PYRIDAZINONES AS PARP7 HIBITORS

Description

FIELD OF THE INVENTION

[0001] The present invention relates to pyridazinones and related compounds which are inhibitors of PARP7 and are useful in the treatment of cancer.BACKGROUND OF THE INVENTION

[0002] Poly(ADP-ribose) polymerases (PARPs) are members of a family of seventeen enzymes that regulate fundamental cellular processes including gene expression, protein degradation, and multiple cellular stress responses (M. S. Cohen, P. Chang, Insights into the biogenesis, function, and regulation of ADP-ribosylation. Nat Chem Biol 14, 236-243 (2018)). The ability of cancer cells to survive under stress is a fundamental cancer mechanism and an emerging approach for novel therapeutics. One member of the PARP family, PARP1, has already been shown to be an effective cancer target in connection to cellular stress induced by DNA damage, either induced by genetic mutation or with cytotoxic chemotherapy, with three approved drugs in the clinic and several others in late stage development ( A. Ohmoto, S. Yachida, Current status of poly(ADP-ribose) polymerase inhibitors and future directions. Onco Targets Ther 10, 5195-5208 (2017)).

[0003] The seventeen members of the PARP family were identified in the human genome based on the homology within their catalytic domains ( S. Vyas, M. Chesarone-Cataldo, T. Todorova, Y. H. Huang, P. Chang, A systematic analysis of the PARP protein family identifies new functions critical for cell physiology. Nat Commun 4, 2240 (2013)). However, their catalytic activities fall into 3 different categories ( S. Vyas et al., Family-wide analysis of poly(ADP-ribose) polymerase activity. Nat Commun 5, 4426 (2014)). The majority of PARP family members catalyze the transfer of mono- ADP-ribose units onto their substrates (monoPARPs), while others (PARP1, PARP2, TNKS, TNKS2) catalyze the transfer of poly-ADP-ribose units onto substrates (polyPARPs). Finally, PARP13 is thus far the only PARP for which catalytic activity could not be demonstrated either in vitro or in vivo.

[0004] The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in regulating multiple cellular functions including proinflammatory responses and xenobiotic metabolism ( S. Feng, Z. Cao, X. Wang, Role of aryl hydrocarbon receptor in cancer. Biochim Biophys Acta 1836, 197-210 (2013); and B. Stockinger, P. Di Meglio, M. Gialitakis, J. H. Duarte, The aryl hydrocarbon receptor: multitasking in the immune system. Annu Rev Immunol 32, 403-432 (2014)). The AHR can be activated by a broad number of ligands including endogenous tryptophan metabolites such as kynurenine ( C. A. Opitz et al., An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197-203 (2011)) and certain polycyclic aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) ( K. W. Bock, Toward elucidation of dioxin-mediated chloracne and Ah receptor functions. Biochem Pharmacol 112, 1-5 (2016)). Activation of the AHR induces target gene expression including genes involved in metabolism such as cytochrome P4501A1 and P4501B1. Activation of AHR also leads to an increase in the AHR target gene, TCDD-inducible poly(ADP-ribose)polymerase (TIPARP, also referred to as PARP7), which functions as a negative regulator of certain AHR transcriptional targets ( L. MacPherson et al., Aryl hydrocarbon receptor repressor and TIPARP (ARTD14) use similar, but also distinct mechanisms to repress aryl hydrocarbon receptor signaling. Int J Mol Sci 15, 7939-7957 (2014); and L. MacPherson et al., 2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase (TIPARP, ARTD14) is a mono-ADP-ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation. Nucleic Acids Res 41, 1604-1621 (2013)).

[0005] PARP7 can also be regulated by other transcription factors and signaling pathways including androgen receptor ( E. C. Bolton et al., Cell- and gene-specific regulation of primary target genes by the androgen receptor. Genes Dev 21, 2005-2017 (2007)), platelet derived growth factor ( J. Schmahl, C. S. Raymond, P. Soriano, PDGF signaling specificity is mediated through multiple immediate early genes. Nat Genet 39, 52-60 (2007)) and hypoxia inducible factor 1 (N. Hao et al., Xenobiotics and loss of cell adhesion drive distinct transcriptional outcomes by aryl hydrocarbon receptor signaling. Mol Pharmacol 82, 1082-1093 (2012)). The PARP7 gene is located on chromosome 3 (3q25) in a region that is frequently amplified in cancers of squamous histology (http: / / www.cbioportal.org / index.do?session_id=5aelbede498eb8b3d565d8b2). A genome-wide association study identified 3q25 as susceptibility loci for ovarian cancer suggesting a role for PARP7 in this cancer type ( E. L. Goode et al., A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat Genet 42, 874-879 (2010)). PARP7 has multiple cellular functions. In the context of AHR signaling PARP7 acts as a negative feedback mechanism to regulate the expression of P4501A1 and P4501B1 ( L. MacPherson et al., Aryl hydrocarbon receptor repressor and TIPARP (ARTD14) use similar, but also distinct mechanisms to repress aryl hydrocarbon receptor signaling. Int J Mol Sci 15, 7939-7957 (2014), and L. MacPherson et al., 2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase (TIPARP, ARTD14) is a mono-ADP-ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation. Nucleic Acids Res 41, 1604-1621 (2013)). PARP7 has also been described to ADP-ribosylate liver X receptors which leads to the modulation of their transcriptional activity ( C. Bindesboll et al., TCDD-inducible poly-ADP-ribose polymerase (TIPARP / PARP7) mono-ADP-ribosylates and co-activates liver X receptors. Biochem J473, 899-910 (2016). During viral infection PARP7 can bind to Sindbis virus (SINV) to promote viral RNA degradation ( T. Kozaki et al., Mitochondrial damage elicits a TCDD-inducible poly(ADP-ribose) polymerase-mediated antiviral response. Proc Natl Acad Sci U S A 114, 2681-2686 (2017)). Also in the context of viral infection, AHR-induced PARP7 can interact with TBK1, a major kinase that is activated during the onset of pathogen-associated molecular pattern pathways leading to an activation of the Type I interferon response and antiviral immunity ( T. Yamada et al., Constitutive aryl hydrocarbon receptor signaling constrains Type I interferon-mediated antiviral innate defense. Nat Immunol 17, 687-694 (2016)). PARP7 was shown to ADP-ribosylate TBK1 which prevents its activation, thereby repressing the Type I interferon response.

[0006] Based on these results from viral infection one could hypothesize that cancer cells can use aberrantly expressed and / or activated PARP7 as a mechanism to evade the host immune system through suppression of the Type I interferons and thereby T cell mediated antitumor immunity. Indeed, in a recent genetic screen to identify tumor factors that suppress T cell activation PARP7 was identified as a hit (D. Pan et al., A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science 359, 770-775 (2018)). PARP7 knockout in a mouse melanoma cell line was shown to increase the proliferation and activation of co-cultured T cells suggesting that PARP7 inhibition may be a viable strategy to activate T cell mediated tumor killing.

[0007] WO 2019 / 055966 A2 describes pyridazinones, and related tautomers and pharmaceutical compositions. WO2016 / 116602 A1 describes methods of treating cancer by administering a TIPARP inhibitor to a patient in need thereof.SUMMARY OF THE INVENTION

[0008] The present invention is directed to a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein constituent members are defined below.

[0009] The present invention is further directed to a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0010] The present invention is further directed to a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. The present disclosure also provides the compounds described herein for use in therapy.

[0011] Any references in the description to methods of treatment refer to the compounds, pharmaceutical compositions, and medicaments of the invention for use in the method of treatment.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 illustrates (A) PARP7 amplification across TCGA primary tumor samples; and (B) PARP7 copy-number amplifications correspond to increased levels of PARP7 mRNA expression levels in TCGA (The Cancer Genome Atlas) lung squamous tumor samples. Figure 2 illustrates the inhibition of cancer cell growth by PARP7 inhibitors (compounds of Examples 18B, 39, 98, and 93A), showing a dose-dependent decrease in growth of NCI-H1373 lung cancer cells. Figure 3 illustrates the induction of interferon-beta (IFN-β) levels by PARP7 inhibitors (compounds of Examples 18B and 98) in CT26 mouse colon cancer cells and RAW264.7 mouse macrophages in the presence of a STING agonist, DMXAA (also known as Vadimezan or ASA404). Figure 4 illustrates the induction of STAT1 phosphorylation by a PARP7 inhibitor in CT26 mouse colon cancer cells and RAW264.7 mouse macrophages. Figure 5 illustrates proliferation in CT26 cells in vitro in the presence of PARP7 inhibitor (compound of Example 18B). Figure 6A illustrates tumor growth in the murine syngeneic model CT26 and in the presence of PARP7 inhibitors (compounds of Examples 98 and 93A). Figure 6B illustrates tumor growth in the murine syngeneic model 4T1 and in the presence of PARP7 inhibitors (compounds of Examples 98 and 93A). Figure 7A illustrates that once daily administration of the PARP7 inhibitor of Example 561 significantly reduces tumor growth in a human NCI-H1373 lung cancer xenograft. Figure 7B illustrates that once or twice daily administration of the PARP7 inhibitor of Example 561 significantly reduces tumor growth in a murine CT26 colon cancer syngeneic model. Figure 8 shows an X-ray powder diffraction (XRPD) pattern of the compound of Example 561 Form A. Figure 9 shows a differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermogram of the compound of Example 561 Form A. Figure 10 shows a dynamic vapor sorption (DVS) isotherm of the compound of Example 561 Form A. DETAILED DESCRIPTION

[0013] The present invention is directed to a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: X is Cl, Br, CH 3 , CF 3 , CN, OCH 3 , cyclopropyl, SCH 3 , or isopropyl; A is a group having the formula (A-2): L is C 1-3 alkylene, O, S, NR Y< , C(=O), C(=O)O, C(=O)NR Y< , S(=O), S(=O)NR Y< , or NR Y< C(=O)NR Y< ; R Y< is H or C 1-4 alkyl; Z is H, Cy Z< , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a< , SR a< , C(O)R b< , C(O)NR c< R d< , C(O)OR a< , OC(O)R b< , OC(O)NR c< R d< , NR c< R d< , NR c< C(O)R b< , NR c< C(O)OR a< , NR c< C(O)NR c< R d< , C(=NR e< )R b< , C(=NR e< )NR c< R d< , NR c< C(=NR e< )NR c< R d< , NR c< S(O)R b< , NR c< S(O) 2 R b< , NR c< S(O) 2 NR c< R d< , S(O)R b< , S(O)NR c< R d< , S(O) 2 R b< , and S(O) 2 NR c< R d< ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl of Z are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy Z< , halo, CN, NO 2 , OR a< , SR a< , C(O)R b< , C(O)NR c< R d< , C(O)OR a< , OC(O)R b< , OC(O)NR c< R d< , C(=NR e< )NR c< R d< , NR c< C(=NR e< )NR c< R d< , NR c< R d< , NR c< C(O)R b< , NR c< C(O)OR a< , NR c< C(O)NR c< R d< , NR c< S(O)R b< , NR c< S(O) 2 R b< , NR c< S(O) 2 NR c< R d< , S(O)R b< , S(O)NR c< R d< , S(O) 2 R b< , and S(O) 2 NR c< R d< ; Cy Z< is selected from C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a1< , SR a1< , C(O)R b1< , C(O)NR c1< R d1< , C(O)OR a1< , OC(O)R b1< , OC(O)NR c1< R d1< , C(=NR e1< )NR c1< R d1< , NR c1< C(=NR e1< )NR c1< R d1< , NR c1< R d1< , NR c1< C(O)R b1< , NR c1< C(O)OR a1< , NR c1< C(O)NR c1< R d1< , NR c1< S(O)R b1< , NR c1< S(O) 2 R b1< , NR c1< S(O) 2 NR c1< R d1< , S(O)R b1< , S(O)NR c1< R d1< , S(O) 2 R b1< , and S(O) 2 NR c1< R d1< , wherein the alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1< , SR a1< , C(O)R b1< , C(O)NR c1< R d1< , C(O)OR a1< , OC(O)R b1< , OC(O)NR c1< R d1< , C(=NR e1< )NR c1< R d1< , NR c1< C(=NR e1< )NR c1< R d1< , NR c1< R d1< , NR c1< C(O)R b1< , NR c1< C(O)OR a1< , NR c1< C(O)NR c1< R d1< , NR c1< S(O)R b1< , NR c1< S(O) 2 R b1< , NR c1< S(O) 2 NR c1< R d1< , S(O)R b1< , S(O)NR c1< R d1< , S(O) 2 R b1< , and S(O) 2 NR c1< R d1< ; each R 13< is independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a4< , SR a4< , C(O)R b4< , C(O)NR c4< R d4< , C(O)OR a4< , OC(O)R b4< , OC(O)NR c4< R d4< , NR c4< R d4< , NR c4< C(O)R b4< , NR c4< C(O)OR a4< , NR c4< C(O)NR c4< R d4< , C(=NR e4< )R b4< , C(=NR e4< )NR c4< R d4< , NR c4< C(=NR e4< )NR c4< R d4< , NR c4< S(O)R b4< , NR c4< S(O) 2 R b4< , NR c4< S(O) 2 NR c4< R d4< , S(O)R b4< , S(O)NR c4< R d4< , S(O) 2 R b4< , and S(O) 2 NR c4< R d4< ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl of said R 13< are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a4< , SR a4< , C(O)R b4< , C(O)NR c4< R d4< , C(O)OR a4< , OC(O)R b4< , OC(O)NR c4< R d4< , NR c4< R d4< , NR c4< C(O)R b4< , NR c4< C(O)OR a4< , NR c4< C(O)NR c4< R d4< , C(=NR e4< )R b4< , C(=NR e4< )NR c4< R d4< , NR c4< C(=NR e4< )NR c4< R d4< , NR c4< S(O)R b4< , NR c4< S(O) 2 R b4< , NR c4< S(O) 2 NR c4< R d4< , S(O)R b4< , S(O)NR c4< R d4< , S(O) 2 R b4< , and S(O) 2 NR c4< R d4< ; Q 1< is a group of formula (B-1): Y 4< , Y 5< , and Y 6< are each independently selected from O, S, NR Y< , C(=O), C(=O)O, C(=O)NR Y< , S(=O), S(=O) 2 , S(=O)NR Y< , S(=O) 2 NR Y< or NR Y< C(=O)NR Y< ; G 1< is -C(R G< )(R H< )- or a group of formula (C-1), (C-2), or (C-3): G 2< is -C(R I< )(R J< )- or a group of formula (C-1), (C-2), or (C-3); R A< , R B< , R C< , R D< , R E< , R F< , R G< , R H< , R I< , R J< , R K< , R L< , R M< , and R N< are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a5< , SR a5< , C(O)R b5< , C(O)NR c5< R d5< , C(O)OR a5< , OC(O)R b5< , OC(O)NR c5< R d5< , C(=NR e5< )NR c5< R d5< , NR c5< C(=NR e5< )NR c5< R d5< , NR c5< R d5< , NR c5< C(O)R b5< , NR c5< C(O)OR a5< , NR c5< C(O)NR c5< R d5< , NR c5< S(O)R b5< , NR c5< S(O) 2 R b5< , NR c5< S(O) 2 NR c5< R d5< , S(O)R b5< , S(O)NR c5< R d5< , S(O) 2 R b5< , and S(O) 2 NR c5< R d5< ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl of said R A< , R B< , R C< , R D< , R E< , R F< , R G< , R H< , R I< , R J< , R K< , R L< , R M< , and R N< are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a5< , SR a5< , C(O)R b5< , C(O)NR c5< R d5< , C(O)OR a5< , OC(O)R b5< , OC(O)NR c5< R d5< , C(=NR e5< )NR c5< R d5< , NR c5< C(=NR e5< )NR c5< R d5< , NR c5< R d5< , NR c5< C(O)R b5< , NR c5< C(O)OR a5< , NR c5< (O)NR c5< R d5< , NR c5< S(O)R b5< , NR c5< S(O) 2 R b5< , NR c5< S(O) 2 NR c5< R d5< , S(O)R b5< , S(O)NR c5< R d5< , S(O) 2 R b5< , and S(O) 2 NR c5< R d5< ; or R G< and R I< together with the carbon atoms to which they are attached and together with Y 5< form a 5-10 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a3< , SR a3< , C(O)R b3< , C(O)NR c3< R d3< , C(O)OR a3< , OC(O)R b3< , OC(O)NR c3< R d3< , NR c3< R d3< , NR c3< C(O)R b3< , NR c3< C(O)OR a3< , NR c3< C(O)NR c3< R d3< , C(=NR e3< )R b3< , C(=NR e3< )NR c3< R d3< , NR c3< C(=NR e3< )NR c3< R d3< , NR c3< S(O)R b3< , NR c3< S(O) 2 R b3< , NR c3< S(O) 2 NR c3< R d3< , S(O)R b3< , S(O)NR c3< R d3< , S(O) 2 R b3< , and S(O) 2 NR c3< R d3< ; or R C< and R E< together form a double bond between the carbon atoms to which they are attached; or R E< and R G< together form a double bond between the carbon atoms to which they are attached; or R I< and R K< together form a double bond between the carbon atoms to which they are attached; or R K< and R M< together form a double bond between the carbon atoms to which they are attached; or R K< , R L< , R M< , and R N< together form a triple bond between the carbon atoms to which they are attached; D 1< and D 2< are each independently selected from N and CH; D 3< , D 4< , D 5< , D 6< , D 7< , D 8< , and D 9< are each independently selected from N and CR X< , wherein each R X< is independently selected from H, halo, and C 1-4 alkyl; D 10< is O, S, NH or CH 2 ; Ring F is a mono- or polycyclic ring selected from C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a6< , SR a6< , C(O)R b6< , C(O)NR c6< R d6< , C(O)OR a6< , OC(O)R b6< , OC(O)NR c6< R d6< , C(=NR e6< )NR c6< R d6< , NR c6< C(=NR e6< )NR c6< R d6< , NR c6< R d6< , NR c6< C(O)R b6< , NR c6< C(O)OR a6< , NR c6< C(O)NR c6< R d6< , NR c6< S(O)R b6< , NR c6< S(O) 2 R b6< , NR c6< S(O) 2 NR c6< R d6< , S(O)R b6< , S(O)NR c6< R d6< , S(O) 2 R b6< , and S(O) 2 NR c6< R a6< , wherein the alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a6< , SR a6< , C(O)R b6< , C(O)NR c6< R d6< , C(O)OR a6< , OC(O)R b6< , OC(O)NR c6< R d6< , C(=NR e6< )NR c6< R d6< , NR c6< C(=NR e6< )NR c6< R d6< , NR c6< R d6< , NR c6< C(O)R b6< , NR c6< C(O)OR a6< , NR c6< C(O)NR c6< R d6< , NR c6< S(O)R b6< , NR c6< S(O) 2 R b6< , NR c6< S(O) 2 NR c6< R d6< , S(O)R b6< , S(O)NR c6< R d6< , S(O) 2 R b6< , and S(O) 2 NR c6< R d6< , each R a< , R b< , R c< , R d< , R a1< , R b1< , R c1< , R d1< , R a3< , R b3< , R c3< , R d3< , R a4< , R b4< , R c4< , R d4< , R a5< , R b5< , R c5< , R d5< , R a6< , R b6< , R c6< , and R d6< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl of said R a< , R b< , R c< , R d< , R a1< , R b1< , R c1< , R d1< , R a2< , R b2< , R c2< , R d2< , R a3< , R b3< , R c3< , R d3< , R a4< , R b4< , R c4< , R d4< , R a5< , R b5< , R c5< , R d5< , R a6< , R b6< , R c6< , and R d6< is optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR a7< , SR a7< , C(O)R b7< , C(O)NR c7< R d7< , C(O)OR a7< , OC(O)R b7< , OC(O)NR c7< R d7< , NR c7< R d7< , NR c7< C(O)R b7< , NR c7< C(O)NR c7< R d7< , NR c7< C(O)OR a7< , C(=NR e7< )NR c7< R d7< , NR c7< C(=NR e7< )NR c3< R d7< , S(O)R b7< , S(O)NR c7< R d7< , S(O) 2 R b7< , NR c7< S(O) 2 R b7< , NR c7< S(O) 2 NR c7< R d7< , and S(O) 2 NR c7< R d7< ; or R c< and R d< together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from CN, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C2-6 alkynyl, CN, OR a7< , SR a7< , C(O)R b7< , C(O)NR c7< R d7< , C(O)OR a7< , OC(O)R b7< , OC(O)NR c7< R d7< , NR c7< R d7< , NR c7< C(O)R b7< , NR c7< C(O)NR c7< R d7< , NR c7< C(O)OR a7< , C(=NR e7< )NR c7< R d7< , NR c7< C(=NR e7< )NR c3< R d7< , S(O)R b7< , S(O)NR c7< R d7< , S(O) 2 R b7< , NR c7< S(O) 2 R b7< , NR c7< S(O) 2 NR c7< R d7< , and S(O) 2 NR c7< R d7< ; or R c3< and R d3< together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from CN, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C2-6 alkynyl, CN, OR a7< , SR a7< , C(O)R b7< , C(O)NR c7< R d7< , C(O)OR a7< , OC(O)R b7< , OC(O)NR c7< R d7< , NR c7< R d7< , NR c7< C(O)R b7< , NR c7< C(O)NR c7< R d7< , NR c7< C(O)OR a7< , C(=NR e7< )NR c7< R d7< , NR c7< C(=NR e7< )NR c3< R d7< , S(O)R b7< , S(O)NR c7< R d7< , S(O) 2 R b7< , NR c7< S(O) 2 R b7< , NR c7< S(O) 2 NR c7< R d7< , and S(O) 2 NR c7< R d7< ; or R c4< and R d4< together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from CN, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C2-6 alkynyl, CN, OR a7< , SR a7< , C(O)R b7< , C(O)NR c7< R d7< , C(O)OR a7< , OC(O)R b7< , OC(O)NR c7< R d7< , NR c7< R d7< , NR c7< C(O)R b7< , NR c7< C(O)NR c7< R d7< , NR c7< C(O)OR a7< , C(=NR e7< )NR c7< R d7< , NR c7< C(=NR e7< )NR c3< R d7< , S(O)R b7< , S(O)NR c7< R d7< , S(O) 2 R b7< , NR c7< S(O) 2 R b7< , NR c7< S(O) 2 NR c7< R d7< , and S(O) 2 NR c7< R d7< ; or R c5< and R d5< together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from CN, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C2-6 alkynyl, CN, OR a7< , SR a7< , C(O)R b7< , C(O)NR c7< R d7< , C(O)OR a7< , OC(O)R b7< , OC(O)NR c7< R d7< , NR c7< R d7< , NR c7< C(O)R b7< , NR c7< C(O)NR c7< R d7< , NR c7< C(O)OR a7< , C(=NR e7< )NR c7< R d7< , NR c7< C(=NR e7< )NR c3< R d7< , S(O)R b7< , S(O)NR c7< R d7< , S(O) 2 R b7< , NR c7< S(O) 2 R b7< , NR c7< S(O) 2 NR c7< R d7< , and S(O) 2 NR c7< R d7< ; or R c6< and R d6< together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from CN, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C2-6 alkynyl, CN, OR a7< , SR a7< , C(O)R b7< , C(O)NR c7< R d7< , C(O)OR a7< , OC(O)R b7< , OC(O)NR c7< R d7< , NR c7< R d7< , NR c7< C(O)R b7< , NR c7< C(O)NR c7< R d7< , NR c7< C(O)OR a7< , C(=NR e7< )NR c7< R d7< , NR c7< C(=NR e7< )NR c3< R d7< , S(O)R b7< , S(O)NR c7< R d7< , S(O) 2 R b7< , NR c7< S(O) 2 R b7< , NR c7< S(O) 2 NR c7< R d7< , and S(O) 2 NR c7< R d7< ; R a7< , R b7< , R c7< , and R d7< are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; each R e< , R e1< , R e3< , R e4< , R e5< , R e6< and R e7< is independently selected from H, C 1-4 alkyl, and CN; a is 0 or 1; b is 0, 1, 2, or 3; c is 0, 1, or 2; d is 0, 1, or 2; m is 0 or 1; n is 0 or 1; p is 0 or 1; q is 0 or 1; r is 0 or 1; s1 is 0, 1, or 2; s2 is 0, 1, 2, or 3; v is 0 or 1; and w is 0 or 1; wherein any aforementioned heteroaryl or heterocycloalkyl group comprises 1, 2, 3, or 4 ring-forming heteroatoms independently selected from O, N, and S; and wherein one or more ring-forming C or N atoms of any aforementioned heterocycloalkyl group is optionally substituted by an oxo (=O) group.

[0014] In some embodiments, L is NR Y< or O. In some embodiments, L is NH 2 or O. In some embodiments, L is NR Y< . In some embodiments, L is O.

[0015] In some embodiments, X is CF 3 , CH 3 , CN, Cl or Br.

[0016] In some embodiments, R Y< is H or C 1-4 alkyl. In some embodiments, R Y< is methyl. In some embodiments, R Y< is H.

[0017] In some embodiments, Z is H, Cy Z< , halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO 2 , OR a< , C(O)R b< , C(O)NR c< R d< , C(O)OR a< , NR c< R d< , and NR c< C(O)R b< ; wherein said C 1-6 alkyl and C 1-6 haloalkyl of Z are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy Z< , halo, CN, NO 2 , OR a< , SR a< , C(O)R b< , C(O)NR c< R d< , C(O)OR a< , OC(O)R b< , OC(O)NR c< R d< , NR c< R d< , and NR c< C(O)R b< . In some embodiments, Z is Cy Z< .

[0018] In some embodiments, Cy Z< is selected from 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a1< , SR a1< , C(0)R b1< , C(O)NR c1< R d1< , C(O)OR a1< , OC(O)R b1< , OC(O)NR c1< R d1< , C(=NR e1< )NR c1< R d1< , NR c1< C(=NR e1< )NR c1< R d1< , NR c1< R d1< , NR c1< C(O)R b1< , NR c1< C(O)OR a1< , NR c1< C(O)NR c1< R d1< , NR c1< S(O)R b1< , NR c1< S(O) 2 R b1< , NR c1< S(O) 2 NR c1< R d1< , S(O)R b1< , S(O)NR c1< R d1< , S(O) 2 R b1< , and S(O) 2 NR c1< R d1< , wherein the alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1< , SR a1< , C(O)R b1< , C(O)NR c1< R d1< , C(O)OR a1< , OC(O)R b1< , OC(O)NR c1< R d1< , C(=NR e1< )NR c1< R d1< , NR c1< C(=NR e1< )NR c1< R d1< , NR c1< R d1< , NR c1< C(O)R b1< , NR c1< C(O)OR a1< , NR c1< C(O)NR c1< R d1< , NR c1< S(O)R b1< , NR c1< S(O) 2 R b1< , NR c1< S(O) 2 NR c1< R d1< , S(O)R b1< , S(O)NR c1< R d1< , S(O) 2 R b1< , and S(O) 2 NR c1< R d1< .

[0019] In some embodiments, Cy Z< is 5-10 membered heteroaryl, optionally substituted by CN, CF 3 , or Cl. In some embodiments, Cy Z< is pyridinyl or pyrimidinyl, each optionally substituted by CN, CF 3 , or Cl. In some embodiments, Cy Z< is 5-10 membered heteroaryl, optionally substituted by CN, C 1-6 alkyl, C 1-6 haloalkyl, halo, or NR c1< R d1< , wherein C 1-6 alkyl is optionally substituted with CN or NR c1< R d1< . In some embodiments, Cy Z< is pyridinyl, pyrimidinyl, or pyrazinyl, each optionally substituted by CN, C 1-6 alkyl, C 1-6 haloalkyl, halo, or NR c1< R d1< , wherein C 1-6 alkyl is optionally substituted with CN or NR c1< R d1< . In some embodiments, Cy Z< is pyridinyl, pyrimidinyl, pyrazinyl, or thiazolyl, each optionally substituted by CN, C 1-6 alkyl, C 1-6 haloalkyl, halo, or NR c1< R d1< , wherein C 1-6 alkyl is optionally substituted with CN or NR c1< R d1< .

[0020] In some embodiments, R a3< is C 1-6 alkyl or H. In some embodiments, R a3< is methyl. In some embodiments, R a3< is H.

[0021] In some embodiments, R c3< and R d3< are each independently selected from C 1-6 alkyl and H. In some embodiments, R c3< is C 1-6 alkyl or H. In some embodiments, R d3< is C 1-6 alkyl or H. In some embodiments, R c3< and R d3< are each methyl. In some embodiments, R c3< and R d3< are each H.

[0022] In some embodiments, m is 1.

[0023] In some embodiments, n is 0. In some embodiments, n is 1.

[0024] In some embodiments, p is 0.In some embodiments, p is 1.

[0025] In some embodiments, q is 0. In some embodiments, q is 1.

[0026] In some embodiments, r is 0.

[0027] In some embodiments, a is 0.

[0028] In some embodiments, A is the group having the formula A-2.

