was hydrogenated at 25 psi for 3 h. The mixture was filtered and concentrated to give the desired product (0.9 g, 89%). LCMS for C24H33NaN3O4 (M+Na)+: m/z = 450.2
Step D: tert-Butyl [3-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2-chloro-5-fluoropyrimidin-4- yl)amino]phenyl}ethyl)phenyl] 'carbamate
Figure imgf000580_0001
NHBoc
To a solution of tert-butyl [3-(2-{5-amino-2-[(tert- butoxycarbonyl)amino]phenyl}ethyl)phenyl] carbamate (0.4 g, 0.9 mmol) and 2,4-dichloro-5- fluoropyrimidine (0.156 g, 0.936 mmol) in NN-dimethylformamide (7 mL) was added potassium carbonate (0.662 g, 4.79 mmol). The resultant mixture was stirred overnight at rt overnight. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography to give the desired product (0.32 g, 61%). LCMS for C28H33ClFNaN5O4 (M+Na)+: m/z = 580.2.
Step E: 2-[2-(3-Aminophenyl)ethyl]-N(4)-(2-chloro-5-fluoropyrimidin-4-yl)benzene-l,4-diamine trihydrochloride
Figure imgf000580_0002
Into the reaction flask was added tert-butyl [3-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2-chloro-5- fluoropyrimidin-4-yl)amino]phenyl}ethyl)phenyl]carbamate (0.32 g, 0.57 mmol), methanol (3 mL), and 4.0 M of hydrogen chloride in 1,4-dioxane (5 mL). The mixture was stirred at rt overnight and concentrated under vacuum to give the desired product as a HCl salt (220 mg, 98%). LCMS for Ci8Hi8ClFN5 (M+H)+: m/z = 358.1.
Step F: 6-Fluoro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine bis(trifluoroacetate)
Figure imgf000581_0001
To a solution of 2-[2-(3-aminophenyl)ethyl]-N(4)-(2-chloro-5-fluoropyrimidin-4-yl)benzene-l,4- diamine trihydrochloride (0.20 g, 0.56 mmol) in 2-methoxyethanol (3 niL) was added 4.00 M of hydrogen chloride in 1,4-dioxane (140 μL). The resultant mixture was heated at 150 0C in the microwave for 15 min. After cooling down and filtration, the cake was further purified by preparative HPLC (pH 2) to give the desired product (100 mg, 56%). LCMS for Ci8Hi7FN5 (M+H)+: m/z = 322.1.
Step G: N-[6-Fluoro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4- yljacetamide bis(trifluoroacetate)
A solution of { l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl} acetic acid (16 mg, 0.063 mmol) (prepared in Example C49,step I), NNN',N'-tetramethyl-0-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (65 mg, 0.17 mmol) in NN-dimethylformamide (0.8 mL) and NN- diisopropylethylamine (26 μL) was stirred for 15 minutes. A solution of 6-fluoro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine bis(trifluoroacetate) (20 mg, 0.06 mmol) in NN-dimethylformamide (0.3 mL) and was added to the previous solution and stirred overnight . The reaction mixture was purified by preparative HPLC (pH 2) to give the desired product (4 mg, 12%). LCMS for C30H3IFN7O3 (M+H)+: m/z = 556.2
Example C53 iV-[6-Methyl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3,4-thiadiazol-2-yl)piperidin-4-yl]acetamide trifluoroacetate
Figure imgf000582_0001
Step A: tert-Butyl [3-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2-chloro-5-methylpyrimidin-4- yl)amino]phenyljethyl)phenyl] carbamate
Figure imgf000582_0002
NHBoc
To a solution of tert-butyl [3-(2-{5-amino-2-[(tert- butoxycarbonyl)amino]phenyl}ethyl)phenyl] carbamate (0.4 g, 0.9 mmol) (prepared in Example C52, step C) and 2,4-dichloro-5-methylpyrimidine (0.152 g, 0.936 mmol) in NN-dimethylformamide (7 mL) was added potassium carbonate (0.662 g, 4.79 mmol). The resultant mixture was stirred overnight at rt overnight. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then dried (Na2SO4), filtered and concentrated to give the residue, which was purified by silica gel column chromatography to give the desired product (0.25 g, 39%). LCMS for C29H37ClN5O4 (M+H)+: m/z = 554.2.
Step B: 2-[2-(3-Aminophenyl)ethyl]-N(4)-(2-chloro-5-methylpyrimidin-4-yl)benzene-l,4-diamine trihydrochloride
Figure imgf000583_0001
Into the reaction flask was added tert-butyl [3-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2-chloro-5- methylpyrimidin-4-yl)amino]phenyl}ethyl)phenyl]carbamate (0.25 g, 0.45 mmol), methanol (3 mL), and 4.0 M of hydrogen chloride in 1,4-dioxane (5 mL). The reaction mixture was stirred at rt for 1 6 h and concentrated to give the desired product (0.21 g, 90%). LCMS for Ci9H2iClN5 (M+H)+: m/z = 354.1.
Step C: 6-Methyl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4A9(21),10,12,16,18-nonaen-12-amine
Figure imgf000583_0002
To a solution of 2-[2-(3-aminophenyl)ethyl]-N(4)-(2-chloro-5-methylpyrimidin-4-yl)benzene-l,4- diamine trihydrochloride (0.16 g, 0.45 mmol) in 2-methoxyethanol (2 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (110 μL). The resultant mixture was heated at 150 0C in the microwave for 15 min. After cooling, water and NaOH (12 Ν) were added to neutralize the mixture to pH = 7. The aqueous layer was extracted with EtOAc four times. The combined organic layers were dried, filtered and concentrated. The residue was purified by silica gel column chromatography to give the desired product as an off-white powder (60 mg, 48%). LCMS for Ci9H20N5 (M+H)+: m/z = 318.2.
Step D: [1-(1, 3, 4-Thiadiazol-2-yl)piperidin-4-yl] 'acetic acid
Figure imgf000583_0003
S-y
Into the reaction flask was added 2-bromo-l,3,4-thiadiazole (0.21 g, 1.3 mmol), methyl piperidin- 4-ylacetate (0.20 g, 1.3 mmol), N-methylpyrrolidinone (2 mL), and triethylamine (0.39 mL). The reaction was sealed and put under microwave at 150 0C for 10 min. After concentration, the crude was purified by silica gel column chromatography to give the ester. The resultant pure ester was then mixed with methanol (2.0 mL) and 1.0 M of sodium hydroxide in water (2.0 mL). The mixture was stirred at rt for 3 h. The mixture was neutralized with HCl (3 M), the white precipitate was collected by vacuum filtration to give the desired product (0.09 g, 80%) as a white solid. LCMS for C9Hi4N3O2S (M+H)+: m/z = 228.1.
Step E.- N-tό-Methyl^AS^-tetraazatetracyclotMJ.l.liSjμi^lSjJdocosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3,4-thiadiazol-2-yl)piperidin-4-yl]acetamide bis(trifluoroacetate) A solution of [1-(1, 3, 4-thiadiazol-2-yl)piperidin-4-yl] acetic acid (14 mg, 0.063 mmol), N,N,N',N'- tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (65 mg, 0.17 mmol) in NN- dimethylformamide (0.8 mL) and NN-diisopropylethylamine (26 μL) was stirred for 15 minutes. A solution of 6-methyl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine (20 mg, 0.06 mmol) in NN-dimethylformamide (0.3 mL) was added to the previous solution and stirred overnight. The reaction mixture was purified by preparative HPLC (pH T) to give the desired product (4 mg, 14%). LCMS for C28H31N8OS (M+H)+: m/z = 527.1
Example C54 2-{l-[(5-Methylisoxazol-3-yl)carbonyl]piperidin-4-yl}-N-[6-methyl-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide trifluoroacetate
Figure imgf000584_0001
The desired compound was prepared as a white powder according to the procedure of Example C53, step E, using 6-methyl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine (15 mg, 47.3 mmol) and { l-[(5-methylisoxazol-3- yl)carbonyl]piperidin-4-yl} acetic acid as the starting materials in 29% yield. LCMS for C31H34N7O3 (M+H)+: m/z = 552.2.
Example C55
6-Chloro-12-(pyrrolidin-3-ylmethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trihydrochloride
Figure imgf000585_0001
Step A: 2-lodo-4-methoxy aniline
Figure imgf000585_0002
To a suspension of 3-iodo-4-nitrophenyl methyl ether (5.0 g, 0.018 mol) in methanol (50 mL), water (5 mL), and acetic acid (10 mL) was added iron (3.00 g, 0.0538 mol) powder in small quantities. When the addition was completed, the reaction mixture was heated at 70 0C overnight. After filtration, the cake was rinsed with EtOAc. The filtrate was concentrated and the residue was diluted with NaHCO3 (aq) and EtOAc. After layer separation, the organic layer was dried, filtered and concentrated to give the desired product (4.0 g, 90%).
Step B: 2,5-Dichloro-N-(3-iodo-4-methoxyphenyl)pyrimidin-4-amine
Figure imgf000585_0003
To a suspension of 3 -iodo-4-methoxy aniline (8.0 g, 0.021 mol) and 2,4,5-trichloropyrimidine (4.13 g, 0.0225 mol) in N,N-dimethylformamide (57 mL) was added potassium carbonate (7.40 g, 0.0536 mol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was filtered to remove K2CO3 and concentrated to give the residue (10 grams). The residue was triturated with EtOAc, and filtered under vacuum. The residue was purified by silica gel column chromatography to give the desired product (2.54 g, 30%). LCMS for CnH9Cl2IN3O (M+H)+: m/z = 396.0, 398.0.
Step C: N-{3-[(E)-2-(5-Aminopyridin-3-yl)vinyl]-4-methoxyphenyl}-2,5-dichloropyrimidin-4-amine
To a solution of 2,5-dichloro-N-(3-iodo-4-methoxyphenyl)pyrimidin-4-amine (2.54 g, 6.41 mmol) in acetonitrile (40 mL), tetrahydrofuran (30 mL), and water (30 mL) was added 5-vinylpyridin-3- amine (1.54 g, 12.8 mmol), sodium carbonate (1.36 g, 12.8 mmol), palladium acetate (43.2 mg, 0.192 mmol), and trisodium 3,3',3"-phosphinetriyltris(4,6-dimethylbenzenesulfonate) (377 mg, 0.577 mmol). The reaction flask was flushed with nitrogen for 10 min. The reaction mixture was heated at 80 0C for 16 hours. LCMS showed clean conversion of iodide. The mixture was concentrated under vacuum. To the residue water (40 mL) and MeOH (20 mL) were added. The resultant solid was collected by vacuum filtration. The cake was washed with water and then fresh methanol to give the desired product (2.22 g, 90%) as a red-yellow solid. LCMS for Ci8H16Cl2N5O (M+H)+: m/z = 388.1.
Step D: N-{3-[2-(5-Aminopyridin-3-yl)ethyl]-4-methoxyphenyl}-2,5-dichloropyrimidin-4-amine
Figure imgf000586_0002
To a solution of N-{3-[(Zζ)-2-(5-aminopyridin-3-yl)vinyl]-4-methoxyphenyl}-2,5- dichloropyrimidin-4-amine (2.25 g, 5.80 mmol) in 1 ,2-dimethoxyethane (2.0 mL), and tetrahydrofuran (100 mL) was added p-toluenesulfonylhydrazide (16.2 g, 86.9 mmol). The reaction mixture was heated to 90 0C when a solution of sodium acetate (11.4 g, 139 mmol) in water (120 mL) was added dropwise over 4 h. The reaction mixture was stirred at 90 0C for 3 h. The reaction mixture was diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate twice. The combined organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the desired product as a yellow foam (1.75 g, 77%). LCMS for CI8HI8CI2NSO (M+H)+: m/z = 390.1
Step E: 6-Chloro-12-methoxy-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene
Figure imgf000587_0001
Into the reaction was added N-{3-[2-(5-aminopyridin-3-yl)ethyl]-4-methoxyphenyl}-2,5- dichloropyrimidin-4-amine (1.75 g, 4.48 mmol), 1,4-dioxane (29 mL), NN-dimethylformamide (29 mL), palladium acetate (30 mg, 0.1 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (90 mg, 0.2 mmol), and cesium carbonate (2.92 g, 8.97 mmol). The mixture was degassed with N2 bubbling and then microwaved at 150 0C for 20 min. After concentration to remove the solvent, 20 mL of water was added to the residue. The formed precipitate was then collcected by vacuum filtration and air dried overnight to give the desired product (1.35 g, 85%). LCMS for Ci8Hi7ClN5O (M+H)+: m/z = 354.1.
Step F: 6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-ol
Figure imgf000587_0002
Into the reaction flask was added 6-chloro-12-methoxy-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene (1.35 g, 3.82 mmol), methylene chloride (20 mL), and 1.0 M of boron tribromide in methylene chloride (19.1 mL). The reaction mixture was stirred at rt overnight. To the mixture was added 1.0 M of sodium bicarbonate in water (30 mL). The precipitate formed was collected by vacuum filtration. The cake was washed with water and methylene chloride, and air dried to provide the desired product (1.25 g, 96%). LCMS for Ci7Hi5ClN5O (M+H)+: m/z = 340.1.
Step G: tert-Butyl 3-{[(methylsulfonyl)oxy]methyljpyrrolidine-l-carboxylate
Figure imgf000588_0001
Into the reaction flask was added tert-butyl 3-(hydroxymethyl)pyrrolidine-l-carboxylate (0.80 g, 4.0 mmol), methylene chloride (20 mL), and methanesulfonyl chloride (0.55 g, 4.8 mmol). The mixture was stirred at 0 0C when triethylamine (1.4 mL) was slowly added. The reaction mixture was stirred at rt for 2 h, followed by the addition of water (5 mL). The aqueous layer was extracted twice with methylene chloride. The combined organic layers were dried over Na2SO4, filtered and concentrated to give the desired product (0.85 g crude) which was used without further purification.
Step H: tert-Butyl 3-({[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}methyl)pyrrolidine-l-carboxylate
Figure imgf000588_0002
Into the reaction was added 6-chloro-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-ol (0.10 g, 0.29 mmol), NN-dimethylformamide (2 mL) and sodium tørt-butoxide (0.034 g, 0.35 mmol). The mixture was stirred at rt for 5 min, then tert-butyl 3-{ [(methylsulfonyl)oxy]methyl}pyrrolidine-l- carboxylate (0.2 g, 0.7 mmol) was added. The reaction mixture was heated at 75 0C overnight. The mixture was purified by preparative LCMS (pH 10) to give the desired product (25 mg, 16%). LCMS for C27H32ClN6O3 (M+H)+: m/z = 523.2. 1H NMR (500 MHz, DMSO-^6): δ 9.55 (s, IH), 9.12 (s, IH), 8.27 (s, IH), 7.19 (d, /= 2.4 Hz, IH), 8.09 (s, IH), 7.99 (s, IH), 7.47 (d, /= 2.6 Hz, IH), 7.03 (dd, /= 8.5, 2.7 Hz, IH), 6.93 (d, / = 8.5 Hz, IH), 4.20 (m, 6H), 2.85 (m, IH), 2.55 (m, 2H), 1.95 (m, 2H), 1.64 (m, 2H), 1.40 (s, 9H).
Step I: 6-Chloro-12-(pyrrolidin-3-ylmethoxy)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene trihydrochloride
Into the reaction was added tert-buiy\ 3-({ [6-chloro-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]oxy}methyl)pyrrolidine-l-carboxylate (0.024 g, 0.046 mmol), methanol (0.5 mL), and 4.0 M of hydrogen chloride in 1,4-dioxane (0.5 mL). The mixture was stirred at rt overnight and concentrated under vacuum to give the desired product (19 mg, 92%). LCMS for C22H24ClN6O (M+H)+: m/z = 423.2.
Example C56
12-[(l-Acetylpyrrolidin-3-yl)methoxy]-6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000589_0001
Into the reaction flask was added 6-chloro-12-(pyrrolidin-3-ylmethoxy)-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene trihydrochloride (6 mg, 0.01 mmol) and N,N-dimethylformamide (0.25 mL), triethylamine (0.0040 mL) and acetyl chloride (14 mg). The mixture was stirred at rt for 5 min. The reaction mixture was diluted with 4 mL of DMF and purified by preparative HPLC (pH 2) to give the desired product (3 mg, 40%). LCMS for C24H26ClN6O2 (M+H)+: m/z = 465.1.
Example C57 2-{[3-({[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}methyl)pyrrolidin-l-yl]sulfonyl}benzonitrile bis(trifluoroacetate)
Figure imgf000590_0001
The desired compound was prepared as a white powder according to the procedure of Example C56, using 6-chloro-12-(pyrrolidin-3-ylmethoxy)-2,4,8, 18,22 pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene trihydrochloride and 2-cyanobenzenesulfonyl chloride as the starting materials in 44% yield. LCMS for C29H27ClN7O3S (M+H)+: m/z = 588.2. 1H NMR (300 MHz, DMSO-^6): δ 9.86 (s, IH), 9.26 (s, IH), 8.80 (s, IH), 8.27 (d, / = 2.2 Hz, IH), 8.22 (d, / = 2.2 Hz, IH), 8.15 (s, IH), 8.13 (dd, /= 7.5, 1.5 Hz, IH), 8.06 (dd, / = 7.7, 1.5 Hz, IH), 7.92 (dd, / = 7.7, 1.5 Hz, IH), 7.85 (dd, /= 7.5, 1.4 Hz, IH), 7.50 (d, / = 2.5 Hz, IH), 7.01 (dd, / = 8.6, 2.6 Hz, IH), 6.84 (d, / = 8.6 Hz, IH), 3.93 (m, IH), 3.80 (dd, / = 9.3, 7.2 Hz, IH), 3.56 QL, J = 1.1 Hz, IH), 3.40 (m, IH), 3.22 (dd, / = 9.8, 7.0 Hz, IH), 3.08 (m, IH), 2.86 (m, 4H), 2.67 (m, IH), 2.06 (m, IH), 1.76 (m, IH).
Example C58
6-Chloro-12-({l-[(5-methylisoxazol-3-yl)carbonyl]pyrrolidin-3-yl}methoxy)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000591_0001
The desired compound was prepared as a white powder according to the procedure of Example C56, using 6-chloro-12-(pyrrolidin-3-ylmethoxy)-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene trihydrochloride and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 25% yield. LCMS for C27H27ClN7O3 (M+H)+: m/z = 532.2.
Example C59
3-({[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}methyl)-N-phenylpyrrolidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000591_0002
The desired compound was prepared as a white powder according to the procedure of Example C56, using 6-chloro-12-(pyrrolidin-3-ylmethoxy)-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene trihydrochloride and phenyl isocyanate as the starting materials in 40% yield. LCMS for C29H29ClN7O2 (M+H)+: m/z = 542.1. Example Dl
6-Chloro-14-thia-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
Figure imgf000592_0001
Step A: 3-[(3-Nitrobenzyl)thio]aniline
Figure imgf000592_0002
A solution of 3-aminobenzenethiol (0.51 niL, 4.8 mmol) and sodium methoxide (0.31 g, 5.8 mmol) in N,N-dimethylformamide (5.3 mL) was stirred at 25 0C for 10 minutes (min). The reaction mixture was treated with a solution of l-(bromomethyl)-3-nitro-benzene (1.0 g, 4.8 mmol) in N,N- dimethylformamide (4.5 mL) dropwise and stirred at 25 0C for 1 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated and washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude brown oil. This material was purified by flash column chromatography to give the desired product (1.2 g, 95%) as a tan oil. LCMS for Ci3Hi3N2O2S (M+H)+: m/z = 261.0.
Step B: 2,5-Dichloro-N-{3-[(3-nitrobenzyl)thio]phenyljpyrimidin-4-amine
Figure imgf000592_0003
A solution of 3-[(3-nitrobenzyl)thio]aniline (0.50 g, 1.9 mmol) in N,N-dimethylformamide (4 mL) at 0 0C was treated with sodium hydride (0.15 g, 3.8 mmol) and stirred at 0 0C for 5 min. The reaction mixture was treated with 2,4,5-trichloropyrimidine dropwise and stirred at 0 0C for 30 min and at 25 0C for 16 h. The reaction mixture was quenched with saturated ammonium chloride (50 mL), poured into saturated sodium bicarbonate (50 mL), and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude brown gum. This material was purified by flash column chromatography but the desired product contained impurities. Repurification by preparative LCMS gave the desired product as a TFA salt. This material was dissolved in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product (0.21 g, 27%) as a free base. LCMS for Ci7H13Cl2N4O2S (M+H)+: m/z = 406.9, 409.0.
Step C: N-{3-[(3-Aminobenzyl)thio]phenyl}-2, 5 -dichloropyrimidin-4-amine trifluoroacetate
Figure imgf000593_0001
A degassed solution of 2,5-dichloro-N-{3-[(3-nitrobenzyl)thio]phenyl}pyrimidin-4-amine (69 mg, 0.17 mmol) in ethyl acetate (260 mL) was treated with 5% palladium on carbon (sulfided) (10 mg) and stirred under an atmosphere of hydrogen using a balloon for 1 h. The reaction mixture was treated with two additional aliquots of 5% palladium on carbon (sulfided) (20 mg) with stirring of 1 h after each addition. The reaction mixture was filtered, washed with ethyl acetate, and concentrated to a crude residue. This material was purified by preparative LCMS to give the desired product (34 mg, 41%) as a TFA salt. LCMS for Ci7H15Cl2N4S (M+H)+: m/z = 377.0, 379.0.
Step D: 6-Chloro-14-thia-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
A solution of N-{3-[(3-aminobenzyl)thio]phenyl}-2,5-dichloropyrimidin-4-amine trifluoroacetate (33 mg, 67 μmol) in 2-methoxyethanol (6.6 mL) was treated with 3.5 M HCl in ethanol (3 mL) and heated in the microwave at 150 0C for 5 min. The reaction mixture was degassed to remove the HCl and concentrated to a crude residue. This material was purified by preparative LCMS to give the desired product (8.4 mg, 27%) as a TFA salt. LCMS for Ci7Hi4ClN4S (M+H)+: m/z = 341.0. 1H NMR (SOO MHz, DMSOd6): δ 9.59 (s, 1 H), 9.20 (s, 1 H), 8.17 (s, 2 H), 7.93 (s, 1 H), 7.21 - 7.15 (m, 3 H), 7.08 - 7.05 (m, 1 H), 7.00 - 6.97 (m, 1 H), 6.91 - 6.88 (m, 1 H), 4.03 (s, 2 H).
Example D2 6-Chloro-15-thia-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
Figure imgf000594_0001
Step A: tert-Butyl {3-[(3-nitrobenzyl)thio]phenyljcarbamate oc
Figure imgf000594_0002
A solution of 3-[(3-nitrobenzyl)thio]aniline (0.60 g, 2.3 mmol) in ethanol (2.5 niL) was treated with di-tert-butyldicarbonate (0.65 g, 3.0 mmol) and stirred at 25 0C for 7 h. The reaction mixture was treated with additional di-tørt-butyldicarbonate (0.25 g, 1.1 mmol) and stirred at 25 0C for 16 h. The reaction mixture was concentrated to a crude oil. This material was purified by flash column chromatography to give the desired product (0.83 g, quantitative yield) as a clear oil. LCMS for Ci8H20N2O4SNa (M+Na)+: m/z = 383.1.
Step B: tert-Butyl (3-[(3-aminobenzyl)thio]phenyl}carbamate
Figure imgf000594_0003
A mixture of iron (0.62 g, 11 mmol) in ethanol (22 mL) was treated with 1 M HCl in water (1.1 mL) and heated at 60 0C for 2 h. The reaction mixture was cooled to 55-60 0C and treated with 5 M ammonium chloride in water (1.9 mL). The reaction mixture was then treated with a solution of tert- butyl {3-[(3-nitrobenzyl)thio]phenyl}carbamate (0.80 g, 2.2 mmol) in ethanol (2.5 mL) while the temperature was kept at 60 0C. The resulting suspension was stirred at 60-65 0C for 30 min. The reaction mixture was cooled to 40 0C, diluted with ethanol, treated with celite, filtered over a pad of celite, and washed with ethanol. The filtrate was concentrated to a tan solid that was diluted with ethyl acetate (50 mL) and saturated sodium bicarbonate (50 mL). The organic layer was separated and washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude tan oil. This material was purified by flash column chromatography to give the desired product (0.63 g, 85%). LCMS for Ci8H23N2O2S (M+H)+: m/z = 331.1.
Step C: tert-Butyl [3-({3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}thio)phenyl]carbamate
BocHN
Figure imgf000595_0001
A solution of tert-butyl {3-[(3-aminobenzyl)thio]phenyl}carbamate (0.55 g, 1.7 mmol) in N,N- dimethylformamide (5.0 mL) was treated with potassium carbonate (0.30 g, 2.2 mmol) and stirred at 25 0C for 5 min. The reaction mixture was treated with 2,4,5-trichloropyrimidine (0.25 mL, 2.2 mmol) and stirred at 25 0C for 16 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated and washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude gum. This material was purified by flash column chromatography to give the desired product (0.67 g, 84%) as a solid. LCMS for C22H22Cl2N4O2SNa (M+Na)+: m/z = 499.0, 501.0.
Step D: 6-Chloro-15-thia-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
A solution of tert-butyl [3-({3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}thio)phenyl]carbamate (0.15 g, 0.31 mmol) in 2-methoxyethanol (15 mL) was treated with 4 M HCl in 1,4-dioxane (8 mL) and heated in the microwave at 150 0C for 5 min. The reaction mixture was concentrated to a crude residue. This material was purified by preparative LCMS to give the desired product (72 mg, 50%) as a TFA salt. LCMS for Ci7H14ClN4S (M+H)+: m/z = 341.0. 1H NMR (300 MHz, DMS0-<i6): δ 9.57 (s, 1 H), 9.42 (s, 1 H), 8.33 (s, 1 H), 8.16 (s, 1 H), 7.91 (s, 1 H), 7.29 (dd, / = 7.9, 7.6 Hz, 1 H), 7.15 (d, / = 7.9 Hz, 1 H), 7.10 - 7.05 (m, 2 H), 6.90 (dd, / = 8.2, 0.9 Hz, 1 H), 6.84 - 6.81 (m, 1 H), 4.11 (s, 2 H).
Example D3
6-Chloro-15-thia-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- I(20),3(22),4,6,9(21),10,12,16,18-nonaene l5-oxide trifluoroacetate
Figure imgf000596_0001
Example D4
6-Chloro-15-thia-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-
I(20),3(22),4,6,9(21),10,12,16,18-nonaene l5,15-dioxide trifluoroacetate
Figure imgf000596_0002
A solution of 6-chloro-15-thia-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate (45 mg, 0.13 mmol) in dichloromethane (7 niL) was treated with ra-chloroperbenzoic acid (44 mg, 0.20 mmol) and was stirred at 0 0C for 1.5 h. The reaction mixture was concentrated and diluted with ethyl acetate (40 mL). The organic layer was washed with 10% NaHSO3 (20 mL), saturated sodium bicarbonate (30 mL), and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude solid. This material was purified by preparative HPLC to give the desired products Example D3 (13 mg, 12%) and Example D4 (24 mg, 37%) as white solids.
Example D3: LCMS for Ci7Hi4ClN4OS (M+H)+: m/z = 357.0. 1H NMR (300 MHz, DMSO-^6): δ 9.70 (s, 1 H), 9.20 (s, 1 H), 8.18 (s, 1 H), 8.08 (dd, /= 1.8, 1.8 Hz, 1 H), 7.84 (s, 1 H), 7.55 - 7.49 (m, 1 H), 7.43 - 7.30 (m, 5 H), 4.39 (d, / = 12.0 Hz, 1 H), 4.23 (d, / = 12.0 Hz, 1 H).
Example D4: LCMS for Ci7Hi4ClN4O2S (M+H)+: m/z = 373.0. 1H NMR (300 MHz, DMSO- d6): δ 9.81 (s, 1 H), 9.22 (s, 1 H), 8.40 (s, 1 H), 8.21 (s, 1 H), 7.97 (s, 1 H), 7.54 - 7.52 (m, 2 H), 7.50 - 7.45 (m, 1 H), 7.37 - 7.34 (m, 2 H), 7.23 - 7.20 (m, 1 H), 4.70 (s, 2 H).
Example D5
6-Chloro-16-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate
Figure imgf000597_0001
Step A: 2-{3-[(2, 5-Dichloropyrimidin-4-yl)amino]phenyl}ethanol
Figure imgf000597_0002
The desired compound was prepared according to the procedure of Example D2, step C, using 2- (3-aminophenyl)ethanol [Bioorg. Med. Chem. 2005, 13, 6703-6712] as the starting material in 86% yield. LCMS for Ci2H12Cl2N3O (M+H)+: m/z = 284.0, 286.0.
Step B: 3-[(5-Chloro-4-{[3-(2-hydroxyethyl)phenyl]amino}pyrimidin-2-yl)amino]phenol
Figure imgf000597_0003
A solution of 2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethanol (0.10 g, 0.35 mmol) and
3-aminophenol (58 mg, 0.53 mmol) in 1,4-dioxane (3.5 mL) was treated with p-toluenesulfonic acid monohydrate (54 mg, 0.28 mmol) and heated at 100 0C for 1 h. The reaction mixture was treated with additional 3-aminophenol (19 mg, 0.18 mmol) and heated at 100 0C for 1 h. The reaction mixture was poured into 10% potassium carbonate (20 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to a crude brown oil. This material was purified by flash column chromatography to give the desired product (0.12 g, 96%) as a light brown solid. LCMS for Ci8Hi8ClN4O2 (M+H)+: m/z = 357.0.
Step C: 6-Chloro-16-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate
A solution of 3-[(5-chloro-4-{ [3-(2-hydroxyethyl)phenyl]amino}pyrimidin-2-yl)amino]phenol (50 mg, 0.10 mmol) and triphenylphospine (44 mg, 0.17 mmol) in tetrahydrofuran (10 mL) at 0 0C was treated with 0.1 M of diisopropylazodicarboxylate in tetrahydrofuran (1.8 mL, 0.18 mmol) and stirred at 25 0C for 2 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (l l mg, 20%) as a white solid. LCMS for Ci8Hi6ClN4O (M+H)+: m/z = 339.1. 1H NMR (300 MHz, DMSO-^6): δ 9.40 (s, 1 H), 9.01 (s, 1 H), 8.09 (s, 1 H), 7.87 - 7.85 (m, 2 H), 7.21 (dd, /= 7.6, 7.6 Hz, 1 H), 7.06 - 7.00 (m, 3 H), 6.64 - 6.61 (m, 1 H), 6.51 (dd, / = 7.9, 1.8 Hz, 1 H), 4.48 - 4.45 (m, 2 H), 2.85 - 2.81 (m, 2 H).
Example D6
6-Chloro-15-oxa-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
Figure imgf000598_0001
Step A: (3-[(2, 5-Dichloropyrimidin-4-yl)amino]phenyl}methanol
Figure imgf000598_0002
The desired compound was prepared according to the procedure of Example D2, step C, using 3- aminobenzyl alcohol as the starting material in 93% yield. LCMS for C11H10CI2N3O (M+H)+: m/z =
270.0, 272.0.
Step B: 3-[(5-Chloro-4-{[3-(hydroxymethyl)phenyl]amino}pyrimidin-2-yl)amino]phenol
Figure imgf000598_0003
The desired compound was prepared according to the procedure of Example D5, step B, using {3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}methanol and 3-aminophenol as the starting materials in 85% yield. LCMS for Ci7Hi6ClN4O2 (M+H)+: m/z = 343.1. Step C: 6-Chloro-15-oxa-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
The desired compound was prepared according to the procedure of Example D5, step C, using 3-[(5- chloro-4-{ [3-(hydroxymethyl)phenyl]amino}pyrimidin-2-yl)amino]phenol as the starting material in 48% yield. LCMS for Ci7H14ClN4O (M+H)+: m/z = 325.0. 1H NMR (400 MHz, DMSO-^6): δ 9.73 (s, 1 H), 9.58 (s, 1 H), 8.16 (s, 1 H), 7.93 (s, 1 H), 7.70 (s, 1 H), 7.27 (dd, / = 7.6, 7.6 Hz, 1 H), 7.20 (d, /= 7.8 Hz, 1 H), 7.04 (d, /= 8.2 Hz, 1 H), 6.97 (dd, /= 8.0, 8.0 Hz, 1 H), 6.50 (d, / = 8.6 Hz, 1 H), 6.44 (d, /= 8.2, 2.0 Hz, I H), 5.14 (s, 2 H).
Example D7
6-Chloro-14-oxa-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
Figure imgf000599_0001
Step A: 2-(3-Nitrophenoxy)tetrahydro-2H-pyran
Figure imgf000599_0002
A solution of ra-nitrophenol (1.8 g, 13 mmol) in dichlorome thane (13 mL) was treated with dihydropyran (1.7 mL, 19 mmol) followed by pyridinium p-toluenesulfonate (0.32 g, 1.2 mmol) and stirred at 25 0C for 16 h. The reaction mixture was diluted with dichloromethane and washed with 1:1 brine/water (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude oil. This material was purified by flash column chromatography to give the desired product (2.5 g, 88%) as a clear oil.
Step B: 3-(Tetrahydro-2H-pyran-2-yloxy)aniline
Figure imgf000599_0003
A solution of 2-(3-nitrophenoxy)tetrahydro-2H-pyran (1.0 g, 4.5 mmol) in methanol (13 mL) was degassed with nitrogen (3 x) and treated with 10% Pd/C (wet Degussa type) (12 mg). The reaction mixture was degassed and stirred under an atmosphere of hydrogen at 25 0C for 2 h. The reaction mixture was filtered to give the desired product (0.87 g, quantitative) as a tan oil. LCMS for CHHI6NO2 (M+H)+: m/z = 194.0.
Step C: 2, 5-Dichloro-N-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrimidin-4-amine
Figure imgf000600_0001
The desired compound was prepared according to the procedure of Example D2, step C, using 3- (tetrahydro-2H-pyran-2-yloxy)aniline as the starting material in 60% yield. LCMS for Ci5Hi6Cl2N3O2 (M+H)+: m/z = 340.0, 342.0.
Step D: 3-[(5-Chloro-2-{[3-(hydroxymethyl)phenyl]amino}pyrimidin-4-yl)amino]phenol
Figure imgf000600_0002
The desired compound was prepared according to the procedure of Example D5, step B, using
2,5-dichloro-N-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrimidin-4-amine and 3-aminobenzyl alcohol as the starting materials in 53% yield. LCMS for Ci7Hi6ClN4O2 (M+H)+: m/z = 343.0.
Step E: 6- Chloro-14-oxa-2, 4, 8, 22-tetraazatetracyclo[14.3.1.1 (3, 7).1 (9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
The desired compound was prepared according to the procedure of Example D5, step C, using 3- [(5-chloro-2-{ [3-(hydroxymethyl)phenyl]amino}pyrimidin-4-yl)amino]phenol as the starting material in 54% yield. LCMS for Ci7Hi4ClN4O (M+H)+: m/z = 325.1. 1H NMR (300 MHz, DMSO-^6): δ 9.66 (s, 1 H), 9.40 (s, 1 H), 8.15 (s, 1 H), 7.88 (s, 1 H), 7.59 (s, 1 H), 7.20 (dd, /= 7.6, 7.6 Hz, 1 H), 7.11 - 7.01 (m, 2 H), 6.89 (d, / = 8.2 Hz, 1 H), 6.71 (d, /= 7.9 Hz, 1 H), 6.56 (dd, / = 8.2, 1.8 Hz, 1 H), 5.14 (s, 2 H).
Example D8 6-Chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate
Figure imgf000601_0001
Step A: 3-[(5-Chloro-2-{[3-(2-hydroxyethyl)phenyl]aminoJpyrimidin-4-yl)amino]phenol
Figure imgf000601_0002
The desired compound was prepared according to the procedure of Example D5, step B, using 2,5-dichloro-N-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrimidin-4-amine and 2-(3- aminophenyl)ethanol [Bioorg. Med. Chem. 2005, 13, 6703-6712] as the starting materials in 65% yield. LCMS for Ci8Hi8ClN4O2 (M+H)+: m/z = 357.1.
Step B: 6- Chloro-14-oxa-2, 4, 8, 23-tetraazatetracyclo[15.3.1.1 (3, 7).1 (9, 13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate
The desired compound was prepared according to the procedure of Example D5, step C, using 3- [(5-chloro-2-{ [3-(2-hydroxyethyl)phenyl]amino}pyrimidin-4-yl)amino]phenol as the starting material in 66% yield. LCMS for Ci8Hi6ClN4O (M+H)+: m/z = 339.1. 1H NMR OOO MHZ5 DMSO-^): δ 9.52 (s, 1 H), 9.27 (s, 1 H), 8.17 (s, 1 H), 7.90 (s, 1 H), 7.67 - 7.66 (m, 1 H), 7.23 - 7.13 (m, 2 H), 6.92 - 6.89 (m, 3 H), 6.48 - 6.81 (m, 1 H), 4.49 - 4.54 (m, 2 H), 2.75 - 2.72 (m, 2 H).
Example D9 6-Chloro-8-methyl-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate
Figure imgf000601_0003
Step A: 2, 5-Dichloro-N-methyl-N-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrimidin-4-amine
Figure imgf000602_0001
A solution of 2,5-dichloro-N-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrimidin-4-amine (110 mg, 0.32 mmol) in acetonitrile (3 mL) was treated with potassium carbonate (89 mg, 0.65 mmol) followed by methyl iodide (60 μL, 0.97 mmol) and heated at 70 0C for 16 h. The reaction mixture was treated with additional methyl iodide (60 μL, 0.97 mmol) and heated at 70 0C for H h. The reaction mixture was cooled to 25 0C, poured into water (30 mL), and extracted with ethyl acetate (50 mL). The organic layer was separated and washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude oil. This material was purified by flash column chromatography to give the desired product (68 mg, 59%) as a clear oil. LCMS for Ci6H18Cl2N3O2 (M+H)+: m/z = 354.0, 356.0.
Step B: 3-[(5-Chloro-2-{[3-(2-hydroxyethyl)phenyl]aminojpyrimidin-4-yl)(methyl)amino]phenol
Figure imgf000602_0002
The desired compound was prepared according to the procedure of Example D5, step B, using 2,5-dichloro-N-methyl-N-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrimidin-4-amine and 2-(3- aminophenyl)ethanol [Bioorg. Med. Chem. 2005, 13, 6703-6712] as the starting materials in 59% yield. LCMS for Ci9H20ClN4O2 (M+H)+: m/z = 371.1.
Step C: 6-Chloro-8-methyl-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate
The desired compound was prepared according to the procedure of Example D5, step C, using 3- [(5-chloro-2-{ [3-(2-hydroxyethyl)phenyl]amino}pyrimidin-4-yl)(methyl)amino]phenol as the starting material in 53% yield. LCMS for Ci9Hi8ClN4O (M+H)+: m/z = 353.1. 1H NMR (300 MHz, DMSO-^6): δ 9.33 (s, 1 H), 8.21 (s, 1 H), 7.41 (s, 1 H), 7.26 (dd, /= 8.2, 7.9 Hz, 1 H), 7.13 - 7.06 (m, 2 H), 6.89 - 6.82 (m, 4 H), 4.50 - 4.46 (m, 2 H), 3.59 (s, 3 H), 2.76 - 2.73 (m, 2 H). Example DlO
6-Chloro-14,17-dioxa-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene trifluoroacetate
Figure imgf000603_0001
Step A: 2-(3-Nitrophenoxy)ethanol
Figure imgf000603_0002
A solution of ra-nitrophenol (2.0 g, 14 mmol), 2-bromoethanol (1.4 niL, 20 mmol), and potassium carbonate (3.0 g, 22 mmol) in N,N-dimethylformamide (10 mL) was heated at 70 0C for 7 h. The reaction mixture was treated with additional 2-bromoethanol (0.5 mL, 7.2 mmol) and potassium carbonate (1.0 g, 7.2 mmol) and heated at 70 0C for 20 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (150 mL). The organic layer was separated and washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to a crude residue. This material was purified by flash column chromatography to give the desired product (1.9 g, 70%) as a white solid. LCMS for C8H10NO4 (M+H)+: m/z = 183.9.
Step B: 2-(3-Aminophenoxy)ethanol
Figure imgf000603_0003
The desired compound was prepared according to the procedure of Example D7, step B, using 2- (3-nitrophenoxy)ethanol as the starting material in quantitative yield. LCMS for C8Hi2NO2 (M+H)+: m/z = 154.1.
Step C: 2-{3-[(2, 5-Dichloropyrimidin-4-yl)amino]phenoxy}ethanol
Figure imgf000604_0001
The desired compound was prepared according to the procedure of Example D2, step C, using 2- (3-aminophenoxy)ethanol as the starting material in 30% yield. LCMS for Ci2Hi2Cl2N3O2 (M+H)+: m/z = 300.0, 302.0.
Step D: 3-[(5-Chloro-4-{[3-(2-hydroxyethoxy)phenyl]amino}pyrimidin-2-yl)amino]phenol
Figure imgf000604_0002
The desired compound was prepared according to the procedure of Example D5, step B, using 2- {3-[(2,5-dichloropyrimidin-4-yl)amino]phenoxy}ethanol and 3-aminophenol as the starting materials in 34% yield. LCMS for Ci8Hi8ClN4O3 (M+H)+: m/z = 373.0.
Step E: 6-Chloro-14, 17-dioxa-2,4,8, 24-tetraazatetracyclo[16.3.1.1(3, 7).1(9, 13)]tetracosa-
1 (22), 3(24), 4, 6, 9(23), 10,12,18, 20-nonaene trifluoroacetate
The desired compound was prepared according to the procedure of Example D5, step C, using 3- [(5-chloro-4-{ [3-(2-hydroxyethoxy)phenyl]amino}pyrimidin-2-yl)amino]phenol as the starting material in 22% yield. LCMS for Ci8Hi6ClN4O2 (M+H)+: m/z = 355.1. 1H NMR (300 MHz, DMSO-^6): δ 9.56
(s, 1 H), 8.74 (s, I H), 8.18 (s, 1 H), 7.94 (dd, / = 2.1, 1.8 Hz, 1 H), 7.87 (dd, /= 2.1, 1.8 Hz, 1 H), 7.24
(dd, /= 8.2, 7.9 Hz, 1 H), 7.13 (dd, / = 8.2, 7.9 Hz, 1 H), 6.99 (d, /= 8.2 Hz, 1 H), 6.81 - 6.75 (m, 2 H),
6.54 (dd, / = 8.2, 1.8 Hz, 1 H), 4.35 - 4.31 (m, 2 H), 4.22 - 4.18 (m, 2 H).
Example DIl
6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene trifluoroacetate
Figure imgf000605_0001
Step A: 3-{[2-(3-Nitrophenoxy)ethyl]thio}aniline
Figure imgf000605_0002
The desired compound was prepared according to the procedure of Example Dl, step A, using 1- (2-bromoethoxy)-3-nitrobenzene as the starting material in 95% yield. LCMS for Ci4Hi5N2O3S (M+H)+: m/z = 291.0.
Step B: 2,5-Dichloro-N-(3-{[2-(3-nitrophenoxy)ethyl]thio}phenyl)pyrimidin-4-amine
Figure imgf000605_0003
The desired compound was prepared according to the procedure of Example D2, step C, using 3-
{ [2-(3-nitrophenoxy)ethyl]thio}aniline as the starting material in 91% yield. LCMS for Ci8Hi5Cl2N4O3S (M+H)+: m/z = 437.0, 439.0.
Step C: N-(3-{[2-(3-Aminophenoxy)ethyl]thiojphenyl)-2, 5 -dichloropyrimidin-4-amine
Figure imgf000605_0004
The desired compound was prepared according to the procedure of Example D2, step B, using 2,5-dichloro-N-(3-{ [2-(3-nitrophenoxy)ethyl]thio}phenyl)pyrimidin-4-amine as the starting material in 83% yield. LCMS for Ci8Hi7Cl2N4OS (M+H)+: m/z = 407.1, 409.0. Step D: 6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- 1 (22), 3 (24), 4, 6, 9(23), 10,12,18, 20-nonaene trifluoroacetate
The desired compound was prepared according to the procedure of Example D2, step D, using N- (3-{ [2-(3-aminophenoxy)ethyl]thio}phenyl)-2,5-dichloropyrimidin-4-amine as the starting material in 40% yield. LCMS for Ci8Hi6ClN4OS (M+H)+: m/z = 371.0. 1H NMR (300 MHz, DMSO-^6): δ 9.54 (S, 1 H), 8.87 (s, 1 H), 8.18 (s, 1 H), 7.96 (s, 1 H), 7.82 (dd, /= 2.1, 2.1 Hz, 1 H), 7.36 - 7.20 (m, 3 H), 7.08 (dd, / = 8.2, 7.9 Hz, 1 H), 6.75 (d, / = 9.1 Hz, 1 H), 6.42 (dd, / = 8.2, 1.8 Hz, 1 H), 4.07 (t, /= 6.4 Hz, 2 H), 3.23 (t, / = 6.4 Hz, 2 H).
Example D12
6-Chloro-14,15-dithia-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
Step A: 3,3'-Dithiodianiline
Figure imgf000606_0001
A solution of 3-aminobenzenethiol (0.85 mL, 8.0 mmol) in dimethyl sulfoxide (0.57 mL, 8.0 mmol) was heated at 85 0C for 4 h. The reaction mixture was poured into a solution of brine (25 mL) and water (25 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated and washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to a crude oil. This material was purified by flash column chromatography to give the desired product (0.97 g, 98%) as a yellow oil. LCMS for CnHi3N2S2 (M+H)+: m/z = 249.0.
Step B: N-{3-[(3-Aminophenyl)dithio]phenyl}-2, 5-dichloropyrimidin-4-amine
Figure imgf000607_0001
The desired compound was prepared according to the procedure of Example D2, step C, using 3,3 -dithiodianiline as the starting material. The desired compound decomposed during the purification, therefore, the crude material was used without further purification.
Step C: 6-Chloro-14,15-dithia-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
The desired compound was prepared according to the procedure of Example D2, step D, using N- {3-[(3-aminophenyl)dithio]phenyl}-2,5-dichloropyrimidin-4-amine as the starting material in 6% yield (2 steps). LCMS for Ci6Hi2ClN4S2 (M+H)+: m/z = 359.0. 1H NMR (300 MHz, DMSOd6): δ 9.77 (s, 1 H), 9.27 (s, 1 H), 8.73 (s, 1 H), 8.58 (s, 1 H), 8.22 (s, 1 H), 7.48 - 7.45 (m, 1 H), 7.41 - 7.39 (m, 2 H), 7.23 - 7.15 (m, 2 H), 7.11 - 7.09 (m, 1 H).
Example D13 6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- I(22),3(24),4,6,9(23),10,12,18,20-nonaene l4-oxide trifluoroacetate
Figure imgf000607_0002
Example D14
6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene 14,14-dioxide trifluoroacetate
Figure imgf000608_0001
The desired compounds were prepared according to the procedures of Example D3 and D4 using ό-chloro-lT-oxa-H-thia-l^^^-tetraazatetracycloflό.3.1.1(3,7).1(9, 13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene trifluoroacetate as the starting material in 40% and 35% yields respectively.
Example D13: LCMS for Ci8Hi6ClN4O2S (M+H)+: m/z = 387.1. 1H NMR OOO MHZ5 DMSO- dβ): δ 9.60 (s, 1 H), 9.18 (s, 1 H), 8.20 (s, 1 H), 8.01 (s, 1 H), 7.69 - 7.60 (m, 2 H), 7.52 (d, / = 7.9 Hz, 1 H), 7.44 (d, / = 8.2 Hz, 1 H), 7.07 (dd, / = 8.2, 7.9 Hz, 1 H), 6.75 (d, / = 8.2 Hz, 1 H), 6.46 (dd, / = 7.9, 1.5 Hz, 1 H), 4.22 - 4.15 (m, 1 H), 3.94 - 3.85 (m, 1 H), 3.60 - 3.50 (m, 1 H), 3.40 - 3.33 (m, 1 H).
Example D14: LCMS for Ci8Hi6ClN4O3S (M+H)+: m/z = 403.1. 1H NMR OOO MHZ5 DMSO- d6): δ 9.64 (s, 1 H), 9.28 (s, 1 H), 8.19 (s, 1 H), 8.05 (s, 1 H), 7.86 - 7.81 (m, 2 H), 7.68 (dd, / = 7.9, 7.9 Hz, 1 H), 7.58 (d, / = 8.5 Hz, 1 H), 7.09 (dd, / = 8.2, 7.9 Hz, 1 H), 6.77 (dd, / = 7.9, 1.5 Hz, 1 H), 6.50 (dd, /= 7.9, 1.8 Hz, 1 H), 4.28 - 4.15 (m, 2 H), 3.93 - 3.89 (m, 2 H).
Example D15
6-Chloro-14-oxa-17-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene trifluoroacetate
Figure imgf000608_0002
Step A: tert-Butyl (3-{[2-(3-nitrophenoxy)ethyl]thio}phenyl)carbamate
Figure imgf000608_0003
A solution of 3-{ [2-(3-nitrophenoxy)ethyl]thio}aniline (0.80 g, 2.8 mmol) in ethanol (5 mL) was treated with di-tørt-butyldicarbonate (1.2 g, 5.5 mmol) and stirred at 25 0C for 16 h. The reaction mixture was concentrated to an oil that was purified by flash column chromatography to give the desired product (1.1 g, 98%). LCMS for Ci9H22N2O5SNa (M+Na)+: m/z = 413.0.
Step B: tert-Butyl (3-{[2-(3-aminophenoxy)ethyl]thio}phenyl)carbamate
Figure imgf000609_0001
The desired compound was prepared according to the procedure of Example D2, step B, using tert-butyl (3-{ [2-(3-nitrophenoxy)ethyl]thio}phenyl)carbamate as the starting material in 74% yield. LCMS for Ci9H25N2O3S (M+H)+: m/z = 361.0.
Step C: tert-Butyl {3-[(2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenoxy}ethyl)thio]phenyl}carbamate
Figure imgf000609_0002
The desired compound was prepared according to the procedure of Example D2, step C, using tert-butyl (3-{ [2-(3-aminophenoxy)ethyl]thio}phenyl)carbamate as the starting material in 97% yield.
LCMS for C23H25Cl2N4O3S (M+H)+: m/z = 507.0, 509.0.
Step D: 6-Chloro-14-oxa-17-thia-2,4,8,24-tetraazatetracyclo[ 16.3.1.1(3,7).1(9,13)]tetracosa-
1 (22), 3 (24), 4, 6, 9(23), 10,12,18, 20-nonaene trifluoroacetate
The desired compound was prepared according to the procedure of Example D2, step D, using tert-butyl {3-[(2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenoxy}ethyl)thio]phenyl}carbamate as the starting material in 26% yield. LCMS for Ci8Hi6ClN4OS (M+H)+: m/z = 371.1. 1H NMR (SOO MHZ,
DMSO-^6): δ 9.58 (s, 1 H), 8.65 (s, 1 H), 8.19 - 8.18 (m, 2 H), 7.88 (s, 1 H), 7.25 - 7.17 (m, 2 H), 7.09 -
7.04 (m, 2 H), 6.96 (d, /= 8.5 Hz, 1 H), 6.64 (dd, / = 8.2, 1.8 Hz, 1 H), 4.22 - 4.18 (m, 2 H), 3.12 - 3.08
(m, 2 H).
Example D16 6-Chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000610_0001
Step A: tert-Butyl {3-[(3-nitrobenzyl)amino]phenyljcarbamate
Figure imgf000610_0002
A solution of tert-butyl (3-aminophenyl)carbamate (0.51 g, 2.4 mmol) and potassium carbonate (0.61 g, 4.4 mmol) in N,N-dimethylformamide (7 mL) was treated with a solution of l-(bromomethyl)-3- nitrobenzene (0.50 g, 2.3 mmol) in N,N-dimethylformamide (3 mL) and stirred at 25 0C for 16 h. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (3 x 75 mL). The combined organic layers were washed with water (3 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude residue. This material was purified by flash column chromatography to give the desired product (0.78 g, 88% [90% pure]) as a solid. LCMS for Ci8H22N3O4 (M+H)+: m/z = 344.2.
