Fused pyridazine derivatives as NLRP3 inhibitors

Abstract

Compounds of formula (I) and pharma- ceutically acceptable salts thereof (wherein α, β, m, R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R a , R b , X 1 , X 2 , X 3 , X 4 and X 8 (I) is defined herein. The disclosure also relates to materials and methods for preparing the compounds of formula (I), pharmaceutical compositions containing them, and their use for treating diseases, disorders, and conditions associated with NLRP3. JPEG2025511819000353.jpg57158

Description

[Technical Field]

[0001] The present invention relates to fused pyridazine derivatives, including 1-amino-4-arylphthalazine, azaphthalazine, and oxaphthalazine derivatives, that are inhibitors of the NLRP3 inflammasome, pharmaceutical compositions containing them, and their use for treating diseases, disorders, and conditions associated with NLRP3, including neurodegenerative diseases such as Parkinson's disease and other diseases, disorders, and conditions of the central nervous system (CNS). [Background technology]

[0002] More than 1% of the world's population suffers from neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and prion diseases, all of which lack effective treatments. The incidence of neurodegenerative diseases is expected to double over the next few decades, particularly affecting aging societies. See I. Fernandez-Cruz and E. Reynaud, "Proteasome Subunits Involved in Neurodegenerative Diseases," Arch Med Res. 52(1):1-14 (2021).

[0003] One of the pathological hallmarks of neurodegenerative diseases is the aggregation of certain proteins into oligomers or fibrils. These conformational changes result in neurotoxicity, leading to inflammation and neurodegeneration. Although the clinical manifestations of these diseases are heterogeneous, they often share common underlying mechanisms and pathophysiology. See BN Dugger and DW Dickson, “Pathology of Neurodegenerative Diseases,” Cold Spring Harbor Perspect Biol. 9(7):a028035 (2017). Indeed, systemic activation of the innate immune system, the first line of host defense against pathogens and tissue damage, and the subsequent neuroinflammation play a key role in the development and progression of these diseases. See S. Amor, F. Puentes, D. Baker, et al., “Inflammation in neurodegenerative diseases,” Immunology 129(2):154-69 (2010). Neuroinflammation is a physiological response to exogenous and endogenous insults targeting the central nervous system (CNS) and represents a protective response in the brain. However, excessive inflammatory responses are harmful to the CNS. See L.I. Labzin, M.T. Heneka, and E. Latz, "Innate Immunity and Neurodegeneration," Annu Rev Med 69:437-449 (2018).

[0004] Microglia, myeloid cells of the CNS, play a key role during the innate immune response in the CNS. They express pattern recognition receptors (PRRs) that enable the host to recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) derived from the host or the environment. See R.M. Ransohoff and M.A. Brown, “Innate immunity in the central nervous system,” J Clin Invest 122(4):1164-71 (2012). PRRs include Toll-like receptors, C-type lectin receptors, RIG-1-like receptors, and nucleotide-binding oligomerization domain-like receptors (NLRs). See P. Broz and V.M. Dixit, “Inflammasomes: mechanism of assembly, regulation, and signaling,” Nat Rev Immunol 16(7):407-20 (2016). PRR binding activates various inflammatory signaling pathways to eliminate infection and repair damaged tissue. Ongoing inflammation, seen in various neurodegenerative diseases, can be maintained by inflammasomes, important innate immune sensors of danger signals. Several different inflammasomes exist, all defined by the PRRs they contain. Among the NLR family of PRRs, NLRs (NLRP1, NLRP3, and NLRC4) and two other PRRs (pyrin and AIM2) are known to form inflammasomes. See D. Zheng, T. Liwinski, and E. Elinav, “Inflammasome activation and regulation: toward a better understanding of complex mechanisms,” Cell Discov 6:36 (2020).

[0005] The NLRP3 (nucleotide-binding domain (NOD)-, leucine-rich repeat-containing domain (LRR), and pyrin domain-containing 3) inflammasome has been the subject of intense interest over the past decade. See N. Kelley, D. Jeltema, Y. Duan, et al., “The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation,” Int J Mol Sci 20(13):3328 (2019). The NLRP3 inflammasome consists of three major components: a pattern recognition receptor (PRR) protein (NLRP3); an apoptosis-associated speck-like protein (ASC) containing a caspase activation and recruitment domain (CARD), which functions as a central adaptor protein; and the proinflammatory caspase, caspase-1. See Kelley et al. (2019). NLRP3 contains three domains: an amino-terminal pyrin domain (PYD), a central NACHT domain with ATPase activity that is important for NLRP3 self-association and oligomerization, and a carboxy-terminal LLR domain (see Broz and Dixit (2016)).

[0006] NLRP3 inflammasome activation involves a two-step process. A first "priming" signal is generated by the detection of PAMPs or DAMPs via TLRs. This priming signal leads to NF-κB-dependent transcriptional upregulation of NLRP3 and pro-IL-1, but also regulates post-translational modifications of NLRP3. See J. Yang, Z. Liu and T.S. Xiao, "Post-translational regulation of inflammasomes," Cell Mol Immunol 14(1):65-79 (2017). This initial trigger is followed by a second "activating" signal (β-amyloid, α-synuclein, and other proteinaceous insults, ATP, crystals, nucleic acids, and toxins), which induces conformational changes in various inflammasome components, subsequently assembling and nucleating oligomerization of monomeric NLRP3, leading to the formation and activation of the NLRP3 inflammasome. See A. Lu, V.G. Magupalli, J. Ruan, et al., “Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes,” Cell 156(6):1193-1206 (2014). This large multimeric protein acts through caspase-1-dependent proteolytic cleavage of several proteins, including pro-interleukin (pro-IL)-18 and pro-IL-1β, into their mature inflammatory cytokines, IL-18 and IL-1β. See Kelley et al. (2019). Caspase-1 also cleaves gasdermin D (GSDMD), which promotes insertion of GSDMD into the plasma membrane to form pores and initiate a specific type of cell death called pyroptosis, which releases soluble intracellular fractions that promote the inflammatory response.See S. L. Fish and B. T. Cookson, “Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages,” Cell Microbiol 8(11):1812-25 (2006).

[0007] In addition to this "canonical" NLRP3 inflammasome activation pathway, a "non-canonical" NLRP3 activation pathway has been described. The non-canonical pathway involves cytosolic LPS-mediated activation of caspase-4 / 5 (or its mouse orthologue, caspase-11), which induces pyroptosis via cleavage of GSDMD and releases high-mobility group box 1 protein (HMGB1), resulting in the production of IL-1β. See M. Lamkanfi and V.M. Dixit, "Mechanisms and functions of inflammasomes," Cell 157(5):1013-22 (2014); F. Shi, Y. Yang, M. Kouadir M, et al., "Inhibition of phagocytosis and lysosomal acidification suppresses neurotoxic prion peptide-induced NALP3 inflammasome activation in BV2 microglia," J Neuroimmunol 260(1-2):121-5 (2013). In both pathways, activation of the NLRP3 inflammasome leads to the production of biologically active forms of the proinflammatory cytokines IL-1β and IL-18, which initiate inflammatory signaling cascades that contribute to neuroinflammation, neuronal injury, and cell death. See S. M. Allan, P. J. Tyrrell, and N. J. Rothwell, "Interleukin-1 and neuronal injury," Nat Rev Immunol, 5(8):629-40 (2005); A. Alboni, D. Cervia, S. Sugama, et al., "Interleukin 18 in the CNS," J Neuroinflammation, 7:9 (2010).

[0008] Heterozygous gain-of-function mutations in the NLRP3 gene are associated with the development of an autoinflammatory condition called cryopyrin-associated periodic syndrome (CAPS). See L. M. Booshehri and H. M. Offman, “CAPS and NLRP3,” J Clin Immunol 39(3):277-286 (2019). This is a rare, inherited autoinflammatory disorder characterized by inflammation throughout the body, the skin, the musculoskeletal system, and the central nervous system, and is estimated to affect approximately 1–3 people per million worldwide. See L. Cuisset, I. Jeru, B. Dumont, et al., “Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France,” Ann Rheum Dis 70(3):495-9 (2011); Erratum in: Ann Rheum Dis 71(7):1264 (2012). Clinicians classify CAPS disorders based on the severity of symptoms. The most severe form of CAPS is known as neonatal-onset multisystem inflammatory disease (NOMID / CINCA). An intermediate form of CAPS is called Muckle-Wells syndrome (MWS). Familial cold autoinflammatory syndrome (FCAS) is a milder form of CAPS that is triggered by cold temperatures. See Booshehri and Hoffman (2019). Current anti-IL-1 therapies (anakinra, rilonacept, canakinumab) have proven successful in treating CAPS, but clinical experience over the past decade has shown that some CAPS patients respond less well over time, requiring higher or more frequent dosing or a switch in therapy.Arthritis Res Ther 15(1):R33(2013);S. Urien, C. Bardin, B. Bader-Meunier, et al al.,“Pharmacokinetics of Anakinra in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes,”BMC Pharmacol Toxicol 14:40(2013).

[0009] Several small molecule inhibitors that block the NLRP3 inflammasome pathway have recently been reported. These include the prototypic NLRP3 inhibitor MCC-950. See R.C. Coll, J.R. Hill, C.J. Day, et al., "MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition," Nat Chem Biol 15(6):556-559 (2019); R.C. Coll, A.A. Robertson, J.J. Chae, et al., "A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases," Nat Med 21(3):248-55 (2015). Other NLRP3 inhibitors include Bay 11-7082, CY-09, oridonin, tranilast, INF-39, glyburide, and JC-124. See W. Jiang, M. Li, F. He, et al., "Inhibition of NLRP3 inflammasome attenuates spinal cord injury-induced lung injury in mice," J Cell Physiol 234(5):6012-6022 (2019). MCC-950 has been used in many studies as a pharmacological tool to validate the NLRP3 inflammasome as a viable drug target for developing therapeutics for human disease. See S. E. Corcoran, R. Halai, and M. Cooper, "Pharmacological Inhibition of the Nod-Like Receptor Family Pyrin Domain Containing 3 Inflammasome with MCC950," Pharmacol Rev 73(3):968-1000 (2021).

[0010] Inhibitors of the NLRP3 inflammasome pathway are expected to be useful in the treatment of neurodegenerative diseases, including Parkinson's disease, and in the treatment of CAPS disorders associated with heterozygous gain-of-function mutations in the NLRP3 gene. Summary of the Invention

[0011] The present invention provides fused pyridazine derivatives, including 1-amino-4-arylphthalazine, azaphthalazine, and oxaphthalazine derivatives, and pharmaceutically acceptable salts thereof. The present invention also provides pharmaceutical compositions containing the fused pyridazine derivatives and their use for treating diseases, disorders, and conditions associated with NLRP3, including Parkinson's disease and other neurodegenerative disorders of the central nervous system.

[0012] One aspect of the present invention is a compound of formula 1:

[0013] [ka]

[0014] or a pharmaceutically acceptable salt thereof, wherein: (A) α is a double bond and β is a double bond; X 1 N and CR 1 is selected from X 2 N and CR 2 is selected from X 3 N and CR 3 is selected from X 4 N and CR 4 are selected from, with the proviso that X 1 , X 2 , X 3 , and X 4 at most one of is N, and R 1 , R 2 , R 3 , and R 4 are each independently selected from the following: (i) hydrogen, halo, hydroxy, cyano, and (ii) C 1-4 Alkyl, C 1-4 Alkoxy, and C 3-6 cycloalkyl (each substituted with 0-3 substituents independently selected from halo); or (B) α is a single bond and β is a single bond; X 1 is CH2, X 2 is NR 2 and CH2, X 3 is NR 3 and CH2, X 4 is CH2, except that X 2 and X 3 At most one of is N, R 2 and R 3 are each independently selected from the following: (i) hydrogen, and (ii) C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 alkylsulfonyl, and C3-6 cycloalkyl (each substituted with 0-3 substituents independently selected from halo); or (C) α is a double bond and β is a single bond; X 1 is CH, X 2 is N, X 3 does not exist, X 4 is NR 4 and R 4 is selected from the following: (i) hydrogen, and (ii) C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 Alkylsulfonyl, and C 3-6cycloalkyl (each substituted with 0-3 substituents independently selected from halo); or (D) α is a single bond and β is a single bond; X 1 is CH2, X 2 is O and X 3 is CH2, or X 2 is CH2 and X 3 is O, X 4 is CH2, m is selected from 0, 1, and 2; R a and R b are hydrogen and C, respectively. 1-4 alkyl, or R a and R b is R a and R b C, along with the carbon atom to which both are attached. 3-6 Forms a cycloalkylidene, with the proviso that if m is 2, then R a and R b At most one of the R a and R b together with the carbon atom to which it is attached, C 3-6 forming a cycloalkylidene, R 5 is selected from the following: (a)C 3-8 Cycloalkyl (substituted with 0 to 5 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); however, m is 0 and X1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R 7 , R 10 and R 11 are each hydrogen, and R 9 If is chloro, then R 5 is not cyclopropyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is cyclopropylmethyl, and R 6 is n-propyl, and R 10 If is hydrogen, then R 7 and R 11 are neither methyl nor ethyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is cyclopropylmethyl, and R 6 is n-propyl, and R 7 is methyl and R 10 and R 11 If each is hydrogen, then R 9 is not hydrogen or hydroxy, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 is n-propyl, and R 7 is methoxy and R 9 and R 11 are each hydrogen, and R 10 If is chloro, then R 5 is not cyclopropylmethyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 is n-propyl, and R 7 , R 10 and R 11 are each hydrogen, and R 9 If is chloro, then R 5 is not cyclopropylmethyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is cyclopropylmethyl, and R 7 , R 9 and R 11 are each methyl, and R 10 If is hydrogen, then R 6 is not methyl, ethyl, n-propyl, or methoxyethyl, m is 0 and X 1 and X 4 are both CH and X 2 and X 3 are both CCl, α and β are both double bonds, and R 5 is cyclopentyl and R 6 , R 7 , R 9 , R 10 and R 11 If each is hydrogen, then X 8 is not N or CH, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R 7 , R 9 , R 10 and R 11 If each is hydrogen, then R5 is not cyclopentyl, cyclohexyl, or cyclooctyl, m is 1 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is cyclohexyl and R b , R 6 , R 7 , R 9 , R 10 , and R 11 If each is hydrogen, then R a is not methyl, ethyl, isopropyl, or n-propyl, m is 1 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R a is methyl and R b , R 6 , R 7 , R 9 and R 11 are each hydrogen, and R 10 If is methoxy, then R 5 is not cyclohexyl, m is 1 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R a is methyl and R b , R 6 , R 9 , R 10 and R 11 are each hydrogen, and R 7 If is methyl, then R 5 is not cyclohexyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8are each CH, α and β are both double bonds, and R 5 is cyclohexyl and R 6 , R 7 and R 11 are each hydrogen, and R 10 If is methyl, then R 9 is not chloro or methyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is cyclohexyl and R 7 is methyl and R 9 is hydroxy and R 10 and R 11 If each is hydrogen, then R 6 is not methyl or ethyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R 7 , R 9 and R 11 are each methyl, and R 10 If is hydrogen, then R 5 is not cyclohexyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R 9 and R 11 are each hydrogen, and R 7 and R 10 If each is methyl, then R 5 is not cyclohexyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X8 are each CH, α and β are both double bonds, and R 6 , R7, R 10 and R 11 are each hydrogen, and R 9 If is methyl, then R 5 is not cycloheptyl, m is 0 and X 1 , X 2 and X 4 are CH2, and X 3 is O and X 8 is CH, α and β are both single bonds, and R 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 If is CF3 or OCF3, then R 5 is not 3-hydroxy-3-methylcyclobutyl, m is 0 and X 1 , X 3 and X 4 are CH2, and X 2 is O and X 8 is CH, α and β are both single bonds, and R 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 If is CF3 or OCF3, then R 5 is not 3-hydroxy-3-methylcyclobutyl, m is 0 and X 1 , X 2 and X 4 are CH2, and X 3 is O and X 8 is CH, α and β are both single bonds, and R 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 If is hydrogen, CF3, OCF3 or cyclobutyl, then R 5 is not 2-hydroxycyclohexyl, m is 0 and X 1 , X 3 and X 4 are CH2, and X 2 is O and X 8 is CH, α and β are both single bonds, and R 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 is hydrogen, chloro, CF3, CHF2, OCF3, OCHF2, OCH3 or cyclobutyl, then R 5 is not 2-hydroxycyclohexyl, m is 0 and X 1 , X 2 and X 4 are CH2, and X 3 is O and X 8 is CH, α and β are both single bonds, and R 6 and R 10 are each hydrogen, and R 7 is hydroxy and R 9 is methyl and R 11 If is fluoro, then R 5 is not 2-hydroxycyclohexyl, m is 0 and X 1 , X 3 and X 4 are CH2, and X 2 is O and X 8 is CH, α and β are both single bonds, and R 6 and R 10 are each hydrogen, and R 7 is hydroxy and R 9 is methyl and R 11 If is fluoro, then R 5 is not 2-hydroxycyclohexyl, m is 0 and X 1 , X 3 and X 4 are CH2, and X 2 is O and X 8 is CH, α and β are both single bonds, and R 6and R 11 are each hydrogen, and R 7 is hydroxy and R 9 is CF3 and R 10 If is fluoro, then R 5 is not 2-hydroxycyclohexyl, m is 0 and X 1 , X 2 and X 4 are CH2, and X 3 is O and X 8 is CH, α and β are both single bonds, and R 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 If is CF3, then R 5 is not 2-cyanocyclohexyl or 2-aminocyclohexyl, and m is 0 and X 1 , X 3 and X 4 are CH2, and X 2 is O and X 8 is CH, α and β are both single bonds, and R 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 If is CF3, then R 5 is not 2-cyanocyclohexyl), (b)C 3-8 Heterocyclyl (up to 3 carbon ring atoms are each independently substituted with 0-2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo) wherein the nitrogen ring atom, if present, is unsubstituted or substituted with a substituent selected from: (I C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (That C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; Here, the C 3-8 heterocyclyl has only one ring heteroatom selected from nitrogen, oxygen, and sulfur; n is selected from 0 and 1; however, m is 0 and X 1 , X 3 , X 4 , and X 8 are CH, and X 2 is CR 2 where α and β are both double bonds, and R 6 , R 7 , R 10 , and R 11 are each hydrogen, and R 2 and R 9 If each is methoxy, then R 5is not: 1-(4-chloro-3-fluorobenzyl)piperidin-4-yl, 1-(4-methylbenzyl)piperidin-4-yl, 1-(3-fluoro-4-methylbenzyl)piperidin-4-yl, 1-(4-fluoro-3-methylbenzyl)piperidin-4-yl, 1-phenethylpiperidin-4-yl, 1-(2-methylbenzyl)piperidin-4-yl, 1-(3,5-dimethylbenzyl)piperidin-4-yl, 1-(4-methoxy-3-methylbenzyl)piperidin-4-yl, 1-(3,4-dichlorobenzyl)piperidin-4-yl, 1-(3-chloro-4-methylbenzyl)piperidin-4-yl, 1-(4-chlorobenzyl)piperidin-4-yl, 1-(3,4-difluorobenzyl)piperidin-4-yl, 1-(3,4-dimethoxybenzyl)piperidin-4-yl 1-(4-bromo-3-methylbenzyl)piperidin-4-yl, 1-(2,4,6-trimethylbenzyl)piperidin-4-yl, 1-(4-chloro-3-methylbenzyl)piperidin-4-yl, 1-(3,4-dimethylbenzyl)piperidin-4-yl, 1-(3-methylbenzyl)piperidin-4-yl, 1-(4-ethylbenzyl)piperidin-4-yl lysin-4-yl, 1-(3-phenylpropyl)piperidin-4-yl, 1-(2,4-dichlorobenzyl)piperidin-4-yl, 1-(3-cyanobenzyl)piperidin-4-yl, 1-(3-chloro-4-fluorobenzyl)piperidin-4-yl, 1-(2,4-dimethylbenzyl)piperidin-4-yl, piperidin-4-yl, or 1-benzylpiperidin-4-yl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R 7 , R 9 , R 10 and R 11 If each is hydrogen, then R 5 is not piperidin-4-yl or 1-benzylpiperidin-4-yl, m is 0 and X 1 , X 2 , X3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R 7 , R 10 and R 11 are each hydrogen, and R 9 If is methoxy, then R 5 is not 1-benzylpiperidin-4-yl, m is 0 and X 1 , X 3 and X 8 are CH, and X 2 is CR 2 and X 4 is CR 4 where α and β are both double bonds, and R 6 , R 7 , R 10 and R 11 are hydrogen and R 2 , R 4 and R 9 If each is methoxy, then R 5 is not 1-benzylpiperidin-4-yl, m is 0 and X 1 , X 3 , X 4 and X 8 are CH, and X 2 is CR 2 where α and β are both double bonds, and R 6 , R 7 , R 9 and R 10 are each hydrogen, and R 2 and R 10 If each is methoxy, then R 5 is not 1-benzylpiperidin-4-yl, m is 2 and R a and R b Each occurrence of is hydrogen, and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R7 , R 9 , R 10 and R 11 If each is hydrogen, then R 5 is not 1-benzylpiperidin-4-yl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is pyrrolidin-3-yl, and R 6 , R 7 , R 10 and R 11 If each is hydrogen, then R 9 is not hydrogen, fluoro or methyl, m is 2 and R a and R b Each occurrence of is hydrogen, and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R 7 , R 10 and R 11 are each hydrogen, and R 9 If is chloro, then R 5 is not pyrrolidin-1-yl, m is 1 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is tetrahydrofuran-2-yl, and R a , R b , R 6 , R 7 , R 10 , and R11 If each is hydrogen, then R 9 is not fluorine or methyl, m is 0 and X 1 , X 2 , X 3, X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R 7 , R 10 and R 11 are each hydrogen, and R 9 If is methoxy, then R 5 is not 6-oxaspiro[2,5]octan-1-yl, m is 0 and X 1 , X 2 and X 4 are CH2, and X 3 is O and X 8 is CH, α and β are both single bonds, and R 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 If is CF3, then R 5 is not piperidin-3-yl or 1-methylpiperidin-3-yl, m is 0 and X 1 , X 3 and X 4 are CH2, and X 2 is O and X 8 is CH, α and β are both single bonds, and R 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 If is CF3, then R 5 is not piperidin-3-yl or 1-methylpiperidin-3-yl, m is 0 and X 1 , X 2 and X 4 are CH2, and X 3 is O and X 8 is CH, α and β are both single bonds, and R 6 and R 10 are each hydrogen, and R 7 is hydroxy and R 9 is CF3, methyl or chloro, and R 11If is fluoro, then R 5 is not 1-methylpiperidin-3-yl, m is 0 and X 1 , X 2 and X 4 are CH2, and X 3 is O and X 8 is CH, α and β are both single bonds, and R 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 If is methyl or chloro, then R 5 is not 1-methylpiperidin-3-yl), (c) Phenyl (halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy, provided that at least one of said substituents is hydroxy; m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is 3-hydroxyphenyl, and R 6 , R 7 , R 10 and R 11 If each is hydrogen, then R 9 is not methyl, methoxy, ethoxy, or chloro, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is 2-hydroxyphenyl, and R 6 , R 7 , R 10 and R 11 If each is hydrogen, then R 9 is not hydrogen, methyl, methoxy or chloro, m is 0 and X1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is 2-hydroxyphenyl, and R 6 , R 7 and R 11 If each is hydrogen, then R 9 and R 10 Neither of them are Chrollo, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is 4-hydroxyphenyl, and R 6 , R 7 , R 10 and R 11 If each is hydrogen, then R 9 is not hydrogen, hydroxy, chloro, methoxy, ethoxy, trifluoromethyl or tert-butyl, m is 0 and X 1 , X 2 , X 3 and X 4 is each CBr, and X 8 is CH, α and β are both double bonds, and R 6 , R 7 , R 10 and R 11 are each hydrogen, and R 9 If is methyl, then R 5 is not 3-hydroxyphenyl or 4-hydroxyphenyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is unsubstituted phenyl, and R 6 , R 7 , R 10 and R 11 If each is hydrogen, then R9 is not hydrogen, chloro, hydroxy, methyl or methoxy, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is unsubstituted phenyl, and R 6 , R 7 and R 10 are each hydrogen, and R 11 If is methyl, then R 9 is not hydrogen or chloro, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R 7 , R 9 and R 10 are each hydrogen, and R 11 If is methyl, then R 5 is not an unsubstituted phenyl, m is 0 and X 1 , X 2 , X 3 and X 4 are CH, and X 8 is N, α and β are both double bonds, and R 6 , R 7 , R 9 , R 10 and R 11 If each is hydrogen, then R 5 is not an unsubstituted phenyl, m is 0 and X 1 , X 4 and X 8 are CH, and X 2 is CR 2 and X 3 is CR 3 where α and β are both double bonds, and R 5 is unsubstituted phenyl, and R 6 , R 7 , R9 , R 10 and R 11 If each is hydrogen, then R 2 and R 3 are not both methyl or both methoxy, m is 1 and X 1 , X 2 , X 3 , X 4 , and X 8 are each CH, α and β are both double bonds, and R a and R b But R a and R b together with the carbon atom to which they are both attached to form a cyclopentylidene, and R 6 , R 7 , R 9 , R 10 and R 11 If each is hydrogen, then R 5 is not unsubstituted phenyl), R 6 is hydrogen and C 1-4 alkyl, X 8 N and CR 8 is selected from R 7 , R 8 and R 11 are each independently selected from the following: (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); and (iii)C 3-8 Cycloalkyl (halo, C 1-4 Alkyl and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; R 9 and R 10 are each independently selected from the following: (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); and (iii)C 3-8 Cycloalkyl (halo, C 1-4 Alkyl and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; or R 9 and R 10 form an ethane-1,2-dioxy moiety bridging the carbon atoms to which they are attached).

[0015] Another aspect of the present invention provides a compound selected from the group of compounds described in the Examples and pharmaceutically acceptable salts thereof.

[0016] A further aspect of the invention provides a compound or a pharmaceutically acceptable salt as defined in the preceding paragraph for use as a pharmaceutical.

[0017] An additional aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, and a pharmaceutically acceptable excipient.

[0018] Another aspect of the present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, for treating a disease, disorder, or condition associated with NLRP3, including a disease, disorder, or condition associated with heterozygous gain-of-function mutations in the NLRP3 gene, such as cryopyrin-associated periodic syndromes (CAPS).

[0019] A further aspect of the invention provides the use of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, for the manufacture of a medicament for treating a disease, disorder, or condition associated with NLRP3, including a disease, disorder, or condition associated with heterozygous gain-of-function mutations in the NLRP3 gene, such as cryopyrin-associated periodic syndromes (CAPS).

[0020] An additional aspect of the present invention provides a method for treating a disease, disorder, or condition associated with NLRP3, including a disease, disorder, or condition associated with a heterozygous gain-of-function mutation in the NLRP3 gene, such as cryopyrin-associated periodic syndromes (CAPS), comprising administering to a subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph.

[0021] Another aspect of the present invention provides a method of treating cryopyrin-associated periodic syndromes (CAPS), including neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS), comprising administering to a subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph.

[0022] A further aspect of the present invention provides a method of treating a disease, disorder, or condition in a subject, comprising administering to the subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, wherein the disease, disorder, or condition is a neurodegenerative disease, disorder, or condition.