[0029] In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is Cl, Br, CH 3 , CF 3 , CN, OCH 3 , cyclopropyl, SCH 3 , or isopropyl; A is a group having the formula (A-2): L is C 1-3 alkylene, O, S, NR Y< , C(=O), C(=O)O, C(=O)NR Y< , S(=O), S(=O)NR Y< , or NR Y< C(=O)NR Y< ; Z is H, Cy Z< , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a< , SR a< , C(O)R b< , C(O)NR c< R d< , C(O)OR a< , OC(O)R b< , OC(O)NR c< R d< , NR c< R d< , NR c< C(O)R b< , NR c< C(O)OR a< , NR c< C(O)NR c< R d< , C(=NR e< )R b< , C(=NR e< )NR c< R d< , NR c< C(=NR e< )NR c< R d< , NR c< S(O)R b< , NR c< S(O) 2 R b< , NR c< S(O) 2 NR c< R d< , S(O)R b< , S(O)NR c< R d< , S(O) 2 R b< , and S(O) 2 NR c< R d< ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl of Z are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy Z< , halo, CN, NO 2 , OR a< , SR a< , C(O)R b< , C(O)NR c< R d< , C(O)OR a< , OC(O)R b< , OC(O)NR c< R d< , C(=NR e< )NR c< R d< , NR c< C(=NR e< )NR c< R d< , NR c< R d< , NR c< C(O)R b< , NR c< C(O)OR a< , NR c< C(O)NR c< R d< , NR c< S(O)R b< , NR c< S(O) 2 R b< , NR c< S(O) 2 NR c< R d< , S(O)R b< , S(O)NR c< R d< , S(O) 2 R b< , and S(O) 2 NR c< R d< ; Cy Z< is selected from C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a1< , SR a1< , C(O)R b1< , C(O)NR c1< R d1< , C(O)OR a1< , OC(O)R b1< , OC(O)NR c1< R d1< , C(=NR e1< )NR c1< R d1< , NR c1< C(=NR e1< )NR c1< R d1< , NR c1< R d1< , NR c1< C(O)R b1< , NR c1< C(O)OR a1< , NR c1< C(O)NR c1< R d1< , NR c1< S(O)R b1< , NR c1< S(O) 2 R b1< , NR c1< S(O) 2 NR c1< R d1< , S(O)R b1< , S(O)NR c1< R d1< , S(O) 2 R b1< , and S(O) 2 NR c1< R d1< , wherein the alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a1< , SR a1< , C(O)R b1< , C(O)NR c1< R d1< , C(O)OR a1< , OC(O)R b1< , OC(O)NR c1< R d1< , C(=NR e1< )NR c1< R d1< , NR c1< C(=NR e1< )NR c1< R d1< , NR c1< R d1< , NR c1< C(O)R b1< , NR c1< C(O)OR a1< , NR c1< C(O)NR c1< R d1< , NR c1< S(O)R b1< , NR c1< S(O) 2 R b1< , NR c1< S(O) 2 NR c1< R d1< , S(O)R b1< , S(O)NR c1< R d1< , S(O) 2 R b1< , and S(O) 2 NR c1< R d1< ; each R 13< is independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a4< , SR a4< , C(O)R b4< , C(O)NR c4< R d4< , C(O)OR a4< , OC(O)R b4< , OC(O)NR c4< R d4< , NR c4< R d4< , NR c4< C(O)R b4< , NR c4< C(O)OR a4< , NR c4< C(O)NR c4< R d4< , C(=NR e4< )R b4< , C(=NR e4< )NR c4< R d4< , NR c4< C(=NR e4< )NR c4< R d4< , NR c4< S(O)R b4< , NR c4< S(O) 2 R b4< , NR c4< S(O) 2 NR c4< R d4< , S(O)R b4< , S(O)NR c4< R d4< , S(O) 2 R b4< , and S(O) 2 NR c4< R d4< ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl of said R 13< are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a4< , SR a4< , C(O)R b4< , C(O)NR c4< R d4< , C(O)OR a4< , OC(O)R b4< , OC(O)NR c4< R d4< , NR c4< R d4< , NR c4< C(O)R b4< , NR c4< C(O)OR a4< , NR c4< C(O)NRC 4< R d4< , C(=NR e4< )R b4< , C(=NR e4< )NR c4< R d4< , NR c4< C(=NR e4< )NR c4< R d4< , NR c4< S(O)R b4< , NR c4< S(O) 2 R b4< , NR c4< S(O) 2 NR c4< R d4< , S(O)R b4< , S(O)NR c4< R d4< , S(O) 2 R b4< , and S(O) 2 NR c4< R d4< ; Q 1< is a group of formula (B-1): Y 4< , Y 5< , and Y 6< are each independently selected from O, S, NR Y< , C(=O), C(=O)O, C(=O)NR Y< , S(=O), S(=O) 2 , S(=O)NR Y< , S(=O) 2 NR Y< or NR Y< C(=O)NR Y< G 1< is -C(R G< )(R H< )- or a group of formula (C-1), (C-2), or (C-3): G 2< is -C(R I< )(R J< )- or a group of formula (C-1), (C-2), or (C-3); R A< , R B< , R C< , R D< , R E< , R F< , R G< , R H< , R I< , R J< , R K< , R L< , R M< , and R N< are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a5< , SR a5< , C(O)R b5< , C(O)NR c5< R d5< , C(O)OR a5< , OC(O)R b5< , OC(O)NR c5< R d5< , C(=NR e5< )NR c5< R d5< , NR c5< C(=NR e5< )NR c5< R d5< , NR c5< R d5< , NR c5< C(O)R b5< , NR c5< C(O)OR a5< , NR c5< C(O)NR c5< R d5< , NR c5< S(O)R b5< , NR c5< S(O) 2 R b5< , NR c5< S(O) 2 NR c5< R d5< , S(O)R b5< , S(O)NR c5< R d5< , S(O) 2 R b5< , and S(O) 2 NR c5< R d5< ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl of said R A< , R B< , R C< , R D< , R E< , R F< , R G< , R H< , R I< , R J< , R K< , R L< , R M< , and R N< are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a5< , SR a5< , C(O)R b5< , C(O)NR c5< R d5< , C(O)OR a5< , OC(O)R b5< , OC(O)NR c5< R d5< , C(=NR e5< )NR c5< R d5< , NR c5< C(=NR e5< )NR c5< R d5< , NR c5< R d5< , NR c5< C(O)R b5< , NR c5< C(O)OR a5< , NR c5< C(O)NR c5< R d5< , NR c5< S(O)R b5< , NR c5< S(O) 2 R b5< , NR c5< S(O) 2 NR c5< R d5< , S(O)R b5< , S(O)NR c5< R d5< , S(O) 2 R b5< , and S(O) 2 NR c5< R d5< ; or R G< and R I< together with the carbon atoms to which they are attached and together with Y 5< form a 5-10 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a3< , SR a3< , C(O)R b3< , C(O)NR c3< R d3< , C(O)OR a3< , OC(O)R b3< , OC(O)NR c3< R d3< , NR c3< R d3< , NR c3< C(O)R b3< , NR c3< C(O)OR a3< , NR c3< C(O)NR c3< R d3< , C(=NR e3< )R b3< , C(=NR e3< )NR c3< R d3< , NR c3< C(=NR e3< )NR c3< R d3< , NR c3< S(O)R b3< , NR c3< S(O) 2 R b3< , NR c3< S(O) 2 NR c3< R d3< , S(O)R b3< , S(O)NR c3< R d3< , S(O) 2 R b3< , and S(O) 2 NR c3< R d3< ; or R C< and R E< together form a double bond between the carbon atoms to which they are attached; or R E< and R G< together form a double bond between the carbon atoms to which they are attached; or R I< and R K< together form a double bond between the carbon atoms to which they are attached; or R K< and R M< together form a double bond between the carbon atoms to which they are attached; or R K< , R L< , R M< , and R N< together form a triple bond between the carbon atoms to which they are attached; D 1< and D 2< are each independently selected from N and CH; D 3< , D 4< , D 5< , D 6< , D 7< , D 8< , and D 9< are each independently selected from N and CR X< , wherein each R X< is independently selected from H, halo, and C 1-4 alkyl; D 10< is O, S, NH or CH 2 ; Ring F is a mono- or polycyclic ring selected from C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a6< , SR a6< , C(O)R b6< , C(O)NR c6< R d6< , C(O)OR a6< , OC(O)R b6< , OC(O)NR c6< R d6< , C(=NR e6< )NR c6< R d6< , NR c6< C(=NR e6< )NR c6< R d6< , NR c6< R d6< , NR c6< C(O)R b6< , NR c6< C(O)OR a6< , NR c6< C(O)NR c6< R d6< , NR c6< S(O)R b6< , NR c6< S(O) 2 R b6< , NR c6< S(O) 2 NR c6< R d6< , S(O)R b6< , S(O)NR c6< R d6< , S(O) 2 R b6< , and S(O) 2 NR c6< R a6< , wherein the alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO 2 , OR a6< , SR a6< , C(O)R b6< , C(O)NR c6< R a6< , C(O)OR a6< , OC(O)R b6< , OC(O)NR c6< R a6< , C(=NR e6< )NR c6< R d6< , NR c6< C(=NR e6< )NR c6< R d6< , NR c6< R d6< , NR c6< C(O)R b6< , NR c6< C(O)OR a6< , NR c6< C(O)NR c6< R d6< , NR c6< S(O)R b6< , NR c6< S(O) 2 R b6< , NR c6< S(O)2NR c6< R d6< , S(O)R 6< , S(O)NR c6< R d6< , S(O) 2 R b6< , and S(O) 2 NR c6< R d6< , each R a< , R b< , R c< , R d< , R a1< , R b1< , R c1< , R d1< , R a3< , R b3< , R c3< , R d3< , R a4< , R b4< , R c4< , R d4< , R a5< , R b5< , R c5,< R d5< R a6< , R b6< , R c6< , and R d6< is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl of said R a< , R b< , R c< , R d< , R a1< , R b1< , R c1< , R d1< , R a2< , R b2< , R c2< , R d2< , R a3< , R b3< , R c3< , R d3< , R a4< , R b4< , R c4< , R d4< , R a5< , R b5< , R c5< , R d5< , R a6< , R b6< , R c6< , and R d6< is optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, OR a7< , SR a7< , C(O)R b7< , C(O)NR c7< R d7< , C(O)OR a7< , OC(O)R b7< , OC(O)NR c7< R d7< , NR c7< R d7< , NR c7< C(O)R b7< , NR c7< C(O)NR c7< R d7< , NR c7< C(O)OR a7< , C(=NR e7< )NR c7< R d7< , NR c7< C(=NR e7< )NR c3< R d7< , S(O)R b7< , S(O)NR c7< R d7< , S(O) 2 R b7< , NR c7< S(O) 2 R b7< , NR c7< S(O) 2 NR c7< R d7< , and S(O) 2 NR c7< R d7< ; or R c< and R d< together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from CN, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C2-6 alkynyl, CN, OR a7< , SR a7< , C(O)R b7< , C(O)NR c7< R d7< , C(O)OR a7< , OC(O)R b7< , OC(O)NR c7< R d7< , NR c7< R d7< , NR c7< C(O)R b7< , NR c7< C(O)NR c7< R d7< , NR c7< C(O)OR a7< , C(=NR e7< )NR c7< R d7< , NR c7< C(=NR e7< )NR c3< R d7< , S(O)R b7< , S(O)NR c7< R d7< , S(O) 2 R b7< , NR c7< S(O) 2 R b7< , NR c7< S(O) 2 NR c7< R d7< , and S(O) 2 NR c7< R d7< ; or R c3< and R d3< together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from CN, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C2-6 alkynyl, CN, OR a7< , SR a7< , C(O)R b7< , C(O)NR c7< R d7< , C(O)OR a7< , OC(O)R b7< , OC(O)NR c7< R d7< , NR c7< R d7< , NR c7< C(O)R b7< , NR c7< C(O)NR c7< R d7< , NR c7< C(O)OR a7< , C(=NR e7< )NR c7< R d7< , NR c7< C(=NR e7< )NR c3< R d7< , S(O)R b7< , S(O)NR c7< R d7< , S(O) 2 R b7< , NR c7< S(O) 2 R b7< , NR c7< S(O) 2 NR c7< R d7< , and S(O) 2 NR c7< R d7< ; or R c4< and R d4< together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from CN, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C2-6 alkynyl, CN, OR a7< , SR a7< , C(O)R b7< , C(O)NR c7< R d7< , C(O)OR a7< , OC(O)R b7< , OC(O)NR c7< R d7< , NR c7< R d7< , NR c7< C(O)R b7< , NR c7< C(O)NR c7< R d7< , NR c7< C(O)OR a7< , C(=NR e7< )NR c7< R d7< , NR c7< C(=NR e7< )NR c3< R d7< , S(O)R b7< , S(O)NR c7< R d7< , S(O) 2 R b7< , NR c7< S(O) 2 R b7< , NR c7< S(O) 2 NR c7< R d7< , and S(O) 2 NR c7< R d7< ; or R c5< and R d5< together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from CN, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C2-6 alkynyl, CN, OR a7< , SR a7< , C(O)R b7< , C(O)NR c7< R d7< , C(O)OR a7< , OC(O)R b7< , OC(O)NR c7< R d7< , NR c7< R d7< , NR c7< C(O)R b7< , NR c7< C(O)NR c7< R d7< , NR c7< C(O)OR a7< , C(=NR e7< )NR c7< R d7< , NR c7< C(=NR e7< )NR c3< R d7< , S(O)R b7< , S(O)NR c7< R d7< , S(O) 2 R b7< , NR c7< S(O) 2 R b7< , NR c7< S(O) 2 NR c7< R d7< , and S(O) 2 NR c7< R d7< ; or R c6< and R d6< together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from CN, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C2-6 alkynyl, CN, OR a7< , SR a7< , C(O)R b7< , C(O)NR c7< R d7< , C(O)OR a7< , OC(O)R b7< , OC(O)NR c7< R d7< , NR c7< R d7< , NR c7< C(O)R b7< , NR c7< C(O)NR c7< R d7< , NR c7< C(O)OR a7< , C(=NR e7< )NR c7< R d7< , NR c7< C(=NR e7< )NR c3< R d7< , S(O)R b7< , S(O)NR c7< R d7< , S(O) 2 R b7< , NR c7< S(O) 2 R b7< , NR c7< S(O) 2 NR c7< R d7< , and S(O) 2 NR c7< R d7< ; R a7< , R b7< , R c7< , and R d7< are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; each R e< , R e1< , R e3< , R e4< , R e5< , R e6< and R e7< is independently selected from H, C 1-4 alkyl, and CN; a is 0 or 1; b is 0, 1, 2, or 3; c is 0, 1, or 2; d is 0, 1, or 2; m is 0 or 1; n is 0 or 1; p is 0 or 1; q is 0 or 1; r is 0 or 1; s1 is 0, 1, or 2; s2 is 0, 1, 2, or 3; v is 0 or 1; and w is 0 or 1; wherein any aforementioned heteroaryl or heterocycloalkyl group comprises 1, 2, 3, or 4 ring-forming heteroatoms independently selected from O, N, and S; and wherein one or more ring-forming C or N atoms of any aforementioned heterocycloalkyl group is optionally substituted by an oxo (=O) group.

[0030] In some embodiments, Q 1< is a group of formula (B-1a):

[0031] In some embodiments, Q 1< is a group of formula (B-1b):

[0032] In some embodiments, Q 1< is a group of formula (B-1c): wherein Z 1< and Z 2< are each independently selected from N and CH, and wherein R is CN, Cl, or CF 3 .

[0033] In some embodiments, X is CF 3 , CH 3 , CN, Cl, or Br.

[0034] In some embodiments, Ring F is 4-10 membered heterocycloalkyl or C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with OR a6< . In some embodiments, Ring F is 4-10 membered heterocycloalkyl or C 3-7 cycloalkyl, each optionally substituted with methyl.

[0035] In some embodiments, Ring F is piperazinyl, piperidinyl, pyrrolidinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 2,8-diazaspiro[4.5]decanyl, 2,5-diazabicyclo[2.2.2]octanyl, 1,4-diazepanyl, azetidinyl, 2,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.4]octanyl, octahydropyrrolo[3,2-b]pyrrolyl, 2,7-diazaspiro[4.4]nonanyl, 2,5-diazabicyclo[2.2.1]heptanyl, octahydropyrrolo[3,4-c]pyrrolyl, or 2,7-diazaspiro[3.5]nonanyl.

[0036] In some embodiments, Ring F is piperazinyl.

[0037] In some embodiments, Ring F is cyclohexyl.

[0038] In some embodiments, Ring F is 4-10 membered heterocycloalkyl, optionally substituted by an oxo (=O) group.

[0039] In some embodiments, Z is Cy Z< , C 1-6 alkyl, or C(O)R b< , wherein said C 1-6 alkyl is optionally substituted by halo. In some embodiments, Z is CF 3 .

[0040] In some embodiments, Cy Z< is selected from 5-10 membered heteroaryl and C 6-10 aryl, optionally substituted by C 1-6 alkyl, CN or CF 3 , wherein said C 1-6 alkyl is optionally substituted with CN.

[0041] In some embodiments, Cy Z< is pyridinyl, pyrimidinyl, or pyrazinyl, optionally substituted by C 1-6 alkyl, CN, Cl, S(O) 2 R b1< , or CF 3 .

[0042] In some embodiments, Cy Z< is pyridinyl, pyrimidinyl, or pyrazinyl, optionally substituted by methyl, CN, Cl, CF 3 , or S(O) 2 CH 3 .

[0043] In some embodiments, Cy Z< is phenyl, optionally substituted with cyanomethyl or CN.

[0044] In some embodiments, R b< is C 1-6 alkyl. In some embodiments, R b< is methyl.

[0045] In some embodiments, Y 4< is O or NR Y< . In some embodiments, Y 4< is O. In some embodiments, Y 4< is NR Y< .

[0046] In some embodiments, Y 5< is O, NR Y< , or C(=O)NR Y< .

[0047] In some embodiments, Y 6< is C(=O) or C(=O)NR Y< .

[0048] In some embodiments, R Y< is H or C 1-4 alkyl. In some embodiments, R Y< is H. In some embodiments, R Y< is methyl.

[0049] In some embodiments, L is O or NR Y< .

[0050] In some embodiments, G 1< is -C(R G< )(R H< )-.

[0051] In some embodiments, G 2< is C-1. In some embodiments, D 1< and D 2< are each CH and D 10< is CH 2 . In some embodiments, D 1< is CH, D 2< is N, and D 10< is CH 2 . In some embodiments, D 3< is CH, D 4< is N, D 5< is CH. In some embodiments, D 10< is CH 2 .

[0052] In some embodiments, b is 0, c is 1, and d is 1. In some embodiments, b is 0, c is 2, and d is 0. In some embodiments, b is 0, c is 0, and d is 0. In some embodiments, b is 0, c is 1, and d is 0.

[0053] In some embodiments, G 2< is C-2. In some embodiments, D 3< , D 4< , and D 5< are each CR X< , wherein each R X< is independently selected from H, halo, and C 1-4 alkyl.

[0054] In some embodiments, G 2< is C-3. In some embodiments, D 6< , D 7< , and D 9< are CR X< , and D 8< is N. In some embodiments, D 6< and D 7< are each N, and D 8< and D 9< are each CR X< . In some embodiments, D 6< , D 7< , D 8< , and D 9< are each CR X< . In some embodiments, D 6< , D 8< , and D 9< are each CR X< , and D 7< is N. In some embodiments, D 6< , D 7< , and D 8< are each CR X< and D 9< is N. In some embodiments, D 6< and D 8< are each N, and D 7< and D 9< are each CR X< .

[0055] In some embodiments, each R X< is H or halo. In some embodiments, R X< is H or F. In some embodiments, R X< is H.

[0056] In some embodiments, G 2< is -C(R I< )(R J< )- In some embodiments, R 13< is C 1-6 alkyl, OR a4< , CN, or NR c4< R d4< , wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo and OR a4< and NR c4< R d4< .

[0057] In some embodiments, R 13< is methyl. In some embodiments, R 13< is CN. In some embodiments, R 13< is CF 3 . In some embodiments, R 13< is amino. In some embodiments, R 13< is aminomethyl.

[0058] In some embodiments, R A< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0059] In some embodiments, R A< is C 1-6 alkyl or H. In some embodiments, R A< is methyl. In some embodiments, R A< is H.

[0060] In some embodiments, R B< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0061] In some embodiments, R B< is C 1-6 alkyl or H. In some embodiments, R B< is methyl. In some embodiments, R B< is H.

[0062] In some embodiments, R C< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0063] In some embodiments, R C< is C 1-6 alkyl or H. In some embodiments, R C< is methyl. In some embodiments, R C< is H.

[0064] In some embodiments, R D< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0065] In some embodiments, R D< is C 1-6 alkyl or H. In some embodiments, R D< is methyl. In some embodiments, R D< is H.

[0066] In some embodiments, R E< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0067] In some embodiments, R E< is C 1-6 alkyl or H. In some embodiments, R E< is methyl. In some embodiments, R E< is H.

[0068] In some embodiments, R F< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0069] In some embodiments, R F< is C 1-6 alkyl or H. In some embodiments, R F< is methyl. In some embodiments, R F< is H.

[0070] In some embodiments, R G< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0071] In some embodiments, R G< is C 1-6 alkyl or H. In some embodiments, R G< is methyl. In some embodiments, R G< is H.

[0072] In some embodiments, R H< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0073] In some embodiments, R H< is C 1-6 alkyl or H. In some embodiments, R H< is methyl. In some embodiments, R H< is H.

[0074] In some embodiments, R I< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0075] In some embodiments, R I< is C 1-6 alkyl or H. In some embodiments, R I< is methyl. In some embodiments, R I< is H.

[0076] In some embodiments, R J< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0077] In some embodiments, R J< is C 1-6 alkyl or H. In some embodiments, R J< is methyl. In some embodiments, R J< is H.

[0078] In some embodiments, R K< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0079] In some embodiments, R K< is C 1-6 alkyl or H. In some embodiments, R K< is methyl. In some embodiments, R K< is H.

[0080] In some embodiments, R L< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0081] In some embodiments, R L< is C 1-6 alkyl or H. In some embodiments, R L< is methyl. In some embodiments, R L< is H.

[0082] In some embodiments, R M< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0083] In some embodiments, R M< is C 1-6 alkyl or H. In some embodiments, R M< is methyl. In some embodiments, R M< is H.

[0084] In some embodiments, R N< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0085] In some embodiments, R N< is C 1-6 alkyl or H. In some embodiments, R N< is methyl. In some embodiments, R N< is H.

[0086] In some embodiments, R I< and R K< together form a double bond between the carbon atoms to which they are attached.

[0087] In some embodiments, R K< and R M< together form a double bond between the carbon atoms to which they are attached.

[0088] In some embodiments, R K< , R L< , R M< , and R N< together form a triple bond between the carbon atoms to which they are attached.

[0089] In some embodiments, R G< and R I< together with the carbon atoms to which they are attached and together with Y 5< form a 5-10 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR a3< , SR a3< , C(O)R b3< , C(O)NR c3< R d3< , C(O)OR a3< , OC(O)R b3< , OC(O)NR c3< R d3< , NR c3< R d3< , NR c3< C(O)R b3< , NR c3< C(O)OR a3< , NR c3< C(O)NR c3< R d3< , C(=NR e3< )R b3< , C(=NR e3< )NR c3< R d3< , NR c3< C(=NR e3< )NR c3< R d3< , NR c3< S(O)R b3< , NR c3< S(O) 2 R b3< , NR c3< S(O) 2 NR c3< R d3< , S(O)R b3< , S(O)NR c3< R d3< , S(O) 2 R b3< , and S(O) 2 NR c3< R d3< .

[0090] In some embodiments, R G< and R I< together with the carbon atoms to which they are attached and together with Y 5< form a tetrahydrofuranyl ring.

[0091] In some embodiments, R a6< is H.

[0092] In some embodiments, R b1< is C 1-6 alkyl. In some embodiments, R b1< is methyl.

[0093] In some embodiments, R a4< is H or C 1-6 alkyl. In some embodiments, R a4< is methyl.

[0094] In some embodiments, R c4< and R d4< are each H.

[0095] In some embodiments, R c5< and R d5< are each H.

[0096] In some embodiments, R Y< is H.

[0097] In some embodiments, a is 0. In some embodiments, a is 1.

[0098] In some embodiments, s1 is 0. In some embodiments, s1 is 1. In some embodiments, s1 is 2.

[0099] In some embodiments, s2 is 0. In some embodiments, s2 is 1. In some embodiments, s2 is 2.

[0100] In some embodiments, v is 0. In some embodiments, v is 1.

[0101] In some embodiments, w is 0. In some embodiments, w is 1.

[0102] In some embodiments, m is 0. In some embodiments, m is 1.

[0103] In some embodiments, n is 0. In some embodiments, n is 1.

[0104] In some embodiments, p is 0. In some embodiments, p is 1.

[0105] In some embodiments, in q is 0. In some embodiments, q is 1.

[0106] In some embodiments, r is 0. In some embodiments, r is 1.

[0107] In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IIIa:

[0108] In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IIIb:

[0109] In some embodiments, R a4< is selected from C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, and 4-10 membered heterocycloalkyl-C 1-4 alkyl, each optionally substituted with C 1-4 alkyl, OR a7< , NR c7< R d7< , C(O)NR c7< R d7< , C(O)R b7< , C(O)OR a7< or NR c7< C(O)R b7< .

[0110] In some embodiments, R a4< is H or C 1-6 alkyl. In some embodiments, R a4< is pyridinyl. In some embodiments, R a4< is phenyl. In some embodiments, R a4< is pyridinylmethyl, pyridinylethyl, tetrahydropyranylmethyl, tetrahydrofuranylmethyl, piperidinylmethyl, piperidinylethyl, morpholinylethyl, piperazinylethyl, pyrrolidinylmethyl. In some embodiments, R a4< is methyl, ethyl, or isopropyl. In some embodiments, R a4< is piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, each optionally substituted by an C 1-4 alkyl, OR a7< , NR c7< R d7< , C(O)NR c7< R d7< , C(O)R b7< , or NR c7< C(O)R b7< . In some embodiments, R a4< is pyrimidinyl.

[0111] In some embodiments, R b4< is C 1-6 alkyl. In some embodiments, R b4< is methyl.

[0112] In some embodiments, R c4< is H or C 1-6 alkyl. In some embodiments, R c4< is methyl.

[0113] In some embodiments, R d4< is H, C 1-6 alkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, optionally substituted with 1, 2, 3 substituents independently selected from C 1-6 alkyl, C(O)R b7< , and C(O)OR a7< . In some embodiments, R d4< is methyl. In some embodiments, R d4< is tetrehydrofuranylmethyl, pyridinylmethyl, pyridinylethyl, morpholinyl, piperidinyl, tetrahydropyranyl, or pyridinyl.

[0114] In some embodiments, R a7< is H or C 1-6 alkyl. In some embodiments, R a7< is methyl.

[0115] In some embodiments, R b7< is H or C 1-6 alkyl.

[0116] In some embodiments, R c7< is H or C 1-6 alkyl.

[0117] In some embodiments, R d7< is H or C 1-6 alkyl.

[0118] In some embodiments, R b7< is H or methyl.

[0119] In some embodiments, R c7< is H or methyl.

[0120] In some embodiments, R d7< is H or methyl.

[0121] In some embodiments, Y 4< is O.

[0122] In some embodiments, Y 5< is O, NR Y< , C(=O), or C(=O)NR Y< .

[0123] In some embodiments, G 1< is -C(R G< )(R H< )-. In some embodiments, G 1< is C-2.

[0124] In some embodiments, D 3< , D 4< , and D 5< are each CR X< , wherein each R X< is independently selected from H, halo, and C 1-4 alkyl.

[0125] In some embodiments, R X< is H.

[0126] In some embodiments, G 2< is -C(R I< )(R J< )-. In some embodiments, G 2< is C-3.

[0127] In some embodiments, D 6< , D 7< , and D 9< are each CR X< , and D 8< is N. In some embodiments, D 6< and D 7< are each N, and D 8< and D 9< are each CR X< . In some embodiments, D 6< , D 7< , D 8< , and D 9< are each CR X< . In some embodiments, D 6< , D 8< , and D 9< are each CR X< , and D 7< is N. In some embodiments, D 6< , D 7< , and D 8< are each CR X< and D 9< is N. In some embodiments, D 6< and D 8< are each N, and D 7< and D 9< are each CR X< . In some embodiments, D 6< and D 9< are each N, and D 7< and D 8< are each CR X< .

[0128] In some embodiments, G 2< is C-1.

[0129] In some embodiments, D 1< and D 2< are each N and D 10< is CH 2 .

[0130] In some embodiments, b is 0, c is 1, and d is 1.

[0131] In some embodiments, Ring F is 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, or C 3-7 cycloalkyl, each optionally substituted with C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with OR a6< . In some embodiments, Ring F is 4-10 membered heterocycloalkyl or C 3-7 cycloalkyl, each optionally substituted with methyl.

[0132] In some embodiments, Ring F is piperazinyl, piperidinyl, pyrrolidinyl, pyridinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 2,8-diazaspiro[4.5]decanyl, 2,5-diazabicyclo[2.2.2]octanyl, 1,4-diazepanyl, azetidinyl, 2,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.4]octanyl, octahydropyrrolo[3,2-b]pyrrolyl, 2,7-diazaspiro[4.4]nonanyl, 2,5-diazabicyclo[2.2.1]heptanyl, octahydropyrrolo[3,4-c]pyrrolyl, 2,7-diazaspiro[3.5]nonanyl, or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine.

[0133] In some embodiments, Ring F is piperazinyl. In some embodiments, Ring F is cyclohexyl. In some embodiments, Ring F is 4-10 membered heterocycloalkyl, optionally substituted by an oxo (=O) group.

[0134] In some embodiments, Z is Cy Z< , CN, C 1-6 alkyl, or C(O)R b< , wherein said C 1-6 alkyl is optionally substituted by halo. In some embodiments, Z is CF 3 , CH 3 , or CN. In some embodiments, Z is H.

[0135] In some embodiments, R b< is C 1-6 alkyl, optionally substituted with CN. In some embodiments, R b< is methyl.

[0136] In some embodiments, Cy Z< is selected from 5-10 membered heteroaryl and C 6-10 aryl, each optionally substituted by C 1-6 alkyl, halo, CN or CF 3 , wherein said C 1-6 alkyl is optionally substituted with CN. In some embodiments, Cy Z< is pyridinyl, pyrimidinyl, or pyrazinyl, each optionally substituted by C 1-6 alkyl, CN, Cl, F, S(O) 2 R b1< , or CF 3 . In some embodiments, Cy Z< is pyridinyl, pyrimidinyl, pyrazinyl, each optionally substituted by methyl, CN, Cl, F, CF 3 , or S(O) 2 CH 3 . In some embodiments, Cy Z< is phenyl, optionally substituted with cyanomethyl or CN.

[0137] In some embodiments, R b1< is C 1-6 alkyl. In some embodiments, R b1< is methyl.

[0138] In some embodiments, R A< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0139] In some embodiments, R A< is C 1-6 alkyl or H. In some embodiments, R A< is methyl. In some embodiments, R A< is H.

[0140] In some embodiments, R B< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0141] In some embodiments, R B< is C 1-6 alkyl or H. In some embodiments, R B< is methyl. In some embodiments, R B< is H.

[0142] In some embodiments, R C< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0143] In some embodiments, R C< is C 1-6 alkyl or H.In some embodiments, R C< is methyl. In some embodiments, R C< is H.

[0144] In some embodiments, R D< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0145] In some embodiments, R D< is C 1-6 alkyl or H. In some embodiments, R D< is methyl. In some embodiments, R D< is H.

[0146] In some embodiments, R E< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0147] In some embodiments, R E< is C 1-6 alkyl or H. In some embodiments, R E< is methyl. In some embodiments, R E< is H.

[0148] In some embodiments, R F< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0149] In some embodiments, R F< is C 1-6 alkyl or H. In some embodiments, R F< is methyl. In some embodiments, R F< is H.

[0150] In some embodiments, R G< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0151] In some embodiments, R G< is C 1-6 alkyl or H. In some embodiments, R G< is methyl. In some embodiments, R G< is H.

[0152] In some embodiments, R H< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0153] In some embodiments, R H< is C 1-6 alkyl or H. In some embodiments, R H< is methyl. In some embodiments, R H< is H.

[0154] In some embodiments, R I< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0155] In some embodiments, R I< is C 1-6 alkyl or H. In some embodiments, R I< is methyl. In some embodiments, R I< is H.

[0156] In some embodiments, R J< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0157] In some embodiments, R J< is C 1-6 alkyl or H. In some embodiments, R J< is methyl. In some embodiments, R J< is H.

[0158] In some embodiments, R K< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0159] In some embodiments, R K< is C 1-6 alkyl or H. In some embodiments, R K< is methyl. In some embodiments, R K< is H.

[0160] In some embodiments, R L< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0161] In some embodiments, R L< is C 1-6 alkyl or H. In some embodiments, R L< is methyl. In some embodiments, R L< is H.

[0162] In some embodiments, R M< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0163] In some embodiments, R M< is C 1-6 alkyl or H. In some embodiments, R M< is methyl. In some embodiments, R M< is H.

[0164] In some embodiments, R N< is H, halo, OR a5< , C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, or C 6-10 aryl-C 1-4 alkyl is optionally substituted with OR a5< or NR c5< R d5< .

[0165] In some embodiments, R N< is C 1-6 alkyl or H. In some embodiments, R N< is methyl. In some embodiments, R N< is H.

[0166] In some embodiments, R K< and R M< together form a double bond between the carbon atoms to which they are attached.

[0167] In some embodiments, R I< and R K< together form a double bond between the carbon atoms to which they are attached In some embodiments, each R X< is H or halo. In some embodiments, R X< is H. In some embodiments, R X< is F

[0168] In some embodiments, Y 6< is C(=O), NR Y< , or C(=O)NR Y< .

[0169] In some embodiments, R Y< is H or C 1-4 alkyl. In some embodiments, R Y< is H. In some embodiments, R Y< is methyl.

[0170] In some embodiments, a is 0.

[0171] In some embodiments, v is 0. In some embodiments, v is 1.

[0172] In some embodiments, w is 0.

[0173] In some embodiments, w is 1.

[0174] In some embodiments, m is 0. In some embodiments, m is 1.

[0175] In some embodiments, n is 0. In some embodiments, n is 1.

[0176] In some embodiments, p is 0. In some embodiments, p is 1.

[0177] In some embodiments, q is 0. In some embodiments, q is 1.

[0178] In some embodiments, r is 1.Reference : Crystalline 5-[[(2S)-]-(3-Oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0179] In some embodiments, the compound of Formula I is 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (see Example 561). The compound of Example 561, 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one, can also be referred to as: (S)-5-((1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one; or (S)-5-(1-(3-Oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propoxy)propan-2-ylamino)-4-(trifluoromethyl)pyridazin-3(2H)-one.

[0180] In some embodiments, 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one is crystalline and has the characteristics of Form A described below. The synthesis and characterization of 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one, including Form A, is described for example in Example 561.

[0181] In some embodiments, Form A has characteristic XRPD peaks selected from about 5.8, about 10.8, about 11.9, and about 17.2 degrees 2-theta. In some embodiments, Form A has at least one characteristic XRPD peak selected from about 5.8, about 10.8, about 11.9, and about 17.2 degrees 2-theta. In some embodiments, Form A has at least two characteristic XRPD peaks selected from about 5.8, about 10.8, about 11.9, and about 17.2 degrees 2-theta. In some embodiments, Form A has a characteristic XRPD peak at about 5.8 degrees 2-theta. In some embodiments, Form A has a characteristic XRPD peak at about 10.8 degrees 2-theta. In some embodiments, Form A has a characteristic XRPD peak at about 11.9 degrees 2-theta. In some embodiments, Form A has a charactersistic XRPD peak at about 17.2 degrees 2-theta.

[0182] In some embodiments, Form A has at least one characteristic XRPD peak selected from about 5.8, about 10.8, about 11.9, about 13.3, about 13.5, about 15.5, and about 17.2 degrees 2-theta. In some embodiments, Form A has at least one characteristic XRPD peak selected from about 5.8, about 10.8, about 11.2, about 11.9, about 12.3, about 13.3, about 13.5, about 15.5, about 17.2, about 17.7, about 18.0, about 18.4, about 19.5, about 21.0, and about 21.6 degrees 2-theta.

[0183] In some embodiments, Form A has at least two characteristic XRPD peaks selected from about 5.8, about 10.8, about 11.9, about 13.3, about 13.5, about 15.5, and about 17.2 degrees 2-theta. In some embodiments, Form A has at least two characteristic XRPD peaks selected from about 5.8, about 10.8, about 11.2, about 11.9, about 12.3, about 13.3, about 13.5, about 15.5, about 17.2, about 17.7, about 18.0, about 18.4, about 19.5, about 21.0, and about 21.6 degrees 2-theta.

[0184] In some embodiments, Form A has at least three characteristic XRPD peaks selected from about 5.8, about 10.8, about 11.9, about 13.3, about 13.5, about 15.5, and about 17.2 degrees 2-theta. In some embodiments, Form A has at least three characteristic XRPD peaks selected from about 5.8, about 10.8, about 11.2, about 11.9, about 12.3, about 13.3, about 13.5, about 15.5, about 17.2, about 17.7, about 18.0, about 18.4, about 19.5, about 21.0, and about 21.6 degrees 2-theta.

[0185] In some embodiments, Form A has at least four characteristic XRPD peaks selected from about 5.8, about 10.8, about 11.9, about 13.3, about 13.5, about 15.5, and about 17.2 degrees 2-theta. In some embodiments, Form A has at least four characteristic XRPD peaks selected from about 5.8, about 10.8, about 11.2, about 11.9, about 12.3, about 13.3, about 13.5, about 15.5, about 17.2, about 17.7, about 18.0, about 18.4, about 19.5, about 21.0, and about 21.6 degrees 2-theta.