Step B: N-(3-Nitrobenzyl)benzene-l,3-diamine bis(trifluoroacetate)
Figure imgf000610_0003
A solution of tert-butyl {3-[(3-nitrobenzyl)amino]phenyl}carbamate (100 mg, 0.3 mmol) in dichloromethane (3 mL) and trifluoroacetic acid (3 mL) was stirred at 25 0C for 1 h. The reaction mixture was concentrated to a crude residue. This material was purified by preparative LCMS to give the desired product (110 mg, 79%) as a solid. LCMS for Ci3H14N3O2 (M+H)+: m/z = 244.0.
Step C: N-(2, 5-Dichloropyrimidin-4-yl)-N'-(3-nitrobenzyl)benzene-l, 3-diamine trifluoroacetate
Figure imgf000611_0001
The desired compound was prepared according to the procedure of Example D2, step C, using N- (3-nitrobenzyl)benzene-l,3-diamine bis(trifluoroacetate) as the starting material in 63% yield after purification by preparative LCMS. LCMS for Ci7H14Cl2N5O2 (M+H)+: m/z = 389.9, 391.9.
Step D: N-(3-Aminobenzyl)-N'-(2,5-dichloropyrimidin-4-yl)benzene-l,3-diamine
Figure imgf000611_0002
A solution of N-(2,5-dichloropyrimidin-4-yl)-N'-(3-nitrobenzyl)benzene-l ,3-diamine trifluoroacetate (67 mg, 0.13 mmol) in methanol (0.51 mL), acetic acid (0.20 mL), and water (0.10 mL) was treated with iron (30 mg, 0.53 mmol) and stirred at 25 0C for 1 h. The reaction mixture was treated with additional iron (25 mg, 0.45 mmol) and stirred at 25 0C for 16 h. The reaction mixture was diluted with methanol (2 mL) and celite was added. The resulting suspension was filtered through a pad of celite and rinsed with methanol. The filtrate was concentrated to give the desired product as a crude residue that was used without further purification.
Step E: 6- Chloro-2,4, 8, 14, 22-pentaazatetracyclo[14.3.1.1 (3, 7).1 (9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
The desired compound was prepared according to the procedure of Example D2, step D, using N- (3-aminobenzyl)-N'-(2,5-dichloropyrimidin-4-yl)benzene-l,3-diamine as the starting material in 14% yield (2 steps: Steps D and E). LCMS for Ci7H15ClN5 (M+H)+: m/z = 324.0. 1H NMR (400 MHz, DMS0-<i6): δ 9.70 (s, 1 H), 9.31 (s, 1 H), 8.15 (s, 1 H), 7.70 (s, 1 H), 7.24 (s, 1 H), 7.18 (dd, / = 7.8, 7.6 Hz, 1 H), 7.05 (d, / = 7.6 Hz, 1 H), 6.93 (dd, / = 7.6, 7.4 Hz, 1 H), 6.85 (d, / = 7.4 Hz, 1 H), 6.50 - 6.40 (m, 2 H), 4.19 (s, 2 H). Example D17
6-Chloro-2,4,8,15,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000612_0001
Step A: tert-Butyl {3-[(3-aminobenzyl)amino]phenyljcarbamate
Figure imgf000612_0002
The desired compound was prepared according to the procedure of Example D2, step B, using tert-butyl {3-[(3-nitrobenzyl)amino]phenyl}carbamate as the starting material in 82% yield after purification by preparative LCMS. LCMS for Ci8H24N3O2 (M+H)+: m/z = 314.1.
Step B: tert-Butyl [3-({3-[(2, 5 -dichloropyrimidin-4-yl)amino] benzyljamino)phenyl] carbamate
Figure imgf000612_0003
The desired compound was prepared according to the procedure of Example D2, step C, using tert-butyl {3-[(3-nitrobenzyl)amino]phenyl}carbamate as the starting material in 44% yield. LCMS for C22H24Cl2N5O2 (M+H)+: m/z = 460.1, 462.0.
Step C: 6-Chloro-2,4,8,15,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) The desired compound was prepared according to the procedure of Example D2, step D, using tert-butyl [3-({3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}amino)phenyl]carbamate as the starting material in 27% yield. LCMS for Ci7Hi5ClN5 (M+H)+: m/z = 324.0. 1H NMR OOO MHZ5 DMSO-^): δ 9.90 (s, 1 H), 9.65 (s, 1 H), 8.19 (s, 1 H), 7.77 (s, 1 H), 7.33 (s, 1 H), 7.27 (dd, /= 7.6, 7.6 Hz, 1 H), 7.16 (d, / = 7.6 Hz, 1 H), 7.01 (d, / = 7.9 Hz, 1 H), 6.88 (dd, / = 7.9, 7.9 Hz, 1 H), 6.37 - 6.27 (m, 2 H), 4.20 (s, 2 H).
Example D18
6-Chloro-14-thia-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate
Figure imgf000613_0001
Step A: 3-{[2-(3-Nitrophenyl)ethyl]thio}aniline
Figure imgf000613_0002
The desired compound was prepared according to the procedure of Example Dl, step A, using 2-
(3-nitrophenyl)ethyl methanesulfonate [WO05/014552] as the starting material in 84% yield. LCMS for Ci4H15N2O2S (M+H)+: m/z = 275.0.
Step B: 2,5-Dichloro-N-(3-{[2-(3-nitrophenyl)ethyl]thio}phenyl)pyrimidin-4-amine
Figure imgf000613_0003
The desired compound was prepared according to the procedure of Example D2, step C, using 3- { [2-(3-nitrophenyl)ethyl]thio}aniline as the starting material in 93% yield. LCMS for Ci8H15Cl2N4O2S (M+H)+: m/z = 420.9, 422.9.
Step C: N-(3-{[2-(3-Aminophenyl)ethyl]thiojphenyl)-2, 5 -dichloropyrimidin-4-amine
Figure imgf000614_0001
The desired compound was prepared according to the procedure of Example D2, step B, using 2,5-dichloro-N-(3-{ [2-(3-nitrophenyl)ethyl]thio}phenyl)pyrimidin-4-amine as the starting material in 79% yield. LCMS for Ci8Hi7Cl2N4S (M+H)+: m/z = 390.9, 393.0.
Step D: 6-Chloro-14-thia-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate
The desired compound was prepared according to the procedure of Example D2, step D, using N- (3-{ [2-(3-aminophenyl)ethyl]thio}phenyl)-2,5-dichloropyrimidin-4-amine as the starting material in 51% yield. LCMS for Ci8Hi6ClN4S (M+H)+: m/z = 354.9. 1H NMR (300 MHz, DMSOd6): δ 9.55 (s, 1 H), 9.22 (s, 1 H), 8.18 (s, 1 H), 8.05 (s, 1 H), 7.98 (s, 1 H), 7.37 - 7.20 (m, 3 H), 7.15 (dd, / = 7.9, 7.6 Hz, 1 H), 6.94 - 6.91 (m, 1 H), 6.82 (d, / = 7.3 Hz, 1 H), 3.25 - 3.20 (m, 2 H), 2.57 - 2.53 (m, 2 H).
Example D19
6-Chloro-16-thia-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene hydrochloride
Figure imgf000614_0002
Step A: tert-Butyl (3-{[2-(3-nitrophenyl)ethyl]thiojphenyl)carbamate
Figure imgf000614_0003
The desired compound was prepared according to the procedure of Example D2, step A, using 3- { [2-(3-nitrophenyl)ethyl]thio}aniline as the starting material in quantitative yield. LCMS for
Ci9H22N2O4SNa (M+Na)+: m/z = 397.0.
Step B: tert-Butyl (3-{[2-(3-aminophenyl)ethyl]thio}phenyl)carbamate
Figure imgf000615_0001
The desired compound was prepared according to the procedure of Example D2, step B, using tert-butyl (3-{ [2-(3-nitrophenyl)ethyl]thio}phenyl)carbamate as the starting material in quantitative yield. LCMS for Ci9H25N2O2S (M+H)+: m/z = 345.0.
Step C: tert-Butyl {3-[(2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenylj ethyl)thio]phenylj 'carbamate
Figure imgf000615_0002
The desired compound was prepared according to the procedure of Example D2, step C, using tert-butyl (3-{ [2-(3-aminophenyl)ethyl]thio}phenyl)carbamate as the starting material in 82% yield. LCMS for C23H25Cl2N4O2S (M+H)+: m/z = 490.9, 492.9.
Step D: 6-Chloro-16-thia-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- 1(21 ),3(23),4,6,9(22),10,12,17,19-nonaene hydrochloride The desired compound was prepared according to the procedure of Example D2, step D, using tert-butyl {3-[(2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl} ethyl)thio]phenyl}carbamate as the starting material in 35% yield. LCMS for Ci8Hi6ClN4S (M+H)+: m/z = 355.0. 1H NMR (300 MHz, DMSO-Cf6): δ 9.79 (s, 1 H), 9.34 (s, 1 H), 8.21 (s, 1 H), 8.13 (s, 1 H), 7.86 (s, 1 H), 7.29 - 7.24 (m, 1 H), 7.19 - 7.11 (m, 2 H), 7.04 - 6.94 (m, 3 H), 3.37 - 3.25 (m, 2 H), 2.76 - 2.72 (m, 2 H).
Example D20
6-Chloro-15-thia-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate
Figure imgf000616_0001
Step A: 3-[(tert-Butoxycarbonyl)amino]benzyl methanesulfonate
Figure imgf000616_0002
A solution of tert-bvXy\ [3-(hydroxymethyl)phenyl]carbamate (0.6 g, 2.7 mmol) [J. Med. Chem. 1989, 32, 807-826] in dichloromethane (8.4 niL) at -10 0C was treated with N,N-diisopropylethylamine (0.7 mL, 4.0 mmol) followed by methanesulfonyl chloride (0.31 mL, 4.0 mmol and stirred at -10 0C for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude yellow oil that was used without further purification. LCMS for Ci3Hi9NO5SNa (M+Νa)+: m/z = 323.9.
Step B: tert-Butyl (3-{[(3-nitrobenzyl)thio]methyl}phenyl)carbamate
Figure imgf000616_0003
A solution of cesium carbonate (0.57 g, 1.8 mmol) in N,N-dimethylformamide (1.8 mL) at 0 0C was treated with (3-nitrophenyl)methanethiol (0.22 mL, 1.6 mmol) dropwise and stirred at 0 0C for 10 min. The reaction mixture was treated with a solution of 3-[(tert-butoxycarbonyl)amino]benzyl methanesulfonate (0.41 g, 1.3 mmol) in N,N-dimethylformamide (2.4 mL) dropwise and stirred at 0 0C for 30 min. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (40 mL) and brine (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to a crude brown oil. This material was purified by flash column chromatography to give the desired product (0.42 g, 84% for 2 steps) as a yellow oil. LCMS for Ci9H22N2O4SNa (M+Na)+: m/z = 396.7.
Step C: tert-Butyl (3-{[(3-aminobenzyl)thio]methyl}phenyl)carbamate
Figure imgf000617_0001
The desired compound was prepared according to the procedure of Example D2, step B, using tert-butyl (3-{ [(3-nitrobenzyl)thio]methyl}phenyl)carbamate as the starting material in 76% yield. LCMS for Ci9H25N2O2S (M+H)+: m/z = 345.0.
Step D: tert-Butyl (3-[({3-[(2, 5-dichloropyrimidin-4-yl)amino]benzyljthio)methyl]phenyljcarbamate
Figure imgf000617_0002
The desired compound was prepared according to the procedure of Example D2, step C, using tert-butyl (3-{ [(3-aminobenzyl)thio]methyl}phenyl)carbamate as the starting material in 84% yield. LCMS for C23H24Cl2N4O2SNa (M+Na)+: m/z = 513.0, 515.0.
Step E: 6-Chloro-15-thia-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate
The desired compound was prepared according to the procedure/conditions of Example D5, step B, using tert-butyl {S-fdS-fCl^-dichloropyrimidin^-y^aminolbenzylJth^methyllphenylJcarbamate as the starting material in 15% yield. LCMS for Ci8Hi6ClN4S (M+H)+: m/z = 355.0. 1H NMR (300 MHz, DMSO-^6): δ 9.60 (s, 1 H), 9.17 (s, 1 H), 8.18 (s, 1 H), 7.99 (s, 1 H), 7.93 (s, 1 H), 7.38 - 7.33 (m, 1 H), 7.25 -7.19 (m, 3 H), 7.00 - 6.94 (m, 2 H), 3.44 (s, 2 H), 3.30 (s, 2 H).
Example D21
6-Chloro-15-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate
Figure imgf000617_0003
Step A: tert-Butyl (3-{[(3-nitrobenzyl)oxy]methyl}phenyl)carbamate
Figure imgf000618_0001
The desired compound was prepared according to the procedure of Example D20, step B, using 3-nitro-benzenemethanol as the starting material in 38% yield. LCMS for Ci9H22N2O5Na (M+Na)+: m/z = 381.0.
Step B: tert-Butyl (3-{[(3-aminobenzyl)oxy]methyljphenyl)carbamate
Figure imgf000618_0002
The desired compound was prepared according to the procedure of Example D2, step B, using tert-butyl (3-{ [(3-nitrobenzyl)oxy]methyl}phenyl)carbamate as the starting material in quantitative yield. LCMS for Ci9H25N2O3 (M+H)+: m/z = 329.1.
Step C: tert-Butyl (3-[({3-[(2, 5-dichloropyrimidin-4-yl)amino]benzyljoxy)methyl]phenyljcarbamate
Figure imgf000618_0003
The desired compound was prepared according to the procedure of Example D2, step C, using tert-butyl (3-{ [(3-aminobenzyl)oxy]methyl}phenyl)carbamate as the starting material in 79% yield. LCMS for C23H24Cl2N4O3Na (M+Na)+: m/z = 497.0, 499.0.
Step D: 6-Chloro-15-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate The desired compound was prepared according to the procedure/conditions of Example D5, step
B, using tert-butyl {3-[({3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}oxy)methyl]phenyl}carbamate as the starting material in 47% yield. LCMS for Ci8Hi6ClN4O (M+H)+: m/z = 339.0. 1H NMR (300 MHz, DMSO-^6): δ 9.60 (s, 1 H), 9.18 (s, 1 H), 8.35 (s, 1 H), 8.17 (s, 1 H), 8.12 (s, 1 H), 7.32 - 7.21 (m, 2 H), 7.15 (dd, / = 7.9, 7.6 Hz, 1 H), 7.07 (d, / = 7.3 Hz, 1 H), 7.00 - 7.96 (m, 1 H), 6.84 (d, / = 7.3 Hz, 1 H), 4.49 (s, 2 H), 4.39 (s, 2 H). Example D22
19-Bromo-6-chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,
13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate
Step A: 3-Bromo-5-[(tert-butoxycarbonyl)amino]benzoic acid
Figure imgf000619_0002
A solution of 3-amino-5-bromobenzoic acid (10 g, 46 mmol) in 1,4-dioxane (46 niL) and water (46 mL) was treated with triethylamine (10 mL, 69 mmol) followed by a solution of di-tert- butyldicarbonate (15 g, 69 mmol) in 1,4-dioxane (46 mL) at 0 0C. The reaction mixture was stirred at 20 0C for 16 h, treated with additional triethylamine (3.2 mL, 23 mmol) and di-tert-butyldicarbonate (5.1 g, 23 mmol), and stirred for another 16 h. The reaction mixture was concentrated, diluted with ethyl acetate (200 mL), and washed with 1 N HCl (2 x 100 mL) and brine (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude tan solid. This material was stirred in boiling toluene (100 mL), cooled, filtered, washed with cold toluene, and dried to give the desired product (13.6 g, 93%) as an off-white solid. LCMS for Ci2Hi5BrNO4 (M+H)+: m/z = 316.0, 318.0.
Step B: tert-Butyl [3-bromo-5-(hydroxymethyl)phenyl]carbamate
Figure imgf000619_0003
A solution of 3-bromo-5-[(tert-butoxycarbonyl)amino]benzoic acid (13.6 g, 43.1 mmol) in tetrahydrofuran (44 mL) at 0 0C was treated with 1 M borane in THF (64.6 mL, 64.6 mmol) dropwise and stirred at 20 0C for 1 h. The reaction mixture was concentrated, diluted with ethyl acetate (200 mL), and washed with 1 M HCl (100 mL) and brine (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a colorless oil that was used without further purification. LCMS for Ci2Hi6BrNO3Na (M+Na)+: m/z = 323.9, 325.9. Step C: tert-Butyl (3-bromo-5-formylphenyl)carbamate
Figure imgf000620_0001
A solution of tert-butyl [3-bromo-5-(hydroxymethyl)phenyl]carbamate (13.3 g, 44.2 mmol) and manganese(IV) oxide (19.2 g, 221 mmol) in 1 ,2-dichloroethane (88 mL) was stirred at 80 0C for 3 h. The reaction mixture was treated with additional manganese(IV) oxide (11.5 g, 132 mmol) and stirred at 80 0C for 16 h. The reaction mixture was filtered over celite (2x) and washed with dichloromethane. The filtrate was concentrated to give the desired product (10.9 g, 82% for 2 steps) as a white solid. LCMS for Ci2Hi4BrNO3Na (M+Na)+: m/z = 321.9, 323.9.
Step D: tert-Butyl (3-bromo-5-vinylphenyl)carbamate
Figure imgf000620_0002
A solution of triphenylmethylphosphonium bromide (28.4 g, 79.5 mmol) in tetrahydrofuran (152 mL) at 0 0C was treated with 2.5 M «-butyllithium in hexanes (31.8 mL, 79.5 mmol) dropwise and stirred at 0 0C for 15 min and at 20 0C for 1 h. The reaction mixture was cooled to 0 0C, treated with a solution of tert-butyl (3-bromo-5-formylphenyl)carbamate (10.9 g, 36.2 mmol) in tetrahydrofuran (55 mL), and stirred at 20 0C for 1 h. The reaction mixture was cooled to 0 0C, quenched with water (50 mL), concentrated to remove most of the tetrahydrofuran, poured into water (150 mL), and extracted with ethyl acetate (200 mL). The aqueous layer was separated and extracted with additional ethyl acetate (100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude tan oil. This material was purified by flash column chromatography to give the desired product (9.9 g, 92%) as a white solid. LCMS for C9H9BrNO2 (PVH>Bu)+H]+H)+: m/z = 241.9, 243.8.
Step E: tert-Butyl [3-bromo-5-(2-hydroxyethyl)phenyl]carbamate
Figure imgf000620_0003
A solution of tert-butyl (3-bromo-5-vinylphenyl)carbamate (0.80 g, 2.7 mmol) in tetrahydrofuran (2.7 mL) was treated with 9-BBN in tetrahydrofuran (16.1 mL, 8.1 mmol) dropwise and stirred for 2 h. The reaction mixture was cooled to 0 0C and treated with ethanol (5 mL), 3 M sodium hydroxide (3.2 mL) and 9 M hydrogen peroxide (3 mL) dropwise. The reaction mixture was heated at 50 0C for 30 min, cooled to 20 0C, poured into brine (25 mL), and extracted with ethyl acetate (100 mL). A small amount of water was added to dissolve the solids that were insoluble in the brine. The organic layer was separated and washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude tan oil. This material was purified by flash column chromatography to give the desired product (0.66 g, 78%) as a colorless foam. LCMS for C9HnBrNO3 ([M-(J- Bu)+H]+H)+: m/z = 259.9, 261.8.
Step F: N-(3-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-2,5-dichloropyrimidin-4-amine
Figure imgf000621_0001
The desired compound was prepared according to the procedure of Example Dl, step B, using 3- { [tert-butyl(dimethyl)silyl]oxy}aniline [WO2005113556] as the starting material in 84% yield. LCMS for Ci6H22Cl2N3OSi (M+H)+: m/z = 370.0, 372.0.
Step G: 3-[(2-{[3-Bromo-5-(2-hydroxyethyl)phenyl]aminoj-5-chloropyrimidin-4-yl)amino]phenol
Figure imgf000621_0002
The desired compound was prepared according to the procedure of Example D5, step B, using N- (3-{ [tert-butyl(dimethyl)silyl]oxy }phenyl)-2,5-dichloropyrimidin-4-amine and tert-butyl [3-bromo-5-(2- hydroxyethyl)phenyl] carbamate as the starting materials in 77% yield. LCMS for Ci8H17BrClN4O2 (M+H)+: m/z = 434.9, 436.9.
Step H: 19-Bromo-6-chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9, 13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate The desired compound was prepared according to the procedure of Example D5, step C, using 3-
[(2-{ [3-bromo-5-(2-hydroxyethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]phenol as the starting material in 36% yield. LCMS for Ci8Hi5BrClN4O (M+H)+: m/z = 416.8, 418.9. 1H NMR (SOO MHZ, DMS0-<i6): δ 9.55 (s, 1 H), 9.23 (s, 1 H), 8.17 (s, 1 H), 7.93 (s, 1 H), 7.59 (dd, / = 2.1, 2.1 Hz, 1 H), 7.23 (dd, / = 8.2, 7.9 Hz, 1 H), 7.12 (s, 2 H), 6.93 - 6.86 (m, 2 H), 4.47 - 4.43 (m, 2 H), 2.70 - 2.67 (m, 2 H).
Example D23
6-Chloro-14-thia-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- I(21),3(23),4,6,9(22),10,12,17,19-nonaene l4-oxide trifluoroacetate
Figure imgf000622_0001
Example D24 6-chloro-14-thia-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- I(21),3(23),4,6,9(22),10,12,17,19-nonaene l4,14-dioxide trifluoroacetate
Figure imgf000622_0002
The desired compounds were prepared according to the procedures of Examples D3 and D4 using
6-chloro-14-thia-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene as the starting material in 18% and 32% yields respectively. Example D23: LCMS for Ci8Hi6ClN4OS (M+H)+: m/z = 370.9. 1H NMR OOO MHZ5 DMSO- d6): δ 9.60 (s, 1 H), 9.37 (s, 1 H), 8.20 (s, 2 H), 7.88 (s, 1 H), 7.65 (dd, / = 7.9, 7.6 Hz, 1 H), 7.58 - 7.50
(m, 2 H), 7.16 (dd, / = 7.9, 7.6 Hz, 1 H), 6.98 - 6.90 (m, 2 H), 3.64 - 3.54 (m, 1 H), 3.41 - 3.33 (m, 1 H),
2.91 - 2.82 (m, 1 H), 2.19 - 2.11 (m, 1 H). Example D24: LCMS for Ci8Hi6ClN4O2S (M+H)+: m/z = 386.9. 1H NMR OOO MHZ5 DMSO- dβ): δ 9.61 (s, 1 H), 9.42 (s, 1 H), 8.47 (s, 1 H), 8.23 (s, 1 H), 7.99 (s, 1 H), 7.70 - 7.64 (m, 3 H), 7.14 (dd,
/ = 7.9, 7.6 Hz, 1 H), 6.94 - 6.87 (m, 2 H), 2.57 - 2.53 (m, 1 H).
Example D25 6-Chloro-19-pyridin-4-yl-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3, 7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene bis(trifluoroacetate)
Figure imgf000623_0001
A solution of 19-bromo-6-chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9, 13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate (40 mg, 96 μmol), 4- pyridinylboronic acid (13 mg, 0.11 mmol), and 2 M sodium carbonate (0.14 mL, 0.29 mmol) in toluene (0.36 mL) and ethanol (0.36 mL) was degassed with nitrogen, treated with tetrakis(triphenylphosphine)palladium(0) (8 mg, 6.7 μmol), and heated at 85 0C for 12 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (4 mg, 7%) as a white solid. LCMS for C23H19ClN5O (M+H)+: m/z = 416.0. 1H NMR (400 MHz, DMSO-^6): δ 9.62 (s, 1 H), 9.20 (s, 1 H), 8.90 (br s, 2 H), 8.19 (s, 1 H), 8.13 - 8.05 (m, 3 H), 7.65 (s, 1 H), 7.52 (s, 1 H), 7.45 (s, 1 H), 7.24 (dd, / = 8.2, 8.0 Hz, 1 H), 6.94 - 6.86 (m, 2 H), 4.57 - 4.54 (m, 2 H), 2.85 - 2.78 (m, 2 H).
Example D26 6-Chloro-19-pyridin-3-yl-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,
7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene bis(trifluoroacetate)
Figure imgf000623_0002
The desired compound was prepared according to the procedure of Example D25 using 3- pyridylboronic acid as the starting material in 24% yield. LCMS for C23Hi9ClN5O (M+H)+: m/z = 416.0. 1H NMR (300 MHz, DMS0-<i6): δ 9.61 (s, 1 H), 9.24 (s, 1 H), 8.99 (s, 1 H), 8.72 (d, / = 4.4 Hz, 1 H), 8.37 (d, / = 7.9 Hz, 1 H), 8.19 (s, 1 H), 8.03 (s, 1 H), 7.80 (dd, / = 7.3, 5.6 Hz, 1 H), 7.68 (s, 1 H), 7.36 (s, 1 H), 7.29 - 7.20 (m, 2 H), 6.94 - 6.85 (m, 2 H), 4.55 (br s, 2 H), 2.82 (br s, 2 H).
Example D27 6-Chloro-19-(2-piperazin-l-ylpyridin-4-yl)-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3, 7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene tris(trifluoroacetate)
Figure imgf000624_0001
A solution of 19-bromo-6-chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9, 13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate (40 mg, 96 μmol), tert-butyl 4-[4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-l-carboxylate (45 mg, 0.12 mmol), and 2 M sodium carbonate (0.14 mL, 0.29 mmol) in toluene (0.36 mL) and ethanol (0.36 mL) was degassed with nitrogen, treated with tetrakis(triphenylphosphine)palladium(0) (8 mg, 6.7 μmol), and heated at 85 0C for 9 h. The reaction mixture was concentrated, stirred in TFA (1.5 mL) for 30 min, concentrated, and purified by preparative LCMS to give the desired product (11 mg, 14%) as a white solid. LCMS for C27H27ClN7O (M+H)+: m/z = 500.0. 1H NMR (300 MHz, DMSOd6): δ 9.59 (s, 1 H), 9.25 (s, 1 H), 8.88 (br s, 2 H), 8.21 - 8.18 (m, 2 H), 8.00 (s, 1 H), 7.67 (s, 1 H), 7.35 - 7.29 (m, 2 H), 7.25 - 7.16 (m, 2 H), 7.00 - 6.80 (m, 3 H), 4.55 (br s, 2 H), 3.80 (br s, 4 H), 3.21 (br s, 4 H), 2.82 (br s, 2 H).
Example D28
6-Chloro-19-phenyl-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9, 13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate
Figure imgf000624_0002
The desired compound was prepared according to the procedure of Example D25 using phenylboronic acid as the starting material in 57% yield. LCMS for C24H20ClN4O (M+H)+: m/z = 415.0. 1H NMR (300 MHz, DMS0-<i6): δ 9.59 (s, 1 H), 9.31 (s, 1 H), 8.19 (s, 1 H), 7.91 (s, 1 H), 7.69 (s, 1 H), 7.60 - 7.57 (m, 2 H), 7.47 - 7.42 (m, 2 H), 7.36 - 7.31 (m, 1 H), 7.25 - 7.19 (m, 3 H), 6.93 - 6.84 (m, 2 H), 4.55 - 4.51 (m, 2 H), 2.85 - 2.80 (m, 2 H).
Example D29
6-Chloro-19-[4-(methylsulfonyl)phenyl]-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,
7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate
Figure imgf000625_0001
The desired compound was prepared according to the procedure of Example D25 using [4- (methylsulfonyl)phenyl]boronic acid as the starting material in 29% yield. LCMS for C2SH22ClN4O3S (M+H)+: m/z = 492.9. 1H NMR (300 MHz, DMSO-^6): δ 9.60 (s, 1 H), 9.27 (s, 1 H), 8.19 (s, 1 H), 8.01 - 7.97 (m, 3 H), 7.87 - 7.84 (m, 2 H), 7.68 (s, 1 H), 7.31 - 7.20 (m, 3 H), 6.94 - 6.86 (m, 2 H), 4.59 - 4.50 (m, 2 H), 3.25 (s, 3 H), 2.85 - 2.78 (m, 2 H).
Example D30
6-Chloro-19-(3,5-dimethyl-lH-pyrazol-4-yl)-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,
7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene bis(trifluoroacetate)
Figure imgf000625_0002
The desired compound was prepared according to the procedure of Example D25 using 3,5- dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole as the starting material in 41% yield. LCMS for C23H22ClN6O (M+H)+: m/z = 433.0. 1H NMR (300 MHz, DMS0-<i6): δ 9.58 (s, 1 H), 9.32 (s, 1 H), 8.19 (s, 1 H), 7.87 (s, 1 H), 7.69 (s, 1 H), 7.24 (dd, / = 8.2, 7.9 Hz, 1 H), 6.94 - 6.85 (m, 3 H), 4.54 - 4.45 (m, 2 H), 2.80 - 2.70 (m, 2 H), 2.22 (s, 6 H).
Example D31 6-Chloro-19-(2-piperazin-l-ylpyrimidin-5-yl)-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3, 7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene tris(trifluoroacetate)
Figure imgf000626_0001
The desired compound was prepared according to the procedure of Example D27 using tert-butyl 4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperazine-l-carboxylate as the starting material in 38% yield. LCMS for C26H26ClN8O (M+H)+: m/z = 501.0. 1H NMR (SOO MHZ5 DMSO-^): δ 9.50 (s, 1 H), 9.19 (s, 1 H), 8.81 (br s, 2 H), 8.68 (s, 2 H), 8.17 (s, 1 H), 7.91 (s, 1 H), 7.69 (s, 1 H), 7.24 - 7.18 (m, 2 H), 7.15 (s, 1 H), 6.93 - 6.89 (m, 1 H), 6.84 (dd, / = 8.2, 2.1 Hz, 1 H), 4.57 - 4.49 (m, 2 H), 3.99 - 3.93 (m, 4 H), 3.19 (br s, 4 H), 2.80 - 2.78 (m, 2 H).
Example D32
6-Chloro-15-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene trifluoroacetate
Figure imgf000626_0002
Step A: tert-Butyl [3-(2-hydroxyethyl)pheny I] carbamate
Figure imgf000626_0003
The desired compound was prepared according to the procedure of Example D 15, step A, using 2-(3-aminophenyl)ethanol as the starting material in quantitative yield. LCMS for Ci3H19NO3Na
(M+Na)+: m/z = 260.0.
Step B: 2-{3-[(tert-Butoxycarbonyl)amino]phenyl}ethyl methane sulfonate
Figure imgf000627_0001
The desired compound was prepared according to the procedure of Example D20, step A, using tert-butyl [3-(2-hydroxyethyl)phenyl]carbamate as the starting material in quantitative yield. LCMS for
Ci4H2INO5SNa (M+Na)+: m/z = 338.0.
Step C: tert-Butyl (3-{2-[(3-nitrobenzyl)thio]ethyljphenyl)carbamate
Figure imgf000627_0002
The desired compound was prepared according to the procedure of Example D20, step B, using 2-{3-[(tert-butoxycarbonyl)amino]phenyl}ethyl methanesulfonate as the starting material in 80% yield. LCMS for C20H24N2O4SNa (M+Na)+: m/z = 411.0.
Step D: tert-Butyl (3-{2-[(3-aminobenzyl)thio]ethyl}phenyl)carbamate
Figure imgf000627_0003
The desired compound was prepared according to the procedure of Example D2, step B, using tert-butyl (3-{2-[(3-nitrobenzyl)thio]ethyl}phenyl)carbamate as the starting material in 71% yield. LCMS for C20H27N2O2S (M+H)+: m/z = 359.0.
Step E: tert-Butyl (3-[2-({3-[(2, 5-dichloropyrimidin-4-yl)amino]benzyl}thio)ethyl]phenyl}carbamate
Figure imgf000627_0004
The desired compound was prepared according to the procedure of Example D2, step C, using tert-butyl (3-{2-[(3-aminobenzyl)thio]ethyl}phenyl)carbamate as the starting material in 83% yield. LCMS for C24H27Cl2N4O2S (M+H)+: m/z = 504.9, 506.9. Step F: 6-Chloro-15-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- 1 (22), 3 (24), 4, 6, 9(23), 10,12,18, 20-nonaene trifluoroacetate
A solution of tert-buiyl {3-[2-({3-[(2,5-dichloropyrimidin-4- yl)amino]benzyl}thio)ethyl]phenyl}carbamate (0.14 g, 0.27 mmol) in 1,4-dioxane (11 niL) was treated with p-toluenesulfonic acid monohydrate (92 mg, 0.48 mmol) and heated at 98 0C for 16 h. The reaction mixture was concentrated and diluted with ethyl acetate (100 mL), saturated sodium bicarbonate (25 mL), and water (25 mL). The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude tan solid. This material was purified by preparative LCMS to give the desired product (24 mg, 18%) as a solid. LCMS for Ci9Hi8ClN4S (M+H)+: m/z = 368.9. 1H NMR (300 MHz, DMS0-<i6): δ 9.50 (s, 1 H), 9.04 (s, 1 H), 8.15 (s, 1 H), 7.92 (s, 1 H), 7.69 (s, 1 H), 7.35 - 7.23 (m, 2 H), 7.12 - 7.04 (m, 2 H), 6.88 (d, / = 9.1 Hz, 1 H), 6.71 (d, / = 7.3 Hz, 1 H), 3.71 (s, 2 H), 2.60 - 2.50 (m, 4 H).
Example D33
6-Chloro-19-(6-piperazin-l-ylpyridin-3-yl)-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,
7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene tris(trifluoroacetate)
Figure imgf000628_0001
The desired compound was prepared according to the procedure of Example D25 using l-[5- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine as the starting material in 76% yield. LCMS for C27H27ClN7O (M+H)+: m/z = 500.0. 1H NMR (300 MHz, DMS0-<i6): δ 9.54 (s, 1 H), 9.24 (s, 1 H), 8.77 (br s, 2 H), 8.40 (d, / = 2.6 Hz, 1 H), 8.18 (s, 1 H), 7.88 - 7.84 (m, 2 H), 7.69 (d, / = 2.1 Hz, 1 H), 7.24 - 7.15 (m, 3 H), 7.03 (d, / = 8.8 Hz, 1 H), 6.92 (d, / = 7.6 Hz, 1 H), 6.84 (dd, / = 8.2, 1.8 Hz, 1 H), 4.55 - 4.50 (m, 2 H), 3.77 - 3.73 (m, 4 H), 3.20 (br s, 4 H), 2.79 (br s, 2 H).
Example D34
6-Chloro-16-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene trifluoroacetate
Figure imgf000629_0001
Step A: 3-{2-[(3-Nitrobenzyl)thio]ethyljaniline
Figure imgf000629_0002
A solution of tert-butyl (3-{2-[(3-nitrobenzyl)thio]ethyl}phenyl)carbamate (0.38 g, 0.97 mmol) in dichloromethane (2 niL) was treated with trifluoroacetic acid and stirred for 30 min. The reaction mixture was concentrated and poured into 10% potassium carbonate (30 mL) and ethyl acetate (100 mL). The organic layer was separated, washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude orange oil. This material was purified by flash column chromatography to give the desired product (0.19 g, 67%) as an orange oil. LCMS for Ci5HnN2O2S (M+H)+: m/z = 289.0.
Step B: 2,5-Dichloro-N-(3-{2-[(3-nitrobenzyl)thio]ethyljphenyl)pyrimidin-4-amine
Figure imgf000629_0003
The desired compound was prepared according to the procedure of Example D2, step C, using 3- {2-[(3-nitrobenzyl)thio]ethyl}aniline as the starting material in 91% yield. LCMS for Ci9Hi7Cl2N4O2S (M+H)+: m/z = 434.9, 436.9.
Step C: N-(3-{2-[(3-Aminobenzyl)thio]ethyl}phenyl)-2, 5-dichloropyrimidin-4-amine
Figure imgf000629_0004
The desired compound was prepared according to the procedure of Example D2, step B, using 2,5-dichloro-N-(3-{2-[(3-nitrobenzyl)thio]ethyl}phenyl)pyrimidin-4-amine as the starting material in 87% yield. LCMS for Ci9Hi9Cl2N4S (M+H)+: m/z = 404.9, 406.9.
Step D: 6-Chloro-16-thia-2,4,8,24-tetraazatetracyclo[ 16.3.1.1(3,7).1(9, 13)]tetracosa- 1 (22), 3 (24), 4, 6, 9(23), 10,12,18, 20-nonaene trifluoroacetate
The desired compound was prepared according to the procedure of Example D32, step F, using N-(3-{2-[(3-aminobenzyl)thio]ethyl}phenyl)-2,5-dichloropyrimidin-4-amine as the starting material in 44% yield. LCMS for Ci9Hi8ClN4S (M+H)+: m/z = 369.0. 1H NMR (300 MHz, DMS0-<i6): δ 9.61 (s, 1 H), 9.20 (s, 1 H), 8.17 (s, 1 H), 7.96 (s, 1 H), 7.57 (s, 1 H), 7.31 (dd, / = 7.6, 7.6 Hz, 1 H), 7.18 - 7.10 (m, 3 H), 6.93 (dd, / = 7.9, 1.2 Hz, 1 H), 6.85 (d, / = 7.6 Hz, 1 H), 3.16 (s, 2 H), 2.86 - 2.81 (m, 2 H).
Example D35
19-[2-(4-Acetylpiperazin-l-yl)pyridin-4-yl]-6-chloro-14-oxa-2,4,8,23- tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene bis(trifluoroacetate)
Figure imgf000630_0001
A solution of 6-chloro-19-(2-piperazin-l-ylpyridin-4-yl)-14-oxa-2,4,8,23- tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene (40 mg, 80 μmol) in dichloromethane (1.2 mL) was treated with triethylamine (22 μL, 0.16 mmol), cooled to 0 0C, and treated with 0.2 M acetyl chloride in dichloromethane (0.48 mL, 96 μmol) dropwise. The reaction mixture was stirred at 20 0C for 1 h, quenched with methanol, and purified by preparative LCMS to give the desired product (37 mg, 52%) as a white solid. LCMS for C29H29ClN7O2 (M+H)+: m/z = 542.1. 1H NMR (300 MHz, DMS0-<i6): δ 9.57 (s, 1 H), 9.25 (s, 1 H), 8.19 (s, 1 H), 8.14 (d, / = 6.2 Hz, 1 H), 8.06 (s, 1 H), 7.66 (dd, / = 2.1, 2.1 Hz, 1 H), 7.44 (s, 1 H), 7.37 - 7.34 (m, 2 H), 7.23 (dd, / = 8.2, 7.9 Hz, 1 H), 7.09 (d, / = 6.2 Hz, 1 H), 6.92 (d, / = 7.9 Hz, 1 H), 6.86 (dd, / = 8.2, 2.1 Hz, 1 H), 4.59 - 4.53 (m, 2 H), 3.78 - 3.61 (m, 8 H), 2.86 - 2.80 (m, 2 H).
Example D36
6-Chloro-19-{2-[4-(methylsulfonyl)piperazin-l-yl]pyridin-4-yl}-14-oxa-2, 4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4, 6,9(22),10,12,17,19-nonaene bis(trifluoroacetate)
Figure imgf000631_0001
A solution of 6-chloro-19-(2-piperazin-l-ylpyridin-4-yl)-14-oxa-2,4,8,23- tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene (40 mg, 80 μmol) in dichloromethane (1.2 mL) was treated with triethylamine (22 μL, 0.16 mmol) followed by 0.2 M methanesulfonyl chloride in dichloromethane (0.48 mL, 96 μmol) dropwise. The reaction mixture was stirred at 20 0C for 1 h, quenched with methanol, and purified by preparative LCMS to give the desired product (36 mg, 49%) as a white solid. LCMS for C28H29ClN7O3S (M+H)+: m/z = 578.0. 1H NMR (300 MHz, DMSOd6): δ 9.57 (s, 1 H), 9.26 (s, 1 H), 8.19 - 8.15 (m, 2 H), 8.03 (s, 1 H), 7.66 (s, 1 H), 7.40 (s, 1 H), 7.34 (s, 1 H), 7.28 (s, 1 H), 7.22 (dd, / = 8.2, 7.9 Hz, 1 H), 7.04 (d, / = 5.9 Hz, 1 H), 6.92 (d, / = 7.9 Hz, 1 H), 6.87 - 6.83 (m, 1 H), 4.59 - 4.53 (m, 2 H), 3.77 (br s, 4 H), 3.24 (br s, 4 H), 2.83 (br s, 2 H).
Example D37 19-[6-(4-Acetylpiperazin-l-yl)pyridin-3-yl]-6-chloro-14-oxa-2,4,8,23- tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene tris(trifluoroacetate)
Figure imgf000632_0001
The desired compound was prepared according to the procedure of Example D35 using 6-chloro- 19-(6-piperazin- 1 -ylpyridin-3-yl)- 14-oxa-2,4, 8 ,23 -tetraazatetracyclo[ 15.3.1.1(3, 7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene as the starting material in 37% yield. LCMS for C29H29ClN7O2 (M+H)+: m/z = 542.0. 1H NMR (300 MHz, DMSO-^6): δ 9.58 (s, 1 H), 9.31 (s, 1 H), 8.32 (d, / = 2.3 Hz, 1 H), 8.19 (s, 1 H), 7.96 (d, / = 8.8 Hz, 1 H), 7.88 (s, 1 H), 6.68 (s, 1 H), 7.24 - 7.11 (m, 4 H), 6.91 (d, / = 7.9 Hz, 1 H), 6.84 (dd, / = 8.2, 1.8 Hz, 1 H), 4.54 (br s, 2 H), 3.65 - 3.56 (m, 8 H), 2.80 (br s, 2 H).
Example D38
6-Chloro-19-{6-[4-(methylsulfonyl)piperazin-l-yl]pyridin-3-yl}-14-oxa-2, 4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4, 6,9(22),10,12,17,19-nonaene bis(trifluoroacetate)
Figure imgf000632_0002
The desired compound was prepared according to the procedure of Example D36 using 6-chloro-
19-(6-piperazin- 1 -ylpyridin-3-yl)- 14-oxa-2,4, 8 ,23 -tetraazatetracyclo[ 15.3.1.1(3, 7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene as the starting material in 45% yield. LCMS for C28H29ClN7O3S (M+H)+: m/z = 578.0. 1H NMR (300 MHz, DMSO-^6): δ 9.58 (s, 1 H), 9.33 (s, 1 H), 8.36 (d, / = 2.3 Hz, 1 H), 8.19 (s, 1 H), 7.92 - 7.87 (m, 2 H), 7.68 (s, 1 H), 7.24 - 7.15 (m, 3 H), 7.08 (d, / = 9.1 Hz, 1 H), 6.91 (d, / = 8.2 Hz, 1 H), 6.85 (d, / = 7.9 Hz, 1 H), 4.54 (br s, 2 H), 3.69 - 3.67 (m, 4 H), 3.23 - 3.21 (m, 4 H), 2.80 (br s, 2 H).
Example D39
4-{4-[6-Chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}piperazine- 1 -carboxamide bis(trifluor oacetate)
Figure imgf000633_0001
A solution of 6-chloro-19-(2-piperazin-l-ylpyridin-4-yl)-14-oxa-2,4,8,23- tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene (40 mg, 80 μmol) in dichloromethane (1 mL) was treated with triethylamine (22 μL, 0.16 mmol) followed by 0.2 M 2-isocyanato-2-methylpropane in dichloromethane (0.5 mL, 100 μmol) dropwise. The reaction mixture was stirred at 20 0C for 16 h, concentrated, treated with trifluoroacetic acid (1.5 mL), and heated at 80 0C for 2 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (25 mg, 35%) as a white solid. LCMS for C28H28ClN8O2 (M+H)+: m/z = 543.0. 1H NMR (300 MHz, DMSOd6): δ 9.53 (s, 1 H), 9.21 (s, 1 H), 8.18 (s, 1 H), 8.12 (dd, / = 6.2 Hz, 1 H), 8.07 (s, 1 H), 7.66 (s, 1 H), 7.44 (s, 1 H), 7.37 (s, 2 H), 7.23 (dd, / = 8.2, 7.9 Hz, 1 H), 7.09 (d, / = 6.2 Hz, 1 H), 6.92 (d, / = 7.9 Hz, 1 H), 6.86 (d, / = 6.4 Hz, 1 H), 4.56 (br s, 2 H), 3.67 (br s, 4 H), 3.48 (br s, 4 H), s.83 (br s, 2 H).
Example D40
4-{5-[6-Chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}piperazine- 1 -carboxamide bis(trifluor oacetate)
Figure imgf000634_0001
The desired compound was prepared according to the procedure of Example D39 using 6-chloro- 19-(6-piperazin- 1 -ylpyridin-3-yl)- 14-oxa-2,4, 8 ,23 -tetraazatetracyclo[ 15.3.1.1(3, 7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene as the starting material in 59% yield. LCMS for C28H28ClN8O2 (M+H)+: m/z = 543.0. 1H NMR (300 MHz, DMSO-^6): δ 9.58 (s, 1 H), 9.30 (s, 1 H), 8.28 (d, / = 2.3 Hz, 1 H), 8.19 (s, 1 H), 7.99 (d, / = 8.8 Hz, 1 H), 7.89 (s, 1 H), 7.68 (d, / = 1.8 Hz, 1 H), 7.25 - 7.16 (m, 4 H), 6.91 (d, / = 9.1 Hz, 1 H), 6.85 (dd, / = 8.2, 2.1 Hz, 1 H), 4.56 - 4.50 (m, 2 H), 3.58 - 3.56 (m, 4 H), 3.46 - 3.43 (m, 4 H), 2.80 (br s, 2 H).
Example D41 iV-(tert-Butyl)-4-{4-[6-chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3, 7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin- 2-yl}piperazine- 1-carboxamide bis(trifluoroacetate)
Figure imgf000634_0002
A solution of 6-chloro-19-(2-piperazin-l-ylpyridin-4-yl)-14-oxa-2,4,8,23- tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene (25 mg, 50 μmol) in dichloromethane (1 mL) was treated with triethylamine (21 μL, 0.15 mmol) followed by 2- isocyanato-2-methylpropane (10 μL, 90 μmol) dropwise. The reaction mixture was stirred at 20 0C for 4 h, concentrated, and purified by preparative HPLC to give the desired product (21 mg, 45%) as a white solid. LCMS for C32H36ClN8O2 (M+H)+: m/z = 599.1. 1H NMR (300 MHz, DMSOd6): δ 9.55 (s, 1 H), 9.22 (s, 1 H), 8.18 (s, 1 H), 8.13 (d, / = 6.2 Hz, 1 H), 8.07 (s, 1 H), 7.66 (s, 1 H), 7.44 (s, 1 H), 7.37 (s, 2 H), 7.23 (dd, / = 8.2, 7.9 Hz, 1 H), 7.09 (d, / = 5.9 Hz, 1 H), 6.92 (d, / = 7.6 Hz, 1 H), 6.86 (dd, / = 7.9, 1.5 Hz, 1 H), 5.95 (s, 1 H), 4.58 - 4.50 (m, 2 H), 3.66 (br s, 4 H), 3.45 (br s, 4 H), 2.87 - 2.80 (m, 2 H), 1.26 (s, 9 H).
Example D42
4-{5-[6-Chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}-iV-phenylpiperazine- 1 -carboxamide bis(trifluor oacetate)
Figure imgf000635_0001
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 19-(6-piperazin- 1 -ylpyridin-3-yl)- 14-oxa-2,4, 8 ,23 -tetraazatetracyclo[ 15.3.1.1(3, 7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene and phenyl isocyanate as the starting materials in 79% yield. LCMS for C34H32ClN8O2 (M+H)+: m/z = 619.1. 1H NMR OOO MHZ5 DMSO- dβ): δ 9.61 (s, 1 H), 9.34 (s, 1 H), 8.62 (s, 1 H), 8.31 (d, / = 2.1 Hz, 1 H), 8.20 (s, 1 H), 8.01 (d, / = 9.1 Hz, 1 H), 7.89 (s, 1 H), 7.68 (s, 1 H), 7.46 (d, / = 7.6 Hz, 2 H), 7.26 - 7.17 (m, 5 H), 6.96 - 6.82 (m, 3 H), 4.54 (br s, 2 H), 3.66 - 3.62 (m, 8 H), 2.83 - 2.78 (m, 2 H).
Example D43
Methyl 6-chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,
13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxylate trifluoroacetate
Figure imgf000636_0001
Step A: 2-({3-[(2, 5-Dichloropyrimidin-4-yl)amino]phenyl}thio)ethanol
Figure imgf000636_0002
A solution of sodium methoxide (2.4 g, 44 mmol) in NN-dimethylformamide (80 mL) was treated with 3-aminobenzenethiol (4.6 g, 37 mmol) and stirred at 20 0C for 15 min. The reaction mixture was cooled to 0 0C, treated with a solution of 2-bromoethanol (3.4 mL, 48 mmol) in NN- dimethylformamide (10 mL), and stirred at 0 0C for 15 min and at 20 0C for 1 h. The reaction mixture was treated with potassium carbonate (10 g, 74 mmol) followed by 2,4,5-trichloropyrimidine (5.5 mL, 48 mmol) and heated at 60 0C for 1 h and stirred at 20 0C for 18 h. The reaction mixture was diluted with 4:1 wateπbrine (1 L) and extracted with ethyl acetate (2 x 250 mL). The combined organic layers were washed with water (3 x 300 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to a crude product. This material was purified by flash column chromatography give the desired product (7.8 g, 68%) as a solid. LCMS for Ci2Hi2Cl2N3OS (M+H)+: m/z = 315.9, 317.9.
Step B: Methyl 3-{[5-chloro-4-({3-[(2-hydroxyethyl)thio]phenyljamino)pyrimidin- 2-yl]amino}-5-hydroxybenzoate
Figure imgf000636_0003
The desired compound was prepared according to the procedure of Example D5, step B, using 2- ({3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}thio)ethanol and methyl 3-amino-5-hydroxybenzoate as the starting materials in 99% yield. LCMS for C20H20ClN4O4S (M+H)+: m/z = 446.9. Step C: Methyl 6-chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracydo[16.3.1.1(3,7).l(9,
13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxylate trifluoroacetate
The desired compound was prepared according to the procedure of Example D5, step C, using methyl 3-{ [5-chloro-4-({3-[(2-hydroxyethyl)thio]phenyl}amino)pyrimidin- 2-yl]amino}-5-hydroxybenzoate as the starting material in 28% yield. LCMS for C2OH18ClN4O3S (M+H)+: m/z = 428.9. 1H NMR (300 MHz, DMS0-<i6): δ 9.76 (s, 1 H), 8.93 (s, 1 H), 8.19 (s, 1 H), 8.11 (dd, J = 2.1, 2.1 Hz, 1 H), 7.90 (s, 1 H), 7.45 (s, 1 H), 7.37 - 7.29 (m, 2 H), 7.22 - 7.18 (m, 1 H), 6.94 (dd, / = 1.8, 1.5 Hz, 1 H), 4.16 - 4.12 (m, 2 H), 3.80 (s, 3 H), 3.28 - 3.24 (m, 2 H).
Example D44
4-{4-[6-Chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}-iV-phenylpiperazine- 1 -carboxamide bis(trifluor oacetate)
Figure imgf000637_0001
The desired compound was prepared according to the procedure of Example D41 using phenyl isocyanate as the starting material in 44% yield. LCMS for C34H32ClN8O2 (M+H)+: m/z = 619.0. 1H NMR (300 MHz, DMSO-^6): δ 9.58 (s, 1 H), 9.25 (s, 1 H), 8.64 (s, 1 H), 8.19 (s, 1 H), 8.15 (d, / = 6.2 Hz, 1 H), 8.07 (s, 1 H), 7.66 (s, 1 H), 7.47 - 7.38 (m, 5 H), 7.26 - 7.20 (m, 3 H), 7.11 (d, / = 5.9 Hz, 1 H), 6.96 - 6.84 (m, 3 H), 4.57 (br s, 2 H), 3.75 (br s, 4 H), 3.67 (br s, 4 H), 2.84 (br s, 2 H).