[0023] An additional aspect of the present invention provides a method of treating a disease, disorder, or condition in a subject comprising administering to the subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, wherein the disease, disorder, or condition is selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion disease.

[0024] Another aspect of the present invention provides an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, and at least one additional pharmacologically active agent. DETAILED DESCRIPTION OF THE INVENTION

[0025] Unless otherwise indicated, this disclosure uses the definitions set forth below.

[0026] "Substituted" refers to a chemical substituent or moiety (e.g., substituted C 1-6 When used in connection with a group (such as an alkyl group or a substituted phenyl group), it means that one or more hydrogen atoms of that substituent or moiety have been replaced with one or more non-hydrogen atoms or groups, provided that valency requirements are met and the substitution results in a chemically stable compound. Unless otherwise indicated, a chemical substituent or moiety is unsubstituted (or not further substituted). For example, referring to a phenyl group without indicating that it is substituted means that the phenyl group does not contain any non-hydrogen substituents. Similarly, referring to a 2-fluorophenyl group without indicating that it is substituted means that the 2-fluorophenyl group does not contain any additional non-hydrogen substituents other than the 2-fluoro substituent.

[0027] "About" or "approximately," when used in connection with a measurable, numerical variable, refers to the indicated value of that variable and all values ​​of that variable within experimental error of the indicated value or within ±10 percent of the indicated value, whichever is greater.

[0028] "Alkyl" refers to straight-chain and branched saturated hydrocarbon groups generally having a specified number of carbon atoms (e.g., C 1-4 Alkyl refers to an alkyl group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms, C 1-6 (Alkyl refers to an alkyl group having 1 to 6 carbon atoms, etc.) Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, n-hexyl, and the like.

[0029] "Alkanediyl" refers to a divalent alkyl group, where alkyl is defined above, generally having a specified number of carbon atoms (e.g., C 1-4 Alkanediyl refers to an alkanediyl group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms, C 1-6 (Alkanediyl refers to an alkanediyl group having 1 to 6 carbon atoms, etc.) Examples of alkanediyl groups include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, propane-2,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, butane-1,1-diyl, isobutane-1,3-diyl, isobutane-1,1-diyl, isobutane-1,2-diyl, and the like.

[0030] "Alkenyl" refers to straight-chain and branched hydrocarbon groups having one or more carbon-carbon double bonds and generally having a specified number of carbon atoms. Examples of alkenyl groups include ethenyl, 1-propen-1-yl, 1-propen-2-yl, 2-propen-1-yl, 1-buten-1-yl, 1-buten-2-yl, 3-buten-1-yl, 3-buten-2-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methyl-1-propen-1-yl, 2-methyl-2-propen-1-yl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, and the like.

[0031] "Alkynyl" refers to a straight or branched chain hydrocarbon group having one or more carbon-carbon triple bonds and generally having a specified number of carbon atoms. Examples of alkynyl groups include ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, 3-butyn-1-yl, 3-butyn-2-yl, 2-butyn-1-yl, and the like.

[0032] "Alkoxy" refers to straight and branched chain saturated hydrocarbon groups attached through an oxygen atom, generally having the specified number of carbon atoms (e.g., C 1-4 Alkoxy refers to an alkoxy group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms, C 1-6 (Alkoxy refers to an alkoxy group having 1 to 6 carbon atoms, etc.) Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, t-butoxy, pent-1-yloxy, pent-2-yloxy, pent-3-yloxy, 3-methylbut-1-yloxy, 3-methylbut-2-yloxy, 2-methylbut-2-yloxy, 2,2,2-trimethyleth-1-yloxy, n-hexoxy, and the like.

[0033] "Alkylcarbonyl" and "alkylsulfonyl" refer to an alkyl group, as defined above, attached through a carbonyl (C(O)) or sulfonyl (SO) group, respectively, and generally having a specified number of carbon atoms, including the carbon atom of the carbonyl group. For example, C 1-4 Alkylcarbonyl refers to an alkylcarbonyl group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms, including the carbonyl portion; C 1-6 Alkylsulfonyl refers to an alkylsulfonyl group having 1 to 6 carbon atoms, etc. Examples of alkylcarbonyl groups include carbonyl (formyl), methylcarbonyl (acetyl), ethylcarbonyl, i-propylcarbonyl, n-propylcarbonyl, etc. Examples of alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, i-propylsulfonyl, n-propylsulfonyl, etc.

[0034] "Halo," "halogen," and "halogeno" may be used interchangeably and refer to fluoro, chloro, bromo, and iodo.

[0035] "Haloalkyl," "haloalkenyl," and "haloalkynyl" refer to alkyl, alkenyl, and alkynyl groups (where alkyl, alkenyl, and alkynyl are defined above) substituted with one or more halogen atoms and generally having a specified number of carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1-chloroethyl, 1,1-dichloroethyl, 1-fluoro-1-methylethyl, 1-chloro-1-methylethyl, and the like.

[0036] "Cycloalkenyl" refers to saturated monocyclic and bicyclic hydrocarbon groups, generally having a specified number of carbon atoms comprising the ring(s) (e.g., C 3-8Cycloalkyl refers to a cycloalkyl group having 3 to 8 carbon atoms as ring members. Bicyclic hydrocarbon groups may include separated rings (two rings with no carbon atoms in common), spiro rings (two rings with one carbon atom in common), fused rings (two rings with two carbon atoms in common and a bond between two common carbon atoms), and bridged rings (two rings with two carbon atoms in common but no common bond). Cycloalkyl groups may be bonded through any ring atom, provided that such bonding does not violate valence requirements, and, where indicated, may optionally contain one or more non-hydrogen substituents, provided that such substitution does not violate valence requirements.

[0037] Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Examples of fused bicyclic cycloalkyl groups include bicyclo[2.1.0]pentanyl (i.e., bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl, and bicyclo[2.1.0]pentan-5-yl), bicyclo[3.1.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.3.0]octanyl, bicyclo[4.2.0]octanyl, bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decanyl, etc. Examples of bridged cycloalkyl groups include bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[4.1.1]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[4.2.1]nonanyl, bicyclo[3.3.2]decanyl, bicyclo[4.2.2]decanyl, bicyclo[4.3.1]decanyl, bicyclo[3.3.3]undecanyl, bicyclo[4.3.2]undecanyl, bicyclo[4.3.3]dodecanyl, and the like. Examples of spirocycloalkyl groups include spiro[3.3]heptanyl, spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, etc. Examples of split bicyclic cycloalkyl groups include those derived from bi(cyclobutane), cyclobutanecyclopentane, bi(cyclopentane), cyclobutanecyclohexane, cyclopentanecyclohexane, bi(cyclohexane), etc.

[0038] "Cycloalkanediyl" refers to a divalent cycloalkyl group, where cycloalkyl is defined above, generally having a specified number of carbon atoms (e.g., C 3-5 Cycloalkanediyl refers to a cycloalkanediyl group having 3 to 5 (i.e., 3, 4, or 5) carbon atoms, C 3-6Cycloalkanediyl refers to a cycloalkanediyl group having 3 to 6 carbon atoms, etc.) Examples of cycloalkanediyl groups include cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and the like.

[0039] "Cycloalkylidene" refers to a divalent monocyclic cycloalkyl group (cycloalkyl is defined above) attached through a single carbon atom of the group and generally having a specified number of carbon atoms comprising the ring (e.g., C 3-6 Cycloalkylidene refers to a cycloalkylidene group having 3 to 6 carbon atoms as ring members.) Examples include cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene.

[0040] "Cycloalkenyl" refers to partially unsaturated monocyclic and bicyclic hydrocarbon groups, generally having a specified number of carbon atoms comprising the ring(s). Like cycloalkyl groups, bicyclic cycloalkenyl groups can include separate rings, spirocyclic, fused, or bridged rings. Similarly, cycloalkenyl groups can be bonded via any ring atom and, where indicated, can optionally contain one or more non-hydrogen substituents, provided that such bond or substitution does not violate valence requirements. Examples of cycloalkenyl groups include partially unsaturated analogs of the above cycloalkyl groups, such as cyclobutenyl (i.e., cyclobuten-1-yl and cyclobuten-3-yl), cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, and the like.

[0041] "Aryl" refers to fully unsaturated monocyclic aromatic hydrocarbons and polycyclic hydrocarbons having at least one aromatic ring, both monocyclic and polycyclic aryl groups generally having a specified number of carbon atoms constituting their ring members (e.g., C 6-14Aryl refers to an aryl group having 6 to 14 carbon atoms as ring members. The group can be attached via any ring atom and, where indicated, can optionally contain one or more non-hydrogen substituents, provided such attachment or substitution does not violate valence requirements. Examples of aryl groups include phenyl, biphenyl, cyclobutabenzenyl, indenyl, naphthalenyl, benzocycloheptanyl, biphenylenyl, fluorenyl, and groups derived from a cycloheptatriene cation.

[0042] "Arylene" refers to a divalent aryl group, where aryl is defined above. Examples of arylene groups include o-phenylene (i.e., benzene-1,2-diyl).

[0043] "Heterocycle" and "heterocyclyl" can be used interchangeably and refer to a saturated or partially unsaturated monocyclic or bicyclic group having ring atoms composed of carbon atoms and one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both monocyclic and bicyclic groups generally have a specified number of carbon atoms in their ring(s) (e.g., C 2-6Heterocyclyl refers to a heterocyclyl group having 2 to 6 carbon atoms and, for example, 1 to 4 heteroatoms as ring members. Like bicyclic cycloalkyl groups, bicyclic heterocyclyl groups can include separate rings, spirocyclic rings, fused rings, and bridged rings. Heterocyclyl groups can be attached via any ring atom and, where indicated, can optionally contain one or more non-hydrogen substituents, but only if such attachment or substitution does not violate valence requirements or result in a chemically unstable compound. Examples of heterocyclyl groups include oxiranyl, thiiranyl, aziridinyl (e.g., aziridin-1-yl and aziridin-2-yl), oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, Examples include 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl, 1,4-diazepanyl, 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2-dihydropyridinyl, 1,2,3,4-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,6-dihydropyrimidinyl, 1,2,3,4-tetrahydropyrimidinyl, and 1,2-dihydropyrazolo[1,5-d][1,2,4]triazinyl.

[0044] "Heterocycle-diyl" refers to a heterocyclyl group (heterocyclyl is defined above) that is attached through two ring atoms of the group. They generally have a specified number of carbon atoms in their ring(s) (e.g., C 2-6Heterocycle-diyl refers to a heterocycle-diyl group having 2 to 6 carbon atoms and, for example, 1 to 4 heteroatoms as ring members.) Examples of heterocycle-diyl groups include polyvalent analogs of the above heterocycle groups, such as morpholin-3,4-diyl, pyrrolidin-1,2-diyl, 1-pyrrolidinyl-2-ylidene, 1-pyridinyl-2-ylidene, 1-(4H)-pyrazolyl-5-ylidene, 1-(3H)-imidazolyl-2-ylidene, 3-oxazolyl-2-ylidene, 1-piperidinyl-2-ylidene, 1-piperazinyl-6-ylidene, and the like.

[0045] "Heteroaromatic" and "heteroaryl" can be used interchangeably and refer to unsaturated monocyclic aromatic groups and polycyclic groups having at least one aromatic ring, each of which has ring atoms composed of carbon atoms and one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both monocyclic and polycyclic groups generally have a specified number of carbon atoms as ring members (e.g., C 1-9Heteroaryl refers to heteroaryl groups having 1 to 9 carbon atoms and, for example, 1 to 4 heteroatoms as ring members, and may also include any bicyclic group in which any of the monocyclic heterocycles listed above is fused to a benzene ring. Heteroaryl groups can be bonded through any ring atom (or ring atom of a fused ring) and, where indicated, can optionally contain one or more non-hydrogen substituents, provided that such bonding or substitution does not violate valence requirements or result in a chemically unstable compound. Examples of heteroaryl groups include monocyclic groups such as pyrrolyl (e.g., pyrrol-1-yl, pyrrol-2-yl, and pyrrol-3-yl), furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0046] Examples of heteroaryl groups also include bicyclic groups, such as benzofuranyl, isobenzofuranyl, benzothienyl, benzo[c]thienyl, 1H-indolyl, 3H-indolyl, isoindolyl, 1H-isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, 1H-indazolyl, 2H-indazolyl, benzotriazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, inyl, 3H-imidazo[4,5-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-c]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 7H-purinyl, indolizinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl, pyrimido[4,5-d]pyrimidinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl ]pyrazinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, benzo[d]thiazolyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, 2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, 4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidinyl, 2,3,6,7-tetrahydro-1H-purinyl, 5H-pyrrolo[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-b]pyridazinyl, and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl.

[0047] "Heteroarylene" refers to heteroaryl groups (heteroaryl is defined above) that are linked through two ring atoms of the group. They generally have a specified number of carbon atoms in their ring(s) (e.g., C 3-5 Heteroarylene refers to a heteroarylene group having 3 to 5 carbon atoms and, for example, 1 to 4 heteroatoms as ring members.) Examples of heteroarylene groups include polyvalent analogs of the heteroaryl groups listed above, such as pyridine-2,3-diyl, pyridine-3,4-diyl, pyrazole-4,5-diyl, pyrazole-3,4-diyl, and the like.

[0048] "Oxo" refers to a double-bonded oxygen (=O).

[0049] "Leaving group" refers to any group that leaves a molecule during a fragmentation process, including substitution, elimination, and addition-elimination reactions. Leaving groups can be nucleofugal (where the leaving group leaves with the electron pair that originally served as the bond between the leaving group and the molecule) or electrofugal (where the leaving group leaves without the electron pair). The ability of a nucleofugal leaving group to leave depends on the strength of its base, with the strongest bases being the weakest leaving groups. Common nucleofugal leaving groups include nitrogen (e.g., from diazonium salts); sulfonates, including alkyl sulfonates (e.g., mesylate), fluoroalkyl sulfonates (e.g., triflate, hexaflate, nonaflate, and tresylate), and aryl sulfonates (e.g., tosylate, brosylate, closylate, and nosylate). Others include carbonates, halide ions, carboxylate anions, phenolate ions, and alkoxides. Some stronger bases, such as NH - and OH - can be made into a better leaving group by treatment with acid. Common electron-free leaving groups include the proton, CO2, and metals.

[0050] "Opposite enantiomer" refers to a molecule that is a non-superimposable mirror image of a reference molecule and can be obtained by inverting all of the chiral centers of the reference molecule. For example, if the reference molecule has S absolute stereochemical configuration, then the opposite enantiomer has R absolute stereochemical configuration. Similarly, if the reference molecule has S,S absolute stereochemical configuration, then the opposite enantiomer has R,R stereochemical configuration, and so on.

[0051] "Stereoisomer(s)" of a compound having a given stereochemical configuration refers to the opposite enantiomer of that compound and any diastereoisomers, including geometric isomers (Z / E) of that compound. For example, if a compound has an S,R,Z stereochemical configuration, then the stereoisomers can include its opposite enantiomer having the R,S,Z configuration, as well as its diastereoisomers having the S,S,Z, R,R,Z, S,R,E, R,S,E, S,S,E, and R,R,E configurations. If the stereochemical configuration of a compound is not specified, then "stereoisomer" refers to any one of the possible stereochemical configurations of the compound.

[0052] "Substantially pure stereoisomer" and variations thereof refer to a sample containing a compound having a particular stereochemical configuration, wherein said sample comprises at least about 95% of the sample.

[0053] "Pure stereoisomer" and variations thereof refer to a sample containing a compound with a particular stereochemical configuration, which comprises at least about 99.5% of the sample.

[0054] "Subject" refers to a mammal, including a human.

[0055] A "pharmaceutically acceptable" substance refers to a substance that is suitable for administration to a subject.

[0056] "Treating" refers to reversing, alleviating, inhibiting the progression of, or preventing the disease, disorder, or condition to which such term applies, or reversing, alleviating, inhibiting the progression of, or preventing one or more symptoms of such disease, disorder, or condition.

[0057] "Treatment" refers to the act of treating, as defined immediately above.

[0058] "Drug," "drug substance," "active pharmaceutical ingredient," and the like refer to compounds (e.g., compounds of Formula 1, including subclass compounds and compounds specifically named herein) that can be used to treat a subject in need thereof.

[0059] An "effective amount" of a drug, a "therapeutically effective amount" of a drug, etc. refer to the amount of drug that can be used to treat a subject, which amount may depend, inter alia, on the weight and age of the subject and the route of administration.

[0060] "Excipient" refers to any diluent or vehicle for a drug.

[0061] A "pharmaceutical composition" refers to a combination of one or more drug substances and one or more excipients.

[0062] The terms "drug product," "pharmaceutical dosage form," "dosage form," "final dosage form," and the like refer to a pharmaceutical composition suitable for treating a subject in need thereof, and may generally be in the form of a tablet, capsule, sachet containing powder or granules, liquid or suspension, patch, film, and the like.

[0063] "NLRP3-associated condition" and similar phrases refer to a disease, disorder, or condition in a subject in which inhibition of the NLRP3 inflammasome pathway can provide a therapeutic or prophylactic benefit.

[0064] The following abbreviations may be used herein: Ac (acetyl); AcO (acetic anhydride); ACN (acetonitrile); AIBN (azo-bis-isobutyronitrile); AmPhos (bis(di-tert-butyl-(4-dimethylaminophenyl)phosphine)dichloropalladium(II)); API (active pharmaceutical ingredient); aq (aqueous solution); BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); Boc( tert-Butoxycarbonyl;BrettPhos(2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl);BrettPhos-Pd-G3([(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate );BTMPO (N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide);Cbz (carbobenzyloxy);dba ​​(dibenzylideneacetone);DBU (1,8-diazabicyclo[5.4.0]undec-7-ene);DCC (1,3-dicyclohexylcarbodiimide);DCE (1,1-dichloroethane);DCM (dichloromethane);DEA (diethylamine);DIAD (diisopropyl azodicarboxylate);DIPEA (N,N-diisopropylethylamine, Hunig's base);DMA (N,N-dimethylacetamide);DMAP (4-dimethylaminopyridine);DME (1,2-dimethoxyethane);DMF (N,N-dimethylformamide);DMP (Dess-Martin periodinane);DMSO (dimethyl sulfoxide);dppf (1,1'-bis(diphenylphosphino)ferrocene);DTT (dithiothreitol);EC 50(effective concentration at half-maximal response); EDA (ethoxylated dodecyl alcohol, Brj® 35); EDC (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide); EDTA (ethylenediaminetetraacetic acid); ee (enantiomeric excess); ELS (evaporative light scattering); eq (equivalent); Et (ethyl); EtN (triethylamine); EtOAc (ethyl acetate); EtOH (ethanol); FA (formic acid); HATU (2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V)); HEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid); HOAc (acetic acid); HOBt (1H-benzo[d][1,2,3]triazol-1-ol); IC 50 (Concentration at 50% inhibition); IPA (Isopropanol); IPAc (Isopropyl acetate); IPE (Isopropyl ether); LDA (Lithium diisopropylamide); LiHMDS (Lithium bis(trimethylsilyl)amide); mCPBA (m-chloroperbenzoic acid); Me (Methyl); MeOH (Methanol); MTBE (Methyl tert-butyl ether); mp (Melting point); NaOt-Bu (Sodium tert-butoxide); NMM (N-Methylmorpholine); NMP (1-Methyl-pyrrolidin-2-one); OTf (Triflate); PE (Petroleum Ether); Ph (Phenyl); pEC 50 (-log 10 (EC 50 ), where EC 50 is given in molar (M) units); pIC 50 (-log 10 (I C 50 ), where IC 50are given in moles (M); Pr (propyl); c-Pr (cyclopropyl), i-Pr (isopropyl); PTFE (polytetrafluoroethylene); PyBOP ((benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate); PyBroP® (bromotripyrrolidinophosphonium hexafluorophosphate); PCy3 (tricyclohexylphosphine); R-BINAP ((R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); RT (room temperature, approximately 20°C to 25°C); SFC (supercritical fluid chromatography); T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide); TBSOTf (tert-butyldimethylsilyl Trifluoromethanesulfonate; TCEP (tris(2-carboxyethyl)phosphine); TFA (trifluoroacetic acid); TFAA (2,2,2-trifluoroacetic anhydride); THF (tetrahydrofuran); TMS (trimethylsilyl); Tris buffer (2-amino-2-hydroxymethyl-propane-1,3-diol buffer); XPhos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl); and XPhos-Pd-G2 (chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)).

[0065] As described below, the present disclosure relates to compounds of Formula 1 and their pharmaceutically acceptable salts. The present disclosure also relates to materials and methods for preparing the compounds of Formula 1, pharmaceutical compositions containing them, and the use of the compounds of Formula 1 and their pharmaceutically acceptable salts (optionally in combination with other pharmacologically active agents) to treat diseases, disorders, or conditions of the CNS, including neurodegenerative diseases, e.g., Parkinson's disease, Alzheimer's disease, and other diseases, disorders, or conditions associated with NLRP3.