[0186] In some embodiments, Form A has an XRPD pattern with characteristic peaks as substantially shown in Figure 8.

[0187] In some embodiments, Form A has an endotherm peak at a temperature of about 174 °C. In some embodiments, Form A shows a weight loss of about 0.5% when heated to about 150 °C. In some embodiments, Form A has a DSC thermogram substantially as depicted in Figure 9. In some embodiments, Form A has a TGA thermogram substantially as depicted in Figure 9. In some embodiments, Form A has a DVS isotherm substantially as depicted in Figure 10.

[0188] In some embodiments, Form A has at least one characteristic XRPD peak selected from about 5.8, about 10.8, about 11.9, and about 17.2 degrees 2-theta; and has an endotherm peak at a temperature of about 174 °C. In some embodiments, Form A has at least one characteristic XRPD peak selected from about 5.8, about 10.8, about 11.9, and about 17.2 degrees 2-theta; and a DSC thermogram substantially as depicted in Figure 9. In some embodiments, Form A has at least one characteristic XRPD peak selected from about 5.8, about 10.8, about 11.9, and about 17.2 degrees 2-theta; and a DVS isotherm substantially as depicted in Figure 10.

[0189] In some embodiments, Form A can be isolated with a crystalline purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form A can be isolated with a crystalline purity greater than about 99%. In some embodiments, Form A can be isolated with a crystalline purity greater than about 99.9%. In some embodiments, Form A is substantially free of other crystalline form. In some embodiments, Form A is substantially free of amorphous form.

[0190] In some embodiments, provided is Form A prepared by precipitating 5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)propan-2-yl]amino]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one from a solution comprising the compound and S1, wherein S1 is a solvent. In some embodiments, S1 is an organic solvent. In some embodiments, S1 is selected from one of the following solvents: ethyl alcohol, methyl isobutyl ketone, isopropyl acetate, methy t-butyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, acetone, dichloromethane, and water. In some embodiments, S1 is a mixture of organic solvents. In some embodiments, S1 is a mixture of acetonitrile and heptane. In some embodiments, S1 is a mixture of isopropyl alcohol and ethyl acetate. In some embodiments, S1 is a mixture of chloroform and ethyl acetate. In some embodiments, S1 is a mixture of 1,4-dioxane and methanol. In some embodiments, S1 is a mixture of NMP and toluene. In some embodiments, S1 is a mixture of petroleum ether and hexanes. In some embodiments, the precipitating is carried out by concentration of the solution, evaporation of solvent, reduction of temperature of the solution, addition of anti-solvent, or combination thereof.

[0191] 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.

[0192] 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 "C 1-6 alkyl" is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.

[0193] At various places in the present specification various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term "pyridinyl," "pyridyl," or "a pyridine ring" may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[0194] 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, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0195] For compounds of the invention in which a variable appears more than once, each variable can be a different moiety independently selected from the group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound, the two R groups can represent different moieties independently selected from the group defined for R.

[0196] As used herein, the phrase "optionally substituted" means unsubstituted or substituted.

[0197] As used herein, the term "substituted" means that a hydrogen atom is replaced by a non-hydrogen group. It is to be understood that substitution at a given atom is limited by valency.

[0198] As used herein, the term "C i-j ," where i and j are integers, employed in combination with a chemical group, designates a range of the number of carbon atoms in the chemical group with i-j defining the range. For example, C 1-6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0199] As used herein, the term "alkyl," employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched. In some embodiments, the alkyl group contains 1 to 7, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, n-heptyl, and the like. In some embodiments, the alkyl group is methyl, ethyl, or propyl.

[0200] As used herein, "alkenyl," employed alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon double bonds. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0201] As used herein, "alkynyl," employed alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon triple bonds. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.

[0202] As used herein, "halo" or "halogen", employed alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, halo is F or Cl.

[0203] As used herein, the term "haloalkyl," employed alone or in combination with other terms, refers to an alkyl group having up to the full valency of halogen atom substituents, which may either be the same or different. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 , and the like.

[0204] As used herein, the term "alkoxy," employed alone or in combination with other terms, refers to a group of formula -O-alkyl. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0205] As used herein, "haloalkoxy," employed alone or in combination with other terms, refers to a group of formula -O-(haloalkyl). In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. An example haloalkoxy group is -OCF 3 .

[0206] As used herein, "amino," employed alone or in combination with other terms, refers to NH 2 .

[0207] As used herein, the term "alkylamino," employed alone or in combination with other terms, refers to a group of formula -NH(alkyl). In some embodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms. Example alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0208] As used herein, the term "dialkylamino," employed alone or in combination with other terms, refers to a group of formula -N(alkyl) 2 . Example dialkylamino groups include dimethylamino, diethylamino, dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and the like. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.

[0209] As used herein, the term "cycloalkyl," employed alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane, cyclohexene, cyclohexane, and the like, or pyrido derivatives of cyclopentane or cyclohexane. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo. Cycloalkyl groups also include cycloalkylidenes. The term "cycloalkyl" also includes bridgehead cycloalkyl groups (e.g., non-aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon, such as admantan-1-yl) and spirocycloalkyl groups (e.g., non-aromatic hydrocarbon moieties containing at least two rings fused at a single carbon atom, such as spiro[2.5]octane and the like). In some embodiments, the cycloalkyl group has 3 to 10 ring members, or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is a C 3-7 monocyclic cycloalkyl group. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl, octahydronaphthalenyl, indanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0210] As used herein, the term "cycloalkylalkyl," employed alone or in combination with other terms, refers to a group of formula cycloalkyl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkyl portion is methylene. In some embodiments, the cycloalkyl portion has 3 to 10 ring members or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl portion is monocyclic. In some embodiments, the cycloalkyl portion is a C 3-7 monocyclic cycloalkyl group.

[0211] As used herein, the term "heterocycloalkyl," employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus. Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused, bridged, or spiro rings) ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a bond in common with) to the non-aromatic heterocycloalkyl ring, for example, 1,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least one bridgehead atom, such as azaadmantan-1-yl and the like) and spiroheterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least two rings fused at a single atom, such as [1,4-dioxa-8-aza-spiro[4.5]decan-N-yl] and the like). In some embodiments, the heterocycloalkyl group has 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, or about 3 to 8 ring forming atoms. In some embodiments, the heterocycloalkyl group has 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8 carbon atoms. In some embodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized to form a carbonyl, an N-oxide, or a sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized. In some embodiments, the heterocycloalkyl portion is a C 2-7 monocyclic heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a morpholine ring, pyrrolidine ring, piperazine ring, piperidine ring, tetrahydropyran ring, tetrahyropyridine, azetidine ring, or tetrahydrofuran ring.

[0212] As used herein, the term "heterocycloalkylalkyl," employed alone or in combination with other terms, refers to a group of formula heterocycloalkyl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkyl portion is methylene. In some embodiments, the heterocycloalkyl portion has 3 to 10 ring members, 4 to 10 ring members, or 3 to 7 ring members. In some embodiments, the heterocycloalkyl group is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl portion is monocyclic. In some embodiments, the heterocycloalkyl portion is a C 2-7 monocyclic heterocycloalkyl group.

[0213] As used herein, the term "aryl," employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., a fused ring system) aromatic hydrocarbon moiety, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, and the like. In some embodiments, aryl groups have from 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the aryl group is phenyl or naphthyl.

[0214] As used herein, the term "arylalkyl," employed alone or in combination with other terms, refers to a group of formula aryl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkyl portion is methylene. In some embodiments, the aryl portion is phenyl. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the arylalkyl group is benzyl.

[0215] As used herein, the term "heteroaryl," employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., a fused ring system) aromatic hydrocarbon moiety, having one or more heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group is a monocyclic or a bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. Example heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl or the like. The carbon atoms or heteroatoms in the ring(s) of the heteroaryl group can be oxidized to form a carbonyl, an N-oxide, or a sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized, provided the aromatic nature of the ring is preserved. In some embodiments, the heteroaryl group has from 3 to 10 carbon atoms, from 3 to 8 carbon atoms, from 3 to 5 carbon atoms, from 1 to 5 carbon atoms, or from 5 to 10 carbon atoms. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

[0216] As used herein, the term "heteroarylalkyl," employed alone or in combination with other terms, refers to a group of formula heteroaryl-alkyl-. In some embodiments, the alkyl portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom(s). In some embodiments, the alkyl portion is methylene. In some embodiments, the heteroaryl portion is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl portion has 5 to 10 carbon atoms.

[0217] 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 inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. 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 may be isolated as a mixture of isomers or as separated isomeric forms.

[0218] 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, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. An example of tautomeric forms, pyridazin-3(2H)-one and pyridazin-3-ol, is depicted below:

[0219] Compounds of the invention 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 include at least one deuterium atom.

[0220] The term, "compound," as used herein is meant to include all stereoisomers, geometric iosomers, tautomers, and isotopes of the structures depicted, unless otherwise specified.

[0221] All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., in the form of hydrates and solvates) or can be isolated.

[0222] 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 it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds 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 compounds of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.

[0223] As used herein, the term "crystalline" or "crystalline form" refers to a crystalline solid form of a chemical compound, including, but not limited to, a single-component or multiple-component crystal form, e.g., including solvates, hydrates, clathrates, and co-crystals. As used herein, "crystalline form" is meant to refer to a certain lattice configuration of a crystalline substance. Different crystalline forms of the same substance typically have different crystalline lattices (e.g., unit cells) which are attributed to different physical properties that are characteristic of each of the crystalline forms. In some instances, different lattice configurations have different water or solvent content. The different crystalline lattices can be identified by solid state characterization methods such as by X-ray powder diffraction (XRPD). Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), solid state NMR, and the like further help identify the crystalline form as well as help determine stability and solvent / water content.

[0224] Crystalline forms of a substance include both solvated (e.g., hydrated) and non-solvated (e.g., anhydrous) forms. A hydrated form is a crystalline form that includes water in the crystalline lattice. Hydrated forms can be stoichiometric hydrates, where the water is present in the lattice in a certain water / molecule ratio such as for hemihydrates, monohydrates, dihydrates, etc. Hydrated forms can also be non-stoichiometric, where the water content is variable and dependent on external conditions such as humidity.

[0225] As used herein, the term "substantially crystalline," means a majority of the weight of a sample or preparation of a salt (or hydrate or solvate thereof) of the invention is crystalline and the remainder of the sample is a non-crystalline form (e.g., amorphous form) of the same compound. In some embodiments, a substantially crystalline sample has at least about 95% crystallinity (e.g., about 5% of the non-crystalline form of the same compound), preferably at least about 96% crystallinity (e.g., about 4% of the non-crystalline form of the same compound), more preferably at least about 97% crystallinity (e.g., about 3% of the non-crystalline form of the same compound), even more preferably at least about 98% crystallinity (e.g., about 2% of the non-crystalline form of the same compound), still more preferably at least about 99% crystallinity (e.g., about 1% of the non-crystalline form of the same compound), and most preferably about 100% crystallinity (e.g., about 0% of the non-crystalline form of the same compound). In some embodiments, the term "fully crystalline" means at least about 99% or about 100% crystallinity.

[0226] Crystalline forms are most commonly characterized by XRPD. An XRPD pattern of reflections (peaks) is typically considered a fingerprint of a particular crystalline form. It is well known that the relative intensities of the XRPD peaks can widely vary depending on, inter alia, the sample preparation technique, crystal size distribution, filters, the sample mounting procedure, and the particular instrument employed. In some instances, new peaks may be observed or existing peaks may disappear, depending on the type of instrument or the settings (for example, whether a Ni filter is used or not). As used herein, the term "peak" refers to a reflection having a relative height / intensity of at least about 4% of the maximum peak height / intensity. Moreover, instrument variation and other factors can affect the 2-theta values. Thus, peak assignments, such as those reported herein, can vary by plus or minus about 0.2° (2-theta), and the term "substantially" as used in the context of XRPD herein is meant to encompass the above-mentioned variations.

[0227] In the same way, temperature readings in connection with DSC, TGA, or other thermal experiments can vary about ±3 °C depending on the instrument, particular settings, sample preparation, etc. For example, with DSC it is known that the temperatures observed will depend on the rate of the temperature change as well as the sample preparation technique and the particular instrument employed. Thus, the values reported herein related to DSC thermograms can vary, as indicated above, by ±3 ° C. Accordingly, a crystalline form reported herein having a DSC thermogram "substantially" as shown in any of the Figures is understood to accommodate such variation.

[0228] As used herein, and unless otherwise specified, the term "about", when used in connection with a numeric value or range of values which is provided to describe a particular solid form (e.g., a specific temperature or temperature range, such as describing a melting, dehydration, or glass transition; a mass change, such as a mass change as a function of temperature or humidity; a solvent or water content, in terms of, for example, mass or a percentage; or a peak position, such as in analysis by, for example, 13< C NMR, DSC, TGA and XRPD), indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the particular solid form.

[0229] 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.

[0230] 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 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. 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).Synthesis

[0231] 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.

[0232] 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 nonreactive 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.

[0233] 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).

[0234] 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., 1< H or 13< C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0235] The expressions, "ambient temperature," "room temperature," and "RT", 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 °C to about 30 °C.

[0236] Compounds of Formula I can be prepared according to numerous preparatory routes known in the literature. Example synthetic methods for preparing compounds of the invention are provided in the Schemes below. Unless noted otherwise, all substituents are as defined herein.

[0237] In the process depicted in Scheme 1, an appropriately substituted, halogen containing compound (i.e., X a< = Cl or Br) of Formula (1-1) is protected as the 2-(trimethylsilyl)ethoxymethyl ether ("SEM") compound of Formula (1-2) by treatment with 2-(trimethylsilyl)ethoxymethyl chloride ("SEM-Cl") in the presence of sodium hydride (NaH).

[0238] Compound of Formula (1-2) can be reacted with a variety of nucleophiles to provide compounds of Formula (I) following deprotection of the SEM protecting group, as shown in Schemes 2-4.

[0239] In the process depicted in Scheme 2, the compound of Formula (1-2) (wherein Y a< is O, NR Y< , or S) is reacted with a compound having Formula (1-3) in the presence of a base (e.g., triethylamine or Cs 2 CO 3 ) to provide a compound of formula (1-4). Deprotection with an acid (e.g., trifluoroacetic acid or hydrochloric acid) provides a compound of Formula (IA).

[0240] In the process depicted in Scheme 3, the compound of Formula (1-2) is reacted with a compound having Formula (1-5) in the presence of a base (e.g., triethylamine or Cs 2 CO 3 ) to provide a compound of Formula (1-6). Deprotection with an acid (e.g., trifluoroacetic acid or hydrochloric acid) provides a compound of Formula (IB).

[0241] In the process depicted in Scheme 4, the compound of Formula (1-2) is reacted with a compound having Formula (1-7) in the presence of a base (e.g., triethylamine or Cs 2 CO 3 ) to provide a compound of Formula (1-8). Deprotection with an acid (e.g., trifluoroacetic acid or hydrochloric acid) provides a compound of Formula (IC). Methods of Use

[0242] Compounds of the invention can inhibit the activity of PARP7. For example, the compounds of the invention can be used to inhibit activity of PARP7 in a cell or in an individual or patient in need of inhibition of the enzyme by administering an inhibiting amount of a compound of the invention to the cell, individual, or patient.

[0243] As PARP7 inhibitors, the compounds of the invention are useful in the treatment of various diseases associated with abnormal expression or activity of PARP7. For example, the compounds of the invention are useful in the treatment of cancer. In some embodiments, the cancers treatable according to the present invention include breast, central nervous system, endometrium, kidney, large intestine, lung, oesophagus, ovary, pancreas, prostate, stomach, head and neck (upper aerodigestive), urinary tract, colon, and others.

[0244] In some embodiments, the cancers treatable according to the present invention include hematopoietic malignancies such as leukemia and lymphoma. Example lymphomas include Hodgkin's or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T-cell lymphoma, hairy cell lymphoma, and Burkett's lymphoma. Example leukemias include acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML).

[0245] Other cancers treatable by the administration of the compounds of the invention include liver cancer (e.g., hepatocellular carcinoma), bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, colon cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, gastrointestinal tumors, head and neck cancer (upper aerodigestive cancer), intestinal cancers, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.

[0246] In some embodiments, the cancer treatable by administration of the compounds of the invention is multiple myeloma, DLBCL, hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer (upper aerodigestive cancer), kidney cancer, prostate cancer, rectal cancer, stomach cancer, thyroid cancer, uterine cancer, and breast cancer.

[0247] The PARP7 inhibitors of the invention may also have therapeutic utility in PARP7-related disorders in disease areas such as cardiology, virology, neurodegeneration, inflammation, and pain, particularly where the diseases are characterized by overexpression or increased activity of PARP7.

[0248] As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

[0249] 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" PARP7 or "contacting" a cell 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 PARP7, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing PARP7.

[0250] As used herein, the term "individual" or "patient," used interchangeably, refers to mammals, and particularly humans.

[0251] 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 in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0252] As used herein the term "treating" or "treatment" refers to 1) inhibiting the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., arresting further development of the pathology and / or symptomatology), or 2) ameliorating the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., reversing the pathology and / or symptomatology).

[0253] As used herein the term "preventing" or "prevention" refers to preventing the disease in an individual who may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease.Combination Therapy

[0254] One or more additional pharmaceutical agents or treatment methods such as, for example, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, immunotherapies, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.), and / or kinase (tyrosine or serine / threonine), epigenetic or signal transduction inhibitors can be used in combination with the compounds of the present invention. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0255] Suitable agents for use in combination with the compounds of the present invention for the treatment of cancer include chemotherapeutic agents, targeted cancer therapies, immunotherapies or radiation therapy. Compounds of this invention may be effective in combination with anti-hormonal agents for treatment of breast cancer and other tumors. Suitable examples are anti-estrogen agents including but not limited to tamoxifen and toremifene, aromatase inhibitors including but not limited to letrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g. prednisone), progestins (e.g. megastrol acetate), and estrogen receptor antagonists (e.g. fulvestrant). Suitable anti-hormone agents used for treatment of prostate and other cancers may also be combined with compounds of the present invention. These include anti-androgens including but not limited to flutamide, bicalutamide, and nilutamide, luteinizing hormone-releasing hormone (LHRH) analogs including leuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists (e.g. degarelix), androgen receptor blockers (e.g. enzalutamide) and agents that inhibit androgen production (e.g. abiraterone).

[0256] Angiogenesis inhibitors may be efficacious in some tumors in combination with FGFR inhibitors. These include antibodies against VEGF or VEGFR or kinase inhibitors of VEGFR. Antibodies or other therapeutic proteins against VEGF include bevacizumab and aflibercept. Inhibitors of VEGFR kinases and other anti-angiogenesis inhibitors include but are not limited to sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib

[0257] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan ™< ), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0258] Other anti-cancer agent(s) include antibody therapeutics to checkpoint or costimulatory molecules such as CTLA-4, PD-1, PD-L1 or 4-1BB, respectively, or antibodies to cytokines (IL-10, TGF-β, etc.). Exemplary cancer immunotherapy antibodies include pembrolizumab, ipilimumab, nivolumab, atezolizumab and durvalumab. Additional anti-cancer agent(s) include antibody therapeutics directed to surface molecules of hematological cancers such as ofatumumab, rituximab and alemtuzumab.

[0259] Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ).Pharmaceutical Formulations and Dosage Forms

[0260] When employed as pharmaceuticals, the compounds of the invention can be administered in the form of pharmaceutical compositions. A pharmaceutical composition refers to a combination of a compound of the invention, or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier. 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 oral, topical (including 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, intranasal, epidermal and transdermal), ocular, or parenteral.

[0261] 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. 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.

[0262] The compositions can be formulated in a unit dosage form. The term "unit dosage form" refers to a physically discrete unit 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.

[0263] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. 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.

[0264] For preparing solid compositions such as tablets, the principal active ingredient is 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, 0.1 to about 500 mg of the active ingredient of the present invention.

[0265] 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.

[0266] 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.

[0267] 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.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] The compounds of the invention can also be formulated in combination with one or more additional active ingredients which can include any pharmaceutical agent such as anti-viral agents, anti-cancer agents, vaccines, antibodies, immune enhancers, immune suppressants, anti-inflammatory agents and the like.EXAMPLES

[0272] The invention is defined by the claims. Any examples falling outside the scope of the claims are provided for reference.

[0273] Equipment: 1< H NMR Spectra were recorded at 300 or 400 MHz using a Bruker AVANCE 300 MHz / 400 MHz spectrometer. NMR interpretation was performed using Bruker Topspin software to assign chemical shift and multiplicity. In cases where two adjacent peaks of equal or unequal height were observed, these two peaks may be labeled as either a multiplet or as a doublet. In the case of a doublet, a coupling constant using this software may be assigned. In any given example, one or more protons may not be observed due to obscurity by water and / or solvent peaks. LCMS equipment and conditions are as follows: 1. LC (basic condition): Shimadzu LC-20AD, Binary Pump, Diode Array Detector. Column: Kinetex 2.6 µm EVO C18 100A, 50*3.0 mm, 2.6 um. Mobile phase: A: Water / 5mM NH 4 HCO 3 , B: Acetonitrile. Flow Rate: 1.2 mL / min at 40 °C. Detector: 254 nm, 220 nm. Gradient stop time, 2.9 min. Timetable: T (min)A(%)B(%)0.0190102.105952.705952.909010 2. LC (acidic condition): Shimadzu LC-20AD, Binary Pump, Diode Array Detector. Column: Ascentis Express C18, 50*3.0 mm, 2.7 um. Mobile phase: A: Water / 0.05%TFA, B: Acetonitrile / 0.05%TFA. Flow Rate: 1.5 mL / min at 40 °C. Detector: 254 nm, 220 nm. Gradient stop time, 2.9 min. Timetable: T (min)A(%)B(%)0.019052.105952.705952.90905 1. S:LCMS-2020, Quadrupole LC / MS, Ion Source: ES-API, TIC: 90~900 m / z, Fragmentor: 60, Drying gas flow: 15 L / min, Nebulizing Gas Flow: 1.5 L / min, Drying gas temperature:250 °C, Vcap: 1100V. 2. Sample preparation: samples were dissolved in ACN or methanol at 1~10 mg / mL, then filtered through a 0.22 µm filter membrane. Injection volume: 1~10 µL.

[0274] XRPD Analysis: For XRPD analysis, PANalytical Empyrean / X' Pert3 X-ray powder diffractometers were used. The XRPD parameters used are listed below:XRPD Parameters

[0275] Parameters CPE-026 (Reflection Mode) CPE-135 (Reflection Mode) CPE-221 (Reflection Mode) ModelEmpyreanX' Pert3X' Pert3X-Ray wavelengthCu, kα, Kα1 (Å): 1.540598, Kα2 (Å): 1.544426Cu, kα, Kα1 (Å): 1.540598, Kα2 (Å): 1.544426Cu, kα, Kα1 (Å): 1.540598, Kα2 (Å): 1.544426Kα2 / Kα1 intensity ratio: 0.50Kα2 / Kα1 intensity ratio: 0.50Kα2 / Kα1 intensity ratio: 0.50X-Ray tube setting45 kV, 40 mA45 kV, 40 mA45 kV, 40 mADivergence slitAutomatic1 / 8°1 / 8°Scan modeContinuousContinuousContinuousScan range (2θ / °)3°~40°3°~40°3°~40°Step size (2θ / °)0.01670.02630.0263Scan step time (s)17.78046.66539.525Test time (s)5 min 30 s5 min 04 s4 min 27 s

[0276] The term "2Th" refers to 2-theta. The term "FWIM" refers to full width at half maximum. The term "rel. int." refers to relative intensity.

[0277] DSC / TGA Analysis: TGA data were collected using a TA Q5000 / Q5500 TGA from TA Instruments. DSC was performed using a TA Q2000 / Q2500 DSC from TA Instruments. Detailed parameters used are listed below:Parameters for TGA and DSC

[0278] Parameters TGA DSC MethodRampRampSample panAluminum, openAluminum, crimpedTemperatureRT- desired temperature25 °C - desired temperatureHeating rate10 °C / min10 °C / minPurge gasN 2 N 2

[0279] DVS Analysis: DVS was measured via a SMS (Surface Measurement Systems) DVS Intrinsic. The relative humidity at 25 °C were calibrated against deliquescence point of LiCl, Mg(NO 3 ) 2 and KCl. Parameters for DVS test are listed below:Parameters for DVS test

[0280] Parameters DVS Temperature25 °CSample size10 ~ 20 mgGas and flow rateN 2 , 200 mL / mindm / dt0.002% / minMin. dm / dt stability duration10 minMax. equilibrium time180 minRH range95% RH-0% RH-95% RHRH step size10% (90% RH-0% RH-90% RH) 5% (95% RH-90% RH and 90% RH-95% RH)RH = relative humidity. dm / dt = rate of change in moisture content over time.

[0281] Definitions: ACN (acetonitrile); Ac 2 O (acetic anhydride); AIBN (2,2'-azobis(2-methylpropionitrile); BHMPO (N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide); Boc (tert-butoxycarbonyl); Boc 2 O (di-tert-butyl dicarbonate); CAN (cerium (IV) ammonium nitrate); CsF (cesium fluoride); CuI (copper iodide); CCl 4 (carbon tetrachloride); CH 3 CN (acetonitrile); CDCl 3 (deuterated chloroform); CD 3 OD (deuterated methanol); Cu(acac) 2 (copper(II) acetylacetonate); Dess Martin (1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DEA (diethylamine); DEAD (diethyl azodicarboxylate); DIAD (diisopropyl azodicarboxylate); DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); DMAP (4-dimethyl aminopyridine); DMSO (dimethylsulfoxide); DMSO-d 6 (deuterated dimethylsulfoxide); DPPA (diphenylphosphoryl azide); eq (equivalent); EDCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); EtOAc (ethyl acetate); EtOH (ethanol); g (gram); h (hour); Grubbs 2nd generation catalyst (1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium; (HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); HOBT (hydroxybenzotriazole); 1< H NMR (proton nuclear magnetic resonance); HCl (hydrochloric acid); Hz (hertz); IPA (iso-propyl alcohol); K 2 CO 3 (potassium carbonate); L (litre); LiCl (lithium chloride); LCMS (liquid chromatography-mass spectrometry); M (molar); MeOH (methanol); mg (milligrams); MHz (megahertz); min (minutes); MtBE (methyl tert-butyl ether); mL (millilitres), mmol (millimoles); Ms 2 O (methanesulfonic anhydride); NaCl (sodium chloride); NaH (sodium hydride); NaHMDS (sodium bis(trimethylsilyl)amide); NH 4 Cl (ammonium chloride); NaN 3 (sodium azide); NBS (N-bromo succinimide); NMP (N-methyl-2-pyrrolidone); Pd(allyl)Cl 2 (Bis(η3-allyl)di(µ-chloro)dipalladium(II)); Pd(dppf)Cl 2 ([1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)); prep-HPLC (preparative high-performance liquid chromatography); ppm (parts per million); PMB (4-methoxy benzyl); Rockphos (2-Di(tert-butyl)phosphino-2,4,6'-triisopropyl-3-methoxy-6-methylbiphenyl)); RT (room temperature); SEM (2-(trimethylsilyl)ethoxymethyl); SEMCl (2-(trimethylsilyl)ethoxymethyl chloride); TBAF (tetrabutyl ammonium fluoride); TEA (triethyl amine); THF (tetrahydrofuran); TsCl (tosyl chloride); tR (retention time); T3P (1-propanephosphonic anhydride); TfOH (trifluoromethanesulfonic acid); TFA (trifluoroacetic acid); TLC (thin layer chromatography); TMSI (iodotrimethyl silane); v / v (volume / volume).Synthesis of Intermediates Int-A1: 2-(Piperazin-1-yl)pyrimidine-5-carbonitrile dihydrochloride

[0282] Step 1: Tert-butyl 4-(5-cyanopyrimidin-2-yl)piperazine-1-carboxylate

[0283] A solution of 2-chloropyrimidine-5-carbonitrile (5 g, 35.83 mmol, 1 equiv), tert-butyl piperazine-1-carboxylate (6.7 g, 35.97 mmol, 1.00 equiv) and K 2 CO 3 (9.9 g, 71.63 mmol, 2.00 equiv) in NMP (80 mL) was stirred for 1 h at 80 °C. The resulting mixture was diluted with 1L of water, and the solids were collected by filtration and dried by oven to afford 8.4 g of the title compound as a white solid. LCMS: [M+H] +< 290.15.Step 2: 2-(Piperazin-1-yl)pyrimidine-5-carbonitrile dihydrochloride

[0284] A solution of tert-butyl 4-(5-cyanopyrimidin-2-yl)piperazine-1-carboxylate (8.4 g, 29.03 mmol, 1 equiv) in HCl / dioxane (40 mL, 4M) was stirred for 1 h at RT, and then the resulting solution was concentrated under vacuum to afford 6.4 g (76%) of the title compound as a white solid. LCMS: [M+H] +< 190.10.Int-A2: 2-(Piperazin-1-yl)-5-(trifluoromethyl)pyrimidine dihydrochloride

[0285] Step 1: Tert-butyl 4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxylate

[0286] A solution of 2-chloro-5-(trifluoromethyl)pyrimidine (100 g, 550 mmol, 1.05 equiv), tert-butyl piperazine-1-carboxylate (96.7 g, 520 mmol, 1 equiv), and K 2 CO 3 (151.8 g, 1100 mmol, 2 equiv) in NMP (800 mL) was stirred for 1 h at 80 °C followed by the addition of 2.5 L of H 2 O. The solids were collected by filtration to afford 190 g (94%) of the title compound as a white solid. LCMS: [M+H] +< 333.16.Step 2: 2-(Piperazin-1-yl)-5-(trifluoromethyl)pyrimidine

[0287] A solution of tert-butyl 4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazine-1-carboxylate (190 g, 571.73 mmol, 1 equiv) in HCl / dioxane (800 mL / 4M) was stirred for 1 h at RT. The solids were collected by filtration to afford 154 g (99%) of the title compound as a white solid. LCMS: [M+H] +< 199.08.Int-A3: 5-Chloro-2-(piperazin-1-yl)pyrimidine dihydrochloride

[0288] Step 1: Tert-butyl 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate

[0289] A solution of 2,5-dichloropyrimidine (19.4 g, 13.00 mmol, 1.05 equiv), tert-butyl piperazine-1-carboxylate (23 g, 12.40 mmol, 1 equiv), and K 2 CO 3 (34 g, 25.00 mmol, 2 equiv) in NMP (500 mL) was stirred for 1 h at 80 °C followed by the addition of 600 mL of H 2 O which was added to the resulting solution. The solids were collected by filtration to afford 41 g crude of the title compound as a white solid. LCMS: [M+H] +< 299.13.Step 2: 5-Chloro-2-(piperazin-1-yl)pyrimidine dihydrochloride

[0290] A solution of tert-butyl 4-(5-chloropyrimidin-2-yl)piperazine-1-carboxylate (41 g, 14.00 mmol, 1 equiv) in HCl / dioxane (500 mL / 4M) was stirred for 1 h at RT. The solids were collected by filtration to afford 26.7 g of the title compound as a white solid. LCMS: [M+H] +< 199.08.Int-A4: 6-(Piperazin-1-yl)pyridine-3-carbonitrile dihydrochloride

[0291] Step 1: Tert-butyl 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate

[0292] A solution of 6-chloropyridine-3-carbonitrile (90 g, 650 mmol, 1.05 equiv), tert-butyl piperazine-1-carboxylate (114.3 g, 620 mmol, 1 equiv), and K 2 CO 3 (171.1 g, 124 mmol, 2 equiv) in NMP (500 mL) was stirred for 1 h at 80 °C followed by the addition of 1.5 L of H 2 O which was added to the resulting solution. The solids were collected by filtration to afford 195 g of title compound as a white solid. LCMS: [M+H] +< 289.17.Step 2: 6-(Piperazin-1-yl)pyridine-3-carbonitrile dihydrochloride

[0293] Tert-butyl 4-(5-cyanopyridin-2-yl)piperazine-1-carboxylate (195 g, 680 mmol, 1 equiv) and HCl / dioxane (800 mL / 4M) was stirred for 1 h at RT. The solids were collected by filtration to afford 160 g of the title compound as a white solid. LCMS: [M+H] +< 189.12.Int-A5: 1-(5-Chloropyridin-2-yl)piperazine dihydrochloride

[0294] Step 1: Tert-butyl 4-(3-chloropyridzn-2-yl)piperazine-1-carboxylate

[0295] A solution of tert-butyl piperazine-1-carboxylate (10 g, 53.69 mmol, 1.00 equiv), NMP (30 mL), potassium carbonate (13.4 g, 96.95 mmol, 1.80 equiv), and 2,5-dichloropyridine (8.7 g, 58.79 mmol, 1.10 equiv) was stirred for 20 h at 110 °C. To the reaction mixture was then added 500 mL of H 2 O. The solids were collected by filtration to afford 10.2 g (64%) of the title compound as a light yellow solid. LCMS: [M+H] +< 298.12.Step2: 1-(5-Chloropyridin-2-yl)piperazine dihydrochloride

[0296] A solution of tert-butyl 4-(5-chloropyridin-2-yl)piperazine-1-carboxylate (10.2 g, 34.25 mmol, 1.00 equiv) and HCl / dioxane (50 mL / 4M) was stirred for 1 h at RT. The solids were collected by filtration to afford 7.4 g (80%) of the title compound as a light yellow solid. LCMS: [M+H] +< 198.07.Int-A6: 5-Chloro-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one

[0297] Step 1: 4, 5-Dibromo-2-[[2-(trimethylsilyl)ethoxy]methyl]-2, 3-dihydropyridazin-3-one

[0298] To a solution of 4,5-dibromo-2,3-dihydropyridazin-3-one (3500 g, 13.78 mol, 1.00 equiv) in DMF (30 L) was added sodium hydride (400 g, 16.56 mol, 1.20 equiv) in batches at 0 °C under nitrogen. The resulting solution was stirred for 1 h at RT followed by addition of [2-(chloromethoxy)ethyl]trimethylsilane (2500 g, 15.2 mol, 1.10 equiv) dropwise at 0 °C. The reaction mixture was stirred for 2 h at RT. The reaction was then quenched by the addition of 30 L of water. The resulting solution was extracted with 3 x 50 L of EtOAc and the organic layers combined. The organic layers were washed with 3 x 30 L of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4.2 kg of title compound. LCMS: [M+H] +< 384.70.Step 2: 4-Bromo-5-chloro-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0299] To a solution of 4,5-dibromo-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (2200 g, 5.73 mol, 1.00 equiv) in NMP (6 L) was added chlorolithium (231 g, 5.73 mol, 1.00 equiv) and the resulting solution was stirred for 4 h at 95 °C. This reaction was repeated again with a 2000 g scale batch. After completion, the two batch reactions were combined and then diluted by the addition of 10 L of water, extracted with 3 x 20 L of EtOAc and the organic layers combined. The organic layers were washed with 3 x 20 L of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:petroleum ether, 1:50, v / v). In total, from 4.2 kg of 4,5-dibromo-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one material starting material, 2.2 kg (59% yield) of title compound was obtained. LCMS: [M+H] +< 340.90.Step 3: 5-Chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0300] To a solution of 4-bromo-5-chloro-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1100 g, 3.23 mol, 1.00 equiv) in NMP (6 L) at RT was added CuI (56 g, 0.64 mol, 0.20 equiv) followed by dropwise addition of methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1865 g, 9.7 mol, 3.00 equiv). The resulting solution was stirred for 2 h at 80 °C. The reaction was then quenched by the addition of 10 L of water and extracted with 3 x 10 L of EtOAc. The organic layers were combined and washed with 3 x 10 L of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc / petroleum ether, 1 / 100, v / v) to afford 1030 g (76%) of the title compound. LCMS: [M+H] +< 329.00. 1< H NMR (300 MHz, CDCl 3 ) δ 7.82 (s, 1H), 5.50 (d, J= 27.3 Hz, 2H), 3.74 (dt, J= 12.9, 8.2 Hz, 2H), 0.97 (td, J= 8.3, 5.0 Hz, 2H), 0.01 (d, J = 2.1 Hz, 9H).Int-A7: 4,5-Dichloro-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0301]

[0302] A solution of 4,5-dichloro-2,3-dihydropyridazin-3-one (10 g, 60.62 mmol, 1 equiv) in DMF (40 mL) was stirred at 0 °C and NaH (2.9 g, 121.23 mmol, 2 equiv) was added at 0 °C in several batches. The mixture was stirred for 30 min at 0 °C followed by the addition of [2-(chloromethoxy)ethyl]trimethylsilane (13 g, 78.80 mmol, 1.3 equiv) slowly at 0 °C. The resulting solution was stirred for an additional 10 min at 0 °C. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 2 x 80 mL of EtOAc and the organic layers combined. The resulting solution was extracted with 3 x 60 mL of NaCl (aq) and the organic layers combined and concentrated under vacuum.