Example D45 iV-Benzyl-4-{4-[6-chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9, 13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}piperazine- 1 -carboxamide bis(trifluor oacetate)
Figure imgf000638_0001
The desired compound was prepared according to the procedure of Example D41 using benzyl isocyanate as the starting material in 35% yield. LCMS for C35H34ClN8O2 (M+H)+: m/z = 633.1. 1H NMR (300 MHz, DMS0-<i6): δ 9.53 (s, 1 H), 9.21 (s, 1 H), 8.18 (s, 1 H), 8.13 (d, / = 6.4 Hz, 1 H), 8.07 (s, 1 H), 7.66 (s, 1 H), 7.44 (s, 1 H), 7.37 (s, 2 H), 7.32 - 7.20 (m, 7 H), 7.09 (d, / = 5.9 Hz, 1 H), 6.92 (d, / = 7.9 Hz, 1 H), 6.86 (dd, / = 8.2, 1.8 Hz, 1 H), 4.56 (br s, 2 H), 4.26 (d, / = 5.3 Hz, 2 H), 3.70 (br s, 4 H), 3.53 (br s, 4 H), 2.83 (br s, 2 H).
Example D46
4-{4-[6-Chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}-iV-cyclopentylpiperazine- 1 -carboxamide bis(trifluor oacetate)
Figure imgf000638_0002
The desired compound was prepared according to the procedure of Example D41 using isocyanatocyclopentane as the starting material in 44% yield. LCMS for C33H36ClN8O2 (M+H)+: m/z = 611.0. 1H NMR (300 MHz, DMSO-^6): δ 9.56 (s, 1 H), 9.24 (s, I H), 8.19 (s, 1 H), 8.12 (d, / = 6.2 Hz, 1 H), 8.07 (s, 1 H), 7.66 (s, 1 H), 7.44 (s, 1 H), 7.37 (s, 2 H), 7.23 (dd, / = 8.2, 7.9 Hz, 1 H), 7.10 (d, / = 6.2 Hz, 1 H), 6.92 (d, / = 7.9 Hz, 1 H), 6.86 (d, / = 10.0 Hz, 1 H), 6.39 (d, / = 6.4 Hz, 1 H), 4.56 (s, 2 H), 3.92 - 3.88 (m, 1 H), 3.66 (br s, 4 H), 3.48 (br s, 4 H), 2.83 (br s, 2 H), 1.82 - 1.70 (m, 2 H), 1.62 - 1.50 (m, 2 H), 1.49 - 1.34 (m, 4 H).
Example D47 iV-(tert-Butyl)-4-{4-[6-chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3, 7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin- 2-yl}piperazine- 1-carboxamide bis(trifluoroacetate)
Figure imgf000639_0001
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 19-(6-piperazin- 1 -ylpyridin-3-yl)- 14-oxa-2,4, 8 ,23 -tetraazatetracyclo[ 15.3.1.1(3,
7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene and 2-isocyanato-2-methylpropane as the starting materials in 72% yield. LCMS for C32H36ClN8O2 (M+H)+: m/z = 599.1. 1H NMR (SOO MHZ, DMSO-^6): δ 9.60 (s, 1 H), 9.31 (s, 1 H), 8.28 (d, / = 2.3 Hz, 1 H), 8.20 (s, 1 H), 8.01 (d, / = 9.7 Hz, 1 H), 7.89 (s, 1 H), 7.68 (s, 1 H), 7.25 - 7.16 (m, 4 H), 6.91 (d, / = 9.4 Hz, 1 H), 6.84 (dd, / = 8.2, 2.1 Hz, 1 H), 5.92 (br s, 1 H), 4.56 - 4.52 (m, 2 H), 3.58 - 3.54 (m, 4 H), 3.44 - 3.40 (m, 4 H), 2.83 - 2.78 (m, 2 H), 1.25 (s, 9 H).
Example D48 iV-Benzyl-4-{4-[6-chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9, 13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}piperazine- 1 -carboxamide bis(trifluor oacetate)
Figure imgf000640_0001
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 19-(6-piperazin- 1 -ylpyridin-3-yl)- 14-oxa-2,4, 8 ,23 -tetraazatetracyclo[ 15.3.1.1(3, 7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene and benzyl isocyanate as the starting materials in 51% yield. LCMS for C35H34ClN8O2 (M+H)+: m/z = 633.1. 1H NMR OOO MHZ5 DMSO- d6): δ 9.58 (s, 1 H), 9.30 (s, 1 H), 8.29 (d, / = 2.1 Hz, 1 H), 8.19 (s, 1 H), 7.98 (d, / = 8.5 Hz, 1 H), 7.89 (s, 1 H), 7.68 (s, 1 H), 7.32 - 7.16 (m, 10 H), 6.91 (d, / = 9.1 Hz, 1 H), 6.84 (dd, / = 7.9, 2.1 Hz, 1 H), 4.54 (br s, 2 H), 4.26 (d, / = 5.3 Hz, 2 H), 3.60 (d, / = 2.9 Hz, 4 H), 3.50 (d, / = 2.9 Hz, 4 H), 2.80 (br s, 2 H).
Example D49
4-{4-[6-Chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}-iV-cyclopentylpiperazine-l- carboxamide bis(trifluoroacetate)
Figure imgf000640_0002
The desired comp was prepared according to the procedure of Example D41 using 6-chloro- 19-(6-piperazin-l-ylpyridin-3-yl)-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3, 7).l(9,13)]tricosa- 1(21), 3(23),4,6,9(22), 10,12,17, 19-nonaene and isocyanatocyclopentane as the starting materials in 52% yield. LCMS for C33H36ClN8O2 (M+H)+: m/z = 611.1. 1H NMR (300 MHz, DMSO-^6): δ 9.57 (s, I H), 9.29 (s, 1 H), 8.29 (d, / = 2.1 Hz, 1 H), 8.19 (s, 1 H), 7.98 (d, / = 8.8 Hz, 1 H), 7.89 (s, 1 H), 7.68 (s, 1 H), 7.25 - 7.16 (m, 4 H), 6.93 - 6.90 (m, 1 H), 6.84 (dd, / = 8.5, 1.8 Hz, 1 H), 6.36 (d, / = 5.6 Hz, 1 H), 4.54 (br s, 2 H), 3.93 - 3.87 (m, 1 H), 3.57 - 3.55 (m, 4 H), 3.50 - 3.40 (m, 4 H), 2.80 (br s, 2 H), 1.83 - 1.70 (m, 2 H), 1.63 - 1.51 (m, 2 H), 1.48 - 1.34 (m, 4 H).
Example D50
6-Chloro-iV-phenyl-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,
7).l(9,13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxamide trifluoroacetate
Figure imgf000641_0001
A solution of methyl 6-chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,
7).l(9,13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxylate (30 mg, 70 μmol) and aniline (13 μL, 0.14 mmol) in dichloromethane (1 mL) was cooled to 0 0C and treated with 2 M trimethylaluminum in toluene (70 μL, 0.14 mmol) dropwise and stirred at 20 0C for 60 h. The reaction mixture was cooled to 0 0C, treated with additional aniline (13 μL, 0.14 mmol) and 2 M trimethylaluminum in toluene (70 μL, 0.14 mmol), and stirred at 20 0C for 60 h. The reaction mixture was diluted with methanol and a small amount of TFA and the resultant suspension was filtered. The filtrate was purified by preparative LCMS to give the desired product (6 mg, 14%) as a solid. LCMS for C25H21ClN5O2S (M+H)+: m/z = 489.9. 1H NMR (300 MHz, DMSO-<i6): δ 10.15 (s, 1 H), 9.74 (s, 1 H), 8.93 (s, 1 H), 8.21 (s, 1 H), 7.99 (d, / = 11.1 Hz, 2 H), 7.72 (d, / = 7.6 Hz, 2 H), 7.38 - 7.22 (m, 6 H), 7.07 (dd, / = 7.0, 7.0 Hz, 1 H), 6.99 (s, 1 H), 4.18 (br s, 2 H), 3.28 (br s, 2 H).
Example D51 iV-Benzyl-6-chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3, 7).l(9,13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxamide trifluoroacetate
Figure imgf000642_0001
Step A: 6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- 1 (22),3(24), 4, 6, 9(23), 10, 12,18, 20-nonaene-20-carboxylic acid
Figure imgf000642_0002
A solution of methyl 6-chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3, 7).l(9,13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxylate (450 mg, 1.1 mmol) in methanol (2.3 mL) and tetrahydrofuran (4.5 mL) was treated with 1 M sodium hydroxide (2.1 mL, 2.1 mmol) dropwise and heated at 60 0C for 16 h. The reaction mixture was cooled to 0 0C and quenched with 1 M HCl (3.2 mL). The resultant suspension was diluted with a small amount of water, filtered, and washed with cold acetonitrile to give the desired product (420 mg, 97%) as a white solid. LCMS for Ci9Hi6ClN4O3S (M+H)+: m/z = 414.9.
Step B: Η-Benzyl-6-chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1{3, 7).l(9,13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxamide trifluoroacetate
A solution of 6-chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxylic acid (30 mg, 72 μmol) and benzylamine (12 μL, 0.11 mmol) in NN-dimethylformamide (1 mL) was treated with N,N-diisopropylethylamine (50 μL, 0.29 mmol) followed by 0.5 M O-(benzotriazol- l-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate in NN-dimethylformamide (0.19 mL, 94 μmol) and stirred at 20 0C for 16 h. The reaction mixture was diluted with methanol (4.9 mL) and TFA (0.1 mL) and the resultant suspension was filtered. The filtrate was purified by preparative LCMS to give the desired product (7 mg, 16%) as a solid. LCMS for C26H23ClN5O2S (M+H)+: m/z = 503.9. 1H NMR (300 MHz, DMSO-^6): δ 9.66 (s, 1 H), 8.91 - 8.88 (m, 2 H), 8.18 (s, 1 H), 7.96 (d, / = 5.6 Hz, 2 H), 7.37 - 7.21 (m, 9 H), 6.94 (s, 1 H), 4.41 (d, / = 5.9 Hz, 2 H), 4.16 - 4.11 (m, 2 H), 3.28 - 3.23 (m, 2 H). Example D52
4-{4-[6-Chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}-iV-cyclopentylpiperazine-l- carboxamide trifluoroacetate
Figure imgf000643_0001
The desired compound was prepared according to the procedure of Example D51, step B, using morpholine as the starting material in 74% yield. LCMS for C23H23ClN5O3S (M+H)+: m/z = 483.9. 1H NMR (300 MHz, DMSO-^6): δ 9.71 (s, 1 H), 8.98 (s, 1 H), 8.21 (s, 1 H), 7.94 (s, 1 H), 7.88 (dd, / = 2.1, 1.8 Hz, 1 H), 7.37 - 7.28 (m, 2 H), 7.22 (dd, / = 7.3, 1.8 Hz, 1 H), 6.78 (s, 1 H), 6.44 (d, / = 1.2 Hz, 1 H), 4.13 - 4.08 (m, 2 H), 3.60 - 3.20 (m, 10 H).
Example D53
6-Chloro-20-[(4-phenylpiperazin-l-yl)carbonyl]-17-oxa-14-thia-2,4,8,24- tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa-l(22),3(24),4,6,9(23), 10,12,18,20-nonaene bis(trifluoroacetate)
Figure imgf000643_0002
The desired compound was prepared according to the procedure of Example D51, step B, using 1-phenylpiperazine as the starting material in 63% yield. LCMS for C29H28ClN6O2S (M+H)+: m/z = 559.0. 1H NMR (300 MHz, DMS0-<i6): δ 9.72 (s, 1 H), 8.98 (s, 1 H), 8.21 (s, 1 H), 7.95 (s, 1 H), 7.90 (s, 1 H), 7.38 - 7.28 (m, 2 H), 7.25 - 7.19 (m, 3 H), 6.96 (d, / = 7.9 Hz, 2 H), 6.83 - 6.78 (m, 2 H), 6.47 (s, 1 H), 4.14 - 4.09 (m, 2 H), 3.70 (br s, 2 H), 3.45 (br s, 2 H), 3.29 - 3.24 (m, 2 H), 3.15 (br s, 4 H).
Example D54 6-Chloro-iV-l,3-thiazol-2-yl-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,
7).l(9,13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxamide trifluoroacetate
Figure imgf000644_0001
The desired compound was prepared according to the procedure of Example D51, step B, using l,3-thiazol-2-amine as the starting material in 10% yield. LCMS for C22Hi8ClN6O2S2 (M+H)+: m/z = 496.9. 1H NMR (300 MHz, DMSO-^6): δ 9.80 (s, 1 H), 9.00 (s, 1 H), 8.21 (s, 1 H), 8.08 (s, 1 H), 7.90 (s, 1 H), 7.54 (d, / = 3.2 Hz, 1 H), 7.39 - 7.34 (m, 3 H), 7.27 - 7.21 (m, 3 H), 4.23 - 4.20 (m, 2 H), 3.33 - 3.30 (m, 2 H).
Example D55
6-Chloro-iV-(l-methyl-lH-benzimidazol-2-yl)-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3, 7).l(9,13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxamide bis(trifluoroacetate)
Figure imgf000644_0002
The desired compound was prepared according to the procedure of Example D51, step B, using 1 -methyl- lH-benzimidazol-2-amine as the starting material in 40% yield. LCMS for C27H23ClN7O2S (M+H)+: m/z = 544.0. 1H NMR (300 MHz, DMS0-<i6): δ 9.85 (s, 1 H), 9.01 (s, 1 H), 8.23 (s, 1 H), 7.98 - 7.96 (m, 2 H), 7.74 (s, 1 H), 7.55 - 7.49 (m, 2 H), 7.36 - 7.22 (m, 7 H), 4.17 - 4.13 (m, 2 H), 3.75 (s, 3 H), 3.30 - 3.26 (m, 2 H).
Example D56 6-Chloro-iV-lH-indol-5-yl-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,
7).l(9,13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxamide trifluoroacetate
Figure imgf000645_0001
The desired compound was prepared according to the procedure of Example D51, step B, using 5-aminoindole as the starting material in 28% yield. LCMS for C27H22ClN6O2S (M+H)+: m/z = 529.0. 1H NMR (300 MHz, DMS0-<i6): δ 11.02 (s, 1 H), 9.97 (s, 1 H), 9.74 (s, 1 H), 8.96 (s, 1 H), 8.21 (s, 1 H), 7.99 - 7.94 (m, 3 H), 7.39 - 7.22 (m, 7 H), 7.02 (s, 1 H), 6.38 (dd, / = 2.3, 2.3 Hz, 1 H), 4.21 - 4.16 (m, 2 H), 3.31 - 3.26 (m, 2 H).
Example D57 iV-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9, 13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]benzamide trifluoroacetate
Figure imgf000645_0002
Step A: 6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[ 16.3.1.1(3,7).1(9,13)]tetracosa- 1 (22), 3 (24), 4, 6, 9(23), 10,12,18, 20-nonaen-20-amine
Figure imgf000645_0003
A solution of ό-chloro-^-oxa-H-thia^/Kδ^-tetraazatetracycloflό.S.1.1(3,7).1(9, 13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxylic acid (0.40 g, 0.95 mmol) in tetrahydrofuran (10 niL) at 0 0C was treated with triethylamine (0.53 mL, 3.8 mmol) and diphenylphosphonic acid (0.45 mL, 2.1 mmol) and stirred at 20 0C for 2 h. The reaction mixture was poured into water (50 mL) and ethyl acetate (150 mL). The ethyl acetate layer was separated, diluted with water (50 mL) and heated at 100 0C for 8 h. The reaction mixture was filtered and the organic layer from the filtrate was separated and washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude yellow. This material was treated with ethyl acetate and filtered. The filtrate was concentrated to give the desired product (0.29 g, 78%) as a tan solid. LCMS for Ci8H17ClN5OS (M+H)+: τalτ = 385.9.
Step B: Η-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[163.1.1{3,7).l{9, 13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]benzamide trifluoroacetate
A solution of ό-chloro-lT-oxa-H-thia^^^^-tetraazatetracycloflό.S.1.1(3,7).1(9, 13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-amine (25 mg, 65 μmol) in tetrahydrofuran (0.5 mL) was treated with 0.2 M benzoyl chloride in dichloromethane (0.24 mL, 49 μmol) and stirred at 20 0C for 1 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (5 mg, 10%) as a solid. LCMS for C25H2IClN5O2S (M+H)+: m/z = 490.0. 1H NMR (300 MHz, DMSO-^6): δ 10.16 (s, 1 H), 9.64 (s, 1 H), 8.92 (s, 1 H), 8.20 (s, 1 H), 8.00 (s, 1 H), 7.90 (d, / = 6.7 Hz, 2 H), 7.60 - 7.47 (m, 4 H), 7.36 - 7.22 (m, 4 H), 6.90 (s, 1 H), 4.11 - 4.06 (m, 2 H), 3.26 - 3.22 (m, 2 H).
Example D58 iV-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9, 13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]-5-methylisoxazole- 3-carboxamide trifluoroacetate
Figure imgf000646_0001
The desired compound was prepared according to the procedure of Example D57, step B, using
5-methylisoxazole-3-carbonyl chloride as the starting material in 10% yield. LCMS for C23H20ClNeO3S (M+H)+: m/z = 495.0. 1H NMR (300 MHz, DMS0-<i6): δ 10.50 (s, 1 H), 9.63 (s, 1 H), 8.87 (s, 1 H), 8.19 (s, 1 H), 7.99 (s, 1 H), 7.62 (s, 1 H), 7.36 - 7.20 (m, 4 H), 6.87 (s, 1 H), 6.63 (s, 1 H), 4.09 - 4.05 (m, 2 H), 3.25 - 3.21 (m, 2 H).
Example D59 iV-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9, 13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]isoxazole- 5-carboxamide trifluoroacetate
Figure imgf000647_0001
The desired compound was prepared according to the procedure of Example D57, step B, using isoxazole-5-carbonyl chloride as the starting material in 31% yield. LCMS for C22Hi8ClN6O3S (M+H)+: m/z = 480.9. 1H NMR (300 MHz, DMSO-^6): δ 10.64 (s, 1 H), 9.71 (s, 1 H), 8.94 (s, 1 H), 8.79 (d, / = 1.5 Hz, 1 H), 8.20 (s, 1 H), 7.99 (s, 1 H), 7.64 (s, 1 H), 7.37 - 7.18 (m, 5 H), 6.88 (s, 1 H), 4.11 - 4.06 (m, 2 H), 3.26 - 3.22 (m, 2 H).
Example D60 iV-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,
13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]isonicotinamide bis(trifluoroacetate)
Figure imgf000647_0002
The desired compound was prepared according to the procedure of Example D57, step B, using isonicotinoyl chloride as the starting material in 26% yield. LCMS for C24H20ClN6O2S (M+H)+: m/z = 491.0. 1H NMR (300 MHz, DMS0-<i6): δ 10.46 (s, 1 H), 9.71 (s, 1 H), 8.94 (s, 1 H), 8.80 - 8.78 (m, 2 H), 8.20 (s, 1 H), 8.00 (s, 1 H), 7.89 - 7.86 (m, 2 H), 7.64 (s, 1 H), 7.37 - 7.19 (m, 4 H), 6.91 (s, 1 H), 4.11 - 4.07 (m, 2 H), 3.27 - 3.22 (m, 2 H). Example D61 iV-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9, 13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]-l-benzofuran- 5-carboxamide trifluoroacetate
Figure imgf000648_0001
The desired compound was prepared according to the procedure of Example D57, step B, using l-benzofuran-5-carbonyl chloride as the starting material in 36% yield. LCMS for C27H21CIN5O3S (M+H)+: m/z = 529.9. 1H NMR (300 MHz, DMS0-<i6): δ 10.21 (s, 1 H), 9.72 (s, 1 H), 9.02 (s, 1 H), 8.26 (d, / = 1.2 Hz, 1 H), 8.22 (s, 1 H), 8.10 (d, / = 2.3 Hz, 1 H), 8.00 (s, 1 H), 7.88 (dd, / = 8.8, 1.5 Hz, 1 H), 7.71 (d, / = 8.5 Hz, 1 H), 7.58 (s, 1 H), 7.37 - 7.22 (m, 4 H), 7.09 (d, / = 1.5 Hz, 1 H), 6.92 (s, 1 H), 4.11 - 4.07 (m, 2 H), 3.27 - 3.23 (m, 2 H).
Example D62 iV-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9, 13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]-2-furamide trifluoroacetate
Figure imgf000648_0002
The desired compound was prepared according to the procedure of Example D57, step B, using 2-furancarbonyl chloride as the starting material in 36% yield. LCMS for C23H19CIN5O3S (M+H)+: m/z = 479.9. 1H NMR (300 MHz, DMSOd6): δ 10.06 (s, 1 H), 9.67 (s, 1 H), 8.97 (s, 1 H), 8.20 (s, 1 H), 7.99 (s, 1 H), 7.91 (d, / = 0.9 Hz, 1 H), 7.58 (s, 1 H), 7.36 - 7.18 (m, 5 H), 6.86 (dd, / = 2.1, 1.8 Hz, 1 H), 6.67 (dd, / = 3.5, 1.8 Hz, 1 H), 4.10 - 4.05 (m, 2 H), 3.26 - 3.21 (m, 2 H). Example D63 iV-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9, 13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]thiophene- 2-carboxamide trifluoroacetate
Figure imgf000649_0001
The desired compound was prepared according to the procedure of Example D57, step B, using 2-thiophenecarbonyl chloride as the starting material in 28% yield. LCMS for C23Hi9ClN5O2S2 (M+H)+: m/z = 495.9. 1H NMR (300 MHz, DMS0-<i6): δ 10.14 (s, 1 H), 9.67 (s, 1 H), 8.95 (s, 1 H), 8.20 (s, 1 H), 7.99 (d, / = 3.2 Hz, 2 H), 7.83 (d, / = 5.0 Hz, 1 H), 7.60 (s, 1 H), 7.37 - 7.13 (m, 5 H), 6.86 (s, 1 H), 4.11 - 4.06 (m, 2 H), 3.27 - 3.22 (m, 2 H).
Example D64 iV-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9, 13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]thiophene- 2-carboxamide trifluoroacetate
Figure imgf000649_0002
The desired compound was prepared according to the procedure of Example D57, step B, using benzeneacetyl chloride as the starting material in 30% yield. LCMS for C26H23ClN5O2S (M+H)+: m/z = 504.0. 1H NMR (300 MHz, DMSO-^6): δ 10.06 (s, 1 H), 9.62 (s, 1 H), 8.92 (s, 1 H), 8.18 (s, 1 H), 7.97 (s, 1 H), 7.52 (s, 1 H), 7.35 - 7.20 (m, 8 H), 6.92 (s, 1 H), 6.84 (s, 1 H), 4.06 - 4.01 (m, 2 H), 3.59 (s, 2 H), 3.23 - 3.18 (m, 2 H).
Example D65 iV-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,
13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]-iV'-phenylurea trifluoroacetate
Figure imgf000650_0001
A solution of 6-chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).1(9, 13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-amine (25 mg, 0.65 mmol) in tetrahydrofuran (0.5 niL) was treated with phenyl isocyanate (9.2 μL, 84 μmol) followed by triethylamine (0.53 mL, 3.8 mmol) and stirred at 20 0C for 2 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (7 mg, 20%) as a solid. LCMS for C25H22ClN6O2S (M+H)+: m/z = 505.0. 1H NMR (300 MHz, DMSO-Cf6): δ 9.60 (s, 1 H), 8.90 (s, 1 H), 8.62 (d, / = 18.7 Hz, 2 H), 8.19 (s, 1 H), 7.99 (s, 1 H), 7.47 - 7.22 (m, 8 H), 6.94 (dd, / = 7.3, 7.0 Hz, 1 H), 6.84 (s, 1 H), 6.67 (s, 1 H), 4.08 - 4.03 (m, 2 H), 3.25 - 3.20 (m, 2 H).
Example D66 iV-Benzyl-iV'-[6-chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3, 7).l(9,13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]urea trifluoroacetate
Figure imgf000650_0002
The desired compound was prepared according to the procedure of Example D65 using benzyl isocyanate as the starting material in 29% yield. LCMS for C26H24ClN6O2S (M+H)+: m/z = 519.0. 1H
NMR (300 MHz, DMS0-<i6): δ 9.48 (s, 1 H), 8.80 (s, 1 H), 8.42 (s, 1 H), 8.16 (s, 1 H), 7.98 (s, 1 H), 7.41 (s, 1 H), 7.34 - 7.19 (m, 8 H), 6.81 (s, 1 H), 6.59 - 6.54 (m, 2 H), 4.25 (d, / = 5.9 Hz, 2 H), 4.05 - 4.00 (m, 2 H), 3.22 - 3.18 (m, 2 H).
Example D67 iV-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,
13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]-iV'-(2-furylmethyl)urea trifluoroacetate
Figure imgf000651_0001
The desired compound was prepared according to the procedure of Example D65 using 2-
(isocyanatomethyl)furan as the starting material in 20% yield. LCMS for C24H22ClN6O3S (M+H)+: m/z = 509.0. 1H NMR (300 MHz, DMSO-^6): δ 9.49 (s, 1 H), 8.82 (s, 1 H), 8.39 (s, 1 H), 8.17 (s, 1 H), 7.98 (s, 1 H), 7.56 (d, / = 0.9 Hz, 1 H), 7.41 (s, 1 H), 7.34 - 7.29 (m, 2 H), 7.25 - 7.20 (m, 2 H), 6.79 (s, 1 H), 7.58 (s, 1 H), 6.49 (dd, / = 5.6, 5.6 Hz, 1 H), 6.37 (dd, / = 3.2, 2.1 Hz, 1 H), 6.22 (d, / = 2.9 Hz, 1 H), 4.23 (d, / = 5.6 Hz, 2 H), 4.05 - 4.01 (m, 2 H), 3.22 - 3.18 (m, 2 H).
Example D68 iV-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9, 13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]benzenesulfonamide trifluoroacetate
Figure imgf000651_0002
A solution of ό-chloro-^-oxa-H-thia^/Kδ^-tetraazatetracycloflό.S.1.1(3,7).1(9, 13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-amine (25 mg, 0.65 mmol) in tetrahydrofuran (0.5 mL) was treated with benzenesulfonyl chloride (8.3 μL, 65 μmol) followed by triethylamine (18 μL, 0.13 mmol) and stirred at 20 0C for 16 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (9 mg, 20%) as a solid. LCMS for C24H21ClN5O3S2 (M+H)+: m/z = 525.9. 1H NMR (300 MHz, DMS0-<i6): δ 10.23 (s, 1 H), 9.66 (s, 1 H), 8.91 (s, 1 H), 8.18 (s, 1 H), 7.91 (s, 1 H), 7.80 (d, / = 7.0 Hz, 2 H), 7.59 - 7.46 (m, 4 H), 7.33 - 7.18 (m, 3 H), 6.63 (s, 1 H), 6.14 (s, 1 H), 3.97 - 3.93 (m, 2 H), 3.18 - 3.13 (m, 2 H). Example D69 iV-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9, 13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]-l,2-dimethyl- lH-imidazole-4-sulfonamide bis(trifluoroacetate)
Figure imgf000652_0001
The desired compound was prepared according to the procedure of Example D68 using 1,2- dimethyl-lH-imidazole-4-sulfonyl chloride as the starting material in 20% yield (the reaction was heated at 60 0C for 16 h). LCMS for C23H23ClN7O3S2 (M+H)+: m/z = 543.9. 1H NMR (300 MHz, DMS0-<i6): δ 10.12 (s, 1 H), 9.57 (s, 1 H), 8.89 (s, 1 H), 8.18 (s, 1 H), 7.94 (s, 1 H), 7.78 (s, 1 H), 7.42 (s, 1 H), 7.34 - 7.19 (m, 3 H), 6.56 (s, 1 H), 6.25 (s, 1 H), 3.98 - 3.96 (m, 2 H), 3.53 (s, 3 H), 3.20 - 3.15 (m, 2 H), 2.33 (s, 3 H).
Example D70 6-Chloro-14-oxa-2,4,8,17,24-pentaazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene bis(trifluoroacetate)
Figure imgf000652_0002
Step A: tert-Butyl (3-{[2-(3-nitrophenoxy)ethyl]amino}phenyl)carbamate
Figure imgf000652_0003
A solution of tert-butyl (3-aminophenyl)carbamate (1.0 g, 4.8 mmol) and potassium carbonate
(1.3 g, 9.6 mmol) in NN-dimethylformamide (10 mL) was treated with a solution of l-(2-bromoethoxy)- 3 -nitrobenzene (1.2 g, 5.0 mmol) in NN-dimethylformamide (5 mL) was stirred at 20 0C for 2 h and at 80 0C for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude residue. This material was purified by flash column chromatography to give the desired product (1.0 g, 56%) as a yellow gum. LCMS for Ci9H24N3O5 (M+H)+: m/z = 374.2.
Step B: tert-Butyl (3-{[2-(3-aminophenoxy)ethyl]aminojphenyl)carbamate
Figure imgf000653_0001
The desired compound was prepared according to the procedure of Example D2, step B, using tert-butyl (3-{ [2-(3-nitrophenoxy)ethyl]amino}phenyl)carbamate as the starting material in 92% yield. LCMS for Ci9H26N3O3 (M+H)+: m/z = 344.1.
Step C: tert-Butyl {3-[(2-{3-[(2, 5-dichloropyrimidin-4-yl)amino]phenoxyjethyl)amino]phenyljcarbamate
Figure imgf000653_0002
The desired compound was prepared according to the procedure of Example D2, step C, using tert-butyl (3-{ [2-(3-aminophenoxy)ethyl]amino}phenyl)carbamate as the starting material in 70% yield. LCMS for C23H26Cl2N5O3 (M+H)+: m/z = 490.0, 492.0.
Step D: 6-Chloro-14-oxa-2,4,8,17,24-pentaazatetracyclo[ 16.3.1.1(3,7).1(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene bis(trifluoroacetate)
The desired compound was prepared according to the procedure of Example D2, step D, using tert-butyl { 3 -[(2- { 3- [(2,5 -dichloropyrimidin-4-yl)amino]phenoxy } ethyl)amino]phenyl } carbamate as the starting material in 12% yield. LCMS for Ci8Hi7ClN5O (M+H)+: m/z = 354.0. 1H NMR (400 MHz, DMS0-<i6): δ 9.34 (s, 1 H), 8.39 (s, 1 H), 8.18 (s, 1 H), 8.13 (dd, / = 2.0, 2.0 Hz, 1 H), 7.54 (s, 1 H), 7.20 (dd, / = 8.2, 8.0 Hz, 1 H), 7.02 (d, / = 8.8 Hz, 1 H), 6.88 (dd, / = 8.0, 7.8 Hz, 1 H), 6.60 - 6.57 (m, 1 H), 6.40 (d, / = 8.6 Hz, 1 H), 6.17 (dd, / = 8.0, 1.2 Hz, 1 H), 5.81 (dd, / = 6.8, 6.6 Hz, 1 H), 4.14 - 4.10 (m, 2 H), 3.30 - 3.24 (m, 2 H).
Example D71 15-Acetyl-6-chloro-2,4,8,15,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
Figure imgf000654_0001
A solution of 6-chloro-2,4,8,15,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) (10 mg, 18 μmol) in acetonitrile (0.28 mL) was treated with pyridine (7.3 μL, 91 μmol) followed by acetic anhydride (2.1 μL, 22 μmol) and stirred for 16 h. The reaction mixture was quenched with a few drops of acetic acid and purified by preparative LCMS to give the desired product (5 mg, 58%) as a solid. LCMS for Ci9Hi7ClN5O (M+H)+: m/z = 366.0. 1H NMR (400 MHz, DMSO-^6): δ 9.61 (s, 1 H), 9.24 (s, 1 H), 8.16 (s, 1 H), 8.06 (dd, / = 2.0, 1.8 Hz, 1 H), 7.93 (s, 1 H), 7.32 - 7.21 (m, 4 H), 7.13 (dd, / = 8.2, 1.4 Hz, 1 H), 6.97 (dd, / = 7.8, 1.2 Hz, 1 H), 4.61 (br s, 2 H), 1.73 (s, 3 H).
Example D72
6-Chloro-17-oxa-2,4,8,14,24-pentaazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene bis(trifluoroacetate)
Figure imgf000654_0002
Step A: N-[2-(3-Nitrophenoxy)ethyl]benzene-l,3-diamine
Figure imgf000655_0001
The desired compound was prepared according to the procedure of D34, step A, using tert-butyl (3-{ [2-(3-nitrophenoxy)ethyl]amino}phenyl)carbamate as the starting material in 82% yield. LCMS for Ci4H16N3O3 (M+H)+: m/z = 274.0.
Step B: N-(2,5-Dichloropyrimidin-4-yl)-N'-[2-(3-nitrophenoxy)ethyl]benzene-l,3- diamine bis(trifluoroacetate)
Figure imgf000655_0002
The desired compound was prepared according to the procedure of Example D2, step C, using N- [2-(3-nitrophenoxy)ethyl]benzene-l,3-diamine as the starting material in 54% yield. LCMS for Ci8Hi6Cl2N5O3 (M+H)+: m/z = 419.9, 421.9.
Step C: N-[2-(3-Aminophenoxy)ethyl]-N'-(2,5-dichloropyrimidin-4-yl)benzene-l,3-diamine
Figure imgf000655_0003
A solution of N-(2,5-dichloropyrimidin-4-yl)-N'-[2-(3-nitrophenoxy)ethyl]benzene-l,3- diamine bis(trifluoroacetate) (100 mg, 0.15 mmol) in methanol (0.63 mL) was treated with acetic acid (0.25 mL, 4.4 mmol), water (0.13 mL, 7.0 mmol), and iron (43 mg, 0.77 mmol) and stirred at 20 0C for 16 h. The reaction mixture was diluted with methanol and treated with celite. The suspension was filtered over a pad of celite and washed with methanol. The filtrate was concentrated to give the desired product (63 mg, 94%) as a crude residue that was used without further purification. Step D: 6-Chloro-17-oxa-2,4,8,14,24-pentaazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene bis(trifluoroacetate)
The desired compound was prepared according to the procedure of Example D2, step C, using N- [2-(3-aminophenoxy)ethyl]-N'-(2,5-dichloropyrimidin-4-yl)benzene-l,3-diamine as the starting material in 21% yield (2 steps). LCMS for Ci8Hi7ClN5O (M+H)+: m/z = 354.0. 1H NMR (300 MHz, DMS0-<i6): δ 9.61 (s, 1 H), 8.33 (s, 1 H), 8.19 (s, 1 H), 7.98 (s, 1 H), 7.68 (s, 1 H), 7.14 - 7.00 (m, 2 H), 6.78 (d, / = 8.5 Hz, 1 H), 6.63 (d, / = 8.5 Hz, 1 H), 6.47 - 6.41 (m, 2 H), 4.10 - 4.04 (m, 2 H), 3.39 - 3.33 (m, 2 H).
Example D73 6-Chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21), 3(23),4,6,9(22),10,12,17,19-nonaene bis(trifluoroacetate)
Figure imgf000656_0001
Step A: tert-Butyl (3-{[(3-nitrobenzoyl)amino]methyljphenyl)carbamate
Figure imgf000656_0002
A solution of tert-butyl [3-(aminomethyl)phenyl]carbamate (2.0 g, 9 mmol) and triethylamine (1.3 mL, 9.5 mmol) in tetrahydrofuran (26 mL) at 0 0C was treated with a solution of 3-nitrobenzoyl chloride (1.8 g, 9.5 mmol) in tetrahydrofuran (7.3 mL) and stirred at 20 0C for 1 h. The reaction mixture was treated with saturated sodium bicarbonate and the aqueous layer was separated and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product (3.5 g, 105%) as a crude off-white solid that was used without further purification. LCMS for Ci5Hi4N3O5 ([M-(^-Bu)-I-H]-I-H)+: m/z = 316.0.
Step B: N-(3-Aminobenzyl)-3-nitrobenzamide hydrochloride
Figure imgf000656_0003
The desired compound was prepared according to the procedure of Example A27, step A, using tert-butyl (3-{ [(3-nitrobenzoyl)amino]methyl}phenyl)carbamate as the starting material in 99% yield (2 steps: Steps A and B). LCMS for Ci4Hi4N3O3 (M+H)+: m/z = 272.0.
Step C: N-{3-[(2,5-Dichloropyrimidin-4-yl)amino]benzylj-3-nitrobenzamide
Figure imgf000657_0001
The desired compound was prepared according to the procedure of Example D2, step C, using N- (3-aminobenzyl)-3-nitrobenzamide hydrochloride as the starting material in 77% yield. LCMS for Ci8Hi4Cl2N5O3 (M+H)+: m/z = 418.0, 420.0.
Step D: 3-Amino-N-{3-[(2,5-dichloropyrimidin-4-yl)amino]benzyljbenzamide
Figure imgf000657_0002
The desired compound was prepared according to the procedure of Example D 16, step D, using N-{3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}-3-nitrobenzamide as the starting material and used in the next step without further purification. LCMS for Ci8Hi6Cl2N5O (M+H)+: m/z = 388.0.
Step E: 6-Chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-16-one
Figure imgf000657_0003
The desired compound was prepared according to the procedure of Example D2, step D, using 6- chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19- nonaen-16-one as the starting material and used in the next step without further purification.
Step F: 6-Chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21), 3(23 ),4, 6,9(22), 10,12,17,19-nonaene bis(trifluoroacetate)
A solution of 6-chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-16-one (25 mg, 71 μmol) in tetrahydrofuran (4 mL) was treated with 1 M borane in tetrahydrofuran (0.26 mL, 0.26 mmol) and refluxed for 3 h. The reaction mixture was concentrated and the crude residue purified by preparative LCMS to give the desired product (3 mg, 2% for 3 steps). LCMS for Ci8H17ClN5 (M+H)+: m/z = 337.9
Example D74
15-Acetyl-6-chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate
Figure imgf000658_0001
Step A: tert-Butyl (3-{[(3-nitrobenzyl)amino]methyl}phenyl)carbamate trifluoroacetate
Figure imgf000658_0002
A solution of tert-butyl [3-(aminomethyl)phenyl]carbamate (0.15 g, 0.65 mmol) and NN- diisopropylethylamine (0.23 mL, 1.3 mmol) in acetonitrile (2 mL) at 60 0C was treated with a solution of l-(bromomethyl) -3 -nitrobenzene (0.15 g, 0.69 mmol) in acetonitrile (1 mL) and stirred at 60 0C for 1 h. The reaction mixture was cooled and purified by preparative LCMS to give the desired product (0.27 g, 87%). LCMS fOr Ci9H24N3O4 (M-FH)+: m/z = 358.1.
Step B: tert-Butyl (3-{[acetyl(3-nitrobenzyl)amino]methyl}phenyl)carbamate
Figure imgf000658_0003
A solution of tert-butyl (3-{ [(3-nitrobenzyl)amino]methyl}phenyl)carbamate trifluoroacetate (0.16 g, 0.34 mmol) in acetonitrile (5.2 mL) was treated with 4-dimethylaminopyridine (8.3 mg, 68 μmol), pyridine (0.14 mL, 1.7 mmol), and acetic anhydride (35 μL, 0.37 mmol) and stirred at 20 0C for 16 h. The reaction mixture was purified by preparative LCMS to give the desired product (95 mg, 70%). LCMS for C2IH25N3O5Na (M+Na)+: m/z = 422.0.
Step C: tert-Butyl (3-{[acetyl(3-aminobenzyl)amino]methyl}phenyl)carbamate trifluoroacetate
Figure imgf000659_0001
The desired compound was prepared according to the procedure of Example D2, step B, usin^ tert-butyl (3-{ [acetyl(3-nitrobenzyl)amino]methyl}phenyl)carbamate as the starting material in 70% yield. LCMS for C2iH27N3O3Na (M+Na)+: m/z = 392.0.
Step D: tert-Butyl {3-[(acetyl{3-[(2,5-dichloropyrimidin-4- yl)amino]benzyljamino)methyl]phenylj 'carbamate trifluoroacetate
Figure imgf000659_0002
The desired compound was prepared according to the procedure of Example D2, step C, using tert-butyl (3-{ [acetyl(3-aminobenzyl)amino]methyl}phenyl)carbamate trifluoroacetate as the starting material in 43% yield. LCMS for C2IH20Cl2N5O3 ([M-(^-Bu)-I-H]-I-H)+: m/z = 459.9, 461.1.
Step E: 15-Acetyl-6-chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate
A solution of tert-butyl {3-[(acetyl{3-[(2,5-dichloropyrimidin-4- yl)amino]benzyl}amino)methyl]phenyl}carbamate trifluoroacetate (10 mg, 16 μmol) in acetonitrile (1.5 mL) was treated with trifluoroacetic acid (75 μL, 0.97 mmol) and heated at 70 0C for 16 h. The reaction mixture was cooled and purified by preparative LCMS to give the desired product (2.5 mg, 32%) as a solid. LCMS fOr C20H19ClN5O (M-I-H)+: m/z = 380.0. 1H NMR (SOO MHZ5 CD3OD): δ 8.14 (d, / = 1.8 Hz, 1 H), 7.78 (s, 1 H), 7.63 - 7.61 (m, 1 H), 7.40 - 7.21 (m, 2 H), 7.19 - 7.05 (m, 3 H), 6.98 - 6.96 (m, 1 H), 4.71 - 4.62 (m, 4 H). Example D75
6-Chloro-2,4,8,14,24-pentaazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene bis(trifluoroacetate)
Figure imgf000660_0001
Step A: tert-Butyl (3-{[3-(3-nitrophenyl)propanoyl]aminojphenyl)carbamate
Figure imgf000660_0002
A solution of 3-(3-nitrophenyl)propanoic acid (0.43 g, 2.2 mmol) and tert-butyl (3- aminophenyl)carbamate (0.50 g, 2.4 mmol) in acetonitrile (16 mL) was treated with O-(benzotriazol-l- yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.2 g, 3.3 mmol) followed by NN- diisopropylethylamine (0.57 mL, 3.3 mmol) and stirred for 16 h. The reaction mixture was concentrated and diluted with brine (80 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude residue. This material was purified by flash column chromatography to give the desired product (0.87 g, 98%) as an off-white foam. LCMS for Ci6H16N3O5 ([M-O Bu)+H]+H)+: m/z = 330.0.
Step B: N-[3-(3-Nitrophenyl)propyl]benzene-l,3-diamine trifluoroacetate
Figure imgf000660_0003
A solution of tert-butyl (3-{ [3-(3-nitrophenyl)propanoyl] amino }phenyl)carbamate (0.10 g, 0.26 mmol) in tetrahydrofuran (2 mL) was treated slowly with a solution of 1 M borane in tetrahydrofuran (0.54 mL, 0.54 mmol) and refluxed for 2 h. The reaction mixture was cooled and treated with 6 M HCl (2 mL) and stirred at 20 0C for 1 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (41 mg, 41%) as a solid. LCMS for Ci5Hi8N3O2 (M+H)+: m/z =
272.0.
Step C: N-(2, 5-Dichloropyrimidin-4-yl)-N'-[3-(3-nitrophenyl)propyl]benzene-l,3- diamine trifluoroacetate
Figure imgf000661_0001
The desired compound was prepared according to the procedure of Example D2, step C, using N- [3-(3-nitrophenyl)propyl]benzene-l,3-diamine trifluoroacetate as the starting material in 55% yield. LCMS for Ci9Hi8Cl2N5O2 (M+H)+: m/z = 418.0, 419.9.
Step D: N-[3-(3-Aminophenyl)propyl]-N'-(2,5-dichloropyrimidin-4-yl)benzene-l,3-diamine
Figure imgf000661_0002
The desired compound was prepared according to the procedure of Example D72, step C, using
N-(2,5-dichloropyrimidin-4-yl)-N'-[3-(3-nitrophenyl)propyl]benzene-l,3- diamine trifluoroacetate as the starting material and used in the next step without further purification.
Step E: 6-Chloro-2,4,8,14,24-pentaazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene bis(trifluoroacetate)
The desired compound was prepared according to the procedure of Example D2, step D, using N- [3-(3-aminophenyl)propyl]-N'-(2,5-dichloropyrimidin-4-yl)benzene-l,3-diamine as the starting material in 12% yield (2 steps). LCMS for Ci9Hi9ClN5 (M+H)+: m/z = 352.0.
Example D76
6-Chloro-2,4,8,17,24-pentaazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaen-16-one trifluoroacetate
Figure imgf000662_0001
Step A: tert-Butyl (3-{[3-(3-aminophenyl)propanoyl]aminoJphenyl)carbamate
Figure imgf000662_0002
The desired compound was prepared according to the procedure of Example D2, step B, using tert-butyl (3-{ [3-(3-nitrophenyl)propanoyl]amino}phenyl)carbamate as the starting material in 97% yield. LCMS for C20H26N3O3 (M+H)+: m/z = 356.0.
Step B: tert-Butyl {3-[(3-{3-[(2,5-dichloropyrimidin-4- yl)amino]phenyl}propanoyl)amino]phenyl}carbamate
BocHN
Figure imgf000662_0003
The desired compound was prepared according to the procedure of Example D2, step C, using tert-butyl (3-{ [3-(3-aminophenyl)propanoyl]amino}phenyl)carbamate as the starting material in 85% yield. LCMS for C20Hi8Cl2N5O3 ([M-(>Bu)+H]+H)+: m/z = 445.9, 448.0.
Step C: 6-Chloro-2,4,8,17,24-pentaazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaen-16-one trifluoroacetate
The desired compound was prepared according to the procedure of Example D32, step F, using tert-butyl {3-[(3-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}propanoyl)amino]phenyl}carbamate as the starting material in 11% yield. LCMS for Ci9Hi7ClN5O (M+H)+: m/z = 366.0.
Example D77 6-Chloro-2,4,8,17,24-pentaazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene bis(trifluoroacetate)
Figure imgf000663_0001
Step A: tert-Butyl {3-[(3-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenylj propyl)amino]phenyljcarbamate
Figure imgf000663_0002
The desired compound was prepared according to the procedure of Example D73, step F, using tert-butyl {3-[(3-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}propanoyl)amino]phenyl}carbamate as the starting material and used in the next step without further purification.
Step B: 6-Chloro-2,4,8,17,24-pentaazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene bis(trifluoroacetate)
The desired compound was prepared according to the procedure of Example D2, step D, using tert-butyl {3-[(3-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl} propyl)amino]phenyl} carbamate as the starting material in 6% yield (2 steps). LCMS for Ci9H19ClN5 (M+H)+: m/z = 352.0. 1H NMR (400 MHz, DMS0-<i6): δ 9.52 (s, 1 H), 8.94 (s, 1 H), 8.20 (s, 1 H), 7.82 (s, 1 H), 7.46 (s, 1 H), 7.27 (dd, / = 7.8, 7.6 Hz, 1 H), 7.17 (d, / = 8.8 Hz, 1 H), 7.02 - 6.96 (m, 2 H), 6.57 (br s, 1 H), 6.40 (br s, 1 H), 2.88 - 2.84 (m, 2 H), 2.73 - 2.69 (m, 2 H), 1.97 - 1.86 (m, 2 H).
Example D78
6-Chloro-2,4,8,16,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21), 3(23),4,6,9(22),10,12,17,19-nonaene bis(trifluoroacetate)
Figure imgf000664_0001
A solution of tert-butyl {3-[({3-[(2,5-dichloropyrimidin-4- yl)amino]phenyl}acetyl)amino]phenyl}carbamate (85 mg, 0.17 mmol) in tetrahydrofuran (1.3 mL) was treated with 1 M borane in tetrahydrofuran (0.37 mL, 0.37 mmol) slowly and refluxed for 1 h. The reaction mixture was concentrated and purified by preparative LCMS to give the uncyclized intermediate. This material, upon concentration of the acidic preparative LCMS fractions, spontaneously cyclized to the desired product (20 mg, 20%) which was purified by preparative LCMS. LCMS for Ci8Hi7ClN5 (M+H)+: m/z = 338.0.
Example D79
6-Chloro-2,4,8,16,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21), 3(23),4,6,9(22),10,12,17,19-nonaene bis(trifluoroacetate)
Figure imgf000664_0002
Step A: tert-Butyl (3-{[(3-nitrophenyl)acetyl]amino}phenyl)carbamate
Figure imgf000664_0003
The desired compound was prepared according to the procedure of Example D75, step A, usin^
(3-nitrophenyl)acetic acid as the starting material in quantitative yield. LCMS for C15H14N3O5 ([M-(t- Bu)+H]+H)+: m/z = 316.0.
Step B: N-(3-Aminophenyl)-2-(3-nitrophenyl)acetamide trifluoroacetate
Figure imgf000665_0001
The desired compound was prepared according to the procedure of Example D34, step A, using tert-butyl (3-{ [(3-nitrophenyl)acetyl]arnino}phenyl)carbamate as the starting material and used in the next step without further purification.
Step C: N-{3-[(2, 5-Dichloropyrimidin-4-yl)amino]phenylj-2-(3-nitrophenyl)acetamide
Figure imgf000665_0002
The desired compound was prepared according to the procedure of Example D2, step C, using N- (3-aminophenyl)-2-(3-nitrophenyl)acetamide trifluoroacetate as the starting material in 72% yield (2 steps). LCMS for Ci8Hi4Cl2N5O3 (M+H)+: m/z = 417.9, 419.9.
Step D: N-(2,5-Dichloropyrimidin-4-yl)-N'-[2-(3-nitrophenyl)ethyl]benzene-l,3-diamine
Figure imgf000665_0003
The desired compound was prepared according to the procedure of Example D73, step F, using N-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}-2-(3-nitrophenyl)acetamide as the starting material in 23% yield. LCMS for Ci8Hi6Cl2N5O2 (M+H)+: m/z = 403.9, 405.9
Step E: N-[2-(3-Aminophenyl)ethyl]-N'-(2,5-dichloropyrimidin-4-yl)benzene-l,3-diamine
Figure imgf000665_0004
The desired compound was prepared according to the procedure of Example D72, step C, using N-(2,5-dichloropyrimidin-4-yl)-N'-[2-(3-nitrophenyl)ethyl]benzene-l,3-diamine as the starting material and used in the next step without further purification.
Step F: 6-Chloro-2,4,8,16,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21), 3(23 ),4, 6,9(22), 10,12,17,19-nonaene bis(trifluoroacetate)
The desired compound was prepared according to the procedure of Example D2, step D, using N- [2-(3-aminophenyl)ethyl]-N'-(2,5-dichloropyrimidin-4-yl)benzene- 1,3 -diamine as the starting material in 10% yield (2 steps). LCMS for Ci8Hi7ClN5 (M+H)+: m/z = 338.0. 1H NMR (SOO MHZ5 CD3OD): 6 8.18 (s, 1 H), 8.13 (s, 1 H), 7.94 (s, 1 H), 7.55 (dd, / = 8.2, 8.2 Hz, 1 H), 7.40 - 7.29 (m, 2 H), 7.23 - 7.16 (m, 2 H), 7.05 - 7.03 (m, 1 H), 3.89 - 3.85 (m, 2 H), 2.81 - 2.77 (m, 2 H).
Example D80
6-Chloro-14-thia-2,4,8,17,24-pentaazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene bis(trifluoroacetate)
Figure imgf000666_0001
Step A: 2-({3-[(2,5-Dichloropyrimidin-4-yl)amino]phenyl}thio)ethanol
Figure imgf000666_0002
A solution of sodium methoxide (2.4 g, 44 mmol) in NN-dimethylformamide (80 mL) was treated with 3-aminobenzenethiol (4.6 g, 37 mmol) and stirred at 20 0C for 15 min. The reaction mixture was cooled to 0 0C, treated with a solution of 2-bromoethanol (3.4 mL, 48 mmol) in NN- dimethylformamide (10 mL), and stirred at 0 0C for 15 min and at 20 0C for 1 h. The reaction mixture was treated with potassium carbonate (10 g, 74 mmol) followed by 2,4,5-trichloropyrimidine (5.5 mL, 48 mmol), heated at 60 0C for 1 h, and stirred at 20 0C for 16 h. The reaction mixture was diluted with 4:1 water/brine (1 L) and extracted with ethyl acetate (2 x 250 mL). The combined organic layers were washed with water (3 x 300 mL) and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to a crude brown oil. This material was purified by flash column chromatography to give the desired product (7.8 g, 68%) as a solid after lyophilization. LCMS for Ci2Hi2Cl2N3OS (M+H)+: m/z = 315.9, 317.9.