[0066] Compounds of Formula I, and pharmaceutically acceptable salts thereof, include the following: (1) (A) α is a double bond and β is a double bond; X 1 N and CR 1 is selected from X 2 N and CR 2 is selected from X 3 N and CR 3 is selected from X 4 N and CR 4 are selected from, with the proviso that X 1 , X 2 , X 3 and X 4 At most one of is N, R 1 , R 2 , R 3 , and R 4 are each independently selected from the following: (i) hydrogen, halo, hydroxy, cyano; and (ii) C 1-4 Alkyl, C 1-4 Alkoxy, and C 3-6 cycloalkyl (each substituted with 0-3 substituents independently selected from halo); or (B) α is a single bond and β is a single bond; X 1 is CH2, X 2 is NR 2 and CH2, X 3 is NR 3 and CH2, X 4 is CH2, except that X 2 and X 3 At most one of is N, R 2 and R 3 are each independently selected from the following: (i) hydrogen; and (ii) C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4Alkylsulfonyl, and C 3-6 cycloalkyl (each substituted with 0-3 substituents independently selected from halo); or (C) α is a double bond and β is a single bond; X 1 is CH, X 2 is N, X 3 does not exist, X 4 is NR 4 and R 4 is selected from the following: (i) hydrogen; and (ii) C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 Alkylsulfonyl, and C 3-6 cycloalkyl (each substituted with 0-3 substituents independently selected from halo); (D) α is a single bond and β is a single bond; X 1 is CH2, X 2 is O and X 3 is CH2, or X 2 is CH2 and X 3 is O, X 4 is CH2, m is selected from 0, 1, and 2; R a and R b are hydrogen and C, respectively. 1-4 alkyl, or R a and R b is R a and R b C, along with the carbon atom to which both are attached. 3-6 Forms a cycloalkylidene, with the proviso that if m is 2, then R a and R b At most one of the R a and R btogether with the carbon atom to which it is attached, C 3-6 forming a cycloalkylidene, R 5 is selected from the following: (a)C 3-8 Cycloalkyl (substituted with 0 to 5 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); however, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R 7 , R 10 and R 11 are each hydrogen, and R 9 If is chloro, then R 5 is not cyclopropyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is cyclopropylmethyl, and R 6 is n-propyl, and R 10 If is hydrogen, then R 7 and R 11 are neither methyl nor ethyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R5 is cyclopropylmethyl, and R 6 is n-propyl, and R 7 is methyl and R 10 and R 11 If each is hydrogen, then R 9 is not hydrogen or hydroxy, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 is n-propyl, and R 7 is methoxy and R 9 and R 11 are each hydrogen, and R 10 If is chloro, then R 5 is not cyclopropylmethyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 is n-propyl, and R 7 , R 10 and R 11 are each hydrogen, and R 9 If is chloro, then R 5 is not cyclopropylmethyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is cyclopropylmethyl, and R 7 , R 9 and R 11 are each methyl, and R 10 If is hydrogen, then R 6 is not methyl, ethyl, n-propyl, or methoxyethyl, m is 0 and X 1 and X 4 are both CH and X2 and X 3 are both CCl, α and β are both double bonds, and R 5 is cyclopentyl and R 6 , R 7 , R 9 , R 10 and R 11 If each is hydrogen, then X 8 is not N or CH, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R 7 , R 9 , R 10 and R 11 If each is hydrogen, then R 5 is not cyclopentyl, cyclohexyl, or cyclooctyl, m is 1 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is cyclohexyl and R b , R 6 , R 7 , R 9 , R 10 , and R 11 If each is hydrogen, then R a is not methyl, ethyl, isopropyl, or n-propyl, m is 1 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R a is methyl and R b , R 6 , R 7 , R 9 and R 11 are each hydrogen, and R 10 If is methoxy, then R5 is not cyclohexyl, m is 1 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R a is methyl and R b , R 6 , R 9 , R 10 and R 11 are each hydrogen, and R 7 If is methyl, then R 5 is not cyclohexyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is cyclohexyl and R 6 , R 7 and R 11 are each hydrogen, and R 10 If is methyl, then R 9 is not chloro or methyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is cyclohexyl and R 7 is methyl and R 9 is hydroxy and R 10 and R 11 If each is hydrogen, then R 6 is not methyl or ethyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R 7 , R 9 and R 11are each methyl, and R 10 If is hydrogen, then R 5 is not cyclohexyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R 9 and R 11 are each hydrogen, and R 7 and R 10 If each is methyl, then R 5 is not cyclohexyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R7, R 10 and R 11 are each hydrogen, and R 9 If is methyl, then R 5 is not cycloheptyl, m is 0 and X 1 , X 2 and X 4 are CH2, and X 3 is O and X 8 is CH, α and β are both single bonds, and R 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 If is CF3 or OCF3, then R 5 is not 3-hydroxy-3-methylcyclobutyl, m is 0 and X 1 , X 3 and X 4 are CH2, and X 2 is O and X 8 is CH, α and β are both single bonds, and R 6 , R 10 and R 11are each hydrogen, and R 7 is hydroxy and R 9 If is CF3 or OCF3, then R 5 is not 3-hydroxy-3-methylcyclobutyl, m is 0 and X 1 , X 2 and X 4 are CH2, and X 3 is O and X 8 is CH, α and β are both single bonds, and R 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 If is hydrogen, CF3, OCF3 or cyclobutyl, then R 5 is not 2-hydroxycyclohexyl, m is 0 and X 1 , X 3 and X 4 are CH2, and X 2 is O and X 8 is CH, α and β are both single bonds, and R 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 is hydrogen, chloro, CF3, CHF2, OCF3, OCHF2, OCH3 or cyclobutyl, then R 5 is not 2-hydroxycyclohexyl, m is 0 and X 1 , X 2 and X 4 are CH2, and X 3 is O and X 8 is CH, α and β are both single bonds, and R 6 and R 10 are each hydrogen, and R 7 is hydroxy and R 9 is methyl and R 11 If is fluoro, then R 5 is not 2-hydroxycyclohexyl, m is 0 and X1 , X 3 and X 4 are CH2, and X 2 is O and X 8 is CH, α and β are both single bonds, and R 6 and R 10 are each hydrogen, and R 7 is hydroxy and R 9 is methyl and R 11 If is fluoro, then R 5 is not 2-hydroxycyclohexyl, m is 0 and X 1 , X 3 and X 4 are CH2, and X 2 is O and X 8 is CH, α and β are both single bonds, and R 6 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 is CF3 and R 10 If is fluoro, then R 5 is not 2-hydroxycyclohexyl, m is 0 and X 1 , X 2 and X 4 are CH2, and X 3 is O and X 8 is CH, α and β are both single bonds, and R 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 If is CF3, then R 5 is not 2-cyanocyclohexyl or 2-aminocyclohexyl, and m is 0 and X 1 , X 3 , and X 4 are CH2, and X 2 is O and X 8 is CH, α and β are both single bonds, and R 6 , R 10 and R 11are each hydrogen, and R 7 is hydroxy and R 9 If is CF3, then R 5 is not 2-cyanocyclohexyl), (b)C 3-8 Heterocyclyl (up to 3 carbon ring atoms are each independently substituted with 0-2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); wherein the nitrogen ring atom, if present, is unsubstituted or substituted with a substituent selected from: (I C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (That C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; Here, the C 3-8heterocyclyl has only one ring heteroatom selected from nitrogen, oxygen, and sulfur; n is selected from 0 and 1; however, m is 0 and X 1 , X 3 , X 4 and X 8 are CH, and X 2 is CR 2 where α and β are both double bonds, and R 6 , R 7 , R 10 and R 11 are each hydrogen, and R 2 and R 9 If each is methoxy, then R 5is not: 1-(4-chloro-3-fluorobenzyl)piperidin-4-yl, 1-(4-methylbenzyl)piperidin-4-yl, 1-(3-fluoro-4-methylbenzyl)piperidin-4-yl, 1-(4-fluoro-3-methylbenzyl)piperidin-4-yl, 1-phenethylpiperidin-4-yl, 1-(2-methylbenzyl)piperidin-4-yl, 1-(3,5-dimethylbenzyl)piperidin-4-yl, 1-(4-methoxy-3-methylbenzyl)piperidin-4-yl, 1-(3,4-dichlorobenzyl)piperidin-4-yl, 1-(3-chloro-4-methylbenzyl)piperidin-4-yl, 1-(4-chlorobenzyl)piperidin-4-yl, 1-(3,4-difluorobenzyl)piperidin-4-yl, 1-(3,4-dimethoxybenzyl)piperidin-4-yl 1-(4-bromo-3-methylbenzyl)piperidin-4-yl, 1-(2,4,6-trimethylbenzyl)piperidin-4-yl, 1-(4-chloro-3-methylbenzyl)piperidin-4-yl, 1-(3,4-dimethylbenzyl)piperidin-4-yl, 1-(3-methylbenzyl)piperidin-4-yl, 1-(4-ethylbenzyl)piperidin-4-yl lysin-4-yl, 1-(3-phenylpropyl)piperidin-4-yl, 1-(2,4-dichlorobenzyl)piperidin-4-yl, 1-(3-cyanobenzyl)piperidin-4-yl, 1-(3-chloro-4-fluorobenzyl)piperidin-4-yl, 1-(2,4-dimethylbenzyl)piperidin-4-yl, piperidin-4-yl, or 1-benzylpiperidin-4-yl; m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R 7 , R 9 , R 10 and R 11 If each is hydrogen, then R 5 is not piperidin-4-yl or 1-benzylpiperidin-4-yl, m is 0 and X 1 , X 2 , X3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R 7 , R 10 and R 11 are each hydrogen, and R 9 If is methoxy, then R 5 is not 1-benzylpiperidin-4-yl, m is 0 and X 1 , X 3 and X 8 are CH, and X 2 is CR 2 and X 4 is CR 4 where α and β are both double bonds, and R 6 , R 7 , R 10 and R 11 are hydrogen and R 2 , R 4 and R 9 If each is methoxy, then R 5 is not 1-benzylpiperidin-4-yl, m is 0 and X 1 , X 3 , X 4 and X 8 are CH, and X 2 is CR 2 where α and β are both double bonds, and R 6 , R 7 , R 9 and R 10 are each hydrogen, and R 2 and R 10 If each is methoxy, then R 5 is not 1-benzylpiperidin-4-yl, m is 2 and R a and R b Each occurrence of is hydrogen, and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R7 , R 9 , R 10 and R 11 If each is hydrogen, then R 5 is not 1-benzylpiperidin-4-yl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is pyrrolidin-3-yl, and R 6 , R 7 , R 10 and R 11 If each is hydrogen, then R 9 is not hydrogen, fluoro or methyl, m is 2 and R a and R b Each occurrence of is hydrogen, and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R 7 , R 10 and R 11 are each hydrogen, and R 9 If is chloro, then R 5 is not pyrrolidin-1-yl, m is 1 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is tetrahydrofuran-2-yl, and R a , R b , R 6 , R 7 , R 10 , and R 11 If each is hydrogen, then R 9 is not fluorine or methyl, m is 0 and X 1 , X 2 , X 3, X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R 7 , R 10 and R 11 are each hydrogen, and R 9 If is methoxy, then R 5 is not 6-oxaspiro[2,5]octan-1-yl, m is 0 and X 1 , X 2 and X 4 are CH2, and X 3 is O and X 8 is CH, α and β are both single bonds, and R 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 If is CF3, then R 5 is not piperidin-3-yl or 1-methylpiperidin-3-yl, m is 0 and X 1 , X 3 and X 4 are CH2, and X 2 is O and X 8 is CH, α and β are both single bonds, and R 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 If is CF3, then R 5 is not piperidin-3-yl or 1-methylpiperidin-3-yl, m is 0 and X 1 , X 2 and X 4 are CH2, and X 3 is O and X 8 is CH, α and β are both single bonds, and R 6 and R 10 are each hydrogen, and R 7 is hydroxy and R 9 is CF3, methyl or chloro, and R 11If is fluoro, then R 5 is not 1-methylpiperidin-3-yl, m is 0 and X 1 , X 2 and X 4 are CH2, and X 3 is O and X 8 is CH, α and β are both single bonds, and R 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 If is methyl or chloro, then R 5 is not 1-methylpiperidin-3-yl), (c) Phenyl (halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy, provided that at least one of said substituents is hydroxy; m is 0 and X 1 , X 2 , X 3 , X 4 , and X 8 are each CH, α and β are both double bonds, and R 5 is 3-hydroxyphenyl, and R 6 , R 7 , R 10 and R 11 If each is hydrogen, then R 9 is not methyl, methoxy, ethoxy, or chloro, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is 2-hydroxyphenyl, and R 6 , R 7 , R 10 and R 11 If each is hydrogen, then R 9 is not hydrogen, methyl, methoxy or chloro, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is 2-hydroxyphenyl, and R 6 , R 7 and R 11 If each is hydrogen, then R 9 and R 10 Neither of them are Chrollo, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is 4-hydroxyphenyl, and R 6 , R 7 , R 10 and R 11 If each is hydrogen, then R 9 is not hydrogen, hydroxy, chloro, methoxy, ethoxy, trifluoromethyl or tert-butyl, m is 0 and X 1 , X 2 , X 3 and X 4 is each CBr, and X 8 is CH, α and β are both double bonds, and R 6 , R 7 , R 10 and R 11 are each hydrogen, and R 9 If is methyl, then R 5 is not 3-hydroxyphenyl or 4-hydroxyphenyl, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is unsubstituted phenyl, and R 6 , R 7 , R 10 and R 11If each is hydrogen, then R 9 is not hydrogen, chloro, hydroxy, methyl or methoxy, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 5 is unsubstituted phenyl, and R 6 , R 7 and R 10 are each hydrogen, and R 11 If is methyl, then R 9 is not hydrogen or chloro, m is 0 and X 1 , X 2 , X 3 , X 4 and X 8 are each CH, α and β are both double bonds, and R 6 , R 7 , R 9 and R 10 are each hydrogen, and R 11 If is methyl, then R 5 is not an unsubstituted phenyl, m is 0 and X 1 , X 2 , X 3 and X 4 are CH, and X 8 is N, α and β are both double bonds, and R 6 , R 7 , R 9 , R 10 and R 11 If each is hydrogen, then R 5 is not an unsubstituted phenyl, m is 0 and X 1 , X 4 and X 8 are CH, and X 2 is CR 2 and X 3 is CR 3 where α and β are both double bonds, and R 5 is unsubstituted phenyl, and R 6 , R7 , R 9 , R 10 and R 11 If each is hydrogen, then R 2 and R 3 are not both methyl or both methoxy, m is 1 and X 1 , X 2 , X 3 , X 4 , and X 8 are each CH, α and β are both double bonds, and R a and R b But R a and R b together with the carbon atom to which they are both attached to form a cyclopentylidene, and R 6 , R 7 , R 9 , R 10 and R 11 If each is hydrogen, then R 5 is not unsubstituted phenyl), R 6 is hydrogen and C 1-4 alkyl, X 8 N and CR 8 is selected from R 7 , R 8 and R 11 are each independently selected from the following: (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); and (iii)C 3-8 Cycloalkyl (halo, C 1-4 Alkyl and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; R 9 and R 10 are each independently selected from the following: (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); and (iii)C 3-8 Cycloalkyl (halo, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; or R 9 and R 10 form ethane-1,2-dioxy moieties bridging the carbon atoms to which they are attached.

[0067] In addition to embodiment (1) of the preceding paragraph, compounds of Formula 1 include those in which: (2) α is a double bond and β is a double bond; X 1 N and CR 1 is selected from X 2 N and CR 2 is selected from X 3 N and CR 3 is selected from X 4 N and CR 4 are selected from, with the proviso that X 1 , X 2 , X 3 and X 4 at most one of is N, and R 1 , R 2 , R 3 , and R 4 are each independently selected from: (i) hydrogen, halo, hydroxy, cyano; and (ii) C 1-4 Alkyl, C 1-4 Alkoxy, and C 3-6 cycloalkyl (each substituted with 0-3 substituents independently selected from halo);

[0068] In addition to embodiment (2) of the preceding paragraph, compounds of Formula 1 include those in which: (3)X 1 is CR 1 and X 2 is CR 2 and X 3 is CR 3 and X 4 is CR 4 is.

[0069] In addition to embodiment (3) of the preceding paragraph, compounds of Formula 1 may also include R 1 , R 2 , R 3 and R 4 are each independently selected from the following: (4)(i) hydrogen, and (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (5)(i) hydrogen, and (ii) C 1-3 Alkyl and C 1-3 alkoxy (each substituted with 0-3 substituents independently selected from halo); (6)(i) hydrogen, and (ii) C 1-3 Alkyl and C 1-3 Alkoxy (each unsubstituted); (7) hydrogen, methyl, and methoxy; (8) hydrogen and methyl; or (9) Hydrogen.

[0070] In addition to embodiment (2) above, compounds of Formula 1 include those in which: (10)X 1 is N and X 2 is CR 2 and X 3 is CR 3 and X 4 is CR 4 is.

[0071] In addition to embodiment (10) of the preceding paragraph, compounds of Formula 1 may also include R 2 , R 3 and R 4 are each independently selected from the following: (11)(i) hydrogen, and (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (12)(i) hydrogen, and (ii) C 1-3 Alkyl and C 1-3 alkoxy (each substituted with 0-3 substituents independently selected from halo); (13)(i) hydrogen, and (ii) C 1-3 Alkyl and C 1-3 Alkoxy (each unsubstituted); (14) hydrogen, methyl, and methoxy; (15) hydrogen and methyl; or (16) Hydrogen.

[0072] In addition to embodiment (2) above, compounds of Formula 1 include those in which: (17)X 1 is CR 1 and X 2 is N and X 3 is CR 3 and X 4 is CR 4 is.

[0073] In addition to embodiment (17) of the preceding paragraph, compounds of Formula 1 may also include R 1 , R 3 and R 4 are each independently selected from the following: (18)(i) hydrogen, and (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (19)(i) hydrogen, and (ii) C 1-3 Alkyl and C 1-3 alkoxy (each substituted with 0-3 substituents independently selected from halo); (20)(i) hydrogen, and (ii) C 1-3 Alkyl and C 1-3 Alkoxy (each unsubstituted); (21) Hydrogen, methyl, and methoxy; (22) hydrogen and methyl; or (23) Hydrogen.

[0074] In addition to embodiment (2) above, compounds of Formula 1 include those in which: (24)X 1 is CR 1 and X 2 is CR 2 and X 3 is N and X 4 is CR 4 is.

[0075] In addition to embodiment (24) of the preceding paragraph, compounds of Formula 1 may also include R 1 , R 2 and R 4 are each independently selected from the following: (25)(i) hydrogen; and (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (26)(i) hydrogen; and (ii) C 1-3 Alkyl and C 1-3 alkoxy (each substituted with 0-3 substituents independently selected from halo); (27)(i) hydrogen, and (ii) C 1-3 Alkyl and C 1-3 Alkoxy (each unsubstituted); (28) Hydrogen, methyl, and methoxy; (29) hydrogen and methyl; or (30) Hydrogen.

[0076] In addition to embodiment (2) above, compounds of Formula 1 include those in which: (31)X 1 is CR 1 and X 2 is CR 2 and X 3 is CR 3 and X 4 is N.

[0077] In addition to embodiment (31) of the preceding paragraph, compounds of Formula 1 may also include R 1 , R 2 and R 3 are each independently selected from the following: (32)(i) hydrogen, and (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (33)(i) hydrogen, and (ii) C 1-3 Alkyl and C 1-3 alkoxy (each substituted with 0-3 substituents independently selected from halo); (34)(i) hydrogen, and (ii) C 1-3 Alkyl and C 1-3 Alkoxy (each unsubstituted); (35) Hydrogen, methyl, and methoxy; (36) hydrogen and methyl; or (37) Hydrogen.

[0078] In addition to embodiment (1) above, compounds of Formula 1 include those in which: (38) α is a single bond, β is a single bond, X 1 is CH2, X 2 is NR 2and CH2, X 3 is NR 3 and CH2, X 4 is CH2, except that X 2 and X 3 At most one of is N, R 2 and R 3 are each independently selected from: (i) hydrogen; and (ii) C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 Alkylsulfonyl, and C 3-6 cycloalkyl (each substituted with 0-3 substituents independently selected from halo);

[0079] In addition to embodiment (38) of the preceding paragraph, compounds of Formula 1 include those in which: (39)X 2 is CH2 and X 3 is CH2, or (40)X 2 is NR 2 and X 3 is CH2.

[0080] In addition to embodiment (40) of the preceding paragraph, compounds of Formula 1 may also include R 2 but includes a selection from the following: (41)C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 Alkylsulfonyl, and C 3-6 cycloalkyl (each substituted with 0-3 substituents independently selected from halo); (42)C 1-3 Alkyl, C 1-3 Alkyl carbonyl, C 1-3 Alkylsulfonyl, and C 3-6 cycloalkyl (each substituted with 0-3 substituents independently selected from halo); (43)C 1-3 Alkyl, C 1-3 Alkyl carbonyl, C 1-3 alkylsulfonyl, and C3-6 cycloalkyl (each unsubstituted); (44) Methyl, ethyl, methylcarbonyl, ethylcarbonyl, methylsulfonyl, ethylsulfonyl, cyclopropyl and cyclobutyl; (45) methyl, ethyl, methylcarbonyl, methylsulfonyl, and cyclopropyl; or (46) Methyl and methylcarbonyl.

[0081] In addition to embodiment (38) above, compounds of Formula 1 include those in which: (47)X 2 is CH 2 and X 3 is NR3.

[0082] In addition to embodiment (47) of the preceding paragraph, compounds of Formula 1 may also be R 3 but includes those selected from the following: (48)C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 Alkylsulfonyl, and C 3-6 cycloalkyl (each substituted with 0-3 substituents independently selected from halo); (49)C 1-3 Alkyl, C 1-3 Alkyl carbonyl, C 1-3 Alkylsulfonyl, and C 3-6 cycloalkyl (each substituted with 0-3 substituents independently selected from halo); (50)C 1-3 Alkyl, C 1-3 Alkyl carbonyl, C 1-3 Alkylsulfonyl, and C 3-6 cycloalkyl (each unsubstituted); (51) Methyl, ethyl, methylcarbonyl, ethylcarbonyl, methylsulfonyl, ethylsulfonyl, cyclopropyl and cyclobutyl; (52) methyl, ethyl, methylcarbonyl, methylsulfonyl, and cyclopropyl; or (53) Methyl and methylcarbonyl.

[0083] In addition to embodiment (1) above, compounds of Formula 1 include those in which: (54) α is a double bond and β is a single bond; X 1 is CH, X 2 is N, X 3 does not exist, X 4 is NR 4 and R 4 is selected from: (i) hydrogen; and (ii) C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 Alkylsulfonyl, and C 3-6 cycloalkyl (each substituted with 0-3 substituents independently selected from halo);

[0084] In addition to embodiment (54) of the preceding paragraph, the compound of Formula 1 may further comprise R 4 but includes those selected from the following: (55)C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 Alkylsulfonyl, and C 3-6 cycloalkyl (each substituted with 0-3 substituents independently selected from halo); (56)C 1-3 Alkyl, C 1-3 Alkyl carbonyl, C 1-3 Alkylsulfonyl, and C 3-6 cycloalkyl (each substituted with 0-3 substituents independently selected from halo); (57)C 1-3 Alkyl, C 1-3 Alkyl carbonyl, C1-3 Alkylsulfonyl, and C 3-6 cycloalkyl (each unsubstituted); (58) Methyl, ethyl, methylcarbonyl, ethylcarbonyl, methylsulfonyl, ethylsulfonyl, cyclopropyl and cyclobutyl; (59) methyl, ethyl, methylcarbonyl, methylsulfonyl, and cyclopropyl; or (60) Methyl and methylcarbonyl.

[0085] In addition to embodiment (1) above, compounds of Formula 1 include those in which: (61) α is a single bond, β is a single bond, X 1 is CH2, X 2 is O and X 3 is CH2, or X 2 is CH2 and X 3 is O, X 4 is CH2.

[0086] In addition to embodiment (61) of the preceding paragraph, compounds of Formula 1 include those in which: (62)X 2 is O and X 3 is CH2, or (63)X 2 is CH2 and X 3 is O.

[0087] In addition to any one of the above embodiments (1) through (63), compounds of Formula 1 include those where m is: (64)0; or (65)1 or 2.

[0088] In addition to embodiment (65) of the preceding paragraph, compounds of Formula 1 include those in which: (66)R a and R b are hydrogen and C, respectively.1-4 independently selected from alkyl, (67)R a and R b are hydrogen and C, respectively. 1-3 independently selected from alkyl, (68)R a and R b are each independently selected from hydrogen and methyl; (69)R a are each methyl, and R b are each hydrogen, (70)R a are each methyl, and R b are each methyl, (71)R a are each hydrogen, and R b are each hydrogen, (72)R a and R b are hydrogen and C, respectively. 1-4 alkyl, or R a and R b is R a and R b together with the carbon atom to which they are attached form a cyclopropylidene or cyclobutylidene, provided that if m is 2, then R a and R b At most one of the R a and R b together with the carbon atom to which it is attached to form a cyclopropylidene or cyclobutylidene, (73)R a and R b are hydrogen and C, respectively. 1-4 alkyl, or R a and R b is R a and R b together with the carbon atom to which they are attached form a cyclopropylidene, provided that if m is 2, then R a and R b At most one of the R a and R btogether with the carbon atom to which is attached to form a cyclopropylidene, (74)R a and R b are hydrogen and C, respectively. 1-3 alkyl, or R a and R b is R a and R b together with the carbon atom to which they are attached form a cyclopropylidene, provided that if m is 2, then R a and R b At most one of the R a and R b together with the carbon atom to which it is attached to form a cyclopropylidene. (75)R a and R b are each independently selected from hydrogen and methyl, or R a and R b is R a and R b together with the carbon atom to which they are attached form a cyclopropylidene, provided that if m is 2, then R a and R b At most one of the R a and R b together with the carbon atom to which is attached, forms a cyclopropylidene, or (76)R a and R b are each hydrogen or R a and R b is R a and R b together with the carbon atom to which they are attached form a cyclopropylidene, provided that if m is 2, then R a and R b At most one of the R a and R b together with the carbon atom to which it is attached to form a cyclopropylidene.

[0089] In addition to any one of the above embodiments (1) to (76), the compound of Formula 1 may also include R 5 includes those where: (77)C 3-8 Cycloalkyl (substituted with 0 to 5 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (78)C 4-7 Cycloalkyl (substituted with 0 to 5 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (79) Cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptan-1-yl, and spiro[3.3]heptan-2-yl, each of which is substituted with 0 to 5 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (80) Cycloalkyl selected from cyclobutyl, cyclohexyl, bicyclo[2.2.1]heptan-1-yl, and spiro[3.3]heptan-2-yl, each of which is substituted with 0 to 5 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (81) Cycloalkyl selected from cyclobutyl, cyclohexyl, and bicyclo[2.2.1]heptan-1-yl, each of which is substituted with 0 to 5 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (82) Cycloalkyl, which is cyclobutyl substituted with 0 to 5 substituents independently selected from the following: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (83) Cycloalkyl, which is cyclohexyl substituted with 0 to 5 substituents independently selected from the following: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); or (84) Cycloalkyl, which is bicyclo[2.2.1]heptan-1-yl, substituted with 0 to 5 substituents independently selected from the following: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo);

[0090] In addition to any one of embodiments (77)-(84) of the preceding paragraph, the compound of Formula 1 may also include R 5 Cycloalkyls include those substituted with 0 to 5 substituents independently selected from: (85)(i) halo, hydroxy, and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (86)(i) halo and hydroxy; (ii) Amino (C1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (87)(i) hydroxy and fluoro; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (88)(i) hydroxy; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (89)(i) halo, hydroxy, cyano, and oxo; (ii) Amino (C 1-3 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (90)(i) halo, hydroxy, cyano, and oxo; (ii) amino (substituted with 0 to 2 substituents independently selected from methyl); and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4alkoxy (each substituted with 0-3 substituents independently selected from halo); (91)(i) halo, hydroxy, cyano, and oxo; (ii) unsubstituted amino, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (92)(i) halo, hydroxy, cyano, and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-3 Alkyl, C 1-3 Alkylcarbonyl, and C 1-3 alkoxy (each substituted with 0-3 substituents independently selected from halo); (93)(i) halo, hydroxy, cyano, and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii) methyl, methylcarbonyl, ethylcarbonyl, methoxy, and ethoxy (each substituted with 0 to 3 substituents independently selected from halo); (94)(i) halo, hydroxy, cyano, and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii) methyl and methoxy (each substituted with 0 to 3 substituents independently selected from halo); (95)(i) hydroxy, (ii) amino (substituted with 0 to 2 substituents independently selected from methyl); and (iii) methyl and methoxy (each substituted with 0 to 3 substituents independently selected from halo); (96)(i) hydroxy, (ii) amino (substituted with 0 to 2 substituents independently selected from methyl); and (iii) methyl and methoxy (each substituted with 0 to 3 substituents independently selected from fluoro); or (97) Hydroxy, dimethylamino, methyl, trifluoromethyl, and methoxy.

[0091] In addition to any one of embodiments (77)-(97) of the preceding paragraph, the compound of Formula 1 may also include R 5 Included are those where cycloalkyl is: (98) Substituted with 0 to 4 substituents; (99) Substituted with 0 to 3 substituents; (100) Substituted with 0 to 2 substituents, (101) Substituted with 0 to 1 substituents, or (102) Unsubstituted.

[0092] In addition to any one of the above embodiments (1) to (76), the compound of Formula 1 may also include R 5 but includes: (103)C 3-8 Heterocyclyl (up to 3 carbon ring atoms are each independently substituted with 0-2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); wherein the nitrogen ring atom, if present, is unsubstituted or substituted with a substituent selected from: (I C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (That C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy); (104)C 3-8 Heterocyclyl, where the ring heteroatoms are selected from nitrogen and oxygen, and up to three carbon ring atoms are each independently substituted with 0-2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); wherein the nitrogen ring atom, if present, is unsubstituted or substituted with a substituent selected from: (I C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (That C3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy); (105)C 3-8 Heterocyclyl (wherein the ring heteroatom is nitrogen and up to three carbon ring atoms are each independently substituted with 0-2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); wherein the nitrogen ring atom is unsubstituted or substituted with a substituent selected from: (I C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (That C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy); (106) Heterocyclyl selected from azetidinyl, piperidinyl, 1-azabicyclo[2.2.1]heptanyl, quinuclidinyl, pyrrolidinyl, 3-azabicyclo[3.1.0]hexan-1-yl, and 2-oxabicyclo[2.2.1]heptan-4-yl (wherein R 5 Up to three carbon ring atoms of a heterocyclyl are each independently substituted with 0 to 2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); where R 5 The nitrogen ring atom of a heterocyclyl, if present, is unsubstituted or substituted with a substituent selected from: (I C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (That C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy); (107) Heterocyclyl selected from azetidin-1-yl, piperidin-2-yl, piperidin-3-yl, 1-azabicyclo[2.2.1]heptan-3-yl, quinuclidin-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 3-azabicyclo[3.1.0]hexan-1-yl, and 2-oxabicyclo[2.2.1]heptan-4-yl (wherein R 5 Up to three carbon ring atoms of a heterocyclyl are each independently substituted with 0 to 2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); where R 5 The nitrogen ring atom of a heterocyclyl, if present, is unsubstituted or substituted with a substituent selected from: (I C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (That C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy); (108)R 5 heterocyclyl selected from piperidinyl, wherein up to three carbon ring atoms of the heterocyclyl are each independently substituted with 0 to 2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); where R 5 The nitrogen ring atom of a heterocyclyl, if present, is unsubstituted or substituted with a substituent selected from: (I C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (That C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n(The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy). (109)R 5 heterocyclyl selected from piperidin-3-yl, wherein up to three carbon ring atoms of the heterocyclyl are each independently substituted with 0 to 2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); where R 5 The nitrogen ring atom of a heterocyclyl is unsubstituted or substituted with a substituent selected from: (I C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (That C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy);

[0093] In addition to any one of embodiments (103)-(109) of the preceding paragraph, the compound of Formula 1 may further comprise R 5 Heterocyclyl includes those in which up to three carbon ring atoms are each independently substituted with 0-2 substituents independently selected from: (110)(i) halo, hydroxy, and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (111)(i) halo and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (112)(i) halo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (113)(i) halo, hydroxy, cyano, and oxo; (ii) Amino (C 1-3 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4alkoxy (each substituted with 0-3 substituents independently selected from halo); (114)(i) halo, hydroxy, cyano, and oxo; (ii) amino (substituted with 0 to 2 substituents independently selected from methyl); and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (115)(i) halo, hydroxy, cyano, and oxo; (ii) unsubstituted amino, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (116)(i) halo, hydroxy, cyano, and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii)C 1-3 Alkyl, C 1-3 Alkylcarbonyl, and C 1-3 alkoxy (each substituted with 0-3 substituents independently selected from halo); (117)(i) halo, hydroxy, cyano, and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii) methyl, methylcarbonyl, ethylcarbonyl, methoxy, and ethoxy (each substituted with 0 to 3 substituents independently selected from halo); (118)(i) halo, hydroxy, cyano, and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl; and (iii) methyl and methoxy (each substituted with 0 to 3 substituents independently selected from halo); (119)(i) halo and oxo; (ii) amino (substituted with 0 to 2 substituents independently selected from methyl); and (iii) methyl and methoxy (each substituted with 0 to 3 substituents independently selected from halo); (120)(i) halo and oxo, (ii) amino (substituted with 0 to 2 substituents independently selected from methyl); and (iii) methyl and methoxy (each substituted with 0-3 substituents independently selected from fluoro); (121) Halo, oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy; (122) Halo, oxo, methyl, ethyl, propyl, and isopropyl; (123) Fluoro, oxo, methyl, ethyl, propyl, and isopropyl; (124) Halo, or (125)Fluoro.