[0303] The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (4 / 96) to afford 9 g (50%) of the title compound as a yellow oil. LCMS: [M-Cl] +< 295.04.Int-A8: 4,5-Dibromo-2-[[2-(trimethylsilyl)ethoxy]|methyl]-2,3-dihydropyridazin-3-one

[0304]

[0305] To a solution of 4,5-dibromo-2,3-dihydropyridazin-3-one (3500 g, 13.78 mol, 1.00 equiv) in DMF (30 L) was added NaH (400 g, 16.56 mol, 1.20 equiv) in batches at 0 °C under nitrogen. The resulting solution was stirred for 1h at RT, then dropwise 2-(chloromethoxy)ethyl]trimethylsilane (2500 g, 15.2 mol, 1.10 equiv) was added at 0 °C and stirred for 2 h at RT. The reaction was then quenched by the addition of 30L of water. The resulting solution was extracted with 3 x 50 L of EtOAc and the organic layers combined. The organic layers were washed with 3 x 30 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 4.2 kg of title compound. LCMS: [M+H] +< 384.70.Int-A9: 3-[2-[(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic acid

[0306] Step 1: Tert-butyl 3-[2-[(5-chloro-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate

[0307] A solution of tert-butyl 3-(2-hydroxyethoxy)propanoate (778.8 mg, 4.09 mmol, 1.00 equiv), Cs 2 CO 3 (2.66 g, 8.16 mmol, 2.00 equiv), and 4,5-dichloro-2-[2-(trimethylsilyl)ethoxy]methyl-2,3-dihydropyridazin-3-one (1.2 g, 4.06 mmol, 1.00 equiv) in ACN (15 mL) was stirred for 3 h at 80 °C. The solids were filtered and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc / petroleum ether (1:1) to afford 200 mg (11%) of title compound as a white solid. LCMS: [M+H] +< 449.01.Step 2: 3-[2-[(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic acid

[0308] A solution of tert-butyl 3-[2-[(5-chloro-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate (10 mg, 0.02 mmol, 1.00 equiv) in TFA (2 mL) and DCM (10 mL) was stirred for 0.5 h at RT. After completion, the crude product was directly concentrated under reduced pressure to afford 776 mg of title compound as a white solid. LCMS: [M+H] +< 263.01.Int-A10: 3-[2-[(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]ethoxy]propanoic acid

[0309] Step 1: Methyl 3-(2-(tert-butoxycarbonylamino)ethoxy)propanoate

[0310] A solution of tert-butyl N-(2-hydroxyethyl)carbamate (6 g, 37.2 mmol, 1.00 equiv), sodium hydride (2 g, 83.3 mmol, 1.50 equiv), methyl 3-bromopropanoate (6.18 g, 37.0 mmol, 1.00 equiv) in THF (40 mL) was stirred overnight at 25 °C. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (1:3, v:v) to afford 1.6 g (17%) of title compound as a colorless oil. LCMS: [M+H] +< 248.14.Step 2: Methyl 3-(2-aminoethoxy)propanoate hydrochloride

[0311] A solution of 3 methyl 3-(2-[[(tert-butoxy)carbonyl]amino]ethoxy)propanoate (1.6 g, 6.47 mmol, 1.00 equiv) in HCl / dioxane (20 mL / 4M) was stirred for 1 h at 25 °C. The resulting mixture was concentrated under vacuum to afford 900 mg (95%) of title compound as a colorless oil. LCMS: [M+H] +< 148.09.Step 3: Methyl 3-[2-[(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]ethoxy]propanoate

[0312] A solution of methyl 3-(2-aminoethoxy)propanoate (955 mg, 6.5 mmol, 1.00 equiv), 4,5-dichloro-2,3-dihydropyridazin-3-one (1.06 g, 6.43 mmol, 1.00 equiv), and TEA (1.95 g, 19.3 mmol, 3.00 equiv) in EtOH (20 mL) was stirred overnight at 80 °C. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with EtOAc / petroleum ether (3:1) to afford 1.2 g (67%) of title compound as a yellow oil. LCMS: [M+H] +< 276.07.Step 4: 3-[2-[(5-Chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]ethoxy]propanoic acid

[0313] A solution of methyl 3-[2-[(5-chloro-6-oxo-1,6-dihydropyridazin-4-yl)amino]ethoxy]propanoate (1.2 g, 4.35 mmol, 1.00 equiv) and LiOH·H 2 O (488 mg, 11.6 mmol, 2.00 equiv) in water (50 mL) and MeOH (50 mL) was stirred overnight at 50°C. The resulting mixture was concentrated under reduced pressure to afford 800 mg (70%) of title compound as a yellow oil. LCMS: [M+H] +< 262.05.Int-A11: 3-(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)propanoic acid

[0314] Step 1: Tert-butyl 3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]ethoxy)propanoate

[0315] A solution of Int-A6 (1.1 g, 3.4 mmol, 1 equiv), Cs 2 CO 3 (2.2 g, 6.8 mmol, 2 equiv), tert-butyl 3-(2-hydroxyethoxy)propanoate (649.2 mg, 3.41 mmol, 1 equiv) in MeCN (20 mL) was stirred for 18 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (16 / 84) to afford 1 g (61%) of title compound as a yellow oil. LCMS: [M+H] +< 483.21.Step 2: 3-(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]oxy]ethoxy)propanoic acid

[0316] A solution of tert-butyl 3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]oxy]ethoxy)propanoate (450 mg, 0.93 mmol, 1 equiv) and TFA (1 mL) in DCM (10 mL) was stirred for 3 h at RT. The resulting mixture was concentrated under reduced pressure and the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN to afford 110 mg (40%) of title compound as a white oil. LCMS: [M+H] +< 297.06.Int-A12: 3-(2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoic acid

[0317] Step 1: Methyl 3-(2-aminoethoxy)propanoate

[0318] A solution of methyl 3-(2-[[(tert-butoxy)carbonyl]amino]ethoxy)propanoate (800 mg, 3.24 mmol, 1 equiv) in HCl / dioxane (10 mL) was stirred for 30 min at RT. The resulting mixture was concentrated under reduced pressure to afford 476 mg of title compound as a yellow crude oil. LCMS: [M+H] +< 148.09.Step 2: Methyl 3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1, 6-dihydropyridazin-4-yl]amino]ethoxy)propanoate

[0319] A solution of methyl 3-(2-aminoethoxy)propanoate (476 mg, 3.23 mmol, 1 equiv), TEA (981.8 mg, 9.70 mmol, 3 equiv), and Int-A6 (1.06 g, 3.23 mmol, 1 equiv) in EtOH (10 mL) was stirred for 60 min at RT. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (28 / 72, v / v) to afford 259 mg (18%) of title compound as a yellow oil. LCMS: [M+H] +< 440.18.Step 3: Methyl 3-(2-[[6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]amino]ethoxy)propanoate

[0320] A solution of methyl 3-(2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoate (259 mg, 0.59 mmol, 1 equiv) in HCl / dioxane (10 mL / 4M) was stirred for 16 h at RT. The resulting mixture was concentrated under reduced pressure to afford 182 mg of title compound as a yellow oil. LCMS: [M+H] +< 310.09.Step 4: 3-(2-[[6-Oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]amino]ethoxy)propanoic acid

[0321] A solution of methyl 3-(2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)propanoate (182 mg, 0.59 mmol, 1 equiv) and LiOH·H 2 O (123.5 mg, 2.94 mmol, 5 equiv) in MeOH (5 mL) and H 2 O (1 mL) was stirred for 3 h at RT. The pH value of the solution was adjusted to 7 with aqueous HCl. The resulting solution was extracted with 3 x 3 mL of DCM and the aqueous layers combined and concentrated under vacuum. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / ACN to afford 100 mg (58%) of title compound as a white solid. LCMS: [M+H] +< 296.08.Int-A13: 3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoic acid

[0322] Step 1: 5-[[(2S)-1-Hydroxypropan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0323] A solution of Int-A6 (8 g, 24 mmol, 1 equiv), TEA (2.463 g, 24 mmol, 1 equiv), and (2S)-2-aminopropan-1-ol (1.829 g, 24 mmol, 1 equiv) in EtOH (60 mL) was stirred for 1 h at 60 °C. The solvent was concentrated under vacuum and the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1 / 1) to afford 5.39 g (58%) of title compound as a yellow oil. LCMS [M+H] +< 367.44.Step 2: 3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate

[0324] A solution of 5-[[(2S)-1-hydroxypropan-2-yl]amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (5.39 g, 15 mmol, 1 equiv), methyl prop-2-enoate (13.24 g, 147 mmol, 10 equiv), and Cs 2 CO 3 (4.773 g, 15 mmol, 1 equiv) in MeCN (50 mL) was stirred for 4 h at 25 °C. The solvent was concentrated under vacuum, the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1 / 1) to afford 3.12 g (42%) of title compound as a white solid. LCMS [M+H] +< 454.53.Step 3: 3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate

[0325] A solution of methyl 3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate (3.12 g, 1 equiv) and TFA (10 mL) in DCM (40 mL) was stirred 0.5 h at 25 °C. The resulting mixture was concentrated under vacuum to afford 2.1 g (93%) of title compound as a white solid.Step 4: 3-[(2S)-2-[[6-Oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]amino]propoxy]propanoic acid

[0326] A solution of methyl 3-[(2S)-2-[[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]propoxy]propanoate (2.12 g, 7 mmol, 1 equiv), LiOH·H2O (1.378 g, 33 mmol, 5 equiv) in MeOH (15 mL) and H 2 O (15 mL) was stirred for 0.5 h at 25 °C. The pH value of the solution was adjusted to 6 with TFA. The resulting mixture was concentrated under vacuum and the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN (6:1) to afford 2.1 g (90%) of title compound as a yellow oil. LCMS [M+H] +< 310.25.Int-A14: 3-[2-[(5-Bromo-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic acid

[0327] Step 1: Tert-butyl 3-[2-[(5-bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate

[0328] A solution of Int-A8 (4 g, 10.4 mmol, 1.0 equiv), tert-butyl 3-(2-hydroxyethoxy)propanoate (1.99 g, 10.4 mmol, 1.0 equiv) and Cs 2 CO 3 (6.82 g, 20.9 mmol, 2 equiv) in MeCN (30 mL) was stirred for 2 h at 60 °C, and then the solid was filtered and the resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether to afford 2.2 g (43%) of title compound as a light yellow oil. LCMS [M+H] +< 493.13, 495.13Step 2: 3-[2-[(5-Bromo-6-oxo-1, 6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic acid

[0329] A solution of tert-butyl 3-[2-[(5-bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate (1.66 g, 1 equiv) and TFA (2 mL) in DCM (10 mL) was stirred for 2 h at RT, and then the resulting solution was concentrated under reduced pressure to afford 380 mg (37%) of title compound as a yellow oil. LCMS [M+H] +< 307.10.Int-A15: 3-[2-[(5-Methyl-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic acid

[0330] Step 1: Tert-butyl 3-(2-((5-methyl-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1, 6-dihydropyridazin-4-yl)oxy)ethoxy)propanoate

[0331] A solution of tert-butyl 3-[2-[(5-bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate (2 g, 4.05 mmol, 1 equiv), methylboronic acid (485.2 mg, 8.11 mmol, 2 equiv), Pd(dppf)Cl 2 (296.6 mg, 0.41 mmol, 0.1 equiv), and CsF (1847.0 mg, 12.16 mmol, 3 equiv) in dioxane (15 mL) and H 2 O (3 mL) was stirred for 2 h at 80 °C. The solvent was concentrated under vacuum and the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether to afford 1.5 g (86%) of title compound as a yellow oil. LCMS [M+H] +< 429.23.Step 2: 3-[2-[(5-Methyl-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic acid

[0332] A solution of tert-butyl 3-[2-[(5-methyl-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate (1.5 g, 1 equiv) in HCl / dioxane (30 mL / 4M) was stirred overnight at 25 °C. The resulting mixture was concentrated under reduced pressure to afford 800 mg (94%) of title compound as a yellow crude oil. LCMS [M+H] +< 243.09.Int-A16: 3-[2-[(5-Cyano-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic acid

[0333] Step 1: 3-[2-[(5-Bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate

[0334] A solution of Int-A8 (4 g, 10.41 mmol, 1 equiv), Cs 2 CO 3 (10.14 g, 31.12 mmol, 2.99 equiv), and tert-butyl 3-(2-hydroxyethoxy)propanoate (3.97 g, 20.87 mmol, 2.00 equiv) in DMF (40 mL) was stirred for 18 h at RT. The reaction was then quenched by the addition of 40 mL of water. The resulting solution was extracted with 3 x 50 mL of EtOAc and the organic layers combined and dried over anhydrous sodium sulfate. The organic layers were concentrated under vacuum and the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1 / 9) to afford 2.2 g (43%) of title compound as a yellow oil. LCMS [M+H] +< 493.13, 495.13. 2 g of 4-bromo-5-(2-hydroxyethoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one was isolated as a by-product of the reaction during purification and was used as a starting material for the synthesis of Int-A19, Step1. LCMS [M+H] +< : 365.05, 367.05.Step 2: Tert-butyl 3-[2-[(5-cyano-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate

[0335] A solution of tert-butyl 3-[2-[(5-bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate (2.2 g, 4.46 mmol, 1 equiv), and CuCN (800 mg, 8.93 mmol, 2.00 equiv) in NMP (20 mL) was stirred for 23 h at 120 °C. The reaction was then quenched by the addition of 20 mL of water and the resulting solution was extracted with 3 x 30 mL of EtOAc and the organic layers were combined and dried over anhydrous calcium chloride. The organic layers were concentrated under reduced pressure and the residue was purified by silica gel column chromatography with EtOAc / petroleum ether (3 / 7) to afford 800 mg (41%) of title compound as a yellow oil. LCMS [M+H] +< 254.07.Step 3: 3-[2-[(5-Cyano-6-oxo-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoic acid

[0336] A solution of tert-butyl 3-[2-[(5-cyano-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoate (800 mg, 1.82 mmol, 1 equiv) in HCl / dioxane (10 mL / 4M) was stirred 18 h at RT. The resulting mixture was concentrated under reduced pressure to afford 350 mg (76%) of title compound as a yellow crude oil. LCMS [M+H] +< 254.07.Int-A17: 2-[5-(Hydroxymethyl)oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl] ethan-1-one

[0337] Step 1: 1-(Benzyloxy)hex-5-en-2-ol

[0338] To a solution of bromo(prop-2-en-1-yl)magnesium (27.4 mL, 1.50 equiv) in THF (20 mL) was added dropwise 2-[(benzyloxy)methyl]oxirane (3 g, 18.27 mmol, 1.00 equiv) under nitrogen at -40 °C. The resulting solution was stirred for 1 h at -40 °C and the resulting solution was quenched by 100 mL with aqueous NH 4 Cl, and extracted with 3 x 100 mL of EtOAc. The organic layers were combined, washed with 1 x 100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1:5) to afford 2.16 g (57%) of title compound as a yellow oil. LCMS [M+H] +< 207.13.Step 2: Methyl (2Z)-7-(benzyloxy)-6-hydroxyhept-2-enoate

[0339] Under nitrogen, a solution of 1-(benzyloxy)hex-5-en-2-ol (2 g, 9.70 mmol, 1.00 equiv), methyl prop-2-enoate (4.17 g, 48.44 mmol, 5.00 equiv) and Grubbs 2nd generation catalyst (82 mg, 0.01 equiv) in DCM (25 mL) was stirred for 4 h at 40 °C. The resulting solution was concentrated under vacuum and the residue was purified by C18 reverse phase chromatography eluting with H 2 O / ACN to afford 1.4 g (55%) of title compound as yellow oil. LCMS [M+H] +< 265.14.Step 3: Methyl 2-[5-[(benzyloxy)methyl]oxolan-2-yl]acetate

[0340] A solution of methyl (2Z)-7-(benzyloxy)-6-hydroxyhept-2-enoate (46 g, 1 equiv) and NaH (0.7 g, 0.1 equiv) in THF (200 mL) was stirred for 12 h at 25 °C. The resulting solution was then quenched with 200 mL of water, extracted with 3 x 200 mL of DCM, and the organic layers combined and washed with 1 x 100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 46 g of title compound as brown oil. LCMS [M+H] +< 265.14.Step 4: 2-[5-[(Benzyloxy)methyl]oxolan-2-yl]acetic acid

[0341] A solution of methyl 2-[5-[(benzyloxy)methyl]oxolan-2-yl]acetate (46 g, 174.03 mmol, 1 equiv) and LiOH·H2O (14.6 g, 350 mmol, 2 equiv) in THF (200 mL) and H 2 O (200 mL) was stirred for 2 h at 25 °C. The resulting solution was washed with 1 x 200 ml of DCM, the aqueous layers was combined and the pH value of the aqueous layer was adjusted to 4 with HCl (1M). After concentration, the residue were dissolved in 100 mL of EtOH and the solids were filtered out. The resulting solution was concentrated under vacuum to afford 40 g (92%) of title compound as a light yellow oil. LCMS [M+H] +< 251.12.Step 5: 2-[5-[(Benzyloxy)methyl]oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethan-1-one

[0342] A solution of 2-[5-[(benzyloxy)methyl]oxolan-2-yl]acetic acid (3 g, 11.99 mmol, 1 equiv), 1-[5-(trifluoromethyl)pyridin-2-yl]piperazine (1.7 g, 7.35 mmol, 0.61 equiv), HATU (4.6 g, 11.99 mmol, 1 equiv), and DIPEA (4.6 g, 35.96 mmol, 3 equiv) in DMF (50 mL) was stirred for 4 h at RT. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3 x 60 mL of EtOAc and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (3 / 2) to afford 3.2 g (58%) of title compound as a yellow oil. LCMS [M+H] +< 464.15.Step 6: 2-[5-(Hydroxymethyl)oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethan-1-one

[0343] Under H 2 (g) atmosphere, a solution 2-[5-[(benzyloxy)methyl]oxolan-2-yl]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethan-1-one (3.2 g, 6.90 mmol, 1 equiv), palladium 10% on carbon (1 g, 9.40 mmol, 1.36 equiv) in MeOH (50 mL) was stirred overnight at 50 °C. The solids were filtered and the resulting mixture was concentrated under reduced pressure to afford 1.7 g (66%) of title compound as a colorless oil. LCMS [M+H] +< 374.10.Int-A18: 1-[5-(Trifluoromethyl)pyridin-2-yl]piperazine

[0344]

[0345] This compound was purchased from commercial sources: CAS [132834-58-3].Int-A19: 6-[4-(3-[2-[(5-Bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

[0346] Step 1: 6-[4-(3-[2-[(5-Bromo-6-oxo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl)oxy]ethoxy]propanoyl)piperazin-1-yl]pyridine-3-carbonitrile

[0347] A solution of 4-bromo-5-(2-hydroxyethoxy)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1.0 g, 2.74 mmol, 1 equiv), Cs 2 CO 3 (2.652 g, 8.14 mmol, 2.97 equiv), and Int-A25 (0.99 g, 4.09 mmol, 1.49 equiv) in DMF (20 mL) was stirred for 24 h at RT. The reaction was then quenched by the addition of 20 mL of water and the resulting solution was extracted with 3 x 30 mL of EtOAc and the organic layers were combined and dried over anhydrous sodium sulfate. The organic layers were concentrated under reduced pressure and the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (9 / 1) to afford 350 mg (21%) of title compound as a yellow oil. LCMS [M+H] +< 609.16.Int-A20: 5-Chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0348] Step 1: 4,5-Dibromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydropyridazin-3-one

[0349] To a solution of 4,5-dibromo-2,3-dihydropyridazin-3-one (250 g, 984.71 mmol, 1 equiv) in DMF (2.5 L) was added NaH (59.1 g, 1477.07 mmol, 1.50 equiv, 60%) in several batches at 0-10 °C. followed by the addition of 1-(chloromethyl)-4-methoxybenzene (230.3 g, 1470.53 mmol, 1.49 equiv) at 0 °C. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of 5 L of water / ice and extracted with 2 x 2.5 L of DCM. The organic layers were combined and concentrated. The solids were washed by MeOH (500 mL x 2) to afford 290 g (79%) of title compound as a solid. LCMS [M+H] +< 378.00.Step 2: 5-Methoxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0350] A solution of 4,5-dibromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydropyridazin-3-one (290 g, 775.33 mmol, 1 equiv), potassium hydroxide (130.5 g, 2326.00 mmol, 3.00 equiv) in MeOH (2.5 L) was stirred for 2 h at RT. The resulting mixture was concentrated to 500 mL and the solids were collected by filtration. The resulting cake was slurried for 1 h in water (1L) to afford 232 g (92%) of title compound as a solid. LCMS [M+H] +< 326.90.Step 3: 5-Methoxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0351] A solution of 4-bromo-5-methoxy-2-[(4-methoxyphenyl)methyl]-2,3-dihydropyridazin-3-one (232 g, 713.49 mmol, 1 equiv), methyl 2,2-difluoro-2-sulfoacetate (411.2 g, 2140.44 mmol, 3.00 equiv), and CuI (67.9 g, 356.52 mmol, 0.50 equiv) in NMP (1.2L) was stirred for 3 h at 100 °C. The reaction was then quenched by the addition of 1.5L of water. The resulting solution was extracted with 3 x 1L of DCM. The organic layers were combined and concentrated. The residue was applied onto a silica gel column with EtOAc / petroleum ether (1 / 1). The collected fractions were combined and concentrated to afford the crude oil to which was added 1L of water. The solids were collected by filtration and washed with 100 mL of MeOH to afford 170 g (76%) of title compound as a solid. LCMS [M+H] +< 315.10.Step 4: 5-Hydroxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0352] To a solution of 5-methoxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (170 g, 540.95 mmol, 1 equiv) in DMF (850 mL) was added TMSI (140 g, 699.67 mmol, 1.29 equiv) dropwise at 20 °C. The resulting solution was stirred for 20 h at 85 °C. The reaction mixture was then quenched by the addition of 850 mL of water and the resulting solution was extracted with 3 x 850 mL of DCM and the organic layers combined and dried over anhydrous sodium sulfate. The organic layers were concentrated under vacuum and the crude product was purified by silica gel column chromatography and then recrystallized with MtBE to afford 120 g (74%) of title compound as a white solid. LCMS [M+H] +< 301.07.Step 5: 5-Chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0353] To a solution of 5-hydroxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (110 g, 366.38 mmol, 1 equiv) in DMF (550 mL) was added oxalic dichloride (93 g, 732.75 mmol, 2.00 equiv) dropwise at 0 - 5 °C. The resulting solution was stirred for 8 h at RT. The reaction was then quenched by the addition of 550 mL of water. The solids were collected by filtration to afford 108 g (93%) of title compound as a white solid. LCMS [M+H] +< 319.04 [M+H] +< , 1< H NMR (30 MHz, DMSO-d 6 ) δ 8.22 (d, J= 0.8 Hz, 1H), 7.33 - 7.22 (m, 2H), 6.94 - 6.84 (m, 2H), 5.18 (s, 2H), 3.71 (s, 3H).Int-A21: 1-[4-[5-(Trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]prop-2-en-1-one

[0354]

[0355] A solution of Int-A2 (2.2 g, 7 mmol, 1 equiv), TEA (2.924 g, 29 mmol, 4 equiv), and prop-2-enoyl chloride (1.954 g, 11 mmol, 10.00 equiv) in MeOH (20 mL) was stirred for 4.5 h at 0 ° C. The solids were filtered out and washed by 30 mL x 2 of EtOAc. The organic layers were then combined, concentrated, and then applied onto a silica gel column with chloroform / methanol (11 / 1) to afford 1.83 g (58%) of the title compound as a yellow solid. LCMS [M+H] +< 287.25.Int-A22: 1-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]prop-2-en-1-one

[0356]

[0357] A solution of Int-A5 (2.4 g, 8.92 mmol, 1.00 equiv), TEA (4 g, 39.5 mmol, 4.00 equiv), and prop-2-enoyl prop-2-enoate (3.64 g, 28.9 mmol, 3.00 equiv) in DCM (20 mL) was stirred for 1.5 h at RT. The solvent was concentrated under vacuum and the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1:1) to afford 1280 mg (57%) of title compound as a yellow oil. LCMS [M+H]+ 252.09.Int-A23: 1-[4-(5-Chloropyrimidin-2-yl)piperazin-1-yl]prop-2-en-1-one

[0358]

[0359] A solution of Int-A3 (1 g, 3.70 mmol, 1.00 equiv), TEA (1.5 g, 14.82 mmol, 4.00 equiv), and prop-2-enoyl prop-2-enoate (700 mg, 5.55 mmol, 1.50 equiv) in DCM (20 mL) was stirred for 1 h at RT. The solvent was concentrated under vacuum and the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (2:3) to afford 720 mg (77%) of title compound as a white solid. LCMS [M+H]+ 253.07.Int-A24: 2-[4-(Prop-2-enoyl)piperazin-1-yl]pyrimidine-5-carbonitrile

[0360]

[0361] A solution of Int-A1 (6.4 g, 33.82 mmol, 1 equiv), prop-2-enoyl prop-2-enoate (5.1 g, 40.44 mmol, 1.20 equiv) and TEA (6.8 g, 67.20 mmol, 1.99 equiv) in DCM (40 mL) was stirred for 1 h at room temperature, then the resulting solution was concentrated under vacuum, and the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (7:3)to afford 3.6 g (43.75%) of the title compound as a white solid. LCMS [M+H]+: 244.12.Int-A25: 6-[4-(Prop-2-enoyl)piperazin-1-yl]pyridine-3-carbonitrile

[0362]

[0363] Prop-2-enoyl prop-2-enoate (17.42 g, 138.132 mmol, 1.30 equiv) was added to a solution of Int-A4 (20 g, 106.251 mmol, 1 equiv), and TEA (32.25 g, 318.752 mmol, 3 equiv) in DCM (500 mL) at -40 °C. The resulting solution was stirred for another 1 h at -40 °C. The reaction was quenched by 500 mL of water and extracted with 2 x 500 mL of DCM. After concentration, the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (70:30) to afford 16.4 g (64%) of title compound as a yellow solid. LCMS [M+H]+ 243.13.Int-A26: 5-(Trifluoromethyl)-2-(4-(vinylsulfonyl)piperazin-1-yl)pyrimidine

[0364]

[0365] A solution of Int-A2, 2-chloroethane-1-sulfonyl chloride, and TEA (305.0 mg, 3.02 mmol, 3.50 equiv) in DCM (6 mL) was stirred for 2 h at RT. The resulting mixture was concentrated under reduced pressure and the residue was eluted onto a silica gel column with EtOAc / petroleum ether (1:5) to afford 210 mg (75.7%) of title compound as a white solid. LCMS [M+H]+ 323.07.Int-A27: 1-[5-(Trifluoromethyl)-1,3-thiazol-2-yl]piperazine hydrochloride

[0366] Step 1: Tert-butyl 4-(5-(trifluoromethyl)thiazol-2-yl)piperazine-1-carboxylate

[0367] A solution of 2-bromo-5-(trifluoromethyl)thiazole (3.00 g, 12.9 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (2.41 g, 12.9 mmol, 1.00 equiv), and Cs 2 CO 3 (8.43 g, 25.9 mmol, 2.00 equiv) in NMP (20.0 mL) was stirred for 1 h at 110 °C. The reaction was then quenched by the addition of 50 mL of water and extracted with 3 x 50 mL of EtOAc. After concentration under reduced pressure, the residue was purified by silica gel column chromatography with EtOAc / petroleum ether (15 / 85) to afford 2.56 g (95%) of title compound as a yellow solid. LCMS [M+H]+ 338.11.Step 2: 1-[5-(Trifluoromethyl)-1,3-thiazol-2-yl]piperazine hydrochloride

[0368] A solution of tert-butyl 4-(5-(trifluoromethyl)thiazol-2-yl)piperazine-1-carboxylate (2.50 g, 7.41 mmol, 1.00 equiv) and HCl (gas) in 1,4-dioxane (20.0 mL) was stirred for 30 min at RT. The resulting mixture was concentrated under vacuum to afford 2.26 g (95%) of the title compound as a white solid. LCMS [M+H]+ 274.03.Int-A28: 5-(Trifluoromethyl)-2-(4-(vinylsulfonyl)piperazin-1-yl)thiazole

[0369]

[0370] A solution of Int-A27 (2.25 g, 9.48 mmol, 1.00 equiv), TEA (4.80 g, 0.047 mmol, 5 equiv), and 2-chloroethane-1-sulfonyl chloride (1.86 g, 0.011 mmol, 1.20 equiv) in DCM (30.0 mL) was stirred for 1 h at 0 °C in a water / ice bath. The reaction mixture was quenched by the addition of MeOH followed by concentration under reduced pressure. The residue was purified by a silica gel column with EtOAc / petroleum ether (18 / 82) to afford 1.74 g (54.9%) of title compound as a white solid. LCMS [M+H]+ 328.03.Int-A29: 5-Mercapto-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0371]

[0372] A solution of Int-A20 (2 g, 6.3 mmol, 1 equiv), NaHS (1.4 g, 25.1 mmol, 4 equiv), and TEA (1.9 g, 18.9 mmol, 3 equiv) in EtOH (10 mL) was stirred for 40 min at 70 °C. After concentration under reduced pressure, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN to afford 1.8 g (90.7%) of title compound as a yellow solid. LCMS [M+H]+ 317.06.Synthesis of Example Compounds Example 1: 5-[5-[(1-acetylpiperidin-4-yl)oxy]-6-fluoro-2,3-dihydro-1 H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0373] Step 1: Synthesis of 1-bromo-4,5-bis(bromomethyl)-2-fluorobenzene