Step B: 2-({3-[(2,5-Dichloropyrimidin-4-yl)amino]phenyljthio)ethyl methanesulfonate
Figure imgf000667_0001
The desired compound was prepared according to the procedure of Example D20, step A, using 2-({3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}thio)ethanol as the starting material and used in the next step without further purification.
Step C: tert-Butyl (3-{[2-({3-[(2,5-dichloropyrimidin-4- yl)amino]phenyljthio)ethyl]aminojphenyl)carbamate
BocHN
Figure imgf000667_0002
A solution of 2-({3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}thio)ethyl methanesulfonate (0.17 g, 0.43 mmol) in NN-dimethylformamide (2 mL) was treated with potassium carbonate (0.15 g, 1.1 mmol) followed by tert-butyl (3-aminophenyl)carbamate (0.17 g, 0.81 mmol) and stirred at 20 0C for 16 h. The reaction mixture was purified by preparative LCMS to give the desired product (23 mg, 10% for 2 steps). LCMS for C23H26Cl2N5O2S (M+H)+: m/z = 505.9, 508.0.
Step D: 6-Chloro-14-thia-2,4,8,17,24-pentaazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene bis(trifluoroacetate)
The desired compound was prepared according to the procedure of Example D2, step D, using tert-butyl (3-{ [2-({3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}thio)ethyl]amino}phenyl)carbamate as the starting material in 37% yield. LCMS for Ci8Hi7ClN5S (M+H)+: m/z = 370.0. 1H NMR (400 MHz, DMS0-<i6): δ 9.41 (s, 1 H), 8.84 (s, 1 H), 8.21 (s, 1 H), 8.05 (s, 1 H), 7.32 - 7.26 (m, 3 H), 7.20 - 7.17 (m, 1 H), 6.89 (dd, / = 8.0, 8.0 Hz, 1 H), 6.40 (d, / = 7.8 Hz, 1 H), 6.18 (d, / = 9.2 Hz, 1 H), 3.11 - 3.07 (m, 2 H), 2.98 - 2.94 (m, 2 H).
Example D81
6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene-19-carbonitrile trifluoroacetate
Figure imgf000668_0001
Step A: 2-{[2-({3-[(2, 5-Dichloropyrimidin-4-yl)amino]phenyl}thio)ethyl]amino}-4- nitrobenzonitrile trifluoroacetate
Figure imgf000668_0002
A solution of 2-({3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}thio)ethanol (0.2 g, 0.63 mmol) in dichloromethane (4.7 mL) was treated with NN-diisopropylethylamine (0.22 mL, 1.3 mmol) followed by methanesulfonyl chloride (73 μL, 0.95 mmol) and stirred at 20 0C for 1 h. The reaction mixture was concentrated to give the intermediate mesylate which was diluted with NN-dimethylformamide (2.4 mL), treated with sodium bromide (0.20 g, 1.9 mmol), and stirred at 70 0C for 2 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to a crude mixture of the intermediate bromide and chloride. This mixture was diluted with NN-dimethylformamide (3 mL), treated with potassium carbonate (0.17 g, 1.3 mmol) followed by 2-hydroxy-4-nitrobenzonitrile (0.16 g, 0.95 mmol), and stirred at 50 0C for 16 h. An attempt to convert the remaining chloro intermediate into product with cesium carbonate (0.25 g, 0.77 mmol) at 80 0C for 6 h was unsuccessful and the chloro intermediate remained unreacted. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to a crude residue. Purification by preparative LCMS gave the desired product (0.12 g, 32%) as a solid. LCMS for Ci9H14Cl2N5O3S (M+H)+: m/z = 461.9, 463.9. Step B: 4-Amino-2-[2-({3-[(2, 5-dichloropyrimidin-4-yl)amino]phenylj thio)ethoxy]benzonitrile
Figure imgf000669_0001
The desired compound was prepared according to the procedure of Example D72, step C, using
2-{ [2-({3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}thio)ethyl]amino}-4- nitrobenzonitrile as the starting material and used in the next step without further purification.
Step C: 6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[ 16.3.1.1(3,7).1(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene-19-carbonitrile trifluoroacetate
The desired compound was prepared according to the procedure of Example D32, step F, using 4- amino-2-[2-({3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl} thio)ethoxy]benzonitrile as the starting material in 8% yield (2 steps). LCMS for Ci9Hi5ClN5OS (M+H)+: m/z = 395.9. 1H NMR (400 MHz, DMS0-<i6): δ 10.06 (s, 1 H), 8.92 (s, 1 H), 8.28 (s, 1 H), 8.08 (s, 1 H), 7.84 (d, / = 1.6 Hz, 1 H), 7.50 (d, / = 8.6 Hz, 1 H), 7.33 - 7.22 (m, 3 H), 6.88 (dd, / = 8.6, 1.8 Hz, 1 H),
4.19 - 4.15 (m, 2 H), 3.27 - 3.23 (m, 2 H).
Example D82
6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene-19-carbonitrile trifluoroacetate
Figure imgf000669_0002
Step A: 4-(2-Bromo-4-nitrophenyl)morpholine
Figure imgf000670_0001
A solution of 2-bromo-l-fluoro-4-nitrobenzene (0.94 g, 4.3 mmol) in NN-dimethylformamide (10 mL) was treated with potassium carbonate (1.5 g, 11 mmol) followed by morpholine (0.56 mL, 6.4 mmol) and stirred at 20 0C for 3 h. The reaction mixture was diluted with sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product (1.0 g, quantitative) which was used without further purification.
Step B: tert-Butyl {3-[(2-morpholin-4-yl-5-nitrophenyl)ethynyl]phenyl}carbamate
Figure imgf000670_0002
A solution of 4-(2-bromo-4-nitrophenyl)morpholine (0.27 g, 0.95 mmol), tert-butyl (3- ethynylphenyl)carbamate, and bis(triphenylphosphine)palladium(II) chloride (67 mg, 95 μmol) in NN- dimethylformamide (4.4 mL) was treated with NN-diisopropylethylamine (0.21 mL, 1.2 mmol) and stirred at 80 0C for 16 h. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude residue. This material was purified by flash column chromatography to give the desired product (0.28 g, 70%) as a solid. LCMS for C23H26N3O5 (M+H)+: m/z = 424.0.
Step C: tert-Butyl {3-[2-(5-amino-2-morpholin-4-ylphenyl)ethyl]phenyljcarbamate
BocHN
Figure imgf000670_0003
A solution of tert-butyl {3-[(2-morpholin-4-yl-5-nitrophenyl)ethynyl]phenyl}carbamate (0.33 g, 0.78 mmol) in methanol (20 mL) was degassed with nitrogen, treated with 10% palladium on carbon (wet Degussa type) (0.33 g, 100 wt%), degassed with nitrogen, and shaken under an atmosphere of hydrogen (50 psi) for 48 h. The reaction mixture was filtered over celite and the filtrate concentrated to give the desired product (0.29 g, 92%) which was used without further purification. LCMS for C23H32N3O3 (M+H)+: m/z = 398.1.
Step D: tert-Butyl [3-(2-{5-[(2,5-dichloropyrimidin-4-yl)amino]-2-morpholin-4- ylphenyljethyl)phenyl] carbamate
Figure imgf000671_0001
The desired compound was prepared according to the procedure of Example D2, step C, using tert-butyl {3-[2-(5-amino-2-morpholin-4-ylphenyl)ethyl]phenyl}carbamate as the starting material in 80% yield. LCMS for C27H32Cl2N5O3 (M+H)+: m/z = 544.0, 546.0.
Step E: 6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracydo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene-19-carbonitrile trifluoroacetate
The desired compound was prepared according to the procedure of Example B 19, step F, using tert-butyl [3-(2-{5-[(2,5-dichloropyrimidin-4-yl)amino]-2-morpholin-4-ylphenyl}ethyl)phenyl]carbamate as the starting material in 50% yield. LCMS for C22H23ClN5O (M+H)+: m/z = 408.0. 1H NMR (400 MHz, DMS0-<i6): δ 9.38 (s, 1 H), 9.18 (s, 1 H), 8.10 (s, 1 H), 7.97 (s, 1 H), 7.78 (d, / = 2.1 Hz, 1 H),
7.10 - 7.05 (m, 3 H), 6.86 (dd, / = 8.0, 1.0 Hz, 1 H), 6.80 (d, / = 7.6 Hz, 1 H), 3.74 - 3.72 (m, 2 H), 3.15
(s, 2 H), 2.94 (s, 4 H), 2.81 - 2.78 (m, 4 H).
Example D83 6-Chloro-12-piperazin-l-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9, 13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000672_0001
Step A: tert-Butyl 4-(2-bromo-4-nitrophenyl)piperazine-l-carboxylate
Figure imgf000672_0002
A solution of 2-bromo-l-fluoro-4-nitrobenzene (0.1 g, 0.45 mmol) and tert-butyl piperazine-1- carboxylate (85 mg, 0.45 mmol) in NN-dimethylformamide (0.9 mL) was treated with potassium carbonate (94 mg, 0.68 mmol) and stirred at 20 0C for 23 h and at 60 0C for 3.5 h. The reaction mixture was diluted with water (10 mL) and ethyl acetate (20 mL). The organic layer was separated, washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a yellow oil. This material was purified by flash column chromatography to give the desired product (0.15 g, 87%) as a yellow solid. LCMS for Ci5H20BrN3O4Na (M+Na)+: m/z = 407.9, 410.1.
Step B: l-(2-Bromo-4-nitrophenyl)piperazine dihydrochloride
Figure imgf000672_0003
A solution of tert-butyl 4-(2-bromo-4-nitrophenyl)piperazine-l -carboxylate (2.3 g, 5.9 mmol) in dichloromethane (15 mL) was treated with 4 M HCl in 1,4-dioxane (15 mL, 59 mmol) and stirred at 20
0C for 3 h. The reaction mixture was concentrated, diluted with a miminal amount of methanol (-15 mL), and added dropwise to ether (300 mL) that was cooled 0 0C. The solid that precipitated was collected by filtration and dried to give the desired product (1.9 g, 89%) which was used in the next step without further purification.
Step C: 2-(Trimethylsilyl)ethyl 4-(2-bromo-4-nitrophenyl)piperazine-l-carboxylate
Figure imgf000673_0001
A solution of l-(2-bromo-4-nitrophenyl)piperazine dihydrochloride (1.9 g, 5.8 mmol) in acetonitrile (50 mL) was treated with l-({ [2-(trimethylsilyl)ethoxy]carbonyl}oxy)pyrrolidine-2,5-dione (1.5 g, 5.9 mmol) followed by water (15 mL) and sodium carbonate (1.9 g, 18 mmol) and stirred at 20 0C for 6 h. The reaction mixture was diluted with ethyl acetate (400 mL) and washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give a residue. This material was purified by flash column chromatography to give the desired product (2.4 g, 87%) as a solid. [TEOC: (2- (trimethylsilyl)ethoxy)carbonyl ]
Step D: 2-(Trimethylsilyl)ethyl 4-[2-({3-[(tert-butoxycarbonyl)amino]phenyljethynyl)- 4-nitrophenyl]piperazine-l-carboxylate
Figure imgf000673_0002
The desired compound was prepared according to the procedure of D82, step B, using 2- (trimethylsilyl)ethyl 4-(2-bromo-4-nitrophenyl)piperazine-l-carboxylate as the starting material in 94% yield. LCMS for C29H38N4O6SiNa (M+Na)+: m/z = 589.1.
Step E: tert-Butyl {3-[2-(5-amino-2-morpholin-4-ylphenyl)ethyl]phenyl}carbamate BocHN
Figure imgf000674_0001
The desired compound was prepared according to the procedure of D82, step C, using 2- (trimethylsilyl)ethyl 4-[2-({3-[(tert-butoxycarbonyl)amino]phenyl}ethynyl)-
4-nitrophenyl]piperazine-l-carboxylate as the starting material in 97% yield. LCMS for C2QH45N4O4Si (M+H)+: m/z = 541.2.
Step F: 2-(Trimethylsilyl)ethyl 4-{2-(2-{3-[(tert-butoxycarbonyl)amino]phenyl}ethyl)- 4-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}piperazine-l-carboxylate
BocHN
Figure imgf000674_0002
The desired compound was prepared according to the procedure of Example D2, step C, using tert-butyl {3-[2-(5-amino-2-morpholin-4-ylphenyl)ethyl]phenyl}carbamate as the starting material in 79% yield. LCMS for C33H45Cl2N6O4Si (M+H)+: m/z = 687.0, 689.0.
Step G: 6-Chloro-12-piperazin-l-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9, 13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
The desired compound was prepared according to the procedure of Example D32, step F, using 2- (trimethylsilyl)ethyl 4- { 2-(2- { 3- [(tørt-butoxycarbonyl)amino]phenyl } ethyl)-
4-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}piperazine-l-carboxylate as the starting material in 55% yield. LCMS for C22H24ClN6 (M+H)+: m/z = 407.0. 1H NMR (400 MHz, DMSO-^6): δ 9.41 (s, 1 H), 9.18 (s, I H), 8.71 (br s, 2 H), 8.11 (s, 1 H), 7.97 (s, I H), 7.81 (s, 1 H), 7.11 - 7.07 (m, 3 H), 6.88 - 6.85 (m, 1 H), 6.80 (d, / = 7.6 Hz, 1 H), 3.25 (br s, 4 H), 3.00 - 2.97 (m, 4 H), 2.93 (s, 4 H). Example D84 iV-(tert-Butyl)-4-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9, 13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperazine-l- carboxamide bis(trifluoroacetate)
Figure imgf000675_0001
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-piperazin-l-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-
1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene bis(trifluoroacetate) as the starting material in 46% yield. LCMS for C27H33ClN7O (M+H)+: m/z = 506.1. 1H NMR (400 MHz, DMSO-^6): δ 9.48 (s, 1 H), 9.33 (br s, 1 H), 8.12 (s, 1 H), 7.94 (s, 1 H), 7.76 (d, / = 1.6 Hz, 1 H), 7.09 - 7.03 (m, 3 H), 6.87 - 6.80 (m, 2 H), 5.84 (s, 1 H), 3.40 (br s, 4 H), 2.95 (s, 4 H), 2.75 - 2.73 (m, 4 H), 1.26 (s, 9 H).
Example D85
12-(4-Acetylpiperazin-l-yl)-6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000675_0002
A solution of 6-chloro-12-piperazin-l-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9, 13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) (20 mg, 32 μmol) and NN- diisopropylethylamine (27 μL, 0.16 mmol) in tetrahydrofuran (0.5 mL) was treated with acetic anhydride (15 μL, 0.16 mmol) and stirred at 20 0C for 16 h. The reaction mixture was treated with 2 M sodium hydroxide (0.16 mL, 0.32 mmol) and stirred at 20 0C for 16 h to remove the undesired acetamide. The reaction mixture was purified by preparative LCMS to give the desired product (10 mg, 47%) as a solid. LCMS for C24H26ClN6O (M+H)+: m/z = 449.0.
Example D86
4-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l,l-dimethylpiperazin-l-ium bis(trifluoroacetate)
Figure imgf000676_0001
A solution of 6-chloro-12-piperazin-l-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9, 13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) (20 mg, 32 μmol) and NN- diisopropylethylamine (27 μL, 0.16 mmol) in dichloromethane (0.3 mL) was treated with methyl iodide (10 μL, 0.16 mmol) and stirred for 16 h. The reaction mixture was purified by preparative LCMS to give the desired product (15 mg, 72%) as a solid. LCMS fOr C24H28ClN6 (M)+: m/z = 435.1. 1H NMR (400 MHz, DMSOd6): 6 9.41 (s, 1 H), 9.17 (s, 1 H), 8.11 (s, 1 H), 7.98 (s, 1 H), 7.81 (d, / = 2.3 Hz, 1 H), 7.30 (d, / = 8.6 Hz, 1 H), 7.11 - 7.07 (m, 2 H), 6.87 (d, / = 9.2 Hz, 1 H), 6.79 (d, / = 7.4 Hz, 1 H), 3.55 - 3.53 (m, 4 H), 3.22 (s, 6 H), 3.15 (br s, 4 H), 2.95 - 2.90 (m, 4 H).
Example D87
4-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperazine-l-carboxamide bis(triflUOroacetate)
Figure imgf000677_0001
A solution of N-(tert-butyl)-4-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9, 13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperazine-l- carboxamide bis(trifluoroacetate) (12 mg, 16 μmol) in trifluoroacetic acid (1 niL) was stirred at 20 0C for 4 h. The reaction mixture was purified by preparative LCMS to give the desired product (8 mg, 72%) as a solid. LCMS for C23H25ClN7O (M+H)+: m/z = 450.0. 1H NMR (300 MHz, CD3OD): δ 8.09 (s, 1 H), 7.74 - 7.69 (m, 2 H), 7.22 - 7.11 (m, 2 H), 7.04 - 7.00 (m, 2 H), 6.87 (d, / = 7.9 Hz, 1 H), 3.60 (br s, 4 H), 3.14 (s, 4 H), 2.89 - 2.87 (m, 4 H).
Example D88 l-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidin-3-amine tris(trifluoroacetate)
Figure imgf000677_0002
Step A: tert-Butyl [l-(2-bromo-4-nitrophenyl)pyrrolidin-3-yl]carbamate
Figure imgf000677_0003
HBoc The desired compound was prepared according to the procedure of Example D83, step A, usin^ tert-butyl pyrrolidin-3-ylcarbamate as the starting material in 93% yield. LCMS for CiSH2IBrN3O4 (M+H)+: m/z = 385.9, 387.9.
Step B: l-(2-Bromo-4-nitrophenyl)pyrrolidin-3-amine dihydrochloride
Figure imgf000678_0001
The desired compound was prepared according to the procedure of Example D83, step B, usin^ tert-butyl [l-(2-bromo-4-nitrophenyl)pyrrolidin-3-yl]carbamate as the starting material in quantitative yield.
Step C: 2-(Trimethylsilyl)ethyl [ 1 -(2-bromo-4-nitrophenyl)pyrrolidin-3-yl] 'carbamate
Figure imgf000678_0002
The desired compound was prepared according to the procedure of Example D83, step C, usin^ l-(2-bromo-4-nitrophenyl)pyrrolidin-3-amine dihydrochloride as the starting material in 91% yield. LCMS for Ci6H25BrN3O4Si (M+H)+: m/z = 429.9, 431.9.
Step D: 2-(Trimethylsilyl)ethyl { l-[2-({ 3-[(tert-butoxycarbonyl)amino]phenyljethynyl)- 4-nitrophenyl]pyrrolidin-3-yl}carbamate
Figure imgf000679_0001
The desired compound was prepared according to the procedure of Example Al l, step C, using 2-(trimethylsilyl)ethyl [l-(2-bromo-4-nitrophenyl)pyrrolidin-3-yl]carbamate and tert-butyl (3- ethynylphenyl)carbamate as the starting materials in 91% yield. LCMS for C2QH39N4OeSi (M+H)+: m/z : 567.2.
Step E: 2-(Trimethylsilyl)ethyl fl-[4-amino-2-(2-{3-[(tert- butoxycarbonyl)amino]phenyljethyl)phenyl]pyrrolidin-3-yljcarbamate
BocHN
Figure imgf000679_0002
The desired compound was prepared according to the procedure of Example D7, step B, using 2-
(trimethylsilyl)ethyl { l-[2-({3-[(tert-butoxycarbonyl)amino]phenyl}ethynyl)-
4-nitrophenyl]pyrrolidin-3-yl}carbamate as the starting material in 84% yield. LCMS for C29H45N4O4Si (M+H)+: m/z = 541.2.
Step F: 2-(Trimethylsilyl)ethyl (l-{2-(2-{3-[(tert-butoxycarbonyl)amino]phenyljethyl)- 4-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}pyrrolidin-3-yl)carbamate BocHN
Figure imgf000680_0001
The desired compound was prepared according to the procedure of Example D2, step C, using 2-
(trimethylsilyl)ethyl { l-[4-amino-2-(2-{3-[(tert-butoxycarbonyl)amino]phenyl}ethyl)phenyl]pyrrolidin-3- yljcarbamate as the starting material in 86% yield. LCMS for C33H45Cl2N6O4Si (M+H)+: m/z = 687.1, 689.1.
Step G: 1 -[6-Chloro-2, 4, 8, 22-tetraazatetracydo[14.3.1.1 (3, 7).1 (9, 13)]docosa-l(20), 3(22),4, 6,9(21), 10,12, 16,18-nonaen-12-yl]pyrrolidin-3-amine tris(trifluoroacetate)
The desired compound was prepared according to the procedure of Example D32, step F, using 2- (trimethylsilyl)ethyl ( 1 - { 2-(2- { 3- [(tørt-butoxycarbonyl)amino]phenyl } ethyl)-
4-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}pyrrolidin-3-yl)carbamate as the starting material in 22% yield. LCMS for C22H24ClN6 (M+H)+: m/z = 407.0.
Example D89
4-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV-(3-cyanophenyl)piperazine- 1 -carboxamide bis(trifluor oacetate)
Figure imgf000680_0002
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-piperazin-l-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9, 13)]docosa-l(20), 3(22),4,6,9(21), 10,12, 16, 18-nonaene bis(trifluoroacetate) and 3-isocyanatobenzonitrile as the starting materials in 35% yield. LCMS for C30H28ClN8O (M+H)+: m/z = 551.0. 1H NMR (SOO MHz, DMSOd6): δ 9.49 (s, 1 H), 9.34 (s, 1 H), 8.95 (s, 1 H), 8.14 (s, 1 H), 7.97 - 7.96 (m, 2 H), 7.79 - 7.75 (m, 2 H), 7.48 - 7.37 (m, 2 H), 7.13 - 7.03 (m, 3 H), 6.89 - 6.82 (m, 2 H), 3.63 (br s, 4 H), 2.99 (s, 4 H), 2.84 (br s, 4 H).
Example D90
4-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV-[4-(trifluoromethyl)phenyl]piperazine- 1 -carboxamide bis(trifluor oacetate)
Figure imgf000681_0001
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-piperazin-l-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) and l-isocyanato-4- (trifluoromethyl)benzene as the starting materials in 41% yield. LCMS for C3OH28ClF3N7O (M+H)+: m/z = 594.0. 1H NMR (400 MHz, DMSO-^6): δ 9.49 (s, 1 H), 9.32 (br s, 1 H), 9.00 (s, 1 H), 8.13 (s, 1 H), 7.96 (s, 1 H), 7.79 (d, / = 2.3 Hz, 1 H), 7.72 - 7.70 (m, 2 H), 7.60 - 7.57 (m, 2 H), 7.12 - 7.03 (m, 3 H), 6.88 - 6.82 (m, 2 H), 3.64 (br s, 4 H), 2.99 (s, 4 H), 2.84 (br s, 4 H).
Example D91 4-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV-[3-(trifluoromethyl)phenyl]piperazine- 1 -carboxamide bis(trifluor oacetate)
Figure imgf000682_0001
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-piperazin-l-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,
13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) and l-isocyanato-3- (trifluoromethyl)benzene as the starting materials in 44% yield. LCMS for C30H28ClF3N7O (M+H)+: m/z = 594.0. 1H NMR (400 MHz, DMSOd6): δ 9.67 (br s, 1 H), 9.55 (br s, 1 H), 8.94 (s, 1 H), 8.18 (s, 1 H), 7.95 - 7.92 (m, 2 H), 7.77 - 7.75 (m, 2 H), 7.47 (dd, / = 8.0, 8.0 Hz, 1 H), 7.27 (d, / = 7.8 Hz, 1 H), 7.14 - 7.02 (m, 3 H), 6.88 - 6.85 (m, 2 H), 3.64 (br s, 4 H), 3.01 (s, 4 H), 2.85 - 2.82 (m, 4 H).
Example D92 4-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),
3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV-phenylpiperazine-l-carboxamide bis(trifluoroacetate)
Figure imgf000682_0002
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-piperazin-l-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,
13)]docosa-l(20),3(22),4,6,9(21), 10,12,16, 18-nonaene bis(trifluoroacetate) and phenyl isocyanate as the starting materials in 39% yield. LCMS fOr C29H29ClN7O (MH-H)+: m/z = 526.1. 1H NMR (400 MHz, DMSO-Cf6): δ 9.51 (s, 1 H), 9.35 (br s, 1 H), 8.59 (s, 1 H), 8.14 (s, 1 H), 7.96 (s, 1 H), 7.78 (s, 1 H), 7.49 7.46 (m, 2 H), 7.25 - 7.21 (m, 2 H), 7.13 - 7.04 (m, 3 H), 6.95 - 6.83 (m, 3 H), 3.61 (br s, 4 H), 2.99 (s, 4 H), 2.84 (br s, 4 H).
Example D93
4-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-iV-(4-cyanophenyl)piperazine- 1 -carboxamide bis(trifluor oacetate)
Figure imgf000683_0001
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-piperazin-l-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,
13)]docosa-l(20),3(22),4,6,9(21), 10,12, 16, 18-nonaene bis(trifluoroacetate) and 4-isocyanatobenzonitrile as the starting materials in 38% yield. LCMS for C30H28ClN8O (M+H)+: m/z = 551.0. 1H NMR (400 MHz, DMSOd6): δ 9.46 (br s, 1 H), 9.29 (br s, 1 H), 9.09 (s, 1 H), 8.13 (s, 1 H), 7.97 (s, 1 H), 7.79 (d, / = 2.3 Hz, 1 H), 7.69 (s, 4 H), 7.12 - 7.03 (m, 3 H), 6.88 - 6.82 (m, 2 H), 3.64 (br s, 4 H), 2.98 (s, 4 H), 2.84 (br s, 4 H).
Example D94
12-(4-Benzoylpiperazin-l-yl)-6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000684_0001
A solution of ό-chloro^-piperazin^-yl^AS^-tetraazatetracyclofH.S.1.1(3,7).1(9, 13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) (30 mg, 47 μmol) and NN- diisopropylethylamine (41 μL, 0.24 mmol) in dichloromethane was treated with benzoyl chloride (11 μL, 95 μmol) and stirred for 16 h. The reaction mixture was purified by preparative LCMS to give the desired product (14 mg, 40%) as a solid. LCMS for C29H27ClN6O (M+H)+: m/z = 511.1. 1H NMR (400 MHz, DMSOd6): δ 9.54 (br s, 1 H), 9.38 (br s, 1 H), 8.14 (s, 1 H), 7.94 (s, 1 H), 7.77 (d, / = 2.3 Hz, 1 H), 7.47 - 7.43 (m, 4 H), 7.12 - 7.02 (m, 3 H), 6.87 - 6.82 (m, 2 H), 3.79 (br s, 2 H), 3.49 (br s, 2 H), 2.97 (s, 4 H), 2.87 - 2.79 (m, 4 H).
Example D95 4-({4-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperazin-l-yl}carbonyl)benzonitrile bis(trifluoroacetate)
Figure imgf000684_0002
The desired compound was prepared according to the procedure of Example D94 using 4- cyanobenzoyl chloride as the starting material in 17% yield. LCMS for C3OH27ClN7O (M+H)+: m/z = 536.1. 1H NMR (400 MHz, DMSO-^6): δ 9.47 (br s, 1 H), 9.28 (br s, 1 H), 8.12 (s, 1 H), 7.96 - 7.93 (m, 3 H), 7.77 (s, 1 H), 7.66 - 7.63 (m, 2 H), 7.10 - 7.03 (m, 3 H), 6.87 - 6.80 (m, 2 H), 3.42 (br s, 4 H), 2.96 (s, 4 H), 2.89 (br s, 2 H), 2.78 (br s, 2 H).
Example D96
6-Chloro-12-{4-[4-(trifluoromethyl)benzoyl]piperazin-l-yl}-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,
7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000685_0001
The desired compound was prepared according to the procedure of Example D94 using 4- (trifluoromethyl)benzoyl chloride as the starting material in 32% yield. LCMS for C30H27CIF3N6O (M+H)+: m/z = 579.1. 1H NMR (400 MHz, DMS0-<i6): δ 9.52 (br s, 1 H), 9.36 (br s, 1 H), 8.14 (s, 1 H), 7.94 (s, 1 H), 7.85 - 7.82 (m, 2 H), 7.77 (d, / = 2.0 Hz, 1 H), 7.69 - 7.66 (m, 2 H), 7.11 - 7.03 (m, 3 H), 6.87 - 6.81 (m, 2 H), 3.82 (br s, 2 H), 3.44 (br s, 2 H), 2.97 (s, 4 H), 2.90 (br s, 2 H), 2.78 (br s, 2 H).
Example D97 (3/?)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-phenylpyrrolidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000685_0002
Step A: tert-Butyl (3R)-3-(2-f[6-chloro-2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]aminoj-2-oxoethyl)pyrrolidine-l-carboxylate
Figure imgf000686_0001
A solution of 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine (0.64 g, 1.9 mmol) and [(3R)-l-(tert- butoxycarbonyl)pyrrolidin-3-yl]acetic acid (0.5 g, 2.2 mmol) in dichloromethane (7 mL) and N,N- dimethylformamide (4.5 mL) was treated with N,N-diisopropylethylamine (0.5 mL, 2.8 mmol) followed by 2.0 M of l-hydroxy-7-azabenzotriazole in N,N-dimethylformamide (0.19 mL) and N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.55 g, 2.8 mmol) and the reaction mixture was stirred at 20 0C overnight. The reaction mixture was concentrated and the resultant solution was added slowly to ice cold water (-200 mL). The solid that precipitated was filtered and collected to give the crude Boc intermediate. This material was used immediately in the next step.
Step B: N-[6-Chloro-2,4, 8,18, 22-pentaazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamidetris(trifluoroacetate)
Figure imgf000686_0002
The crude Boc intermediate from Step A was dissolved in dichloromethane (10 mL), treated with 4.0 M hydrogen chloride in 1,4-dioxane (10 mL) and stirred at 20 0C for 4 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (0.75 g, 50%) as a solid. LCMS for C23H25ClN7O (M+H)+: m/z = 450.0. Step C: (3R)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracydo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22), 4,6, 9(21), 10, 12,16, 18-nonaen-12-yl] amino} -2-oxoethyl)-N-phenylpyrrolidine-l-carboxamide bis(trifluoroacetate) The desired compound was prepared according to the procedure of Example D41 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamidetris(trifluoroacetate) and phenyl isocyanate as the starting materials in 83% yield. LCMS for C30H30ClN8O2 (M+H)+: m/z = 569.0.
Example D98
(3/?)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-(4-cyanophenyl)pyrrolidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000687_0001
The desired compound was prepared according to the procedure of Example D41 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamidetris(trifluoroacetate) and 4-isocyanatobenzonitrile as the starting materials in 51% yield. LCMS for C3IH29ClN9O2 (M+H)+: m/z = 594.0.
Example D99
(3/?)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-(3-cyanophenyl)pyrrolidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000688_0001
The desired compound was prepared according to the procedure of Example D41 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamidetris(trifluoroacetate) and 3-isocyanatobenzonitrile as the starting materials in 64% yield. LCMS for C3IH29ClN9O2 (M+H)+: m/z = 594.0.
Example DlOO
(3/?)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-(2-cyanophenyl)pyrrolidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000688_0002
The desired compound was prepared according to the procedure of Example D41 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamidetris(trifluoroacetate) and 2-isocyanatobenzonitrile as the starting materials in 48% yield. LCMS for C3iH29ClΝ9O2 (M+H)+: m/z = 594.0.
Example DlOl (3/?)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-pyridin-3-ylpyrrolidine-l- carboxamide tris(trifluoroacetate)
Figure imgf000689_0001
The desired compound was prepared according to the procedure of Example D41 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 2-isocyanatopyridine as the starting materials in 84% yield. LCMS for C29H29ClN9O2 (M+H)+: m/z = 570.0.
Example D102
(3/?)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-(4-fluorophenyl)pyrrolidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000689_0002
The desired compound was prepared according to the procedure of Example D41 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen- 12-yl] -2-[(3R)-pyrrolidin-3 -yl] acetamide tris(trifluoroacetate) and 1 -fluoro-4-isocyanatobenzene as the starting materials in 73% yield. LCMS for C30H29ClFN8O2 (M+H)+: m/z = 587.0.
Example D103
(3/?)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-(3-fluorophenyl)pyrrolidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000690_0001
The desired compound was prepared according to the procedure of Example D41 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamidetris(trifluoroacetate) and l-fluoro-3-isocyanatobenzene as the starting materials in 58% yield. LCMS for C30H29ClFN8O2 (M+H)+: m/z = 587.0.
Example D104 (3/?)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(2-fluorophenyl)pyrrolidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000691_0001
The desired compound was prepared according to the procedure of Example D41 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamidetris(trifluoroacetate) and l-fluoro-2-isocyanatobenzene as the starting materials in 85% yield. LCMS for C30H29ClFN8O2 (M+H)+: m/z = 587.1.
Example D105 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3/?)-l-(isoxazol-5-ylcarbonyl)pyrrolidin-3- yl]acetamide bis(trifluoroacetate)
Figure imgf000691_0002
The desired compound was prepared according to the procedure of Example D94 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen- 12-yl] -2-[(3R)-pyrrolidin-3 -yl] acetamidetris(trifluoroacetate) and isoxazole-5 -carbonyl chloride as the starting materials in 59% yield. LCMS for C27H26ClN8O3 (M+H)+: m/z = 545.1.
Example D106 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3/?)-l-[(l-methyl-lH-pyrazol-3- yl)carbonyl]pyrrolidin-3-yl}acetamide bis(trifluoroacetate)
Figure imgf000692_0001
The desired compound was prepared according to the procedure of Example D94 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamidetris(trifluoroacetate) and l-methyl-lH-pyrazole-3- carbonyl chloride as the starting materials in 67% yield. LCMS for C28H29ClN9O2 (M+H)+: m/z = 558.1.
Example D107 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3/?)-l-[(l-methyl-lH-pyrazol-4- yl)carbonyl]pyrrolidin-3-yl}acetamide bis(trifluoroacetate)
Figure imgf000692_0002
The desired compound was prepared according to the procedure of Example D94 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen- 12-yl] -2-[(3R)-pyrrolidin-3 -yl] acetamidetris(trifluoroacetate) and 1 -methyl- 1 H-pyrazole-4- carbonyl chloride as the starting materials in 67% yield. LCMS for C28H29ClN9O2 (M+H)+: m/z = 558.0.
Example D108 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3/?)-l-[(5-methylisoxazol-4- yl)carbonyl]pyrrolidin-3-yl}acetamide bis(trifluoroacetate)
Figure imgf000693_0001
The desired compound was prepared according to the procedure of Example D94 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamidetris(trifluoroacetate) and 5-methylisoxazole-4-carbonyl chloride as the starting materials in 92% yield. LCMS for C28H28ClN8O3 (M+H)+: m/z = 559.1.
Example D109 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3/?)-l-[(5-methylisoxazol-3- yl)carbonyl]pyrrolidin-3-yl}acetamide bis(trifluoroacetate)
Figure imgf000693_0002
The desired compound was prepared according to the procedure of Example D94 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamidetris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 46% yield. LCMS for C28H28ClN8O3 (M+H)+: m/z = 559.0. Example DIlO iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3/?)-l-(l,3-thiazol-2-ylcarbonyl)pyrrolidin-3- yl]acetamide bis(trifluoroacetate)
Figure imgf000694_0001
The desired compound was prepared according to the procedure of Example D94 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamidetris(trifluoroacetate) and l,3-thiazole-2-carbonyl chloride as the starting materials in 57% yield. LCMS for C27H26ClN8O2S (M+H)+: m/z = 561.1.
Example Dill iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3/?)-l-[(l-methyl-lH-imidazol-5- yl)carbonyl]pyrrolidin-3-yl}acetamide tris(trifluoroacetate)
Figure imgf000694_0002
The desired compound was prepared according to the procedure of Example D94 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen- 12-yl] -2-[(3R)-pyrrolidin-3 -yl] acetamidetris(trifluoroacetate) and 1 -methyl- 1 H-imidazole-5- carbonyl chloride hydrochloride as the starting materials in 23% yield. LCMS for C28H29ClN9O2 (M+H)+: m/z = 558.1. Example D112 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3/?)-l-(methylsulfonyl)pyrrolidin-3-yl]acetamide bis(trifluoroacetate)
Figure imgf000695_0001
The desired compound prepared according to the procedure of Example D20, step A, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamidetris(trifluoroacetate) as the starting material in 75% yield. LCMS for C24H27ClN7O3S (M+H)+: m/z = 528.1.
Example D113
(3S)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-phenylpyrrolidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000695_0002
Step A: N-[6-Chloro-2,4, 8,18, 22-pentaazatetracyclo[14.3.1.1(3, 7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)ψyrrolidin-3-yl]acetamide tris(trifluoroacetate)
Figure imgf000696_0001
The desired compound was prepared according to the procedure of Example D97, step A, using [(35)- l-(tert-butoxycarbonyl)pyrrolidin-3-yl] acetic acid as the starting material in 54% yield. LCMS for
C23H25ClN7O (M+H)+: m/z = 450.0.
Step B: (3S)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-
1(20), 3(22), 4,6, 9(21), 10, 12,16, 18-nonaen-12-yl] amino} -2-oxoethyl)-N-phenylpyrrolidine-l-carboxamide bis(trifluoroacetate)
The desired compound was prepared according to the procedure of Example D41 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and phenyl isocyanate as the starting materials in 99% yield. LCMS for C30H30ClN8O2 (M+H)+: m/z = 569.1.
Example D114 (3S)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(4-cyanophenyl)pyrrolidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000696_0002
The desired compound was prepared according to the procedure of Example D41 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 4-isocyanatobenzonitrile as the starting materials in 60% yield. LCMS for C3IH29ClN9O2 (M+H)+: m/z = 594.0.
Example D115
(3S)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-(3-cyanophenyl)pyrrolidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000697_0001
The desired compound was prepared according to the procedure of Example D41 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 3-isocyanatobenzonitrile as the starting materials in 77% yield. LCMS for C3iH29ClΝ9O2 (M+H)+: m/z = 594.1.
Example D116
(3S)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-(2-cyanophenyl)pyrrolidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000698_0001
The desired compound was prepared according to the procedure of Example D41 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 2-isocyanatobenzonitrile as the starting materials in 77% yield. LCMS for C3iH29CiΝ9O2 (M+H)+: m/z = 594.1.
Example D117
(3S)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-pyridin-3-ylpyrrolidine-l- carboxamide tris(trifluoroacetate)
Figure imgf000698_0002
The desired compound was prepared according to the procedure of Example D41 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 3-isocyanatopyridine as the starting materials in 93% yield. LCMS fOr C29H29ClN9O2 (M-I-H)+: m/z = 570.0.
Example D118 (3S)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-(4-fluorophenyl)pyrrolidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000699_0001
The desired compound was prepared according to the procedure of Example D41 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and l-fluoro-4-isocyanatobenzene as the starting materials in 79% yield. LCMS for C30H29ClFN8O2 (M+H)+: m/z = 587.0.
Example D119
(3S)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-(3-fluorophenyl)pyrrolidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000699_0002
The desired compound was prepared according to the procedure of Example D41 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and l-fluoro-3-isocyanatobenzene as the starting materials in 80% yield. LCMS for C30H29ClFN8O2 (M+H)+: m/z = 587.0.
Example D120 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-l-(isoxazol-5-ylcarbonyl)pyrrolidin-3- yl]acetamide bis(trifluoroacetate)
Figure imgf000700_0001
The desired compound was prepared according to the procedure of Example D94 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and isoxazole-5-carbonyl chloride as the starting materials in 81% yield. LCMS for C27H26ClN8O3 (M+H)+: m/z = 545.0.
Example D121 N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3S)-l-[(l-methyl-lH-pyrazol-3- yl)carbonyl]pyrrolidin-3-yl}acetamide bis(trifluoroacetate)
Figure imgf000700_0002
The desired compound was prepared according to the procedure of Example D94 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and l-methyl-lH-pyrazole-3- carbonyl chloride as the starting materials in 82% yield. LCMS for C28H29ClN9O2 (M+H)+: m/z = 558.1.
Example D122 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3S)-l-[(l-methyl-lH-pyrazol-4- yl)carbonyl]pyrrolidin-3-yl}acetamide bis(trifluoroacetate)
Figure imgf000701_0001
The desired compound was prepared according to the procedure of Example D94 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and l-methyl-lH-pyrazole-4- carbonyl chloride as the starting materials in 72% yield. LCMS for C28H29ClN9O2 (M+H)+: m/z = 558.1.
Example D123
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3S)-l-[(5-methylisoxazol-4- yl)carbonyl]pyrrolidin-3-yl}acetamide bis(trifluoroacetate)
Figure imgf000702_0001
The desired compound was prepared according to the procedure of Example D94 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 5-methylisoxazole-4-carbonyl chloride as the starting materials in 91% yield. LCMS for C28H28ClN8O3 (M+H)+: m/z = 559.0.
Example D124 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3S)-l-[(5-methylisoxazol-3- yl)carbonyl]pyrrolidin-3-yl}acetamide bis(trifluoroacetate)
Figure imgf000702_0002
The desired compound was prepared according to the procedure of Example D94 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 76% yield. LCMS for C28H28ClN8O3 (M+H)+: m/z = 559.0.
Example D125 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-l-(l,3-thiazol-2-ylcarbonyl)pyrrolidin-3- yl]acetamide bis(trifluoroacetate)
Figure imgf000703_0001
The desired compound was prepared according to the procedure of Example D94 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and l,3-thiazole-2-carbonyl chloride as the starting materials in 83% yield. LCMS for C27H26ClN8O2S (M+H)+: m/z = 561.0.
Example D126 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3S)-l-[(l-methyl-lH-imidazol-5- yl)carbonyl]pyrrolidin-3-yl}acetamide tris(trifluoroacetate)
Figure imgf000703_0002
The desired compound was prepared according to the procedure of Example D94 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and l-methyl-lH-imidazole-5- carbonyl chloride hydrochloride as the starting materials in 20% yield. LCMS for C28H29ClN9O2
(M+H)+: m/z = 558.0. Example D127 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-l-(methylsulfonyl)pyrrolidin-3-yl]acetamide bis(trifluoroacetate)
Figure imgf000704_0001
The desired compound was prepared according to the procedure of Example D20, step A, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) as the starting material in 78% yield. LCMS for C24H27ClN7O3S (M+H)+: m/z = 528.0.
Example D128 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3/?)-l-(lH-l,2,4-triazol-3-ylcarbonyl)pyrrolidin- 3-yl]acetamide bis(trifluoroacetate)
Figure imgf000704_0002
The desired compound was prepared according to the procedure of Example D97, step A, using
N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamidetris(trifluoroacetate) and lH-l,2,4-triazole-3-carboxylic acid as the starting materials in 58% yield. LCMS for C26Η26ClΝi0O2 (M+H)+: m/z = 545.0. Example D129-a iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3/?)-l-(lH-l,2,3-triazol-4-ylcarbonyl)pyrrolidin- 3-yl]acetamide bis(trifluoroacetate)
Figure imgf000705_0001
The desired compound was prepared according to the procedure of Example D97, step A, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamidetris(trifluoroacetate) and 4-carboxy-l,2,3-triazole as the starting materials in 78% yield. LCMS for C26H26ClNi0O2 (M+H)+: m/z = 545.0.
Example D129-b iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3/?)-l-(lH-pyrazol-4-ylcarbonyl)pyrrolidin-3- yl]acetamide bis(trifluoroacetate)
Figure imgf000705_0002
The desired compound was prepared according to the procedure of Example D97, step A, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamidetris(trifluoroacetate) and lH-pyrazole-4-carboxylic acid as the starting materials in 51% yield. LCMS for C27Η27CIN9O2 (M+H)+: τalτ = 544.0.
Example D130 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3/?)-l-(lH-pyrazol-3-ylcarbonyl)pyrrolidin-3- yl]acetamide bis(trifluoroacetate)
Figure imgf000706_0001
The desired compound was prepared according to the procedure of Example D97, step A, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamidetris(trifluoroacetate) and lH-pyrazole-3-carboxylic acid as the starting materials in 62% yield. LCMS for C27Η27CIΝ9O2
(M+H)+: τalτ = 544.0.
Example D131 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-l-(lH-l,2,4-triazol-3-ylcarbonyl)pyrrolidin- 3-yl]acetamide bis(trifluoroacetate)
Figure imgf000706_0002
The desired compound was prepared according to the procedure of Example D97, step A, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and lH-l,2,4-triazole-3-carboxylic acid as the starting materials in 68% yield. LCMS for C26Η26CIΝ10O2 (M+H)+: m/z = 545.0.
Example D132 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-l-(lH-l,2,3-triazol-4-ylcarbonyl)pyrrolidin- 3-yl]acetamide bis(trifluoroacetate)
Figure imgf000707_0001
The desired compound was prepared according to the procedure of Example D97, step A, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 4-carboxy-l,2,3-triazole as the starting materials in 87% yield. LCMS for C26H26ClNi0O2 (M+H)+: m/z = 545.0.
Example D133 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-l-(lH-pyrazol-4-ylcarbonyl)pyrrolidin-3- yl]acetamide bis(trifluoroacetate)
Figure imgf000708_0001
The desired compound was prepared according to the procedure of Example D97, step A, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and lH-pyrazole-4-carboxylic acid as the starting materials in 66% yield. LCMS for C27Η27CIΝ9O2
(M+H)+: m/z = 544.0.
Example D134 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-l-(lH-pyrazol-3-ylcarbonyl)pyrrolidin-3- yl]acetamide bis(trifluoroacetate)
Figure imgf000708_0002
The desired compound was prepared according to the procedure of Example D97, step A, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and lH-pyrazole-3-carboxylic acid as the starting materials in 66% yield. LCMS for C27Η27CIΝ9O2
(M+H)+: m/z = 544.0.
Example D135 (3S)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-(2-fluorophenyl)pyrrolidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000709_0001
The desired compound was prepared according to the procedure of Example D41 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and l-fluoro-2-isocyanatobenzene as the starting materials in 87% yield. LCMS for C30H29ClFN8O2 (M+H)+: m/z = 587.0.
Example D136
2-[(3/?)-l-(l,3-Benzothiazol-2-yl)pyrrolidin-3-yl]-iV-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide tris(trifluoroacetate)
Figure imgf000709_0002
The desired compound was prepared according to the procedure of Example A 157 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) as the starting material in 60% yield. LCMS for C30H28ClN8OS (M+H)+: m/z = 583.0. Example D137
2-[(3S)-l-(l,3-Benzothiazol-2-yl)pyrrolidin-3-yl]-iV-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide tris(trifluoroacetate)
Figure imgf000710_0001
The desired compound was prepared according to the procedure of Example A 157 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) as the starting material in 69% yield. LCMS for C30H28ClN8OS (M+H)+: m/z = 583.0.
Example D138
2-[l-(l,3-Benzothiazol-2-yl)azetidin-3-yl]-iV-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide tris(trifluoroacetate)
Figure imgf000710_0002
The desired compound was prepared according to the procedure of Example A 157 using 2- azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]acetamide tris(trifluoroacetate) as the starting material in 35% yield. LCMS for C29H26ClN8OS (M+H)+: m/z = 569.0.
Example D139 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3/?)-l-[l,3]oxazolo[5,4-6]pyridin-2-ylpyrrolidin- 3-yl]acetamide tris(trifluoroacetate)
Figure imgf000711_0001
The desired compound was prepared according to the procedure of Example Al 18 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) as the starting material in 7% yield.
LCMS for C29H27ClN9O2 (M+H)+: m/z = 568.1.
Example D140 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-l-[l,3]oxazolo[5,4-6]pyridin-2-ylpyrrolidin- 3-yl]acetamide tris(trifluoroacetate)
Figure imgf000711_0002
The desired compound was prepared according to the procedure of Example Al 18 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) as the starting material in 10% yield. LCMS for C29H27ClN9O2 (M+H)+: m/z = 568.1.
Example D141 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-[l,3]oxazolo[5,4-6]pyridin-2-ylazetidin-3- yl)acetamide tris(trifluoroacetate)
Figure imgf000712_0001
The desired compound was prepared according to the procedure of Example Al 18 using 2- azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-
1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]acetamide tris(trifluoroacetate) as the starting material in
28% yield. LCMS for C28H25ClN9O2 (M+H)+: m/z = 554.0.
Example D142 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(l-methyl-lH-pyrazol-4-yl)carbonyl]azetidin- 3-yl}acetamide bis(trifluoroacetate)
Figure imgf000713_0001
The desired compound was prepared according to the procedure of Example D94 using 2- azetidin-S-yl-N-tό-chloro-l^^Jδ^l-pentaazatetracyclofH.S.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and 1-methyl-lH- pyrazole-4-carbonyl chloride as the starting materials in 50% yield. LCMS for C27Η27CIΝ9O2 (M+H)+: m/z = 544.0.
Example D143 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{l-[(5-methylisoxazol-3-yl)carbonyl]azetidin-3- yljacetamide bis(trifluoroacetate)
Figure imgf000713_0002
The desired compound was prepared according to the procedure of Example D94 using 2- azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]acetamide tris(trifluoroacetate) and 5-methylisoxazole-3- carbonyl chloride as the starting materials in 87% yield. LCMS for C27H26ClN8O3 (M+H)+: m/z = 545.0.
Example D144 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(isoxazol-5-ylcarbonyl)azetidin-3-yl]acetamide bis(trifluoroacetate)
Figure imgf000714_0001
The desired compound was prepared according to the procedure of Example D94 using 2- azetidin-S-yl-N-tό-chloro-l^^Jδ^l-pentaazatetracyclofH.S.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]acetamide tris(trifluoroacetate) and isoxazole-5-carbonyl chloride as the starting materials in 68% yield. LCMS for C26H24ClN8O3 (M+H)+: m/z = 531.0.
Example D145 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3-thiazol-2-ylcarbonyl)azetidin-3- yl]acetamide bis(trifluoroacetate)
Figure imgf000714_0002
The desired compound was prepared according to the procedure of Example D94 using 2- azetidin-3-yl-N-[6-chloro-2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and l,3-thiazole-2- carbonyl chloride as the starting materials in 66% yield. LCMS for C26H24ClN8O2S (M+H)+: m/z : 547.2. Example D146 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(methylsulfonyl)azetidin-3-yl]acetamide bis(trifluoroacetate)
Figure imgf000715_0001
The desired compound was prepared according to the procedure of Example D20, step A, using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]acetamide tris(trifluoroacetate) as the starting material in 19% yield. LCMS fOr C23H25ClN7O3S (MH-H)+: m/z = 514.0.
Example D147 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(lH-l,2,4-triazol-3-ylcarbonyl)azetidin-3- yl]acetamide bis(trifluoroacetate)
Figure imgf000715_0002
The desired compound was prepared according to the procedure of Example D97, step A, using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and lH-l,2,4-triazole-3- carboxylic acid as the starting materials in 57% yield. LCMS for C25H24ClNi0O2 (M+H)+: m/z = 531.0.
Example D148 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(lH-l,2,3-triazol-4-ylcarbonyl)azetidin-3- yl]acetamide bis(trifluoroacetate)
Figure imgf000716_0001
The desired compound was prepared according to the procedure of Example D97, step A, usin^ 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-
I(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and 4-carboxy-l,2,3- triazole as the starting materials in 72% yield. LCMS for C25H24ClNi0O2 (M+H)+: m/z = 531.0.
Example D149 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(lH-pyrazol-4-ylcarbonyl)azetidin-3- yl]acetamide bis(trifluoroacetate)
Figure imgf000717_0001
The desired compound was prepared according to the procedure of Example D97, step A, using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and lH-pyrazole-4- carboxylic acid as the starting materials in 49% yield. LCMS for C26H25ClN9O2 (M+H)+: m/z = 530.0.
Example D150 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(lH-pyrazol-5-ylcarbonyl)azetidin-3- yl]acetamide bis(trifluoroacetate)
Figure imgf000717_0002
The desired compound was prepared according to the procedure of Example D97, step A, using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and lH-pyrazole-5- carboxylic acid as the starting materials in 66% yield. LCMS for C26H25ClN9O2 (M+H)+: m/z = 530.0.
Example D151 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3,4-thiadiazol-2-yl)azetidin-3-yl]acetamide tris(trifluoroacetate)
Figure imgf000718_0001
The desired compound was prepared according to the procedure of Example A 157 using 2- azetidin-3-yl-N-[6-chloro-2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- I(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and 2-bromo-l,3,4- thiadiazole as the starting materials in 20% yield. LCMS for C24H23ClN9OS (M+H)+: m/z = 520.0.