[0094] In addition to any one of embodiments (103)-(125) of the preceding paragraph, compounds of Formula 1 include those in which: (126) The above R 5 up to two carbon ring atoms of a heterocyclyl are each substituted; (127) The above R 5 At most one carbon ring atom of a heterocyclyl is substituted; (128) The above R 5 at least one carbon ring atom of a heterocyclyl is substituted; (129) The above R 5 None of the carbon ring atoms of a heterocyclyl is substituted.

[0095] In addition to any one of embodiments (103)-(129) of the preceding paragraph, the compound of Formula 1 may further comprise R 5 C3-8 Included are heterocyclyls in which the nitrogen ring atom, if present, is unsubstituted or substituted with a substituent selected from: (130)(i)C 1-3 Alkyl, C 1-3 Alkylcarbonyl, and C 1-3 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (That C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (131)(i)C 1-3 alkyl, methylcarbonyl, ethylcarbonyl, methylsulfonyl, and ethylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (That C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4substituted with 0 to 3 substituents independently selected from alkoxy); (132) (i) methyl, ethyl, isopropyl, methylcarbonyl, and methylsulfonyl (each substituted with 0 to 3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (That C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (133) (i) methyl, ethyl, isopropyl, methylcarbonyl, methylsulfonyl (each substituted with 0 to 3 substituents selected from fluoro); (ii) C 3-8 Cycloalkyl-(CH2) n (That C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (134) (i) Methyl, ethyl, isopropyl, methylcarbonyl, methylsulfonyl (each unsubstituted), (ii) C3-8 Cycloalkyl-(CH2) n (That C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (135)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-5 Cycloalkyl-(CH2) n (That C 3-5 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (136)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-5 Cycloalkyl-(CH2) n (That C3-5 The cycloalkyl moiety can be halo, C 1-3 Alkyl, C 1-3 Alkyl carbonyl, C 1-3 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (137)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-5 Cycloalkyl-(CH2) n (That C 3-5 The cycloalkyl moiety can be halo, C 1-3 Alkyl, and C 1-3 substituted with 0 to 3 substituents independently selected from alkoxy, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (138)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-5 Cycloalkyl-(CH2) n (That C 3-5 The cycloalkyl moiety is C 1-3 Alkyl, and C 1-3substituted with 0 to 3 substituents independently selected from alkoxy, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (139)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-5 Cycloalkyl-(CH2) n (That C 3-5 the cycloalkyl moiety is substituted with 0-3 substituents independently selected from halo, methyl, and methoxy; and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (140)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-5 Cycloalkyl-(CH2) n (That C 3-5 the cycloalkyl moiety is substituted with 0-3 substituents independently selected from fluoro, methyl, and methoxy; and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (141)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-5 Cycloalkyl-(CH2) n (That C 3-5 the cycloalkyl moiety is substituted with 0-3 substituents independently selected from methyl and methoxy; and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (142)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-5 Cycloalkyl-(CH2) n (That C 3-5 the cycloalkyl portion is unsubstituted), and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (143)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (That C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-3 Alkyl, and C 1-3 substituted with 0 to 3 substituents independently selected from alkoxy; (144)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (That C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n wherein the phenyl and pyridinyl portions are substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, methyl, and methoxy; (145)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (That C 3-8The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n wherein the phenyl and pyridinyl portions are substituted with 0 to 3 substituents independently selected from halo, hydroxy, methyl, and methoxy; (146)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (That C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n wherein the phenyl and pyridinyl portions are substituted with 0 to 3 substituents independently selected from fluoro, chloro, hydroxy, methyl, and methoxy; (147)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (That C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n wherein the phenyl and pyridinyl portions are substituted with 0 to 3 substituents independently selected from fluoro, hydroxy, methyl, and methoxy; (148)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (That C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (wherein the phenyl and pyridinyl moieties are unsubstituted), (149) (i) methyl, ethyl, isopropyl, methylcarbonyl, methylsulfonyl (each substituted with 0 to 3 substituents selected from fluoro); (ii) C 3-5 Cycloalkyl-(CH2) n (That C 3-5 the cycloalkyl moiety is substituted with 0-3 substituents independently selected from fluoro, methyl, and methoxy; and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n wherein the phenyl and pyridinyl portions are substituted with 0 to 3 substituents independently selected from fluoro, hydroxy, methyl, and methoxy; (150) (i) methyl, ethyl, isopropyl, methylcarbonyl, methylsulfonyl (each substituted with 0 to 3 substituents selected from fluoro); (ii) C 3-5 Cycloalkyl-(CH2) n (That C 3-5 the cycloalkyl moiety is substituted with 0-3 substituents independently selected from methyl and methoxy; and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n wherein the phenyl and pyridinyl portions are substituted with 0 to 3 substituents independently selected from fluoro, hydroxy, methyl, and methoxy; (151) (i) methyl, ethyl, isopropyl, methylcarbonyl, methylsulfonyl (each substituted with 0 to 3 substituents selected from fluoro); (ii) C 3-5 Cycloalkyl-(CH2) n (That C 3-5 the cycloalkyl moiety is substituted with 0-3 substituents independently selected from methyl and methoxy; and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (wherein the phenyl and pyridinyl moieties are unsubstituted), (152) (i) methyl, ethyl, isopropyl (each substituted with 0 to 3 substituents selected from fluoro); and (ii) C 3-5 Cycloalkyl-(CH2) n (That C 3-5 the cycloalkyl moiety is substituted with 0-3 substituents independently selected from methyl and methoxy; (153)(i) Methyl, ethyl and isopropyl, and (ii) C 3-5 Cycloalkyl-(CH2) n (That C 3-5the cycloalkyl moiety is substituted with 0-3 substituents independently selected from methyl and methoxy; (154) Methyl, ethyl, isopropyl and C 3-5 Cycloalkyl-(CH2) n ,or (155) Methyl, ethyl, isopropyl and cyclopropyl.

[0096] In addition to any one of embodiments (103)-(155) of the preceding paragraph, compounds of Formula 1 include those in which: (156)R 5 is C 3-8 heterocyclyl and n is 0, or (157)R 5 is C 3-8 heterocyclyl, and n is 1.

[0097] In addition to any one of the above embodiments (1) to (76), the compound of Formula 1 may also include R 5 However, the following phenyl groups are included: (158) Halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0-3 substituents independently selected from alkoxy, provided that at least one of said substituents is hydroxy; (159) Halo, hydroxy, cyano, C 1-3 Alkyl, and C 1-3 substituted with 0-3 substituents independently selected from alkoxy, provided that at least one of said substituents is hydroxy; (160) substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, methyl, and methoxy, provided that at least one of the substituents is hydroxy; (161) Substituted with 0 to 2 substituents independently selected from halo, hydroxy, cyano, methyl, and methoxy, provided that at least one of the substituents is hydroxy; (162) unsubstituted or hydroxy-substituted; or (163) Unsubstituted.

[0098] In addition to any one of embodiments (1) through (163) of the preceding paragraph, the compound of Formula 1 may also include R 6 is selected from the following: (164) Hydrogen and C 1-3 alkyl; (165) Hydrogen and methyl; (166) Methyl; or (167)Hydrogen.

[0099] In addition to any one of embodiments (1) through (167) of the preceding paragraph, compounds of Formula 1 include those in which: (168)X 8 is CR 8 is.

[0100] In addition to any one of embodiments (1) through (168) of the preceding paragraph, the compound of Formula 1 may also include R 7 , R 8 and R 11 each of which is independently selected from the following: (169)(i) hydrogen, halo, and hydroxy; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); and (iii)C 3-8 Cycloalkyl (halo, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (170) (i) hydrogen, halo, and hydroxy; and (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (171) (i) hydrogen, halo, and hydroxy; and (ii) C 1-3 Alkyl and C 1-3 alkoxy (each substituted with 0-3 substituents independently selected from halo); (172) (i) hydrogen, halo, and hydroxy; and (ii) methyl and methoxy (each substituted with 0 to 3 substituents independently selected from halo); (173) (i) hydrogen, halo, and hydroxy; and (ii) methyl and methoxy (each substituted with 0 to 3 fluoro).

[0101] In addition to any one of the above embodiments (1) through (168), the compound of Formula 1 may also include R 7 and R 8 are both hydrogen, and R 11 is selected from the following: (174) (i) hydrogen, halo, and hydroxy; and (ii) C 1-3 Alkyl and C 1-3 alkoxy (each substituted with 0-3 substituents independently selected from halo); (175) (i) hydrogen, halo, and hydroxy; and (ii) methyl and methoxy (each substituted with 0 to 3 substituents independently selected from halo); (176) (i) hydrogen, halo, and hydroxy; and (ii) methyl and methoxy (each substituted with 0 to 3 fluoro).

[0102] In addition to any one of embodiments (1) through (176) of the preceding paragraph, the compound of Formula 1 may also include R 9 and R 10 each of which is independently selected from the following: (177)(i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); and (iii)C 3-8 Cycloalkyl (halo, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (178)(i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-3 alkoxy (each substituted with 0-3 substituents independently selected from halo); (iii)C 3-8 Cycloalkyl (halo, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (179)(i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 alkyl and methoxy (each substituted with 0-3 substituents independently selected from halo); (iii)C 3-8 Cycloalkyl (halo, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (180)(i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 alkyl and methoxy (each substituted with 0-3 fluoro), and (iii)C 3-8 Cycloalkyl (halo, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (181)(i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); and (iii)C 3-5 Cycloalkyl (halo, C 1-4 Alkyl, and C1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (182)(i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); and (iii)C 3-5 Cycloalkyl(C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (183)(i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); and (iii)C 3-5 Cycloalkyl(C 1-3 Alkyl, and C 1-3 substituted with 0 to 3 substituents independently selected from alkoxy; (184)(i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); and (iii)C 3-5 cycloalkyl (substituted with 0-3 substituents independently selected from methyl and methoxy); (185)(i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); and (iii) cyclopropyl, and cyclobutyl (each substituted with 0 to 3 substituents independently selected from methyl and methoxy); (186)(i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-3 alkoxy (each substituted with 0-3 substituents independently selected from halo); (iii)C 3-5 Cycloalkyl(C 1-3 Alkyl, and C 1-3 substituted with 0 to 3 substituents independently selected from alkoxy; (187)(i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-3 alkoxy (each substituted with 0-3 fluoro); and (iii)C 3-5 Cycloalkyl(C 1-3 Alkyl, and C 1-3 substituted with 0 to 3 substituents independently selected from alkoxy; or (188)(i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-3 alkoxy (each substituted with 0-3 fluoro); and (iii)C 3-5 cycloalkyl (substituted with 0-3 substituents independently selected from methyl and methoxy);

[0103] Compounds of Formula 1 include embodiments (1) through (188) described in the preceding paragraphs, and compounds specifically named in the Examples, and may exist as salts, complexes, solvates, hydrates, and liquid crystals. Similarly, compounds of Formula 1 that are salts may exist as complexes, solvates, hydrates, and liquid crystals.

[0104] The compounds of Formula 1 can form pharmaceutically acceptable complexes, salts, solvates, and hydrates. These salts include acid addition salts (including diacids) and base salts. Pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid, as well as non-toxic salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Such salts include acetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, and isethionate. Salts include phosphate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate salts.

[0105] Pharmaceutically acceptable base salts include salts derived from bases, including metal cations such as alkali or alkaline earth metal cations, and amines. Examples of suitable metal cations include sodium, potassium, magnesium, calcium, zinc, and aluminum. Examples of suitable amines include arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine, lysine, N-methylglucamine, olamine, 2-amino-2-hydroxymethyl-propane-1,3-diol, and procaine. For a discussion of useful acid addition salts and base salts, see S.M. Berge et al., J.Pharm.Sci.(1977)66:1-19. Also see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use(2002).

[0106] Pharmaceutically acceptable salts can be prepared using various methods. For example, a compound of Formula 1 can be reacted with an appropriate acid or base to obtain the desired salt. Alternatively, a precursor of the compound of Formula 1 can be reacted with an acid or base to remove acid- or base-labile protecting groups or to open the lactone or lactam group of the precursor. In addition, a salt of the compound of Formula 1 can be converted to another salt (or free form) by treating it with an appropriate acid or base or by contacting it with an ion exchange resin. If the salt precipitates from solution after the reaction, it can be recovered by filtration or by isolating the salt by evaporation. The degree of ionization of the salt can vary from completely ionized to almost non-ionized.

[0107] Compounds of Formula 1 can exist in a range of solid states, from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a substance lacks long-range order at the molecular level and can exhibit the physical properties of either a solid or a liquid, depending on temperature. Typically, such substances do not produce distinctive X-ray diffraction patterns and are more formally described as liquids, although they exhibit the properties of a solid. Upon heating, a change from solid to liquid properties occurs, characterized by a change of state, typically second-order ("glass transition"). The term "crystalline" refers to a solid phase in which a substance has an internal structure with regular order at the molecular level and produces a distinctive X-ray diffraction pattern with distinct peaks. Such substances, when heated sufficiently, also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase transition, typically first-order ("melting point").

[0108] The compound of formula 1 can exist in unsolvated and solvated forms. The term "solvate" describes a molecular complex containing a compound and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" refers to a solvate in which the solvent is water. Pharmaceutically acceptable solvates include those in which the solvent may be isotopically substituted (e.g., DO, acetone-d6, DMSO-d6).

[0109] A currently accepted classification system for solvates and hydrates of organic compounds distinguishes between isolated site, channel, and metal ion-coordinated solvates and hydrates. See, for example, KR Morris (HGBrittain ed.) Polymorphism in Pharmaceutical Solids (1995). Isolated site hydrates and solvates are those in which the solvent (e.g., water) molecules are isolated from direct contact with each other by intervening molecules of the organic compound. In channel solvates, the solvent molecules reside in lattice channels where they are next to other solvent molecules. In metal ion-coordinated solvates, the solvent molecules are bound to the metal ion.

[0110] When the solvent or water is tightly bound, the complex has a well-defined stoichiometry independent of humidity. However, when the solvent or water is weakly bound, as in the case of channel solvates and hygroscopic compounds, the water or solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will typically be observed.

[0111] The compounds of Formula 1 may also exist as multicomponent complexes (other than salts and solvates) in which the compound (drug) and at least one other component are present in stoichiometric or non-stoichiometric amounts. This type of complex includes inclusion complexes (drug-host inclusion complexes) and cocrystals. The latter is typically defined as a crystalline complex of neutral molecular components bound together by non-covalent interactions, but may also be a complex of a neutral molecule with a salt. Cocrystals can be prepared by melt crystallization, recrystallization from a solvent, or by physically grinding the components together. See, for example, O. Almarsson and MJ Zaworotko, Chem. Commun. (2004) 17:1889-1896. For a review of multicomponent complexes, see JK Haleblian, J. Pharm. Sci. (1975) 64(8):1269-88.

[0112] Compounds of Formula 1 can exist in a mesomorphic state (mesophase or liquid crystal) when subjected to appropriate conditions. The mesomorphic state is between the true crystalline state and the true liquid state (either melt or dissolve). Liquid crystallinity resulting from a change in temperature is described as "thermotropic," while liquid crystallinity resulting from the addition of a second component, such as water or another solvent, is described as "lyotropic." Compounds with the potential to form lyotropic mesophases are described as "amphiphilic," and include polar ionic moieties (e.g., -COO-Na + , -COO-K + , -SO3-Na + ) or polar nonionic moiety (-N - N +(CH3)3, etc. See, for example, N.H. Hartshorne and A. Stuart, Crystals and the Polarizing Microscope (4th ed., 1970).

[0113] Each compound of Formula 1 may exist as a polymorph, stereoisomer, tautomer, or some combination thereof, may be isotopically labeled, may result from administration of a prodrug, or may form a metabolite following administration.

[0114] A "prodrug" refers to a compound that has little or no pharmacological activity but can be converted into a compound with the desired pharmacological activity when metabolized in vivo. Prodrugs can be prepared by replacing appropriate functional groups present in a pharmacologically active compound with a "promoiety," as described, for example, in H. Bundgaar, Design of Prodrugs (1985). Examples of prodrugs include ester, ether, or amide derivatives of the compounds of Formula 1 that contain carboxylic acid, hydroxy, or amino functional groups, respectively. For a detailed discussion of prodrugs, see, for example, T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," ACS Symposium Series 14 (1975) and EB Roche ed., Bioreversible Carriers in Drug Design (1987).

[0115] "Metabolite" refers to a compound formed in vivo upon administration of a pharmacologically active compound. Examples include hydroxymethyl, hydroxy, secondary amino, primary amino, phenol, and carboxylic acid derivatives of compounds of Formula 1 bearing methyl, alkoxy, tertiary amino, secondary amino, phenyl, and amido groups, respectively.

[0116] The compounds of Formula 1 can exist as stereoisomers resulting from the presence of one or more asymmetric centers, one or more double bonds, or both. The stereoisomers can be pure, substantially pure, or mixtures. Such stereoisomers can also result from acid addition or base salts in which the counterion is optically active (e.g., when the counterion is D-lactate or L-lysine).

[0117] Compounds of Formula 1 can exist as tautomers, which are isomers resulting from tautomerization. Tautomeric isomerism includes, for example, imine-enamine, keto-enol, oxime-nitroso, and amide-imidic acid tautomerism.

[0118] Compounds of formula 1 may exhibit more than one type of isomerism.

[0119] Geometric (cis / trans) isomers may be separated by conventional techniques such as chromatography or fractional crystallization.

[0120] Conventional techniques for preparing or isolating compounds of a specific stereochemical configuration include chiral synthesis from appropriate optically pure precursors or resolution of the racemate (or racemate of a salt or derivative), for example, using chiral high-pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) can be reacted with an appropriate optically active compound, for example, an alcohol, or, if the compound of Formula 1 contains an acidic or basic moiety, with an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereoisomeric mixture can be separated by chromatography, fractional crystallization, or the like, and the appropriate diastereoisomer can be converted to a compound with the required stereochemical configuration. For a further discussion of techniques for separating stereoisomers, see E.L. Eliel and S.H. Wilen, Stereochemistry of Organic Compounds (1994).

[0121] Compounds of Formula 1 may have isotopic variations in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Suitable isotopes for inclusion in compounds of Formula 1 include, for example, isotopes of hydrogen, such as 2 H and 3 H; isotopes of carbon, e.g., 11 C. 13 C, and 14 C; isotopes of nitrogen, e.g., 13 N and 15 N; isotopes of oxygen, e.g., 15 O. 17 O, and 18 O; isotopes of sulfur, e.g., 35 S; isotopes of fluorine, e.g., 18 F; isotopes of chlorine, e.g., 36 Cl; as well as isotopes of iodine, e.g., 123 I and 125 Isotopic variants (e.g., deuterium, 2 The use of H) can provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) due to increased metabolic stability. Additionally, certain isotopic variations of the disclosed compounds may be substituted with radioactive isotopes (e.g., tritium, 3 H, or 14 C) can be incorporated, which can be useful for drug and / or substrate tissue distribution studies. 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds can be prepared by processes analogous to those described elsewhere in this disclosure, using the appropriate isotopically labeled reagent in place of an unlabeled reagent.

[0122] The compounds of Formula 1 can be prepared using the techniques described below. Some of the methods and examples may omit details of common reactions, including oxidations, reductions, and the like, separation techniques (extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like), and analytical procedures, which are known to those skilled in the art of organic chemistry. Details of such reactions and techniques can be found in several treatises, including Richard Larock, Comprehensive Organic Transformations (1999), and the multi-volume series, Compendium of Organic Synthetic Methods (since 1974), edited by Michael B. Smith et al. Starting materials and reagents can be obtained from commercial sources or prepared using literature methods. Some of the reaction schemes may omit minor products resulting from chemical transformations (e.g., alcohols from the hydrolysis of esters, CO from the decarboxylation of diacids, and the like). Additionally, in some cases, reaction intermediates may be used in subsequent steps without isolation or purification (i.e., in situ).

[0123] In the methods and examples that follow, certain compounds can be prepared using protecting groups that prevent undesired chemical reactions outside of the reactive site. Protecting groups can also be used to enhance the solubility of the compound or otherwise modify its physical properties. For a discussion of protecting group strategies, a description of materials and methods for installing and removing protecting groups, and a summary of useful protecting groups for common functional groups such as amines, carboxylic acids, alcohols, ketones, and aldehydes, see T.W. Greene and P.G. Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000).

[0124] Generally, chemical transformations described throughout this specification can be carried out using substantially stoichiometric amounts of reactants, although certain reactions can benefit from using an excess of one or more reactants. Additionally, although many of the reactions disclosed throughout this specification can be carried out at about room temperature (RT) and ambient pressure, some reactions may be carried out at elevated pressures or using higher (e.g., reflux conditions) or lower temperatures (e.g., −78° C. to 0° C.), depending on reaction kinetics, yield, etc. All references in this disclosure and claims to stoichiometric ranges, temperature ranges, pH ranges, etc., include the indicated endpoints, regardless of whether the word “range” is explicitly used.

[0125] Many chemical transformations may also employ one or more compatible solvents, which can affect the reaction rate and yield. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, nonpolar solvents, or some combination. Representative solvents include saturated aliphatic hydrocarbons (e.g., n-pentane, n-hexane, n-heptane, n-octane, cyclohexane, methylcyclohexane); aromatic hydrocarbons (e.g., benzene, toluene, xylene); halogenated hydrocarbons (e.g., methylene chloride, chloroform, carbon tetrachloride); aliphatic alcohols (e.g., methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, 2-methyl-propan-1-ol, butan-2-ol, 2-methyl-propan-2-ol, pentan-1-ol, 3-methyl-butan-1-ol, hexane-1-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol, 2-(2-methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol, 2-(2 ethers (e.g., diethyl ether, diisopropyl ether, dibutyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, 1-methoxy-2-(2-methoxy-ethoxy)-ethane, 1-ethoxy-2-(2-ethoxy-ethoxy)-ethane, tetrahydrofuran, 1,4-dioxane); ketones (e.g., acetone, methyl ethyl ketone); esters (methyl acetate, ethyl acetate); nitrogen-containing solvents (e.g., formamide, N,N-dimethylformamide, acetonitrile, N-methyl-pyrrolidone, pyridine, quinoline, nitrobenzene); sulfur-containing solvents (e.g., carbon disulfide, dimethyl sulfoxide, tetrahydro-thiophene-1,1-dioxide); and phosphorus-containing solvents (e.g., hexamethylphosphoric acid triamide).

[0126] In the following schemes, substituent identifiers (e.g., α, β, m, R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , Ra , R b , X 1 , X 2 , X 3 , X 4 and X 8 ) are as defined above for Formula 1. As noted above, some of the starting materials and intermediates may contain protecting groups, which are removed prior to the formation of the final product. In such cases, the substituent identifiers refer to the moieties defined in Formula 1 and those moieties bearing the appropriate protecting groups. For example, a starting material or intermediate in a synthetic method may contain a potentially reactive (secondary) amine. In such cases, the amine may include moieties with or without, for example, a Boc or Cbz group attached to the amine.

[0127] Schemes A and B show general methods for preparing compounds of Formula 1. According to Scheme A, a 1,4-dihalophthalazine derivative or analog (A1, where X is Cl) is reacted with an amine (A2) in the presence of a base (e.g., DIPEA, K2CO3, etc.) and a solvent (e.g., ACN, DMSO, NMP, etc.) at elevated temperatures (e.g., 80°C to 150°C) to provide a halophthalazine amine (A3). The amine (A3) can then be converted to a diboronic acid or ester (A4, where, for example, each R 12 is H or C 1-4 alkyl) to give compounds of formula 1 directly or indirectly, for example after removal of protecting groups, further elaboration of functional groups, separation of stereoisomers or positional isomers, etc.

[0128] Alternatively, as shown in Scheme B, 1,4-dihalophthalazine derivatives or analogs (A1) can first be reacted with a diboronic acid or ester (A4) in the presence of a palladium catalyst, a base, and a solvent as shown in Scheme A. The resulting aromatic-substituted halophthalazine (B1) is then reacted with an amine (A2) in the presence of a base and a solvent at elevated temperature as described for Scheme A to afford either directly or after removal of protecting groups, further elaboration of functional groups, separation of stereoisomers or regioisomers, etc.

[0129] The methods shown in this scheme can be modified as desired. For example, protecting groups can be added or removed, and the products can be further elaborated, for example, via alkylation, acylation, hydrolysis, oxidation, reduction, amidation, sulfonation, alkynation, etc., to obtain the desired final product. Furthermore, any intermediates or final products that contain a mixture of stereoisomers can be optionally purified by chiral column chromatography (e.g., supercritical fluid chromatography) or by derivatization with optically pure reagents, as described above, to obtain the desired stereoisomer.

[0130] [ka]

[0131] [ka]

[0132] The compounds of Formula 1 (including the compounds named above, as well as pharmaceutically acceptable complexes, salts, solvates, and hydrates thereof) should be evaluated for biopharmaceutical properties such as solubility and solution stability versus pH, permeability, etc. to select an appropriate dosage form and route of administration. Compounds intended for pharmaceutical use may be administered as crystalline or amorphous products, and may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, lyophilization, spray drying, evaporative drying, microwave drying, or radio frequency drying.

[0133] The compounds of formula 1 can be administered alone, in combination with each other, or in combination with one or more pharmacologically active compounds different from the compounds of formula 1. Generally, one or more of these compounds are administered as a pharmaceutical composition (formulation) in combination with one or more pharmaceutically acceptable excipients. The choice of excipient depends, inter alia, on the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Useful pharmaceutical compositions and methods for their preparation can be found, for example, in A. R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000).

[0134] The compound of formula 1 can be orally administered. Oral administration can include swallowing, in which case the compound enters the bloodstream through the gastrointestinal tract. Alternatively, or additionally, oral administration can include mucosal administration (e.g., buccal, sublingual, supragingual), so that the compound enters the bloodstream through the oral mucosa.

[0135] Formulations suitable for oral administration include solid, semi-solid, and liquid systems, such as tablets; soft or hard capsules containing multiparticulates or nanoparticles, liquids, or powders; lozenges (which may be filled with liquid); chewable tablets; gels; fast-dispersing dosage forms; films; vaginal suppositories; sprays; and buccal / mucoadhesive patches.Liquid formulations include suspensions, solutions, syrups, and elixirs.Such formulations can be used as fillers in soft or hard capsules (e.g., those made from gelatin or hydroxypropylmethylcellulose), and typically contain a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or suitable oil), and one or more emulsifiers, suspending agents, or both.Liquid formulations can also be prepared by reconstituting solids (e.g., from sachets).

[0136] The compounds of Formula 1 may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents (2001) 11(6):981-986.

[0137] For tablet dosage forms, depending on the dosage, the active pharmaceutical ingredient (API) may comprise from about 1 wt% to about 80 wt% of the dosage form, or more typically from about 5 wt% to about 60 wt% of the dosage form. In addition to the API, tablets may contain one or more disintegrants, binders, diluents, surfactants, glidants, lubricants, antioxidants, colorants, flavorings, preservatives, and taste-masking agents. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, C 1-6 Included are alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, disintegrants comprise from about 1 wt% to about 25 wt%, or from about 5 wt% to about 20 wt% of the dosage form.