[0374] A solution of 1-bromo-2-fluoro-4,5-dimethylbenzene (5 g, 24.62 mmol, 1 equiv), NBS (10.85 g, 60.96 mmol, 2.476 equiv), AIBN (1.98 g, 12.06 mmol, 0.490 equiv) in CCl 4 (50mL) was stirred for 12 h at 80 °C. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN to afford 5.4 g (61 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 360.80 [M+H] +< .Step 2: Synthesis of 5-bromo-6-fluoro-2,3-dihydro-1H-isoindole

[0375] A solution of 1-bromo-4,5-bis(bromomethyl)-2-fluorobenzene (3 g, 8.31 mmol, 1 equiv) in NH 3 / MeOH (300mL,1M) was stirred for 2 h at 5 °C. The resulting mixture was concentrated under vacuum to afford 2.8 g (crude) of the title compound as a yellow solid. LCMS (ESI, m / z): 215.97 [M+H] +< .Step 3: Synthesis of 5-(5-bromo-6-fluoro-2,3-dihydro-1 H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0376] A solution of 5-bromo-6-fluoro-2,3-dihydro-1H-isoindole (1.2 g, 5.55 mmol, 1 equiv), Int-A6 (2.17 g, 6.60 mmol, 1.188 equiv), TEA (1.7 g, 16.80 mmol, 3.025 equiv) in EtOH (40 mL) was stirred for 2 h at 80°C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (15 / 85) to afford 870 mg (30.81%) of the title compound as a brown solid. LCMS (ESI, m / z): 510.06 [M+H] +< .Step 4: Synthesis of 5-(5-fluoro-6-hydroxy-2, 3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0377] A solution of 5-(5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (850 mg, 1.67 mmol, 1 equiv), LiOH·H 2 O (154.6 mg, 3.68 mmol, 2.203 equiv), BHMPO (287 mg,0.84 mmol, 0.5 equiv), Cu(acac) 2 (220 mg,0.84 mmol , 0.5 equiv) in DMSO (16 mL) and H 2 O (4 mL) was stirred for 2 h at 80°C. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3x30 ml of EtOAc and the organic layers combined and dried over anhydrous sodium sulfate. After concentration, the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (25 / 75) to afford 260 mg (35 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 446.14 [M+H] +< .Step 5: Synthesis of tert-butyl 4-([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy[methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate

[0378] A solution of 5-(5-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (260 mg, 0.58 mmol, 1 equiv), tert-butyl 4-iodopiperidine-1-carboxylate (362.6 mg, 1.17 mmol, 1.997 equiv), K 2 CO 3 (126 mg, 0.91 mmol, 1.562 equiv) in DMF (20 mL) was stirred for 12 h at 80°C. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3x30 ml of EtOAc and the organic layers combined and dried over anhydrous sodium sulfate. After concentration, the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (20 / 80) to afford 500 mg (crude) of the title compound as brown oil. LCMS (ESI, m / z): 629.25 [M+H] +< .Step 6: Synthesis of 5-[5-fluoro-6-(piperidin-4-yloxy)-2, 3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0379] A solution of tert-butyl 4-([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate (500 mg, 0.80 mmol, 1 equiv) in HCl / dioxane (5 mL) was stirred for 12 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN to afford 330 mg (crude) of the title compound as a yellow oil. LCMS (ESI, m / z): 399.25 [M+H] +< .Step 7: Synthesis of 5-[5-[(1-acetylpiperidin-4-yl)oxy]-6-fluoro-2, 3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0380] A solution of 5-[5-fluoro-6-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (330 mg, 0.83 mmol, 1 equiv), Ac 2 O (85.2 mg, 0.83 mmol, 1.007 equiv), TEA (372 mg, 3.68 mmol, 4.438 equiv) in DCM (5 mL) was stirred for 1 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (44 mg, 12 %) as a white solid. LCMS (ESI, m / z): 441.39 [M+H] +< , 1< HNMR (DMSO-d 6 , 300 MHz) δ: 12.52 (s, 1H), 7.96 (s, 1H), 7.29 (dd, J= 11.8, 9.4 Hz, 2H), 4.90 (br, 4H), 4.59 (dt, J = 8.0, 4.2 Hz, 1H), 3.83 (dd, J = 13.3, 6.4 Hz, 1H), 3.73 - 3.61 (m, 1H), 3.59-3.47(m,1H),3.39 - 3.13 (m, 1H), 2.01-1.81 (m, 5H), 1.88-1.42 (m, 2H).Example 2: 5-[4-[(1-acetylpiperidin-4-yl)oxy]-7-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0381] Step 1: Synthesis of 2-benzyl-4-bromo-7-fluoro-2,3-dihydro-1H-isoindole

[0382] A solution of 1-bromo-2,3-bis(bromomethyl)-4-fluorobenzene (2.2 g, 6.10 mmol, 1 equiv), phenylmethanamine (0.66 g, 6.16 mmol, 1.010 equiv), KHCO 3 (1.5 g, 14.98 mmol, 2.457 equiv) in ACN (200 mL) was stirred for 3 h at 75°C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (5 / 95) to afford 660 mg (35 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 306.02 [M+H] +< .Step 2: Synthesis of 2-benzyl-4-fluoro-7-methoxy-2,3-dihydro-1H-isoindole

[0383] A solution of MeOH (5 mL), 2-benzyl-4-bromo-7-fluoro-2,3-dihydro-1H-isoindole (700 mg, 2.29 mmol, 1 equiv), Pd 2 (allyl) 2 Cl 2 (56.0 mg, 0.15 mmol, 0.067 equiv), RockPhos (107.2 mg, 0.23 mmol, 0.100 equiv), Cs 2 CO 3 (1492.1 mg, 4.58 mmol, 2.003 equiv) in Toluene (12mL) was stirred for 3 h at 80°C in an oil bath with the atmosphere of nitrogen. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (5 / 95) to afford 500 mg (85 %) of the title compound as yellow oil. LCMS (ESI, m / z): 258.12 [M+H] +< .Step 3: Synthesis of 2-benzyl-7-fluoro-2, 3-dihydro-1H-isoindol-4-ol

[0384] A solution of 2-benzyl-4-fluoro-7-methoxy-2,3-dihydro-1H-isoindole (500 mg, 1.94 mmol, 1 equiv) in DCM (5 mL) was stirred at 0°C.To this was added BBr 3 (5 mL, 52.89 mmol, 27.217 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 12 h at room temperature. The reaction was then quenched by the addition of 10 mL of methanol. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (15 / 85) to afford 456 mg (96.5 %) of the title compound as a white solid. LCMS (ESI, m / z): 244.11 [M+H] +< .Step 4: Synthesis of 7-fluoro-2,3-dihydro-1H-isoindol-4-ol hydrochloride

[0385] A solution of 2-benzyl-7-fluoro-2,3-dihydro-1H-isoindol-4-ol (400 mg, 1.64 mmol, 1 equiv), Pd / C (40.1 mg), HCl (1M, 3 mL). The resulting solution was stirred for 1 h at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. This resulted in 210 mg (67 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 154.06 [M+H] +< .Step 5: Synthesis of 5-(4-fluoro-7-hydroxy-2, 3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0386] A solution of 7-fluoro-2,3-dihydro-1H-isoindol-4-ol hydrochloride (100 mg, 0.53 mmol, 1 equiv), Int-A6 (214 mg, 0.65 mmol, 1.234 equiv), TEA (194.7 mg, 1.92 mmol, 3.648 equiv) in EtOH (3 mL) was stirred for 2 h at 80°C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether to afford 140 mg (60 %) of the title compound as yellow oil. LCMS (ESI, m / z): 446.14 [M+H] +< .Step 6: Synthesis of tert-butyl 4-([7-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy[methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)piperidine-1-carboxylate

[0387] A solution of 5-(4-fluoro-7-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (400 mg, 0.90 mmol, 1 equiv), tert-butyl 4-iodopiperidine-1-carboxylate (558 mg, 1.79 mmol, 1.997 equiv), K 2 CO 3 (193.8 mg, 1.40 mmol, 1.562 equiv) in DMF (5 mL) was stirred for 4 days at 80°C. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3x30 ml of EtOAc and the organic layers combined and dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (50 / 50) to afford 130 mg (23 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 629.27 [M+H] +< .Step 7: Synthesis of 5-[4-fluoro-7-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0388] A solution of tert-butyl 4-([7-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)piperidine-1-carboxylate (130 mg, 0.21 mmol, 1.00 equiv) in hydrogen chloride / dioxane (10 mL) was stirred for 16 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN to afford 80 mg (96%) of the title compound as a white solid. LCMS (ESI, m / z): 399.14 [M+H] +< .Step 8: Synthesis of 5-[4-[(1-acetylpiperidin-4-yl)oxy]-7-fluoro-2, 3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0389] A solution of TEA (90 mg, 0.89 mmol, 3.00 equiv), 5-[4-fluoro-7-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (80 mg, 0.20 mmol, 1.00 equiv), Ac2O (20.65 mg, 0.20 mmol, 1.00 equiv) in DCM (5 mL) was stirred for 2 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (18.5 mg, 21 %) as a white solid. LCMS (ESI, m / z): 441.39 [M+H] +< , 1< HNMR (DMSO-d 6 , 300 MHz) δ 12.56 (s, 1H), 8.11 (s, 1H), 7.15 - 7.07 (m, 2H), 5.02 (s, 2H), 4.92 (s, 2H), 4.68 (dt, J = 6.6, 3.4 Hz,1H), 3.74 - 3.57 (m, 2H), 3.45 - 3.32 (m, 2H), 2.02 (s, 3H), 2.00 - 1.84 (m, 2H), 1.72 - 1.51 (m, 2H).Example 3: 5-[4-fluoro-6-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one; formic acid

[0390] Step 1: Synthesis of methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate

[0391] A solution of methyl 4-bromo-6-fluoro-2-methylbenzoate (10 g, 40.48 mmol, 1.00 equiv), NBS (7.23 g, 40.62 mmol, 1.10 equiv) and AIBN (3.33 g, 20.28 mmol, 0.50 equiv) in CCl 4 (150 mL) was stirred for 12 h at 80°C , and then the resulting solution was concentrated under vacuum and the crude product was purified by C18 reverse phase chromatography eluting with H2O / CH 3 CN to afford 10 g (76 %) of the title compound as yellow oil. LCMS (ESI, m / z): 324.88 [M+H] +< .Step 2: Synthesis of 5-bromo-7-fluoro-2,3-dihydro-1H-isoindol-1-one

[0392] A solution of 4-bromo-2-(bromomethyl)-6-fluorobenzoate (10 g, 30.68 mmol, 1.00 equiv) in NH 3 (gas) / MeOH (40 mL, 7M) was stirred for 40 min at 40°C, and then the resulting solution was concentrated under vacuum to afford 9.1 g (crude) of the title compound as an off-white solid.. LCMS (ESI, m / z): 230.04 [M+H] +< .Step 3: Synthesis of tert-butyl 5-bromo-7-fluoro-1-oxo-2, 3-dihydro-1H-isoindole-2-carboxylate

[0393] To a solution of 5-bromo-7-fluoro-2,3-dihydro-1H-isoindol-1-one (9.1 g, 39.56 mmol, 1.00 equiv) and DMAP (977 mg, 8.00 mmol, 0.20 equiv) in THF (70 mL), was added (Boc) 2 O (12.99 g, 59.52 mmol, 1.50 equiv), and the resulting solution was stirred for 2 h at room temperature, and then the resulting solution was concentrated under vacuum, The crude product was purified by C18 reverse phase chromatography eluting with H2O / CH 3 CN to afford 5.7 g (44 %) of the title compound as a white solid. LCMS (ESI, m / z): 330.15 [M+H] +< .Step 4: Synthesis of 6-bromo-4-fluoro-2,3-dihydro-1H-isoindole

[0394] Under nitrogen, to a solution of tert-butyl 5-bromo-7-fluoro-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate (5.7 g, 17.26 mmol, 1.00 equiv) and NaBH4 (7.9 g, 208.83 mmol, 12.00 equiv) in THF (60 mL), BF3 / Et2O (36.9 g, 15.00 equiv, 1M) added dropwise, and then the resulting solution was stirred for 3 h at 70°C. The resulting solution was quenched by the addition of 200 mL of water, extracted with 3x200 mL of EtOAc and the organic layers combined, washed with 1x200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum, and then the residue was applied onto a silica gel column eluting with DCM / methanol (2:3) to give 2.05 g (55 %) of the title compound ndole as an off-white solid. LCMS (ESI, m / z): 216.05 [M+H] +< .Step 5: Synthesis of 5-(6-bromo-4-fluoro-2, 3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0395] A solution of 6-bromo-4-fluoro-2,3-dihydro-1H-isoindole (2.05 g, 9.49 mmol, 1.00 equiv), 5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (3.12 g, 9.49 mmol, 1.00 equiv) and TEA (2.88 g, 28.46 mmol, 3.00 equiv) in ethanol (20 mL) was stirred for 2 h at 60°C, and then the resulting solution was concentrated under vacuum, and then the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1:5) to afford 2.1 g (44 %) of the title compound as a light brown solid. LCMS (ESI, m / z): 508.39 [M+H] +< .Step 6: Synthesis of 5-(4-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0396] A solution of 5-(6-bromo-4-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (2 g, 3.93 mmol, 1.00 equiv), BHMPO (135 mg, 0.41 mmol, 0.10 equiv), Cu(acac) 2 (103 mg, 0.39 mmol, 0.10 equiv) and LiOH·H 2 O (363 mg, 8.64 mmol, 2.20 equiv), DMSO (20 mL) and water(5 mL) was stirred for 12 h at 80°C, and then the solids were filtered out, and the resulting solution was diluted with 100 mL of H 2 O, extracted with 3x100 mL of EtOAc and the organic layers combined, washed with 1x100 mL of brine and concentrated under vacuum, and then the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (3:1) to afford 680 mg (39 %) of the title compound as a green solid. LCMS (ESI, m / z): 446.14 [M+H] +< .Step 7: Synthesis of tert-butyl 4-([7-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy[methyl]-1,6-dihydropyridazin-4-yl]-2, 3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate

[0397] A solution of 5-(4-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (300 mg, 0.67 mmol, 1.00 equiv), tert-butyl 4-iodopiperidine-1-carboxylate (629 mg, 2.02 mmol, 3.00 equiv) and potassium carbonate (279 mg, 2.02 mmol, 3.00 equiv) in DMF (5 mL) was stirred for 12 h at 80 °C, and then the resulting solution was diluted with 50 mL of H 2 O, extracted with 3x50 mL of EtOAc and the organic layers combined, washed with 1x50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum, and then the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (3:1) to give 153 mg (36 %) of the title compound as yellow oil. LCMS (ESI, m / z): 629.27 [M+H] +< .Step 8: Synthesis of 5-[4-fluoro-6-(piperidin-4-yloxy)-2, 3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one; formic acid

[0398] A solution of tert-butyl 4-([7-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate (135 mg, 0.21 mmol, 1.00 equiv) in HCl(gas) / dioxane (6 mL, 4M) was stirred for 2 h at room temperature, and then the resulting solution was concentrated under vacuum, and then the crude product was further purified by Pre-HPLC yielding the title compound (34.2 mg, 36 %) as a white solid. LCMS (ESI, m / z): 399.05 [M+H] +< . 1< HNMR (DMSO-d 6 , 300MHz): δ 12.54 (s, 1H) ,8.32 (s, 1H), 8.02 (s, 1H), 6.91 (s, 1H),6.87 (d, J = 11.4 Hz, 1H), 4.96 (d, J = 12.2 Hz, 4H), 4.53 (dr, 1H), 3.05 (dr, 2H), 2.79 (dr, 2H), 2.01-1.97 (m, 2H), 1.62-1.60 (m, 2H).Example 4: 5-[6-[(1-acetylpiperidin-4-yl)oxy]-4-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0399]

[0400] A solution of 5-[4-fluoro-6-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one; formic acid (110 mg, 0.28 mmol, 1.00 equiv), TEA (90 mg, 0.89 mmol, 3.00 equiv) and Ac 2 O (150 mg, 1.47 mmol, 5.00 equiv) in DCM (20 mL) was stirred for 4 h at room temperature, and then the resulting solution was concentrated under vacuum, and then the residue was purified by Prep-HPLC yielding the title compound (18.3 mg, 15 %) as a white solid. LCMS (ESI, m / z): 441.05 [M+H] +< . 1< HNMR (DMSO-d 6 , 300MHz): δ 12.56 (s, 1H), 8.03 (s, 1H), 6.92 (d, J = 2.0 Hz, 1H), 6.86 (dd, J = 11.2, 2.0 Hz, 1H), 4.96 (d, J = 12.2 Hz, 4H), 4.63 (dt, J = 8.1, 4.3 Hz, 1H), 3.88-3.84 (m, 1H), 3.69-3.64 (m, 1H), 3.32-3.30 (m, 1H), 3.22-3.14 (m, 1H), 2.01 (s, 3H), 1.94-1.88 (m, 2H), 1.67-1.56 (m, 1H), 1.53-1.39 (m, 1H).Example 5: 5-[6-[(1-acetylpiperidin-4-yl)oxy]-5-fluoro-1-methyl-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0401] Step 1: synthesis of 4-bromo-2-(bromomethyl)-5-fluorobenzoate

[0402] A solution of methyl 4-bromo-5-fluoro-2-methylbenzoate (9.5 g, 38.45 mmol, 1.00 equiv), AIBN (3.15 g, 19.18 mmol, 0.50 equiv), NBS (10.31 g, 57.93 mmol, 1.50 equiv) in CCl 4 (100 mL) was stirred for 1 overnight at 80 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1 / 50) to afford 12.5 g of the title compound as yellow crude oil. LCMS (ESI, m / z): 324.88 [M+H] +< .Step 2: Synthesis of 5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-1-one

[0403] A solution of methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate (12.5 g, 38.35 mmol,1.00 equiv) in NH 3 / MeOH(150mL, 7M) was stirred for 3 h at 40 °C. The solids were collected by filtration after the resulting solution was cooled to room temperature. This resulted in 7.1 g (80 %) of the title compound as a white solid. LCMS (ESI, m / z): 229.95 [M+H] +< .Step 3: Synthesis of tert-butyl 5-bromo-6-fluoro-1-oxo-2, 3-dihydro-1H-isoindole-2-carboxylate

[0404] A solution 5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-1-one (7.1 g, 30.87 mmol, 1.00 equiv), 4-dimethylaminopyridine (759 mg, 6.21 mmol, 0.20 equiv), (Boc) 2 O (8 g, 36.66 mmol, 1.20 equiv) in THF (100 mL) was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 2x100 mL of EtOAc and the organic layers combined and concentrated under vacuum. This resulted in 9.8 g (96 %) of the title compound as a white solid. LCMS (ESI, m / z): 330.01 [M+H] +< .Step 4: Synthesis of tert-butyl 5-bromo-6-fluoro-3-methyl-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate

[0405] A solution of tert-butyl 5-bromo-6-fluoro-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate (500 mg, 1.51 mmol, 1.00 equiv) in THF (5 mL) was stirred at -70 °C . This was followed by the addition of NaHMDS in THF (1.8 mL, 1.20 equiv, 1M) with stirring at -70 °C. The resulting solution was stirred for 30 min at -70 °C. To this was added iodomethane (213.7 mg, 1.51 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x10 mL of EtOAc and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1 / 15) to afford 210 mg (40 %) of the title compound as a brown solid. LCMS (ESI, m / z): 344.02 [M+H] +< .Step 5: Synthesis of tert-butyl 6-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-isoindole-2-carboxylate

[0406] A solution of tert-butyl 5-bromo-6-fluoro-3-methyl-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate (210 mg, 0.61 mmol, 1.00 equiv), NaBH 4 (220 mg, 5.97 mmol, 10.00 equiv), BH 3 .Et 2 O (0.86 mL, 12.00 equiv) in THF (5 mL) was stirred for 3 h at 70 °C . The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x10 mL of EtOAc and the organic layers combined. The resulting mixture was washed with 2x10 mL of brine. The resulting mixture was concentrated under vacuum. This resulted in 180 mg (89 %) of the title compound as yellow oil. LCMS (ESI, m / z): 330.04 [M+H] +< .Step 6: Synthesis of 6-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-isoindole hydrochloride

[0407] A solution of tert-butyl 6-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-isoindole-2-carboxylate (180 mg, 0.55 mmol, 1.00 equiv) in HCl / dioxane(5 mL, 4M) was stirred for 2 h at room temperature. The solids were collected by filtration to afford 130 mg (89 %) of the title compound as yellow crude oil. LCMS (ESI, m / z): 229.99 [M+H] +< .Step 7: Synthesis of 5-(6-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0408] A solution of 5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (161 mg, 0.49 mmol, 1.00 equiv), TEA (100 mg, 0.99 mmol, 2.00 equiv), 6-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-isoindole hydrochloride (130 mg, 0.49 mmol, 1.00 equiv) in ethanol (5 mL) was stirred for 3h at 40 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1 / 6) to afford 114 mg (45 %) of the title compound as yellow oil. LCMS (ESI, m / z): 522.08 [M+H] +< .Step 8: Synthesis of 5-(5-fluoro-6-hydroxy-1-methyl-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0409] A solution of 5-(6-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1.5 g, 2.87 mmol, 1.00 equiv), BHMPO (472 mg, 1.43 mmol, 0.50 equiv), Cu(acac) 2 (376 mg, 1.44 mmol, 0.50 equiv), LiOH·H 2 O (241 mg, 5.74 mmol, 2.00 equiv) in DMSO (20 mL) and water(5 mL) was stirred for 2 hr at 80°C. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x20 mL of EtOAc and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column eiuting with EtOAc / petroleum ether (1 / 3) to afford 136 mg (10 %) of the title compound as a brown solid. LCMS (ESI, m / z): 460.19 [M+H] +< .Step 9: Synthesis of tert-butyl 4-([6-fluoro-3-methyl-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy[methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate

[0410] A solution of 5-(5-fluoro-6-hydroxy-1-methyl-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (136 mg, 0.30 mmol, 1.00 equiv), potassium carbonate (81.6 mg, 0.59 mmol, 2.00 equiv), tert-butyl 4-iodopiperidine-1-carboxylate (276 mg, 0.89 mmol, 3.00 equiv) in DMF (10 mL) was stirred for 3 days at 80 °C. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x10 mL of EtOAc and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1 / 4) to afford 190 mg of the title compound as yellow crude oil. LCMS (ESI, m / z): 643.29 [M+H] +< .Step 10: Synthesis of 5-[5-fluoro-1-methyl-6-(piperidin-4-yloxy)-2, 3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0411] A solution of tert-butyl 4-([6-fluoro-3-methyl-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)piperidine-1-carboxylate (180 mg, 0.28 mmol, 1 equiv) in HCl / dioxane (5 mL) was stirred for 12 hr at room temperature. The resulting mixture was concentrated under vacuum to afford 200 mg (crude) of the title compound as yellow oil.Step 11: Synthesis of 5-[6-[(1-acetylpiperidin-4-yl)oxy]-5-fluoro-1-methyl-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0412] A solution of 5-[5-fluoro-1-methyl-6-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (120 mg, 0.29 mmol, 1 equiv), acetic anydride (30 mg, 0.29 mmol, 1.010 equiv), TEA (131 mg, 1.29 mmol, 4.449 equiv) in DCM (5 mL) was stirred for 2 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (9.9 mg, 7.5 %) as a white solid. LCMS (ESI, m / z): 455.42 [M+H] +< , 1< HNMR (DMSO-d 6 , 300 MHz) δ: 12.60 (s, 1H), 8.12 (s, 1H), 7.30 (s, 1H), 7.27(s, 1H), 5.64 (d, J = 6.9 Hz, 1H), 5.05 (d, J = 14.8 Hz, 1H),4.80 - 4.65 (br, 1H), 4.50 (d, J = 14.8 Hz, 1H), 3.90 - 4.75 (m, 1H), 3.73 - 3.56 (m, 1H), 3.40-3.20 (m, 2H), 2.03 (s, 3H), 1.95 - 1.80 (m, 2H), 1.72- 1.80 (m, 2H), 1.49 - 1.43 (m,3H).Example 6: 5-[2-[(1-methylpiperidin-4-yl)oxy]-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0413] Step 1: Synthesis of 5-[2-chloro-5H, 6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0414] A solution of 2-chloro-SH,6H,7H-pyrrolo[3,4-b]pyridin-6-yl hydrochloride (5 g, 26.31 mmol, 1.00 equiv), TEA (8 g, 79.06 mmol, 3.00 equiv), 5-chloro-4-(trifluoromethyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydropyridazin-3-one (14.3 g, 43.49 mmol, 1.00 equiv) in EtOH (30 mL) was stirred for 2 h at 80 °C. The solvent was concentrated under vacuum and the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1 / 4) to afford 9.3 g (79 %) of the title compound as yellow oil. LCMS (ESI, m / z): 447.12 [M+H] +< .Step 2: Synthesis of 5-[2-hydroxy-5H, 6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0415] A solution of 5-[2-chloro-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1.2 g, 2.69 mmol, 1.00 equiv), t-BuBrettphos (196 mg, 0.15 equiv), K 3 PO 4 (1.711 g, 8.06 mmol, 3.00 equiv), Pd(OAc) 2 (61 mg, 0.27 mmol, 0.10 equiv) in dioxane (15 mL) and water (5 mL) under nitrogen atmosphere was stirred for 2 h at 100 °C. The solvent was concentrated under vacuum and the residue was applied onto a silica gel column eluting with DCM / methanol (9 / 1) to afford 700 mg (61 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 429.15 [M+H] +< .Step 3: Synthesis of tert-butyl 4-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy[methyl]-1,6-dihydropyridazin-4-yl]-5H, 6H, 7H-pyrrolo[3, 4-b]pyridin-2-yl]oxy)piperidine-1-carboxylate

[0416] A solution of 5-[2-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (500 mg, 1.17 mmol, 1.00 equiv), Ag 2 CO 3 (640 mg, 2.00 equiv), tert-butyl 4-iodopiperidine-1-carboxylate (1 g, 3.21 mmol, 3.00 equiv) in DMF (15 mL) was stirred for 4 h at 80 °C. The resulting solution was diluted with 15 mL of water and extracted with 3x15 mL of EtOAc, the organic layers combined. The resulting solution was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1 / 4) to afford 500 mg (73 %) of the title compound as yellow oil. LCMS (ESI, m / z): 612.28 [M+H] +< .Step 4: Synthesis of 5-[2-(piperidin-4-yloxy)-5H,6H, 7H-pyrrolo[3, 4-b]pyridin-6-yl]-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0417] A solution of tert-butyl 4-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-2-yl]oxy)piperidine-1-carboxylate (500 mg, 0.82 mmol, 1.00 equiv) in HCl / dioxane (20 mL,4M) was stirred overnight at 25°C. The resulting solution was concentrated under vacuum to afford 200 mg (64 %) of the title compound as yellow crude oil. LCMS (ESI, m / z): 382.14 [M+H] +< .Step 5: Synthesis of 5-[2-[(1-methylpiperidin-4-yl)oxy]-5H, 6H, 7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0418] A solution of 5-(2-(piperidin-4-yloxy)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (200 mg, 0.52 mmol, 1.00 equiv), (HCHO) n (45 mg, 3.00 equiv), acetic acid (60 mg, 1.00 mmol, 2.00 equiv), NaBH 3 CN (95 mg, 1.51 mmol, 3.00 equiv) in MeOH (5 mL) was stirred for overnight at 25 °C. After concentration, the residue was purified by Prep-HPLC yielding the title compound (27.8 mg, 13 %) as a white solid. LCMS (ESI, m / z): 396.16 [M+H] +< , 1< H NMR (300 MHz, Methanol-d 4 ) δ: 8.08 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 5.12 (dq, J = 8.1, 4.1 Hz, 1H), 5.02 (s, 2H), 4.92 (s, 2H), 2.78 (m, 2H), 2.35 (m, 5H), 2.09 (dd, J = 11.9, 7.5 Hz, 2H), 1.86 (qd, J = 11.8, 10.1, 3.5 Hz, 2H).Example 7: 5-[3-(piperidin-4-yloxy)-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0419] Step 1: Synthesis of 5-[3-bromo-5H, 6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0420] A solution of 3-bromo-5H,6H,7H-pyrrolo[3,4-b]pyridine hydrochloride (1 g, 4.25 mmol, 1.00 equiv) in ethanol (5 mL), 5-chloro-4-(trifluoromethyl)-2-[2-(trimethylsilyl)ethoxy]methyl-2,3-dihydropyridazin-3-one (1.6 g, 4.87 mmol, 1.15 equiv) and TEA (1.2 mL) was stirred for 1 h at 80 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with EtOAc / petroleum ether (1:2). This resulted in 1.5 g (72 %) of the title compound as a solid. LCMS (ESI, m / z): 491.07 [M+H] +< .Step 2: Synthesis of 5-[3-hydroxy-5H, 6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0421] A solution of 5-[3-bromo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1 g, 2.04 mmol, 1.00 equiv), Pd(OAc) 2 (92 mg, 0.41 mmol, 0.20 equiv), t-BuBrettphos (200 mg), K 3 PO 4 (1.3 g, 6.12 mmol, 3.01 equiv) in dioxane / H 2 O (12.5 mL) was stirred for 4 h at 80 °C under an inert atmosphere of nitrogen. The resulting solution was extracted with 250 mL of EtOAc. The resulting mixture was washed with 2x50 mL of water and 1x50 mL of Brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM / methanol (9:1). This resulted in 680 mg (78 %) of the title compound as a solid. LCMS (ESI, m / z): 429.16 [M+H] +< .Step 3: Synthesis of tert-butyl 4-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy[methyl]-1,6-dihydropyridazin-4-yl]-5H, 6H, 7H-pyrrolo[3, 4-b]pyridin-3-yl]oxy)piperidine-1-carboxylate as oil.