Example D152 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3-thiazol-2-yl)azetidin-3-yl]acetamide tris(trifluoroacetate)
Figure imgf000718_0002
A solution of 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine (15 mg, 0.04 mmol), [l-(l,3-thiazol-2-yl)azetidin-3- yl]acetic acid (11 mg, 0.06 mmol), and N,N,N,N-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (59 mg, 0.16 mmol) in N,N-dimethylformamide (0.5 mL) was treated with triethylamine (22 μL, 0.16 mmol) and stirred at room temperature overnight. The reaction mixture was purified via preparative LCMS to give the desired product (3 mg, 8%) as a solid. LCMS for
C25H24ClN8OS (M+H)+: m/z = 519.1.
Example D153 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-pyridin-2-ylazetidin-3-yl)acetamide tris(trifluoroacetate)
Figure imgf000719_0001
The desired compound was prepared according to the procedure of Example D 152 using (1- pyridin-2-ylazetidin-3-yl)acetic acid as the starting materials in 13% yield. LCMS for C27H26ClN8O
(M+H)+: m/z = 513.1.
Example D154 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3-thiazol-2-yl)pyrrolidin-3-yl]acetamide tris(trifluoroacetate)
Figure imgf000719_0002
The desired compound was prepared according to the procedure of Example D152 using [1-(1,3- thiazol-2-yl)pyrrolidin-3-yl] acetic acid as the starting materials in 8% yield. LCMS for C26H26C1N8OS
(M+H)+: m/z = 533.1.
Example D155 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3,4-thiadiazol-2-yl)pyrrolidin-3-yl]acetamide tris(trifluoroacetate)
Figure imgf000720_0001
The desired compound was prepared according to the procedure of Example D 152 using [1-
(1, 3, 4-thiadiazol-2-yl)pyrrolidin-3-yl] acetic acid as the starting materials in 8% yield. LCMS for
C25H25ClN9OS (M+H)+: m/z = 534.2.
Example D156 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-pyridin-2-ylpyrrolidin-3-yl)acetamide tris(trifluoroacetate)
Figure imgf000720_0002
The desired compound was prepared according to the procedure of Example D 152 using (1- pyridin-2-ylpyrrolidin-3-yl)acetic acid as the starting materials in 21% yield. LCMS for C2SH2SClN8O
(M+H)+: m/z = 527.2.
Example D157 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-pyridin-4-ylpyrrolidin-3-yl)acetamide tris(trifluoroacetate)
Figure imgf000721_0001
The desired compound was prepared according to the procedure of Example D 152 using (1- pyridin-4-ylpyrrolidin-3-yl)acetic acid as the starting materiasl in 13% yield. LCMS for C2SH28CINSO
(M+H)+: τalτ = 527.2.
Example D158 iV-(l-Acetylpiperidin-4-yl)-6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate)
Figure imgf000721_0002
Step A: Benzyl 4-[(2-iodo-4-nitrophenyl)amino]piperidine-l-carboxylate
Figure imgf000722_0001
The desired compound was prepared according to the procedure of Example D83, step A, using l-fluoro-2-iodo-4-nitrobenzene and benzyl 4-aminopiperidine-l-carboxylate as the starting materials in
64% yield. LCMS for Ci9H21IN3O4 (M+H)+: m/z = 482.0.
Step B: Benzyl 4-[(4-amino-2-iodophenyl)amino]piperidine-l-carboxylate
Figure imgf000722_0002
The desired compound was prepared according to the procedure of Example D 16, step D, using benzyl 4- [(2-iodo-4-nitrophenyl)amino]piperidine-l-carboxylate as the starting material in 51% yield. LCMS for
Ci9H23IN3O2 (M+H)+: m/z = 452.0.
Step C: Benzyl 4-({4-[(2,5-dichloropyrimidin-4-yl)amino]-2-iodophenyl}amino)piperidine-l-carboxylate
Figure imgf000722_0003
The desired compound was prepared according to the procedure of Example D2, step C, using benzyl 4-[(4-amino-2-iodophenyl)amino]piperidine-l-carboxylate as the starting material in 85% yield.
LCMS for C23H23Cl2IN5O2 (M+H)+: m/z = 598.0, 600.0.
Step D: Benzyl 4-({2-[(E)-2-(5-aminopyridin-3-yl)vinyl]-4-[(2,5-dichloropyrimidin-4- yl)amino]phenyl}amino)piperidine-l-carboxylate
Figure imgf000723_0001
The desired compound was prepared according to the procedure of Example B334, step G, using benzyl 4-( { 4-[(2,5-dichloropyrimidin-4-yl)amino] -2-iodophenyl } amino)piperidine- 1 -carboxylate and 5- vinylpyridin-3 -amine as the starting materials in 75% yield. LCMS for C3OH30Cl2N7O2 (M+H)+: m/z = 590.2, 592.1.
Step E: Benzyl 4-({2-[2-(5-aminopyridin-3-yl)ethyl]-4-[(2,5-dichloropyrimidin-4- yl)amino]phenyl}amino)piperidine-l -carboxylate
Figure imgf000723_0002
The desired compound was prepared according to the procedure of Example B334, step H, using benzyl 4-({2-[(i?)-2-(5-aminopyridin-3-yl)vinyl]-4-[(2,5-dichloropyrimidin-4- yl) amino] phenyl }amino)piperidine-l -carboxylate as the starting material in 85% yield. LCMS for
C30H32Cl2N7O2 (M+H)+: m/z = 592.2, 594.2.
Step F: Benzyl 4-{[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}piperidine-l-carboxylate
Figure imgf000724_0001
The desired compound was prepared according to the procedure of Example B20, step H, using benzyl 4-( { 2- [2-(5 -aminopyridin-3-yl)ethyl] -4- [(2,5 -dichloropyrimidin-4- yl)amino]phenyl}amino)piperidine-l-carboxylate as the starting material in 63% yield. LCMS for
C30H31ClN7O2 (M+H)+: m/z = 556.2.
Step G: 6-Chloro-N-piperidin-4-yl-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tetrakis(trifluoroacetate)
Figure imgf000724_0002
A solution of benzyl 4-{ [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}piperidine-l-carboxylate (0.22 g, 0.39 mmol) in dichloromethane (8 mL) was treated with iodotrimethylsilane (0.14 mL, 0.98 mmol) and stirred at 25 0C for 30 min. The reaction mixture was quenched with 1 M HCl (0.2 mL) and concentrated to a crude residue. This material was purified by preparative LCMS to give the desired product (0.20 g, 66%) as a solid. LCMS for C22H25ClN7 (M+H)+: m/z = 422.1.
Step H: N-(l-Acetylpiperidin-4-yl)-6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate)
The desired compound was prepared according to the procedure of Example D94 using 6-chloro- N-piperidin-4-yl-2,4, 8 , 18 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7).1 (9, 13)] docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-amine tris(trifluoroacetate) and acetyl chloride as the starting materials in 57% yield. LCMS for C24H27ClN7O (M+H)+: m/z = 464.2.
Example D159
6-Chloro-iV-[l-(phenylacetyl)piperidin-4-yl]-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate)
Figure imgf000725_0001
The desired compound was prepared according to the procedure of Example D94 using 6-chloro- N-piperidin-4-yl-2,4, 8 , 18 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7).1 (9, 13)] docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-amine tris(trifluoroacetate) and benzeneacetyl chloride as the starting materials in 29% yield. LCMS for C30H3ICIN7O (M+H)+: m/z = 540.2.
Example D160 ό-Chloro-iV-il-tCS-methylisoxazol-S-yOcarbonyllpiperidin^-yll^^^jlS^- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate)
Figure imgf000725_0002
The desired compound was prepared according to the procedure of Example D94 using 6-chloro- N-piperidin-4-yl-2,4, 8 , 18 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7).1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate) and 5-methylisoxazole-3- carbonyl chloride as the starting materials in 52% yield. LCMS for C27H28ClN8O2 (M+H)+: m/z = 531.2.
Example D161
12-[2-(l-Acetylpiperidin-4-yl)ethoxy]-6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Step A: 2-Iodo-4-nitroaniline
Figure imgf000726_0001
A solution of iodine monochloride (25.8 mL, 514 mmol) in water (220 mL) at 0 0C was treated with concentrated hydrogen chloride (87 mL, 2800 mmol) and stirred until the iodine monochloride dissolved. This cooled ICl solution was then added to a solution of p-nitroaniline (71 g, 510 mmol) in water (590 mL) and concentrated hydrogen chloride (50 mL, 2000 mmol) and stirred at 20 0C for 3 hours. The reaction mixture was filtered, washed with water, and dried to give the desired product (132 g, 94%) as a yellow solid. LCMS for C6H6IN2O2 (M+H)+: m/z = 264.7 .
Step B: l-Fluoro-2-iodo-4-nitrobenzene
Figure imgf000726_0002
A solution of nitrosonium tetrafluoroborate (24 g, 0.21 mol) in dichloromethane (200 mL) at 0 °C was treated with a solution of 2-iodo-4-nitroaniline (50 g, 0.19 mol) in dichloromethane (350 mL) and stirred at 0 0C for 1 h. The dichloromethane was concentrated to about half volume and the reaction mixture was treated with 1 ,2-dichlorobenzene (300 mL). The remaining dichloromethane was further concentrated in vacuo. The resultant 1 ,2-dichlorobenzene suspension was heated at 110 0C for 1 h, cooled to 20 0C, and treated with water (200 mL) and dichloromethane (500 mL). The reaction mixture was filtered over celite and the celite was washed with dichloromethane and water. The aqueous layer of the filtrate was separated and extracted with dichloromethane (2x). The combined organic layers were washed with 20% sodium thiosulfate and brine, dried over anhydrous sodium sulfate, and filtered. The dichloromethane was removed under standard conditions while the 1 ,2-dichlorobenzene was removed via vacuum distillation to give a crude dark oil. This material was purified by distillation to give the desired product (19 g, 38%) as a solid.
Step C: tert-Butyl 4-[2-(2-iodo-4-nitrophenoxy)ethyl]piperidine-l-carboxylate
Figure imgf000727_0001
A solution of sodium hydride (0.16 g, 3.9 mmol) in tetrahydrofuran (10 mL) at 0 0C was treated with a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-l-carboxylate (0.82 mL, 3.7 mmol) in tetrahydrofuran (5 mL) and stirred at 0 0C for 30 minutes. The reaction mixture was treated with a solution of l-fluoro-2-iodo-4-nitrobenzene (1.0 g, 3.7 mmol) in tetrahydrofuran (5 mL) and heated at 70 0C for 16 h. The reaction mixture was concentrated, diluted with ethyl acetate, and washed with water. The aqueous layer was separated and extracted with additional ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered, and concentrated to a crude brown oil. Purification by flash column chromatography gave the desired product (1.4 g, 81%) as a yellow oil. LCMS for Ci8H25IN2O5Na (M+Na)+: m/z = 499.0 .
Step D: tert-Butyl 4-[2-(4-amino-2-iodophenoxy)ethyl]piperidine-l-carboxylate
Figure imgf000727_0002
The desired compound was prepared according to the procedure of Example D2, step B, using tert-butyl 4-[2-(2-iodo-4-nitrophenoxy)ethyl]piperidine-l-carboxylate as the starting material in 99% yield. LCMS for Ci8H27IN2O3Na (M+Na)+: m/z = 469.0.
Step E: tert-Butyl 4-(2-{4-[(2,5-dichloropyrimidin-4-yl)amino]-2-iodophenoxyjethyl)piperidine-l- carboxylate
Figure imgf000728_0001
The desired compound was prepared according to the procedure of Example D2, step C, using tert-butyl 4-[2-(4-amino-2-iodophenoxy)ethyl]piperidine-l-carboxylate as the starting material in 87% yield. LCMS for C22H27Cl2IN4O3Na (M+Na)+: m/z = 615.0.
Step F: tert-Butyl 4-(2-{2-[(E)-2-(5-aminopyridin-3-yl)vinyl]-4-[(2, 5 -dichloropyrimidin-4- yl)amino]phenoxy}ethyl)piperidine-l -carboxylate
Figure imgf000728_0002
The desired compound was prepared according to the procedure of Example B334, step G, usin^ tert-butyl 4-(2-{4-[(2,5-dichloropyrimidin-4-yl)amino]-2-iodophenoxy}ethyl)piperidine-l -carboxylate and 5-vinylpyridine-3-amine as the starting materials in 99% yield. LCMS for C29H35Cl2N6O3 (M+H)+: m/z = 585.3, 587.2.
Step G: tert-Butyl 4-(2-{2-[2-(5-aminopyridin-3-yl)ethyl]-4-[(2,5-dichloropyrimidin-4- yl)amino]phenoxy}ethyl)piperidine-l -carboxylate
Figure imgf000729_0001
The desired compound was prepared according to the procedure of Example B334, step H, usin^ tert-butyl 4-(2-{2-[(E)-2-(5-aminopyridin-3-yl)vinyl]-4-[(2,5-dichloropyrimidin-4- yl) amino] phenoxy}ethyl)piperidine-l-carboxylate as the starting material in 86% yield. LCMS for C29H37Cl2N6O3 (M+H)+: m/z = 587.2, 589.2.
Step H: tert-Butyl 4-(2-f[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxyjethyl)piperidine-l-carboxylate
Figure imgf000729_0002
The desired compound was prepared according to the procedure of Example B20, step H, using tert-butyl 4-(2-{2-[2-(5-aminopyridin-3-yl)ethyl]-4-[(2,5-dichloropyrimidin-4- yl) amino] phenoxy}ethyl)piperidine-l-carboxylate as the starting material. This material was used in the next step without further purification.
Step I: 6-Chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000730_0001
The desired compound was prepared according to the procedure of Example D 16, step B, using tert-butyl A-(I- { [6-chloro-2,4, 8 , 18 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)piperidine-l-carboxylate as the starting material in 48% yield (2 steps). LCMS for C24H28ClN6O (M+H)+: m/z = 451.1.
Step J: 12-[2-(l-Acetylpiperidin-4-yl)ethoxy]-6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) The desired compound was prepared according to the procedure of Example D94 using 6-chloro-
12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and acetyl chloride as the starting materials in 66% yield. LCMS fOr C26H30ClN6O2 (MH-H)+: m/z = 493.1.
Example D162
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-iV-phenylpiperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000730_0002
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate)and phenyl isocyanate as the starting materials in 50% yield. LCMS for C31H33ClN7O2 (M+H)+: m/z = 570.1.
Example D163
2-{[4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)piperidin-l- yl]sulfonyl}benzonitrilebis(trifluoroacetate)
Figure imgf000731_0001
The desired compound was prepared according to the procedure of Example D20, step A, using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and 2-cyanobenzenesulfonyl chloride as the starting materials in 62% yield. LCMS for C31H31CIN7O3S (M+H)+: m/z = 616.0.
Example D164
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-iV-(2-methyl-3-furyl)piperidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000732_0001
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and 3-isocyanato-2-methylfuran as the starting materials in 8% yield. LCMS for C30H33ClN7O3 (M+H)+: m/z = 574.1.
Example D165
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-iV-(2-furylmethyl)piperidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000732_0002
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and 2-(isocyanatomethyl)furan as the starting materials in 40% yield. LCMS for C30H33ClN7O3 (M+H)+: m/z = 574.1.
Example D166 4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-iV-3-thienylpiperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000733_0001
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-
12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and 3-isocyanatothiophene as the starting materials in 30% yield. LCMS for C29H31ClN7O2S (M+H)+: m/z = 576.0.
Example D167
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-iV-2-thienylpiperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000733_0002
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-
12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and 2-isocyanatothiophene as the starting materials in 20% yield. LCMS for C29H31ClN7O2S (M+H)+: m/z = 576.0. Example D168
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-iV-(4-fluorophenyl)piperidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000734_0001
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and l-fluoro-4-isocyanatobenzene as the starting materials in 40% yield. LCMS for C3IH32ClFN7O2 (M+H)+: m/z = 588.2.
Example D169
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-iV-(3-fluorophenyl)piperidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000734_0002
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and l-fluoro-3-isocyanatobenzene as the starting materials in 60% yield. LCMS for C3iH32ClFN7O2 (M+H)+: m/z = 588.1. Example D170
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-iV-(2-fluorophenyl)piperidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000735_0001
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and l-fluoro-2-isocyanatobenzene as the starting materials in 40% yield. LCMS for C3IH32ClFN7O2 (M+H)+: m/z = 588.1.
Example D171
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-iV-(3,5-dimethylisoxazol-4-yl)piperidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000735_0002
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 4-isocyanato-3,5-dimethylisoxazole as the starting materials in 50% yield. LCMS for C30H34ClN8O3 (M+H)+: m/z = 589.1.
Example D172
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-iV-(4-methyl-2-thienyl)piperidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000736_0001
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-
1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and 2-isocyanato-4-methylthiophene as the starting materials in 34% yield. LCMS for C30H33ClN7O2S (M+H)+: m/z = 590.0.
Example D173 4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-iV-(2-cyanophenyl)piperidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000736_0002
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and 2-isocyanatobenzonitrile as the starting materials in 40% yield. LCMS for C32H32ClN8O2 (M+H)+: m/z = 595.0.
Example D174
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-iV-(4-cyanophenyl)piperidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000737_0001
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and 4-isocyanatobenzonitrile as the starting materials in 40% yield. LCMS for C32H32ClN8O2 (M+H)+: m/z = 595.0.
Example D175
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-N-(2,2-dimethyl-2,3-dihydro-l- benzofuran-7-yl)piperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000738_0001
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 7-isocyanato-2,2-dimethyl-2,3- dihydro-1-benzofuran as the starting materials in 60% yield. LCMS for C35H39ClN7O3 (M+H)+: m/z = 640.1.
Example D176
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-iV-(6-morpholin-4-ylpyridin-2- yl)piperidine- 1-carboxamide tris(trifluoroacetate)
Figure imgf000738_0002
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 4-(6-isocyanatopyridin-2- yl)morpholine as the starting materials in 45% yield. LCMS for C34H39ClN9O3 (M+H)+: m/z = 656.2.
Example D177 6-Chloro-12-{2-[l-(pyrazin-2-ylcarbonyl)piperidin-4-yl]ethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000739_0001
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-
12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-
1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and pyrazine-2-carbonyl chloride as the starting materials in 50% yield. LCMS for C29H30ClN8O2 (M+H)+: m/z = 557.0.
Example D178
6-Chloro-12-(2-{l-[(5-methylisoxazol-4-yl)carbonyl]piperidin-4-yl}ethoxy)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000739_0002
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-
12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 5-methylisoxazole-4-carbonyl chloride as the starting materials in 40% yield. LCMS for C29H31ClN7O3 (M+H)+: m/z = 560.0. Example D179
6-Chloro-12-(2-{l-[(2-chloropyridin-3-yl)carbonyl]piperidin-4-yl}ethoxy)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000740_0001
The desired compound was prepared according to the procedure of Example D94 using 6-chloro- 12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and 2-chloronicotinoyl chloride as the starting materials in 30% yield. LCMS for C3OH30Cl2N7O2 (M+H)+: m/z = 590.0, 592.0.
Example D180
6-Chloro-12-{2-[l-(pyridin-3-ylcarbonyl)piperidin-4-yl]ethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000740_0002
The desired compound was prepared according to the procedure of Example D94 using 6-chloro- 12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and nicotinoyl chloride hydrochloride as the starting materials in 50% yield. LCMS for C30H3iClN7O2 (M+H)+: m/z = 556.1. Example D181
6-Chloro-12-[2-(l-isonicotinoylpiperidin-4-yl)ethoxy]-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000741_0001
The desired compound was prepared according to the procedure of Example D94 using 6-chloro- 12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and isonicotinoyl chloride hydrochloride as the starting materials in 30% yield. LCMS for C30H31ClN7O2 (M+H)+: m/z = 556.1.
Example D182
4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-iV-pyridin-3-ylpiperidine-l-carboxamide tris(trifluoroacetate)
Figure imgf000741_0002
The desired compo w prepared according to the of Example D41 using 6-chloro- 12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and 3-isocyanatopyridine as the starting materials in 20% yield. LCMS for C30H32ClN8O2 (M+H)+: m/z = 571.0.
Example D183 Methyl [4-01110^-19-0X0-18-0X3-2,6,8,20,25- pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa-l(23),3(25),4,6,9(24),10,12,16,21- nonaen-20-yl]acetate trifluoroacetate
Figure imgf000742_0001
Step A: tert-Butyl (2-hydroxy-5-nitrophenyl)carbamate
Figure imgf000742_0002
The desired compound was prepared according to the procedure of Example D2, step A, using 2- amino-4-nitrophenol as the starting material in 82% yield. LCMS for CnHi4N2O5Na (M+Na)+: m/z = 277.0.
Step B: tert-Butyl (2-hydroxy-3-iodo-5-nitrophenyl)carbamate
Figure imgf000742_0003
A solution of tert-butyl (2-hydroxy-5-nitrophenyl)carbamate (4.2 g, 16 mmol) in methanol (18 mL) at 0 0C was treated with sodium bicarbonate (3.0 g, 36 mmol) followed by N,N,N- trimethyl(phenyl)methanaminium dichloroiodanuide (6.3 g, 18 mmol) and stirred at 20 0C for 16 h. The reaction mixture was filtered and washed with 25% MeOH/CH2Cl2 (200 mL). The filtrate was concentrated and diluted with ethyl acetate (300 mL) and 0.5 M HCl (100 mL). The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude gummy solid. This material was concentrated from hexanes (2x) to give the desired product (5.7 91%) as an orange solid. LCMS for CnH13IN2O5Na (M+Na)+: m/z = 402.8.
Step C: 7-Iodo-5-nitro-l,3-benzoxazol-2(3H)-one
Figure imgf000743_0001
A solution of tert-butyl (2-hydroxy-3-iodo-5-nitrophenyl)carbamate (1.0 g, 2.6 mmol) and NN- carbonyldiimidazole (0.47 g, 2.9 mmol) in THF (6 mL) was stirred at reflux for 1 h. The reaction mixture was concentrated, diluted with ethyl acetate (100 mL), washed with 1 Ν HCl (50 mL), water (20 mL), and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude solid. This material was concentrated from hexanes (2x) to give the desired product (5.7 g, 91%) as an orange solid. This material was purified by flash column chromatography to give the desired product (0.66 g, 82%) as a yellow solid. LCMS for C7H4IN2O4 (M+H)+: m/z = 306.8.
Step D: Methyl (7-iodo-5-nitro-2-oxo-l,3-benzoxazol-3(2H)-yl)acetate
Figure imgf000743_0002
A solution of 7-iodo-5-nitro-l,3-benzoxazol-2(3H)-one (1.6 g, 5.3 mmol) in NN- dimethylformamide (11 mL) at 0 0C was treated with potassium carbonate (1.2 g, 8.4 mmol) followed by methyl bromoacetate (0.75 mL, 7.9 mmol) and stirred at 20 0C for 2 h. The reaction mixture was added drop wise to a solution of IM HCl (100 mL) at 0 0C and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude solid. This material was washed with cold methanol to give the desired product (1.6 g, 79%) as a solid. LCMS for Ci0H8IN2O6 (M+H)+: m/z = 378.8.
Step E: Methyl [7-({3-[(tert-butoxycarbonyl)amino]phenyl}ethynyl)-5-nitro-2-oxo-l, 3-benzoxazol-3(2H)- yljacetate BocHN
Figure imgf000744_0001
The desired compound was prepared according to the procedure of Example B5, step C, using methyl (7-iodo-5-nitro-2-oxo-l,3-benzoxazol-3(2H)-yl)acetate and tert-butyl (3-ethynylphenyl)carbamate as the starting materials in quantitative yield. LCMS for C2SH2IN3O8Na (M+Na)+: m/z = 490.0.
Step F: Methyl [5-amino-7-(2-{3-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-2-oxo-l,3-benzoxazol-
3(2H)-yl]acetate
Figure imgf000744_0002
The desired compound was prepared according to the procedure of Example D82, step C, using methyl [T-dS-fCtert-butoxycarbony^aminolphenylJethyny^-S-nitro-l-oxo-l^-benzoxazol-SClH)- yl] acetate as the starting material in 94% yield. LCMS for C23H27N3O6Na (M+Na)+: m/z = 464.0.
Step G: Methyl [7-(2-{3-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-5-[(2,5-dichloropyrimidin-4- yl)amino]-2-oxo-l,3-benzoxazol-3(2H)-yl] 'acetate
Figure imgf000744_0003
The desired compound was prepared according to the procedure of Example D2, step C, using methyl [5-amino-7-(2-{3-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-2-oxo-l,3-benzoxazol-3(2H)- yl] acetate as the starting material in 70% yield. LCMS for C27H27Cl2N5O6Na (M+Na)+: m/z = 609.9. Step H: Methyl [4-chloro-19-oxo-18-oxa-2,6,8,20,25- pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa-l(23),3(25),4,6,9(24),10,12,16,21-nonaen- 20-yl]acetate trifluoroacetate
The desired compound was prepared according to the procedure of Example D32, step F, using methyl [7-(2-{3-[(ter^butoxycarbonyl)amino]phenyl}ethyl)-5-[(2,5-dichloropyrimidin-4-yl)amino]-2- oxo-1, 3-benzoxazol-3(2H)-yl]acetate as the starting material in 20% yield. LCMS for 022H19ClN5O4
(M+H)+: τalτ = 452.0.
Example D184
4-Chloro-18-oxa-2,6,8,20,25-pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa- l(23),3(25),4,6,9(24),10,12,16,21-nonaen-19-one
Figure imgf000745_0001
Step A: 7-Iodo-5-nitro-3-{[2-(trimethylsilyl)ethoxy]methylj-l,3-benzoxazol-2(3H)-one
Figure imgf000745_0002
A solution of 7-iodo-5-nitro-l,3-benzoxazol-2(3H)-one (0.76 g, 2.5 mmol) in N,N- dimethylformamide (5 mL) at 0 0C was treated with N,N-diisopropylethylamine (0.65 mL, 3.7 mmol) followed by [β-(trimethylsilyl)ethoxy] methyl chloride (0.61 mL, 3.5 mmol) dropwise and stirred at 20 0C for 1 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 0.5 M HCl (50 mL), brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a crude oil. This material was purified by flash column chromatography to give the desired product (0.93 g, 86%) as a yellow oil.
Step B: tert-Butyl {3-[(5-nitro-2-oxo-3-{[2-(trimethylsilyl)ethoxy]methylj-2,3-dihydro-l,3-benzoxazol-7- yl)ethynyl]phenyl}carbamate BocHN
Figure imgf000746_0001
The desired compound was prepared according to the procedure of Example B5, step C, using 7- iodo-5-nitro-3-{ [2-(trimethylsilyl)ethoxy] methyl }-l, 3 -benzoxazol-2(3H)-on and tert-butyl (3- ethynylphenyl)carbamate as the starting materials in quantitative yield. LCMS for C2OH31N3O7SiNa
(M+Na)+: m/z = 548.0.
Step C: tert-Butyl {3-[2-(5-amino-2-oxo-3-{[2-(trimethylsilyl)ethoxy]methylj-2,3-dihydro-l,3- benzoxazol-7-yl)ethyl]phenylj 'carbamate
BocHN
Figure imgf000746_0002
The desired compound was prepared according to the procedure of Example D82, step C, usin^ tert-butyl {S-fCS-nitro-l-oxo-S-l fl-^rimethylsily^ethoxyJmethylJ-l^-dihydro-l^-benzoxazol-?- yl)ethynyl]phenyl}carbamate as the starting material in 46% yield. LCMS for C2OH37N3O5SiNa
(M+Na)+: m/z = 522.1.
Step D: tert-Butyl {3-[2-(5-[(2,5-dichloropyrimidin-4-yl)amino]-2-oxo-3-{[2- (trimethylsilyl)ethoxy]methyl}-2,3-dihydro-l, 3-benzoxazol- 7 -yl)ethyl]phenyl} carbamate
BocHN
Figure imgf000746_0003
The desired compound was prepared according to the procedure of Example D2, step C, using tert-butyl {3-[2-(5-amino-2-oxo-3-{ [2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-l, 3-benzoxazol -7- yl)ethyl]phenyl} carbamate as the starting material in 92% yield. LCMS for C30H37Cl2N5O5SiNa
(M+Na)+: m/z = 668.0. Step E: 4-Chloro-20-{[2-(trimethylsilyl)ethoxy]methyl}-18-oxa-2,6,8,20,25- pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa-l(23),3(25),4,6,9(24),10,12,16,21-nonaen- 19 -one
Figure imgf000747_0001
The desired compound was prepared according to the procedure of Example D32, step F, using tert-butyl {3-[2-(5-[(2,5-dichloropyrimidin-4-yl)amino]-2-oxo-3-{ [2-(trimethylsilyl)ethoxy]methyl}-2,3- dihydro-l,3-benzoxazol-7-yl)ethyl]phenyl}carbamate as the starting material in 51% yield. LCMS for
C25H29ClN5O3Si (M+H)+: m/z = 510.0.
Step F: 4- Chloro-18-oxa-2, 6, 8, 20, 25-pentaazapentacyclo[14.6.1.1 (3, 7).1 (9, 13).0(17, 21)]pentacosa- l(23),3(25),4,6,9(24),10,12,16,21-nonaen-19-one
A solution of 4-chloro-20-{ [2-(trimethylsilyl)ethoxy]methyl}-18-oxa-2,6,8,20,25- pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa-l(23),3(25),4,6,9(24),10,12,16,21-nonaen- 19-one (25 mg, 49 μmol) in TFA (1.5 mL) was stirred at 20 0C for 30 min. The reaction mixture was concentrated and reconcentrated from dichloromethane to a residue. This residue was dissolved in THF (1.5 mL) and treated with 20 M of ammonia in water (1 mL, 20 mmol) dropwise and stirred at 20 0C for 1 h. The reaction mixture was poured into water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product (19 mg, quantitative) as a white solid. LCMS for Ci9Hi5ClN5O2 (M+H)+: m/z = 380.0.
Example D185
2-[4-Chloro-19-oxo-18-oxa-2,6,8,20,25-pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa- l(23),3(25),4,6,9(24),10,12,16,21-nonaen-20-yl]-iV-phenylacetamide trifluoroacetate
Figure imgf000748_0001
Step A: [4-Chloro-19-oxo-18-oxa-2,6,8,20,25- pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa-l(23),3(25),4,6,9(24),10,12,16,21-nonaen-
20-yl]aceticacid
Figure imgf000748_0002
A solution of methyl [4-chloro-19-oxo-18-oxa-2,6,8,20,25- pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa-l(23),3(25),4,6,9(24),10,12,16,21-nonaen- 20-yl]acetate (0.23 g, 0.51 mmol) in dichloromethane (15 mL) at -78 0C was treated with 1 M of boron tribromide in dichloromethane (1.5 mL, 1.5 mmol) and stirred at 20 0C for 16 h. The reaction mixture was cooled to 0 0C, treated with additional 1 M of boron tribromide in dichloromethane (1.5 mL, 1.5 mmol), and stirred at 20 0C for 6 h. The reaction mixture was cooled to 0 0C, quenched with 0.5 M HCl (10 mL) dropwise, concentrated and filtered. The brown solid that was collected was washed with water and dried. This material was diluted with dichloromethane (20 mL), cooled to 0 0C, treated with 1 M of boron tribromide in dichloromethane (1.5 mL, 1.5 mmol), and stirred at 20 0C for 24 h. The reaction mixture was cooled to 0 0C, quenched with 0.5 M HCl (10 mL) dropwise, concentrated and filtered. The brown solid that was collected was washed with water and dried to give the desired product (0.15 g, 67%) as a tan solid. LCMS for C2IH17ClN5O4 (M+H)+: m/z = 438.0.
Step B: 2-[4-Chloro-19-oxo-18-oxa-2,6,8,20,25- pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa-l(23),3(25),4,6,9(24),10,12,16,21-nonaen- 20-yl]-N-phenylacetamide trifluoroacetate
The desired compound was prepared according to the procedure of Example D 152 using [4- chloro-19-oxo-18-oxa-2,6,8,20,25-pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa- l(23),3(25),4,6,9(24),10,12,16,21-nonaen-20-yl]aceticacid and aniline as the starting materials in 20% yield. LCMS for C27H22ClN6O3 (M+H)+: m/z = 513.0.
Example D186 iV-Benzyl-2-[4-chloro-19-oxo-18-oxa-2,6,8,20,25- pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa-l(23),3(25),4,6,9(24),10,12,16,21- nonaen-20-yl]acetamide trifluoroacetate
Figure imgf000749_0001
The desired compound was prepared according to the procedure of Example D 152 using [4- chloro-lQ-oxo-lδ-oxa^ΛS^O^S-pentaazapentacyclotH.ό.l.1(3,7). l(9,13).0(17,21)]pentacosa- l(23),3(25),4,6,9(24),10,12,16,21-nonaen-20-yl]aceticacid and benzylamine as the starting materials in
30% yield. LCMS for C28H24ClN6O3 (M+H)+: m/z = 527.0.
Example D187 4-Chloro-20-(2-morpholin-4-yl-2-oxoethyl)-18-oxa-2,6,8,20,25- pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa-l(23),3(25),4,6,9(24),10,12,16,21- nonaen-19-one trifluoroacetate
Figure imgf000749_0002
The desired compound was prepared according to the procedure of Example D 152 using [4- chloro-19-oxo-18-oxa-2,6,8,20,25-pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa- l(23),3(25),4,6,9(24),10,12,16,21-nonaen-20-yl]aceticacid and morpholine as the starting materials in
31% yield. LCMS for C25H24ClN6O4 (M+H)+: m/z = 507.0. Example D188
4-Chloro-20-[2-oxo-2-(4-phenylpiperazin-l-yl)ethyl]-18-oxa-2,6,8,20,25- pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa-l(23),3(25),4,6,9(24),10,12,16,21- nonaen-19-one bis(trifluoroacetate)
Figure imgf000750_0001
The desired compound was prepared according to the procedure of Example D 152 using [4- chloro-19-oxo-18-oxa-2,6,8,20,25-pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa- l(23),3(25),4,6,9(24),10,12,16,21-nonaen-20-yl]aceticacid and 1-phenyl-piperazine as the starting materials in 26% yield. LCMS for C3IH29ClN7O3 (M+H)+: m/z = 582.0. 0
Example D189
6-Chloro-19-(morpholin-4-ylmethyl)-14-oxa-2,4,8,23- tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene bis(trifluoroacetate)
Figure imgf000750_0002
A solution of 19-bromo-6-chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene (25 mg, 60 μmol), potassium trifluoro(morpholin-4- ylmethyl)borate(l-) (15 mg, 72 μmol), cesium carbonate (59 mg, 0.18 mmol), dicyclohexyl(2',4',6'- triisopropylbiphenyl-2-yl)phosphine (3.4 mg, 7.2 μmol), and palladium acetate (0.81 mg, 36 μmol) in 5.10 M of water in THF (0.5 mL, 2.5 mmol) that was previously degassed with nitrogen was heated in a sealed tube at 80 0C for 24 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (14 mg, 35%) as a white solid. LCMS for C23H25ClN5O2 (M+H)+: m/z = 438.0.
Example D190 6-Chloro-19-[(4-methylpiperazin-l-yl)methyl]-14-oxa-2,4,8,23- tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene tris(trifluoroacetate)
Figure imgf000751_0001
The desired compound was prepared according to the procedure of Example D 189 using potassium trifluoro[(4-methylpiperazin-l-yl)methyl]borate(l-) as the starting material in 38% yield.
LCMS for C24H28ClN6O (M+H)+: m/z = 451.0.
Example D191
6-Chloro-19-(piperazin-l-ylmethyl)-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene tris(trifluoroacetate)
Figure imgf000751_0002
Step A: tert-Butyl 4-{[6-chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]methyljpiperazine-l-carboxylate
Figure imgf000751_0003
The desired compound was prepared according to the procedure of Example D 189 using potassium { [4-(tert-butoxycarbonyl)piperazin-l-yl] methyl }(trifluoro)borate(l-) as the starting material. The desired product was used in the next step without further purification.
Step B: 6-Chloro-19-(piperazin-l-ylmethyl)-14-oxa-2,4,8,23- tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene tris(trifluoroacetate) A solution of tert-butyl 4-{
Figure imgf000752_0001
tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19- yl] methyl }piperazine-l-carboxylate in TFA (1.5 mL) was stirred at 20 0C for 15 min, concentrated, and purified by preparative LCMS to give the desired product (15 mg, 32% for 2 steps) as a white solid. LCMS for C23H26ClN6O (M+H)+: m/z = 437.0.
Example D192 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamidebis(trifluoroacetate)
Figure imgf000752_0002
Step A: tert-Butyl 4-{[6-chloro-14-oxa-2,4,8,23-tetraazatetracydo[ 15.3.1.1(3,7).1(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]methyl}piperazine-l-carboxylate
Figure imgf000752_0003
The desired compound was prepared according to the procedure of Example D 152 using 6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine bis(trifluoroacetate) and [(35)- l-(tert-butoxycarbonyl)piperidin-3-yl] acetic acid as the starting materials. The crude reaction product was purified by preparative LCMS to give the desired product which was used immediately in the next step.
Step B: N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamidebis(trifluoroacetate) A solution of tert-butyl (3S)-3-(2-{ [6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}- 2-oxoethyl)piperidine-l-carboxylate in TFA (2 mL) was stirred at 20 0C for 15 min, concentrated, and purified by preparative LCMS to give the desired product (63 mg, 21% for 2 steps) as a solid. LCMS for C25H28ClN6O (M+H)+: m/z = 463.0.
Example D193 iV-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3/?)-piperidin-3-yl]acetamidebis(trifluoroacetate)
Figure imgf000753_0001
The desired compound was prepared according to the procedure of Example D 192 using [(3R)-I-
(tert-butoxycarbonyl)piperidin-3-yl] acetic acid as the starting material in 15% yield. LCMS for C25H28ClN6O (M+H)+: m/z = 463.0.
Example D194 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-piperidin-3- yl]acetamidetris(trifluoroacetate)
Figure imgf000753_0002
The desired compound prepared according to the procedure of Example D 192 using 6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine tris(trifluoroacetate) as the starting material in 44% yield. LCMS for C24H27CIN7O (M+H)+: τalτ = 464.0.
Example D195 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3fl)-piperidin-3- yl]acetamidetris(trifluoroacetate)
Figure imgf000754_0001
The desired compound was prepared according to the procedure of Example D 192 using 6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-amine tris(trifluoroacetate) and [(3R)- l-(tert-butoxycarbonyl)piperidin-3-yl] acetic acid as the starting materials in 39% yield. LCMS for C24H27ClN7O (M+H)+: m/z = 464.0.
Example D196 (3S)-3-(2-{[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-phenylpiperidine-l- carboxamide trifluoroacetate
Figure imgf000754_0002
The desired compound was prepared according to the procedure of Example D41 using N- [6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamide bis(trifluoroacetate) and phenyl isocyanate as the starting materials in 40% yield. LCMS for C32H33ClN7O2 (M+H)+: m/z = 582.2.
Example D197
(3/?)-3-(2-{[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-phenylpiperidine-l- carboxamide trifluoroacetate
Figure imgf000755_0001
The desired compound was prepared according to the procedure of Example D41 using N- [6 - chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide bis(trifluoroacetate) and phenyl isocyanate as the starting materials in 50% yield. LCMS for C32H33ClN7O2 (M+H)+: m/z = 582.0.
Example D198 (3S)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-phenylpiperidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000755_0002
The desired compound was prepared according to the procedure of Example D41 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamide tris(trifluoroacetate) and phenyl isocyanate as the starting materials in 70% yield. LCMS for C3IH32ClN8O2 (M+H)+: m/z = 583.0.
Example D199
(3/?)-3-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-iV-phenylpiperidine-l- carboxamide bis(trifluoroacetate)
Figure imgf000756_0001
The desired compound was prepared according to the procedure of Example D41 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide tris(trifluoroacetate) and phenyl isocyanate as the starting materials in 60% yield. LCMS for C3iH32ClΝ8O2 (M+H)+: m/z = 583.1.
Example D200
2-[(3S)-l-Acetylpiperidin-3-yl]-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide trifluoroacetate
Figure imgf000756_0002
The desired compound was prepared according to the procedure of Example D94 using N- [6 - chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-piperidin-3-yl]acetamide bis(trifluoroacetate) and acetyl chloride as the starting materials in 67% yield. LCMS for C27H30ClN6O2 (M+H)+: m/z = 505.1. Example D201
2-[(3/?)-l-Acetylpiperidin-3-yl]-iV-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide trifluoroacetate
Figure imgf000757_0001
The desired compound was prepared according to the procedure of Example D94 using N- [6- chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide bis(trifluoroacetate) and acetyl chloride as the starting materials in 78% yield. LCMS for C27H30ClN6O2 (M+H)+: m/z = 505.0.
Example D202
2-[(3S)-l-Benzoylpiperidin-3-yl]-iV-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide trifluoroacetate
Figure imgf000757_0002
The desired compound was prepared according to the procedure of Example D94 using N- [6 - chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamide bis(trifluoroacetate) and benzoyl chloride as the starting materials in 71% yield. LCMS for C32H32ClN6O2 (M+H)+: m/z = 567.0.
Example D203 2-[(3/?)-l-Benzoylpiperidin-3-yl]-iV-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide trifluoroacetate
Figure imgf000758_0001
The desired compound was prepared according to the procedure of Example D94 using N- [6 - chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide bis(trifluoroacetate) and benzoyl chloride as the starting materials in 71% yield. LCMS for C32H32ClN6O2 (M+H)+: m/z = 567.0.
Example D204
2-[(3S)-l-Acetylpiperidin-3-yl]-iV-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide bis(trifluoroacetate)
Figure imgf000758_0002
The desired compound was prepared according to the procedure of Example D94 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-piperidin-3-yl]acetamide tris(trifluoroacetate) and acetyl chloride as the starting materials in 77% yield. LCMS for C26H29ClN7O2 (M+H)+: m/z = 506.0.
Example D205 2-[(3/?)-l-Acetylpiperidin-3-yl]-iV-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide bis(trifluoroacetate)
Figure imgf000759_0001
The desired compound was prepared according to the procedure of Example D94 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide tris(trifluoroacetate) and acetyl chloride as the starting materials in 55% yield. LCMS for C26H29ClN7O2 (M+H)+: m/z = 506.0.
Example D206
2-[(3S)-l-Benzoylpiperidin-3-yl]-iV-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide bis(trifluoroacetate)
Figure imgf000759_0002
The desired compound was prepared according to the procedure of Example D94 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-piperidin-3-yl]acetamide tris(trifluoroacetate) and benzoyl chloride as the starting materials in 61% yield. LCMS for C3IH3IClN7O2 (M+H)+: m/z = 568.0.
Example D207 2-[(3/?)-l-Benzoylpiperidin-3-yl]-iV-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide bis(trifluoroacetate)
Figure imgf000760_0001
The desired compound was prepared according to the procedure of Example D94 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide tris(trifluoroacetate) and benzoyl chloride as the starting materials in 51% yield. LCMS for C3iH31ClΝ7O2 (M+H)+: m/z = 568.0.
Example D208 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3S)-l-[(5-methylisoxazol-3- yl)carbonyl]piperidin-3-yl}acetamide bis(trifluoroacetate)
Figure imgf000760_0002
The desired compound was prepared according to the procedure of Example D94 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamide tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 60% yield. LCMS for C29H30ClN8O3 (M+H)+: m/z = 573.0.
Example D209 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3/?)-l-[(5-methylisoxazol-3- yl)carbonyl]piperidin-3-yl}acetamide bis(trifluoroacetate)
Figure imgf000761_0001
The desired compound was prepared according to the procedure of Example D94 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 60% yield. LCMS for C29H30ClN8O3 (M+H)+: m/z = 573.1.
Example D210 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)ethanesulfonamide bis(trifluoroacetate)
Figure imgf000761_0002
The desired compound was prepared according to the procedure of Example D20, step A, using 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21), 10,12,16,18- nonaen-12-amine tris(trifluoroacetate) and 2-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)ethanesulfonyl chloride as the starting materials in 20% yield. LCMS for C27H23ClN7O4S (M+H)+: m/z = 575.9.
Example D211 2-[(3S)-l-(l,3-Benzothiazol-2-yl)piperidin-3-yl]-iV-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide tris(trifluoroacetate)
Figure imgf000762_0001
The desired compound was prepared according to the procedure of Example A 157 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-piperidin-3-yl]acetamide tris(trifluoroacetate) as the starting material in 40% yield.
LCMS for C3IH30ClN8OS (M+H)+: m/z = 597.0.
Example D212
2-[(3/?)-l-(l,3-Benzothiazol-2-yl)piperidin-3-yl]-iV-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide tris(trifluoroacetate)
Figure imgf000762_0002
The desired compound was prepared according to the procedure of Example A 157 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide tris(trifluoroacetate) as the starting material in 30% yield.
LCMS for C3iH30ClΝ8OS (M+H)+: m/z = 597.0.
Example D213 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-l-[l,3]oxazolo[5,4-6]pyridin-2-ylpiperidin-3- yl]acetamide tris(trifluoroacetate)
Figure imgf000763_0001
The desired compound was prepared according to the procedure of Example Al 18 using N- [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(35)-piperidin-3-yl]acetamide tris(trifluoroacetate) as the starting material in 20% yield.
LCMS for C30H29ClN9O2 (M+H)+: m/z = 582.0.
Example D214 iV-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3/?)-l-[l,3]oxazolo[5,4-b]pyridin-2-ylpiperidin-3- yl]acetamide tris(trifluoroacetate)
Figure imgf000763_0002
The desired compound was prepared according to the procedure of Example Al 18 using N- [6 - chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide tris(trifluoroacetate) as the starting material in 20% yield.
LCMS for C30H29ClN9O2 (M+H)+: m/z = 582.0.
Example D215 Benzyl 4-(2-{[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}ethyl)piperidine-l-carboxylate
Figure imgf000764_0001
Step A: Benzyl 4-[2-({2-[2-(5-aminopyridin-3-yl)ethyl]-4-[(2,5-dichloropyrimidin-4- yl)amino]phenyl}amino)ethyl]piperidine- 1 -carboxylate
Figure imgf000764_0002
The desired compound was prepared according to the procedure of Example D158, steps A-E, using benzyl 4-(2-aminoethyl)piperidine-l -carboxylate as the starting material. LCMS for C32H36Cl2N7O2
(M+H)+: m/z = 620.2, 622.1.
Step B: Benzyl 4-(2-{[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}ethyl)piperidine-l-carboxylate
The desired compound was prepared according to the procedure of Example B20, step H, using benzyl 4-[2-({2-[2-(5-aminopyridin-3-yl)ethyl]-4-[(2,5-dichloropyrimidin-4- yl)amino]phenyl}amino)ethyl]piperidine-l -carboxylate as the starting material in 58% yield. LCMS for
C32H35ClN7O2 (M+H)+: m/z = 584.2.
Example D216
6-Chloro-iV-(2-piperidin-4-ylethyl)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tetrakis(trifluoroacetate)
Figure imgf000765_0001
A solution of benzyl 4-(2-{ [6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl] amino }ethyl)piperidine-l-carboxylate (25 mg, 43 μmol) in acetic acid (0.7 mL) and ethanol (2 mL) was degassed with nitrogen and treated with 10% palladium on carbon (25 mg, 21 μmol) followed by 1,4- cyclohexadiene (41 μL, 0.43 mmol) and stirred at 20 0C for 60 h. The reaction mixture was filtered over celite and purified by preparative LCMS to give the desired product (11 mg, 28%) as a yellow solid.
LCMS for C24H29ClN7 (M+H)+: m/z = 450.2.
Example D217
2,4,8,18,22-Pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene bis(trifluoroacetate)
Figure imgf000765_0002
Step A: 2-Chloro-N-(3-iodophenyl)pyrimidin-4-amine
Figure imgf000765_0003
A solution of 2,4-dichloropyrimidine (3.0 g, 20 mmol) and N,N-diisopropylethylamine (4.2 mL, 24 mmol) in N-methylpyrrolidinone (20 mL) was treated with 3-iodoaniline (2.4 mL, 20 mmol) dropwise and heated at 120 0C for 2 h. The reaction mixture was concentrated, diluted with ethyl acetate (150 mL), and washed with water (150 mL). The aqueous layer was separated and extracted with ethyl acetate (150 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a crude oil. This material was purified by flash column chromatography to give the desired product (3.2 mg, 48%) as a tan solid. LCMS for CioH8ClIN3
(M+H)+: m/z = 331.9.
Step B: N-{3-[(E)-2-(5-Aminopyridin-3-yl)vinyl]phenylj-2-chloropyrimidin-4-amine
Figure imgf000766_0001
The desired compound was prepared according to the procedure of Example B334, step G, using 2-chloro-N-(3-iodophenyl)pyrimidin-4-amine as the starting material in 70% yield. LCMS for
Ci7Hi5ClN5 (M+H)+: m/z = 324.1.
Step C: N-{3-[2-(5-Aminopyridin-3-yl)ethyl]phenyl}-2-chloropyrimidin-4-amine
Figure imgf000766_0002
The desired compound was prepared according to the procedure of Example B334, step H, using N-{3-[(ii)-2-(5-aminopyridin-3-yl)vinyl]phenyl}-2-chloropyrimidin-4-amine as the starting material in 65% yield. LCMS for Ci7Hi7ClN5 (M+H)+: m/z = 326.1.
Step D: 2,4,8,18,22-Pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene bis(trifluoroacetate)
The desired compound was prepared according to the procedure of Example B20, step H, using N-{3-[2-(5-aminopyridin-3-yl)ethyl]phenyl}-2-chloropyrimidin-4-amine as the starting material in 40% yield. LCMS for CnHi6N5 (M+H)+: m/z = 290.1.
Example D218 6-Chloro-iV-(2-{l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl}ethyl)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate)
Figure imgf000767_0001
The desired compound was prepared according to the procedure of Example D94 using 6-chloro- N-(2-piperidin-4-ylethyl)-2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tetrakis(trifluoroacetate) and 5-methylisoxazole-3- carbonyl chloride as the starting materials in 55% yield. LCMS for C29H32ClN8O2 (M+H)+: m/z = 559.2.
Example D219 iV-[2-(l-Acetylpiperidin-4-yl)ethyl]-6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate)
Figure imgf000767_0002
The desired compound was prepared according to the procedure of Example D94 using 6-chloro- N-(2-piperidin-4-ylethyl)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-amine tetrakis(trifluoroacetate) and acetyl chloride as the starting materials in 50% yield. LCMS for C26H3IClN7O (M+H)+: m/z = 492.1.
Example D220 6-Chloro-iV-{2-[l-(2,4-difluorobenzoyl)piperidin-4-yl]ethyl}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate)
Figure imgf000768_0001
The desired compound was prepared according to the procedure of Example D94 using 6-chloro- N-(2-piperidin-4-ylethyl)-2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- I(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tetrakis(trifluoroacetate) and 2,4-difluorobenzoyl chloride as the starting materials in 30% yield. LCMS for C3IH31ClF2N7O (M+H)+: m/z = 590.1.
Example D221
6-Chloro-iV-(2-{l-[(2-fluorophenyl)sulfonyl]piperidin-4-yl}ethyl)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate)
Figure imgf000768_0002
The desired compound was prepared according to the procedure of Example D20, step A, using 6-chloro-N-(2-piperidin-4-ylethyl)-2,4, 8 , 18 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7).1 (9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tetrakis(trifluoroacetate) and 2- fluorobenzenesulphonyl chloride as the starting materials in 50% yield. LCMS for C30H32ClFN7O2S
(M+H)+: m/z = 608.1. Example D222
2-{[4-(2-{[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}ethyl)piperidin-l-yl]sulfonyl}benzonitrile tris(trifluoroacetate)
Figure imgf000769_0001
The desired compound was prepared according to the procedure of Example D20, step A, using 6-chloro-N-(2-piperidin-4-ylethyl)-2,4, 8 , 18 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7).1 (9, 13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-amine tetrakis(trifluoroacetate) and 2-cyanobenzenesulfonyl chloride as the starting materials in 60% yield. LCMS for C3IH32ClN8O2S (M+H)+: m/z = 615.2.