[0138] Binders are generally used to give tablet formulations cohesion.Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and calcium hydrogen phosphate dihydrate.

[0139] Tablets may also include surfactants, such as sodium lauryl sulfate and polysorbate 80, and glidants, such as silicon dioxide and talc. When present, the surfactants may comprise from about 0.2 wt% to about 5 wt% of the tablet, and the glidants may comprise from about 0.2 wt% to about 1 wt% of the tablet.

[0140] Tablets may also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants may comprise from about 0.25 wt% to about 10 wt%, or from about 0.5 wt% to about 3 wt% of the tablet.

[0141] Tablet blends may be compressed directly or by roller compaction to form tablets. Tablet blends, or portions of the blends, may alternatively be wet-, dry-, or melt-granulated, melt-congealed, or extruded prior to tableting. If desired, one or more of the components may be sized by sieving or milling, or both, prior to blending. The final dosage form may comprise one or more layers, may be coated or uncoated, or may be encapsulated. An exemplary tablet may contain up to about 80 wt% API, about 10 wt% to about 90 wt% binder, about 0 wt% to about 85 wt% diluent, about 2 wt% to about 10 wt% disintegrant, and about 0.25 wt% to about 10 wt% lubricant. For a discussion of blending, granulating, milling, sieving, tabletting, coating, and descriptions of alternative techniques for preparing drug products, see A.R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000); H.A. Lieberman et al. (ed.), Pharmaceutical Dosage Forms: Tablets, Vol. 1-3 (2nd ed., 1990); and D.K. Parikh & C.K. Parikh, Handbook of Pharmaceutical Granulation Technology, Vol. 81 (1997).

[0142] Consumable oral films for human or veterinary use are flexible, water-soluble or water-swellable thin film dosage forms that can be fast-dissolving or mucoadhesive. In addition to the API, typical films contain one or more film-forming polymers, binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity modifiers, and solvents. Other film ingredients can include antioxidants, colorants, flavors and flavor enhancers, preservatives, saliva stimulants, cooling agents, cosolvents (including oils), emollients, bulking agents, antifoaming agents, surfactants, and taste masking agents. Some components of the formulation can perform more than one function.

[0143] In addition to dosage requirements, the amount of API in the film can depend on its solubility. If water-soluble, the API will typically comprise about 1 wt% to about 80 wt% of the non-solvent components (solutes) in the film, or about 20 wt% to about 50 wt% of the solutes in the film. Less soluble APIs may comprise a larger proportion of the composition, typically up to about 88 wt% of the non-solvent components in the film.

[0144] The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids, and typically comprises from about 0.01 wt% to about 99 wt% or from about 30 wt% to about 80 wt% of the film formulation.

[0145] Film dosage forms are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper, which may be carried out in a drying oven or tunnel (e.g., in a combined coating and drying apparatus), a freeze-drying machine, or a vacuum oven.

[0146] Solid formulations useful for oral administration can include immediate-release formulations and modified-release formulations. Modified-release formulations include delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, and programmed-release. For a general description of suitable modified-release formulations, see U.S. Patent No. 6,106,864. For details of other useful release technologies, such as high-energy dispersions and osmotic and coated particles, see Verma et al., Pharmaceutical Technology Online (2001) 25(2):1-14.

[0147] The compound of formula 1 can also be directly administered into the bloodstream, muscle or internal organs of the subject.The techniques suitable for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.The device suitable for parenteral administration includes needle-type (including microneedle) injector, needle-free injector and infusion device.

[0148] Parenteral formulations are typically aqueous solutions, which may contain excipients such as salts, carbohydrates, and buffers (e.g., pH of about 3 to about 9). However, for some applications, the compounds of Formula 1 may be more suitably formulated as sterile, non-aqueous solutions or as a dry form for use with a suitable vehicle, such as sterile, pyrogen-free water. Preparation of parenteral formulations under sterile conditions (e.g., by lyophilization) can be readily accomplished using standard pharmaceutical techniques.

[0149] The solubility of compounds used in the preparation of parenteral solutions can be increased by using appropriate formulation techniques, such as incorporating solubility enhancers. Formulations for parenteral administration may be formulated for immediate release or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. Thus, the compound of Formula 1 can be formulated as a suspension, solid, semisolid, or thixotropic liquid for administration as an implanted depot that provides modified release of the active compound. Examples of such formulations include drug-coated stents and semisolids and suspensions containing drug-loaded poly(DL-lactic-co-glycolic acid) (PGLA) microspheres.

[0150] The compounds of Formula 1 may also be administered topically, intradermally, or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Topical formulations may also include penetration enhancers. See, for example, Finnin and Morgan, J. Pharm. Sci. 88(10):955-958 (1999).

[0151] Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free (e.g., Powderject™ and Bioject™) injection. Formulations for topical administration may be formulated to be immediate or modified release, as described above.

[0152] The compound of formula 1 can also be administered intranasally or by inhalation, typically in the form of dry powder, aerosol spray, or nasal drops.An inhaler can be used to administer the dry powder, which includes API only, a powder blend of API and a diluent such as lactose, or mixed-component particles including API and a phospholipid such as phosphatidylcholine.When used intranasally, the powder can also include a bioadhesive agent such as chitosan or cyclodextrin. A pressurized container, pump, sprayer, atomizer, or nebulizer may be used to generate an aerosol spray from a solution or suspension containing the API, one or more agents for dispersing, solubilizing, or extending the release of the API (e.g., EtOH, with or without water), one or more solvents that function as propellants (e.g., 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane), and an optional surfactant, such as sorbitan trioleate, oleic acid, or oligolactic acid. Atomizers that use electrohydrodynamics to generate a fine mist may also be used.

[0153] Prior to use in a dry powder or suspension formulation, the drug product is usually milled to a particle size suitable for delivery by inhalation (typically 90% of the particles by volume have a largest dimension less than 5 microns). This can be achieved by any suitable size reduction method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing, high pressure homogenization, or spray drying.

[0154] Capsules, blisters, and cartridges (made, for example, from gelatin or hydroxypropylmethylcellulose) for use in an inhaler or insufflator may be formulated containing a powder mix of the active compound, a suitable powder base such as lactose or starch, and a performance modifier such as L-leucine, mannitol, or magnesium stearate. Lactose may be anhydrous or the monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0155] Solution formulations suitable for use in atomizers that use electrohydrodynamics to generate a fine mist may contain about 1 μg to about 20 mg of API per actuation, and actuation volumes may vary from about 1 μl to about 100 μl. A typical formulation may include one or more compounds of Formula 1, propylene glycol, sterile water, EtOH, and NaCl. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

[0156] Formulations for inhaled administration, intranasal administration, or both, may be formulated to be immediate or modified release, using, for example, PGLA. Suitable flavors, such as menthol and levomenthol, or suitable sweeteners, such as saccharin or saccharin sodium, may be added to such formulations intended for inhaled / intranasal administration.

[0157] For dry powder inhalers and aerosols, the dosage unit is determined by utilizing a valve that delivers a metered amount. The unit is typically designed to administer a metered dose or "puff" containing from about 10 μg to about 1000 μg of API. The overall daily dose typically ranges from about 100 μg to about 10 mg, which may be administered in a single dose or, more usually, in divided doses throughout the day.

[0158] The active compound may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a conventional suppository base, but various alternatives may be used where appropriate. Preparations for rectal or vaginal administration may be formulated as immediate release and / or modified release, as described above.

[0159] The compound of Formula 1 may be administered directly to the eye or ear, typically in the form of droplets of a micronized suspension or solution in pH-adjusted, isotonic, sterile saline. Other formulations suitable for ocular and otic administration include ointments, gels, biodegradable implants (e.g., absorbent gel sponges, collagen), non-biodegradable implants (e.g., silicone), wafers, lenses, and microparticle or vesicular systems such as niosomes or liposomes. The formulation may contain one or more polymers and preservatives, such as benzalkonium chloride. Typical polymers include cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose), and heteropolysaccharide polymers (e.g., gellan gum). Such formulations may also be delivered by iontophoresis. Formulations for ocular or otic administration may be formulated for immediate or modified release, as described above.

[0160] The compounds of Formula 1 may be combined with soluble macromolecular entities, such as cyclodextrin and its derivatives, and polyethylene glycol-containing polymers, to improve their solubility, dissolution rate, taste-masking, bioavailability, or stability. For example, API-cyclodextrin complexes are generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the API, cyclodextrins may be used as auxiliary additives, i.e., carriers, diluents, or solubilizers. Alpha-, beta-, and gamma-cyclodextrins are commonly used for these purposes. See, for example, WO91 / 11172, WO94 / 02518, and WO98 / 55148.

[0161] As noted above, one or more compounds of Formula 1, including those specifically named above, and pharmaceutically active complexes, salts, solvates, and hydrates thereof, can be combined with each other or with one or more other active pharmaceutically active compounds to treat various diseases, conditions, and disorders. In such cases, the active compounds may be combined in a single dosage form, as described above, or provided in the form of a kit suitable for simultaneous administration of the compositions. A kit includes (1) two or more different pharmaceutical compositions, at least one of which contains a compound of Formula 1, and (2) a device for separately holding the two pharmaceutical compositions (e.g., a divided bottle or a divided foil packet). An example of such a kit is a common blister pack used to package tablets or capsules. The kit is suitable for administering different types of dosage forms (e.g., oral and parenteral), or for administering different pharmaceutical compositions at different dosing intervals, or for titrating different pharmaceutical compositions relative to each other. To aid patient compliance, the kit typically includes instructions for administration and may provide a memory aid.

[0162] When administered to a human patient, the total daily dose of the claimed and disclosed compounds typically ranges from about 0.1 mg to about 3000 mg, depending on the route of administration. For example, oral administration may require a total daily dose of about 1 mg to about 3000 mg, while intravenous administration may require a total daily dose of only about 0.1 mg to about 300 mg. The total daily dose may be administered in a single dose or in divided doses and, at the physician's discretion, may fall outside the typical ranges set forth above. These dosages are based on an average human subject weighing about 60 kg to about 70 kg, although a physician would be able to determine the appropriate dose for patients (e.g., infants) weighing outside this weight range.

[0163] As described above, the compounds of Formula 1 can be used to treat diseases, disorders, and conditions in which inhibition of the NLRP3 inflammasome pathway is indicated, including diseases, disorders, or conditions associated with heterozygous gain-of-function mutations in the NLRP3 gene, such as cryopyrin-associated periodic syndromes (CAPS), which may include neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

[0164] The compounds of Formula 1 can be used to treat neurodegenerative diseases, disorders, and conditions associated with NLRP3. These can include frontotemporal lobar degeneration, Lewy body disease, vascular disease, traumatic brain injury, substance or drug use, HIV infection, prion diseases, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion diseases, Alzheimer's disease, and other forms of dementia (i.e., severe or mild neurocognitive disorders) associated with one or more medical conditions. The compounds of Formula 1 can also be used to treat severe or mild neurocognitive disorders associated with depression, schizophrenia, bipolar disorder, and autism.

[0165] The claimed and disclosed compounds may be combined with one or more other pharmacologically active compounds or therapies to treat one or more disorders, diseases, or conditions in which inhibition of the NLRP3 inflammasome pathway is indicated. Such combinations may provide significant therapeutic benefits, including reduced side effects, improved treatment capabilities for underserved patient populations, or synergistic activity. For example, the compounds of Formula 1, including the compounds specifically named above, and their pharmaceutically acceptable complexes, salts, solvates, and hydrates, may be administered simultaneously, sequentially, or separately in combination with one or more compounds or therapies for treating Alzheimer's disease. Such compounds or therapies include beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., apazone, aspirin, celecoxib, diclofenac (with or without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, choline and magnesium salicylate, salsalate, and sulindac), vitamin E, and anti-amyloid antibodies. Specific examples of compounds used to treat Alzheimer's disease include donepezil, rivastigmine, memantine, and galantamine.

[0166] In addition to drugs used to improve cognition, the compounds of Formula 1 may be combined with sedatives, hypnotics, anxiolytics, antipsychotics, tranquilizers, and other medications used to treat Alzheimer's disease. For example, the compounds of Formula 1 may be combined with one or more drugs (antidepressants) (atypical or typical antipsychotics) for treating depression and / or schizophrenia, including amitriptyline, amoxapine, aripiprazole, asenapine, bupropion, chlordiazepoxide, citalopram, chlorpromazine, clozapine, desipramine, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, fluphenazine , haloperidol, iloperidone, imipramine, isocarboxazid, lamotrigine, levomilnacipran, lurasidone, mirtazapine, nefazodone, nortriptyline, olanzapine, paliperidone, paroxetine, perphenazine, phenelzine, protriptyline, quetiapine, risperidone, selegiline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, vilazodone, and vortioxetine, and ziprasidone.

[0167] Similarly, the compounds of Formula 1 may be combined with one or more agents for treating anxiety (antianxiety medications), including benzodiazepines (alprazolam, chlordiazepoxide, clobazepam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, prazepam, quazepam, temazepam, and triazolam), antihistamines (hydroxyzine), non-benzodiazepines (eszopiclone, zaleplon, zolpidem, and zopiclone), and buspirone.

[0168] The compounds of Formula 1 may also be combined with one or more agents for treating epilepsy (antiepileptic or anticonvulsant drugs), including acetazolamide, carbamazepine, clobazam, clonazepam, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide.

[0169] biological activity

[0170] The biological activity of the compounds of formula 1 with respect to NLRP3 can be determined using the following in vitro method.

[0171] IL-1β assay (IC 50 (reported as

[0172] Monocytic THP-1 cells (ATCC: TIB-202) are maintained in RPMI medium (Life Technologies, catalog number A10491-01) according to the supplier's instructions. RPMI is supplemented with 10% heat-inactivated fetal bovine serum (Hyclone catalog number SH30396.03). Cells are differentiated into macrophages by adding 25 ng / mL IFN-γ (PeproTech, catalog number 300-02-100UG) for 24 hours at 37°C / 5% CO2. The medium is replaced with fresh medium without FBS, and the cells are treated with 50 ng / mL LPS (priming step) for 24 hours at 37°C / 5% CO2 (LPS-EK: Invivogen, catalog number tlrl-peklps). The medium is replaced with fresh medium without FBS. Cells were seeded at 40,000 cells per well into 384-well flat-bottom cell culture plates (Costar 3764) containing compounds (added at 1:1000) in a 1:3.16 serial dilution series in DMSO and incubated at 37°C / 5% CO2 for 30 minutes. 2.5 mM ATP (Sigma catalog no. A3377) was added to activate the NLRP3 inflammasome, and the cells were incubated at 37°C / 5% CO2 for 2 hours. At the end of the incubation period, 40 μL of supernatant was removed, and IL-1β levels were monitored using an ELISA (human IL-1β ELISA, R&D systems, catalog no. DY201) according to the manufacturer's instructions.

[0173] TNF-α Assay Description (IC 50 (reported as

[0174] Monocytic THP-1 cells (ATCC:TIB-202) are maintained in RPMI medium (Life Technologies, catalog number A10491-01) according to the supplier's instructions. RPMI is supplemented with 10% heat-inactivated fetal bovine serum (Hyclone catalog number SH30396.03). Cells are differentiated into macrophages by adding 25 ng / mL IFN-γ for 24 hours at 37°C / 5% CO2. The medium is replaced with fresh medium without FBS. Cells are seeded at 40,000 cells per well into 384-well flat-bottom cell culture plates (Costar 3764) containing compounds (added at 1:1000) in a 1:3.16 serial dilution series in DMSO and incubated for 30 minutes at 37°C / 5% CO2. The NF-κB pathway is activated by the addition of 50 ng / mL LPS, and the cells are incubated for 3 hours at 37° C. / 5% CO. At the end of the incubation period, the supernatant (40 μL) is removed and IL-1β levels are monitored using an ELISA (human TNF-α ELISA, R&D systems, catalog number DY201) according to the manufacturer's instructions.

[0175] Data interpretation

[0176] I C 50 The value is Y=[bottom+(top-bottom)] / (1+10^[(Log IC 50 The percentage of inhibition is calculated from a plot of the inhibitor concentration versus the percentage of inhibition by fitting a logistic curve according to [(-X)·Hill slope] (where Y is the % inhibition at inhibitor concentration X, "bottom" is the lowest inhibition value, i.e., 0%, "top" is the maximum inhibition value, i.e., 100%, and "Hill slope" represents the slope of the sigmoidal curve between the "bottom" and "top" values). Curve fitting was performed using internally developed software.

[0177] The following in vitro assay can be used to assess the ability of compounds of formula 1 to cross the blood-brain barrier and enter the CNS.

[0178] MDCK-MDR1 assay (reported as apparent permeability and efflux ratio)

[0179] Madin-Darby canine kidney (MDCK) cells transfected with multidrug resistance protein 1 (MDR1) were maintained in Dulbecco's modified Eagle's medium (DMEM, Fisher Scientific catalog number 10569044) according to the supplier's instructions. DMEM was supplemented with 10% heat-inactivated fetal bovine serum (Gibco catalog number 16000-044), penicillin-streptomycin (100 units / mL) (Gibco catalog number 15140122), and the P-gp inducer colchicine (200 nM) (Sigma catalog number C9754). Cells were plated at 6.25 x 10 per well onto the apical side of an HTS-Transwell-96 plate (0.4 μm pore size, Corning catalog number 3381) using 75 μL and 250 μL of DMEM medium for the apical and basolateral wells, respectively. 3Cells are seeded at a density of 1000 μg / well and incubated at 37°C / 5% CO2. After 72 hours, fresh DMEM medium is replaced in the apical and basolateral compartments, and cells are allowed to grow to a monolayer for 144 hours before experimental incubation begins. Incubations are performed in Hank's Balanced Salt Solution (HBSS, Fisher Scientific catalog number 14025134) at pH 7.4 with 1% bovine serum albumin (Sigma, catalog number A9418) and 10 mM HEPES (Fisher Scientific, catalog number 15630080). DMEM medium is removed, and cells are rinsed with warm (37°C) HBSS. HBSS containing test compound at a substrate concentration of 1 μM (0.1% v / v DMSO) is added to either the apical or basolateral compartment (75 μL or 250 μL, respectively), and blank HBSS buffer lacking test compound is added to only one compartment. The cells are incubated for 60 minutes at 37°C / 5% CO2. At the end of the incubation period, 50 μL of sample is removed from each receiver compartment and diluted with 150 μL of acetonitrile (Fisher Scientific, Catalog No. A996SK4) + 0.1% formic acid (Sigma, Catalog No. F0507). The samples are centrifuged at 2000 rcf for 10 minutes at 4°C, after which 100 μL of supernatant is transferred to a new microplate and diluted with 100 μL of HPLC-grade water (Fisher Scientific, Catalog No. W64). Samples are analyzed using a triple quadrupole mass spectrometer API-5500QTrap (ABSciex, serial number AU23291006) with an attached autosampler and a high performance liquid chromatography pump instrument optimized for detection of the test article via a Kinetix 2.1 x 50 mm C18 100 Å column (Phenomenex, catalog number 00B-4605-AN).

[0180] Apparent permeability (P app ) values ​​and emission ratios are calculated using the following equations:

[0181]

number

[0182] In the formula, P appA-B is the apparent permeability from the apical well to the basolateral well, and P appB-A is the apparent permeability from the basolateral well to the apical well, and Conc BL is the basolateral well concentration, and Conc AP is the apical well concentration and A is the well surface area (cm 2 ) and in the above assay is 0.143 cm 2 where t is the incubation time (seconds), which is 3600 seconds in the above assay, and ER is the P-gp-mediated efflux ratio. [Example]

[0183] The following examples are intended to be illustrative and non-limiting and represent specific embodiments of the present invention.

[0184] For many of the compounds in the examples below, 1 H nuclear magnetic resonance (NMR) spectra were obtained. Characteristic chemical shifts (δ) are given in parts per million downfield from tetramethylsilane using conventional abbreviations for major peak designations, including s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). The following abbreviations are used for common solvents: CDCl3 (deuterated chloroform), DMSO-d6 (deuterated dimethyl sulfoxide), CD3OD (deuterated methanol), CD3CN (deuterated acetonitrile), and THF-d8 (deuterated tetrahydrofuran). Mass spectra ([M+H] + m / z for were recorded using electrospray ionization (ESI-MS) or atmospheric pressure chemical ionization (APCI-MS) mass spectrometry.

[0185] Where indicated, intermediate preparations and example compounds are purified by HPLC. Tables 1-3 list the columns, mobile phases, and gradients used for some of the HPLC separations.

[0186] [Table 1]

[0187] [Table 2]

[0188] [Table 3]

[0189] In the preparations and examples, supercritical fluid chromatography (SFC) may be used to separate the enantiomers. Table 4 lists the equipment, materials, and conditions for some SFC separations.

[0190] [Table 4]

[0191] In addition to HPLC, some preparations and examples may use flash chromatography or preparative thin layer chromatography (TLC). Preparative TLC is typically performed on silica gel 60F. 254 Carry out on plates.

[0192] After chromatographic separation, the solvent can be removed and the product dried in a centrifugal evaporator (e.g., GeneVac™), rotary evaporator, vacuum flask, etc. Reactions in an inert (e.g., nitrogen) or reactive (e.g., H) atmosphere are typically carried out at a pressure of about 1 atmosphere (14.7 psi).

[0193] Preparation 1: 5,5-Difluoro-1-methylpiperidin-3-amine

[0194] [ka]

[0195] Step 1: tert-butyl (5,5-difluoro-1-methylpiperidin-3-yl)carbamate

[0196] [ka]

[0197] A mixture of tert-butyl (5,5-difluoropiperidin-3-yl)carbamate (500 mg, 2.12 mmol) and aqueous formaldehyde (343.49 mg, 4.23 mmol, 315.12 μL, 37% purity) in THF (1 mL) was stirred at 25° C. for 1 h. Formic acid (203.34 mg, 4.23 mmol) was added dropwise, and the mixture was stirred at 70° C. for 1 h. The reaction mixture was quenched with NH 3 .HO (5 mL) and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® SepaFlash® 12 g silica gel column) using a gradient of 0-20% DCM in MeOH (35 mL / min) to give the title compound (310 mg, crude). ESI-MS m / z [M+H] + 251.1.

[0198] Step 2: 5,5-Difluoro-1-methylpiperidin-3-amine

[0199] A mixture of tert-butyl (5,5-difluoro-1-methylpiperidin-3-yl)carbamate (310 mg, 1.24 mmol) and HCl in dioxane (4 M, 5 mL) was stirred at 20° C. for 15 hours and then concentrated under reduced pressure. The resulting residue was triturated with EtOAc (15 mL) for 30 minutes and filtered. The filter cake was dried under vacuum to give the HCl salt of the title compound as a colorless oil (240 mg, crude). ESI-MS m / z [M+H] + 151.1

[0200] Preparation 2: 1-Cyclopropylpiperidin-3-amine

[0201] [ka]

[0202] Step 1: tert-butyl (1-cyclopropylpiperidin-3-yl)carbamate

[0203] [ka]

[0204] To a mixture of tert-butyl piperidin-3-ylcarbamate (3 g, 14.98 mmol) in THF (72 mL) and MeOH (8.1 mL) was added 4Å molecular sieves (3 g) and (1-ethoxycyclopropoxy)trimethylsilane (7.83 g, 44.94 mmol, 9.03 mL), followed by acetic acid (10.79 g, 179.75 mmol, 10.28 mL) and NaBHCN (2.82 g, 44.94 mmol). The mixture was stirred at 65 °C for 16 h. The resulting suspension was filtered and concentrated. The crude product was diluted with aqueous NaHCO (50 mL) and extracted with DCM (100 mL × 3). The organic layer was washed with anhydrous N a2 After drying over SO, filtering, and concentrating under reduced pressure, the resulting residue was purified by column chromatography (DCM / MeOH=1:0 to 10:1) to give the title compound as a colorless oil (6.5 g, 90%). 1 H NMR (400MHz, CD3Cl) δppm4.92-5.27(m,1H),3.73(brs,1H),2.49-2.81(m,4H),1.67(brs,4H),1.55(brs,1H),1.45(s,9H),0.47(brd,J=6.27Hz,4H).

[0205] Step 2: 1-Cyclopropylpiperidin-3-amine

[0206] To a mixture of tert-butyl (1-cyclopropylpiperidin-3-yl)carbamate (4.9 g, 20.39 mmol), HCl in dioxane (4 M, 50.97 mL) was added in one portion at 25° C. under N. The mixture was stirred at 25° C. for 1 h. Excess HCl / dioxane was removed under reduced pressure to give a yellow solid, which was triturated with EtOAc (80 mL). The solid was collected by filtration and dried under vacuum to give the dihydrochloride salt of the title compound as a white solid (2.8 g, 64%). 1 H NMR(400MHz,DMSO-d6)δppm0.65-0.96(m,2H),1.02-1.24(m,2H),1.45-1.69(m,1H),1.90(br d,J=3.26Hz,2H),2.03-2.20(m,1H),2.84-3.10(m,1H),2.89-3.00(m,1H),3.40-3.52(m,1H),3.45(br d,J=11.80Hz,1H),3.61(brd,J=9.03Hz,2H),8.70(br s,3H),11.49(br s,1H).

[0207] Preparation 3: (R)-1-Cyclopropylpiperidin-3-amine

[0208] [ka]

[0209] Step 1: tert-Butyl (R)-(1-cyclopropylpiperidin-3-yl)carbamate

[0210] [ka]

[0211] To tert-butyl (R)-piperidin-3-ylcarbamate (3 g, 14.98 mmol) in THF (72 mL) and MeOH (8.1 mL) were added 4Å molecular sieves (3 g, 14.98 mmol), (1-ethoxycyclopropoxy)trimethylsilane (7.83 g, 44.94 mmol, 9.03 mL), acetic acid (10.79 g, 179.75 mmol, 10.28 mL), and NaBHCN (2.82 g, 44.94 mmol). The mixture was stirred at 65 °C for 16 h. LC-MS showed that the desired product was formed as the major component, and TLC (DCM / MeOH = 10:1) showed the reaction was complete (R of the desired product). f =0.43). The suspension was filtered and concentrated. The crude product was diluted with aqueous NaHCO3 (50 mL) and extracted with DCM (100 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, DCM / MeOH = 1:0 to 10:1) to give the HCl salt of the title compound as a white solid (3.5 g, 97%). 1 H NMR(400MHz,DMSO-d6)δppm0.27(brs,2H),0.39(br d,J=3.51Hz,2H),1.04-1.20(m,1H),1.37(s,9H),1.52-1.72(m,3H),1.87-2 .12(m,2H),2.68-2.95(m,2H),3.21-3.32(m,1H),6.51-6.79(m,1H);ESI-MS m / z [M+H] + 241.2.

[0212] Step 2: (R)-1-Cyclopropylpiperidin-3-amine

[0213] To tert-butyl (R)-(1-cyclopropylpiperidin-3-yl)carbamate (0.5 g, 2.08 mmol) was added HCl in dioxane (4 M, 10 mL). The mixture was stirred at 25° C. for 2 hours. LC-MS showed that the starting material was consumed. The reaction mixture was concentrated under reduced pressure to give the HCl salt of the title compound (350 mg, 95.2%), which was used without further purification. 1H NMR(400MHz,DMSO-d6)δppm0.81(br d,J=6.48Hz,2H),1.04-1.24(m,2H),1.46-1.67(m,1H),1.89(br s,2H),2.00-2.14(m,1H),2.79-3.20(m,4H),3.54-3.71(m,1H),8.59(br s,2H);ESI-MS m / z [M+H] + 141.1.