[0422] A solution of 5-[3-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethyl-silyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (190 mg, 0.44 mmol, 1.00 equiv), Ag 2 CO 3 (370 mg) and tert-butyl 4-iodopiperidine-1-carboxylate (450 mg, 1.45 mmol, 3.26 equiv) in DMF (5 mL) was stirred for 2 h at 80 °C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with DCM / methanol (95:5). This resulted in 60 mg (22 %) of the title compound as oil. LCMS (ESI, m / z): 612.28 [M+H] +< .Step 4: Synthesis of 5-[3-(piperidin-4-yloxy)-5H, 6H, 7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0423] To a stirred solution of tert-butyl 4-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-3-yl]oxy)piperidine-1-carboxylate (60 mg, 0.10 mmol, 1.00 equiv) in DCM (5 mL), trifluoroacetic acid (2 mL) was added. The resulting solution was stirred for 1 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (13.1 mg, 35 %) as an off-white solid. LCMS (ESI, m / z): 382.15 [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (d, J = 2.7 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J = 2.6 Hz, 1H), 4.93 (s, 2H), 4.86 (s, 2H), 4.49 (tt, J = 8.6, 3.9 Hz, 1H), 3.05 - 2.95 (m, 2H), 2.71 - 2.60 (m, 2H), 2.00 - 1.90 (m, 2H), 1.58 - 1.44 (m, 2H).Example 8: 5-[3-[(1-acetylpiperidin-4-yl)oxy]-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoro-methyl)-2,3-dihydropyridazin-3-one

[0424]

[0425] To a stirred solution of 5-[3-(piperidin-4-yloxy)-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (150 mg, 0.39 mmol, 1.00 equiv) in pyridine (5 mL), Ac 2 O (0.5 mL) was added. The resulting solution was stirred for 2 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yieldng the title compound (50.4 mg, 30 %) as a white solid. LCMS (ESI, m / z): 424.05 [M+H] +< . 1< H NMR (300 MHz, Methanol-d 4 ) δ 8.22 (d, J = 2.6 Hz, 1H), 8.08 (s, 1H), 7.53 (d, J = 2.6 Hz, 1H), 5.09 (s, 2H), 4.97 (s, 2H), 4.78 - 4.67 (m, 1H), 3.94 - 3.73 (m, 2H), 3.61 - 3.44 (m, 2H), 2.14 (s, 3H), 2.11 - 1.93 (m, 2H), 1.88 - 1.67 (m, 2H).Example 9: 5-[4-(piperidin-4-yloxy)-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0426] Step 1: Synthesis of 5-[4-bromo-5H, 6H, 7H-pyrrolo[3, 4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0427] A solution of 5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (2.3 g, 7.00 mmol, 1.00 equiv), 4-bromo-5H,6H,7H-pyrrolo[3,4-b]pyridine hydrobromide (1.95 g, 6.97 mmol, 1.00 equiv), TEA (3.6 g, 35.58 mmol, 5.00 equiv) in EtOH (30 mL) was stirred for 2 h at 80 °C. The solvent was concentrated under vacuum and the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1 / 4) to afford 1.1 g (32 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 491.06 [M+H] +< .Step 2: Synthesis of 5-[4-hydroxy-5H, 6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0428] A solution of 5-[4-bromo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (400 mg, 0.81 mmol, 1.00 equiv), Pd(OAc) 2 (19 mg, 0.08 mmol, 0.10 equiv), K 3 PO 4 (520 mg, 2.45 mmol, 3.00 equiv), t-BuBrettphos (60 mg, 0.15 equiv) in dioxane (10 mL) and water (3 mL) under nitrogen atmosphere was stirred for 2 h at 100 °C. The solvent was concentrated under vacuum and the residue was applied onto a silica gel column eluting with DCM / methanol (19 / 1) to afford 215 mg (62 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 429.15 [M+H] +< .Step 3: Synthesis of tert-butyl 4-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy[methyl]-1,6-dihydropyridazin-4-yl]-5H, 6H, 7H-pyrrolo[3, 4-b]pyridin-4-yl]oxy)piperidine-1-carboxylate

[0429] A solution of 5-[4-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (250 mg, 0.58 mmol, 1.00 equiv), Ag 2 CO 3 (322 mg, 2.00 equiv), tert-butyl 4-iodopiperidine-1-carboxylate (545 mg, 1.75 mmol, 3.00 equiv) in DMF (15 mL) was stirred for 4 h at 80 °C. The resulting solution was diluted with 15 mL of water and extracted with 3x15 mL of EtOAc, the organic layers combined. The resulting solution was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with DCM / methanol (19 / 1) to afford 240 mg (67%) of the title compound as a yellow solid. LCMS (ESI, m / z): 612.28 [M+H] +< .Step 4: Synthesis of 5-[4-(piperidin-4-yloxy)-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0430] A solution of tert-butyl 4-([6-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-4-yl]oxy)piperidine-1-carboxylate (240 mg, 0.39 mmol, 1.00 equiv) in dioxane / HCl (15 mL,4 M) was stirred for 1 overnight at 25°C. After concentration, the residue was purified by Prep-HPLC yielding the title compound (31.5 mg, 21 %) as a white solid. LCMS (ESI, m / z): 382.14 [M+H] +< , 1< H NMR (400 MHz, Methanol-d 4 ) δ: 8.36 (d, J = 6.0 Hz, 1H), 8.11 (s, 1H), 7.07 (d, J = 6.1 Hz, 1H), 5.03 (d, J = 11.7 Hz, 4H), 4.78 (dq, J = 8.3, 4.1 Hz, 1H), 3.11 (dt, J = 12.9, 4.6 Hz, 2H), 2.79 (ddd, J = 12.7, 9.2, 3.2 Hz, 2H), 2.39 - 1.85 (m, 2H), 1.75 (dtd, J = 13.0, 8.9, 3.8 Hz, 2H).Example 10: 5-[4-[2-(morpholin-4-yl)ethoxy]-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0431] Step 1: Synthesis of 5-[4-[2-(morpholin-4-yl)ethoxy]-5H,6H, 7H-pyrrolo[3, 4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxyjmethyl]-2,3-dihydropyridazin-3-one

[0432] A solution of 5-[4-hydroxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (200 mg, 0.47 mmol, 1.00 equiv), Ag 2 CO 3 (387 mg, 3.00 equiv), NaI (140 mg, 2.00 equiv), 4-(2-chloroethyl)morpholine (280 mg, 1.87 mmol, 4.00 equiv) in DMF (15 mL) was stirred for 2 h at 80 °C. The resulting solution was diluted with 15 mL of water and extracted with 3x15 mL of EtOAc, the organic layers combined. The resulting solution was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with DCM / methanol (9 / 1) to afford 200 mg (79 %) of the title compound as yellow oil. LCMS (ESI, m / z): 542.23 [M+H] +< .Step 2: Synthesis of 5-[4-[2-(morpholin-4-yl)ethoxy]-5H,6H, 7H-pyrrolo[3, 4-b]pyridin-6-yl]-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0433] A solution of 5-[4-[2-(morpholin-4-yl)ethoxy]-SH,6H,7H-pyrrolo[3,4-b]pyridin-6-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (80 mg, 0.15 mmol, 1.00 equiv) in dioxane / HCl (15 mL,4 M) was stirred for overnight at 25 °C. After concentration, the residue was purified by Prep-HPLC yielding the title compound (22.6 mg, 37 %) as a white solid. LCMS (ESI, m / z): 412.15 [M+H]+, 1< H NMR (300 MHz, Methanol-d4) ð: 8.40 (d, J = 5.9 Hz, 1H), 8.11 (s, 1H), 7.06 (d, J = 6.0 Hz, 1H), 5.04 (d, J = 11.1 Hz, 4H), 4.38 (t, J = 5.5 Hz, 2H), 3.91 - 3.56 (m, 4H), 2.89 (t, J = 5.4 Hz, 2H), 2.77 - 2.51 (m, 4H).Example 11: 5-[6-methoxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0434] Step 1: Synthesis of 5-[6-chloro-1H, 2H, 3H-pyrrolo[3, 4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0435] A solution of 5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (6 g, 18.25 mmol, 1.00 equiv), TEA (5.5 g, 54.35 mmol, 3.00 equiv), 6-chloro-1H,2H,3H-pyrrolo[3,4-c]pyridine hydrochloride (3.5 g, 18.32 mmol, 1.00 equiv) in ethanol (70mL) was stirred for 3 h at 80 °C. The reaction mixture was concentrated under vacuum and the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (4 / 6) to afford 4.9 g (60 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 447.12 [M+H] +< .Step 2: Synthesis of 5-[6-methoxy-IH, 2H, 3H-pyrrolo[3, 4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0436] A solution of 5-[6-chloro-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (500 mg, 1.12 mmol, 1.00 equiv), [Pd(ally)Cl] 2 (41 mg, 0.11 mmol, 0.10 equiv), Rockphos (53 mg, 0.11 mmol, 0.10 equiv), Cs 2 CO 3 (730 mg, 2.24 mmol, 2.00 equiv), methanol (76 mg, 2.37 mmol, 2.12 equiv) in toluene (10 mL) was stirred for 3 h under an atmosphere of nitrogen at 80 °C . The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (3 / 7) to afford 336 mg (68 %) of the title compound as yellow oil. LCMS (ESI, m / z): 443.16 [M+H] +< .Step 3: Synthesis of 5-[6-methoxy-IH, 2H, 3H-pyrrolo[3, 4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0437] A solution of 5-[6-methoxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (336 mg, 0.76 mmol, 1.00 equiv) in hydrogen chloride / dioxane (10 mL) was stirred for 12 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (44.3 mg ,19 %) as a white solid. LCMS (ESI, m / z): 313.25 [M+H] +< , 1< H NMR (400 MHz, DMSO-d 6 ) δ: 12.56 (s, 1H), 8.19 (d, J = 1.1 Hz, 1H), 8.00 (s, 1H), 6.88 - 6.83 (m, 1H), 4.98-4.93 (m, 4H), 3.86 (s, 3H).Example 12: 5-[6-(piperidin-4-yloxy)-1H,2H,3H-pyrrolo[3,4-c]|pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one.

[0438] Step 1: Synthesis of 5-[6-hydroxy-1H, 2H, 3H-pyrrolo[3, 4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0439] A solution of 5-[6-chloro-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (2.5 g, 5.59 mmol, 1.00 equiv), Pd(OAc) 2 (125 mg, 0.56 mmol, 0.10 equiv), t-Bubrettphos (407 mg, 0.84 mmol, 0.15 equiv), K 3 PO 4 (2.4 g, 11.31 mmol, 2.00 equiv) in dioxane (40 mL) and water (4 mL) was stirred for 3 h at 100 °C. The reaction mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with DCM / methanol (9 / 1) to afford 890 mg (37 %) of the title compound as a brown solid. LCMS (ESI, m / z): 429.15 [M+H].Step 2: Synthesis of tert-butyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy[methyl]-1,6-dihydropyridazin-4-yl]-1H,2H, 3H-pyrrolo[3, 4-c]pyridin-6-yl]oxy)piperidine-1-carboxylate

[0440] A solution of 5-[6-hydroxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (870 mg, 2.03 mmol, 1.00 equiv), Ag 2 CO 3 (1.13 g, 2.00 equiv), tert-butyl 4-iodopiperidine-1-carboxylate (1.27 g, 4.08 mmol, 2.00 equiv) in DMF (25mL) was stirred for 10h at 80 °C. The resulting solution was diluted with 20 mL of water and extracted with 3x100 ml of EtOAc .The organic layers combined, washed with 3x100mL of brine, dried over Na 2 SO 4 . The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (3 / 7) to afford 1.21 g (97 %) of the title compound as yellow oil. LCMS (ESI, m / z): 612.28 [M+H].Step 3: Synthesis of of 5-[6-(piperidin-4-yloxy)-1H,2H, 3H-pyrrolo[3, 4-c]pyridin-2-yl]-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0441] A solution of 5 tert-butyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-6-yl]oxy)piperidine-1-carboxylate (1.21 g, 1.98 mmol, 1.00 equiv) in hydrogen chloride / dioxane (20 mL) was stirred for 2.5 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (17.3 mg, 2 %) as a white solid. LCMS (ESI, m / z): 382.35 [M+H] +< , 1< H NMR (400 MHz, Methanol-d4) δ: 8.17 - 8.11 (m, 1H), 8.07 (s, 1H), 6.81 (d, J = 1.1 Hz, 1H), 5.14 (dt, J = 8.6, 4.5 Hz, 1H), 5.02 (m, 4H), 3.16 - 3.07 (m, 2H), 2.79 (ddd, J = 12.7, 9.4, 3.2 Hz, 2H), 2.13 - 2.01 (m, 2H), 1.72 (dtd, J = 13.0, 9.0, 3.8 Hz, 2H).Example 13: 5-[6-(piperidin-4-yloxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0442]

[0443] A solution of 5-[6-(piperidin-4-yloxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (290 mg, 0.76 mmol, 1.00 equiv), TEA (154 mg, 1.52 mmol, 2.00 equiv), Ac 2 O (93 mg, 0.91 mmol, 1.20 equiv) in DCM (10mL) was stirred for 2 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (100.1 mg, 31 %) as white solid. LCMS (ESI, m / z): 424.39[M+H] +< , 1< H NMR (300 MHz, Methanol-d 4 ) δ: 8.18 - 8.11 (m, 1H), 8.06 (s, 1H), 6.82 (d, J = 1.0 Hz, 1H), 5.28 (dq, J = 7.5, 3.7 Hz, 1H), 4.89 (m, 4H), 3.98 - 3.83 (m, 1H), 3.79 (ddd, J = 11.5, 7.3, 3.8 Hz, 1H), 3.48 (dd, J = 15.3, 6.4 Hz, 2H), 2.13 (s, 3H), 2.11 - 1.94 (m, 2H), 1.89 - 1.65 (m, 2H).Example 14: 5-[5-[2-(dimethylamino)ethoxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one; formic acid

[0444] Step 1: Synthesis of 5-(5-fluoro-6-hydroxyisoindolin-2-yl)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one.

[0445] A solution of 5-(5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (508 mg, 1.00 mmol, 1.00 equiv), Cu(acac) 2 (27 mg, 0.10 equiv), BHMPO (35 mg, 0.10 equiv), LiOH.H 2 O (89 mg, 3.72 mmol, 2.10 equiv), water(1 mL) in DMSO (4 mL) was stirred for 3 h at 80°C. The solution was quenched with 20 ml water , then extracted with EtOAc (3 x 30 mL) and the organic layers combined. After concentrated under vacuum the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (7:3) to afford 180 mg (40 %) of the title compound as brown oil. LCMS (ESI, m / z):446.15 [M+H] +< .Step 2: Synthesis of 5-[-5-[2-(dimethylamino)ethoxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxylmethyl]-2,3-dihydropyridazin-3-one

[0446] A solution of 5-(5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (254 mg, 0.50 mmol, 1.00 equiv), 2-(dimethylamino)ethan-1-ol (222.5 mg, 2.50 mmol, 5.00 equiv), [Pd(allyl)Cl] 2 (18.3 mg, 0.05 mmol, 0.10 equiv), Rockphos (23.4 mg, 0.05 mmol, 0.10 equiv), Cs 2 CO 3 (326 mg, 1.00 mmol, 2.00 equiv) in Toluene (20 mL) was stirred for 3 h at 80°C. The resulting mixture was concentrated, the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (5 / 95) to afford 97 mg (38 %) of the title compound as a brown oil. LCMS (ESI, m / z): 517.00 [M+H] +< .Step 3: Synthesis of 5-[5-[2-(dimethylamino)ethoxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one; formic acid

[0447] A solution of 5-[5-[2-(dimethylamino)ethoxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (88 mg, 0.17 mmol, 1.00 equiv) in HCl / dioxane (15 mL) was stirred for 2 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (19.5 mg, 26 %) as a white solid. LCMS (ESI, m / z): 387.10 [M+H] +< , 1< HNMR (300 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.05 (s, 1H), 7.24 - 7.21 (m, 2H), 5.04 - 5.01 (m, 4H), 4.39 (t, J = 5.1 Hz, 2H), 3.52 - 3.40 (m, 2H), 2.87 (s, 6H).Example 15: 5-[4-(pyridin-3-ylmethoxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0448] Step 1: Synthesis of 2-bromo-3, 4-bis(bromomethyl)pyridine

[0449] A solution of 2-bromo-3,4-dimethylpyridine (5 g, 26.87 mmol, 1.00 equiv), NBS (10 g, 56.19 mmol, 2.00 equiv) and AIBN (2.22 g, 13.52 mmol, 0.50 equiv) in CCl 4 (40 mL) was stirred for 2 h at 80°C, and then the resulting solution was concentrated under vacuum, and then the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (2:98) to afford 5.7 g (62%) of the title compound as red oil. LCMS (ESI, m / z): 341.81 [M+H]+.Step 2: Synthesis of 4-bromo-2-[(4-methylbenzene)sulfonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine

[0450] A solution of 2-bromo-3,4-bis(bromomethyl)pyridine (2.7 g, 7.85 mmol, 1.00 equiv) and sodium hydride (380 mg, 15.83 mmol, 1.20 equiv) in DMF (20 mL), TosNH2 (1.485 g, 1.10 equiv) was added in, and then the resulting solution was stirred for 0.5 h at 0 °C, and stirred for another 1 h at 25 °C, and then the resulting solution was quenched by the addition of 50 mL of water, extracted with 3x15 mL of EtOAc and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (3:7) to afford 2 g (72 %) of the title compound as a light yellow solid. LCMS (ESI, m / z): 353.23 [M+H] +< .Step 3: Synthesis of 4-bromo-1H,2H,3H-pyrrolo[3,4-c]pyridine hydrobromide

[0451] A solution of 4-bromo-2-[(4-methylbenzene)sulfonyl]-1H,2H,3H-pyrrolo[3,4-c]pyridine (2 g, 5.66 mmol, 1.00 equiv) and Phenol (3.2 g, 6.00 equiv) in 48% HBr / HOAc (5 mL) and acetic acid (10 mL) was stirred for 1 overnight at 90 °C, and then the resulting solution was concentrated under vacuum, and the crude product purified by re-crystallization from EtOAc to afford 1.4 g (88 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 199.05 [M+H] +< .Step 4: Synthesis of (5-[4-bromo-1H,2H, 3H-pyrrolo[3, 4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0452] A solution of 4-bromo-1H,2H,3H-pyrrolo[3,4-c]pyridine hydrobromide (1.4 g, 5.00 mmol, 1.00 equiv), 5-chloro-4-(trifluoromethyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydropyridazin-3-one (2.55 g, 7.76 mmol, 1.10 equiv) and TEA (2.15 g, 21.25 mmol, 3.00 equiv) in ethanol (15 mL) was stirred for 2h at 60°C, and then the resulting solution was concentrated under vacuum, and then the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (4:6) to afford 400 mg (16 %) of the title compound as a dark green solid. LCMS (ESI, m / z): 491.38 [M+H] +< .Step 5: Synthesis of 5-[4-(pyridin-3-ylmethoxy)-1H,2H, 3H-pyrrolo[3, 4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0453] A solution of 5-[4-bromo-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (150 mg, 0.31 mmol, 1.00 equiv), (Pd(allyl)Cl) 2 (14 mg, 0.10 equiv), Rockphos (11 mg, 0.10 equiv), pyridin-3-ylmethanol (134 mg, 1.23 mmol, 4.00 equiv) and Cs 2 CO 3 (200 mg, 0.61 mmol, 2.00 equiv) in toluene (5 mL) was stirred for 2 h at 80 °C under an atmosphere of nirtrogen, and then the resulting solution was concentrated under vacuum, and then the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (6:4) to affrod 80 mg (50 %) of the title compound as yellow oil. LCMS (ESI, m / z): 520.19 [M+H] +< .Step 6: Synthesis of 5-[4-(pyridin-3-ylmethoxy)-1H, 2H, 3H-pyrrolo[3, 4-c]pyridin-2-yl]-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0454] A solution of 5-[4-(pyridin-3-ylmethoxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (200 mg, 0.38 mmol, 1.00 equiv), in HCl / dioxane (5 mL, 4M) was stirred overnight at room temperature, and then the resulting solution was concentrated under vacuum, and then the residue was purified by Prep-HPLC yielding the title compound (2.7 mg, 2.0 %) as a white solid. LCMS (ESI, m / z): 390.15 [M+H]+, 1< HNMR (DMSO-d 6 , 400MHz) δ 8.71 (d, J= 1.6Hz, 1H), 8.54 (dd, J = 4.8, 1.6Hz, 1H), 8.16 (d, J = 5.6Hz, 1H), 8.07 (s, 1H), 7.90 (d, J = 8.0Hz, 1H), 7.43 (dd, J = 8.4, 4.8Hz, 1H), 7.13 (d, J = 5.2Hz, 1H), 5.51 (s, 2H), 4.97 (d, J = 11.6Hz, 4H).Example 16: 5-[4-(piperidin-4-yloxy)-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0455] Step 1: Synthesis of 5-[4-bromo-1H,2H, 3H-pyrrolo[3, 4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0456] A solution of (4-bromo-1H,2H,3H-pyrrolo[3,4-c]pyridine hydrobromide (700 mg, 2.50 mmol, 1.00 equiv), TEA (1.07 g, 10.57 mmol, 3.00 equiv), 5-chloro-4-(trifluoromethyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydropyridazin-3-one (1.25 g, 3.80 mmol, 1.10 equiv) in ethanol (20 mL, 1.00 equiv) was stirred for 2 h at 60°C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (4 / 6) to afford 300 mg (24 %) of the title compound as a dark green solid. LCMS (ESI, m / z): 493.06[M+H] +< .Step 2: Synthesis of 5-[4-hydroxy-1H, 2H, 3H-pyrrolo[3, 4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0457] A solution of 5-[4-bromo-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (440 mg, 0.90 mmol, 1.00 equiv), t-BuBrettphos (65 mg, 0.15 equiv), K 3 PO 4 (571 mg, 2.69 mmol, 3.00 equiv), Pd(OAc) 2 (20 mg, 0.09 mmol, 0.10 equiv) in dioxane (5 mL) and water (1 mL) was stirred for 1 h at 100 °C. The reaction mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with ethyl DCM / methanol (95 / 5) to afford 125 mg (33 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 429.15 [M+H].Step 3: Synthesis of tert-butyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy[methyl]-1,6-dihydropyridazin-4-yl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-4-yl]oxy)piperidine-1-carboxylate

[0458] A solution of 5-[4-hydroxy-1H,2H,3H-pyrrolo[3,4-c]pyridin-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (115 mg, 0.27 mmol, 1.00 equiv), Ag 2 CO 3 (149 mg, 0.54 mmol, 20.00 equiv), tert-butyl 4-iodopiperidine-1-carboxylate (168 mg, 0.54 mmol, 2.00 equiv) in DMF (10 mL) was stirred for 48 h at 80 °C. The resulting solution was diluted with 20mL of water and extracted with 3x20 ml of EtOAc .The organic layers combined, washed with 3x40 mL of brine, dried over Na 2 SO 4 . The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1 / 1) to afford 146 mg (89 %) of the title compound as yellow oil. LCMS (ESI, m / z): 612.28 [M+H].Step 4: Synthesis of 5-[4-(piperidin-4-yloxy)-1H,2H, 3H-pyrrolo[3, 4-c]pyridin-2-yl]-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0459] A solution of 5 tert-butyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-1H,2H,3H-pyrrolo[3,4-c]pyridin-4-yl]oxy)piperidine-1-carboxylate (146 mg, 0.24 mmol, 1.00 equiv) in methanol (2 mL) and hydrogen chloride / Et2O (10 mL) was stirred for 4 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (6 mg, 7 %) as a brown solid. LCMS (ESI, m / z): 382.35 [M+H] +< , 1< H NMR (400 MHz, DMSO-d 6 ) δ: 12.56(s,1H), 8.14 - 8.03 (m, 2H), 7.04 (d, J = 5.3 Hz, 1H), 5.18 (dt, J = 9.0, 4.8 Hz, 1H), 4.97-4.94 (m, 2H), 4.88 - 4.83 (m, 2H), 2.97 (dd, J = 11.0, 6.4 Hz, 2H), 2.62 (t, J = 10.0 Hz, 2H), 1.94 (dd, J = 12.5, 8.1 Hz, 2H), 1.60 - 1.47 (m, 2H).Example 17: 5-(5-[[(pyridin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0460] Step 1: Synthesis of 5-(5-bromo-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0461] A solution of 5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (3.29 g, 10.01 mmol, 1.00 equiv), 5-bromo-2,3-dihydro-1H-isoindole hydrochloride (2.35 g, 10.02 mmol, 1.00 equiv), TEA (2.02 g, 19.96 mmol, 2.00 equiv) in ethanol (50 mL) was stirred for 3 hours at 40 °C . The solvent was concentrated under vacuum and the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1 / 5) to afford 3.65 g (74 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 490.07 [M+H] +< .Step 2: Synthesis of 2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindole-5-carbonitrile

[0462] A solution of 5-(5-bromo-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1.3 g, 2.65 mmol, 1 equiv), Pd(PPh 3 ) 4 (0.6 g, 0.52 mmol, 0.196 equiv), Zn(CN) 2 (0.62 g, 5.28 mmol, 1.991 equiv) in NMP (15 mL) was stirred for 2 hours at 120 degrees C in an oil bath. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3x30 ml of EtOAc dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (25 / 75) to afford 1.8 g crude of the title compound as yellow oil. LCMS (ESI, m / z): 437.15 [M+H] +< .Step 3: Synthesis of 5-[5-(aminomethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0463] A solution of 2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindole-5-carbonitrile (1 g, 2.29 mmol, 1.00 equiv), Palladium carbon (500 mg), hydrogen chloride (0.2 mL) in ethanol (20 mL) was stirred for 2 days at 30 °C under the atmosphere of hydrogen with the pressure of 30 atm. The solids were filtered out and the filtration was concentrated under vacuum. The residue was applied onto a silica gel column eluting with DCM / methanol (96:4) to afford 700 mg (69 %) of the title compound as yellow oil. LCMS (ESI, m / z): 441.19 [M+H] +< .Step 4: Synthesis of 5-(5-[[(pyridin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0464] A solution of 5-[5-(aminomethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (200 mg, 0.45 mmol, 1.00 equiv), Pd 2 (dba) 3 .CHCl 3 (50 mg, 0.05 mmol, 0.10 equiv), Xantphos (28 mg, 0.05 mmol, 0.10 equiv), 4-bromopyridine (152 mg, 0.96 mmol, 2.00 equiv), Cs 2 CO 3 (315 mg, 2.00 equiv) in dioxane (15 mL) was stirred for 2 h at 100°C in an oil bath under the atmosphere of nitrogen. After concentration the residue was applied onto a silica gel column eluting with DCM / methanol (9:1) to afford 130 mg (55%) of the title compound as a yellow solid. LCMS (ESI, m / z): 518.21 [M+H] +< .Step 5 : Synthesis of 5-(5-[[(pyridin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0465] A solution of 5-(5-[[(pyridin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (130 mg, 0.25 mmol, 1.00 equiv) in hydrogen chloride / dioxane (20 mL) was stirred for 14 h at room temperature. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 9 with saturated sodium bicarbonate aqueous. The resulting solution was extracted with DCM and the organic layers combined and dried over anhydrous sodium sulfate. After concentration the residue was applied onto a silica gel column eluting with DCM / methanol (9:1) .Then the residue was further purified by Prep-HPLC yielding the title compound (35.7 mg 37 %) as a white solid. LCMS (ESI, m / z): 388.13 [M+H] +< , 1< HNMR (DMSO-d 6 , 400 MHz) δ: 12.52 (s, 1H), 8.00 (d, J = 5.2 Hz, 3H), 7.38 - 7.27 (m, 3H), 7.25 (t, J = 6.1 Hz, 1H), 6.54 - 6.48 (m, 2H), 4.95 (d, J = 9.1 Hz, 4H), 4.36 (d, J = 6.1 Hz, 2H).Example 18 Isomer A: 6-[4-[(3-[[(1R)-2-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile and Example 18 Isomer B: 6-[4-[(3-[[(1S)-2-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl] pyridine-3-carbonitrile

[0466] Step 1: 5-[1-(Hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0467] A solution of 5-chloro-4-(trifluoromethyl)-2-[2-(trimethylsilyl)ethoxy]methyl-2,3-dihydropyridazin-3-one (Int-A6, 4.8 g, 14.60 mmol, 1.00 equiv), 2,3-dihydro-1H-isoindol-1-ylmethanol hydrochloride (2.7 g, 14.54 mmol, 1.00 equiv) and TEA (4.4 g, 43.48 mmol, 2.99 equiv) in ethanol (100 mL) was stirred for 1 h at 60 °C , and then the resulting solution was concentrated under vacuum and the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (45:55) to afford 2.9 g (45 %) of the title compound as a brown solid. LCMS: [M+H] +< 442.17.Step 2: Methyl 3-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoate

[0468] Under nitrogen, a solution of 5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (2.93 g, 6.64 mmol, 1.00 equiv), methyl 3-bromobenzoate (2.84 g, 13.21 mmol, 1.99 equiv), Pd(allyl)Cl 2 (243 mg), Rockphos (311 mg) and Cs 2 CO 3 (4.3 g, 13.20 mmol, 1.99 equiv) in Toluene (100 mL) was stirred for 18 h at 80 °C. The resulting solution was concentrated under vacuum and then the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1:3) to afford 3 g (79 %) of the title compound as a brown solid. LCMS: [M+H] +< 576.21.Step 3: 3-([2-[6-Oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoic acid

[0469] A solution of methyl 3-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoate (1.15 g, 2.00 mmol, 1.00 equiv) and LiOH (240 mg, 10.02 mmol, 5.02 equiv) in THF (12 mL) and water (3 mL) was stirred for 3 h at 60 °C. The resulting solution was concentrated under vacuum and the residue was diluted with 10 mL of H 2 O, and then the pH value of the solution was adjusted to 5 with HCl (36.5%). The solid was collected by filtration to afford 1.1 g (98 %) of the title compound as a light yellow solid. LCMS: [M+H] +< 562.19.Step 4: 3-([2-[6-Oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]-2, 3-dihydro-1H-isoindol-1-yl]methoxy)benzoic acid

[0470] A solution of 3-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoic acid (1.1 g, 1.96 mmol, 1.00 equiv) in HCl / dioxane (20 mL, 4M) was stirred for 3 h at RT, and then the resulting solution was concentrated under vacuum to afford 1 g of the title compound as a crude brown solid. LCMS: [M+H] +< 432.11.Step 5: 6-[4-[(3-[[(R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile and 6-[4-[(3-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl[methoxy[phenyl)carbonyl[piperazin-1-yl[pyridine-3-carbonitrile

[0471] A solution of 3-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoic acid (500 mg, 1.16 mmol, 1.00 equiv), HATU (528 mg, 1.39 mmol, 1.20 equiv), DIPEA (449 mg, 3.47 mmol, 3.00 equiv) and Int-A4 (240 mg, 1.27 mmol, 1.1equiv) in DMF (5 mL) was stirred for 2 h at RT. After concentration by reduced pressure, the resulting solution was purified by C18 reverse phase chromatography eluting with H 2 O / ACN. The residue was further purified by Prep-HPLC and Chiral-Prep-HPLC (CHIRAL Repaired IA, 5 µm, 0.46 x 10 cm column, eluting with a gradient of (Hexanes:DCM = 3:1) (0.1%DEA):EtOH = 50:50, at a flow rate of 1 mL / min) yielding the title compounds as white solids. The absolute stereochemistry was assigned based on a protein X-ray crystal structure obtained of Example 18 Isomer B which confirmed (S)-absolute stereochemistry and was observed to be the more potent enantiomer. Example 18 Isomer A: 153.2 mg, 22%, LCMS: [M+H] +< 602.05, 1< H NMR (300 MHz, Methanol-d 4 ) δ 8.43 (d, J = 1.8Hz, 1H), 8.42 (s, 1H), 7.79 (dd, J = 9.0, 2.4 Hz, 1H), 7.53 - 7.50 (m, 1H), 7.41 - 7.35 (m, 4H), 7.05 - 6.99 (m, 2H), 6.94 - 6.87 (m, 2H), 6.20 (s, 1H), 5.33 (d, J = 14.8 Hz, 1H), 4.68 (d, J = 14.7 Hz, 1H), 4.53 (dd, J = 10.2, 3.3 Hz, 1H), 4.29 (dd, J = 10.2, 6.6 Hz, 1H), 3.91-3.44 (m, 8H). tR =4.369 min. Example 18 Isomer B: 153.3 mg, 22%, 1< H NMR (300 MHz, Methanol-d 4 ) δ 8.43 (d, J = 1.8Hz, 1H), 8.38 (s, 1H), 7.79 (dd, J = 9.0, 2.4 Hz, 1H), 7.52-7.50 (m, 1H), 7.41-7.35 (m, 4H), 7.04-6.99 (m, 2H), 6.94-6.87 (m, 2H), 6.19 (s, 1H), 5.32 (d, J = 14.7 Hz, 1H), 4.67 (d, J = 14.7 Hz, 1H), 4.53 (dd, J = 10.2, 3.6 Hz, 1H), 4.26 (dd, J = 10.2, 6.6 Hz, 1H), 3.92 - 3.41 (m, 8H). LCMS: [M+H] +< 602.05. tR = 5.955 min.Example 19: 5-[5-fluoro-6-[2-(morpholin-4-yl)ethoxy]-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0472] Step 1: Synthesis of 5-[5-fluoro-6-[2-(morpholin-4-yl)ethoxy]-2, 3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0473] A solution of 5-(5-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (200 mg, 0.45 mmol, 1 equiv), 4-(2-chloroethyl)morpholine hydrochloride (99.6 mg, 0.54 mmol, 1.192 equiv), K 2 CO 3 (123.6 mg, 0.89 mmol, 1.992 equiv) in DMF (10 mL) was stirred for 12 h at 80°C. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3x15 ml of EtOAc and the organic layers combined and dried over anhydrous sodium sulfate. The organic layers concentrated under vacuum .The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (90 / 10) to afford 180 mg (72 %) of the title compound as yellow oil. LCMS (ESI, m / z): 559.23 [M+H] +< .Step 2: Synthesis of 5-[5-fluoro-6-[2-(morpholin-4-yl)ethoxy]-2, 3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0474] A solution of 5-[5-fluoro-6-[2-(morpholin-4-yl)ethoxy]-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (180 mg, 0.32 mmol, 1 equiv) in HCl / dioxane (10 mL) was stirred for 12 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (52.1mg , 37.8 %) as a white solid. LCMS (ESI, m / z): 429.38 [M+H] +< , 1< HNMR (DMSO-d6, 300 MHz) δ: 12.55 (s, 1H), 7.98 (s, 1H), 7.27 (m, 2H), 4.91 (m, 4H), 4.18 (t, J= 5.7 Hz, 2H), 3.64 - 3.54 (m, 4H), 3.31 (m, 2H), 2.73 (t, J = 5.7 Hz, 2H), 2.48 (m, 2H).Example 20: 5-[5-fluoro-6-(piperidin-4-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0475] Step 1: Synthesis of tert-butyl 4-[([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1, 6-dihydropyridazin-4-yl]-2, 3-dihydro-1H-isoindol-5-yl]oxy)methyl]piperidine-1-carboxylate

[0476] A solution of 5-(5-fluoro-6-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1 g, 2.24 mmol, 1.00 equiv), potassium carbonate (3.1 g, 22.43 mmol, 10.00 equiv), tert-butyl 4-(iodomethyl)piperidine-1-carboxylate (4.4 g, 13.53 mmol, 6.00 equiv) in DMF (15 mL) was stirred for 1.5 h at 80°C. The solution was quenched with 50 ml water, then the resulting solution was extracted with EtOAc (3 x 60 mL) and the organic layers combined. The solution was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (5 / 95) to afford 1 g (69 %) of the title compound as a white solid. LCMS (ESI, m / z): 643.30 [M+H] +< .Step 2: Synthesis of 5-[5-fluoro-6-(piperidin-4-ylmethoxy)-2, 3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0477] A solution of tert-butyl 4-[([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy)methyl]piperidine-1-carboxylate (200 mg, 0.31 mmol, 1.00 equiv), trifluoroacetic acid (2 mL) in DCM (10 mL) was stirred for 3 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (24.2 mg, 19 %) as a white solid. LCMS (ESI, m / z): 413.10 [M+H] +< , 1< HNMR (DMSO-d6, 300 MHz) δ 7.98 (d, J = 13.8 Hz, 1H), 7.28 - 7.18 (m, 2H), 4.90 - 4.88 (m, 4H), 3.87 (dd, J = 6.4, 3.9 Hz, 2H),3.01 - 2.95 (m, 2H), 2.45 -2.44 (m, 2H), 1.84 (d, J = 4.2 Hz, 1H), 1.75 - 1.58 (m, 2H), 1.22 -1.13 (m, 2H).Example 21: 5-[5-[(1-acetylpiperidin-4-yl)methoxy]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0478]