Example D223
8-Methyl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene trifluoroacetate
Figure imgf000769_0002
Step A: 2-Chloro-N-(3-iodophenyl)-N-methylpyrimidin-4-amine
Figure imgf000769_0003
A solution of 2-chloro-N-(3-iodophenyl)pyrimidin-4-amine (1.1 g, 3.3 mmol) and potassium carbonate (0.92 g, 6.6 mmol) in N,N-dimethylformamide (6.6 mL) was treated with methyl iodide (0.52 mL, 8.3 mmol) and stirred at 20 0C for 5 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (200 mL). The organic layer was separated and washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a crude solid. This material was purified by flash column chromatography to give the desired product (0.87 g, 75%) as a tan oil. LCMS for C11Hi0CUN3 (M+H)+: m/z = 346.0.
Step B: tert-Butyl [3-((E)-2-{3-[(2-chloropyrimidin-4-yl)(methyl)amino]phenyljvinyl)phenyl]carbamate
BocHN
Figure imgf000770_0001
The desired compound was prepared according to the procedure of Example B334, step G, usin^ 2-chloro-N-(3-iodophenyl)-N-methylpyrimidin-4-amine and tert-butyl (3-vinylphenyl)carbamate as the starting materials in 76% yield. LCMS for C24H26ClN4O2 (M+H)+: m/z = 437.1.
Step C: tert-Butyl [3-(2-{3-[(2-chloropyrimidin-4-yl)(methyl)amino]phenyl}ethyl)phenyl]carbamate
Figure imgf000770_0002
The desired compound was prepared according to the procedure of Example B334, step H, using tert-butyl [3-((ii)-2-{3-[(2-chloropyrimidin-4-yl)(methyl)amino]phenyl}vinyl)phenyl]carbamate as the starting material in 65% yield. LCMS for C24H28ClN4O2 (M+H)+: m/z = 439.1.
Step D: 8-Methyl-2, 4, 8, 22-tetraazatetracyclo[14.3.1.1 (3, 7).1 (9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene trifluoroacetate
The desired compound was prepared according to the procedure of Example D2, step D, using tert-butyl [3-(2-{3-[(2-chloropyrimidin-4-yl)(methyl)amino]phenyl}ethyl)phenyl]carbamate as the starting material in 20% yield. LCMS for Ci9H19N4 (M+H)+: m/z = 303.1.
Example D224 8-Methyl-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000771_0001
Step A: N-{3-[(E)-2-(5-aminopyridin-3-yl)vinyl]phenyl}-2-chloro-N-methylpyrimidin-4-amine
Figure imgf000771_0002
The desired compound was prepared according to the procedure of Example B334, step G, using 2-chloro-N-(3-iodophenyl)-N-methylpyrimidin-4-amine as the starting material in 90% yield. LCMS for
Ci8H17ClN5 (M+H)+: m/z = 338.1.
Step B: N-{3-[2-(5-Aminopyridin-3-yl)ethyl]phenyl}-2-chloro-N-methylpyrimidin-4-amine
Figure imgf000771_0003
The desired compound was prepared according to the procedure of Example B334, step H, using N-{3-[(ii)-2-(5-aminopyridin-3-yl)vinyl]phenyl}-2-chloro-N-methylpyrimidin-4-amine as the starting material in 49% yield. LCMS for Ci8H19ClN5 (M+H)+: m/z = 340.0.
Step C: 8-Methyl-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
The desired compound was prepared according to the procedure of Example B20, step H, using N-{3-[2-(5-aminopyridin-3-yl)ethyl]phenyl}-2-chloro-N-methylpyrimidin-4-amine as the starting material in 32% yield. LCMS fOr Ci8Hi8N5 (MH-H)+: m/z = 304.1. Example D225
6-Chloro-12-(piperidin-4-ylmethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000772_0001
The desired compound was prepared according to the procedure of Example D 161, steps C-I using 4-hydroxymethyl-piperidine-l-carboxylic acid tert-butyl ester as the starting material. LCMS for
C23H26ClN6O (M+H)+: m/z = 437.1.
Example D226 6-Chloro-12-({l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl}methoxy)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000772_0002
The desired compound was prepared according to the procedure of Example D94 using 6-chloro- 12-(piperidin-4-ylmethoxy)-2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 60% yield. LCMS for C28H29ClN7O3 (M+H)+: m/z = 546.2.
Example D227 12-[(l-Acetylpiperidin-4-yl)methoxy]-6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000773_0001
The desired compound was prepared according to the procedure of Example D94 using 6-chloro- 12-(piperidin-4-ylmethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and acetyl chloride as the starting materials in 66% yield. LCMS for C25H28ClN6O2 (M+H)+: m/z = 479.1.
Example D228
4-({[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}methyl)-iV-phenylpiperidine-l-carboxamide bis(trifluoroacetate)
Figure imgf000773_0002
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-(piperidin-4-ylmethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and phenyl isocyanate as the starting materials in 40% yield. IXMS for C30H31ClN7O2 (M+H)+: m/z = 556.1.
Example D229
6-Chloro-12-(2-oxo-2-piperazin-l-ylethoxy)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000774_0001
Step A: tert-Butyl (2-iodo-4-nitrophenoxy)acetate
Figure imgf000774_0002
A solution of 2-iodo-4-nitrophenol (2.2 g, 8.3 mmol), tert-bvXy\ bromoacetate (1.6 mL, 11 mmol), and potassium carbonate (2.3 g, 17 mmol) in N,N-dimethylformamide (20 mL) was stirred at 20 0C for 60 h. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (500 mL). The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to a crude oil. This material was purified by flash column chromatography to give the desired product (2.0 g, 60%).
Step B: tert-Butyl (4-amino-2-iodophenoxy)acetate
Figure imgf000774_0003
The desired compound was prepared according to the procedure of Example D2, step B, usin^ tert-butyl (2-iodo-4-nitrophenoxy)acetate as the starting material in quantitative yield. LCMS for Ci2Hi7INO3 (M+H)+: m/z = 350.1.
Step C: tert-Butyl {4-[(2,5-dichloropyrimidin-4-yl)amino]-2-iodophenoxy}acetate
111
Figure imgf000775_0001
The desired compound was prepared accordin αg to th0e^ procedure of Example tert-butyl (4-amino-2-iodophenoxy)acetate as the starting material in 89% yield. LCMS for
Ci6Hi7Cl2IN3O3 (M+H)+: m/z = 495.9, 497.9.
Step D: tert-Butyl {4-[(2,5-dichloropyrimidin-4-yl)amino]-2-iodophenoxy}acetate
Figure imgf000775_0002
The desired compound w prepared according to procΛedure of Example B334, step G, using tert-butyl {4-[(2,5-dichloropyrimidin-4-yl)amino]-2-iodophenoxy}acetate as the starting material in 76% yield. LCMS for C23H24Cl2N5O3 (M+H)+: m/z = 488.0, 490.0.
Step E: tert-Butyl (2-[2-(5-aminopyridin-3-yl)ethyl]-4-[(2,5-dichloropyrimidin-4- yl)amino]phenoxy} acetate
Figure imgf000775_0003
The desired compound was prepared according to the procedure of Example B334, step H, using tert-butyl {4-[(2,5-dichloropyrimidin-4-yl)amino]-2-iodophenoxy}acetate as the starting material in 92% yield. LCMS for C23H26Cl2N5O3 (M+H)+: m/z = 490.0, 492.0. Step F: tert-Butyl {[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4A9(21),10,12,16,18-nonaen-12-yl]oxyJacetate
Figure imgf000776_0001
The desired compound was prepared according to the procedure of Example B20, step H, using tert-butyl {2-[2-(5-aminopyridin-3-yl)ethyl]-4-[(2,5-dichloropyrimidin-4-yl)amino]phenoxy}acetate as the starting material in 60% yield. LCMS for C23H25ClN5O3 (M+H)+: m/z = 454.1.
Step G: f[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetic acid dihydrochloride
Figure imgf000776_0002
A solution of tert-butyl { [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetate (0.76 g, 1.7 mmol) in 4 M HCl in 1,4 dioxane (30 mL, 120 mmol) was heated at 70 0C for 1 h. The reaction mixture was concentrated to a solid that was suspended in diethyl ether, filtered, and washed with diethyl ether to give the desired product (0.82 g, 104%) as a white solid. LCMS for Ci9Hi7ClN5O3 (M+H)+: m/z = 398.0.
Step H: tert-Butyl 4-(f[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxyjacetyl)piperazine-l-carboxylate
Figure imgf000776_0003
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and tert-butyl piperazine-1-carboxylate as the starting materials. LCMS for C23H25CIN5O3 (M+H)+: m/z = 454.1. This material was used immediately in the next step.
Step I: 6-Chloro-12-(2-oxo-2-piperazin-l-ylethoxy)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) The desired compound was prepared according to the procedure of Example D 192, step B, using tert-butyl 4-({ [6-chloro-2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]oxy}acetyl)piperazine-l-carboxylate as the starting material in 44% yield (2 steps). LCMS for C23H25ClN7O2 (M+H)+: m/z = 466.2.
Example D230
6-Chloro-12-{2-oxo-2-[4-(l,3-thiazol-2-yl)piperazin-l-yl]ethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000777_0001
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and l-(l,3-thiazol-2-yl)piperazine as the starting materials in 63% yield. LCMS for C26H26ClN8O2S (M+H)+: m/z = 549.0.
Example D231
6-Chloro-12-[2-oxo-2-(4-pyridin-2-ylpiperazin-l-yl)ethoxy]-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000778_0001
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and N-(2-pyridyl)piperazine as the starting materials in 64% yield. LCMS for C28H28ClN8O2 (M+H)+: m/z = 543.0.
Example D232
6-Chloro-12-[2-oxo-2-(4-pyrazin-2-ylpiperazin-l-yl)ethoxy]-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000778_0002
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and 2-piperazin-l-ylpyrazine as the starting materials in 60% yield. LCMS for C27H27ClN9O2 (M+H)+: m/z = 544.0.
Example D233
6-Chloro-12-[2-oxo-2-(4-pyrimidin-2-ylpiperazin-l-yl)ethoxy]-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000779_0001
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and 2-piperazin-l-ylpyrimidine as the starting materials in 60% yield. LCMS fOr C27H27ClN9O2 (MH-H)+: m/z = 544.0.
Example D234
6-Chloro-12-[2-oxo-2-(4-phenylpiperazin-l-yl)ethoxy]-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000779_0002
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and 1-phenylpiperazine as the starting materials in 53% yield. LCMS fOr C29H29ClN7O2 (MH-H)+: m/z = 542.0.
Example D235
2-[4-({[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazin-l-yl]benzonitrile tris(trifluoroacetate)
Figure imgf000780_0001
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and 2-piperazin-l-ylbenzonitrile as the starting materials in
45% yield. LCMS for C30H28ClN8O2 (M+H)+: m/z = 567.1.
Example D236
4-[4-({[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazin-l-yl]benzonitrile tris(trifluoroacetate)
Figure imgf000780_0002
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and 4-piperazin-l-ylbenzonitrile as the starting materials in
48% yield. LCMS for C30H28ClN8O2 (M+H)+: m/z = 567.0.
Example D237
6-Chloro-12-{2-[4-(4-methylpyridin-2-yl)piperazin-l-yl]-2-oxoethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000781_0001
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and l-(4-methylpyridin-2-yl)piperazine as the starting materials in 52% yield. LCMS for C29H30ClN8O2 (M+H)+: m/z = 557.0.
Example D238
2-[4-({[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazin-l-yl]nicotinonitrile tris(trifluoroacetate)
Figure imgf000781_0002
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and 2-piperazin-l-ylnicotinonitrile as the starting materials in 20% yield. LCMS for C29H27ClN9O2 (M+H)+: m/z = 568.0.
Example D239
6-[4-({[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazin-l-yl]nicotinonitrile tris(trifluoroacetate)
Figure imgf000782_0001
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and 6-piperazin-l-ylnicotinonitrile as the starting materials in 45% yield. LCMS for C29H27ClN9O2 (M+H)+: m/z = 568.0.
Example D240
6-Chloro-12-{2-[4-(6-chloropyridin-2-yl)piperazin-l-yl]-2-oxoethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000782_0002
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and l-(6-chloropyridin-2-yl)piperazine as the starting materials in 61% yield. LCMS for C28H27Cl2N8O2 (M+H)+: m/z = 577.0.
Example D241
6-Chloro-12-{2-[4-(2-methoxyphenyl)piperazin-l-yl]-2-oxoethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000783_0001
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and l-(2-methoxyphenyl)piperazine as the starting materials in 51% yield. LCMS for C30H31ClN7O3 (M+H)+: m/z = 572.1.
Example D242
6-Chloro-12-{2-[4-(4-fluorophenyl)piperazin-l-yl]-2-oxoethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000783_0002
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and N-(4-fluorophenyl)piperazine as the starting materials in 42% yield. LCMS for C29H28ClFN7O2 (M+H)+: m/z = 560.0.
Example D243
6-Chloro-12-[2-oxo-2-(4-pyridin-4-ylpiperazin-l-yl)ethoxy]-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000784_0001
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and l-pyridin-4-ylpiperazine as the starting materials in 42% yield. LCMS for C28H28ClN8O2 (M+H)+: m/z = 543.1.
Example D244
6-Chloro-12-{2-[4-(4-chloropyridin-2-yl)piperazin-l-yl]-2-oxoethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000784_0002
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and l-(4-chloropyridin-2-yl)piperazine as the starting materials in 44% yield. LCMS for C28H27Cl2N8O2 (M+H)+: m/z = 577.0.
Example D245
6-Chloro-12-[2-(4-furo[3,2-c]pyridin-4-ylpiperazin-l-yl)-2-oxoethoxy]-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000785_0001
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and 4-piperazin-l-ylfuro[3,2-c]pyridine as the starting materials in 47% yield. LCMS for C30H28ClN8O3 (M+H)+: m/z = 583.1.
Example D246
6-Chloro-12-{2-[4-(5-methylpyridin-2-yl)piperazin-l-yl]-2-oxoethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000785_0002
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and l-(5-methylpyridin-2-yl)piperazine as the starting materials in 49% yield. LCMS for C29H30ClN8O2 (M+H)+: m/z = 557.0.
Example D247
6-Chloro-12-{2-[4-(4,6-dichloropyridin-2-yl)piperazin-l-yl]-2-oxoethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000786_0001
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and l-(4,6-dichloropyridin-2-yl)piperazine as the starting materials in 30% yield. LCMS for C28H26Cl3N8O2 (M+H)+: m/z = 611.0, 613.0.
Example D248
6-Chloro-12-(2-oxo-2-{4-[6-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl}ethoxy)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000786_0002
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and l-[6-(trifluoromethyl)pyridin-2-yl]piperazine as the starting materials in 40% yield. LCMS for C29H27ClF3N8O2 (M+H)+: m/z = 611.0.
Example D249
6-Chloro-12-{2-[4-(3-methoxypyridin-2-yl)piperazin-l-yl]-2-oxoethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000787_0001
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and l-(3-methoxypyridin-2-yl)piperazine as the starting materials in 51% yield. LCMS for C29H30ClN8O3 (M+H)+: m/z = 573.1.
Example D250
12-{2-[4-(l,2-Benzisoxazol-3-yl)piperazin-l-yl]-2-oxoethoxy}-6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000787_0002
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and 3-piperazin-l-yl-l,2-benzisoxazole as the starting materials in 30% yield. LCMS for C30H28ClN8O3 (M+H)+: m/z = 583.1.
Example D251
6-Chloro-12-(2-{4-[(5-methylisoxazol-3-yl)carbonyl]piperazin-l-yl}-2-oxoethoxy)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000788_0001
The desired compound was prepared according to the procedure of Example D94 using 6-chloro- 12-(2-oxo-2-piperazin-l-ylethoxy)-2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 80% yield. LCMS for C28H28ClN8O4 (M+H)+: m/z = 575.0.
Example D252
12-[2-(4-Acetylpiperazin-l-yl)-2-oxoethoxy]-6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000788_0002
The desired compound was prepared according to the procedure of Example D94 using 6-chloro- 12-(2-oxo-2-piperazin-l-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and acetyl chloride as the starting materials in 88% yield. LCMS for C25H27ClN7O3 (M+H)+: m/z = 508.0.
Example D253
6-Chloro-12-(2-{4-[(2-fluorophenyl)sulfonyl]piperazin-l-yl}-2-oxoethoxy)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000789_0001
The desired compound was prepared according to the procedure of Example D20, step A, using 6-chloro-12-(2-oxo-2-piperazin-l-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and 2-fluorobenzenesulphonyl chloride as the starting materials in 50% yield. LCMS for C29H28ClFN7O4S (M+H)+: m/z = 624.0.
Example D254
2-{[4-({[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazin-l-yl]sulfonyl}benzonitrile bis(trifluoroacetate)
Figure imgf000789_0002
The desired compound was prepared according to the procedure of Example D20, step A, using 6-chloro-12-(2-oxo-2-piperazin-l-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9, 13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and 2-cyanobenzenesulfonyl chloride as the starting materials in 50% yield. LCMS for C30H28ClN8O4S (M+H)+: m/z = 631.0.
Example D255
6-Chloro-12-{2-oxo-2-[4-(pyridin-3-ylmethyl)piperazin-l-yl]ethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000790_0001
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and l-(pyridin-3-ylmethyl)piperazine dihydrochloride as the starting materials in 42% yield. LCMS for C29H30ClN8O2 (M+H)+: m/z = 557.0.
Example D256
6-Chloro-12-{2-oxo-2-[4-(pyridin-4-ylmethyl)piperazin-l-yl]ethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000790_0002
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and l-(pyridin-4-ylmethyl)piperazine as the starting materials in 45% yield. LCMS for C29H30ClN8O2 (M+H)+: m/z = 557.1.
Example D257
6-Chloro-12-(2-oxo-2-{4-[5-(2-thienyl)-lH-pyrazol-3-yl]piperidin-l-yl}ethoxy)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000791_0001
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and 4-[5-(2-thienyl)-lH-pyrazol-3-yl]piperidine dihydrochloride as the starting materials in 39% yield. LCMS for C3IH30ClN8O2S (M+H)+: m/z = 613.0.
Example D258
6-Chloro-12-(2-oxo-2-{4-[3-(2-thienyl)-l,2,4-oxadiazol-5-yl]piperidin-l-yl}ethoxy)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000791_0002
The desired compound was prepared according to the procedure of Example D 152 using { [6- chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaen-12-yl]oxy} acetic acid dihydrochloride and 4-[3-(2-thienyl)-l,2,4-oxadiazol-5-yl]piperidine as the starting materials in 41% yield. LCMS for C30H28ClN8O3S (M+H)+: m/z = 615.0.
Example D259
6-Chloro-12-{2-[4-(2,4-difluorobenzoyl)piperazin-l-yl]-2-oxoethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000792_0001
The desired compound was prepared according to the procedure of Example D94 using 6-chloro- 12-(2-oxo-2-piperazin-l-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 2,4-difluorobenzoyl chloride as the starting materials in 30% yield. LCMS for C30H27ClF2N7O3 (M+H)+: m/z = 606.0.
Example D260
6-Chloro-12-{2-[4-(isoxazol-5-ylcarbonyl)piperazin-l-yl]-2-oxoethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000792_0002
The desired compound was prepared according to the procedure of Example D94 using 6-chloro- 12-(2-oxo-2-piperazin-l-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and isoxazole-5-carbonyl chloride as the starting materials in 60% yield. LCMS for C27H26ClN8O4 (M+H)+: m/z = 561.0.
Example D261
Methyl 4-({[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazine-l-carboxylate bis(trifluoroacetate)
Figure imgf000793_0001
The desired compound was prepared according to the procedure of Example D94 using 6-chloro- 12-(2-oxo-2-piperazin-l-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and methyl chloroformate as the starting materials in 60% yield. LCMS fOr C25H27ClN7O4 (MH-H)+: m/z = 524.1.
Example D262
6-Chloro-12-{2-[4-(methoxyacetyl)piperazin-l-yl]-2-oxoethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000793_0002
The desired compound was prepared according to the procedure of Example D94 using 6-chloro- 12-(2-oxo-2-piperazin-l-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and methoxyacetyl chloride as the starting materials in 77% yield. LCMS fOr C26H29ClN7O4 (MH-H)+: m/z = 538.1.
Example D263
6-Chloro-12-{2-[4-(ethylsulfonyl)piperazin-l-yl]-2-oxoethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000794_0001
The desired compound was prepared according to the procedure of Example D20, step A, using 6-chloro-12-(2-oxo-2-piperazin-l-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and ethanesulfonyl chloride as the starting materials in 60% yield. LCMS for C25H29ClN7O4S (M+H)+: m/z = 558.0.
Example D264
4-({[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)-iV-phenylpiperazine-l-carboxamide bis(trifluoroacetate)
Figure imgf000794_0002
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-(2-oxo-2-piperazin-l-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and phenyl isocyanate as the starting materials in 70% yield. LCMS for C30H30ClN8O3 (M+H)+: m/z = 585.0.
Example D265
4-({[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)-iV-methylpiperazine-l-carboxamide bis(trifluoroacetate)
Figure imgf000795_0001
The desired compound was prepared according to the procedure of Example D41 using 6-chloro- 12-(2-oxo-2-piperazin-l-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and methyl isocyanate as the starting materials in 70% yield. LCMS fOr C25H28ClN8O3 (MH-H)+: m/z = 523.1.
Example D266
6-Chloro-12-(2-{4-[(5-methyl-lH-pyrazol-3-yl)carbonyl]piperazin-l-yl}-2-oxoethoxy)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate)
Figure imgf000795_0002
The desired compound was prepared according to the procedure of Example D 152 using 6- chloro- 12-(2-oxo-2-piperazin- 1 -ylethoxy)-2,4,8 , 18 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaenetris(trifluoroacetate) and 5-methyl-lH-pyrazole-3-carboxylic acid as the starting materials in 50% yield. LCMS for C28H29ClN9O3 (M+H)+: m/z = 574.0.
Example D267 l-{[4.({[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazin-l- yl]carbonyl}cyclopropanecarbonitrile bis(trifluoroacetate)
Figure imgf000796_0001
The desired compound was prepared according to the procedure of Example D 152 using 6- chloro- 12-(2-oxo-2-piperazin- 1 -ylethoxy)-2,4,8 , 18 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaenetris(trifluoroacetate) and 1-cyanocyclopropanecarboxylic acid as the starting materials in 60% yield. LCMS for C28H28ClN8O3 (M+H)+: m/z = 559.1.
Example D268
4-({[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazine-l-sulfonamide bis(trifluoroacetate)
Figure imgf000796_0002
The desired compound was prepared according to the procedure of Example A72 using 6-chloro- 12-(2-oxo-2-piperazin-l-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaenetris(trifluoroacetate) as the starting material in 30% yield. LCMS for C23H26ClN8O4S (M+H)+: m/z = 545.0.
Example D269
3-[4-({[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazin-l-yl]-3-oxopropanenitrile bis(trifluoroacetate)
Figure imgf000797_0001
The desired compound was prepared according to the procedure of Example D94 using 6-chloro- 12-(2-oxo-2-piperazin-l-ylethoxy)-2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 3-[(2,5-dioxopyrrolidin-l-yl)oxy]-3- oxopropanenitrile as the starting materials in 60% yield. LCMS for C2OH26ClN8O3 (M+H)+: m/z = 533.0.
Example D270
4-({[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazine-l-carboxamide bis(trifluoroacetate)
Figure imgf000797_0002
The desired compound was prepared according to the procedures of Example D41, using 6- chloro- 12-(2-oxo-2-piperazin- 1 -ylethoxy)-2,4,8 , 18 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaene tris(trifluoroacetate) and 2-isocyanato-2-methylpropane as the starting materials, and Example D87 in 60% yield (2 steps). LCMS for C24H26ClN8O3 (M+H)+: m/z = 509.0.
Example D271
6-Chloro-12-{2-oxo-2-[4-(tetrahydrofuran-3-ylcarbonyl)piperazin-l-yl]ethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000798_0001
The desired compound was prepared according to the procedure of Example D 152 using 6- chloro- 12-(2-oxo-2-piperazin- 1 -ylethoxy)-2,4,8 , 18 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaenetris(trifluoroacetate) and tetrahydrofuran-3-carboxylic acid as the starting materials in 50% yield. LCMS for C28H31ClN7O4 (M+H)+: m/z = 564.1.
Example D272
6-Chloro-12-{2-oxo-2-[4-(tetrahydrofuran-2-ylcarbonyl)piperazin-l-yl]ethoxy}-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate)
Figure imgf000798_0002
The desired compound was prepared according to the procedure of Example D 152 using 6- chloro- 12-(2-oxo-2-piperazin- 1 -ylethoxy)-2,4,8 , 18 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaenetris(trifluoroacetate) and tetrahydro-2-furancarboxylic acid as the starting materials in 70% yield. LCMS for C28H3IClN7O4 (M+H)+: m/z = 564.1.
Example AAl: In vitro JAK Kinase Assay
One or more compounds herein were tested for inhibitory activity of JAK targets according to the following in vitro assay described in Park et al. , Analytical Biochemistry 1999, 269, 94-104. The catalytic domains of human JAKl (a.a. 837-1142), JAK2 (a.a. 828-1132) and JAK3 (a.a. 781-1124) with an N-terminal His tag were expressed using baculovirus in insect cells and purified. The catalytic activity of JAKl, JAK2 or JAK3 was assayed by measuring the phosphorylation of a biotinylated peptide. The phosphorylated peptide was detected by homogenous time resolved fluorescence (HTRF). IC50S of compounds were measured for each kinase in the reactions that contain the enzyme, ATP and 500 nM peptide in 50 mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg/mL (0.01%) BSA. The ATP concentration in the reactions was 90 μM for JAKl, 30 μM for JAK2 and 3 μM for JAK3. Reactions were carried out at room temperature for 1 hr and then stopped with 20 μL 45 mM EDTA, 300 nM SA-APC, 6 nM Eu-Py20 in assay buffer (Perkin Elmer, Boston, MA). Binding to the Europium labeled antibody took place for 40 minutes and HTRF signal was measured on a Fusion plate reader (Perkin Elmer, Boston, MA).
Example AA2: In vitro JAK Kinase Assay
One or more compounds herein were tested for inhibitory activity of JAK targets according to the following in vitro assay described in Park et al. , Analytical Biochemistry 1999, 269, 94-104. The catalytic domains of human JAKl (a.a. 837-1142), JAK2 (a.a. 828-1132) and JAK3 (a.a. 781-1124) with an N-terminal His tag were expressed using baculovirus in insect cells and purified. The catalytic activity of JAKl, JAK2 or JAK3 was assayed by measuring the phosphorylation of a biotinylated peptide. The phosphorylated peptide was detected by homogenous time resolved fluorescence (HTRF). IC50S of compounds were measured for each kinase in the reactions that contain the enzyme, 1000 μM ATP, and 500 nM peptide in 50 mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg/mL (0.01%) BSA. Reactions were carried out at room temperature for 1 hr and then stopped with 20 μL 45 mM EDTA, 300 nM SA-APC, 6 nM Eu-Py20 in assay buffer (Perkin Elmer, Boston, MA). Binding to the
Europium labeled antibody took place for 40 minutes and HTRF signal was measured on a Fusion plate reader (Perkin Elmer, Boston, MA).
Example BB: Cellular Assays One or more compounds herein were tested for inhibitory activity of JAK targets according to at least one of the following cellular assays.
Cancer cell lines dependent on cytokines and hence JAK/STAT signal transduction, for growth, were plated at 6000 cells per well (96 well plate format) in RPMI 1640, 10% FBS, and 1 nG/mL of appropriate cytokine. Compounds were added to the cells in DMSO/media (final concentration 0.2% DMSO) and incubated for 72 hours at 37 0C, 5% CO2. The effect of compound on cell viability was assessed using the CellTiter-Glo Luminescent Cell Viability Assay (Promega) followed by TopCount (Perkin Elmer, Boston, MA) quantitation. Potential off-target effects of compounds were measured in parallel using a non-JAK driven cell line with the same assay readout. All experiments were performed in duplicate. The above cell lines can also be used to examine the effects of compounds on phosphorylation of JAK kinases or potential downstream substrates such as STAT proteins, Akt, Shp2, or Erk. These experiments can be performed following an overnight cytokine starvation, followed by a brief preincubation with compound (2 hours or less) and cytokine stimulation of approximately 1 hour or less. Proteins are then extracted from cells and analyzed by techniques familiar to those schooled in the art including Western blotting or ELISAs using antibodies that can differentiate between phosphorylated and total protein. These experiments can utilize normal or cancer cells to investigate the activity of compounds on tumor cell survival biology or on mediators of inflammatory disease. For example, with regards to the latter, cytokines such as IL-6, IL-12, IL-23, or IFN can be used to stimulate JAK activation resulting in phosphorylation of STAT protein(s) and potentially in transcriptional profiles (assessed by array or qPCR technology) or production and/or secretion of proteins, such as IL- 17. The ability of compounds to inhibit these cytokine mediated effects can be measured using techniques common to those schooled in the art.
Compounds herein can also be tested in cellular models designed to evaluate their potency and activity against mutant JAKs, for example, the JAK2V617F mutation found in myeloid proliferative disorders. These experiments often utilize cytokine dependent cells of hematological lineage (e.g. BaF/3) into which the wild-type or mutant JAK kinases are ectopically expressed (James, C, et al. Nature 434:1144-1148; Staerk, J., et al JBC 280:41893-41899). Endpoints include the effects of compounds on cell survival, proliferation, and phosphorylated JAK, STAT, Akt, or Erk proteins. Certain compounds herein have been or can be evaluated for their activity inhibiting T-cell proliferation. Such as assay can be considered a second cytokine (i.e. JAK) driven proliferation assay and also a simplistic assay of immune suppression or inhibition of immune activation. The following is a brief outline of how such experiments can be performed. Peripheral blood mononuclear cells (PBMCs) are prepared from human whole blood samples using Ficoll Hypaque separation method and T-cells (fraction 2000) can be obtained from PBMCs by elutriation. Freshly isolated human T-cells can be maintained in culture medium (RPMI 1640 supplemented with 10% fetal bovine serum, 100 U/mL penicillin, 100 μg/mL streptomycin) at a density of 2 x 106 cells/mL at 37 0C for up to 2 days. For IL -2 stimulated cell proliferation analysis, T-cells are first treated with Phytohemagglutinin (PHA) at a final concentration of 10 μg/mL for 72 hours. After washing once with PBS, 6000 cells/well are plated in 96- well plates and treated with compounds at different concentrations in the culture medium in the presence of 100 U/mL human IL-2 (ProSpec-Tany TechnoGene; Rehovot, Israel). The plates are incubated at 37 0C for 72 hours and the proliferation index is assessed using CellTiter-Glo Luminescent reagents following the manufactory suggested protocol (Promega; Madison, WI). Example CC: In vivo anti-tumor efficacy
Compounds herein can be evaluated in human tumor xenograft models in immune compromised mice. For example, a tumorigenic variant of the INA- 6 plasmacytoma cell line can be used to inoculate SCID mice subcutaneously (Burger, R., et al. Hematol J. 2:42-53, 2001). Tumor bearing animals can then be randomized into drug or vehicle treatment groups and different doses of compounds can be administered by any number of the usual routes including oral, Lp., or continuous infusion using implantable pumps. Tumor growth is followed over time using calipers. Further, tumor samples can be harvested at any time after the initiation of treatment for analysis as described above (Example B) to evaluate compound effects on JAK activity and downstream signaling pathways. In addition, selectivity of the compound(s) can be assessed using xenograft tumor models that are driven by other know kinases {e.g. Bcr-Abl) such as the K562 tumor model.
Example DD: Murine Skin Contact Delayed Hypersensitivity Response Test
Compounds herein can also be tested for their efficacies (of inhibiting JAK targets) in the T-cell driven murine delayed hypersensitivity test model. The murine skin contact delayed-type hypersensitivity (DTH) response is considered to be a valid model of clinical contact dermatitis, and other T-lymphocyte mediated immune disorders of the skin, such as psoriasis {Immunol Today. 1998 Jan;19(l):37-44). Murine DTH shares multiple characteristics with psoriasis, including the immune infiltrate, the accompanying increase in inflammatory cytokines, and keratinocyte hyperproliferation. Furthermore, many classes of agents that are efficacious in treating psoriasis in the clinic are also effective inhibitors of the DTH response in mice (Agents Actions. 1993 Jan;38(l-2): 116-21).
On Day 0 and 1, Balb/c mice are sensitized with a topical application, to their shaved abdomen with the antigen 2,4,dinitro-fluorobenzene (DNFB). On day 5, ears are measured for thickness using an engineer's micrometer. This measurement is recorded and used as a baseline. Both of the animals' ears are then challenged by a topical application of DNFB in a total of 20 μL (10 μL on the internal pinna and 10 μL on the external pinna) at a concentration of 0.2%. Twenty-four to seventy-two hours after the challenge, ears are measured again. Treatment with the test compounds was given throughout the sensitization and challenge phases (day -1 to day 7) or prior to and throughout the challenge phase (usually afternoon of day 4 to day 7). Treatment of the test compounds (in different concentration) was administered either systemically or topically (topical application of the treatment to the ears). Efficacies of the test compounds are indicated by a reduction in ear swelling comparing to the situation without the treatment. Compounds causing a reduction of 20% or more were considered efficacious. In some experiments, the mice are challenged but not sensitized (negative control). The inhibitive effect (inhibiting activation of the JAK-STAT pathways) of the test compounds can be confirmed by immunohistochemical analysis. Activation of the JAK-STAT pathway(s) results in the formation and translocation of functional transcription factors. Further, the influx of immune cells and the increased proliferation of keratinocytes should also provide unique expression profile changes in the ear that can be investigated and quantified. Formalin fixed and paraffin embedded ear sections
(harvested after the challenge phase in the DTH model) are subjected to immunohistochemical analysis using an antibody that specifically interacts with phosphorylated STAT3 (clone 58El 2, Cell Signaling Technologies). The mouse ears are treated with test compounds, vehicle, or dexamethasone (a clinically efficacious treatment for psoriasis), or without any treatment, in the DTH model for comparisons. Test compounds and the dexamethasone can produce similar transcriptional changes both qualitatively and quantitatively, and both the test compounds and dexamethasone can reduce the number of infiltrating cells. Both systemically and topical administration of the test compounds can produce inhibitive effects, i.e., reduction in the number of infiltrating cells and inhibition of the transcriptional changes.
Example EE: In vivo anti-inflammatory activity
Compounds herein can be evaluated in rodent or non-rodent models designed to replicate a single or complex inflammation response. For instance, rodent models of arthritis can be used to evaluate the therapeutic potential of compounds dosed preventatively or therapeutically. These models include but are not limited to mouse or rat collagen-induced arthritis, rat adjuvant-induced arthritis, and collagen antibody-induced arthritis. Autoimmune diseases including, but not limited to, multiple sclerosis, type I- diabetes mellitus, uveoretinitis, thyroditis, myasthenia gravis, immunoglobulin nephropathies, myocarditis, airway sensitization (asthma), lupus, or colitis may also be used to evaluate the therapeutic potential of compounds herein. These models are well established in the research community and are familiar to those schooled in the art (Current Protocols in Immunology, VoI 3., Coligan, J.E. et al, Wiley Press.; Methods in Molecular Biology: Vol. 225, Inflammation Protocols., Winyard, P.G. and Willoughby, D.A., Humana Press, 2003.).
Example FF: pALK assay
To determine the activity of numerous compounds on the phosphorylation of ALK in cells, an ELISA method testing lymphoma cell lysates was developed. Human lymphoma cells were treated with examples for 4 hours. Cells were lysed in lysis buffer (Cell Signaling #9803, Danvers, MA) supplemented with complete mini protease inhibitor cocktail tablets (Roche Applied Science, Indianapolis, IN) on ice and after 15 minutes, lysates were cleared by centrifugation. According to the manufacturer's instructions, lysates were placed in wells precoated with anti-phospho-ALK antibody (Cell Signaling #7324, Danvers, MA) and allowed to incubate overnight at 4 0C. After washing, an anti- ALK antibody is added to wells. Colorimetric (TMB) detection of HRP-linked anti-mouse IgG is used to quantify relative levels of phospho-ALK.
Example GG: Cell proliferation assay
The activity of numerous compounds on ALK driven proliferation was assessed using Karpas- 299 human anaplastic lymphoma cells. Cells were seeded at 2500 cells per well in clear bottom 96 well plates. On the first day, replicate plates were treated with various concentrations of compounds or processed using the manufacturer's instructions for Cell Titer GIo (Promega, Madison, WI) to determine baseline levels. After 72 hours, the dosed plate was processed using Cell Titer GIo. After calculating the specific proliferation of cells in the presence of compounds, IC50S were determined using Prism software (GraphPad Software, San Diego, CA).
Example HH: ALK HTRF kinase assay Materials: Recombinant Human Anaplastic Lymphoma Kinase was purchased from Invitrogen, Carlsbad, CA. Peptide substrate (Biotin-KKKGPWLEEEEEAYGWLDF-amide) was custom synthesized at EZBiolab, Westfield, IN. Streptavidin conjugated SureLight-Allophycocyania and LANCE Eu-W1024 labeled anti-phosphotyrosine antibody were from Perkin-Elmer, Boston, MA. Microplates were from Corning Inc., Acton, MA. All other reagents were from Sigma, St. Louis, MO.
HTRF kinase assay: 40 μL reactions were run in black 384 well polystyrene plates in assay buffer (50 rnM Tris, pH 7.8, 100 mM NaCl, 0.1 mg/mL BSA, 5 mM DTT), containing 0.5 μM Biotinylated peptide substrate, 10 mM MgCl2, 90 μM ATP, and 0.25 nM enzyme for 2 hours at 25 0C. Reactions were stopped by addition of 20 μL assay buffer supplemented with an additional 50 mM NaCl, 0.4 mg/mL BSA, 45 mM EDTA, 4.5 nM LANCE Eu-W1024 labeled anti-phosphotyrosine antibody and 200 nM streptavidin conjugated SureLight-allophycocyanin. Plates were read in Fusion OC-FP instrument (Perkin-Elmer). The concentrations needed to reach 50% inhibition, the IC50 value, were determined by fitting the assay signal to the following equation using Graphpad Prizm.
Signal = Bottom + (Top - Bottom)/(l+10Λ((Log(IC50)-Log[I])*Hill Slope) Bottom and Top refer to the post and pre -transition baselines, respectively.
The IC50 values (or the percentage inhibition of the sample compounds at a concentration of 500 nM or 1 mM) for the example compounds of invention with respect one or more of JAK/ ALK according to one or more methods in Examples AAl, AA2, and HH are provided in Tables Al, Bl, Cl, and Dl as follows. Table Al
Figure imgf000804_0001
Figure imgf000805_0001
Figure imgf000806_0001
Figure imgf000807_0001
Figure imgf000809_0001
Figure imgf000810_0001
Figure imgf000811_0001
a. when the experiment limit is set as "a" and the IC50 measurement of the example compound exceeds the limit, then the IC50 data is shown as "> a" b. "— " designates that the IC50 is not available due to no measurement c. when the data is shown as a number in percentage, the measurement is the percentage inhibition of the example compound at a concentration of 500 nM or 1 mM.
Table Bl
Figure imgf000812_0001
Figure imgf000813_0001
Figure imgf000814_0001
Figure imgf000815_0001
Figure imgf000816_0001
Figure imgf000817_0001
Figure imgf000818_0001
Figure imgf000819_0001
Figure imgf000820_0001
Figure imgf000821_0001
Figure imgf000822_0001
a. when the experiment limit is set as "a" and the IC50 measurement of the example compound exceeds the limit, then the IC50 data is shown as "> a" b. "— " designates that the IC50 is not available due to no measurement c. when the data is shown as a number in percentage, the measurement is the percentage inhibition of the example compound at a concentration of 500 nM or 1 mM.
Table Cl
Figure imgf000823_0001
Figure imgf000824_0001
Figure imgf000825_0001
a. when the experiment limit is set as "a" and the IC50 measurement of the example compound exceeds the limit, then the IC50 data is shown as "> a" b. when the data is shown as a number in percentage, the measurement is the percentage inhibition of the example compound at a concentration of 500 nM or 1 mM. c. "— " designates that the IC50 is not available due to no measurement
Table Dl
Figure imgf000825_0002
Figure imgf000826_0001
Figure imgf000827_0001
Figure imgf000828_0001
Figure imgf000829_0001
Figure imgf000830_0001
Figure imgf000831_0001
Figure imgf000832_0001
Figure imgf000833_0001
a. when the experiment limit is set as "a" and the IC50 measurement of the example compound exceeds the limit, then the IC50 data is shown as "> a" b. "— " designates that the IC50 is not available due to no measurement
Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present application is herein incorporated by reference in its entirety.

Claims

What is claimed is:
1. A compound of Formula I:
Figure imgf000834_0001
I or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein: represents a single bond or a double bond;
X1 is N or CR1;
X2 is N or CR2;
X3 is N or CR3;
Y is O, S, S(O), S(O)2, CR'R", or NR4;
A1 and A2 are each, independently, selected from CR2, N, NR6, O, and S;
B1, B2, E1, and E2 are each, independently, selected from CR5, N, NR6, O, and S;
D1 and D2 are each, independently, selected from a bond, CR5, N, NR6, O, and S; wherein the ring containing A1, B1, D1, and E1 is a 5- or 6-membered aromatic ring and wherein the ring containing A2, B2, D2, and E2 is a 5- or 6-membered aromatic ring;
L1 and L2 are each, independently selected from a bond, -(CRV)n-, -O-(CR7R8)m-CR10=, -S-(CR7R8)m-CR10=, -(CR7R8)m-CR10=, -(CR7R8)m-NR9-, -(CR7R8)m-N=, -(CR7R8)m-O-, -(CRV)1n-S-, -(CRV)1n-S(O)-, -(CRV)1n-S(O)2-, -(CRV)1n-C(O)-, -C(O)NR9-, -(CRV)1n-C(O)O-, -(CRV)1n-NR9C(O)NR9-, -(CRV)1n-OC(O)NR9-, -(CRV)1n-NR9C(O)O-, -(CR7R8)m-NR9-S(O)2NR9-, -(CRV)1n-S(O)NR9-, and -(CRV)1n-S(O)2NR9-; wherein at least one of L1 and L2 is other than a bond;
R1 and R3 are each, independently, selected from H, halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci- 6 haloalkyl, CN, NO2, SF5, 0Ra2, SR"2, C(0)Rb2, C(O)NRc2Rd2, C(O)OR"2, 0C(0)Rb2, OC(O)NRc2Rd2, NRC 2 R d2 NR c2 C(O)R b2 NRc2C(O)NRc2Rd2, NRc2C(O)ORa2, C(=NR8)NRc2Rd2, NRc2C(=NR8)NRc2Rd2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, NRc2S(O)2Rb2, and S(O)2NRc2Rd2; each R2 is, independently, selected from H, halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, CN, NO2, SF5, 0Ra2, SR"2, C(0)Rb2, C(O)NRc2Rd2, C(O)OR"2, 0C(0)Rb2, OC(O)NRc2Rd2, NRC 2 R d2 NR^C(0)R b2 NR c2c(O)NRc2Rd2, NRc2C(O)ORa2, C(=NR8)NRc2Rd2, NRc2C(=NR8)NRc2Rd2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, NRc2S(O)2Rb2, and S(O)2NRc2Rd2; each R5 is, independently, H, Cy1, halo, Ci-6 alkyl, C2-β alkenyl, C2-β alkynyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halosulfanyl, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(S)Rbl, C(S)NRclRdl, C(0)0Ral, 0C(0)Rbl, -W^-Y^Z1, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(S)Rbl, NRclC(S)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, or P(0)0Rel0Rfl, wherein each of said C^6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Q-6 haloalkyl, Cy1, halosulfanyl, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(S)Rbl, C(S)NRclRdl, C(0)0Ral, 0C(0)Rbl, -W^-Y^Z1, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(S)Rbl, NRclC(S)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl; or two adjacent R5 on the same ring can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halosulfanyl, Cy1, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, SF5, C(S)Rbl, C(S)NRclRdl, C(0)0Ral, 0C(0)Rbl, -W^Q^-Z1, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(S)Rbl, NRclC(S)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(O)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl, wherein each of said Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, Cy1,
Figure imgf000835_0001
halosulfanyl, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0CH2C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl;
R4 and R6 are each, independently, selected from H, Cy2, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, -W2-X2-Y2-Z2, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, C(=NR8)NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl, wherein each of said Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2-β alkenyl, C2-β alkynyl, Ci-6 haloalkyl, Cy2, halosulfanyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, -W2- Q2 γ 2 Z 2 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, S(O)2NRclRdl, P(Rfl)2, P(ORel)2, P(0)RelRfl, and P(0)0Rel0Rfl;
R7, R8, and R10 are each, independently, selected from H, Cy3, halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, -W3-Q3-Y3-Z3, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl, wherein each of said Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Q-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, halosulfanyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, Cy3, -W3-Q3-Y3-Z3, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl; each R9 is, independently, H, Cy4, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, -W4-Q4-Y4-Z4, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, C(=NR8)NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, or P(0)0Rel0Rfl, wherein each of said Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci-6 haloalkyl, halosulfanyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, Cy4, -W4- Q4-Y4-Z4, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl;
Rlla, Rllb, R12a, R12b, and R13 are each, independently, selected from H, Cy3, halo, Q-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, S(0)2NRclRdl, P(Rfl)2, P(0Rel)2, P(0)RelRfl, and P(0)0Rel0Rfl, wherein each of said Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2-β alkenyl, C2-β alkynyl, Ci-6 haloalkyl, halosulfanyl, CN, NO2, ORal, SRal, SF5, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, Cy3, -W3-Q3-Y3- Z3, 0C(0)NRclRdl, NRclRdl, NRclC(O)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, S(O)2NRclRdl, P(Rfl)2, P(ORel)2, P(0)RelRfl, and P(0)0Rel0Rfl;
R' and R" are each, independently, selected from H, halo, Ci-4 alkyl, C2.4 alkenyl, C2.4 alkynyl, Ci_4 haloalkyl, CN, NO2, OR"2, SRa2, C(0)Rb2, C(O)NRc2Rd2, C(0)0Ra2, 0C(0)Rb2, OC(O)NRc2Rd2, NRC 2 R d2 NR^C(0)R b2 NR c2c(O)NRc2Rd2, NRc2C(O)ORa2, C(=NR8)NRc2Rd2, NRc2C(=NR8)NRc2Rd2, NRclS(0)2NRclRdl, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, NRc2S(O)2Rb2, and S(O)2NRc2Rd2;
W1, W2, W3, W4, and W5 are each, independently, selected from absent, W6, Ci-6 alkylenyl, C2.6 alkenylenyl, C2_6 alkynylenyl, (CRllaRllb)plO(CRllaRllb)p2, (CRllaRllb)plS(CRllaRllb)p2, (CRl laRllb)piNRe(CRllaRllb)p2, (CRllaRllb)piC(O)(CRllaRllb)p2, (CRllaRllb)piC(S)(CRllaRllb)p2, (CRl laRllb)piC(0)0(CRllaRllb)p2, (CRllaRllb)piC(O)NRe(CRllaRllb)p2, (CRllaRllb)piC(S)NRe(CRllaRllb)p2, (CRl laRllb)piS(O)(CRllaRllb)p2, (CRllaRllb)piS(O) 2(CRllaRllb)p2, (CRllaRllb)piS(O)NRe(CRllaRllb)p2, (CR111R1 lb)pi S(O)2NR6CCR111R1 lb)p2, (CR1 laR! lb)piNReC(O)NRf(CR1 laR! lb)p2, (CRl laRllb)piNReC(S)NRf(CRllaRllb)p2, (CRllaRllb)piNReS(O)2NRf(CRllaRllb)p2,
Figure imgf000837_0001
(CR1 laR! lb)piNReC(=NR8)NRf(CR1 laR! lb)p2, 0(CR1 laR! lb) qiC(O) , S(CRllaRllb) qiC(O), NRe(CRllaRllb) qiC(0), C(0)(CRllaRllb) qiC(0), NRe(CRllaRllb) qiNRf, 0(CRl laRllb)qiNRf, and 0(CRllaRllb) qi0, wherein each of the Ci_6 alkylenyl, C2_6 alkenylenyl and C2_6 alkynylenyl is optionally substituted by 1 , 2, or 3 substituents independently selected from halo, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(0)Rb, NRcC(0)NRcRd, NRcC(0)0Ra, C(=NR8)NRcRd, NRcC(=NR8)NRcRd, NRcS(0)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(0)2Rb, and S(0)2NRcRd; each W6 is independently selected from NRelooC(0)NRf lo° and NRe200C(O)CR13Rf 200, wherein Rel0° and Rf 10° together with the intervening NC(O)N moiety to which they are attached form a 4-7 membered heterocycloalkyl group which is optionally substituted by 1 , 2, or 3 substituents each independently selected from Q-6 alkyl, Q-6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, halo, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(0)Rb, NRcC(0)NRcRd, NRcC(0)0Ra, C(=NR8)NRcRd, NRcC(=NR8)NRcRd, NRcS(0)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, NRcS(0)2Rb, and S(0)2NRcRd, and wherein Re200 and Rf 200 together with the intervening NC(O)CR13 moiety to which they are attached form a 4-7 membered heterocycloalkyl group which is optionally substituted by 1, 2, or 3 substituents each independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2_6 alkynyl, halo, CN, NO2, 0Ra, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR8)NRcRd, NRcC(=NR8)NRcRd, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd;
Q1) Q2' Q3' Q4' and Q5 are each, independently, selected from aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-β alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halo, CN, NO2, ORa, SRa, SF5, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(O)Rb, NRcC(0)NRcRd, NRcC(0)0Ra, C(=NR8)NRcRd, NRcC(=NR8)NRcRd, NRcS(0)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, NRcS(0)2Rb, and S(0)2NRcRd;
Y1, Y2, Y3, Y4, and Y5 are each, independently, selected from absent, Ci_6 alkylenyl, C2.6 alkenylenyl, C2_6 alkynylenyl, (CR12aR12b)p3O(CR12aR12b)p4, (CR12aR12b)p3S(CR12aR12b)p4, (CR12aR12b)p3NRe(CR12aR12b)P4, (CR12aR12b)P3C(O)(CR12aR12b)P4, (CR12aR12b)p3C(S)(CR12aR12b)P4, (CR12aR12b)p3C(O)O(CR12aR12b)P4, (CR12aR12b)p3C(O)NRe(CR12aR12b)P4, (CR12aR12b)p3C(S)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O)(CR12aR12b)P4, (CR12aR12b)p3S(O) 2(CR12aR12b)P4, (CR12aR12b)p3S(O)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O)2NRe(CR12aR12b)P4, (CR12aR12b)p3NReC(O)NRf(CR12aR12b)P4, (CR12aR12b)p3NReC(S)NRf(CR12aR12b)P4, (CR12aR12b)p3NReS(O)2NRf(CR12aR12b)P4,
(CR12aR12b)p3C(=NR8)NRe(CR12aR12b)P4, (CR12aR12b)p3NReC(=NR8)NRf(CR12R12b)P4, O(CR12aR12b)q2C(O), S(CR12aR12b)q2C(O), NRe(CR12aR12b)q2C(O), NRe(CR12aR12b)q2NRf, O(CR12aR12b)q2NRf, and O(CR12aR12b)q2O, wherein each of the Ci-6 alkylenyl, C2_6 alkenylenyl and C2_6 alkynylenyl is optionally substituted by 1, 2 or 3 substituents independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-β alkenyl, C2. 6 alkynyl, halo, CN, NO2, ORa, SRa, SF5, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(0)Rb, NRcC(0)NRcRd, NRcC(0)0Ra, C(=NR8)NRcRd, NRcC(=NR8)NRcRd, NRcS(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, NRcS(0)2Rb, and S(0)2NRcRd;
Z1, Z2, Z3, Z4, and Z5 are each, independently, selected from H, halo, CN, NO2, OH, Ci-6 alkoxy, Ci_6 haloalkoxy, amino, Ci-6 alkylamino, C2.8 dialkylamino, Ci-6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the Ci-6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, SF5, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(0)Rd, NRcC(0)0Ra, NRcS(0)2Rb, NRcS(0)2NRcRd; S(O)Rb, S(0)NRcRd, S(O)2Rb, and S(0)2NRcRd;
Cy1, Cy2, Cy3, and Cy4 are each, independently, selected from aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2-β alkenyl, C2-β alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, SF5, Cy5, -Lbl- Cy5, -W5-Q5-Y5-Z5, Ci_6 haloalkyl, halosulfanyl, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl;
Cy5 and Cy6 are each, independently, selected from aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halosulfanyl, CN, NO2, ORa2, SR12, SF5, C(0)Rb2, C(O)NRc2Rd2, C(S)NRc2Rd2, C(O)OR"2, 0C(0)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NR02C(O)OR"2, C(=NR8)NRc2Rd2, NRc2C(=NR8)NRc2Rd2, NRc2S(O)2NRc2Rd2, S(0)Rb2, S(O)NRc2Rd2, S(O)2Rb2, NRc2S(O)2Rb2, and S(O)2NRc2Rd2;
Lbl and Lb2 are each, independently, selected from Q-4 alkylenyl, 0, S, C(O), C(S), C(0)NRc2, C(S)NRc2, C(O)O, 0C(0)NRc2, NRc2, NRc2C(O)NRd2, NRc2C(S)NRd2, C(=NR8)NRc2, NRc2C(=NR8)NRd2, NRc2S(O)2NRd2, S(O), S(0)NRc2, S(O)2, and S(O)2NRc2, wherein said Ci_4 alkylenyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 substituents each independently selected from halo, CN, Ci_6 alkyl, Ci-6 haloalkyl, OH, Ci-6 alkoxy, Ci-6 haloalkoxy, NH2, NH(Ci-4 alkyl), and N(Ci-4 alkyl)2;
Ral, Rbl, Rcl, and Rdl are each, independently, selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci-6 alkyl, Ci-6 haloalkyl, C2_6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Ci_6 alkyl, halo, CN, Cy 6b, - TL b2-Cy 66, OR ^"22, S C1TRi 3a-2Z, S C1TFT5, / C~i(O)R , C(0)NRc2R dd.22, / C~i( /Sc1)RbZ, C(S)NRc2R dd.2Z, C(0)0Ra2, 0C(0)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NRc2C(S)Rb2, NRc2C(S)NRc2Rd2, NR02C(O)OR"2, C(=NR8)NRc2Rd2, NRc2C(=NR8)NRc2Rd2, NRc2S(O)2NRc2Rd2, S(0)Rb2, S(O)NRc2Rd2, S(O)2Rb2, NRc2S(O)2Rb2, and S(O)2NRc2Rd2; or Rcl and Rdl together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from Q-6 alkyl, Q-6 haloalkyl, halo, CN, Cy6, -Lb2-Cy6, OR12, SRa2, SF5, C(0)Rb2, C(O)NRc2Rd2, C(S)Rb2, C(S)NRc2Rd2, C(0)0Ra2, 0C(0)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)NRc2Rd2, NRc2C(S)Rb2, NRc2C(S)NRc2Rd2, NR02C(O)OR"2, C(=NR8)NRc2Rd2, NRc2C(=NR8)NRc2Rd2, NRc2S(O)2NRc2Rd2, S(0)Rb2, S(O)NRc2Rd2, S(O)2Rb2, NRc2S(O)2Rb2, and S(O)2NRc2Rd2; each Rel is, independently, H, Ci_6 alkyl, Ci_6 haloalkyl, C2-β alkenyl, (Ci_6 alkoxy)-Ci_6 alkyl, C2-β alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocycloalkylalkyl ; each Rfl is, independently, H, Ci_6 alkyl, Ci_6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl;
R*12, Rb2, Rc2, and Rd2 are each, independently, selected from H, Ci_6 alkyl, Ci_6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci_6 alkyl, Ci_6 haloalkyl, C2.6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1 , 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci_6 alkyl, Ci_6 alkoxy, Ci_6 haloalkyl, and Ci_6 haloalkoxy; or Rc2 and Rd2 together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, Ci_6 alkyl, Ci_6 alkoxy, Ci_6 haloalkyl, and Ci-6 haloalkoxy; each Ra is independently selected from H, Ci_6 alkyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl, wherein each of the Ci_6 alkyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from OH, CN, amino, halo, Ci-6 alkyl, Ci_6 haloalkyl, Ci_6 alkoxy, Ci_6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; each Rb is independently selected from H, Ci_6 alkyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the Ci_6 alkyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from OH, amino, halo, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
Rc and Rd are independently selected from H, CM0 alkyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the CM0 alkyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2-β alkenyl, C2-β alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from OH, amino, halo, Ci_6 alkyl, Ci-βhaloalkyl, Ci-βhaloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group that is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from OH, amino, halo, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; and
Re and Rf are each, independently, selected from H, CM0 alkyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein each of the CM0 alkyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted by OH, amino, halo, Ci-6 alkyl, Ci_6 haloalkyl, Ci_6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl ; each Rg is, independently, H, CN, or NO2; each pi is, independently, 0, 1, or 2; each p2 is, independently, 0, 1, or 2; each p3 is, independently, 0, 1, or 2; each p4 is, independently, 0, 1, or 2; each ql is, independently, 1 or 2; each q2 is, independently, 1 or 2; each n is, independently, 1, 2, or 3; and each m is, independently, 0, 1, or 2, with the provisos:
(a) when the ring containing A1, B1, D1, and E1 is a benzene ring optionally substituted by one Ci-4 alkoxy, the ring containing A2, B2, D2, and E2 is a benzene ring optionally substituted by one Ci-4 alkoxy, one of L1 and L2 is -C(O)NR9-, and the other is -(CRV)1n-O-, then LlzzzzL2 is other than -C(O)-NR9- (CRV)2-O-;
(b) when the ring containing A1, B1, D1, and E1 is a benzene ring optionally substituted by one Ci-4 alkoxy, the ring containing A2, B2, D2, and E2 is a benzene ring optionally substituted by one Ci-4 alkoxy, one of L1 and L2 is -(CRV)1n-C(O)-, the other is -(CRV)1n-NR9-, and LlzzzzL2 is -(CRV)1n-C(O)- NR9-(CR V)1n-, then at least one of m is 0; (c) when the ring containing A1, B1, D1, and E1 is a benzene ring optionally substituted by one Ci-4 alkoxy, the ring containing A2, B2, D2, and E2 is a benzene ring optionally substituted by one Ci-4 alkoxy, L l=zzzL 2 is .c(O)-NR9-(CR7R8)-, X2 is N, X1 is CR1, and X3 is CR3, then at least one of R1 and R3 is other than H; d) when the ring containing A1, B1, D1, and E1 is a benzene ring optionally substituted by one Ci-4 alkoxy, the ring containing A2, B2, D2, and E2 is a benzene ring optionally substituted by one Ci-4 alkoxy, and both L1 and L2 are selected from -(CR7R8)m-O, then L1=ZZZL2 is other than -O-(CR7R8)4-O-; (e) when the ring containing A1, B1, D1, and E1 is a benzene ring optionally substituted by one Ci-4 alkoxy, the ring containing A2, B2, D2, and E2 is a benzene ring optionally substituted by one Ci-4 alkoxy, and both L1 and L2 are selected from -O-(CR7R8)m-CR10=, then L1=ZZZL2 is other than -0-(CR7R8)- CR10=CR10-(CR7R8)-O-; and
(f) when L1 is -S(O) 2-, L2 is -NH-, X2 is N, X1 is CH, and X3 is C-Br, Y is -NH-, the ring containing A1, B1, D1, and E1 is a benzene ring, and the ring containing A2, B2, D2, and E2 is a benzene ring, then the ring containing A2, B2, D2, and E2 is other than a benzene ring optionally substituted by OH.