[0214] Preparation 4: (R)-1-(1-methylcyclopropyl)piperidin-3-amine

[0215] [ka]

[0216] Step 1: tert-Butyl (R)-(1-acetylpiperidin-3-yl)carbamate

[0217] [ka]

[0218] To a mixture of tert-butyl (R)-piperidin-3-ylcarbamate (1 g, 4.99 mmol) and DIPEA (1.94 g, 14.98 mmol, 2.61 mL) in DCM (15 mL) was added AcO (560.71 mg, 5.49 mmol, 514.42 μL). The mixture was stirred at 20 °C for 12 h. TLC (DCM / MeOH = 10:1) showed complete consumption of the starting material (R f =0.25), one new main spot was formed (R f =0.53). The mixture was washed with HO (20 mL), concentrated in vacuo, and the resulting residue was purified by flash chromatography (ISCO® SepaFlash® 24 g silica gel column) using a gradient of 0-3% MeOH in DCM (35 mL / min). The title compound was obtained as a white solid (1 g, 83%). 1H NMR(400MHz,DMSO-d6)δppm1.38(m,11H),1.59-1.83(m,2H),1.90-2.02(m,3H) ,2.42(dd,J=12.1,10.2Hz,1H),2.89-3.09(m,1H),3.18-3.30(m,1H),3.59(br t,J=13.3Hz,1H),3.71-4.17(m,1H),6.75-7.06(m,1H).

[0219] Step 2: tert-butyl (R)-(1-(1-methylcyclopropyl)piperidin-3-yl)carbamate

[0220] [ka]

[0221] To a solution of tert-butyl (R)-(1-acetylpiperidin-3-yl)carbamate (900 mg, 3.71 mmol) and Ti(i-PrO) (2.11 g, 7.43 mmol, 2.19 mL) in THF (15 mL) was added EtMgBr (3 M, 6.19 mL) dropwise at 0 °C. The mixture was stirred at 20 °C for 12 h. TLC (EtOAc / MeOH = 20:1) showed that approximately 40% of the starting material remained (R f =0.68), one major new spot was detected (R f =0.66). The reaction mixture was quenched with HO (2 mL) and filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash chromatography (ISCO® SepaFlash® 20 g silica gel column) using a gradient of 0-5% MeOH in DCM (35 mL / min). The title compound was obtained as a colorless gum (160 mg, 16.9%). 1H NMR(400MHz,DMSO-d6)δppm0.29(brs,2H),0.41(br s,2H),0.97(s,3H),1.03-1.23(m,2H),1.37(s,9H),1.48-1.74(m,2H),2.02-2.14(m,1H),2.18-2.29(m,1H),2.59(br d,J=11.3Hz,1H),2.75(br d,J=6.9Hz,1H),3.25(br s,1H),6.60(br d,J=7.1Hz,1H).

[0222] Step 3: (R)-1-(1-methylcyclopropyl)piperidin-3-amine

[0223] A mixture of tert-butyl (R)-(1-(1-methylcyclopropyl)piperidin-3-yl)carbamate (160 mg, 629.01 μmol) in HCl / dioxane (4 M, 5 mL) was stirred at 20° C. for 12 h. TLC (EtOAc / MeOH=20:1) showed that the starting material was completely consumed (R f =0.66). The mixture was concentrated in vacuo to give the HCl salt of the title compound as a yellow solid (120 mg, crude), which was used without further purification. 1 H NMR(400MHz,DMSO-d6)δppm0.72-0.82(m,2H),1.31(s,5H),1.51-1.66(m,1H),1. 74-2.14(m,3H),3.06-3.33(m,3H),3.40-3.50(m,1H),3.62-3.94(m,1H),8.53(br s,2H),11.27(br s,1H).

[0224] Preparation 5: (3R,5R)-1-Cyclopropyl-5-fluoropiperidin-3-amine

[0225] [ka]

[0226] Step 1: tert-butyl ((3R,5R)-1-cyclopropyl-5-fluoropiperidin-3-yl)carbamate

[0227] [ka]

[0228] A solution of tert-butyl ((3R,5R)-5-fluoropiperidin-3-yl)carbamate (0.327 g, 1.50 mmol) in THF (5 mL), MeOH (5 mL), and acetic acid (1.0 mL) was treated with (1-ethoxycyclopropoxy)trimethylsilane (0.523 g, 3.00 mmol), followed by sodium cyanoborohydride (0.283 g, 4.50 mmol). The reaction mixture was stirred at 60 °C overnight and then partitioned between EtOAc and saturated aqueous NaHCO. The aqueous phase was extracted with EtOAc. The organic layers were combined, dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography (ISCO® RediSep Rf Gold® 40 g silica gel column) with ELS detection using a gradient of 0–100% EtOAc in heptane. Evaporation of product-containing fractions gave the title compound as a white solid (0.333 g, 86%). ESI-MS m / z [M+H] + 259.0.

[0229] Step 2: (3R,5R)-1-Cyclopropyl-5-fluoropiperidin-3-amine A solution of tert-butyl ((3R,5R)-1-cyclopropyl-5-fluoropiperidin-3-yl)carbamate (0.333 g, 1.29 mmol) in dioxane (6.45 mL) was treated with HCl (4 M in dioxane, 1.61 mL, 6.45 mmol). The reaction mixture was stirred at room temperature over the weekend. A small amount of MeOH was added to ensure the mixture was homogeneous. The reaction mixture was concentrated to dryness in vacuo to give the dihydrochloride salt of the title compound (crude 351.5 mg, assumed quantitative 298 mg, purity 84%), which was used without further purification. ESI-MS m / z [M+H] + 159.2.

[0230] Preparation 6: 3-((4-chlorophthalazin-1-yl)amino)phenol

[0231] [ka]

[0232] To a solution of 3-aminophenol (548.27 mg, 5.02 mmol) in EtOH (10 mL) was added 1,4-dichlorophthalazine (1 g, 5.02 mmol). The mixture was stirred at 80 °C for 15 h. LC-MS showed that 1,4-dichlorophthalazine was completely consumed. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (ISCO® SepaFlash® 24 g silica gel column) using a gradient of 0-50% EtOAc in petroleum ether (30 mL / min). The title compound was obtained as a white solid (778.7 mg, crude). ESI-MS m / z [M+H] + 271.9.

[0233] Preparation 7: 2-((4-chlorophthalazin-1-yl)amino)phenol

[0234] [ka]

[0235] The title compound was prepared similarly to Preparation 6 using 2-aminophenol and 1,4-dichlorophthalazine and obtained as a yellow solid. ESI-MS m / z [M+H] + 272.

[0236] Preparation 8: 3-((4-chlorophthalazin-1-yl)amino)phenol

[0237] [ka]

[0238] A solution of 3-aminophenol (200 mg, 1.83 mmol) and 1,4-dichlorophthalazine (364.78 mg, 1.83 mmol) in EtOH (5 mL) was stirred at reflux (80 °C) for 5 h. The reaction mixture was then concentrated and purified by flash chromatography (ISCO® SepaFlash® 24 g silica gel column) using a gradient of 0-60% EtOAc in petroleum ether (35 mL / min). The title compound was obtained as a yellow solid (300 mg, 60.3%). ESI-MS m / z [M+H] + 272.0.

[0239] Preparation 9: 3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)phenol and 3-((4-chloropyrido[3,4-d]pyridazin-1-yl)amino)phenol

[0240] [ka]

[0241] A mixture of 1,4-dichloropyrido[3,4-d]pyridazine (100 mg, 499.94 μmol), 3-aminophenol (54.56 mg, 499.94 μmol), and TFA (114.01 mg, 999.88 μmol, 74.03 μL) in tert-BuOH (8 mL) was stirred at 25 °C for 16 h. LC-MS showed one main peak with the desired m / z. The reaction mixture was filtered to give a residue, which was purified by preparative HPLC (Method B) to give the mixture of title compounds as a yellow solid (63.3 mg, 46.4%). ESI-MS m / z [M+H] + 273.0.

[0242] Preparation 10: 4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine

[0243] [ka]

[0244] A mixture of 1-methylpiperidin-3-amine (586 mg, 4.88 mmol), 1,4-dichlorophthalazine (1022 mg, 4.88 mmol), and sodium carbonate (1044 mg, 9.76 mmol) in DMF (10 mL) was stirred at 130 °C for 30 min at normal absorbance in a microwave reactor. The reaction mixture was then diluted with HO (15 mL), and the product was extracted with EtOAc (40 mL × 2). The organic extracts were combined, dried over NaSO, filtered, rinsed with EtOAc, and concentrated by rotary evaporation to give the crude product (6.09 g) as a yellow-orange oil. The crude material was dissolved in toluene (2 mL) and purified by medium-pressure chromatography (RediSep Rf Gold® 80 g silica gel column) using a gradient of 0–15% MeOH in DCM. Pure fractions were combined, concentrated by rotary evaporation, and dried in vacuo to give the title compound as a yellow foam (544 mg, 40.3%). 1H NMR(400MHz,CDCl3)δppm1.63-3.02(m,11H),4.53-4.80(m,1H),5.81-6.16(m,1H),7.75-8.01(m,3H),8.11-8.23(m,1H);ESI-MS m / z [M+H] + 277.0.

[0245] Preparation 11: (R)-4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine

[0246] [ka]

[0247] A mixture of 1,4-dichlorophthalazine (500 mg, 2.51 mmol), (R)-1-methylpiperidin-3-amine (344.22 mg, 3.01 mmol), and DIPEA (649.34 mg, 5.02 mmol, 875.13 μL) in DMSO (4 mL) was stirred at 100° C. for 12 h. LC-MS showed one main peak with the desired m / z. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (Method B) to give the formate salt of the title compound as a yellow solid (360 mg, crude). ESI-MS m / z [M+H] + 277.

[0248] Preparation 12: 4-chloro-N-methyl-N-(1-methylpiperidin-3-yl)phthalazin-1-amine

[0249] [ka]

[0250] To a 5 mL vial equipped with a stir bar was added N,1-dimethylpiperidin-3-amine (107 mg, 0.835 mmol), sodium carbonate (177 mg, 1.669 mmol), and 1,4-dichlorophthalazine (166 mg, 0.835 mmol) in DMF (2 mL). The mixture was stirred at 130 °C in a microwave reactor (Biotage® Initiator) for 30 minutes. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® RediSep Rf Gold® 24 g silica gel column) using a gradient of 0-20% MeOH in DCM. The product-containing fractions were concentrated under reduced pressure to give the title compound (14.7 mg, 6.1%). ESI-MS m / z [M+H] + 291.2.

[0251] Preparation 13: (R)-4-chloro-8-methyl-N-(1-methylpiperidin-3-yl)phthalazin-1-amine and (R)-4-chloro-5-methyl-N-(1-methylpiperidin)-3-yl)phthalazin-1-amine

[0252] [ka]

[0253] Step 1: 5-Methylphthalazine-1,4-diol

[0254] [ka]

[0255] To a solution of 4-methylisobenzofuran-1,3-dione (3 g, 18.50 mmol) in EtOH (30 mL) was added hydrazine hydrate (2.78 g, 55.51 mmol, 2.70 mL). The mixture was stirred at 100° C. for 12 hours. LC-MS showed that the desired mass of product was obtained. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was triturated with EtOH (50 mL) for 30 minutes and filtered. The filter cake was dried under vacuum to give the title compound as a white solid (2.6 g, 87%). 1 H NMR(400MHz,DMSO-d6)δppm2.80(s,3H),7.56(d,J=7.4Hz,1H),7.68(t,J=7.7Hz,1H),7.89(d,J=7.9Hz,1H);ESI-MS m / z [M+H] + 177.1.

[0256] Step 2: 1,4-Dichloro-5-methylphthalazine

[0257] [ka]

[0258] A mixture of 5-methylphthalazine-1,4-diol (500 mg, 2.84 mmol), POCl3 (12.38 g, 80.71 mmol, 7.50 mL), and DIPEA (1.83 g, 14.19 mmol, 2.47 mL) was stirred at 100 °C for 2 h. LC-MS indicated that the desired product was formed as the major component. The mixture was concentrated in vacuo, and the resulting residue was purified by flash chromatography (ISCO® SepaFlash® 24 g silica gel column) using a gradient of 0–30% EtOAc in petroleum ether (35 mL / min). The title compound was obtained as a white solid (170 mg, 28.1%). 1 H NMR(400MHz,DMSO-d6)δppm3.00(s,3H),8.01-8.13(m,2H),8.24(dd,J=7.8,1.1Hz,1H).

[0259] Step 3: (R)-4-chloro-8-methyl-N-(1-methylpiperidin-3-yl)phthalazin-1-amine and (R)-4-chloro-5-methyl-N-(1-methylpiperidin)-3-yl)phthalazin-1-amine

[0260] A mixture of 1,4-dichloro-5-methylphthalazine (170 mg, 797.89 μmol), (R)-1-methylpiperidin-3-amine (136.66 mg, 1.20 mmol), and DIPEA (206.24 mg, 1.60 mmol, 277.95 μL) in DMSO (2 mL) was stirred at 100 °C for 12 h. LC-MS showed one main peak with the desired m / z. The mixture was filtered. The filtrate was concentrated and purified by preparative HPLC (YMC-Actus Triart C18-5 μm, 30 mm × 150 mm column) using a gradient of 50–70% ACN in water (containing 0.05% NH3H2O) to give the title compound mixture as a yellow solid (50 mg, crude). ESI-MS m / z [M+H] + 291.1.

[0261] Preparation 14: 1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0262] [ka]

[0263] To a solution of 1,4-dichloropyrido[3,4-d]pyridazine (500 mg, 2.50 mmol) in DMF (10 mL) was added CsCO (1.63 g, 5.00 mmol) and 1-methylpiperidin-3-amine (1.08 g, 5.75 mmol, 2HCl). The mixture was stirred at 100 °C for 10 h and then concentrated in vacuo. The resulting residue was purified by preparative HPLC (Method B) to give the mixture of title compounds as a white solid (150 mg, 21.6%). ESI-MS m / z [M+H] + 278.2.

[0264] Preparation 15: (R)-4-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine and (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0265] [ka]

[0266] The mixture of title compounds was prepared in a similar manner to Preparation 14 using (R)-1-methylpiperidin-3-amine (100 mg, 875.75 μmol) and 1,4-dichloropyrido[3,4-d]pyridazine (175.17 mg, 875.75 μmol) and obtained as a yellow solid (120 mg, 48.8%). ESI-MS m / z [M+H] + 278.0.

[0267] Preparation 16: (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0268] [ka]

[0269] To a yellow suspension of (R)-1-methylpiperidin-3-amine dihydrochloride (1871 mg, 10.0 mmol) and 1,4-dichloropyrido[3,4-d]pyridazine (2000 mg, 10.0 mmol) in DMSO (20.499 mL) was added DIPEA (8.7 mL, 50.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes and then heated to 100° C. in an oil bath for 21 hours. The reaction mixture was cooled to room temperature, diluted with HO (80 mL), and extracted with EtOAc (160 mL × 2). The organic extracts were combined, dried over NaSO, filtered, rinsed with EtOAc, and concentrated by rotary evaporation to give a crude mixture of products (4.0 g) as a red oil. The crude mixture was dissolved in toluene (6 mL) and purified by medium-pressure chromatography (Shoko Scientific Purif-Pack® NH-60 μm, 46 × 220 mm, 200 g spherical silica gel column) using a gradient of 0 to 100% EtOAc in heptane. Early fractions were combined, concentrated by rotary evaporation, and dried in vacuo to give the first crop of the title compound as a yellow-orange foam (0.797 g). Later fractions were combined, concentrated by rotary evaporation, and dried in vacuo to give an impure mixture of products (1.093 g). The impure mixture was dissolved in toluene (5 mL) and purified by medium-pressure chromatography (Shoko Scientific Purif-Pack® NH-60 μm, 46 mm × 110 mm, 120 g spherical silica gel column) using a gradient of 0 to 100% EtOAc in heptane. The initial fractions were combined, concentrated by rotary evaporation, and dried in vacuo to give a second crop of the title compound (0.394 g) as an orange foam (total 1191 mg, 42.9%). 1H NMR(400MHz,DMSO-d6)δppm1.42(qd,J=11.80,4.02Hz,1H),1.51-1.65(m,1H), 1.70-1.79(m,1H),1.85-2.01(m,3H),2.20(s,3H),2.66-2.75(m,1H),3.04(br dd,J=10.29,3.51Hz,1H),4.28-4.39(m,1H),7.74(d,J=7.53Hz,1H),7.85(dd ,J=5.65,0.88Hz,1H),9.05(d,J=5.52Hz,1H),9.80(d,J=0.75Hz,1H);ESI-MS m / z [M+H] + 278.1.

[0270] Preparation 17: cis-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol and cis-3-((4-chloropyrido[3,4-d]pyridazin-1-yl)amino)-1-methylcyclobutan-1-ol

[0271] [ka]

[0272] To a mixture of cis-3-amino-1-methyl-cyclobutanol hydrochloride (69 mg, 0.500 mmol) and 1,4-dichloropyrido[3,4-d]pyridazine (100 mg, 0.500 mmol) in DMSO (1.0249 mL) was added DIPEA (0.44 mL, 2.50 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes and then at 100° C. in an oil bath for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (4 mL), and the crude product was extracted with EtOAc (8 mL × 3). The organic extracts were combined, dried over Na2SO4, filtered, rinsed with EtOAc, and concentrated by rotary evaporation to give a crude mixture of products as a yellow-orange oil (0.27 g). The crude mixture was dissolved in toluene (2 mL) and purified by medium pressure chromatography (HP RediSep Rf Gold® 12 g silica gel column) using a gradient of 0 to 100% EtOAc in heptane. Product-containing fractions were combined, concentrated by rotary evaporation, and dried in vacuo to give the mixture of title compounds as a yellow-orange solid (97.4 mg). 1 H NMR(400MHz,DMSO-d6)δppm1.32(s,3H),2.07-2.24(m,2H),2.42-2.48(m,2H) ,4.04-4.27(m,1H),4.89-5.13(m,1H),7.85(dd,J=5.65,0.88Hz,1H),8.22(br d,J=5.77Hz,1H),9.05(d,J=5.52Hz,1H),9.80(d,J=0.75Hz,1H);ESI-MS m / z [M+H] + 265.0.

[0273] Preparation 18: 4-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)bicyclo[2.2.1]heptan-1-ol

[0274] [ka]

[0275] The title compound was prepared analogously to Preparation 17 using 4-aminonorbornan-1-ol hydrochloride (27 mg, 0.165 mmol) and 1,4-dichloropyrido[3,4-d]pyridazine (33 mg, 0.165 mmol) and obtained as a yellow solid (21 mg, 43%). 1 H NMR(400MHz,DMSO-d6)δppm1.56-1.68(m,2H),1.69-1.83(m,2H),2.00(s,2H),2.05-2.19(m,4H),4.87- 5.05(m,1H),7.84(dd,J=5.52,1.00Hz,1H),7.90(s,1H),9.04(d,J=5.77Hz,1H),9.82(d,J=0.75Hz,1H). ESI-MS m / z [M+H] + 291.0.

[0276] Preparation 19: 1-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0277] [ka]

[0278] Step 1: Dimethyl 2-methylpyridine-3,4-dicarboxylate

[0279] [ka]

[0280] To a mixture of dimethyl 2-chloropyridine-3,4-dicarboxylate (1 g, 4.36 mmol) and Pd(dppf)Cl.CHCl (177.83 mg, 217.75 μmol) in dioxane (25 mL) was added dimethylzinc (1 M, 13.07 mL, 3 equiv.). The reaction mixture was heated at 80° C. for 12 h. LC-MS indicated that the starting material was consumed and the desired MS was observed. The reaction mixture was quenched with water (40 mL) and filtered through a pad of Celite®, which was rinsed with water (10 mL) and EtOAc (30 mL). The filtrate was extracted with EtOAc (50 mL × 2). The organic phase was dried over NaSO and concentrated in vacuo. The resulting residue was purified by flash chromatography (ISCO® SepaFlash® 12 g silica gel column) using a gradient of 20-25% EtOAc in petroleum ether (40 mL / min). The title compound was obtained as a yellow solid (800 mg, 71.6% yield, 81.6% purity). ESI-MS m / z [M+H] + 210.2.

[0281] Step 2: 5-Methylpyrido[3,4-d]pyridazine-1,4-diol

[0282] [ka]

[0283] A solution of dimethyl 2-methylpyridine-3,4-dicarboxylate (800 mg, 3.82 mmol) in N2H4.HO (9.68 g, 189.58 mmol, 81.53 μL, 98% purity) was stirred at 70 °C for 12 h. LC-MS showed that the starting material had been consumed. The reaction mixture was concentrated in vacuo to give a solid, which was triturated with ACN (30 mL) to give the title compound as a yellow solid (780 mg, crude).

[0284] Step 3: 1,4-Dichloro-5-methylpyrido[3,4-d]pyridazine

[0285] [ka]

[0286] A mixture of 5-methylpyrido[3,4-d]pyridazine-1,4-diol (150 mg, 846.69 μmol) and DIPEA (547.15 mg, 4.23 mmol, 737.39 μL) in POCl3 (5 mL) was stirred at 100 °C for 1 h. The mixture was concentrated in vacuo. The residue was diluted with DCM / DIPEA (1:1, 50 mL) and concentrated in vacuo. The residue was purified by flash chromatography (ISCO® SepaFlash® 12 g silica gel column) using a gradient of 0-1% MeOH in DCM (25 mL / min). The title compound was obtained as a yellow solid (100 mg, 55.2%). ESI-MS m / z [M+H] + 214.

[0287] Step 4: 1-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0288] A mixture of 1,4-dichloro-5-methylpyrido[3,4-d]pyridazine (100 mg, 467.18 μmol), 1-methylpiperidin-3-amine (174.83 mg, 934.36 μmol, 2HCl), and DIPEA (301.90 mg, 2.34 mmol, 406.87 μL) in DMSO (1 mL) was stirred at 90° C. for 12 h. The reaction mixture was purified by preparative HPLC (Method B) to give the mixture of title compounds as a yellow gum (90 mg). ESI-MS m / z [M+H] + 292.

[0289] Preparation 20: 1-chloro-7-methyl-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-7-methyl-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0290] [ka]

[0291] Step 1: Dimethyl 6-methylpyridine-3,4-dicarboxylate

[0292] [ka]

[0293] To a mixture of dimethyl 6-chloropyridine-3,4-dicarboxylate (740 mg, 3.22 mmol) and Pd(dppf)Cl2.CHCl2 (131.59 mg, 161.14 μmol) in dioxane (20 mL) was added dimethylzinc (1 M, 9.67 mL, 3 equiv.). The mixture was heated at 80 °C for 12 h and then quenched with water (40 mL). The reaction mixture was filtered through a pad of Celite® and rinsed with water (10 mL) and EtOAc (30 mL). The filtrate was extracted with EtOAc (50 mL × 2). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product. The residue was purified by flash chromatography (ISCO® SepaFlash® 12 g silica gel column) using a gradient of 19–21% EtOAc in petroleum ether (40 mL / min). The title compound was obtained as a yellow solid (540 mg, 71.0%). ESI-MS m / z [M+H] + 210.2.

[0294] Step 2: 7-Methylpyrido[3,4-d]pyridazine-1,4-diol

[0295] [ka]

[0296] A solution of dimethyl 6-methylpyridine-3,4-dicarboxylate (540 mg, 2.58 mmol) in N2H4.HO (7.40 g, 144.95 mmol, 7.19 mL, 98% purity) was stirred at 70 °C for 12 h. The reaction mixture was concentrated in vacuo to give a solid, which was triturated with ACN (30 mL) to give the title compound as a yellow solid (580 mg, crude). ESI-MS m / z [M+H] + 178.1.

[0297] Step 3: 1,4-Dichloro-7-methylpyrido[3,4-d]pyridazine

[0298] [ka]

[0299] A mixture of 7-methylpyrido[3,4-d]pyridazine-1,4-diol (200 mg, 1.13 mmol) and DIPEA (729.51 mg, 5.64 mmol, 983.17 μL) in POCl3 (5 mL) was stirred at 100 °C for 1 h. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by flash chromatography (ISCO® SepaFlash® 12 g silica gel column) using a gradient of 0 to 1% MeOH in DCM (25 mL / min). The title compound was obtained as a yellow solid (200 mg, 82.8%). ESI-MS m / z [M+H] + 214.

[0300] Step 4: 1-chloro-7-methyl-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-7-methyl-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0301] A mixture of 1,4-dichloro-7-methylpyrido[3,4-d]pyridazine (200 mg, 934.36 μmol), 1-methylpiperidin-3-amine (349.66 mg, 1.87 mmol, 2HCl), and DIPEA (603.78 mg, 4.67 mmol, 813.72 μL) in DMSO (2 mL) was stirred at 100° C. for 1 h. The reaction mixture was purified by preparative HPLC (Method C) to give the mixture of title compounds (100 mg) as a yellow solid. ESI-MS m / z [M+H] + 292.

[0302] Preparation 21: 1-chloro-7-methoxy-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-7-methoxy-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0303] [ka]

[0304] Step 1: Dimethylpyridine-3,4-dicarboxylate

[0305] [ka]

[0306] To a mixture of pyridine-3,4-dicarboxylic acid (10 g, 59.84 mmol) in MeOH (200 mL) was added H2SO4 (8 mL). The mixture was stirred at 80 °C for 16 h and then concentrated under reduced pressure. The concentrate was diluted with water (20 mL) and neutralized with solid NaHCO3 until no CO2 evolution occurred. The aqueous phase was extracted with EtOAc (200 mL x 3), and the combined organic layers were washed with HO, dried over Na2SO3, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (ISCO® SepaFlash® 80 g silica gel column) using a gradient of 0-50% EtOAc in petroleum ether (45 mL / min). The title compound was obtained as a colorless oil (8.0 g, 53%). ESI-MS m / z [M+H] + 196.1.

[0307] Step 2: 3,4-Bis(methoxycarbonyl)pyridine 1-oxide

[0308] [ka]

[0309] A mixture of dimethylpyridine-3,4-dicarboxylate acid (8.0 g, 40.99 mmol) and mCPBA (12.48 g, 61.48 mmol, 85% purity) in DCM (150 mL) was stirred at 20 °C for 12 h, then filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (ISCO® SepaFlash® 80 g silica gel column) using a gradient of 0-99% EtOAc in petroleum ether (45 mL / min). The title compound was obtained as a white solid (5.3 g, 61%). ESI-MS m / z [M+H] + 212.1.