[0479] A solution of 5-[5-fluoro-6-(piperidin-4-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (325.35 mg, 0.79 mmol, 1.00 equiv), TEA (227.25 mg, 2.25 mmol, 4.00 equiv), Ac2O (45.9 mg, 0.45 mmol, 1.00 equiv) in DCM (15 mL) was stirred for 2 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (68.2 mg, 19 %) as a white solid. LCMS (ESI, m / z): 455.05 [M+H] +< , 1< HNMR (Methanol- d 4 , 300 MHz) δ 8.04 (s, 1H), 7.14 (dd, J = 9.2, 4.7 Hz, 2H), 5.00 - 4.99 (s, 4H), 4.59 (d, J = 12.9 Hz, 1H), 4.06 - 3.84 (m, 3H), 3.25 - 3.13 (m, 1H), 2.80 - 2.56 (m, 1H), 2.13 (s, 3H), 2.12 - 2.11 (m, 1H), 2.04 - 1.84 (m, 2H), 1.50 - 1.22 (m, 2H).Example 22: 5-[5-fluoro-6-[(1-methylpiperidin-4-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0480]

[0481] A solution of 5-[5-fluoro-6-(piperidin-4-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (150 mg, 0.36 mmol, 1.00 equiv), (HCHO)n (62.1 mg, 3.00 equiv), acetic acid (0.5 mL), NaBH3CN (43.47 mg, 0.69 mmol, 3.00 equiv) in methanol (15 mL) was stirred for 15 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (57.9 mg, 37 %) as a white solid. LCMS (ESI, m / z): 427.10 [M+H] +< , 1< HNMR (Methanol-d4, 300 MHz) δ 8.04 (s, 1H), 7.12 (dd, J = 9.2, 4.5 Hz, 2H),4.96 (s, 4H) 3.93 (d, J = 5.7 Hz, 2H), 2.95 (d, J = 11.5 Hz, 2H), 2.31 (s, 3H), 2.11 (t, J = 6.3 Hz, 2H), 1.98 - 1.81 (m, 3H), 1.65 - 1.26 (m, 2H).Example 23: 5-(5-fluoro-6-[[(piperidin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0482] Step 1: Synthesis of 6-fluoro-2-[6-oxo-5-(trifluoromethy)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2, 3-dihydro-1H-isoindole-5-carbonitrile

[0483] A solution of 6-fluoro-2,3-dihydro-1H-isoindole-5-carbonitrile (600 mg, 3.70 mmol, 1 equiv), 5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1.45 g, 4.41 mmol, 1.192 equiv), TEA (1.12 g, 11.07 mmol, 2.991 equiv) in EtOH (15 mL) was stirred for 2 h at 80°C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (15 / 85) to afford 1.2 g (71 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 455.14 [M+H] +< .Step 2: Synthesis of 5-[5-(aminomethyl)-6-jluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0484] A solution of 6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindole-5-carbonitrile (3 g, 6.60 mmol, 1 equiv), Pd / C (300 mg, 2.82 mmol, 0.427 equiv) in EtOH (30 mL) was stirred 7 days at room temperature with an atmosphere of hydrogen. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with DCM / methanol (93 / 7) to afford 1.58 g (52.2 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 459.18 [M+H] +< .Step 3: Synthesis of tert-butyl 4-[([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-]-[[2-(trimethylsilyl)ethoxy]methyl]-1, 6-dihydropyridazin-4-yl]-2, 3-dihydro-1H-isoindol-5-yl]methyl)amino]piperidine-1-carboxylate

[0485] A solution of 5-[5-(aminomethyl)-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (200 mg, 0.44 mmol, 1 equiv), tert-butyl 4-oxopiperidine-1-carboxylate (104.6 mg, 0.52 mmol, 1.204 equiv), NaBH 3 CN (137.34 mg, 2.19 mmol, 5.010 equiv) in MeOH (10 mL) was stirred for 2 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN to afford 100 mg (35.7 %) of the title compound as yellow oil. LCMS (ESI, m / z): 642.30 [M+H] +< .Step 4: Synthesis of 5-(5-fluoro-6-[[(piperidin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0486] A solution of tert-butyl 4-[([6-fluoro-2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-5-yl]methyl)amino]piperidine-1-carboxylate (100 mg, 0.16 mmol, 1 equiv) in HCl / dioxane (12 mL) was stirred for 12 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (20.4mg, 31.8 %) as a white solid. LCMS (ESI, m / z): 412.40 [M+H] +< , 1< HNMR (300 MHz, DMSO-d 6 ) δ: 8.01 (s, 1H), 7.48 (d, J = 6.7 Hz, 1H), 7.21 (d, J = 10.0 Hz, 1H), 4.95 (s, 4H), 3.77 (s, 2H), 2.91 (d, J = 12.0 Hz, 2H), 2.47 - 2.33 (m, 3H), 1.77 (d, J = 11.9 Hz, 2H), 1.13 (m, 2H).Example 24: 5-(5-[[(1-acetylpiperidin-4-yl)amino]methyl]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0487] Step 1: Synthesis of 5-(5-[[(1-acetylpiperidin-4-yl)amino]methyl]-6-fluoro-2, 3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0488] A solution of 5-[5-(aminomethyl)-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (300 mg, 0.65 mmol, 1 equiv), 1-acetylpiperidin-4-one (110.6 mg, 0.78 mmol, 1.197 equiv), NaBH 3 CN (206 mg, 3.28 mmol, 5.01 equiv) in MeOH (10 mL) was stirred 2 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN to afford 250 mg (65.5 %) of the title compound as yellow oil. LCMS (ESI, m / z): 584.26 [M+H] +< .Step 2: Synthesis of 5-(5-[[(1-acetylpiperidin-4-yl)amino]methyl]-6-fluoro-2, 3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0489] A solution of 5-(5-[[(1-acetylpiperidin-4-yl)amino]methyl]-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (250 mg, 0.43 mmol, 1 equiv) in HCl / dioxane (12 mL) was stirred for 12 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (70.3 mg, 36.2 %) as a white solid. LCMS (ESI, m / z): 454.43 [M+H] +< , 1< HNMR (300 MHz, DMSO-d 6 ) δ: 12.56 (s, 1H), 8.01 (s, 1H), 7.49 (d, J = 6.8 Hz, 1H), 7.21 (d, J = 10.0 Hz, 1H), 4.95 (s, 4H), 4.14 (d, J = 13.1 Hz, 1H), 3.78 (s, 2H), 3.78 - 3.72 (m, 1H), 3.05 (t, J = 11.3 Hz, 1H), 2.79 - 2.56 (m, 2H), 2.38-2.22(m, 1H), 1.99 (s, 3H), 1.88 - 1.72 (m, 2H), 1.33 -1.12 (m, 2H).Example 25: 5-(5-fluoro-6-[[(1-methylpiperidin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0490] Step 1: Synthesis of 5-(5-fluoro-6-[[(1-methylpiperidin-4-yl)amino]methyl]-2, 3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0491] A solution of 5-[5-(aminomethyl)-6-fluoro-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (300 mg, 0.65 mmol, 1 equiv), 1-methylpiperidin-4-one (89.4 mg, 0.79 mmol, 1.208 equiv), NaBH 3 CN (206.01 mg, 3.28 mmol, 5.010 equiv) in MeOH (10 mL) was stirred 2 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN to afford 200 mg (55 %) of the title compound as yellow oil. LCMS (ESI, m / z): 556.27 [M+H] +< .Step 2: Synthesis of 5-(5-fluoro-6-[[(1-methylpiperidin-4-yl)amino]methyl]-2, 3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0492] A solution of 5-(5-fluoro-6-[[(1-methylpiperidin-4-yl)amino]methyl]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (200 mg, 0.36 mmol, 1 equiv) in HCl / dioxane (12 mL) was stirred for 12 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (41.0 mg, 26.8 %) as a white solid. LCMS (ESI, m / z): 426.42 [M+H] +< , 1< HNMR (300 MHz, DMSO-d 6 ) δ:12.52 (s, 1H), 7.97 (s, 1H), 7.44 (d, J = 6.8 Hz, 1H), 7.17 (d, J = 10.0 Hz, 1H), 4.92 (s, 4H), 3.72 (s, 2H), 2.66 (d, J = 11.2 Hz, 2H), 2.34 - 2.24 (m, 1H), 2.10 (s, 3H), 1.89 - 1.70 (m, 5H), 1.34 - 1.16 (m, 2H).Example 26: 5-[5-fluoro-6-(morpholin-4-yl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0493] Step 1: Synthesis of 5-[5-fluoro-6-(morpholin-4-yl)-2, 3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0494] A solution of 5-(5-bromo-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (300 mg, 0.59 mmol, 1 equiv), morpholine (62 mg, 0.71 mmol, 1.206 equiv), Pd 2 (dba) 3 (108 mg, 0.12 mmol, 0.200 equiv), Xantphos (68.2 mg, 0.12 mmol, 0.200 equiv), t-BuOK (131.7 mg, 1.17 mmol, 1.989 equiv) in Toluene (10 mL) was stirred for 12 h at 80°C with an inert atmosphere of nitrogen. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (25 / 75) to afford 170 mg (56 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 515.20 [M+H] +< .Step 2: Synthesis of 5-[5-fluoro-6-(morpholin-4-yl)-2, 3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0495] A solution of 5-[5-fluoro-6-(morpholin-4-yl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (170 mg, 0.33 mmol, 1 equiv) in HCl / dioxane (10 mL) was stirred for 12 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (20.7 mg , 16.3 %) as a white solid. LCMS (ESI, m / z): 385.33 [M+H] +< , 1< HNMR (DMSO-d 6 , 300 MHz) δ 12.54 (s, 1H), 7.98 (s, 1H), 7.22 (d, J = 12.4 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 4.91 (br, 4H), 3.79 -3.68 m, 4H), 3.04 - 2.94 (m, 4H).Example 27: 5-(4-[[1-(diphenylmethyl)piperidin-4-yl]oxy]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0496] Step 1: Synthesis of tert-butyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2, 3-dihydro-1H-isoindol-4-yl]oxy)piperidine-1-carboxylate

[0497] A solution of 5-(4-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1.1 g, 2.57 mmol, 1.00 equiv), potassium carbonate (1.8 g, 13.02 mmol, 5.00 equiv), tert-butyl 4-iodopiperidine-1-carboxylate (4.0 g, 12.86 mmol, 5.00 equiv) in DMF (30 mL) was stirred for 3 days at 80 °C in an oil bath. After concentration, the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1:3) to afford 1.3 g (83 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 611.28 [M+H] +< .Step 2: Synthesis of 5-[4-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0498] A solution of tert-butyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)piperidine-1-carboxylate (600 mg, 0.98 mmol, 1.00 equiv) in hydrogen chloride / dioxane (120 ml, 1M) was stirred for 12 h at room temperature. After concentration, the residue was applied onto a silica gel column eluting with DCM / methanol (2:1) to afford 270 mg (54 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 511.23 [M+H] +< Step 3: Synthesis of 5-(4-[[1-(diphenylmethyl)piperidin-4-yl]oxy]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0499] A solution of 5-[4-(piperidin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (250 mg, 0.49 mmol, 1.00 equiv), TEA (99 mg, 0.98 mmol, 2.00 equiv), [bromo(phenyl)methyl]benzene (241 mg, 0.98 mmol, 2.00 equiv) in dioxane (8 mL) was stirred for 2 days at 100 °C in an oil bath. After concentration, the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1:3) to afford 154 mg (46 %) of the title compound as a solid. LCMS (ESI, m / z): 677.31 [M+H] +< .Step 4: Synthesis of 5-(4-[[1-(diphenylmethyl)piperidin-4-yl]oxy]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0500] A solution of 5-(4-[[1-(diphenylmethyl)piperidin-4-yl]oxy]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (154 mg, 0.23 mmol, 1.00 equiv) in hydrogen chloride / dioxane (15 mL) was stirred for 12 h at room temperature. After concentration, the residue was applied onto a silica gel column with DCM / methanol (2:1) and the crude product was purified by Prep-HPLC yielding the title compound (15.7 mg 13 %) as a white solid. LCMS (ESI, m / z): 547.22 [M+H] +< , 1< H NMR (DMSO-d 6 , 300 MHz) δ: 12.51 (s, 1H), 8.01 (s, 1H), 7.41 (d, J = 7.4 Hz, 4H), 7.31 - 7.15 (m, 7H), 6.97-6.90 (dd, J = 14.1, 7.9 Hz, 2H), 4.95 (s, 2H), 4.84 (s, 2H), 4.53-4.49 (dr, 1H), 4.35 (s, 1H), 2.58-2.51 (m, 2H), 2.27-2.22 (m, 2H), 1.93-1.91 (dr, 2H), 1.74-1.68 (dr, 2H).Example 28: 5-(5-[[1-(diphenylmethyl)piperidin-4-yl]oxy]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0501] Step 1: Synthesis of 1-(diphenylmethyl)piperidin-4-ol

[0502] A solution of piperidin-4-ol (5 g, 49.43 mmol, 1.00 equiv), TEA (5 g, 49.41 mmol, 1.00 equiv), [bromo(phenyl)methyl]benzene (9 g, 36.42 mmol, 0.80 equiv) in THF (30 mL) was stirred for 2 days at room temperature. After concentration, the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1:2) to afford 3.8 g (29 %) of the title compound as a solid. LCMS (ESI, m / z): 268.16 [M+H] +< .Step 2: Synthesis of 1-(diphenylmethyl)piperidin-4-yl methanesulfonate

[0503] A solution of 1-(diphenylmethyl)piperidin-4-ol (3.8 g, 14.21 mmol, 1.00 equiv), MsCl (1.44 g, 1.10 equiv), TEA (1.52 g, 15.02 mmol, 2.00 equiv) in DCM (20 mL) was stirred for 30 min at room temperature. The resulting solution was extracted with of DCM and the organic layers combined and concentrated under vacuum to afford 3.2 g (65 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 346.14 [M+H] +< .Step 3: Synthesis of 5-(5-[[1-(diphenylmethyl)piperidin-4-yl]oxy]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0504] A solution of 5-(5-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (400 mg, 0.94 mmol, 1.00 equiv), potassium carbonate (1.3 g, 9.41 mmol, 10.00 equiv), 1-(diphenylmethyl)piperidin-4-yl methanesulfonate (649 mg, 1.88 mmol, 2.00 equiv) in DMF (40 mL) was stirred for 2 days at 80°C in an oil bath. After concentration, the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1:3) to afford 200 mg (32 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 677.31 [M+H] +< .Step 4: Synthesis of 5-(5-[[1-(diphenylmethyl)piperidin-4-yl]oxy]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2, 3-dihydropyridazin-3-one

[0505] A solution of 5-(5-[[1-(diphenylmethyl)piperidin-4-yl]oxy]-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (200 mg, 0.30 mmol, 1.00 equiv) in hydrogen chloride / dioxane (20 mL) was stirred for 12 h at room temperature. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1:2). The crude product was purified by Prep-HPLC yielding the title compound (14.3 mg 9 %) as a white solid. LCMS (ESI, m / z): 547.22 [M+H] +< , 1< H NMR (Methanol-d 4 , 300 MHz) δ: 8.02 (s, 1H), 7.45-7.42 (d, J = 7.8 Hz, 4H), 7.31 - 7.14 (m, 7H), 6.92 - 6.87 (m, 2H), 4.97-4.94 (d, J = 8.4 Hz, 4H), 4.41 (dr, 1H), 4.29 (s, 1H), 2.72 (dr, 2H), 2.27-2.21 (m, 2H), 2.03-1.97 (m, 2H), 1.78-1.71 (m, 2H).Example 29: 6-(4-[[3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)phenyl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

[0506] Step 1: Synthesis of 5-[(2-hydroxyethyl)(methyl)amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0507] A solution of 5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1 g, 3.04 mmol, 1.00 equiv), TEA (600 mg, 5.93 mmol, 2.00 equiv), 2-(methylamino)ethan-1-ol (1.1 g, 14.65 mmol, 5.00 equiv) in ethanol (14 mL) was stirred for 2 h at 60 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (8:1) to afford 1.1 g (98 %) of the title compound as yellow oil. LCMS (ESI, m / z): 368.15 [M+H] +< .Step 2: Synthesis of methyl 3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)benzoate

[0508] A solution of 5-[(2-hydroxyethyl)(methyl)amino]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (800 mg, 2.18 mmol, 1.00 equiv), [Pd(allyl)Cl] 2 (80 mg, 0.22 mmol, 0.10 equiv), rockphos (102 mg, 0.22 mmol, 0.10 equiv), Cs 2 CO 3 (1.4 g, 4.30 mmol, 2.00 equiv), methyl 3-bromobenzoate (466 mg, 2.17 mmol, 1.00 equiv) in toulene (12 mL) was stirred for 2 h at 85 degrees C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (3:2) to afford 700 mg (64 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 502.19 [M+H] +< .Step 3: Synthesis of methyl 3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]amino]ethoxy)benzoate

[0509] A solution of methyl 3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]amino]ethoxy)benzoate (700 mg, 1.40 mmol, 1.00 equiv) in hydrogen chloride / dioxane (30 mL) was stirred for 14 h at room temperature. The resulting mixture was concentrated under vacuum to afford 600 mg crude of the title compound as yellow oil. LCMS (ESI, m / z):372.11 [M+H] +< .Step 4: Synthesis of 3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)benzoic acid

[0510] A solution of methyl 3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)benzoate (700 mg, 1.89 mmol, 1 equiv), LiOH·H 2 O (553 mg, 13.18 mmol, 6.990 equiv) in methanol (10 mL) was stirred for 4 h at room temperature. The resulting solution was extracted with 2x20 ml of EtOAc and the acqueous combined. The pH value of the solution was adjusted to 2 with HCl (10 %). The solids were collected by filtration to afford 380 mg (56. %) of the title compound as a yellow solid. LCMS (ESI, m / z): 358.09 [M+H] +< .Step 5: Synthesis of 6-(4-[[3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]amino]ethoxy)phenyl]carbonyl]piperazin-1-yl)pyridine-3-carbonitrile

[0511] A solution of 3-(2-[methyl[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]amino]ethoxy)benzoic acid (100 mg, 0.28 mmol, 1 equiv), HATU (111 mg, 0.29 mmol, 1.043 equiv), DIPEA (108 mg, 0.84 mmol, 2.986 equiv), Int-A4 (58.1 mg, 0.31 mmol, 1.103 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (98.0mg , 66.4 %) as a white solid. LCMS (ESI, m / z): 528.50 [M+H] +< , 1< H NMR (300 MHz, DMSO-d 6 ) δ: 12.51 (s, 1H), 8.52 (d, J = 2.3 Hz, 1H), 8.06 (s, 1H), 7.90 (d, J = 9.1, 2.4 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.05 - 6.89 (m, 4H), 4.26 (t, J = 5.0 Hz, 2H), 3.86 (t, J = 5.1 Hz, 2H), 3.62 - 3.52 (m, 6H), 3.33 (m, 2H), 3.10 (d, J = 2.3 Hz, 3H).Example 30 Isomer A: (R)-4-(Trifluoromethyl)-5-(1-((3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)phenoxy)methyl)isoindolin-2-yl)pyridazin-3(2H)-one and Example 30 Isomer B: (S)-4-(Trifluoromethyl)-5-(1-((3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)phenoxy)methyl)isoindolin-2-yl)pyridazin-3(2H)-one

[0512]

[0513] A solution of 3-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoic acid (300 mg, 0.70 mmol, 1.00 equiv), HATU (278 mg, 0.73 mmol, 1.05 equiv), DIPEA (269 mg, 2.08 mmol, 3.00 equiv), and Int-A18 (161 mg, 0.70 mmol, 1.00 equiv) in DCM (2 mL) was stirred overnight at 25 °C. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / ACN. The residue was further purified by Prep-HPLC and Chiral-Prep-HPLC (CHIRALPAK IA-3, 3 µm, 0.46 x 5 cm column, eluting with a gradient of MtBE (10 mM NH 3 ):EtOH=80:20, at a flow rate of 1 mL / min) yielding the title compounds as yellow solids. The absolute stereochemistry was assigned based on a protein X-ray crystal structure obtained of Example 18 Isomer B which confirmed (S)-absolute stereochemistry and was observed to be the more potent enantiomer (see Table A-1).

[0514] Example 30 Isomer A: 76.1 mg, 42 %, LCMS: [M+H] +< 645.20, 1< H NMR (400 MHz, Methanol-d 4 ) δ 8.40 - 8.39(d, J = 3.5 Hz, 2H), 7.78 - 7.76 (dd, J = 9.1, 2.6 Hz, 1H), 7.53 - 7.51 (m, 1H), 7.42 - 7.37 (m, 4H), 7.05 - 7.00 (m, 2H), 6.94 - 6.92 (m, 2H), 6.20 (dr, 1H), 5.33 - 5.29 (d, J = 14.7 Hz, 1H), 4.68 - 4.64 (d, J = 14.8 Hz, 1H), 4.54 - 4.50 (dd, J = 10.3, 3.5 Hz, 1H), 4.29 - 4.25 (dd, J = 10.2, 6.8 Hz, 1H), 3.83 - 3.53 (m, 8H). tR = 1.562 min. Example 30 Isomer B: 76.1 mg, 42 %, LCMS: [M+H] +< 645.20, tR = 1.562 min.Example 31: 6-[4-[(3-[[(2R)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

[0515] Step 1: Synthesis of 5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0516] A solution of 5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (15 g, 45.62 mmol, 1 equiv), (2R)-pyrrolidin-2-ylmethanol (4.6 g, 45.48 mmol, 0.997 equiv), TEA (14 g, 138.35 mmol, 3.033 equiv) in EtOH (200 mL) was stirred for 4 h at 60 °C. The resulting mixture was concentrated under vacuum. The residue was crystallized with Et 2 O to afford 8.6 g (47.9 %) of the title compound as a white solid. LCMS (ESI, m / z): 394.17 [M+H] +< .Step 2: Synthesis of methyl 3-[[(2R)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate

[0517] A solution of 5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (8.6 g, 21.86 mmol, 1 equiv), methyl 3-bromobenzoate (5.2 g, 24.18 mmol, 1.106 equiv), Rockphos (1.02 g, 2.18 mmol, 0.100 equiv), Cs 2 CO 3 (14.2 g, 43.58 mmol, 1.994 equiv), Pd 2 (allyl) 2 Cl 2 (0.798 g, 2.18 mmol, 0.100 equiv) in Toluene (100 mL) was stirred for 12 h at 80 °C with an inert atmosphere of nitrogen. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (20 / 80) to afford 7.1 g (61.6 %) of the title compound as yellow oil. LCMS (ESI, m / z): 528.21 [M+H] +< .Step 3: Synthesis of methyl 3-[[(2R)-1-[6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate

[0518] A solution of 3-[[(2R)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate (9.1 g, 17.25 mmol, 1 equiv) in HCl / dioxane (100 mL) was stirred for 12 h at room temperature. The resulting mixture was concentrated under vacuum to afford 9.5 g (crude) of the title compound as yellow oil. LCMS (ESI, m / z): 398.12 [M+H] +< .Step 4: Synthesis of 3-[[(2R)-]-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoic acid

[0519] A solution of 3-[[(2R)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate (1.5 g, 3.78 mmol, 1 equiv), LlOH·H 2 O (0.795 g, 18.94 mmol, 5.0 equiv) in MeOH (30 mL) was stirred for 4 h at room temperature. The resulting solution was extracted with 3x30 ml of EtOAc. The pH value of the solution was adjusted to 2 with HCl (12 M). The solids were collected by filtration to afford 600 mg (41 %) of the title compound as a white solid. LCMS (ESI, m / z): 384.11 [M+H] +< .Step 5: Synthesis of 6-[4-[(3-[[(2R)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

[0520] A solution of 3-[[(2R)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoic acid (100 mg, 0.26 mmol, 1 equiv), HATU (103.7 mg, 0.27 mmol, 1.045 equiv), DIPEA (100.6 mg, 0.78 mmol, 2.984 equiv), Int-A4 (54 mg, 0.29 mmol, 1.100 equiv) in DMF (2 mL) was stirred for 2 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (76.9 mg, 53 %) as a white solid. LCMS (ESI, m / z): 554.54 [M+H] +< , 1< HNMR (DMSO-d 6 , 300 MHz) δ: 12.44 (s, 1H), 8.53 (d, J = 2.3 Hz, 1H), 8.15 (s, 1H), 7.91 (dd, J = 9.1, 2.4 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 6.98 (dd, J = 18.8, 8.6 Hz, 4H), 4.83 (s, 1H), 4.15 (dd, J = 10.4, 4.0 Hz, 1H), 4.04 (dd, J = 10.3, 6.0 Hz, 1H), 3.67- 3.48 (m, 9H), 3.30 (d, J = 8.9 Hz, 1H), 2.23 (s, 1H), 1.99 (d, J = 6.7 Hz, 1H), 1.93 - 1.81 (m, 2H).Example 32: 6-[4-[(3-[[(2S)-1-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

[0521] Step 1: -5-[(2S)-2-(Hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0522] A solution of 5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (10 g, 30.41 mmol, 1.00 equiv), TEA (13.4 g, 132.42 mmol, 3.00 equiv), (S)-pyrrolidin-2-ylmethanol (3.4 g, 33.61 mmol, 1.10 equiv) in ethanol (60 mL) was stirred for 2 h at 60 °C. The resulting mixture was concentrated under vacuum and the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (26:74) to afford 5 g (42 %) of the title compound. LCMS (ESI, m / z): 394.18 [M+H]+Step 2: Synthesis of methyl 3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate

[0523] A solution of 5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (1 g, 2.54 mmol, 1.00 equiv), [Pd(allyl)Cl] 2 (93 mg, 0.10 equiv), Rockphos (119 mg, 0.10 equiv), Cs 2 CO 3 (2.5 g, 7.67 mmol, 3.00 equiv), methyl 3-bromobenzoate (1.09 g, 5.07 mmol, 2.00 equiv) in toluene (80 mL) was stirred for 20 h at 80 °C. The solvent was concentrated under vacuum and the residue was applied onto a silica gel column eluting with EtOAc / hexane (1:1) to afford 969 mg (72 %) of the title compound as a brown oil. LCMS (ESI, m / z): 528.22 [M+H] +< .Step 3: Synthesis of 3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoic acid

[0524] A solution of methyl 3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoate (969 mg, 1.84 mmol, 1.00 equiv), LiOH (220 mg, 9.19 mmol, 5.00 equiv ), water (4 mL) in methanol (20 mL) was stirred for 3 h at room temperature. The pH value of the solution was adjusted to 5 with hydrogen chloride. The solvent was concentrated under vacuum and the residue was applied onto a silica gel column eluting with EtOAc / hexane (1:1) to afford 900 mg (95%) of the title compound as a brown solid. LCMS (ESI, m / z): 514.20 [M+H] +< .Step 4: Synthesis of 3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoic acid

[0525] A solution 3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoic acid (900 mg, 1.75 mmol, 1.00 equiv) in hydrogen chloride / dioxane (30 mL) was stirred for 3 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN to afford 600 mg (89 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 384.12 [M+H] +< .Step 5: Synthesis of 6-[4-[(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

[0526] A solution of 3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoic acid (200 mg, 0.52 mmol, 1.00 equiv), HATU (239.4 mg, 0.63 mmol, 1.20 equiv), DIPEA (205.11 mg, 1.59 mmol, 3.00 equiv), Int-A4 nitrile (118.44 mg, 0.63 mmol, 1.20 equiv) in DMF (3 mL) was stirred for 3 h at room temperature. After concentration, The residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN yielding the title compound (132.9 mg, 46 %) as a white solid. LCMS (ESI, m / z): 554.05 [M+H] +< , 1< HNMR (300 MHz, Methanol- d 4 ) δ 8.44 (s, 1H), 8.24 (s, 1H), 7.78 (dd, J = 9.1, 2.4 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.17 - 7.00 (m, 2H), 7.00 - 6.84 (m, 2H), 4.86 (d, J= 4.1 Hz, 1H), 4.25 (dd, J= 10.3, 3.7 Hz, 1H), 4.07 (dd, J= 10.3, 6.9 Hz, 1H), 3.98 - 3.62 (m, 7H), 3.61 - 3.37 (m, 3H), 2.47 - 2.25 (m, 1H), 2.07 (dd, J= 11.4, 5.7 Hz, 1H), 1.88 - 1.84 (m, 2H).Example 33: 6-[3-(hydroxymethyl)-4-[(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl] pyridine-3-carbonitrile

[0527] Step 1: Synthesis of tert-butyl 4-(5-cyanopyridin-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate

[0528] A solution of tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate (780 mg, 3.61 mmol, 1.20 equiv), 6-chloropyridine-3-carbonitrile (520 mg, 3.75 mmol, 1.00 equiv), DIPEA (780 mg, 6.04 mmol, 2.00 equiv) in NMP (15 mL) was stirred for 8 h at 100°C. The resulting solution was quenched with water. The resulting solution was extracted with of EtOAc and the organic layers combined .After concentrated under vacuum. The residue was applied onto a silica gel column with EtOAc / petroleum ether (1:1) to afford of 900 mg (75 %) of the title compound as a solid. LCMS (ESI, m / z): 319.18 [M+H] +< .Step 2: Synthesis of 6-[3-(hydroxymethyl)piperazin-1-yl]pyridine-3-carbonitrile

[0529] A solution of tert-butyl 4-(5-cyanopyridin-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (900 mg, 2.83 mmol, 1.00 equiv) in hydrogen chloride / dioxane (15 mL) was stirred for 0.5 h at room temperature. The resulting mixture was concentrated under vacuum to afford 600 mg of the title compound as a solid. LCMS (ESI, m / z): 219.15 [M+H] +< .Step 3: Synthesis of 6-[3-(hydroxymethyl)-4-[(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

[0530] A solution of 3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoic acid (114.9 mg, 0.30 mmol, 1.00 equiv), HATU (136.8 mg, 0.36 mmol, 1.20 equiv), DIPEA (116.1 mg, 0.90 mmol, 3.00 equiv), 6-[3-(hydroxymethyl)piperazin-1-yl]pyridine-3-carbonitrile (78.48 mg, 0.36 mmol, 1.20 equiv) in DMF (3 mL) was stirred for 3 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (35.2 mg, 20 %) as a white solid. LCMS (ESI, m / z): 584.10 [M+H] +< , 1< HNMR (300 MHz, Methanol-d4) δ 8.50 (s, 1H), 8.24 (d, J = 5.0 Hz, 1H), 7.77 (dd, J = 9.1, 2.4 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.07 - 6.86 (m, 4H), 4.87 - 4.83 (m, 2H), 4.54 (s, 2H), 4.37 - 3.89 (m, 3H), 3.72 - 3.41 (m, 3H), 3.44 (t, J = 8.9 Hz, 2H), 3.28 - 3.01 (m, 2H), 2.49 - 2.22 (m, 1H), 2.07 (dd, J = 11.2, 5.6 Hz, 1H), 2.00 - 1.69 (m, 2H).Example 34: 6-[2-oxo-4-[(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

[0531] Step 1: Synthesis of tert-butyl 4-(5-cyanopyridin-2-yl)-3-oxopiperazine-1-carboxylate .