2. The compound of claim 1 , or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein the ring containing A1, B1, D1, and E1 is a 6-membered aromatic ring; B1, D1, and E1 are each, independently, CR5 or N; and A1 is CR2 or N.
3. The compound of claim 1 or 2, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein the ring containing A1, B1, D1, and E1 is a 6-membered aromatic ring; B1,
D1, and E1 are each, independently, CR5; and A1 is CR2.
4. The compound of any one of claims 1-3 or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein the ring containing A1, B1, D1, and E1 is selected from pyridine and pyrimidine rings.
5. The compound of any one of claims 1-4, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein the ring containing A1, B1, D1, and E1 is a pyridine ring.
6. The compound of claim 5, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein D1 is N.
7. The compound of claim 5, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein E1 is N.
8. The compound of claim 5, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein B1 is N.
9. The compound of claim 1 , or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein the ring containing A1, B1, D1, and E1 is a 5-membered aromatic ring.
10. The compound any one of claims 1-9, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein the ring containing A2, B2, D2, and E2 is a 6-membered aromatic ring; B2 D2, and E2 are each, independently, CR5 or N; and A2 is CR2 or N.
11. The compound any one of claims 1 -10, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein the ring containing A2, B2, D2, and E2 is a 6-membered aromatic ring; B2 D2, and E2 are each, independently, CR5; and A2 is CR2.
12. The compound any one of claims 1 -11 , or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein X1 is CR1.
13. The compound any one of claims 1-12, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein X2 is N.
14. The compound any one of claims 1-13, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein X3 is CR3.
15. The compound any one of claims 1-14, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein Y is NR4.
16. The compound of any one of claims 1-15, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein Y is NH.
17. The compound of claim 1 , or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein: the ring containing A1, B1, D1, and E1 is a 6-membered aromatic ring; BB11,, DD11,, aamnd E1 are each, independently, CR5 or N; A1 is CH; the ring containing A2, B2, D2, and E2 is a 6-membered aromatic ring;
B2, D2, and E2 are each, independently, CR5 or N;
A2 is CH;
X1 Is CR1;
X2 is N;
X3 is CR3; and
Y is NR4.
18. The compound of claim 17, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein: one of B1, D1, and E1 is N, and the other two are each independently CR5;
R1 is H;
R3 is H, halo, methyl, or Ci haloalkyl; and
R4 is H or Ci_3 alkyl.
19. The compound any one of claims 1-18, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein L1 and L2 are each, independently, selected from a bond, -(CR7R8)n-, -O- (CRV)1n-CR10=, -S-(CR7R8)m-CR10=, -(CR7R8)m-CR10=, -(CR7R8)m-NR9-, -(CR7R8)m-O-, -(CR7R8)m-S-, - (CR7R8)m-S(O)-, -(CR7RVS(O)2-, -(CR7R8)m-C(O)-, -C(O)NR9-, -(CR7R8)m-C(O)O-, -(CR7R8)m- NR9C(O)NR9-, -(CR7R8)m-OC(O)NR9-, -(CR7R8)m-NR9C(O)O-, -(CR7R8)m-NR9-S(O)2NR9-, -(CR7R8)m- S(O)NR9-, and -(CR7R8)m-S(O)2NR9-.
20. The compound of any one of claims 1-18, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein L1 and L2 together form -CR10=CR10-, -(CH2)2-, -(CH2)-0-, - (CH2)-S-, -(CH2)-S(O)-, -(CH2)-S(O)2-, -(CH2)-NR9-, -C(O)-NR9-, -S(O)2-NR9-, S-S-, -(CH2)2-O-, - (CH2)2-S-, -(CH2)2-S(O)-, -(CH2)2-S(O)2-, -(CH2)2-C(O)-, -(CH2)2-NR9-, -(CH2)-S(O)2-NH-, -(CH2)-NH- S(O)2-, -(CH2)-C(0)-NH-, -(CH2)-NH-C(0)-, -(CH2)-O-(CH2)-, -(CH2)-S-(CH2)-, -(CH2)-NR9-(CH2)-, - (CH2)3-NR9-, -(CH2)2-S-(CH2)-, -O-(CH2)2-O-, -O-(CH2)2-S-, -O-(CH2)2-S(O)-, -O-(CH2)2-S(O)2-, -S- (CHz)2-S-, -NR9-(CH2)2-S-, or -NR9-C(O)-(CH2)2-.
21. The compound of any one of claims 1-18, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein L1 and L2 together form -CH=CH-, -(CH2V, -(CH2)-0-, - (CHz)-S-, -(CHz)-S(O)-, -(CH2)-S(O)2-, -(CH2)-NR9-, -C(O)-NH-, -S(O)2-NH-, S-S-, -(CH2)Z-O-, - (CH2)Z-S-, -(CHz)2-S(O)-, -(CHz)2-S(O)2-, -(CHz)2-C(O)-, -(CHz)2-NR9-, -(CHz)-S(O)2-NH-, -(CHz)-NH- S(O)2-, -(CHz)-C(O)-NH-, -(CHz)-NH-C(O)-, -(CHz)-O-(CH2)-, -(CH2)-S-(CH2)-, -(CH2)-NR9-(CH2)-, - (CH2)3-NR9-, -(CHz)2-S-(CH2)-, -O-(CH2)2-O-, -O-(CH2)2-S-, -O-(CH2)2-S(O)-, -O-(CH2)2-S(O)2-, -S- (CH2)2-S-, -NR9-(CH2)2-S-, or -NH-C(O)-(CH2)2-, wherein each R9 is independently selected from H, Ci-6 alkyl, and C(0)Rbl, and wherein Rbl is selected from Ci-6 alkyl, aryl, and heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-6 alkyl, and Ci-6 haloalkyl.
22. The compound of any one of claims 1-18, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein L1 and L2 together form -(CH2)2-.
23. The compound of any one of claims 1-18, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein one of L1 and L2 is selected from -(CR7R8)m-O-, -(CR7R8)m- S-, -(CR7R8)m-S(O)-, and -(CR7R8)m- S(O)2-; and the other is selected from a bond, -(CR7R8X1-, - (CRV)1n-O-, -(CR7RVS-, -(CR7RVS(O)-, and -(CR7R8)m-S(O)2-.
24. The compound of any one of claims 1-18, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein:
L1 and L2 together form -(CR7RVS-, -(CR7RVO-, -(CR7R8)trS(O)-, -(CR7R8)trS(O) 2-, -S- (CR7RVs-, -0-(CR7RVs-, -0-(CR7R8X2-S(O)-, -O-(CR7R8)t2-S(O) 2-, -S-S-, -(CR7R8X3-O- (CR7R8X4-, -(CR7RVs-(CR7R8X4-, -(CRV)0- S(O)-(CR7R8X4-, or -(CR7RVS(O) 2-(CR7R8X4-; tl is 1, 2, or 3; t2 is 1 or 2; t3 is 1, 2, or 3; and t4 is 1 or 2.
25. The compound of any one of claims 1-18, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein L1 and L2 together form -(CH2)-S-, -(CH2)-S(0)-, -(CH2)- S(O)2-, -(CHz)-O-, -(CH2)Z-O-, -O-(CH2) 2-O-, -0-(CH2) 2-S-, -O-(CH2) 2-S(O)-, or -0-(CH2) 2- S(O)2-.
26. The compound of any one of claims 1-25, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein R1 and R3 are each, independently, selected from H, halo, Ci_3 alkyl, and Ci_3 haloalkyl.
27. The compound of any one of claims 1-25, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein R1 is H and R3 is selected from H, halo, Ci-3 alkyl, and Ci-3 haloalkyl.
28. The compound of any one of claims 1-25, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein R1 is H and R3 is selected from halo, Ci alkyl, and Ci haloalkyl.
29. The compound of any one of claims 1-25, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein R1 is H and R3 is selected from halo.
30. The compound of any one of claims 1-25, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein R1 is H and R3 is Cl.
31. The compound of any one of claims 1-30, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each R2 is, independently, selected from H, F, Cl, CH3, and CF3.
32. The compound of any one of claims 1-30, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each R2 is H.
33. The compound of any one of claims 1-32, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each R5 is, independently, selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, Cy1, -W'-Q'-Y'-Z1, CN, NO2, SF5, ORal, C(O)Rbl, C(0)NRclRdl, C(O)ORal, NRclRdl, NRclC(0)Rbl, S(O)2Rbl, NRclS(O)2NRclRdl, NRclS(O)2Rbl, and S(O)2NRclRdl, wherein each of said Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, or Ci_6 haloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents each independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, halosulfanyl, Cy1,
Figure imgf000846_0001
CN, NO2, SF5, ORal, SRal, C(O)Rbl, C(0)NRclRdl, C(O)ORal, OC(O)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(O)2NRclRdl,S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, S(O)2NRclRdl, P(Rfl)2, P(ORel)2, P(O)RelRfl, and P(O)ORelORfl.
34. The compound of any one of claims 1-32, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein: each R5 is, independently, selected from H, halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, Cy1, -W'-Q'-Y'-Z1, CN, NO2, ORal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclS(0)2NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl, wherein each of said Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, or Ci_6 haloalkyl, is optionally substituted by 1, 2, 3, 4 or 5 substituents each independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, halosulfanyl, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, NRclS(O)2NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl;
Ral, Rbl, Rcl, and Rdl are each, independently, selected from H, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of said Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_4 alkyl, Ci_4 haloalkyl, Ci-4 hydroxylalkyl, Ci-4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OH, SH, O(Ci_4 alkyl), O(Ci_4 haloalkyl), O(aryl), O(arylalkyl), S(Ci_4 alkyl), S(Ci_4 haloalkyl), S(aryl), S(arylalkyl), amino, Ci-4 alkylamino, C2.8 dialkylamino, C(=0)H,
Figure imgf000847_0001
alkyl), C(=O)-(arylalkyl), C(=0)NH2, C(=0)NH(Ci_4 alkyl), C(=0)N(Ci_4 alkyl)2, C(=0)0H, CC=O)O-(C1-4 alkyl), CC=O)O- (arylalkyl), 0C(=0)H, OCC=O)-(C1-4 alkyl), OC(=O)-(arylalkyl), 0C(=0)NH2, 0C(=0)NH(Ci_4 alkyl), OC(=O)NH-(arylalkyl), 0C(=0)N(Ci_4 alkyl)2, NHC(=0)-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=0)0-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHS(=O)2-(Ci_4 alkyl), NHS(=O)2-(arylalkyl), NHS(=O)2-NH(Ci_4 alkyl), NHS(=O)2-N(Ci_4 alkyl)2, NHS(=O)2-NH(arylalkyl), SC=O)2-CC1-4 alkyl), S(=O)2-(arylalkyl), S(=O)2NH2, S(=O)2NH(Ci_4 alkyl), and S(=O)2NH(arylalkyl); or Rcl and Rdl together with the N atom to which they are attached form a 4-, 5-, 6- or 7- membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 hydroxylalkyl, Ci-4 cyanoalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, OH, SH, 0(Ci-4 alkyl), 0(C1-4 haloalkyl), O(aryl), O(arylalkyl), S(Ci-4 alkyl), S(Ci-4 haloalkyl), S(aryl), S(arylalkyl), amino, Q-4 alkylamino, C2.8 dialkylamino, C(=0)H, C(=O)-(C1-4 alkyl), C(=O)-(arylalkyl), C(=0)NH2, CC=O)NH(Ci- 4 alkyl), C(=0)N(Ci_4 alkyl)2, C(=0)0H, CC=O)O-(C1-4 alkyl), C(=O)O-(arylalkyl), 0C(=0)H, OCC=O)- (C1-4 alkyl), OC(=O)-(arylalkyl), OC(=O)NH2, OC(=O)NH(Ci_4 alkyl), OC(=O)NH-(arylalkyl), OC(=O)N(Ci_4 alkyl)2, NHC(=O)-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHC(=O)O-(Ci_4 alkyl), NHC(=O)O-(arylalkyl), NHS(=O)2-(Ci_4 alkyl), NHS(=O)2-(arylalkyl), NHS(=O)2-NH(Ci_4 alkyl), NHS(=O)2-N(Ci_4 alkyl)2, NHS(=O)2-NH(arylalkyl), S(=O)2-(Ci_4 alkyl), S(=O)2-(arylalkyl), S(=O)2NH2, S(=O)2NH(Ci_4 alkyl), and S(=O)2NH(arylalkyl).
35. The compound of any one of claims 1-32, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each R5 is, independently, selected from H, halo, Ci_6 alkyl, Ci_6 haloalkyl, Cy1, -W^Q^-Z1, CN, ORal, C(O)Rbl, C(0)NRclRdl, C(O)ORal, NRclRdl, NRclC(0)Rbl, S(O)2Rbl, NRclS(O)2NRclRdl, NRclS(O)2Rbl, and S(O)2NRclRdl, wherein each of said C^6 alkyl, C2_6 alkenyl, C2.6 alkynyl, or Ci_6 haloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents each independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, halosulfanyl, Cy1, - W^Q^-Z1, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, and S(O)2NRclRdl.
36. The compound of any one of claims 1-32, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein at least one R5 is Cy1.
37. The compound of any one of claims 1-32, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein:. at least one R5 is Cy1; each Cy1 is independently selected from aryl and heteroaryl, each optionally substituted with 1 , 2, or 3 substituents independently selected from Ci_6 alkyl, C(O)-O-(Ci_4 alkyl), S(O)2-(Ci_4 alkyl), and piperazinyl, wherein the piperazinyl is optionally substituted with 1 or 2 subsituents independently selected from Ci_6 alkyl, arylalkyl, aryl, heteroaryl, C(0)Rbl, S(O)2Rbl, C(0)NRclRdl, and S(O)2NRclRdl.
38. The compound of any one of claims 1-32, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein at least one R5 is -W1 -Q1 -Y1 -Z1.
39. The compound of any one of claims 1-32, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein at least one R5 is -Q^-Y^Z1, -(CH^-Q^-Y^Z1, - 0(CRllaRllb)qiC(0)-Q1-Y1-Z1, -O(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piC(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, - (CRllaRllb)piC(O)NRe-Q1-Y1-Z1, -NRe(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)p2NReC(O)-Q1-Y1-Z1, - (CRl laRllb)p1NRe-Q1-Y1-Z1, -(CRllaRllb)p10(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRl lb)piS(CRllaRllb)p2-Q1-Y1- Z1, -(CRl laRllb)piS(O)(CRllaRllb)p2-Q1-Y1-Z1, -(CRl laRllb)piS(O)2(CRllaRllb)p2-Q1-Y1-Z1, - (CRl laRllb)piNRe(CRllaRllb)P2-Q1-Y1-Z1, -NReS(O)(CRllaRllb)pi-Q1-Y1-Z1, -S(O)NR6CCR111R11^p2-Q1- Y^Z1, -NReS(O)2(CRllaRllb)p1-Q1-Y1-Z1, -S^zNR'CCR11^11^^1^1^1, -NR6C(O)(CR111R11^pI-Q1- Y^Z1, -C(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, or -NReC(O)NRf(CRllaRllb)p2-Q1-Y1-Z1.
40. The compound of any one of claims 1-32, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein at least one R5 is -(CRllaRllb)piO(CRllaRllb)p2-Q1-Y1-Z1, - (CRl laRllb)piS(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piS(O)(CRllaRllb)p2-Q1-Y1-Z1, - (CRl laRllb)piS(O)2(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRl lb)piNRe(CRllaRllb)p2-Q1-Y1-Z1, - NReS(O)(CRllaRllb)p1-Q1-Y1-Z1, -S(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, -NReS(O)2(CRllaRllb)pi-Q1-Y1-Z1, - S(O)2NRe(CRllaRllb)p2-Q1-Y1-Z1, -NReC(O)(CRllaRllb)pi-Q1-Y1-Z1, -C(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, or -NR6C(O)NR^CR111R111^2-Q1 -Y1 -Z1.
41. The compound of any one of claims 1-32, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein at least one R5 is -Q1^-Z1, -(CH2)-Q1-Y1-Z1, - 0(CRl laRllb)qiC(0)-Q1-Y1-Z1, -O(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piC(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, - (CRl laRllb)piC(O)NRe-Q1-Y1-Z1, -NRe(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)p2NReC(O)-Q1-Y1-Z1, -
(CRl laRllb)piNRe-Q1-Y1-Z1, -(CRllaRllb)pi0(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piNRe(CRllaRllb)p2-Q1- Y1-Z1, -NReS(O)2(CRllaRllb)pi-Q1-Y1-Z1, -NReC(O)(CRllaRllb)pi-Q1-Y1-Z1, -C(O)NRe(CRllaRllb)p2-Q1- Y^Z1, or -NReC(O)NRf(CRllaRllb)p2-Q1-Y1-Z1.
42. The compound of any one of claims 38-41, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each Q1 is independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci_6 alkyl, Ci_6 haloalkyl, C2.8 alkoxyalkyl, Ci_6 alkoxy, Ci_6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino.
43. The compound of any one of claims 38-41, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each Q1 is independently selected from cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino.
44. The compound of any one of claims 38-41, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each Q1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2_8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Q-6 alkylamino and C2.8 dialkylamino.
45. The compound of any one of claims 1-32, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein at least one R5 is -W^-Q1 -Y1 -Z1.
46. The compound of any one of claims 38-45, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each Y1 is independently selected from absent, (CH2),
(CR12aR12b)P3O(CR12aR12b)P4, (CR12aR12b)p3S(CR12aR12b)P4, (CR12aR12b)P3NRe(CR12aR12b)P4, (CR12aR12b)p3C(O)(CR12aR12b)P4, (CR12aR12b)p3C(O)O(CR12aR12b)P4, C(S)NR6,
(CR12aR12b)p3C(O)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O)2(CR12aR12b)P4, (CR12aR12b)p3S(O)2NRe(CR12aR12b)P4, and (CR12aR12b)p3NReC(O)NRf(CR12aR12b)p4.
47. The compound of any one of claims 38-45, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each Y1 is independently selected from absent,
(CR12aR12b)p3O(CR12aR12b)P4, (CR12aR12b)p3S(CR12aR12b)P4, (CR12aR12b)p3NRe(CR12aR12b)p4, (CR12aR12b)p3C(O)(CR12aR12b)P4, (CR12aR12b)p3C(O)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O) 2(CR12aR12b)P4, (CR12aR12b)p3S(O)2NRe(CR12aR12b)P4, and (CR12aR12b)p3NReC(O)NRf(CR12aR12b)p4.
48. The compound of any one of claims 38-45, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each Y1 is independently selected from absent, (CH2),
(CR12aR12b)p3C(O)(CR12aR12b)P4, (CR12aR12b)p3C(O)O(CR12aR12b)P4, C(S)NR6, (CR12aR12b)p3C(O)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O) 2(CR12aR12b)p4, and (CR12aR12b)p3NReC(O)NRf(CR12aR12b)p4.
49. The compound of any one of claims 38-48, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each Z1 is independently selected from H, OH, CN, Ci-6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein each of the Ci_6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2-β alkenyl, C2-β alkynyl, Ci_6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(0)Rd, NRcC(0)0Ra, NRcS(O)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, and S(0)2NRcRd.
50. The compound of any one of claims 38-49, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each Z1 is independently selected from aryl, cycloalkyl, heteroaryl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(0)Rd, NRcC(0)0Ra, NRcS(O)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, and S(0)2NRcRd.
51. The compound of any one of claims 1-50, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein R7, R8, and R10 are each, independently, selected from H, Ci_4 alkyl, OH, Ci_6 alkoxy, Ci_6 haloalkoxy, and C2.8 alkoxyalkoxy.
52. The compound of any one of claims 1-51, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each n is, independently, 1 or 2.
53. The compound of any one of claims 1-52, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each m is, independently, 0 or 1.
54. The compound of any one of claims 1-53 or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein the compound is a compound of Formula Ilia, IHb, IHc, IHd, IHe, IHf, HIg, IHh, IVa, IVb, IVc, IVd, or Va:
Figure imgf000852_0001
Ilia IHb
Figure imgf000852_0002
IIIc IHd
Figure imgf000852_0003
IHe IHf
Figure imgf000852_0004
Ills IHh
Figure imgf000853_0001
IVc IVd
Figure imgf000853_0002
Va wherein:
D1, E1, D2, and E2 are each, independently, CR5 or N; each RQ is independently selected from selected from Ci_6 alkyl, Ci_6 haloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, halo, CN, NO2, ORa, SRa, SF5, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)NRcRd, NRcC(O)ORa, C(=NR8)NRcRd, NRcC(=NR8)NRcRd, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, NRcS(O)2Rb, and S(O)2NRcRd; plO is O or 1; pi 1 is 0 or 1; and tlO is O, 1, 2, 3, 4, or 5.
55. The compound of claim 54 or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein : each R5 is, independently, H, Cy1, halo, Ci_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci_6 haloalkyl, halosulfanyl, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(S)Rbl, C(S)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(S)Rbl, NRclC(S)NRclRdl, NRclC(0)0Ral, NRclS(O)2NRclRdl, S(O)Rbl, S(O)NRclRdl, S(O)2Rbl, NRclS(O)2Rbl, S(O)2NRclRdl, or -W^Q^-Z1; or two adjacent R5 on the same ring can link to form a fused cycloalkyl or fused heterocycloalkyl group, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, Ci_6 alkyl, C2-6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, Cy1, CN, NO2, ORal, SRal, C(0)Rbl, C(0)NRclRdl, SF5, C(S)Rbl, C(S)NRclRdl, C(0)0Ral, 0C(0)Rbl,
Figure imgf000854_0001
0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(S)Rbl, NRclC(S)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl, wherein each of the Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 haloalkyl, Cy1, -W^Q^-Z1, CN, NO2, SF5, ORal, SRal, C(0)Rbl, C(0)NRclRdl, C(0)0Ral, 0C(0)Rbl, 0CH2C(0)Rbl, 0C(0)NRclRdl, NRclRdl, NRclC(0)Rbl, NRclC(0)NRclRdl, NRclC(0)0Ral, C(=NR8)NRclRdl, NRclC(=NR8)NRclRdl, NRclS(0)NRclRdl, S(O)Rbl, S(0)NRclRdl, S(O)2Rbl, NRclS(0)2Rbl, and S(0)2NRclRdl.
56. The compound of claim 54 or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein at least one R5 is -W1 -Q1 -Y1 -Z1.
57. The compound of claim 54, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein at least one R5 is -Q^Y^Z1, -(CH^-Q^Y^Z1, -0(CRllaRllb)qiC(0)-Q1-Y1-Z1, -
Figure imgf000854_0002
- (CRllaRllb)piC(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, - (CRllaRllb)piC(O)NRe-Q1-Y1- Z1,
Figure imgf000854_0003
-(CRllaRllb)p2NReC(O)-Q1-Y1-Z1, -(CRllaRllb)piNRe-Q1-Y1-Z1, - (CRllaRllb)pi0(CRllaRllb)p2-Q1-Y1-Z1, -(CRllaRllb)piNRe(CRllaRllb)p2-Q1-Y1-Z1, -
NReS(O)2(CRllaRllb)p1-Q1-Y1-Z1, -NReC(O)(CRllaRllb)pl-Q1-Y1-Z1, -C(O)NRe(CRllaRllb)p2-Q1-Y1-Z1, or -NR6C(O)NR^CR111R11^p2-Q1 -Y1 -Z1.
58. The compound of claim 56 or 57, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each Q1 is independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6haloalkyl, C2.8 alkoxyalkyl, Q-6 alkoxy, Ci-6haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(O)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino.
59. The compound of claim 56 or 57, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each Q1 is independently selected from cycloalkyl and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(0)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino.
60. The compound of claim 56 or 57, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each Q1 is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, CN, NO2, OH, Ci-6 alkyl, Ci-6 haloalkyl, C2.8 alkoxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2.8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(0)0Ra, C(0)NRcRd, amino, Ci-6 alkylamino and C2.8 dialkylamino.
61. The compound of any one of claims 56-60, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each Y1 is independently selected from absent, (CH2),
(CR12aR12b)p3C(O)(CR12aR12b)P4, (CR12aR12b)p3C(O)O(CR12aR12b)P4, (CR12aR12b)p3C(O)NRe(CR12aR12b)P4, (CR12aR12b)p3S(O) 2(CR12aR12b)P4, and (CR12aR12b)p3NReC(O)NRf(CR12aR12b)p4.
62. The compound of any one of claims 56-61, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein each Z1 is independently selected from H, OH, CN, Ci-6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein each of the Ci-6 alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, Ci-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NRcC(0)Rd, NRcC(0)0Ra, NRcS(O)2Rb, NRcS(O)2S(O)2NRcRd, S(O)Rb, S(0)NRcRd, S(O)2Rb, and S(0)2NRcRd.
63. A compound of claim 1 selected from:
(14Z)-6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,14,16,18-decaene;
6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
2,4,8,22-Tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene;
6-Chloro-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-16-one;
6-Chloro-19-methyl-17-morpholin-4-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-19-methyl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-10-(isopropylsulfonyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
( 14Z)-6-Methyl-2,4, 8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,7).1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,14,16,18-decaene;
6-Methyl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
Methyl 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxylate;
6-Bromo-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxylic acid;
6-Chloro-N-(3-chloro-4-fluorophenyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxamide; 6-Chloro- 11 - [(4-methylpiperazin- 1 -yl)carbonyl] -2,4, 8 ,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-N-(4-morpholin-4-ylphenyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxamide;
6-Chloro-N- [4-(2-hydroxyethyl)phenyl] -2,4, 8 ,22-tetraazatetracyclo[ 14.3.1.1 (3,7).1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxamide;
6-Chloro-N-(pyridin-4-ylmethyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxamide; l-{ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]carbonyl}piperidin-3-ol;
6-Chloro-N-(3-chlorophenyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxamide;
6-Chloro-N-(2-chlorophenyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxamide;
6-Chloro-N-(4-chlorophenyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxamide;
N-(tert-Butyl)-6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-sulfonamide;
6-Bromo-N-(tert-butyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-sulfonamide;
6-Bromo-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-sulfonamide;
6-Chloro-2,4,8,15,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-14-one; ό-Chloro-lό-thia^^^JS^S-pentaazatetracycloflS.S.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene 16,16-dioxide;
6-Chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-14-one;
6-Chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-16-one;
6-Chloro-15-thia-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene 15, 15 -dioxide;
6-Chloro- 14-thia-2,4, 8 , 15 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)]docosa- I(20),3(22),4,6,9(21),10,12,16,18-nonaene l4,14-dioxide; 6-Chloro-15-thia-2,4,8, 16,23-pentaazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- I(21),3(23),4,6,9(22),10,12,17,19-nonaene l5,15-dioxide;
6-Chloro-15-thia-2,4,8, 14,23-pentaazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- I(21),3(23),4,6,9(22),10,12,17,19-nonaene l5,15-dioxide;
6-Chloro-2,4,8,14,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-15-one;
6-Chloro- 14-thia-2,4, 8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,7).1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-15-thia-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-15-thia-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- I(20),3(22),4,6,9(21),10,12,16,18-nonaene l5-oxide;
6-Chloro-15-thia-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- I(20),3(22),4,6,9(21),10,12,16,18-nonaene l5,15-dioxide;
6-Chloro-16-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-15-oxa-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-14-oxa-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-8-methyl-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-14,17-dioxa-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene; ό-Chloro-π-oxa-H-thia^^^^-tetraazatetracycloflό.S.1.1(3,7). l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene; ό-Chloro-HJS-dithia^^^^-tetraazatetracyclofH.S.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene; ό-Chloro-π-oxa-H-thia^^^^-tetraazatetracycloflό.S.1.1(3,7). l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene 14-oxide; ό-Chloro-π-oxa-H-thia^^^^-tetraazatetracycloflό.S.1.1(3,7). l(9,13)]tetracosa- I(22),3(24),4,6,9(23),10,12,18,20-nonaene l4,14-dioxide; 6-Chloro-14-oxa-17-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene; and
6-Chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene, or pharmaceutically acceptable salt thereof.
64. A compound of claim 1 selected from:
(14Z)-6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,14,16,18-decaene;
6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
2,4,8,22-Tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene;
6-Chloro-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-16-one;
6-Chloro-19-methyl-17-morpholin-4-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-19-methyl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-10-(isopropylsulfonyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
4-({ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)-N-(4-cyanophenyl)piperazine-l- carboxamide;
4-(6-Chloropyridin-3-yl)-4-({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazine-l-carboxamide;
4-({ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)-N-(l-methyl-lH-indol-4-yl)piperazine-l- carboxamide;
12- [2-(4- Acetylpiperazin- 1 -yl)-2-oxoethoxy] -6-chloro-2,4, 8 ,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene; 4-({ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)-N-phenylpiperazine-l-carboxamide;
6-Chloro-12-(cyclopentyloxy)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
2-{ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetamide;
2-{ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}-N-phenylpropanamide; tert-Butyl 4-({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazine-l-carboxylate;
2-{ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}-N-phenylacetamide;
N-Benzyl-4-(2-{ [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino}-2-oxoethyl)piperidine-l-carboxamide;
12-[2-(4-Acetylpiperazin-l-yl)-2-oxoethoxy]-6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-l l-methoxy-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-ol;
2-{ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]oxy}acetyl)acetamide;
2-{ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]oxy}-N-phenylacetamide;
6-Chloro-10-methoxy-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-10-ol; tert-Butyl 4-({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)piperidine-l-carboxylate;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide; l-Acetyl-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide; l-Benzoyl-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide; l-(l,3-Benzodioxol-5-ylcarbonyl)-N-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]piperidine-4-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-(2-furoyl)piperidine-4-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-(4-cyanobenzoyl)piperidine-4-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-[(3,5-dimethylisoxazol-4-yl)carbonyl]piperidine-4- carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-(phenylacetyl)piperidine-4-carboxamide;
N(4)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N(l)-phenylpiperidine-l,4-dicarboxamide;
N(4)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N(l)-(4-cyanophenyl)piperidine-l,4-dicarboxamide;
N(4)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N(l)-(3-methoxyphenyl)piperidine-l,4-dicarboxamide;
N(4)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N(l)-[2-(methylthio)phenyl]piperidine-l,4- dicarboxamide;
N(l)-(6-Chloropyridin-3-yl)-N(4)-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yljpiperidine- 1 ,4-dicarboxamide ;
N(4)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N(l)-(l-methyl-lH-indol-4-yl)piperidine-l,4- dicarboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-(phenylsulfonyl)piperidine-4-carboxamide; l-(Anilinocarbonothioyl)-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide; N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3-carboxamide;
(3R)-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide; l-Acetyl-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3-carboxamide; l-Benzoyl-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3-carboxamide;
N(3)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N(l)-ethylpiperidine-l,3-dicarboxamide;
N(3)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N(l)-phenylpiperidine-l,3-dicarboxamide;
(3R)-l-Acetyl-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide;
(3R)-l-Benzoyl-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide;
(3R)-N(3)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N(l)-ethylpyrrolidine-l,3-dicarboxamide;
(3R)-N(3)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N(l)-phenylpyrrolidine-l,3-dicarboxamide;
2-(l-Acetylpiperidin-4-yl)-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide;
2-(l-Benzoylpiperidin-4-yl)-N-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
4-(2-{ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-ethylpiperidine-l-carboxamide;
4-(2-{ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino}-2-oxoethyl)-N-phenylpiperidine-l-carboxamide;
N(4)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N(l)-ethylpiperidine-l,4-dicarboxamide; Ethyl ({ [4-({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino}carbonyl)piperidin-l-yl]carbonyl}amino)acetate;
N(4)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N(l)-cyclopentylpiperidine-l,4-dicarboxamide;
N(3)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N(l)-cyclopentylpiperidine-l,3-dicarboxamide;
(3R)-N(3)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N(l)-cyclopentylpyrrolidine-l,3-dicarboxamide;
4-(2-{ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-cyclopentylpiperidine-l- carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-cyanoacetamide;
2-[(Anilinocarbonyl)amino]-N-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
3-[(Anilinocarbonyl)amino]-N-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]propanamide;
(2S)-2-[(Anilinocarbonyl)amino]-N-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3- hydroxypropanamide ;
(2S)-N(2)-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N(l)-phenylpyrrolidine-l,2-dicarboxamide; tert-Butyl 4-(2- { [6-chloro-2,4,8 , 18 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7).1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)piperidine-l-carboxylate;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide; l^Aminosulfony^-N-to-chloro^^^^-tetraazatetracyclofH.S.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide; l^Aminosulfony^-N-to-chloro^^^^-tetraazatetracyclofH.S.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3-carboxamide;
(S^-l^Aminosulfony^-N-to-chloro^^^^-tetraazatetracyclofH.S.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-3-carboxamide; 2-[l-(Aminosulfonyl)piperidin-4-yl]-N-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
2-(l-Acetylpiperidin-4-yl)-N-[6-chloro-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide; and
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa-
1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino}-2-oxoethyl)-N-phenylpiperidine-l-carboxamide, or pharmaceutically acceptable salts thereof or quaternary ammonium salt thereof.
65. A compound of claim 1 selected from:
2- [ 1 -( Aminosulf onyl)piperidin-4-yl] -N- [6 -chloro-
2,4,8, 18,22pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(methylsulfonyl)piperidin-4-yl]acetamide;
4-(2-{ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N,N-dimethylpiperidine-l- carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(dimethylamino)sulfonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(isopropylsulfonyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(ethylsulfonyl)piperidin-4-yl]acetamide;
4-(2-{ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-isopropylpiperidine-l- carboxamide;
N-^ert-Buty^^^-l fo-chloro^^^^-tetraazatetracyclofH.S.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino}-2-oxoethyl)piperidine-l-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4- yljacetamide; N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(pyrazin-2-ylcarbonyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2,2-dimethylpropanoyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-isobutyrylpiperidin-4-yl)acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-propionylpiperidin-4-yl)acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(methylsulfonyl)pyrrolidin-3-yl]acetamide;
3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-phenylpyrrolidine-l- carboxamide;
3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-methylpyrrolidine-l- carboxamide;
2-( 1 - Acetylpyrrolidin-3 -yl)-N- [6-chloro-2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N,N-dimethylpiperidine-l- carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(dimethylamino)sulfonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(isopropylsulfonyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(ethylsulfonyl)piperidin-4-yl]acetamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-isopropylpiperidine-l- carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-methylpiperidine-l-carboxamide; N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(pyrazin-2-ylcarbonyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-isobutyrylpiperidin-4-yl)acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-propionylpiperidin-4-yl)acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-pyrrolidin-3-ylacetamide;
(2S)-N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-hydroxypropanamide;
2-Amino-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide;
S-Amino-N-tό-chloro^^^^-tetraazatetracyclofH.S.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]propanamide;
(2S)-2-Amino-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-hydroxypropanamide;
(2S)-N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-2-carboxamide;
N-tό-Chloro^^^Jδ^-pentaazatetracyclotH.S.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2,2-dimethylpropanoyl)piperidin-4-yl]acetamide;
N-(tert-Butyl)-4-(2-{ [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino} -2 -oxoethyl)piperidine-l-carboxamide; tert-Butyl-4-(2-{ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)piperazine-l-carboxylate;
N-tό-Chloro^^^Jδ^-pentaazatetracyclotH.S.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperazin-l-acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3piperidin-4-ylpropanamide;
N-[6-Chloro-2,4,8,18,22-pentaaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3piperidin-4-ylpropanamide; N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(4-[l,3]oxazolo[5,4-b]pyridin-2-ylpiperazin-l- yl)acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{4-[(5-methylisoxazol-3-yl)carbonyl]piperazin-l- yljacetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-[(5-methylisoxazol-3-yl)carbonyl]piperidine-4- carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-[(5-methylisoxazol-3-yl)carbonyl]piperidine-3- carboxamide;
(3R)-N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-[(5-methylisoxazol-3-yl)carbonyl]pyrrolidine-4- carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{4-[(5-methylisoxazol-3-yl)carbonyl]piperazin-l- yljacetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-{ l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4- yljpropanamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-{ l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4- yljpropanamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-[l,3]oxazolo[5,4-b]pyridin-2-ylpiperidin-4- yl)acetamide;
2-(4-Acetylpiperazin-l-yl)-N-[6-chloro-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(isoxazol-5-ylcarbonyl)piperidin-4-yl]acetamide; N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(l-methyl-lH-pyrazol-4-yl)carbonyl]piperidin-4- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(l-methyl-lH-pyrazol-3-yl)carbonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(5-methylisoxazol-4-yl)carbonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(4-methyl-l,3-oxazol-5-yl)carbonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3-thiazol-2-ylcarbonyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(l-methyl-lH-imidazol-5yl)carbonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(isoxazol-3-ylcarbonyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(lH-l,2,4-triazol-3-ylcarbonyl)piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(lH-l,2,3-triazol-4-ylcarbonyl)piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,2,5-oxadiazol-3-ylcarbonyl)piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3-oxazol-2-ylcarbonyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-isopropylpiperidin-4-yl)acetamide; 4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(2-cyanophenyl)piperidine-l- carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(3-cyanophenyl)piperidine-l- carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(4-cyanophenyl)piperidine-l- carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-pyridin-3-ylpiperidine-l- carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(3,5-dimethylisoxazol-4- yl)piperidine- 1 -carboxamide ;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(2-fluorophenyl)piperidine-l- carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(3-fluorophenyl)piperidine-l- carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(4-fluorophenyl)piperidine-l- carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(2-methylphenyl)piperidine-l- carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(3-methylphenyl)piperidine-l- carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(4-methylphenyl)piperidine-l- carboxamide; 4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(2-methoxyphenyl)piperidine-l- carboxamide;
4-(2-{ [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(3-methoxyphenyl)piperidine-l- carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(4-methoxyphenyl)piperidine-l- carboxamide; and
N-Benzyl-4-(2-{ [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)piperidine-l-carboxamide, or pharmaceutically acceptable salts thereof or quaternary ammonium salt thereof, or 4-(2-{ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-l,l-dimethylpiperidinium bis(trifluoroacetate).
66. A compound of claim 1 selected from:
(14Z)-6-Methyl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,14,16,18-decaene;
6-Methyl-2,4, 8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,7).1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Bromo-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
Methyl 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxylate;
6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxylic acid;
6-Chloro-N-(3-chloro-4-fluorophenyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxamide;
6-Chloro- 11 - [(4-methylpiperazin- 1 -yl)carbonyl] -2,4, 8 ,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-N-(4-morpholin-4-ylphenyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxamide; 6-Chloro-N- [4-(2-hydroxyethyl)phenyl] -2,4, 8 ,22-tetraazatetracyclo[ 14.3.1.1 (3,7).1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxamide;
6-Chloro-N-(pyridin-4-ylmethyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxamide; l-{ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]carbonyl}piperidin-3-ol;
6-Chloro-N-(3-chlorophenyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxamide;
6-Chloro-N-(2-chlorophenyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxamide;
6-Chloro-N-(4-chlorophenyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-carboxamide;
N-(tert-Butyl)-6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-sulfonamide;
6-Bromo-N-(tert-butyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-sulfonamide;
6-Bromo-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-l l-sulfonamide;
6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine di;
6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine;
6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-amine;
Methyl 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-12-carboxylate;
[6-Chloro-2,4, 8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methanol;
[6-Chloro-2,4, 8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]methanol;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea tri;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide; N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]cyclopropanecarboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-methoxyacetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]nicotinamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-methyl-lH-pyrazole-3-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-phenylacetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-furamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]thiophene-2-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-methylbenzamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-methoxybenzamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyridine-2-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-fluorobenzamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]isonicotinamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3,5-dimethylisoxazole-4-carboxamide;
2-Chloro-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzamide;
3-Chloro-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzamide;
4-Chloro-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzamide; N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrazine-2-carboxamide;
4-(Acetylamino)-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-methylbenzamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-methylbenzamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-fluorobenzamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-fluorobenzamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-methyl-lH-pyrrole-2-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-methyl-lH-imidazole-5-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l,3-thiazole-2-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]isoxazole-5-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]propanamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-methylpropanamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]butanamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]cyclobutanecarboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2,2-dimethylpropanamide ;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-furamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]cyclopentanecarboxamide; N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-methylbutanamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]thiophene-3-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]cyclohexanecarboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-cyanobenzamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-cyanobenzamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-methoxybenzamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-methoxybenzamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-5-methylisoxazole-3-carboxamide;
6-Chloro-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]nicotinamide;
2-Chloro-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]nicotinamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l,3-benzodioxole-5-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]quinoxaline-2-carboxamide;
4-tert-Butyl-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l,3-benzothiazole-2-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(trifluoromethyl)benzamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-(trifluoromethyl)benzamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-6-(trifluoromethyl)nicotinamide; N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-methyl-l,3-oxazole-5-carboxamide; and
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-benzofuran-5-carboxamide, or pharmaceutically acceptable salts thereof or quaternary ammonium salt thereof.
67. A compound of claim 1 selected from:
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrazolo[l,5-a]pyridine-3-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidine-l-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(dimethylamino)benzamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-phenylurea;
N-(2-Chlorophenyl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea;
N-(3-Chlorophenyl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea;
N-(4-Chlorophenyl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea;
N-(tert-Butyl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-cyclopentylurea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-3-thienylurea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(3-methylphenyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-methylphenyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(4-methylphenyl)urea; N-benzyl-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(3,5-dimethylisoxazol-4-yl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(3-cyanophenyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(4-cyanophenyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-ethylphenyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(4-ethylphenyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(3-ethylphenyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(3-methoxyphenyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(4-methoxyphenyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-methoxyphenyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2,3-dihydro-lH-inden-5-yl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-isopropylphenyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-propylphenyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-ethoxyphenyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[2-(methylthio)phenyl]urea;
N-[2-(Chloromethyl)phenyl]-N'-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(5,6,7,8-tetrahydronaphthalen-l-yl)urea; N-(2-tert-Butylphenyl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[2-(trifluoromethyl)phenyl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[3-(trifluoromethyl)phenyl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2,6-dichlorophenyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-methylurea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-ethylurea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-isopropylurea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-furylmethyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-methyl-3-furyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-cyclohexylurea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(4-methyl-2-thienyl)urea;
N-(6-Chloropyridin-3-yl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea;
N-(2-Chloro-6-methylphenyl)-N'-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea;
N-(5-Chloro-2-methylphenyl)-N'-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-l-naphthylurea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(l-methyl-lH-indol-4-yl)urea;
N-(2-sec-Butylphenyl)-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea; N-l-Adamantyl-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[2-(difluoromethoxy)phenyl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2,2-dimethyl-2,3-dihydro-l-benzofuran-7-yl)urea;
N-Biphenyl-2-yl-N'-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[2-(trifluoromethoxy)phenyl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[4-(trifluoromethoxy)phenyl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(6-morpholin-4-ylpyridin-2-yl)urea;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-furylmethyl)urea;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-methylurea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzenesulfonamide;
2-Chloro-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzenesulfonamide;
3-Chloro-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzenesulfonamide;
4-Chloro-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]benzenesulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methanesulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]ethanesulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]propane-l-sulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]propane-2-sulfonamide; N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-methyl-lH-imidazole-4-sulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-5-methylisoxazole-4-sulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]thiophene-2-sulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l-phenylmethanesulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-methylbenzenesulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-methylbenzenesulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-methylbenzenesulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l,2-dimethyl-lH-imidazole-4-sulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3,5-dimethylisoxazole-4-sulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-cyanobenzenesulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-cyanobenzenesulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-cyanobenzenesulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-methoxybenzenesulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-methoxybenzenesulfonamide; and
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]cyclopropanesulfonamide, or pharmaceutically acceptable salts thereof or quaternary ammonium salt thereof.