[0310] Step 3: Dimethyl 6-chloropyridine-3,4-dicarboxylate and dimethyl 2-chloropyridine-3,4-dicarboxylate

[0311] [ka]

[0312] A mixture of dimethyl 3,4-bis(methoxycarbonyl)pyridine 1-oxide (2.3 g, 10.89 mmol) and POCl (16.70 g, 108.92 mmol, 10.12 mL) in CHCl (13 mL) was stirred at 85 °C for 18 h. The reaction mixture was then filtered and concentrated under reduced pressure to give a residue, which was neutralized with solid NaHCO until no CO evolution occurred. The aqueous phase was extracted with EtOAc (30 mL × 3). The organic layers were combined, washed with HO (20 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (ISCO® SepaFlash® 40 g silica gel column) using a gradient of 0-20% EtOAc in petroleum ether (60 mL / min) to give dimethyl 6-chloropyridine-3,4-dicarboxylate as a white solid (850 mg, 33.3%) and dimethyl 2-chloropyridine-3,4-dicarboxylate as a white solid (780 mg, 27.4%). ESI-MS m / z [M+H] + 230.

[0313] Step 4: Dimethyl 6-methoxypyridine-3,4-dicarboxylate

[0314] [ka]

[0315] A solution of dimethyl 6-chloropyridine-3,4-dicarboxylate (2.60 g, 11.32 mmol) and NaOMe (3.06 g, 56.62 mmol) in MeOH (20 mL) was stirred at 70 °C for 16 h. The reaction mixture was acidified to pH 4 with aqueous HCl. The aqueous phase was extracted with EtOAc (30 mL × 3), and the combined organic layers were washed with water (10 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound was obtained as a white solid (2 g, 75% yield, 95% purity). ESI-MS m / z [M+H]+ 226.

[0316] Step 5: 7-Methoxypyrido[3,4-d]pyridazine-1,4-diol

[0317] [ka]

[0318] A solution of dimethyl 6-methoxypyridine-3,4-dicarboxylate (1 g, 4.44 mmol) and NHNH.HO (1.56 g, 31.16 mmol, 1.51 mL) in EtOH (10 mL) was stirred at 60 °C for 1 h under a N atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue that was purified by recrystallization from EtOAc (10 mL) to give the title compound as a yellow solid (500 mg, 56.5%). ESI-MS m / z [M+H] + 194.

[0319] Step 6: 1,4-Dichloro-7-methoxypyrido[3,4-d]pyridazine

[0320] [ka]

[0321] A mixture of 7-methoxypyrido[3,4-d]pyridazine-1,4-diol (500 mg, 2.59 mmol) in POCl (5 mL) was degassed and purged with N (3x), then stirred at 100 °C for 1 h under N, filtered, and concentrated under reduced pressure. The concentrate was dissolved in DCM (15 mL), neutralized to pH 7 by dropwise addition of DIPEA, and concentrated. The residue was purified by flash chromatography (ISCO SepaFlash 4 g silica gel column) using a gradient of 0-30% EtOAc in petroleum ether (60 mL / min). The title compound was obtained as a red solid (110 mg, 17.7%). ESI-MS m / z [M+H] + 230.

[0322] Step 7: 1-chloro-7-methoxy-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-7-methoxy-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0323] A mixture of 1,4-dichloro-7-methoxypyrido[3,4-d]pyridazine (110 mg, 444.68 μmol), 1-methylpiperidin-3-amine dihydrochloride (166.41 mg, 889.37 μmol), and CsCO (579.55 mg, 1.78 mmol) in DMF (1.5 mL) was degassed and purged with N (3×). The mixture was stirred at 100° C. for 16 hours under a N atmosphere, then filtered, concentrated under reduced pressure, and purified by preparative HPLC (Method A) to give 1-chloro-7-methoxy-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine as a yellow solid (50 mg, 37%) and 4-chloro-7-methoxy-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine as a yellow solid (30 mg, 22%). ESI-MS m / z [M+H] + 308.1.

[0324] Preparation 22: (R)-4-chloro-N-(1-(2-fluoroethyl)piperidin-3-yl)phthalazin-1-amine

[0325] [ka]

[0326] Step 1: tert-butyl (R)-(1-(2-fluoroethyl)piperidin-3-yl)carbamate

[0327] [ka]

[0328] To a mixture of tert-butyl (R)-piperidin-3-ylcarbamate (15 g, 74.90 mmol) and 1-bromo-2-fluoroethane (19.02 g, 149.79 mmol) in ACN (80 mL) was added NaI (5.61 g, 37.45 mmol) and K2CO3 (51.76 g, 374.48 mmol). The mixture was stirred at 15 °C for 12 h, then diluted with HO (150 mL) and extracted with EtOAc (200 mL × 2). The organic layers were combined, washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® SepaFlash® 220 g silica gel column) using a gradient of 0 to 100% EtOAc in petroleum ether (85 mL / min). The title compound was obtained as a white solid (14.3 g, 77.5%). ESI-MS m / z [M+H] + 247.1.

[0329] Step 2: (R)-1-(2-fluoroethyl)piperidin-3-amine

[0330] [ka]

[0331] A mixture of tert-butyl (R)-(1-(2-fluoroethyl)piperidin-3-yl)carbamate (7 g, 28.42 mmol) in HCl / dioxane (4 M, 20 mL) was stirred at 18 °C for 12 hours and then concentrated under reduced pressure to give the dihydrochloride salt of the title compound as a white solid (6.1 g, 98% yield, 100% purity). ELSD-MS m / z [M+H] + 147.1.

[0332] Step 3: (R)-4-chloro-N-(1-(2-fluoroethyl)piperidin-3-yl)phthalazin-1-amine

[0333] To a mixture of (R)-1-(2-fluoroethyl)piperidin-3-amine (1.5 g, 10.26 mmol) and 1,4-dichlorophthalazine (2.45 g, 12.31 mmol) in DMSO (10 mL) was added DIPEA (5.30 g, 41.04 mmol, 7.15 mL). The mixture was stirred at 100 °C for 12 h, then diluted with HO (50 mL) and extracted with EtOAc (50 mL × 3). The organic layers were combined, washed with brine (150 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® SepaFlash® 40 g silica gel column) using a gradient of 0 to 100% EtOAc in petroleum ether (35 mL / min). The title compound was obtained as a yellow solid (1.1 g, crude). ESI-MS m / z [M+H] + 309.

[0334] Preparation 23: (R)-1-chloro-N-(1-(2-fluoroethyl)piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0335] [ka]

[0336] To a mixture of (R)-1-(2-fluoroethyl)piperidin-3-amine (1.5 g, 10.26 mmol) and 1,4-dichloropyrido[3,4-d-]pyridazine (2.46 g, 12.31 mmol) in DMSO (10 mL) was added DIPEA (5.30 g, 41.04 mmol, 7.15 mL). The mixture was stirred at 100 °C for 12 h, then diluted with HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (150 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® SepaFlash® 40 g silica gel column) using a gradient of 0 to 100% EtOAc in petroleum ether (40 mL / min). The title compound was obtained as a brown oil (2 g, crude). ESI-MS m / z [M+H]+ 310.

[0337] Preparation 24: 1-chloro-N-(1-chloropropylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-N-(1-cyclopropylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0338] [ka]

[0339] To a mixture of 1,4-dichloropyrido[3,4-d]pyridazine (300 mg, 1.50 mmol) and 1-cyclopropylpiperidin-3-amine (479.58 mg, 2.25 mmol, 2HCl) in DMSO (3 mL) was added DIPEA (1.94 g, 15.00 mmol, 2.61 mL) in one portion under N at 25° C. The mixture was stirred at 100° C. for 12 h and then purified by preparative HPLC (Method C) to give 1-chloro-N-(1-cyclopropylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine as a yellow solid (160 mg, 26.6%); 1 H NMR(400MHz,DMSO-d6)δppm0.30-0.37(m,2H),0.38-0.47(m,2H),1.39-1.56(m,2H),1.63-1.69(m,1H),1.69-1.77(m,1H),1.99(br d,J=9.54Hz,1H),2.18(br t,J=10.29Hz,2H),2.90(br d,J=11.04Hz,1H),3.24(br d,J=7.53Hz,1H),4.25(br d,J=6.78Hz,1H),7.74(br d,J=7.53Hz,1H),7.84(d,J=5.52Hz,1H),9.01-9.10(m,1H),9.78(s,1H);ESI-MS m / z [M+H] + 304.1; and 4-chloro-N-(1-cyclopropylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine as a yellow solid (96 mg, 16%); 1H NMR(400MHz,DMSO-d6)δppm0.29-0.46(m,4H),1.39-1.56(m,2H),1.64(tt,J=6.56,3.48Hz,1H),1.69-1.78(m,1H),1.99(br d,J=9.29Hz,1H),2.16(br t,J=10.29Hz,2H),2.89(br d,J=11.04Hz,1H),3.23(br dd,J=10.42,3.64Hz,1H),4.20-4.30(m,1H),7.73(d,J=7.53Hz,1H),7.82-7.89(m,1H),9.05(d,J=5.52Hz,1H),9.78(s,1H);ESI-MS m / z [M+H] + 304.1.

[0340] Preparation 25: 4-chloro-N-((3R,5R)-1-cyclopropyl-5-fluoropiperidin-3-yl)phthalazin-1-amine

[0341] [ka]

[0342] To a mixture of (3R,5R)-1-cyclopropyl-5-fluoropiperidin-3-amine dihydrochloride (214 mg, 0.778 mmol) and DIPEA (543 μL, 3.11 mmol) in NMP (3.89 mL) was added 1,4-dichlorophthalazine (155 mg, 0.778 mmol). The mixture was stirred at 125 °C overnight and then diluted with water and aqueous NaHCO3. The organic phase was extracted with EtOAc (3x), washed with aqueous NaHCO3, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (ISCO® RediSep Rf Gold® 24 g silica gel column) using a gradient of 10 to 100% EtOAc in heptane. Product-containing fractions were concentrated in vacuo to give the title compound as an orange oil (81.5 mg, 33%). ESI-MS m / z [M+H] + 321.3.

[0343] Preparation 26: 1-chloro-4-(4-chlorophenoxy)phthalazine

[0344] [ka]

[0345] To a solution of 1,4-dichlorophthalazine (1 g, 5.02 mmol), 4-chlorophenol (645.89 mg, 5.02 mmol, 493.05 μL) in DMF (10 mL) was added K2CO3 (1.39 g, 10.05 mmol). The mixture was stirred at 25 °C for 15 h. LC-MS showed one main peak with the desired m / z. The reaction mixture was concentrated under reduced pressure to remove the solvent, dissolved in H2O (30 mL), and extracted with EtOAc (30 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.09 g, crude). ESI-MS m / z [M+H] + 290.9.

[0346] Preparation 27: 1-chloro-4-(4-chloro-2-fluorophenyl)phthalazine

[0347] [ka]

[0348] A mixture of 1,4-dichlorophthalazine (1 g, 5.02 mmol), (4-chloro-2-fluorophenyl)boronic acid (963.65 mg, 5.53 mmol), Pd(dppf)Cl.CHCl (410.29 mg, 502.42 μmol), and NaCO (1.60 g, 15.07 mmol) in dioxane (2 mL) was degassed and purged with N (3×). The mixture was stirred at 100 °C for 1 h under N and then concentrated in vacuo. The crude product was purified by flash chromatography (ISCO® SepaFlash® 12 g silica gel column) using a gradient of 0–15% EtOAc in petroleum ether (45 mL / min). The title compound was obtained as a white solid (500 mg, 33.9%). ESI-MS m / z [M+H] + 292.9.

[0349] Preparation 28: 1-chloro-4-(4-chlorophenyl)phthalazine

[0350] [ka]

[0351] The title compound (2.6 g, 38%) was prepared analogously to preparation 27 using 1,4-dichlorophthalazine (5 g, 25.12 mmol) and (4-chlorophenyl)boronic acid (3.93 g, 25.12 mmol). ESI-MS m / z [M+H] + 274.8.

[0352] Preparation 29: 4-chloro-1-(4-methoxyphenyl)pyrido[3,4-d]pyridazine

[0353] [ka]

[0354] Step 1: 4-(4-Methoxybenzoyl)nicotinic acid

[0355] [ka]

[0356] To a solution of furo[3,4-c]pyridine-1,3-dione (5 g, 33.53 mmol) in THF (50 mL) was added bromo-(4-methoxyphenyl)magnesium (0.5 M, 53.65 mL) dropwise over 30 min at −78 °C. The reaction mixture was stirred at −78 °C for 1 h under a N atmosphere. LC-MS showed one main peak with the desired mass. The reaction was quenched by slowly adding HO (20 mL). The mixture was stirred for 30 min and then filtered. The filter cake was rinsed with THF (15 mL × 3) and dried in vacuo to give the title compound as a white solid (6 g, 70%). 1 H NMR(400MHz,DMSO-d6)δ3.87(s,3H),6.93-7.10(m,2H),7.18-7.36(m,1H),7.49-7.74(m,2H),8.60-8.83(m,1H),9.10-9.30(m,1H);ESI-MS m / z [M+H] + 258.2.

[0357] Step 2: 1-(4-Methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol

[0358] [ka]

[0359] A mixture of 4-(4-methoxybenzoyl)nicotinic acid (2 g, 7.77 mmol, 1 equiv.), hydrazine hydrochloride (798.93 mg, 11.66 mmol), and EtN (1.57 g, 15.55 mmol, 2.16 mL) in EtOH (10 mL) was stirred at 90 °C for 12 h. LC-MS showed one peak with the desired mass. The reaction mixture was concentrated, triturated with ACN (25 mL), and filtered. The filter cake was collected and dried to give the title compound as a white solid (4.3 g, crude). 1H NMR(400MHz,DMSO-d6)δppm3.85(s,3H),7.09-7.16(m,2H),7.53-7.64(m,3H),8.96-9.04(m,1H),9.46-9.57(m,1H);ESI-MS m / z [M+H] + 254.1.

[0360] Step 3: 4-chloro-1-(4-methoxyphenyl)pyrido[3,4-d]pyridazine

[0361] To a mixture of 1-(4-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol (1 g, 3.95 mmol) in POCl3 (10 mL) was added DIPEA (1.53 g, 11.85 mmol, 2.06 mL). The mixture was stirred at 100 °C for 1 h. LC-MS showed a single peak with the desired mass. The reaction mixture was concentrated under reduced pressure, dissolved in DCM (5 mL), and adjusted to pH 7-8 by adding DIPEA. The mixture was concentrated and then purified by flash chromatography (ISCO® SepaFlash® 20 g silica gel column) using a gradient of 0-35% EtOAc in petroleum ether (40 mL / min). The title compound was obtained as a yellow solid (320 mg, 1.18 mmol, 29.8% yield, 90% purity). 1 H NMR(400MHz,DMSO-d6)δppm3.84-3.93(m,3H),7.15-7.28(m,2H),7.82(br d,J=8.76Hz,2H),7.91-8.01(m,1H),9.14-9.26(m,1H),9.73-9.80(m,1H);ESI-MS m / z [M+H] + 271.9.

[0362] Preparation 30: 8-chloro-5-(4-methoxyphenyl)pyrido[2,3-d]pyridazine

[0363] [ka]

[0364] To a solution of 5,8-dichloropyrido[2,3-d]pyridazine (200 mg, 999.88 μmol), (4-methoxyphenyl)boronic acid (151.94 mg, 999.88 μmol), and NaCO (211.95 mg, 2.00 mmol) in toluene (5 mL) and HO (1.25 mL) was added Pd(PPh) (115.54 mg, 99.99 μmol) in one portion. The mixture was degassed and purged with N (3×), then stirred at 90 °C for 12 h under N. The reaction mixture was filtered, and the filtrate was concentrated and purified by preparative HPLC (Method B). The title compound was obtained as a yellow solid (43 mg, 16%). 1 H NMR(400MHz,DMSO-d6)δppm3.89(s,3H),7.21(d,J=8.40Hz,2H),7.74(d,J=8.40H z,2H),8.09-8.12(m,1H),8.50(d,J=8.40Hz,1H),9.42(d,J=2.80Hz,1H);ESI-MS m / z [M+H] + 272.0.

[0365] Preparation 31: 1-chloro-4-(4-methoxyphenyl)-5,6,7,8-tetrahydrophthalazine

[0366] [ka]

[0367] A mixture of 1,4-dichloro-5,6,7,8-tetrahydrophthalazine (160 mg, 787.91 μmol), (4-methoxyphenyl)boronic acid (179.59 mg, 1.18 mmol), Pd(PPh3)4 (91.05 mg, 78.79 μmol), KF (91.55 mg, 1.58 mmol, 36.92 μL, 2 equiv.), and K3PO4 (334.49 mg, 1.58 mmol) in toluene (5 mL) was degassed and purged with N2 (3x). The mixture was stirred at 130 °C for 1 h under a N2 atmosphere and then concentrated in vacuo. The crude product was purified by preparative HPLC (Method B). The title compound was obtained as a white solid (110 mg, 50.8%). ESI-MS m / z [M+H] + 275.0.

[0368] Preparation 32: 4-chloro-7-(4-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyridazine

[0369] [ka]

[0370] Step 1: Methyl 5-(chlorocarbonyl)-1-methyl-1H-pyrazole-4-carboxylate

[0371] [ka]

[0372] To a 100 mL round-bottom flask containing 4-(methoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (0.5 g, 2.72 mmol) in THF (10 mL) was added sulfur dichloride (0.394 mL, 5.43 mmol) dropwise. The mixture was heated under reflux overnight and then concentrated to dryness to give the title compound, which was used without further purification.

[0373] Step 2: Methyl 5-(4-methoxybenzoyl)-1-methyl-1H-pyrazole-4-carboxylate

[0374] [ka]

[0375] To a 100 mL round-bottom flask containing methyl 5-(chlorocarbonyl)-1-methyl-1H-pyrazole-4-carboxylate (0.551 g, 2.72 mmol) in toluene (6 mL) was added dropwise a solution of 1-methylpyrrolidin-2-one (0.261 mL, 2.72 mmol) in toluene (6 mL) at 0° C. The mixture was stirred at 0° C. for 15 minutes and then cooled to −10° C. Next, (4-methoxyphenyl)magnesium bromide (4.53 mL, 2.267 mmol) in toluene was added dropwise. The mixture was stirred at 0° C. for 1 hour, then quenched with saturated NH4Cl and extracted with EtOAc. The organic phases were combined, washed with brine, dried over MgSO4, and concentrated to give the title compound as a brown syrup, which was used without further purification. ESI-MS m / z [M+H] + :275.1.

[0376] Step 3: 7-(4-Methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyridazin-4-ol

[0377] [ka]

[0378] To a 150 mL pressure vial was added methyl 5-(4-methoxybenzoyl)-1-methyl-1H-pyrazole-4-carboxylate (0.620 g, 2.26 mmol) and hydrazine HCl (0.929 g, 13.56 mmol) in acetic acid (8 mL) to give a brown suspension. The reaction mixture was heated at reflux for 5 days and then concentrated under reduced pressure. The residue was neutralized with saturated aqueous NaHCO3, and the aqueous phase was extracted with EtOAc. The organic phases were combined, washed with brine, dried over MgSO4, and concentrated to give the title compound as a brown solid (0.162 g, 28%). ESI-MS m / z [M+H] + 257.1.

[0379] Step 4: 4-chloro-7-(4-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyridazine

[0380] To a 100 mL round-bottom flask was added 7-(4-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyridazin-4-ol (0.162 g, 0.632 mmol), POCl (0.236 mL, 2.53 mmol), and N,N-dimethylaniline (0.321 mL, 2.53 mmol) in dioxane (8 mL) to give a tan solution. The mixture was heated at 90 °C for 30 min and then concentrated under reduced pressure. The residue was treated with saturated aqueous NaHCO and extracted with EtOAc. The organic phases were combined, washed with brine, dried over MgSO, concentrated, and dried under high vacuum to give the title compound (crude) as a tan solid (180 mg, 100% yield). ESI-MS m / z [M+H] + 275.3.

[0381] Preparation 33: tert-Butyl (3R,5S)-3-((4-chlorophthalazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate

[0382] [ka]

[0383] A mixture of tert-butyl (3R,5S)-3-amino-5-fluoro-piperidine-1-carboxylate (370 mg, 1.70 mmol), 1,4-dichlorophthalazine (404.88 mg, 2.03 mmol), and DIPEA (1.10 g, 8.48 mmol, 1.48 mL) in DMSO (5 mL) was stirred at 100 °C for 12 h. The mixture was diluted with HO (30 mL) and extracted with EtOAc (30 mL × 3). The organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography (ISCO® SepaFlash® 20 g silica gel column) using a gradient of 0–50% EtOAc in petroleum ether (40 mL / min). The title compound was obtained as a yellow oil (310 mg, crude). ESI-MS m / z [M+H] + 381.1.

[0384] Preparation 34: tert-Butyl (3R,5S)-3-((4-chlorophthalazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate

[0385] [ka]

[0386] The title compound was prepared analogously to Preparation 33 using tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (0.873 g, 4.00 mmol) and 1,4-dichlorophthalazine (0.796 g, 4.00 mmol) to give a pale yellow foam (0.630 g, 41%). ESI-MS m / z [M+H] + 381.3.

[0387] Preparation 35: tert-Butyl (3R,5S)-3-((4-(4-chlorophenyl)phthalazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate

[0388] [ka]

[0389] The title compound was prepared analogously to Preparation 33 using tert-butyl (3R,5R)-3-((4-chlorophthalazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate (0.240 g, 0.630 mmol), 2-(4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.188 g, 0.788 mmol) and aqueous KCO (2 M, 0.945 mL, 1.89 mmol). The title compound was obtained as an off-white solid (75.6 mg, 26%). ESI-MS m / z [M+H] + 457.3.

[0390] Preparation 36: tert-Butyl (3R,5R)-3-fluoro-5-((4-(4-methoxyphenyl)phthalazin-1-yl)amino)piperidine-1-carboxylate

[0391] [ka]

[0392] The title compound was prepared analogously to Preparation 33 using tert-butyl (3R,5R)-3-((4-chlorophthalazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate (0.152 g, 0.400 mmol), 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.117 g, 0.500 mmol), and aqueous KCO (2 M, 0.600 mL, 1.20 mmol). The title compound was obtained as a pale yellow semi-solid (100.8 mg, 56%). ESI-MS m / z [M+H] + 453.4.

[0393] Preparation 37: tert-Butyl (3R,5R)-3-fluoro-5-((4-(2-fluoro-4-methoxyphenyl)phthalazin-1-yl)amino)piperidine-1-carboxylate

[0394] [ka]

[0395] The title compound was prepared similarly to preparation 33 using (2-fluoro-4-methoxyphenyl)boronic acid. ESI-MS m / z [M+H] + 471.4.

[0396] Preparation 38: tert-butyl (3R,5R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)-5-fluoropiperidine-1-carboxylate and tert-butyl (3R,5R)-3-((4-chloropyrido[3,4-d]pyridazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate

[0397] [ka]

[0398] A mixture of 1,4-dichloropyrido[3,4-d]pyridazine (100 mg, 499.94 μmol), tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (163.68 mg, 749.91 μmol), DIPEA (323.07 mg, 2.50 mmol, 435.40 μL), and NaI (74.94 mg, 499.94 μmol) in DMSO (2 mL) was degassed and purged with N (3×). The mixture was stirred at 90 °C for 1 h under a N atmosphere, then diluted with HO (30 mL) and extracted with EtOAc (40 mL × 2). The organic layers were combined, dried over anhydrous NaSO, and filtered. The filtrate was evaporated in vacuo to give the title compound mixture as a red solid (500 mg, crude). ESI-MS m / z [M+H] + 382.

[0399] Preparation 39: tert-Butyl (3R,5S)-3-((4-(4-chlorophenyl)phthalazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate

[0400] [ka]

[0401] To a solution of tert-butyl (3R,5S)-3-((4-chlorophthalazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate (270 mg, 708.95 μmol), (4-chlorophenyl)boronic acid (144.12 mg, 921.64 μmol), and CsCO (461.98 mg, 1.42 mmol) in dioxane (5 mL) and HO (1 mL) was added Pd(dppf)Cl (103.75 mg, 141.79 μmol). The mixture was stirred at 100 °C for 12 h under N and then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (SiO, DCM / MeOH = 1:0 to 20:1). The title compound was obtained as a yellow solid (320 mg, crude). ESI-MS m / z [M+H] + 457.2.

[0402] Preparation 40: tert-Butyl (3R,5R)-3-((4-(4-chloro-2-fluorophenyl)phthalazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate

[0403] [ka]

[0404] To a solution of 1-chloro-4-(4-chloro-2-fluorophenyl)phthalazine (100 mg, 341.15 μmol) in dioxane (1 mL) was added BINAP (10.62 mg, 17.06 μmol), tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (89.36 mg, 409.38 μmol), Pd(OAc) (7.66 mg, 34.12 μmol), and CsCO (333.46 mg, 1.02 mmol). The mixture was stirred at 100 °C for 1 h. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by flash chromatography (ISCO® SepaFlash® 12 g silica gel column) using a gradient of 0–45% EtOAc in petroleum ether (85 mL / min). The title compound was obtained as an orange solid (55 mg, 34%). ESI-MS m / z [M+H]+ 475.2.

[0405] Preparation 41: N-((3R,5R)-5-fluoropiperidin-3-yl)-4-(4-methoxyphenyl)phthalazin-1-amine

[0406] [ka]

[0407] A solution of tert-butyl (3R,5R)-3-fluoro-5-((4-(4-methoxyphenyl)phthalazin-1-yl)amino)piperidine-1-carboxylate (0.358 g, 0.791 mmol) in dioxane (1.98 mL) was treated with HCl (4 M in dioxane, 1.98 mL, 7.91 mmol). The mixture was stirred at room temperature for 45 min. A few drops of MeOH were added and the mixture was stirred for an additional 15 min. The reaction mixture was concentrated in vacuo. The residue was taken up in MeOH and filtered through a hydrophilic PTFE 0.45 μm syringe filter (VWR®). The filtrate was purified by preparative HPLC (Method C) over two injections. Evaporation of the product-containing fractions gave the title compound as a yellow-orange oil (0.191 g, 68%). ESI-MS m / z [M+H] + 353.3.

[0408] Preparation 42: tert-butyl (3R,5R)-3-fluoro-5-((1-(4-methoxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylate and tert-butyl (3R,5R)-3-fluoro-5-((4-(4-methoxyphenyl)pyrido[3,4-d]pyridazin-1-yl)amino)piperidine-1-carboxylate

[0409] [ka]

[0410] A mixture of tert-butyl (3R,5R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)-5-fluoropiperidine-1-carboxylate and tert-butyl (3R,5R)-3-((4-chloropyrido[3,4-d]pyridazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate (190 mg, 497.60 μmol), (4-methoxyphenyl)boronic acid (113.42 mg, 746.40 μmol), Pd(dppf)Cl (40.64 mg, 49.76 μmol), and CsCO (324.26 mg, 995.20 μmol) in dioxane (1 mL) was degassed and purged with N (3×). The mixture was stirred at 90 °C for 1 h under N2, then dispersed in HO (30 mL) and extracted with EtOAc (40 mL × 2). The organic layers were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo and purified by preparative HPLC (Method B) to give tert-butyl (3R,5R)-3-fluoro-5-((1-(4-methoxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylate (60 mg, 24.8% yield, 93.3% purity) and tert-butyl (3R,5R)-3-fluoro-5-((4-(4-methoxyphenyl)pyrido[3,4-d]pyridazin-1-yl)amino)piperidine-1-carboxylate (20 mg, 8.6% yield, 97.1% purity) as white solids. ESI-MS m / z [M+H] + 454.3.