[0532] A solution of tert-butyl 3-oxopiperazine-1-carboxylate (2.0g, 10.00 mmol, 1.00 equiv), tripotassium phosphate (4.24 g, 20.00 mmol, 2.00 equiv), CuI (95.0 mg, 0.50 mmol, 0.05 equiv), 6-bromopyridine-3-carbonitrile (1.82 g, 10.00 mmol, 1.00 equiv), (1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (142.0 mg, 1.00 mmol, 0.10 equiv) in dioxane (80 mL) was stirred for 3 h at 110°C. The resulting mixture was concentrated under vacuum and the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (6:1) to afford 1.2 g (40 %) of the title compound as a white solid. LCMS (ESI, m / z): 303.15 [M+H] +< .Step 2: Synthesis of 6-(2-oxopiperazin-1-yl)pyridine-3-carbonitrile

[0533] A solution of tert-butyl 4-(5-cyanopyridin-2-yl)-3-oxopiperazine-1-carboxylate (200 mg, 0.66 mmol, 1.00 equiv) in hydrogen chloride / dioxane (20 mL) was stirred for 0.5 h at room temperature. The resulting mixture was concentrated under vacuum to afford 170 mg crude of the title compound as a white solid. LCMS (ESI, m / z): 203.10[M+H] +< .Step 3: Synthesis of 6-[2-oxo-4-[(3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

[0534] A solution of 3-[[(2S)-1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]pyrrolidin-2-yl]methoxy]benzoic acid (300 mg, 0.78 mmol, 1.00 equiv), HATU (296.4 mg, 0.78 mmol, 1.20 equiv), DIPEA (251.55 mg, 1.95 mmol, 3.00 equiv), 6-(2-oxopiperazin-1-yl)pyridine-3-carbonitrile (131.3 mg, 0.65 mmol, 1.20 equiv) in DMF (3 mL, 3.00 equiv) was stirred for 2 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC yielding the title compound (7.9 mg, 2 %) as a white solid. LCMS (ESI, m / z): 568.20 [M+H] +< , 1< HNMR (300 MHz, Chloroform-d) δ 10.69 (s, 1H), 8.68 (d, J= 2.3 Hz, 1H), 8.36 (d, J = 8.9 Hz, 1H), 8.08 - 7.79 (m, 2H), 7.49 - 7.29 (m, 1H), 7.05 (d, J = 7.6, 1.2 Hz, 1H), 6.99 (d, J= 2.1 Hz, 2H), 4.64 (dd, J = 6.0, 4.8 Hz, 1H), 4.48 (s, 2H), 4.23 (s, 2H), 4.11 (dd, J = 9.8, 4.2 Hz, 1H), 4.06 - 3.56 (m, 4H), 3.45 (dd, J = 10.9, 6.0 Hz, 1H), 2.40 (t, J= 6.3 Hz, 1H), 2.19 - 2.00 (m, 1H), 1.95 - 1.72 (m, 2H).Example 35: 6-[4-[(4-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile and 6-[4-[(4-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

[0535] Step 1: Synthesis of methyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoate

[0536] A solution of 5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (440 mg, 1.00 mmol, 1.00 equiv), [Pd(allyl)Cl]2 (37 mg, 0.10 mmol, 0.10 equiv), Rockphos (47 mg, 0.10 mmol, 0.10 equiv), Cs2CO3 (970 mg, 2.98 mmol, 2.00 equiv), and methyl 4-bromobenzoate (430 mg, 2.00 mmol, 2.00 equiv) in Toluene (10 mL) was stirred for 5 h at 80 °C. The reaction was then quenched by the addition of 150 mL of water. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with EtOAc / petroleum ether (1 / 4) to afford 470 mg (82 %) of the title compound as yellow oil. LCMS (ESI, m / z): 576.21 [M+H] +< .Step 2: Synthesis of 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1, 6-dihydropyridazin-4-yl]-2, 3-dihydro-1H-isoindol-1-yl]methoxy)benzoic

[0537] A solution of methyl 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxymethyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoate (470 mg, 0.82 mmol, 1.00 equiv), water (2 mL), and LiOH (100 mg, 4.18 mmol, 5.00 equiv) in THF (8 mL) was stirred for 1 overnight at 60 °C under N 2 (g) atmosphere. The pH value of the solution was adjusted to 5-6 with hydrogen chloride (6 M). The resulting solution was extracted with 2x200 mL of EtOAc and the organic layers combined and concentrated under vacuum, to afford 400 mg (87 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 562.19 [M+H] +< .Step 3: Synthesis of 4-([2-[6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]-2, 3-dihydro-1H-isoindol-1-yl]methoxy)benzoic

[0538] A solution of 4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoic acid (400 mg, 0.71 mmol, 1.00 equiv) in hydrogen chloride / dioxane (20 mL) was stirred for 1 overnight at 25 °C. The resulting mixture was concentrated under vacuum to afford 300 mg (98 %) of the title compound as a black solid. LCMS (ESI, m / z): 432.11 [M+H] +< .Step 4: Synthesis of 6-[4-[(4-[[(]S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile, and 6-[4-[(4-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]phenyl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile.

[0539] A solution of 4-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)benzoic acid (350 mg, 0.81 mmol, 1.00 equiv), Int-A4 (153 mg, 0.81 mmol, 1.00 equiv), DIPEA (300 mg, 2.32 mmol, 3.00 equiv), and HATU (313 mg, 0.82 mmol, 1.01 equiv) in DMF (3 mL) was stirred for 1 h at 25 °C. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then Chiral-Prep-HPLC yielding (after arbitrary assignment of the stereochemistry) the title compounds, respectively, isomer A 54.1 mg (54 %) as a yellow solid. LCMS (ESI, m / z):602.20 [M+H] +< , 1< H NMR (400 MHz, Methanol-d 4 ) δ 8.44 - 8.39 (m, 2H), 7.79-7.76 (dd, J= 9.1, 2.4 Hz, 1H), 7.54-7.51 (d, J= 5.8 Hz, 1H), 7.43-7.37 (td, J = 5.5, 5.0, 2.0 Hz, 5H), 6.98-6.96 (m, 2H), 6.91-6.88 (m, 1H), 6.21 (s, 1H), 5.33-5.29(d, J = 14.7 Hz, 1H), 4.67 - 4.62 (m, 1H), 4.55-4.52 (dd, J= 10.4, 3.5 Hz, 1H), 4.31-4.27 (dd, J= 10.3, 6.8 Hz, 1H), 3.79-3.50 (m, 8H) . tR = 3.517 min (CHIRALPAK IG-3, 0.46*10cm;3um, MtBE(0.1%DEA):EtOH=70:30, 1.0mL / min) and isomer B 48.6 mg (49 %) as a yellow solid. LCMS (ESI, m / z): 602.20 [M+H] +< , tR = 3.515 min (CHIRALPAK IG-3, 0.46*10cm;3um, MtBE(0.1%DEA):EtOH=70:30, 1.0mL / min).Example 36: 6-[4-[(2-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]pyridin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile and 6-[4-[(2-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]pyridin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

[0540] Step 1: Synthesis of methyl 2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2, 3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-4-carboxylate

[0541] A solution of 5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (441 mg, 1.00 mmol, 1.00 equiv), [Pd(allyl)Cl] 2 (36.6 mg, 0.10 mmol, 0.10 equiv), Rockphos (46.8 mg, 0.10 mmol, 0.10 equiv), Cs 2 CO 3 (65.2 mg, 0.20 mmol, 2.00 equiv), methyl 2-bromopyridine-4-carboxylate (430 mg, 1.99 mmol, 2.00 equiv) in toluene (10 mL) was stirred for 3 h at 80 °C. The solvent was concentrated under vacuum and the residue was applied onto a silica gel column eiluting with EtOAc / petroleum ether (3:7) to afford 420 mg (73 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 577.21 [M+H] +< .Step 2: Synthesis of 2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-4-carboxylic acid.

[0542] A solution of methyl 2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxymethyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-4-carboxylate (420 mg, 0.73 mmol, 1.00 equiv), LiOH (87.6 mg, 3.66 mmol, 5.00 equiv), water (2 ml) in methanol (10 ml) was stirred for 3 h at room temperature. The pH value of the solution was adjusted to 5 with hydrogen chloride. The solvent was concentrated under vacuum and the residue was applied onto a silica gel column eluting with acetate / petroleum ether (2:1) to afford 300mg (73 %) of the title compound as a solid. LCMS (ESI, m / z): 563.20 [M+H] +< .Step 3: Synthesis of 2-([2-[6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-4-carboxylic acid.

[0543] A solution of 2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-4-carboxylic acid (300 mg, 0.52 mmol, 1.00 equiv) in hydrogen chloride / dioxane (20 mL) was stirred for 2 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN to afford 261 mg crude of the title compound as a solid. LCMS (ESI, m / z): 433.11 [M+H] +< .Step 4: Synthesis of 6-[ 4-[(2-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxypyridin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile and 6-[4-[(2-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]-2, 3-dihydro-1H-isoindol-1-ylmethoxy[pyridin-4-yl)carbonyl[piperazin-1-yl[pyridine-3-carbonitrile

[0544] A solution of 2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyridine-4-carboxylic acid (261 mg, 0.60 mmol, 1.00 equiv), HATU (277.4 mg, 0.73 mmol, 1.20 equiv), DIPEA (309.6 mg, 2.40 mmol, 4.00 equiv), Int-A4 (136.3 mg, 0.72 mmol, 1.20 equiv) in DMF (3 mL) was stirred for 2 h at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC and Chiral-Prep-HPLC yielding the title compounds. The absolute stereochemistry was assigned based on a protein X-ray crystal structure obtained of Example 18 Isomer B which confirmed (S)-absolute stereochemistry and was observed to be the more potent enantiomer.

[0545] Example 36 Isomer A: (11 mg, 20 %) as a white solid. LCMS (ESI, m / z): 603.10 [M+H]+, 1< HNMR (Methanol-d4, 300 MHz) δ: 8.45 (d, J = 2.1 Hz, 1H), 8.35 (s, 1H), 8.25 (d, J= 5.2 Hz, 1H), 7.79 (dd, J= 9.1, 2.4 Hz, 1H), 7.50 (d, J = 4.2 Hz 1H), 7.40 (d, J = 2.0 Hz, 3H), 7.02 (dd, J= 5.2, 1.3 Hz, 1H), 6.92 (d, J = 8.9 Hz, 1H), 6.74 (s, 1H), 6.18 (t, J = 2.1 Hz, 1H), 5.24 (d, J= 14.7 Hz, 1H), 4.84 (d, J = 4.2 Hz, 1H), 4.75 - 4.71 (m, 1H), 4.70 - 4.64 (m, 1H), 3.86 (s, 4H), 3.74-3.68 (m, 2H), 3.61-3.49 (m, 2H). tR = 2.208 min (CHIRALPAK IG-3, 0.46*5cm;3um, Hex : DCM= 1:1 (0.1%DEA):EtOH=30:70, 1.0mL / min)

[0546] Example 36 Isomer B: (10.7 mg, 10 %) as a white solid. LCMS (ESI, m / z): 603.10 [M+H] +< . tR = 2.947 min(CHIRALPAK IG-3, 0.46*5cm;3um, Hex : DCM= 1:1 (0.1%DEA):EtOH=30:70, 1.0mL / min).Example 37: 5-[[(2S)-1-(3-Oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)butan-2-yl]oxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0547] Step 1: 3-[(2S)-2-Hydroxybutoxy]-1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propan-1-one

[0548] A solution of Int-20 (1 g, 3.49 mmol, 1 equiv), (2S)-butane-1,2-diol (1574.1 mg, 17.47 mmol, 5 equiv), and Cs 2 CO 3 (2276.4 mg, 6.99 mmol, 2.00 equiv) in MeCN (10 mL) was stirred for 4 h at 75 ° C. The resulting solution was diluted with 300 mL of DCM. The resulting mixture was washed with 45 mLx2 of H 2 O and 45 mLx2 of saturated sodium chloride aqueous solution. The residue was applied onto a silica gel column with DCM / EtOAc (1 / 1) to afford 1.16 g (81.2 %) of the title compound as yellow solids. LCMS (ESI, m / z): 377.37 [M+H] +< Step 2: 2-[(4-Methoxyphenyl)methyl]-5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)butan-2-yl]oxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0549] A solution of 3-[(2S)-2-hydroxybutoxy]-1-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propan-1-one (0.37 g, 0.98 mmol, 1 equiv), Cs 2 CO 3 (0.64 g, 1.96 mmol, 2 equiv), and 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (0.939 g, 1.96 mmol, 3.00 equiv) in MeCN (6 mL) was stirred for 18 h at 80 ° C . The resulting solution was diluted with 300 mL of EtOAc. The resulting mixture was washed with 45 mLx2 of water and 45 mLx2 of saturated sodium chloride, then dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with EtOAc / petroleum ether (2 / 3) to afford 0.28 g (32.0 %) of the title compound as white solids. LCMS (ESI, m / z): 721.85 [M+H] +< Step 3: 5-[[(2S)-1-(3-Oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)butan-2-yl]oxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one

[0550] A solution of 2-[(4-methoxyphenyl)methyl]-5-[[(2S)-1-(3-oxo-3-[4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]propoxy)butan-2-yl]oxy]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (0.27 g, 0.410 mmol, 1 equiv), and H 2 SO 4 (0.402 g, 4.1 mmol, 10 equiv) in TFA (7 mL) was stirred for 3 days at 25 ° C. The reaction mixture was cooled with a water / ice bath. The resulting solution was diluted with 300 mL of DCM. The resulting mixture was washed with 45 mL x 2 of water and 45 mLx2 of saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated. The residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN yielding the title compound (16.1 mg, 33.7 %) as white solids. LCMS (ESI, m / z): 539.25 [M+H] +< , 1< H-NMR (400 MHz, DMSO-d 6 ) δ: 13.22 (s, 1H), 8.74 (s, 2H), 8.28 (s, 1H), 5.01 (d, J= 6.7 Hz, 1H), 3.86 - 3.75 (m, 4H), 3.76 - 3.58 (m, 3H), 3.54 - 3.50 (m, 5H), 2.55 (d, J= 6.3 Hz, 2H), 1.71 - 1.58 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H).Example 38 Isomer A: 6-[4-[(2-[[(1S)-2-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]pyrimidin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile and Example 38 Isomer B: 6-[4-[(2-[[(1R)-2-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy]pyrimidin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

[0551] Step 1: Methyl 2-([2-[6-oxo-5-(trifluoromethyl)-]-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrimidine-4-carboxylate

[0552] A solution of 5-[1-(hydroxymethyl)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (500 mg, 1.13 mmol, 1.00 equiv), (Pd(allyl)Cl) 2 (53 mg, 0.10 equiv), Rockphos (41 mg, 0.10 equiv), Cs 2 CO 3 (1.1 mg, 3.00 equiv), methyl 2-chloropyrimidine-4-carboxylate (292 mg, 1.69 mmol, 1.50 equiv) in toluene (10 mL) under nitrogen condition was stirred for overnight at 85 °C. The solvent was concentrated under vacuum and the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1 / 1) to afford 420 mg (64 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 578.20 [M+H] +< Step 2: Synthesis of methyl 2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2, 3-dihydro-1H-isoindol-1-yl]methoxy)pyrimidine-4-carboxylate

[0553] A solution of methyl 2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxymethyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrimidine-4-carboxylate (420 mg, 0.73 mmol, 1.00 equiv) in dioxane / HCl (20 mL,4 M) was stirred for overnight at 25°C. The solvent was concentrated under vacuum to afford 300 mg (92 %) of the title compound as yellow oil. LCMS (ESI, m / z): 448.12 [M+H] +< Step 3: Synthesis of 2-([2-[6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]-2, 3-dihydro-1H-isoindol-1-yl]methoxy)pyrimidine-4-carboxylic acid

[0554] A solution of methyl 2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrimidine-4-carboxylate (400 mg, 0.89 mmol, 1.00 equiv), LiOH.H 2 O (200 mg, 4.77 mmol, 5.00 equiv) in MeOH (10 mL) and water (2 mL) was stirred for 2 h at 25 °C. The resulting solution was concentrated under vacuum. The residue was diluted with 3 mL of water, then the pH value of the solution was adjusted to 2 with hydrochloricacid and the solid was filtered to afford 215 mg (55 %) of the title compound as a pink solid. LCMS (ESI, m / z): 434.10 [M+H] +< Step 4: Synthesis of 6-[ 4-[(2-[[(1R)-2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2, 3-dihydro-1H-isoindol-1-yl]methoxy]pyrimidin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile and 6-[4-[(2-[[(1S)-2-[6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]-2, 3-dihydro-1H-isoindol-1-yl]methoxy]pyrimidin-4-yl)carbonyl]piperazin-1-yl]pyridine-3-carbonitrile

[0555] A solution of 2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-1-yl]methoxy)pyrimidine-4-carboxylic acid (100 mg, 0.23 mmol, 1.00 equiv), HOBT (47 mg, 0.35 mmol, 1.50 equiv), EDCI (67 mg, 0.35 mmol, 1.50 equiv), DIPEA (90 mg, 0.70 mmol, 3.00 equiv), Int-A4 (87 mg, 0.46 mmol, 2.00 equiv) in DMF (3 mL) was stirred for overnight at 25 °C. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN. Then the residue was further purified by Prep-HPLC and Chiral-Prep-HPLC yielding the title compounds. The absolute stereochemistry was assigned based on a protein X-ray crystal structure obtained of Example 18 Isomer B which confirmed (S)-absolute stereochemistry and was observed to be the more potent enantiomer.

[0556] Isomer A (6.1 mg, 23 %) as a white solid. LCMS (ESI, m / z): 604.20 [M+H]+, 1< H NMR (300 MHz, DMSO-d6) δ: 12.57 (s, 1H), 8.69 (d, J = 4.9 Hz, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.31 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.48 (s, 1H), 7.38 (d, J = 9.9 Hz, 3H), 7.28 (d, J = 4.9 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 6.14 (s, 1H), 5.04 (d, J = 14.4 Hz, 1H), 4.90 (d, J = 11.8 Hz, 1H), 4.71 - 4.41 (m, 2H), 3.97 - 3.55 (m, 6H), 3.40 (m, 2H). tR = 4.448 min (CHIRALPAK IC-3, 0.46*10cm;3um, MtBE(0.1%DEA):EtOH=80:20, 1.0mL / min) and isomer B (6.4 mg, 25 %) as a white solid. LCMS (ESI, m / z): 604.20 [M+H] +< , tR = 5.550 min (CHIRALPAK IC-3, 0.46*10cm;3um, MtBE(0.1%DEA):EtOH=80:20, 1.0mL / min).Example 39: 6-[4-([3-[2-([2-[6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]phenyl]carbonyl)piperazin-1-yl]pyridine-3-carbonitrile

[0557] Step 1: Synthesis of 5-[4-(2-hydroxyethoxy)-2, 3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0558] A solution of 5-(4-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (2 g, 4.68 mmol, 1.00 equiv), potassium carbonate (3.2 g, 23.15 mmol, 5.00 equiv), 2-bromoethan-1-ol (2.9 g, 23.21 mmol, 5.00 equiv) in DMF (30 mL, 5.00 equiv) was stirred for 12 h at 80 °C in an oil bath. The reaction mixture was diluted with H 2 O (200 mL). The resulting solution was extracted with EtOAc (4x100 mL) and the organic layers were combined. After concentration, the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1:4) to afford 1.35 g (61 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 472.18 [M+H] +< Step 2: Synthesis of methyl 3-[2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]benzoate

[0559] Under nitrogen, a solution of 5-[4-(2-hydroxyethoxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (675 mg, 1.43 mmol, 1.00 equiv), [Pd(allyl)Cl] 2 (67 mg, 0.10 equiv), Rockphos (52 mg, 0.10 equiv), CS 2 CO 3 (932 mg, 2.86 mmol, 2.00 equiv), methyl 3-bromobenzoate (612 mg, 2.85 mmol, 2.00 equiv) in Toluene (10 mL) was stirred for 12 h at 80 °C in an oil bath. After filtration, the filtrate was concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1:1) to afford 624 mg (72 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 606.22 [M+H] +< Step 3: Synthesis of methyl 4-[2-([2-[6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]benzoate

[0560] A solution of methyl 4-[2-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]benzoate (624 mg, 1.03 mmol, 1.00 equiv) in hydrogen chloride / dioxane (20 mL) was stirred for 12 h at room temperature. After concentration, the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (1:2) to afford 400 mg (82 %) of the title compound as a yellow solid. LCMS (ESI, m / z): 476.22 [M+H] +< Step 4: Synthesis of 4-[2-([2-[6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]-2, 3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]benzoic acid

[0561] A solution of methyl 4-[2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]benzoate (400 mg, 0.84 mmol, 1.00 equiv), LiOH (120 mg, 5.01 mmol, 5.00 equiv) in MeOH (5 mL) and water (1 mL) was stirred for 2 h at room temperature. The pH value of the solution was adjusted to 3 with hydrogen chloride. The solids were collected by filtration to afford 260 mg (67 %) of the title compound as a gray solid. LCMS (ESI, m / z): 462.12 [M+H] +< Step 5: Synthesis of 6-[4-([3-[2-([2-[6-oxo-5-(trifluoromethyl)-1, 6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]phenyl]carbonyl)piperazin-1-yl]pyridine-3-carbonitrile

[0562] A solution of 3-[2-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]-2,3-dihydro-1H-isoindol-4-yl]oxy)ethoxy]benzoic acid (260 mg, 0.56 mmol, 1.00 equiv), HATU (232 mg, 0.61 mmol, 1.00 equiv), DIPEA (315 mg, 2.44 mmol, 4.00 equiv), Int-A4 (115 mg, 0.61 mmol, 1.00 equiv) in DMF (2 mL) was stirred for 30 min at room temperature. After concentration, the residue was purified by C18 reverse phase chromatography eluting with H 2 O / CH 3 CN yielding the title compound (89.8 mg, 25 %) as a white solid. LCMS (ESI, m / z): 632.22 [M+H] +< , 1< H NMR (Methanol-d 4 , 400 MHz) δ: 8.43 - 8.41 (d, J = 2.3 Hz, 1H), 8.03 (s, 1H), 7.77 - 7.74 (dd, J = 9.1, 2.3 Hz, 1H), 7.44 - 7.30 (dt, J = 25.9, 7.9 Hz, 2H), 7.14 - 6.95 (m, 5H), 6.89 - 6.86 (d, J = 9.0 Hz, 1H), 5.02 - 4.98 (m, 2H), 4.92 - 4.88 (m, 2H), 4.47 - 4.43 (m, 4H), 3.91 - 3.53 (m, 8H).Example 40: 6-(4-[[3-([1-[6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl]piperidin-2-yl]methoxy)phenyl]carbonyl] piperazin-1-yl)pyridine-3-carbonitrile

[0563] Step 1: Synthesis of 5-[2-(hydroxymethyl)piperidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one

[0564] A solution of 5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydropyridazin-3-one (2 g, 6.08 mmol, 1.00 equiv), piperidin-2-ylmethanol (772.3 mg, 6.71 mmol, 1.10 equiv) and TEA (1.35796 g, 13.42 mmol, 2.00 equiv) in ethanol (40 mL) was stirred for 2h at 60 °C, and then the resulting solution was concentrated under vacuum, and then the residue was applied onto a silica gel column eluting with EtOAc / petroleum ether (3:1) to afford 639 mg (26 %) of the ...

Claims

1. A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: X is Cl, Br, CH3, CF3, CN, OCH3, cyclopropyl, SCH3, or isopropyl; A is a group having the formula (A-2): L is C1-3 alkylene, O, S, NRY, C(=O), C(=O)O, C(=O)NRY, S(=O), S(=O)NRY, or NRYC(=O)NRY; RY is H or C1-4 alkyl; Z is H, CyZ, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rb, NRc(O)ORa, NRcC(O)NRcRd, C(=NRe)Rb, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of Z are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from CyZ, halo, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; CyZ is selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRc1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; each R13 is independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, C(=NRe4)Rb4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of said R13 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, C(=NRe4)Rb4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; Q1 is a group of formula (B-1): Y4, Y5, and Y6 are each independently selected from O, S, NRY, C(=O), C(=O)O, C(=O)NRY, S(=O), S(=O)2, S(=O)NRY, S(=O)2NRY or NRYC(=O)NRY; G1 is -C(RG)(RH)- or a group of formula (C-1), (C-2), or (C-3): G2 is -C(RI)(RJ)- or a group of formula (C-1), (C-2), or (C-3); RA, RB, RC, RD, RE, RF, RG, RH, RI, RJ, RK, RL, RM, and RN are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)NRc5Rd5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5,NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of said RA, RB, RC, RD, RE, RF, RG, RH, RI, RJ, RK, RL, RM, and RN are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5; or RG and RI together with the carbon atoms to which they are attached and together with Y5 form a 5-10 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, C(=NRe3)Rb3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3S(O)Rb3, NRS(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3; or RC and RE together form a double bond between the carbon atoms to which they are attached; or RE and RG together form a double bond between the carbon atoms to which they are attached; or RI and RK together form a double bond between the carbon atoms to which they are attached; or RK and RM together form a double bond between the carbon atoms to which they are attached; or RK, RL, RM, and RN together form a triple bond between the carbon atoms to which they are attached; D1 and D2 are each independently selected from N and CH; D3, D4, D5, D6, D7, D8, and D9 are each independently selected from N and CRX, wherein each RX is independently selected from H, halo, and C1-4 alkyl; D10 is O, S, NH or CH2; Ring F is a mono- or polycyclic ring selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa6, SRa6, C(O)Rb6, C(O)NRc6Ra6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, C(=NRc6)NRc6Rd6, NRc6C(=NRe6)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NR6C(O)NRc6Wd6, NRc6S(O)Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, and S(O)2NRc6Ra6, wherein the alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, ORa6, SRa6, C(O)Rb6, C(O)NRc6Ra6, C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, C(=NRe6)NRc6Rd6, NRc6C(=NRc6)NRc6Rd6, NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, NRc6S(O)Rb6, NRc6S(O)2Rb6, NRc6S(O)2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O)2Rb6, and S(O)2NRc6Ra6, each Ra, Rb, Rc, Rd, Ra, Rb1, Rc1, Rd1, Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, Rd4, Ra5, Rb5, Rc5, Rd5, Ra6, Rb6, Rc6, and Rd6 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of said Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, Rd2, Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, Rd4, Ra5, Rb5, Rc5, Rd5, Ra6, Rb6, Rc6, and Rd6 is optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(=NRe7)NRc7Rd7, NRc7C(=NRe7)NRc3Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7; or Rc and Rd together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from CN, halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)Rc7Rd7, NRc7C(O)ORa7, C(=NRe7)NRc7Rd7, NRc7C(=NRe7)NRc3Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7; or Rc3 and Rd3 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from CN, halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(=NRe7)NRc7Rd7, NRc7C(=NRe7)NRc3Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7; or Rc4 and Rd4 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from CN, halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(=NRe7)NRc7Rd7, NRc7C(=NRe7)NRc3Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7; or Rc5 and Rd5 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from CN, halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NW7C(O)NW7W7, NRc7C(O)ORa7, C(=NRe7)NRc7Rd7, NRc7C(=NRe7)NRc3Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7; or Rc6 and Rd6 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from CN, halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa7, SRa7, C(O)Rb7, C(O)NRc7Rd7, C(O)ORa7, OC(O)Rb7, OC(O)NRc7Rd7, NRc7Rd7, NRc7C(O)Rb7, NRc7C(O)NRc7Rd7, NRc7C(O)ORa7, C(=NRe7)NRe7Rd7, NRc7C(=NRe7)NRc3Rd7, S(O)Rb7, S(O)NRc7Rd7, S(O)2Rb7, NRc7S(O)2Rb7, NRc7S(O)2NRc7Rd7, and S(O)2NRc7Rd7; Ra7, Rb7, Rc7, and Rd7 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; each Re, Re1, Re3, Re4, Re5, Re6 and Re7 is independently selected from H, C1-4 alkyl, and CN; a is 0 or 1; b is 0, 1, 2, or 3; c is 0, 1, or 2; d is 0, 1, or 2; m is 0 or 1; n is 0 or 1; p is 0 or 1; q is 0 or 1; r is 0 or 1; s1 is 0, 1, or 2; s2 is 0, 1, 2, or 3; v is 0 or 1; and w is 0 or 1; wherein any aforementioned heteroaryl or heterocycloalkyl group comprises 1, 2, 3, or 4 ring-forming heteroatoms independently selected from O, N, and S; and wherein one or more ring-forming C or N atoms of any aforementioned heterocycloalkyl group is optionally substituted by an oxo (=O) group.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Q1 is a group of: or or wherein Z1 and Z2 are each independently selected from N and CH, and wherein R is CN, Cl, or CF3.

3. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein X is CF3, CH3, CN, Cl, or Br.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein Ring F is 4-10 membered heterocycloalkyl or C3-7 cycloalkyl optionally substituted with C1-6 alkyl, wherein said C1-6 alkyl is optionally substituted with ORa6; optionally wherein (a) Ring F is 4-10 membered heterocycloalkyl or C3-7 cycloalkyl, each optionally substituted with methyl; or (b) Ring F is piperazinyl, piperidinyl, pyrrolidinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 2,8-diazaspiro[4.5]decanyl, 2,5-diazabicyclo[2.2.2]octanyl, 1,4-diazepanyl, azetidinyl, 2,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.4]octanyl, octahydropyrrolo[3,2-b]pyrrolyl, 2,7-diazaspiro[4.4]nonanyl, 2,5-diazabicyclo[2.2.1]heptanyl, octahydropyrrolo[3,4-c]pyrrolyl, or 2,7-diazaspiro[3.5]nonanyl; or (c) Ring F is piperazinyl; or (d) Ring F is cyclohexyl; or (e) Ring F is 4-10 membered heterocycloalkyl, optionally substituted by an oxo (=O) group.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Z is CyZ, C1-6 alkyl, or C(O)Rb, wherein said C1-6 alkyl is optionally substituted by halo; optionally Z is CF3.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein CyZ is: (a) selected from 5-10 membered heteroaryl and C6-10 aryl, optionally substituted by C1-6 alkyl, CN or CF3, wherein said C1-6 alkyl is optionally substituted with CN; or (b) pyridinyl, pyrimidinyl, or pyrazinyl, optionally substituted by C1-6 alkyl, CN, Cl, S(O)2Rb1, or CF3; or (c) pyridinyl, pyrimidinyl, or pyrazinyl, optionally substituted by methyl, CN, Cl, CF3, or S(O)2CH3; or (d) phenyl, optionally substituted with cyanomethyl or CN; optionally wherein Rb is C1-6 alkyl; or optionally wherein Rb is methyl.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein Y4 is: (a) O or NRY; or (b) O; or (c) NRY; optionally wherein Y5 is O, NRY, or C(=O)NRY; further optionally wherein Y6 is C(=O) or C(=O)NRY.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein RY is: (a) H or C1-4 alkyl; or (b) H; or (c) methyl.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein L is O or NRY; optionally wherein G1 is -C(RG)(RH)-; further optionally wherein G2 is C-1.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein (i) D1 and D2 are each CH and D10 is CH2; or (ii) D1 is CH, D2 is N, and D10 is CH2; or (iii) D3 is CH, D4 is N, D5 is CH.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein D10 is CH2.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein: (a) b is 0, c is 1, and d is 1; or (b) b is 0, c is 2, and d is 0; or (c) b is 0, c is 0, and d is 0; or (d) b is 0, c is 1, and d is 0.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein: (a) G2 is C-2; optionally wherein D3, D4, and D5 are each CRX, wherein each RX is independently selected from H, halo, and C1-4 alkyl; or (b) G2 is C-3.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein: (a) D6, D7, and D9 are CRX, and D8 is N; or (b) D6 and D7 are each N, and D8 and D9 are each CRX; or (c) D6, D7, D8, and D9 are each CRX; or (d) D6, D8, and D9 are each CRX, and D7 is N; or (e) D6, D7, and D8 are each CRX and D9 is N; or (f) D6 and D8 are each N, and D7 and D9 are each CRX.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein each RX is: (a) H or halo; or (b) H or F; or (c) H; optionally wherein, G2 is -C(RI)(RJ)-.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R13 is: (a) C1-6 alkyl, ORa4, CN, or NRc4Rd4, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo and ORa4 and NRc4Rd4; or (b) methyl; or (c) CN; or (d) CF3; or (e) amino; or (f) aminomethyl.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein: (a) RA is (i) H, halo, ORa5, C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl, wherein said C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl is optionally substituted with ORa5 or NRc5Rd5; or (ii) C1-6 alkyl or H; and / or (b) RB is (i) H, halo, ORa5, C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl, wherein said C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl is optionally substituted with ORa5 or NRc5Rd5; or (ii) C1-6 alkyl or H; and / or (c) RC is (i) H, halo, ORa5, C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl, wherein said C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl is optionally substituted with ORa5 or NRc5Rd5; or (ii) C1-6 alkyl or H; and / or (d) RD is (i) H, halo, ORa5, C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl, wherein said C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl is optionally substituted with ORa5 or NRc5Rd5; or (ii) C1-6 alkyl or H; and / or (e) RE is (i) H, halo, ORa5, C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl, wherein said C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl is optionally substituted with ORa5 or NRc5Rd5; or (ii) RE is C1-6 alkyl or H; and / or (f) RF is (i) H, halo, ORa5, C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl, wherein said C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl is optionally substituted with ORa5 or NRc5Rd5; or (ii) C1-6 alkyl or H; and / or (g) RG is H, halo, ORa5, C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl, wherein said C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl is optionally substituted with ORa5 or NRc5Rd5; or (ii) C1-6 alkyl or H; and / or (h) RH is (i) H, halo, ORa5, C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl, wherein said C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl is optionally substituted with ORa5 or NRc5Rd5; or (ii) C1-6 alkyl or H; and / or (i) RI is (i) H, halo, ORa5, C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl, wherein said C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl is optionally substituted with ORa5 or NRc5Rd5; or (ii) C1-6 alkyl or H; and / or (j) RJ is (i) H, halo, ORa5, C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl, wherein said C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl is optionally substituted with ORa5 or NRc5Rd5; or (ii) C1-6 alkyl or H; and / or (k) RK is (i) H, halo, ORa5, C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl, wherein said C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl is optionally substituted with ORa5 or NRc5Rd5; or (ii) C1-6 alkyl or H; and / or (l) RL is (i) H, halo, ORa5, C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl, wherein said C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl is optionally substituted with ORa5 or NRc5Rd5; or (ii) C1-6 alkyl or H; and / or (m) RM is (i) H, halo, ORa5, C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl, wherein said C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl is optionally substituted with ORa5 or NRc5Rd5; or (ii) C1-6 alkyl or H; and / or (n) RN is (i) H, halo, ORa5, C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl, wherein said C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, or C6-10 aryl-C1-4 alkyl is optionally substituted with ORa5 or NRc5Rd5; or (ii) C1-6 alkyl or H.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein: (a) RI and RK together form a double bond between the carbon atoms to which they are attached; or (b) RK and RM together form a double bond between the carbon atoms to which they are attached; or (c) RK, RL, RM, and RN together form a triple bond between the carbon atoms to which they are attached; or (d) RG and RI together with the carbon atoms to which they are attached and together with Y5 form a 5-10 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Ra3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, C(=NRe3)Rb3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3; or (e) RG and RI together with the carbon atoms to which they are attached and together with Y5 form a tetrahydrofuranyl ring.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, having: (a) (b) 20. A pharmaceutical composition comprising a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

21. A compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a patient in need of treatment; optionally wherein said cancer is breast cancer, cancer of the central nervous system, endometrium cancer, kidney cancer, large intestine cancer, lung cancer, oesophagus cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, head and neck cancer (upper aerodigestive cancer), urinary tract cancer, or colon cancer.