68. A compound of claim 1 selected from: 3-({ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}sulfonyl)benzoic acid;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]quinoline-8-sulfonamide;
N-[4-({ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}sulfonyl)phenyl]acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(trifluoromethyl)benzenesulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-(trifluoromethyl)benzenesulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(trifluoromethyl)benzenesulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-methyl-3,4-dihydro-2H-l,4-benzoxazine-7- sulfonamide; tert-Butyl (3S)-3-[({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino}carbonyl)amino]pyrrolidine-l-carboxylate;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-pyrrolidin-3-yl]urea;
N-[(3S)-l-Acetylpyrrolidin-3-yl]-N'-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea;
(3S)-3-[({ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]-N-methylpyrrolidine-l- carboxamide;
N-[(3S)-l-Benzoylpyrrolidin-3-yl]-N'-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-l-(pyridin-3-ylcarbonyl)pyrrolidin-3-yl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-l-(methylsulfonyl)pyrrolidin-3-yl]urea;
N-[(3S)-l-Benzylpyrrolidin-3-yl]-N'-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea; tert-Butyl (3R)-3- [( { [6-chloro-2,4,8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,7).1 (9, 13)] docosa- l(20),3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino}carbonyl)amino]pyrrolidine-l-carboxylate; N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3R)-pyrrolidin-3-yl]urea;
N-[(3R)- 1 -Benzoylpyrrolidin-3 -yl] -N'- [6-chloro-2,4, 8 ,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea;
N-[(3R)-l-Acetylpyrrolidin-3-yl]-N'-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3R)-l-(methylsulfonyl)pyrrolidin-3-yl]urea;
(3R)-3-[({ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino}carbonyl)amino]pyrrolidine-l-sulfonamide; tert-Butyl 4-[({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18 -nonaen-12-yl] amino Jcarbonyl) amino] piperidine-1-carboxylate;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-piperidin-4-ylurea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[l-(methylsulfonyl)piperidin-4-yl]urea;
4-[({ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]piperidine-l-sulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]sulf amide; tert-Butyl {2-[({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}carbamate;
N-{2-[({ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}acetamide;
N-{2-[({ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}methanesulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-{ [(isopropylamino)carbonyl]amino}ethyl)urea;
N-{2-[({ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}benzamide;
N-{2-[({ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}pyridine-2-carboxamide;
6-Chloro-l l-(piperazin-l-ylmethyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene; 6-Chloro- 11 - { [4-(4-fluorobenzyl)piperazin- 1 -yljmethyl } -2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 11 -( { 4-[4-(pyrimidin-2-yloxy)benzyl]piperazin- 1 -yl } methyl)-2,4, 8 ,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 11 - { [4-(4-nitrobenzyl)piperazin- 1 -yl] methyl } -2,4,8 ,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 11 - [(4- { 4-[(4-chlorophenyl)sulfonyl]benzyl Jpiperazin- 1 -yl)methyl] -2,4, 8 ,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene; ll-({4-[(4-Bromo-2-thienyl)methyl]piperazin-l-yl}methyl)-6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 11 - { [4-(4-methoxybenzyl)piperazin- 1 -yljmethyl } -2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 11 - { [4-(3-methoxybenzyl)piperazin- 1 -yljmethyl } -2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 11 - { [4-(4-chlorobenzyl)piperazin- 1 -yl] methyl } -2,4, 8 ,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-N-phenyl-2,4, 8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-12-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]pyridine-2-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]-N'-phenylurea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]benzenesulfonamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]-l,3-benzothiazole-2-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]-5-methylisoxazole-3-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]isoxazole-5-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]-l-methyl-lH-pyrazole-3-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]-l-methyl-lH-imidazole-5-carboxamide; N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]-l,3-thiazole-2-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]-4-methyl-l,3-oxazole-5-carboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]cyclobutanecarboxamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]-N'-(4-cyanophenyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]-N'-(2-fluorophenyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]-N'-(3-fluorophenyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]-N'-cyclopentylurea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-l l-yl]-2-cyanobenzenesulfonamide;
6-Chloro- 11 - { [4-(6-chloropyridin-2-yl)piperazin- 1 -yljmethyl } -2,4, 8 ,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 11 - { [4-(2-chloropyrimidin-4-yl)piperazin- 1 -yl] methyl } -2,4,8 , 22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene; tert-Butyl (3R)-3-({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}amino)pyrrolidine-l-carboxylate; tert-Butyl (3S)-3-({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}amino)pyrrolidine-l-carboxylate; tert-ButyM-l fo-chloro^^^^-tetraazatetracyclofH.S.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}piperazine-l-carboxylate;
(3R)-N-{ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}pyrrolidin-3-amine;
(3S)-N-{ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}pyrrolidin-3-amine;
6-Chloro-12-(piperazin-l-ylmethyl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
12- [(4- Acetylpiperazin- 1 -yl)methyl] -6-chloro-2,4, 8 ,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene; N-[(3S)-l-Acetylpyrrolidin-3-yl]-N'-[6-chloro-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea;
N-[(3S)-l-benzoylpyrrolidin-3-yl]-N'-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-l-(cyclopropylcarbonyl)pyrrolidin-3-yl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-l-isobutyrylpyrrolidin-3-yl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-l-(isoxazol-5-ylcarbonyl)pyrrolidin-3-yl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-l-(l,3-thiazol-2-ylcarbonyl)pyrrolidin-3- yl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-{(3S)-l-[(l-methyl-lH-pyrazol-3- yl)carbonyl]pyrrolidin-3-yl}urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-l-(pyridin-2-ylcarbonyl)pyrrolidin-3-yl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-l-isonicotinoylpyrrolidin-3-yl]urea; and
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-l-(4-cyanobenzoyl)pyrrolidin-3-yl]urea, or pharmaceutically acceptable salts thereof or quaternary ammonium salt thereof.
69. A compound of claim 1 selected from:
6-Chloro-2,4,8,15,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-14-one;
6-Chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-15-one;
6-Chloro-16-thia-2,4,8, 15,23-pentaazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- I(21),3(23),4,6,9(22),10,12,17,19-nonaene l6,16-dioxide;
6-Chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-14-one; 6-Chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-16-one;
6-Chloro-15-thia-2,4,8, 14,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- I(20),3(22),4,6,9(21),10,12,16,18-nonaene l5,15-dioxide;
6-Chloro- 14-thia-2,4, 8 , 15 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)]docosa- I(20),3(22),4,6,9(21),10,12,16,18-nonaene l4,14-dioxide;
6-Chloro-15-thia-2,4,8, 16,23-pentaazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- I(21),3(23),4,6,9(22),10,12,17,19-nonaene l5,15-dioxide;
6-Chloro-15-thia-2,4,8, 14,23-pentaazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- I(21),3(23),4,6,9(22),10,12,17,19-nonaene l5,15-dioxide;
6-Chloro-2,4,8,14,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-15-one;
6-Chloro-2,4,8,16,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-15-one;
6-Chloro-2,4,8,17,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Fluoro-2,4,8,17,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
(14Z)-6-Chloro-2,4,8,17,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,14,16,18-decaene;
6-Chloro-2,4,8,19,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Fluoro-2,4,8,19,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-2,4,8,20,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Fluoro-2,4,8,20,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
(14Z)-6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,14,16,18-decaene; and
6-Fluoro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene, or pharmaceutically acceptable salts thereof or quaternary ammonium salt thereof.
70. A compound of claim 1 selected from:
6-Chloro- 14-thia-2,4, 8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,7).1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-15-thia-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-15-thia-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene 15-oxide;
6-Chloro-15-thia-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene 15, 15 -dioxide; ό-Chloro-lό-oxa^Aδ^-tetraazatetracyclollS.S.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-15-oxa-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-14-oxa-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene; ό-Chloro-H-oxa^^^^S-tetraazatetracycloflS.S.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-8-methyl-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-14,17-dioxa-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene; ό-Chloro-π-oxa-H-thia^^^^-tetraazatetracycloflό.S.1.1(3,7). l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene; ό-Chloro-HJS-dithia^^^^-tetraazatetracyclofH.S.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene; ό-Chloro-π-oxa-H-thia^^^^-tetraazatetracycloflό.S.1.1(3,7). l(9,13)]tetracosa- I(22),3(24),4,6,9(23),10,12,18,20-nonaene l4-oxide; ό-Chloro-π-oxa-H-thia^^^^-tetraazatetracycloflό.S.1.1(3,7). l(9,13)]tetracosa- I(22),3(24),4,6,9(23),10,12,18,20-nonaene l4,14-dioxide; ό-Chloro-H-oxa-π-thia^^^^-tetraazatetracycloflό.S.1.1(3,7). l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene; 6-Chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-2,4,8,15,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-14-thia-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-16-thia-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-15-thia-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-15-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
19-Bromo-6-chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-14-thia-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene 14-oxide;
6-chloro-14-thia-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene 14,14-dioxide;
6-Chloro-19-pyridin-4-yl-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-19-pyridin-3-yl-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro- 19-(2-piperazin- 1 -ylpyridin-4-yl)- 14-oxa-2,4, 8 ,23- tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-19-phenyl-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro- 19- [4-(methylsulfonyl)phenyl] - 14-oxa-2,4, 8 ,23- tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-19-(3,5-dimethyl-lH-pyrazol-4-yl)-14-oxa-2,4,8,23- tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-19-(2-piperazin-l-ylpyrimidin-5-yl)-14-oxa-2,4,8,23- tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-15-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene; 6-Chloro-19-(6-piperazin-l-ylpyridin-3-yl)-14-oxa-2,4,8,23- tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-16-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene;
19- [2-(4- Acetylpiperazin- 1 -yl)pyridin-4-yl] -6-chloro- 14-oxa-2,4, 8 ,23 - tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro- 19- { 2- [4-(methylsulfonyl)piperazin- 1 -yl]pyridin-4-yl } - 14-oxa-2,4,8 ,23- tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
19- [6-(4- Acetylpiperazin- 1 -yl)pyridin-3-yl] -6-chloro- 14-oxa-2,4, 8 ,23 - tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro- 19- { 6- [4-(methylsulfonyl)piperazin- 1 -yl]pyridin-3 -yl } - 14-oxa-2,4,8 ,23- tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
4-{4-[6-Chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}piperazine-l-carboxamide;
4-{5-[6-Chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}piperazine-l-carboxamide;
N-(tert-Butyl)-4-{4-[6-chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}piperazine-l-carboxamide;
4-{5-[6-Chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}-N-phenylpiperazine-l-carboxamide;
Methyl 6-chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxylate;
4-{4-[6-Chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}-N-phenylpiperazine-l-carboxamide;
N-Benzyl-4-{4-[6-chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}piperazine-l-carboxamide;
4-{4-[6-Chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}-N-cyclopentylpiperazine-l-carboxamide;
N-(tert-Butyl)-4-{4-[6-chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}piperazine-l-carboxamide;
N-Benzyl-4-{4-[6-chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}piperazine-l-carboxamide;
4-{4-[6-Chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}-N-cyclopentylpiperazine-l-carboxamide; 6-Chloro-N-phenyl-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).1(9, 13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxamide;
N-Benzyl-6-chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).1(9, 13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxamide;
4-{4-[6-Chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7). l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaen-19-yl]pyridin-2-yl}-N-cyclopentylpiperazine-l-carboxamide;
6-Chloro-20- [(4-phenylpiperazin- 1 -yl)carbonyl] - 17-oxa- 14-thia-2,4,8 ,24- tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaene;
6-Chloro-N- 1 ,3 -thiazol-2-yl- 17-oxa- 14-thia-2,4,8 ,24- tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaene-20- carboxamide;
6-Chloro-N-( 1 -methyl- 1 H-benzimidazol-2-yl)- 17-oxa- 14-thia-2,4,8 ,24- tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaene-20- carboxamide;
6-Chloro-N- 1 H-indol-5-yl- 17-oxa- 14-thia-2,4,8 ,24- tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaene-20- carboxamide;
N-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]benzamide;
N-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]-5-methylisoxazole-3-carboxamide;
N-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]isoxazole-5-carboxamide;
N-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]isonicotinamide;
N-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]-l-benzofuran-5-carboxamide;
N-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]-2-furamide;
N-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]thiophene-2-carboxamide;
N-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]thiophene-2-carboxamide; N-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]-N'-phenylurea;
N-Benzyl-N'- [6-chloro- 17-oxa- 14-thia-2,4,8 ,24- tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa-l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]urea;
N-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]-N'-(2-furylmethyl)urea;
N-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]benzenesulfonamide;
N-[6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaen-20-yl]-l,2-dimethyl-lH-imidazole-4-sulfonamide;
6-Chloro-14-oxa-2,4,8,17,24-pentaazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene;
15-Acetyl-6-chloro-2,4,8,15,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-17-oxa-2,4,8,14,24-pentaazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene;
6-Chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene ;
15-Acetyl-6-chloro-2,4,8,15,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-2,4,8,14,24-pentaazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene;
6-Chloro-2,4,8,17,24-pentaazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaen-16-one;
6-Chloro-2,4,8,17,24-pentaazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene;
6-Chloro-2,4,8,16,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-2,4,8,16,23-pentaazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa- l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro-14-thia-2,4,8,17,24-pentaazatetracyclo[16.3.1.1(3,7). l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene;
6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene-19-carbonitrile; 6-Chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).l(9,13)]tetracosa- l(22),3(24),4,6,9(23),10,12,18,20-nonaene-19-carbonitrile;
6-Chloro-12-piperazin-l-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
N-(tert-Butyl)-4-[6-chloro-2,4, 8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperazine-l-carboxamide;
12-(4-Acetylpiperazin-l-yl)-6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
4-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperazine-l-carboxamide; l-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]pyrrolidin-3-amine;
4-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N-(3-cyanophenyl)piperazine-l-carboxamide;
4-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N-[4-(trifluoromethyl)phenyl]piperazine-l- carboxamide;
4-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N-[3-(trifluoromethyl)phenyl]piperazine-l- carboxamide;
4-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N-phenylpiperazine-l-carboxamide;
4-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N-(4-cyanophenyl)piperazine-l-carboxamide;
12-(4-Benzoylpiperazin-l-yl)-6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
4-({4-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperazin-l-yl}carbonyl)benzonitrile; and
6-Chloro- 12- { 4- [4-(trifluoromethyl)benzoyl]piperazin- 1 -yl } -2,4, 8 ,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene, or pharmaceutically acceptable salts thereof or quaternary ammonium salt thereof, or 4-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-l,l-dimethylpiperazin-l-ium bis(trifluoroacetate).
71. A compound of claim 1 selected from:
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(3,5-dimethylisoxazol-4-yl)carbonyl]piperidin-4- yljacetamide;
2-[ 1 -( 1 ,3 -Benzothiazol-2-yl)piperidin-4-yl] -N- [6-chloro-2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-[l,3]oxazolo[5,4-b]pyridin-2-ylpiperidin-4- yl)acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3-thiazol-2-yl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-methyl-3-furoyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(3-methyl-2-furoyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(5-methyl-2-furoyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(5-methyl-lH-pyrazol-3-yl)carbonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(l-methyl-lH-imidazol-2-yl)carbonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(3-methylisoxazol-4-yl)carbonyl]piperidin-4- yljacetamide ;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(4-methyl-l,2,5-oxadiazol-3- yl)carbonyl]piperidin-4-ylJacetamide;
2-{ l-[(4-Amino-l,2,5-oxadiazol-3-yl)carbonyl]piperidin-4-ylJ-N-[6-chloro-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide; N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(isothiazol-5-ylcarbonyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(5-fluoropyrimidin-2-yl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-pyridin-2-ylpiperidin-4-yl)acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-pyrazin-2-ylpiperidin-4-yl)acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-pyrimidin-2-ylpiperidin-4-yl)acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(6-methylpyridazin-3-yl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3,4-thiadiazol-2-yl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(5-methyl-lH-pyrazol-3-yl)carbonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(4-methylpyridin-2-yl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(3-cyanopyridin-2-yl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(4-cyanopyridin-2-yl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(5-cyanopyridin-2-yl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(6-chloropyridin-2-yl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(6-fluoropyridin-2-yl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-methylpyrimidin-4-yl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3,4-thiadiazol-2-yl)piperidin-4-yl]acetamide; N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(pyridin-3-ylcarbonyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-isonicotinoylpiperidin-4-yl)acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(4-cyanobenzoyl)piperidin-4-yl]acetamide trifluoroacetate;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(3-cyanobenzoyl)piperidin-4-yl]acetamide trifluoroacetate;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(pyridin-3-ylcarbonyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-isonicotinoylpiperidin-4-yl)acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(4-cyanobenzoyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(3-cyanobenzoyl)piperidin-4-yl]acetamide;
2-(l-Benzoylpiperidin-4-yl)-N-[6-chloro-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(4-fluorobenzoyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2,4-difluorobenzoyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(phenylsulfonyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(3-methoxyphenyl)sulfonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(4-methoxyphenyl)sulfonyl]piperidin-4- yljacetamide; N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(2-cyanophenyl)sulfonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(4-cyanophenyl)sulfonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(5-methylisoxazol-4-yl)sulfonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-furylsulfonyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(pyridin-3-ylsulfonyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(4-fluorobenzoyl)piperidin-4-yl]acetamide trifluoroacetate;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2,4-difluorobenzoyl)piperidin-4-yl]acetamide trifluoroacetate;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(phenylsulfonyl)piperidin-4-yl]acetamide trifluoroacetate;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(3-methoxyphenyl)sulfonyl]piperidin-4- yljacetamide trifluoroacetate;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(4-methoxyphenyl)sulfonyl]piperidin-4- yljacetamide trifluoroacetate;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(2-cyanophenyl)sulfonyl]piperidin-4- yljacetamide trifluoroacetate;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(4-cyanophenyl)sulfonyl]piperidin-4- yljacetamide trifluoroacetate; N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(5-methylisoxazol-4-yl)sulfonyl]piperidin-4- yljacetamide trifluoroacetate;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-furylsulfonyl)piperidin-4-yl]acetamide trifluoroacetate;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(pyridin-3-ylsulfonyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(5-cyclopropylisoxazol-4-yl)carbonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(5-isopropylisoxazol-3-yl)carbonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(3-methoxyisoxazol-5-yl)carbonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(4-methyl-l,3-thiazol-5-yl)carbonyl]piperidin-4- yljacetamide;
2- { 1 - [(2- Amino- 1 ,3-thiazol-4-yl)carbonyl]piperidin-4-yl J -N- [6-chloro-2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(5-isopropylisoxazol-4-yl)carbonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-phenylpiperidin-4-yl)acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-cyanophenyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(4-cyanophenyl)piperidin-4-yl]acetamide; 2- [ 1 -(3-Chloro-2-cyanophenyl)piperidin-4-yl] -N-[6-chloro-2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(2-chlorophenyl)sulfonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-{ [2-(trifluoromethyl)phenyl]sulfonyl}piperidin-4- yl)acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(2-methylphenyl)sulfonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(2-fluorophenyl)sulfonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-{ [2-(trifluoromethoxy)phenyl]sulfonyl}piperidin- 4-yl)acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(3-cyanophenyl)sulfonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(l-methyl-lH-imidazol-4-yl)sulfonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(l,2-dimethyl-lH-imidazol-4- yl)sulfonyl]piperidin-4-yl}acetamide;
N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(3,5-dimethylisoxazol-4-yl)sulfonyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(2,4-dimethyl-l,3-thiazol-5-yl)sulfonyl]piperidin- 4-yl}acetamide; N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-cyano-3-methoxyphenyl)piperidin-4- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-cyano-3-fluorophenyl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[2-cyano-3-(trifluoromethyl)phenyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-cyano-3-methylphenyl)piperidin-4- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[2-cyano-5-(trifluoromethyl)phenyl]piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(3-cyano-6-methylpyridin-2-yl)piperidin-4- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(3-cyano-4,6-dimethylpyridin-2-yl)piperidin-4- yljacetamide;
2-[l-(5-Chloro-4-cyanopyridin-3-yl)piperidin-4-yl]-N-[6-chloro-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yljacetamide;
2-[ 1 -(6-Chloro-3 -cyano-5 -fluoropyridin-2-yl)piperidin-4-yl] -N- [6-chloro-2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-pyridin-4-ylpiperidin-4-yl)acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(3-fluoropyridin-4-yl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(2-fluoropyridin-4-yl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(cyanoacetyl)piperidin-4-yl]acetamide; N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3-oxazol-2-yl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(5-methylisoxazol-3-yl)piperidin-4-yl]acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(5-methylisoxazol-3-yl)piperidin-4-yl]acetamide trifluoroacetate;
6-Chloro-12-{2-oxo-2-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl]ethoxy}-2,4,8, 18,22pentaazatetracyclo[14.3.1.1(3,7).1(9,13)] docosal(20),3(22),4,6,9(21),10,12,16,18- nonaene; tert-Butyl [(3R)-l-({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)pyrrolidin-3-yl]carbamate; tert-Butyl 3-[({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino}carbonyl)amino]piperidine-l-carboxylate;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-piperidin-3-ylurea ;
N'-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N,N-dimethylurea ;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-cyclopropylurea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-hydroxyethyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-hydroxy-l-methylethyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-methoxyethyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-lH-l,2,4-triazol-3-ylurea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-l,3-thiazol-2-ylurea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(pyridin-4-ylmethyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-methoxy-l-methylethyl)urea; N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(5-methyl-l,3-thiazol-2-yl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(4-methyl-l,3-thiazol-2-yl)urea;
2-[({ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]-l,3-thiazole-4-carboxylic acid;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-lH-tetrazol-5-ylurea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(5-chloro-l,3-thiazol-2-yl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-pyridin-2-ylurea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-morpholin-4-ylethyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-pyrrolidin-l-ylethyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[2-(l-methylpyrrolidin-2-yl)ethyl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[2-(2-oxopyrrolidin-l-yl)ethyl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-piperidin-l-ylethyl)urea; tert-Butyl 4- { 2- [( { [6-chloro-2,4, 8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,7).1 (9, 13)] docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino}carbonyl)amino]ethyl}piperazine-l-carboxylate;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-piperazin-l-ylethyl)urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-l-methylpyrrolidin-3-yl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-l-pyrimidin-2-ylpyrrolidin-3-yl]urea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-{ l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4- yljurea; N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-{ l-[(5-methylisoxazol-4-yl)carbonyl]piperidin-4- yljurea;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-{(3S)-l-[(5-methylisoxazol-3-yl)carbonyl]pyrrolidin- 3 -yljurea;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-{(3S)-l-[(5-methylisoxazol-4-yl)carbonyl]pyrrolidin- 3 -yljurea;
N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-l-(lH-pyrazol-4-ylcarbonyl)pyrrolidin-3- yljurea;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-l-(lH-pyrazol-5-ylcarbonyl)pyrrolidin-3- yljurea;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-{(3S)-l-[(l-methyl-lH-pyrazol-4- yl)carbonyl]pyrrolidin-3-yl}urea;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-{(3S)-l-[(5-cyclopropylisoxazol-3- yl)carbonyl]pyrrolidin-3-yl}urea;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-l-(isoxazol-5-ylcarbonyl)pyrrolidin-3-yl]urea;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-{(3S)-l-[(l-methyl-lH-pyrazol-3- yl)carbonyl]pyrrolidin-3-yl}urea;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-{(3S)-l-[(4-methyl-l,3-oxazol-5- yl)carbonyl]pyrrolidin-3-yl Jurea ;
N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-{(3S)-l-[(3,5-dimethylisoxazol-4- yl)carbonyl]pyrrolidin-3-yl Jurea; N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-[(3S)-l-[l,3]oxazolo[5,4-b]pyridin-2-ylpyrrolidin-3- yl]urea;
6-Chloro-N-(4-methylpyrimidin-2-yl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine;
2-{ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}pyrimidin-4-ol;
Ethyl 2- { [6-chloro-2,4, 8 ,22-tetraazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-l,3-oxazole-4-carboxylate;
6-Chloro-N-(4-phenylpyrimidin-2-yl)-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine;
2-Chloro-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-6-methylpyrimidine-4-carboxamide;
N-[4-(4-Aminopiperidin- 1 -yl)pyrimidin-2-yl] -6-chloro-2,4, 8 ,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine;
N-[4-(4-Aminopiperidin- 1 -yl)pyrimidin-2-yl] -6-chloro-2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine;
N-[(3S)-l-Benzylpyrrolidin-3-yl]-N'-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N- methylurea;
N-[(3S)-l-Benzylpyrrolidin-3-yl]-N'-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N- methylurea;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperazine-l-carboxamide;
4-Benzoyl-N-[6-chloro-2,4,8 , 18 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperazine-l-carboxamide;
4-Benzyl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperazine-l-carboxamide;
N'-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N-methyl-N-[(3S)-pyrrolidin-3-yl]urea;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-pyridin-2-ylpiperazine-l-carboxamide; N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-pyridin-2-ylpiperazine-l-carboxamide;
N-[(3S)-l-Benzoylpyrrolidin-3-yl]-N'-[6-chloro-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N- methylurea;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-phenylpiperazine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-pyridin-4-ylpiperazine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-pyrazin-2-ylpiperazine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(2-fluorophenyl)piperazine-l-carboxamide;
6-Chloro-N-[4-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-ylcarbonyl)-l,3-oxazol-2-yl]-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(4-fluorophenyl)piperazine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(2-methoxyphenyl)piperazine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(4-methoxyphenyl)piperazine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(2-cyanophenyl)piperazine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-[5-(trifluoromethyl)pyridin-2-yl]piperazine-l- carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]piperazine- 1-carboxamide ;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(4-cyanophenyl)piperazine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(3-methoxyphenyl)piperazine-l-carboxamide; N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(2-chlorophenyl)piperazine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(3-chlorophenyl)piperazine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(4-chlorophenyl)piperazine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(6-methylpyrazin-2-yl)piperazine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-pyrimidin-2-ylpiperazine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(5-cyanopyridin-2-yl)piperazine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(3-cyanopyridin-2-yl)piperazine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-phenylpyrrolidine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-pyrazin-2-ylpyrrolidine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-phenylpiperidine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]hexahydropyrrolo[l,2-a]pyrazine-2(lH)-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- a]pyrazine-7(8H)-carboxamide;
4-Acetyl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperazine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(methylsulfonyl)piperazine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-(phenylsulfonyl)piperazine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-methyl-4-phenylpiperazine-l-carboxamide; N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-(phenylsulfonyl)pyrrolidine-l-carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-4-cyano-4-phenylpiperidine-l-carboxamide;
N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-cyanourea;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-hydroxyurea;
N-{2-[({ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino}carbonyl)amino]ethyl}ethanesulfonamide;
N-{2-[({ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino}carbonyl)amino]ethyl}propane-l -sulfonamide;
N-{2-[({ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- 1(20), 3(22),4,6,9(21), 10,12,16, 18 -nonaen-12-yl] amino Jcarbonyl) amino] ethyl Jcyclopropanesulfonamide;
N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N'-(2-{ [(dimethylamino)sulfonyl]amino}ethyl)urea;
N-{2-[({ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}benzenesulfonamide;
5-Chloro-N-{2-[({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}thiophene-2-sulfonamide;
6-Chloro-N-{2-[({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}pyridine-3-sulfonamide;
N-{2-[({ [6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}-l-methyl-lH-pyrazole-3- sulfonamide;
6-Chloro-N-[l,3]oxazolo[5,4-b]pyridin-2-yl-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine; l-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N-methylmethanamine;
N-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}-N-methyl-l-[(5-methylisoxazol-3- yl)carbonyl]piperidine-4-carboxamide; N-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}-l-(isoxazol-5-ylcarbonyl)-N-methylpiperidine- 4-carboxamide;
N(4)-{ [6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}-N(4)-methyl-N(l)-phenylpiperidine-l,4- dicarboxamide;
N-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}-N-methyl-l-pyrimidin-2-ylpiperidine-4- carboxamide; l-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N-methyl-N-(piperidin-4-ylmethyl)methanamine;
2-[(4-{ [{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}(methyl)amino]methyl}piperidin-l- yl) sulf onyl] benzonitrile ; l-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N-methyl-N-{ [l-(phenylsulfonyl)piperidin-4- yl] methyl } methanamine ; l-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N-methyl-N-({ l-[(5-methylisoxazol-4- yl) sulf onyl] piperidin-4-yl } methyl)methanamine ; l-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N-({ l-[(l,2-dimethyl-lH-imidazol-4- yl)sulfonyl]piperidin-4-yl}methyl)-N-methylmethanamine; l-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N-methyl-N-({ l-[(5-methylisoxazol-3- yl)carbonyl] piperidin-4-yl } methyl)methanamine ; l-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N-{ [l-(isoxazol-5-ylcarbonyl)piperidin-4-yl]methyl}-N- methylmethanamine ;
1 -( 1 -Acetylpiperidin-4-yl)-N- { [6-chloro-2,4,8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl] methyl } -N-methylmethanamine ; l-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-N-methyl-N-({ l-[(4-methyl-l,3-oxazol-5- yl)carbonyl]piperidin-4-yl}methyl)methanamine;
4-{ [{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}(methyl)amino]methyl}-N-pyridin-3- ylpiperidine-1 -carboxamide;
4-{ [{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]methyl}(methyl)amino]methyl}-N-(2-methyl-3- furyl)piperidine- 1 -carboxamide ; and
6-Chloro-12-(lH-pyrazol-4-yl)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene, or pharmaceutically acceptable salts thereof or quaternary ammonium salt thereof.
72. A compound of claim 1 selected from:
14-Benzoyl-6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 14-(pyridin-2-ylcarbonyl)-2,4, 8 , 14,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 14-(4-methylbenzoyl)-2,4, 8 , 14,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7).1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-14-(2-thienylcarbonyl)-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
14-Butyryl-6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-14-(pyridin-3-ylcarbonyl)-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
Methyl 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene-12-carboxylate;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(lH-indol-3-yl)acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(3-methylisoxazol-5-yl)acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(lH-tetrazol-5-yl)acetamide; N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(3-thienyl)acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(lH-imidazol-4-yl)acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(2-methyl-lH-indol-3-yl)acetamide;
2-(l-Benzothien-3-yl)-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(2-furyl)acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-methyl-lH-indol-3-yl)acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(2-methyl-l,3-thiazol-4-yl)acetamide ;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-pyridin-3-ylacetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-pyridin-4-ylacetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-pyridin-2-ylacetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(2-thienyl)acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(2,4-dimethyl-l,3-thiazol-5-yl)acetamide;
2-(lH-Benzimidazol-2-yl)-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide;
2-(l,2-Benzisoxazol-3-yl)-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(2,5-dimethyl-l,3-thiazol-4-yl)acetamide;
2-(l-Benzofuran-3-yl)-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-3-(4-methyl-l,3-thiazol-5-yl)propanamide; N-[6-Huoro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4- yljacetamide;
6-Methyl-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine;
2- { 1 - [(5-Methylisoxazol-3 -yl)carbonyl]piperidin-4-yl } -N- [6-methyl-2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
N-[6-Huoro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4- yljacetamide;
N-[6-Methyl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3,4-thiadiazol-2-yl)piperidin-4-yl]acetamide;
2- { 1 - [(5-Methylisoxazol-3 -yl)carbonyl]piperidin-4-yl } -N- [6-methyl-2,4, 8 ,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yljacetamide;
6-Chloro-12-(pyrrolidin-3-ylmethoxy)-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
12- [( 1 - Acetylpyrrolidin-3-yl)methoxy] -6-chloro-2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
2-{ [3-({ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}methyl)pyrrolidin-l-yl]sulfonyl}benzonitrile;
6-Chloro-12-({ l-[(5-methylisoxazol-3-yl)carbonyl]pyrrolidin-3-yl}methoxy)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
3-({ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}methyl)-N-phenylpyrrolidine-l-carboxamide;
(3R)-3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-phenylpyrrolidine-l- carboxamide;
(3R)-3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(4-cyanophenyl)pyrrolidine-l- carboxamide; (3R)-3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(3-cyanophenyl)pyrrolidine-l- carboxamide;
(3R)-3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(2-cyanophenyl)pyrrolidine-l- carboxamide;
(3R)-3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-pyridin-3-ylpyrrolidine-l- carboxamide;
(3R)-3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(4-fluorophenyl)pyrrolidine-l- carboxamide;
(3R)-3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(3-fluorophenyl)pyrrolidine-l- carboxamide;
(3R)-3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(2-fluorophenyl)pyrrolidine-l- carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-l-(isoxazol-5-ylcarbonyl)pyrrolidin-3- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3R)-l-[(l-methyl-lH-pyrazol-3- yl)carbonyl]pyrrolidin-3-yl}acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3R)-l-[(l-methyl-lH-pyrazol-4- yl)carbonyl]pyrrolidin-3-yl}acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3R)-l-[(5-methylisoxazol-4-yl)carbonyl]pyrrolidin- 3-yl}acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3R)-l-[(5-methylisoxazol-3-yl)carbonyl]pyrrolidin- 3-yl}acetamide; N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-l-(l,3-thiazol-2-ylcarbonyl)pyrrolidin-3- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3R)-l-[(l-methyl-lH-imidazol-5- yl)carbonyl]pyrrolidin-3-yl}acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-l-(methylsulfonyl)pyrrolidin-3-yl]acetamide;
(3S)-3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-phenylpyrrolidine-l- carboxamide;
(3S)-3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(4-cyanophenyl)pyrrolidine-l- carboxamide;
(3S)-3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(3-cyanophenyl)pyrrolidine-l- carboxamide;
(3S)-3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(2-cyanophenyl)pyrrolidine-l- carboxamide;
(3S)-3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-pyridin-3-ylpyrrolidine-l- carboxamide;
(3S)-3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(4-fluorophenyl)pyrrolidine-l- carboxamide;
(3S)-3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(3-fluorophenyl)pyrrolidine-l- carboxamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-l-(isoxazol-5-ylcarbonyl)pyrrolidin-3- yljacetamide; N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3S)-l-[(l-methyl-lH-pyrazol-3- yl)carbonyl]pyrrolidin-3-yl}acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3S)-l-[(l-methyl-lH-pyrazol-4- yl)carbonyl]pyrrolidin-3-yl}acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3S)-l-[(5-methylisoxazol-4-yl)carbonyl]pyrrolidin- 3-yl}acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3S)-l-[(5-methylisoxazol-3-yl)carbonyl]pyrrolidin- 3-yl}acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-l-(l,3-thiazol-2-ylcarbonyl)pyrrolidin-3- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3S)-l-[(l-methyl-lH-imidazol-5- yl)carbonyl]pyrrolidin-3-yl}acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-l-(methylsulfonyl)pyrrolidin-3-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-l-(lH-l,2,4-triazol-3-ylcarbonyl)pyrrolidin-3- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-l-(lH-l,2,3-triazol-4-ylcarbonyl)pyrrolidin-3- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-l-(lH-pyrazol-4-ylcarbonyl)pyrrolidin-3- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-l-(lH-pyrazol-3-ylcarbonyl)pyrrolidin-3- yl]acetamide; N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-l-(lH-l,2,4-triazol-3-ylcarbonyl)pyrrolidin-3- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-l-(lH-l,2,3-triazol-4-ylcarbonyl)pyrrolidin-3- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-l-(lH-pyrazol-4-ylcarbonyl)pyrrolidin-3- yl]acetamide ;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-l-(lH-pyrazol-3-ylcarbonyl)pyrrolidin-3- yl]acetamide;
(3S)-3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)-N-(2-fluorophenyl)pyrrolidine-l- carboxamide;
2-[(3R)-l-(l,3-Benzothiazol-2-yl)pyrrolidin-3-yl]-N-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
2-[(3S)-l-(l,3-Benzothiazol-2-yl)pyrrolidin-3-yl]-N-[6-chloro-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
2-[l-(l,3-Benzothiazol-2-yl)azetidin-3-yl]-N-[6-chloro-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-l-[l,3]oxazolo[5,4-b]pyridin-2-ylpyrrolidin-3- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-l-[l,3]oxazolo[5,4-b]pyridin-2-ylpyrrolidin-3- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-[l,3]oxazolo[5,4-b]pyridin-2-ylazetidin-3- yl)acetamide; N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(l-methyl-lH-pyrazol-4-yl)carbonyl]azetidin-3- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{ l-[(5-methylisoxazol-3-yl)carbonyl]azetidin-3- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(isoxazol-5-ylcarbonyl)azetidin-3-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3-thiazol-2-ylcarbonyl)azetidin-3-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(methylsulfonyl)azetidin-3-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(lH-l,2,4-triazol-3-ylcarbonyl)azetidin-3- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(lH-l,2,3-triazol-4-ylcarbonyl)azetidin-3- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(lH-pyrazol-4-ylcarbonyl)azetidin-3-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(lH-pyrazol-5-ylcarbonyl)azetidin-3-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3,4-thiadiazol-2-yl)azetidin-3-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3-thiazol-2-yl)azetidin-3-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-pyridin-2-ylazetidin-3-yl)acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3-thiazol-2-yl)pyrrolidin-3-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[l-(l,3,4-thiadiazol-2-yl)pyrrolidin-3-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-pyridin-2-ylpyrrolidin-3-yl)acetamide; N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l-pyridin-4-ylpyrrolidin-3-yl)acetamide;
N-(I - Acetylpiperidin-4-yl)-6-chloro-2,4,8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine;
6-Chloro-N- [ 1 -(phenylacetyl)piperidin-4-yl] -2,4,8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine;
6-Chloro-N- { 1 - [(5-methylisoxazol-3 -yl)carbonyl]piperidin-4-yl } -2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine;
12-[2-( 1 - Acetylpiperidin-4-yl)ethoxy] -6-chloro-2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-N-phenylpiperidine-l-carboxamide;
2-{ [4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)piperidin-l-yl]sulfonyl}benzonitrile;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-N-(2-methyl-3-furyl)piperidine-l- carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-N-(2-furylmethyl)piperidine-l-carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-N-3-thienylpiperidine-l-carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-N-2-thienylpiperidine-l-carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-N-(4-fluorophenyl)piperidine-l-carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-N-(3-fluorophenyl)piperidine-l-carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-N-(2-fluorophenyl)piperidine-l-carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-N-(3,5-dimethylisoxazol-4-yl)piperidine-l- carboxamide; 4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-N-(4-methyl-2-thienyl)piperidine-l- carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-N-(2-cyanophenyl)piperidine-l-carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-N-(4-cyanophenyl)piperidine-l-carboxamide;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-N-(2,2-dimethyl-2,3-dihydro-l-benzofuran-7- yl)piperidine- 1 -carboxamide ;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-N-(6-morpholin-4-ylpyridin-2-yl)piperidine- 1 -carboxamide;
6-Chloro- 12- { 2- [ 1 -(pyrazin-2-ylcarbonyl)piperidin-4-yl]ethoxy } -2,4,8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-12-(2-{ l-[(5-methylisoxazol-4-yl)carbonyl]piperidin-4-yl}ethoxy)-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-12-(2-{ l-[(2-chloropyridin-3-yl)carbonyl]piperidin-4-yl}ethoxy)-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 12- { 2- [ 1 -(pyridin-3-ylcarbonyl)piperidin-4-yl]ethoxy } -2,4,8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 12- [2-( 1 -isonicotinoylpiperidin-4-yl)ethoxy] -2,4,8,18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}ethyl)-N-pyridin-3-ylpiperidine-l-carboxamide;
Methyl [4-011^0-19-0X0-18-0X3-2,6,8,20,25- pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa-l(23),3(25),4,6,9(24),10,12,16,21-nonaen- 20-yl] acetate;
4-Chloro-18-oxa-2,6,8,20,25-pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa- l(23),3(25),4,6,9(24),10,12,16,21-nonaen-19-one;
2-[4-Chloro-19-oxo-18-oxa-2,6,8,20,25- pentaazapentacyclo[14.6.1.1(3,7). l(9,13).0(17,21)]pentacosa-l(23),3(25),4,6,9(24),10,12,16,21-nonaen- 20-yl] -N-phenylacetamide; N-Benzyl-2-[4-chloro-19-oxo-18-oxa-2,6,8,20,25- pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa-l(23),3(25),4,6,9(24),10,12,16,21-nonaen- 20-yl]acetamide;
4-Chloro-20-(2-morpholin-4-yl-2-oxoethyl)-18-oxa-2,6,8,20,25- pentaazapentacyclo[14.6.1.1(3,7). l(9,13).0(17,21)]pentacosa-l(23),3(25),4,6,9(24),10,12,16,21-nonaen- 19-one;
4-Chloro-20-[2-oxo-2-(4-phenylpiperazin-l-yl)ethyl]-18-oxa-2,6,8,20,25- pentaazapentacyclo[14.6.1.1(3,7).l(9,13).0(17,21)]pentacosa-l(23),3(25),4,6,9(24),10,12,16,21-nonaen- 19-one;
6-Chloro-19-(morpholin-4-ylmethyl)-14-oxa-2,4,8,23- tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro- 19- [(4-methylpiperazin- 1 -yl)methyl] - 14-oxa-2,4, 8 ,23 - tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
6-Chloro- 19-(piperazin- 1 -ylmethyl)- 14-oxa-2,4, 8 ,23 - tetraazatetracyclo[15.3.1.1(3,7).l(9,13)]tricosa-l(21),3(23),4,6,9(22),10,12,17,19-nonaene;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamide;
N-[6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamide;
N-tό-Chloro^^^Jδ^-pentaazatetracyclotH.S.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide;
(3S)-3-(2-{ [6-Chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino} -2 -oxoethy^-N-phenylpiperidine-l-carboxamide;
(S^-S^-l fo-Chloro^^^^-tetraazatetracyclofH.S.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino} -2 -oxoethy^-N-phenylpiperidine-l-carboxamide;
(3S)-3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino} -2 -oxoethy^-N-phenylpiperidine-l-carboxamide;
(3R)-3-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21), 10,12,16, 18-nonaen-12-yl]amino} -2 -oxoethy^-N-phenylpiperidine-l-carboxamide;
2-[(3S)-l-Acetylpiperidin-3-yl]-N-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide; l-tCS^-l-Acetylpiperidin-S-ylJ-N-tθ-chloro-l^^^l- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
2-[(3S)-l-Benzoylpiperidin-3-yl]-N-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
2-[(3R)-l-Benzoylpiperidin-3-yl]-N-[6-chloro-2,4,8,22- tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
2-[(3S)-l-Acetylpiperidin-3-yl]-N-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
2-[(3R)-l-Acetylpiperidin-3-yl]-N-[6-chloro-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
2-[(3S)-l-Benzoylpiperidin-3-yl]-N-[6-chloro-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
2-[(3R)-l-Benzoylpiperidin-3-yl]-N-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3S)-l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-3- yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-{(3R)-l-[(5-methylisoxazol-3-yl)carbonyl]piperidin- 3 -yljacetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)ethanesulfonamide;
2-[(3S)-l-(l,3-Benzothiazol-2-yl)piperidin-3-yl]-N-[6-chloro-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yljacetamide; 2- [(3R)- 1 -( 1 ,3 -Benzothiazol-2-yl)piperidin-3-yl] -N- [6-chloro-2 ,4,8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-l-[l,3]oxazolo[5,4-b]pyridin-2-ylpiperidin-3- yl]acetamide;
N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-l-[l,3]oxazolo[5,4-b]pyridin-2-ylpiperidin-3- yl]acetamide;
Benzyl 4-(2-{ [6-chloro-2,4,8, 18,22-pentaazatetracyclo[14.3.1. l(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}ethyl)piperidine-l-carboxylate;
6-Chloro-N-(2-piperidin-4-ylethyl)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine;
2,4,8,18,22-Pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18- nonaene;
6-Chloro-N-(2- { 1 -[(5 -methylisoxazol-3-yl)carbonyl]piperidin-4-yl } ethyl)-2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine;
N-[2-( 1 -Acetylpiperidin-4-yl)ethyl] -6-chloro-2,4,8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine;
6-Chloro-N- { 2- [ 1 -(2,4-difluorobenzoyl)piperidin-4-yl] ethyl } -2,4,8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine;
6-Chloro-N-(2-{ l-[(2-fluorophenyl)sulfonyl]piperidin-4-yl}ethyl)-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine;
2-{ [4-(2-{ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}ethyl)piperidin-l-yl]sulfonyl}benzonitrile;
8-Methyl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
8-Methyl-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-12-(piperidin-4-ylmethoxy)-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-12-({ l-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl}methoxy)-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene; 12- [( 1 - Acetylpiperidin-4-yl)methoxy] -6 -chloro-2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
4-( { [6-Chloro-2,4,8 , 18 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}methyl)-N-phenylpiperidine-l-carboxamide;
6-Chloro- 12-(2-oxo-2-piperazin- 1 -ylethoxy)-2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 12- { 2-oxo-2- [4-( 1 ,3-thiazol-2-yl)piperazin- 1 -yl] ethoxy } -2,4,8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 12- [2-oxo-2-(4-pyridin-2-ylpiperazin- 1 -yl)ethoxy] -2,4,8,18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 12- [2-oxo-2-(4-pyrazin-2-ylpiperazin- 1 -yl)ethoxy] -2,4,8,18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 12- [2-oxo-2-(4-pyrimidin-2-ylpiperazin- 1 -yl)ethoxy] -2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 12- [2-oxo-2-(4-phenylpiperazin- 1 -yl)ethoxy] -2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
2-[4-({ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazin-l-yl]benzonitrile;
4-[4-({ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazin-l-yl]benzonitrile;
6-Chloro- 12- { 2- [4-(4-methylpyridin-2-yl)piperazin- 1 -yl] -2-oxoethoxy } -2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
2-[4-({ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazin-l-yl]nicotinonitrile;
6-[4-({ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazin-l-yl]nicotinonitrile ;
6-Chloro- 12- { 2- [4-(6-chloropyridin-2-yl)piperazin- 1 -yl] -2-oxoethoxy } -2,4,8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 12- { 2- [4-(2-methoxyphenyl)piperazin- 1 -yl] -2-oxoethoxy } -2,4,8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene ;
6-Chloro- 12- { 2- [4-(4-fluorophenyl)piperazin- 1 -yl] -2-oxoethoxy } -2,4,8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 12- [2-oxo-2-(4-pyridin-4-ylpiperazin- 1 -yl)ethoxy] -2,4,8,18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene; 6-Chloro- 12- { 2- [4-(4-chloropyridin-2-yl)piperazin- 1 -yl] -2-oxoethoxy } -2,4,8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 12- [2-(4-furo[3 ,2-c]pyridin-4-ylpiperazin- 1 -yl)-2-oxoethoxy] -2,4,8,18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 12- { 2- [4-(5-methylpyridin-2-yl)piperazin- 1 -yl] -2-oxoethoxy } -2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 12- { 2- [4-(4,6-dichloropyridin-2-yl)piperazin- 1 -yl] -2-oxoethoxy } -2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 12-(2-oxo-2- { 4-[6-(trifluoromethyl)pyridin-2-yl]piperazin- 1 -yl } ethoxy)-2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene ;
6-Chloro- 12- { 2- [4-(3-methoxypyridin-2-yl)piperazin- 1 -yl] -2-oxoethoxy } -2,4,8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
12- { 2- [4-( 1 ,2-Benzisoxazol-3 -yl)piperazin- 1 -yl] -2-oxoethoxy } -6-chloro-2,4,8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene ;
6-Chloro-12-(2-{4-[(5-methylisoxazol-3-yl)carbonyl]piperazin-l-yl}-2-oxoethoxy)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene ;
12-[2-(4-Acetylpiperazin-l-yl)-2-oxoethoxy]-6-chloro-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene ;
6-Chloro- 12-(2- { 4-[(2-fluorophenyl)sulfonyl]piperazin- 1 -yl } -2-oxoethoxy)-2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
2-{ [4-({ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazin-l-yl]sulfonyl}benzonitrile;
6-Chloro- 12- { 2-oxo-2- [4-(pyridin-3-ylmethyl)piperazin- 1 -yl] ethoxy } -2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene ;
6-Chloro- 12- { 2-oxo-2- [4-(pyridin-4-ylmethyl)piperazin- 1 -yl] ethoxy } -2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-12-(2-oxo-2-{4-[5-(2-thienyl)-lH-pyrazol-3-yl]piperidin-l-yl}ethoxy)-2,4,8,18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro-12-(2-oxo-2-{4-[3-(2-thienyl)-l,2,4-oxadiazol-5-yl]piperidin-l-yl}ethoxy)-2,4,8, 18,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 12- { 2- [4-(2,4-difluorobenzoyl)piperazin- 1 -yl] -2-oxoethoxy } -2,4,8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 12- { 2- [4-(isoxazol-5-ylcarbonyl)piperazin- 1 -yl] -2-oxoethoxy } -2,4,8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene; Methyl 4-({ [6-chloro-2,4,8, 18,22-pentaazatetracyclo[14.3.1.1(3,7). l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazine-l-carboxylate ;
6-Chloro- 12- { 2- [4-(methoxyacetyl)piperazin- 1 -yl] -2-oxoethoxy } -2,4,8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 12- { 2- [4-(ethylsulfonyl)piperazin- 1 -yl] -2-oxoethoxy } -2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
4-( { [6-Chloro-2,4,8 , 18 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)-N-phenylpiperazine-l-carboxamide;
4-( { [6-Chloro-2,4,8 , 18 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)-N-methylpiperazine-l-carboxamide;
6-Chloro-12-(2-{4-[(5-methyl-lH-pyrazol-3-yl)carbonyl]piperazin-l-yl}-2-oxoethoxy)- 2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene; l-{ [4-({ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazin-l- yl] carbonyl } cyclopropanecarbonitrile ;
4-( { [6-Chloro-2,4,8 , 18 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazine-l-sulfonamide;
3-[4-({ [6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazin-l-yl]-3-oxopropanenitrile;
4-( { [6-Chloro-2,4,8 , 18 ,22-pentaazatetracyclo[ 14.3.1.1 (3 ,7) .1 (9, 13)] docosa- l(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetyl)piperazine-l-carboxamide;
6-Chloro- 12- { 2-oxo-2- [4-(tetrahydrofuran-3 -ylcarbonyl)piperazin- 1 -yl] ethoxy } -2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene;
6-Chloro- 12- { 2-oxo-2- [4-(tetrahydrofuran-2-ylcarbonyl)piperazin- 1 -yl] ethoxy } -2,4, 8 , 18 ,22- pentaazatetracyclo[14.3.1.1(3,7).l(9,13)]docosa-l(20),3(22),4,6,9(21),10,12,16,18-nonaene; or pharmaceutically acceptable salts thereof or quaternary ammonium salt thereof.
73. A composition comprising a compound of any one of claims 1-72, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, and at least one pharmaceutically acceptable carrier.
74. A method of treating an autoimmune disease in a patient comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1-72, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof.
75. The method of claim 74 wherein said autoimmune disease is selected from a skin disorder, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ankylosing spondylitis, myasthenia gravis, immunoglobulin nephropathies, and autoimmune thyroid disorder.
76. A method of treating a disease in a patient comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1-72, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, wherein said disease is selected from a skin disorder, an autoimmune bullous skin disorder, pemphigus vulgaris (PV), bullous pemphigoid (BP), psoriasis, psoriasis vulgaris, atopic dermatitis, alopecia areata, psoriasis, atopic dermatitis, alopecia areata, skin rash, skin irritation, skin sensitization, contact dermatitis, allergic contact dermatitis, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, ankylosing spondylitis, myasthenia gravis, immunoglobulin nephropathies, allergy or an allergic condition, asthma, food allergy, atopic dermatitis, rhinitis, a viral disease, Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster Virus (VZV), Human Papilloma Virus (HPV), cancer, a solid tumor, prostate cancer, renal cancer, hepatic cancer, colorectal cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi' s sarcoma,melanoma, hematological cancer or malignancy, skin cancer, lymphoma, leukemia, multiple myeloma, acute lymphoblastic leukemia, Chronic Lymphocytic Leukemia (CLL), myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), cutaneous T-cell lymphoma (CTCL) cutaneous B-cell lymphoma, Sezary syndrome, mycosis fungoides, a lymphoma related disease, Castleman's disease, Waldenstrom's macroglobulinemia, Poems syndrome, a paraneoplastic syndrome associated with cytokine production in cancer, a myeloproliferative disorder (MPD), polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis with myeloid metaplasia (MMM), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), polycythemia vera (PV), hypereosinophilic syndrome (HES), primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (Post-PV MF), post- essential thrombocythemia myelofibrosis (Post-ET MF), inflammation or an inflammatory disease, an inflammatory disease of the eye, an inflammatory disease of the respiratory tract, inflammatory myopathy, Systemic Inflammatory Response Syndrome (SIRS), septic shock, dry eye disorder, iritis, uveitis, scleritis, conjunctivitis, rhinitis, sinusitis, bronchitis, chronic obstructive pulmonary disease, myocarditis, organ transplant rejection, allograft rejection, graft versus host disease, an ischemia reperfusion injury or a disease or condition related to an inflammatory ischemic event, anorexia, cachexia, or fatigue resulting from or associated with cancer, restenosis, sclerodermitis, fibrosis, diabetic retinopathy or neurodegeneration, an anaplastic large cell lymphoma, a non-Hodgkin lymphoma, lung cancer, and autoimmune thyroid disorder.
77. A method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1-72, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof.
78. A method of treating myelofibrosis with myeloid metaplasia (MMM) in a patient comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 -72, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof.
79. A compound of any one of claims 1-72, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, for use as a medicament.
80. Use of a compound of any one of claims 1-72, or pharmaceutically acceptable salt thereof or quaternary ammonium salt thereof, in the manufacture of a medicament.
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