[0411] Preparation 43: tert-butyl (3R,5R)-3-((1-(4-chlorophenyl)pyrido[3,4-d]pyridazin-4-yl)amino)-5-fluoropiperidine-1-carboxylate and tert-butyl (3R,5R)-3-((4-(4-chlorophenyl)pyrido[3,4-d]pyridazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate

[0412] [ka]

[0413] The title compound was prepared analogously to Preparation 42 using a mixture of tert-butyl (3R,5R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)-5-fluoropiperidine-1-carboxylate (200 mg, 523.79 μmol) and tert-butyl (3R,5R)-3-((4-chloropyrido[3,4-d]pyridazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate and (4-chlorophenyl)boronic acid (122.86 mg, 785.69 μmol). (3R,5R)-tert-butyl 3-((4-(4-chlorophenyl)pyrido[3,4-d]pyridazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate (20 mg, 8.2%) and (3R,5R)-tert-butyl 3-((1-(4-chlorophenyl)pyrido[3,4-d]pyridazin-4-yl)amino)-5-fluoropiperidine-1-carboxylate (45 mg, crude) were obtained as white solids, respectively. ESI-MS m / z [M+H] + 458.2.

[0414] Preparation 44: tert-butyl (3R,5R)-3-fluoro-5-((1-(4-fluoro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylate and tert-butyl (3R,5R)-3-fluoro-5-((4-(4-fluoro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-1-yl)amino)piperidine-1-carboxylate

[0415] [ka]

[0416] The title compound was prepared analogously to Preparation 42 using a mixture of tert-butyl (3R,5R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)-5-fluoropiperidine-1-carboxylate and tert-butyl (3R,5R)-3-((4-chloropyrido[3,4-d]pyridazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate (300 mg, 785.69 μmol), and (4-fluoro-2-methoxyphenyl)boronic acid (267.05 mg, 1.57 mmol). The title compounds tert-butyl (3R,5R)-3-fluoro-5-((1-(4-fluoro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylate (110 mg, 28.8% yield, 97% purity) and tert-butyl (3R,5R)-3-fluoro-5-((4-(4-fluoro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-1-yl)amino)piperidine-1-carboxylate (60 mg, μmol, 8.1% yield, 50% purity) were obtained as white solids. ESI-MS m / z [M+H] + 472.1.

[0417] Preparation 45: tert-Butyl (3R,5R)-3-fluoro-5-((1-(2-fluoro-4-methoxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylate

[0418] [ka]

[0419] The title compound was prepared analogously to Preparation 42 using a mixture of tert-butyl (3R,5R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)-5-fluoropiperidine-1-carboxylate and tert-butyl (3R,5R)-3-((4-chloropyrido[3,4-d]pyridazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate (650 mg, 1.70 mmol), and (2-fluoro-4-methoxyphenyl)boronic acid (578.60 mg, 3.40 mmol). The title compound was obtained as a white solid (170 mg, 20.8% yield, 98% purity). ESI-MS m / z [M+H] + 472.1.

[0420] Preparation 46: tert-butyl (3R,5R)-3-((1-(4-chloro-2-fluorophenyl)pyrido[3,4-d]pyridazin-4-yl)amino)-5-fluoropiperidine-1-carboxylate and tert-butyl (3R,5R)-3-((4-(4-chloro-2-fluorophenyl)pyrido[3,4-d]pyridazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate

[0421] [ka]

[0422] The mixture of title compounds was prepared analogously to Preparation 42 using a mixture of tert-butyl (3R,5R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)-5-fluoropiperidine-1-carboxylate and tert-butyl (3R,5R)-3-((4-chloropyrido[3,4-d]pyridazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate (200 mg, 523.79 μmol) and (4-chloro-2-fluorophenyl)boronic acid (182.66 mg, 1.05 mmol). The mixture of title compounds was obtained as a yellow solid (110 mg, 39.7%). ESI-MS m / z [M+H] + 476.3.

[0423] Preparation 47: tert-Butyl-5-((4-(4-chlorophenyl)phthalazin-1-yl)amino)-3,3-difluoropiperidine-1-carboxylate

[0424] [ka]

[0425] A mixture of tert-butyl 5-amino-3,3-difluoropiperidine-1-carboxylate (118 mg, 0.500 mmol) and 1-chloro-4-(4-chlorophenyl)phthalazine (275 mg, 0.500 mmol) in NMP (2.5 mL) was treated with KCO (207 mg, 1.50 mmol). The reaction mixture was stirred at 150 °C for 2 days, then diluted with water and extracted with EtOAc (3x). The organic phases were combined, washed with saturated aqueous NaHCO, dried over NaSO, filtered, and concentrated under reduced pressure to give the (crude) title compound as a brown oil (237 mg). ESI-MS m / z [M+H] + 475.3.

[0426] Preparation 48: 1-(4-chlorophenyl)-N-(piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0427] [ka]

[0428] Step 1: tert-Butyl 3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylate

[0429] [ka]

[0430] A mixture of 1,4-dichloropyrido[3,4-d]pyridazine (0.200 g, 1 mmol), tert-butyl 3-aminopiperidine-1-carboxylate (0.200 g, 1.000 mmol), and KCO (0.415 g, 3.00 mmol) in DMSO (3.33 mL) was stirred at 100° C. overnight. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC. The title compound was obtained as an off-white solid. ESI-MS m / z [M+H] + 364.4.

[0431] Step 2: tert-Butyl 3-((1-(4-chlorophenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylate

[0432] [ka]

[0433] A mixture of tert-butyl 3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylate (0.364 g, 1.00 mmol), (4-chlorophenyl)boronic acid (0.156 g, 1.00 mmol), Pd(PPh3)4 (0.116 g, 0.100 mmol), and K2CO3 (0.415 g, 3.00 mmol) in toluene (3.47 mL) and water (0.694 mL) was degassed and purged with N2. The mixture was stirred at 90 °C for 1 h under a N2 atmosphere and then concentrated under reduced pressure. DMF (3 mL) was added, and the mixture was filtered. The filtrate was purified by preparative HPLC. The title compound was obtained as an off-white solid (0.440 g). ESI-MS m / z [M+H] + 440.3.

[0434] Step 3: 1-(4-chlorophenyl)-N-(piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0435] A mixture of tert-butyl 3-((1-(4-chlorophenyl)pyrido[3,4-d]pyridazin-4-yl)amino)piperidine-1-carboxylate (0.440 g, 1 mmol) and TFA (1 mL, 12.98 mmol) in DCM (10 mL) was stirred at room temperature overnight. The reaction was concentrated in vacuo to give the title compound as an off-white solid. ESI-MS m / z [M+H] + 340.2.

[0436] Preparation 49: 1,4-Dichloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazine

[0437] [ka]

[0438] Step 1: Methyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydro-2H-pyran-3-carboxylate

[0439] [ka]

[0440] To a solution of methyl 4-oxotetrahydropyran-3-carboxylate (8 g, 50.58 mmol) in THF (100 mL) was added NaH (2.43 g, 60.70 mmol, 60% purity) at −78° C. After stirring for 1 h, a solution of N-(5-chloro-2-pyridyl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (23.84 g, 60.70 mmol) in THF (50 mL) was added dropwise, and the mixture was stirred at 20° C. for 12 h. TLC (petroleum ether / EtOAc = 5:1) showed that the starting material was completely consumed. The mixture was quenched with saturated aqueous NH4Cl (300 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were concentrated in vacuo. The resulting crude product was purified by flash chromatography (ISCO® SepaFlash® 80 g silica gel column) using a gradient of 0 to 15% EtOAc in petroleum ether (60 mL / min) to afford the title compound as a colorless oil (11 g, 75%). 1 H NMR (400MHz, CDCl3) δppm2.51-2.55(m,2H),3.81(s,3H),3.87-3.90(t,J=5.6Hz,2H),4.43-4.45(t,J=2.8Hz,2H).

[0441] Step 2: Dimethyl 5,6-dihydro-2H-pyran-3,4-dicarboxylate

[0442] [ka]

[0443] A mixture of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydro-2H-pyran-3-carboxylate (8 g, 27.57 mmol), Pd(dppf)Cl.CHCl (2.25 g, 2.76 mmol), and DIPEA (10.69 g, 82.70 mmol, 14.40 mL) in MeOH (120 mL) was stirred at 60 °C under CO (20 psi) for 12 h. LC-MS showed complete consumption of the starting material and one main peak with the desired m / z. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The resulting crude product was purified by flash chromatography (ISCO® SepaFlash® 80 g silica gel column) using a gradient of 0–15% EtOAc in petroleum ether (60 mL / min) to give the title compound (5 g, 91%). 1 H NMR(400MHz,CDCl3)δppm2.44-2.47(m,2H),3.78(s,3H),3.79-3.82(m,5H),4.34-4.35(t,J=2.8Hz,2H);ESI-MS m / z [M+H] + 201.1.

[0444] Step 3: 5,6-Dihydro-2H-pyran-3,4-dicarboxylic acid

[0445] [ka]

[0446] A mixture of dimethyl 5,6-dihydro-2H-pyran-3,4-dicarboxylate (6 g, 29.97 mmol), NaOH (7.19 g, 179.83 mmol) in HO (60 mL) and MeOH (60 mL) was stirred at 50 °C for 1 h. TLC showed complete consumption of the starting material. The mixture was concentrated in vacuo to remove MeOH. The aqueous layer was extracted with DCM (30 mL × 2), and the organic layer was discarded. To the aqueous layer was added HCl (3 M, 60 mL), and the mixture was evaporated to dryness in vacuo. The residue was triturated with DCM / MeOH (10:1, 500 mL × 2) for 30 min and filtered. The filtrate was dried over NaSO, filtered, and concentrated in vacuo. The residue was diluted with DCM / MeOH (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound as a yellow oil (4.7 g, crude). 1 H NMR (400MHz, CDCl3) δppm2.51 (s, 2H), 3.79-3.85 (m, 2H), 4.40 (s, 2H), 8.76 (s, 2H).

[0447] Step 4: 6,7-Dihydro-3H-furo[3,4-c]pyran-1,3(4H)-dione

[0448] [ka]

[0449] A solution of 5,6-dihydro-2H-pyran-3,4-dicarboxylic acid (4.7 g, 27.30 mmol) in AcO (109.00 g, 1.07 mol, 100 mL) was stirred at 100 °C for 4 h. TLC showed one major new spot with low polarity. The mixture was concentrated in vacuo to give the title compound as a yellow oil (4.8 g, crude).

[0450] Step 5: 7,8-Dihydro-5H-pyrano[3,4-d]pyridazine-1,4-diol

[0451] [ka]

[0452] A mixture of 6,7-dihydro-3H-furo[3,4-c]pyran-1,3(4H)-dione (4.8 g, 31.14 mmol) and NHNH.HO (6.54 g, 128.00 mmol, 6.35 mL, 98% purity) in THF (100 mL) was stirred at 70 °C for 3 h. A white suspension was observed. The mixture was concentrated in vacuo, and the resulting residue was triturated with EtOH (100 mL) for 30 min and filtered. The filter cake was dried in vacuo to give the title compound as a white solid (2.8 g, 53%). 1 H NMR(400MHz,DMSO-d6)δppm2.37-2.39(t,J=5.6Hz,2H),3.77-3.79(t,J=5.6Hz,2H),4.32(s,2H).

[0453] Step 6: 1,4-Dichloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazine

[0454] [ka]

[0455] A mixture of 7,8-dihydro-5H-pyrano[3,4-d]pyridazine-1,4-diol (2.7 g, 16.06 mmol), POCl3 (89.10 g, 581.10 mmol, 54.00 mL), and DIPEA (10.38 g, 80.29 mmol, 13.98 mL) was stirred at 100 °C for 2 h. TLC showed one major new spot with low polarity. The mixture was concentrated in vacuo, and the resulting residue was diluted with DCM (50 mL). The mixture was purified by distillation with DIPEA at 0 °C. The resulting solution was adjusted to H8 and added dropwise to saturated aqueous NaHCO3 (50 mL) at 0 °C, followed by extraction with DCM / MeOH (10:1, 80 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (ISCO® SepaFlash® 80 g silica gel column) using a gradient of 0-50% EtOAc in petroleum ether (60 mL / min). The title compound was obtained as a white solid (1.7 g, 52%). 1H NMR (400MHz, DMSO-d6) δppm2.76-7.78(t,J=5.6Hz,2H),3.93-3.96(t,J=5.6Hz,2H),4.66(s,2H).

[0456] Preparation 50: (R)-4-chloro-N-(1-methylpiperidin-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-amine and (R)-1-chloro-N-(1-methylpiperidin-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-amine

[0457] [ka]

[0458] A vial was charged with 1,4-dichloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazine (500 mg, 2.44 mmol), (R)-1-methylpiperidin-3-amine (556.90 mg, 4.88 mmol), and DIPEA (1.58 g, 12.19 mmol, 2.12 mL) in NMP (5 mL). The vial was sealed, and the reaction mixture was heated in a microwave reactor at 170 °C for 1 h. LC-MS showed a peak with the desired m / z. The reaction mixture was purified by preparative HPLC (Xtimate C18-10 μm, 40 mm × 150 mm column) using a gradient of 15–45% ACN in water (containing 0.05% NH3HO) to give the title compound mixture (400 mg) as a yellow gum. ESI-MS m / z [M+H] + 283.1.

[0459] Preparation 51: 4-chloro-1-(4-methoxyphenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine and 1-chloro-4-(4-methoxyphenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine

[0460] [ka]

[0461] A mixture of 1,4-dichloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazine (100 mg, 487.71 μmol), (4-methoxyphenyl)boronic acid (88.93 mg, 585.25 μmol), Pd(dppf)Cl.CHCl (79.66 mg, 97.54 μmol), and NaCO (155.07 mg, 1.46 mmol) in dioxane (2 mL) and HO (0.5 mL) was degassed and purged with N (3×), then stirred at 100 °C for 2 h under a N atmosphere. LC-MS indicated the desired product had formed. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by flash chromatography (ISCO® SepaFlash® 4 g silica gel column) using a gradient of 0–25% EtOAc in petroleum ether (18 mL / min). A mixture of the title compounds was obtained as a white solid (60mg). 1 H NMR (400MHz, DMSO-d6) δ 2.75-2.90 (m, 4H), 3.83 (s, 8H), 4.57-4.76 (m, 4H), 6.90-7.22 (m, 4H), 7.37-7.84 (m, 4H).

[0462] Preparation 52: (R)-4-chloro-N-(1-methylpiperidin-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-amine

[0463] [ka]

[0464] Preparation 53: (R)-1-chloro-N-(1-methylpiperidin-3-yl)7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-amine

[0465] [ka]

[0466] To a solution of 1,4-dichloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazine (200 mg, 975.41 μmol) in NMP (3 mL) was added DIPEA (630.33 mg, 4.88 mmol, 849.50 μL) and (R)-1-methylpiperidin-3-amine (365.02 mg, 1.95 mmol, 2HCl). The mixture was stirred in a microwave reactor at 170 °C for 1 h and then purified by preparative HPLC (Phenomenex C18-3 μm, 30 mm × 75 mm column) using a gradient of 13–43% ACN in water (10 mM NH4HCO3) to give the mixture of title compounds as a white solid (70 mg, crude). The title compounds were separated by chiral SFC (DAICEL CHIRALPAK® AD-10 μm, 30 mm × 250 mm column) using a mobile phase of CO and 35% EtOH (containing 0.1% NH HO). The title compound of Preparation 52 was obtained as a white solid (32 mg, 12%). 1 H NMR(400MHz,DMSO-d6)δppm1.23(s,1H),1.42(br dd,J=6.19,2.56Hz,1H),1.60(br d,J=11.51Hz,1H),1.71-1.93(m,1H),2.28-2.41(m,2H)2.55-2.73(m,1H),2.86(br d,J=2.88Hz,1H),3.10(br s,1H),3.87(t,J=5.63Hz,1H),4.14-4.31(m,1H),4.43(br s,1H),5.98(br d,J=1.75Hz,1H);ESI-MS m / z [M+H] + 283.1. The title compound of Preparation 53 was obtained as a white solid (28 mg, 10%). 1H NMR(400MHz,DMSO-d6)δppm1.41(br d,J=9.63Hz,1H),1.48-1.61(m,1H),1.65-1.77(m,1H),1.78-1.90(m,1H),2.06(br d,J=7.13Hz,2H)2.20-2.37(m,4H),2.62-2.76(m,1H),2.97(br d,J=8.13Hz,1H),3.90(t,J=5.50Hz,2H),4.13-4.25(m,1H),4.50(s,2H),5.00(s,1H),6.06(br d,J=7.25Hz,1H),7.35(s,1H);ESI-MS m / z [M+H] + 283.1.

[0467] Preparation 54: 4-chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-amine

[0468] [ka]

[0469] Preparation 55: 1-chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-amine

[0470] [ka]

[0471] Step 1: tert-butyl (3R,5R)-3-((4-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate and tert-butyl (3R,5R)-3-((1-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)amino)-5-fluoropiperidine-1-carboxylate

[0472] [ka]

[0473] A mixture of 1,4-dichloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazine (3 g, 14.63 mmol), tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (3.83 g, 17.56 mmol), BINAP (1.82 g, 2.93 mmol), CsCO (9.53 g, 29.26 mmol), and Pd(dba) (1.34 g, 1.46 mmol) in toluene (20 mL) was stirred at 100 °C for 12 h under N. LC-MS showed one main peak with the desired m / z. The mixture was filtered, and the filter cake was washed with DCM / MeOH (10 / 1, 60 mL). The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (ISCO® SepaFlash® 40 g silica gel column) using a gradient of 0-10% MeOH in DCM (24 mL / min) to give the mixture of title compounds as a yellow solid (2.9 g, crude). ESI-MS m / z [M+H] + 387.0.

[0474] Step 2: 4-chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-amine and 1-chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-amine

[0475] A mixture of tert-butyl (3R,5R)-3-((4-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)amino)-5-fluoropiperidine-1-carboxylate and tert-butyl (3R,5R)-3-((1-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)amino)-5-fluoropiperidine-1-carboxylate (2.8 g) and formaldehyde (434.71 mg, 14.48 mmol, 398.82 μL) in formic acid (50 mL) was stirred at 80 °C for 1.5 h. LC-MS showed one main peak with the desired m / z. The mixture was concentrated in vacuo, and the resulting residue was diluted with HO (30 mL) and extracted with DCM (10 mL × 2). The organic layer was discarded. The aqueous layer was adjusted to pH 8-9 with NaHCO3 and extracted with DCM / MeOH (10:1, 50 mL x 3). The combined organic layers were concentrated in vacuo to give the crude product. The title compounds were separated by chiral SFC (DAICEL CHIRALPAK® AD-10 μm, 30 mm x 250 mm column) using a mobile phase of CO2 and 50% EtOH (containing 0.1% NH3H2O). The title compound of Preparation 54 was obtained as a yellow solid (380 mg, 44.4%). 1 H NMR(400MHz,DMSO-d6)δppm1.62-1.82(m,1H),1.91(br t,J=10.0Hz,1H),2.16(br s,2H),2.20(s,3H),2.43(br ESI-MS m / z [M+H] + 301.0. Obtained the title compound of Preparation 55 as a yellow solid (310 mg, 36.3%). 1H NMR(400MHz,DMSO-d6)δppm1.55-1.77(m,1H),1.87(t,J=10.1Hz,1H),2.00-2.18(m,2H),2.20(s,3H),2.60(br t,J=5.4Hz,2H),2.83-3.01(m,2H),3.88(t,J=5.6Hz,2H),4.37-4.52(m,3H),4.76-5.09(m,1H),5.90(d,J=7.8Hz,1H);ESI-MS m / z [M+H] + 301.0.

[0476] Preparation 56: 4-chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-amine (Alternative Synthesis)

[0477] [ka]

[0478] Preparation 57: 1-chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-amine (Alternative Synthesis)

[0479] [ka]

[0480] To a solution of 1,4-dichloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazine (9 g, 43.89 mmol), (3R,5R)-5-fluoro-1-methylpiperidin-3-amine (10.80 g, 52.67 mmol, 2HCl) in toluene (270 mL) was added BINAP (8.20 g, 13.17 mmol), Pd(OAc) (1.97 g, 8.78 mmol), and CsCO (71.51 g, 219.47 mmol). The mixture was stirred at 120 °C for 12 h under N. LC-MS showed that the starting material had been consumed and the desired mass had been obtained. The reaction mixture was evaporated to dryness, and the resulting residue was purified by flash chromatography (ISCO® SepaFlash® 220 g silica gel column) using a gradient of 0 to 6% DCM in MeOH (100 mL / min) to give the mixture of desired compounds as a yellow solid (7 g, 93% purity). The products were separated by SFC (DAICEL CHIRALPAK® AD-10 μm, 50 mm × 250 mm column) using a mobile phase of CO2 and 30% IPA (containing 0.1% NH3HO). The title compound of Preparation 56 was obtained as a yellow solid (2.8 g, 21% yield, 99% purity). 1 H NMR(400MHz,DMSO-d6)δppm1.62-1.82(m,1H),1.91(br t,J=10.01Hz,1H),2.03-2.24(m,5H),2.40-2.47(m,2H),2.79-2.98(m,2H),3.90( t,J=5.57Hz,2H),4.36-4.55(m,3H),4.78-5.07(m,1H),6.00-6.14(m,1H);ESI-MS m / z [M+H] + 301.1. The title compound of Preparation 57 was obtained as a yellow solid (3.2 g, 24% yield, 97% purity). 1H NMR(400MHz,DMSO-d6)δppm1.57-1.75(m,1H),1.81-1.92(m,1H),2.04-2.21(m,5H),2.59(br t,J=5.44Hz,2H),2.81-2.97(m,2H),3.82-3.91(m,2H),4.37-4.50(m,3H),4.83-5.02(m,1H),5.89(d,J=7.88Hz,1H);ESI-MS m / z [M+H] + 301.1.

[0481] Example 1: 3-((4-(4-methoxyphenyl)phthalazin-1-yl)amino)phenol

[0482] [ka]

[0483] To a solution of 3-((4-chlorophthalazin-1-yl)amino)phenol (100 mg, 368.05 μmol) and (4-methoxyphenyl)boronic acid (67.11 mg, 441.66 μmol) in toluene (0.5 mL), EtOH (0.1 mL), and HO (0.1 mL) was added Pd(PPh) (127.59 mg, 110.42 μmol) and NaCO (117.03 mg, 1.10 mmol) at 25 °C. The reaction mixture was stirred at 100 °C under a N atmosphere for 1 h, then concentrated under reduced pressure and purified by preparative HPLC (Method B). The title compound was obtained as a yellow solid (28.3 mg, 21.5% yield, 96% purity). 1 H NMR(400MHz,CD3Cl)δppm3.88(s,3H),6.43(br d,J=8.1Hz,1H),6.76(d,J=8.6Hz,1H),7.03(d,J=8.6Hz,2H),7.09(t,J=8.1Hz,1H),7.57 (d,J=8.7Hz,3H),7.74-7.86(m,2H),7.92(d,J=7.5Hz,1H),8.22(d,J=7.7Hz,1H);ESI-MS m / z [M+H] + 344.1.

[0484] Example 2: 4-(6-(difluoromethyl)pyridin-3-yl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine

[0485] [ka]

[0486] A mixture of 4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine (20 mg, 0.072 mmol), 2-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (28 mg, 0.11 mmol), aqueous KCO (3 M, 20 mg, 0.14 mmol), and AmPhos PdCl (5 mg, 7 μmol) in ACN (0.8 mL) was heated at 80 °C for 18 h, then filtered and purified by preparative HPLC (Method C). The title compound was obtained as a solid (15 mg, 52%). 1 H NMR(400MHz,CD3OD)δppm1.64-1.85(m,2H),1.87-1.96(m,1H),2.04-2.13(m,1H),2.29-2.44(m,5H),2.69-2.80(m,1H),3.11-3.22(m,1) H),4.58-4.68(m,1H),6.71-7.02(m,1H),7.83-7.89(m,1H),7.89-8.01(m,3H),8.26-8.32(m,1H),8.37-8.44(m,1H),8.89-8.97(m,1H). ESI-MS m / z [M+H] + 370.2.

[0487] Example 3: 3-((4-(4-(1-methylcyclopropyl)phenyl)phthalazin-1-yl)amino)phenol

[0488] [ka]

[0489] The title compound was prepared as in Example 2 using 3-((4-chlorophthalazin-1-yl)amino)phenol and 4,4,5,5-tetramethyl-2-(4-(1-methylcyclopropyl)phenyl)-1,3,2-dioxaborolane as an orange solid (2.9 mg, 13.4%). ESI-MS m / z [M+H] + 368.2.

[0490] Example 4: 3-((4-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)phthalazin-1-yl)amino)phenol

[0491] [ka]

[0492] The title compound was prepared in the same manner as in Example 2 using 3-((4-chlorophthalazin-1-yl)amino)phenol and 4,4,5,5-tetramethyl-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)-1,3,2-dioxaborolane and obtained as a yellow solid (6 mg, 24.2%). 1 H NMR(400MHz,CD3OD)δppm1.16-1.28(m,2H),1.43-1.54(m,2H),6.93-7.02(m,1H),7.06-7.11 (m,2H),7.44(t,J=7.67Hz,1H),7.70-7.79(m,4H),8.12-8.26(m,3H),8.79(d,J=7.28Hz,1H). ESI-MS m / z [M+H] + 422.2.

[0493] Example 5: 3-((4-(4-(tert-butyl)phenyl)phthalazin-1-yl)amino)phenol

[0494] [ka]

[0495] The title compound was prepared similarly to Example 2 using 3-((4-chlorophthalazin-1-yl)amino)phenol and 2-(4-tert-butylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and obtained as an orange solid (1.7 mg, 7.8%). 1 H NMR(400MHz,CD3OD)δppm1.44(s,9H),6.93(d,J=7.57Hz,1H),7.08-7.13(m,2H),7. 42(t,J=7.49Hz,1H),7.64-7.74(m,4H),8.17-8.28(m,3H),8.78(d,J=7.61Hz,1H). ESI-MS m / z [M+H] + 370.2.

[0496] Example 6: 3-((4-(3-cyclobutylphenyl)phthalazin-1-yl)amino)phenol

[0497] [ka]

[0498] The title compound was prepared similarly to Example 2 using 3-((4-chlorophthalazin-1-yl)amino)phenol and 2-(3-cyclobutylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and obtained as a pale yellow solid (2.5 mg, 11.5%). ESI-MS m / z [M+H] + 368.2.

[0499] Example 7: 3-((4-(4-isopropylphenyl)phthalazin-1-yl)amino)phenol

[0500] [ka]

[0501] The title compound was prepared in the same manner as in Example 2 using 3-((4-chlorophthalazin-1-yl)amino)phenol and 2-(4-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and obtained as a pale yellow solid (2.1 mg, 10.0%). ESI-MS m / z [M+H] + 356.2.

[0502] Example 8: 3-((4-(4-cyclopropyl-2-fluorophenyl)phthalazin-1-yl)amino)phenol

[0503] [ka]

[0504] The title compound was prepared similarly to Example 2 using 3-((4-chlorophthalazin-1-yl)amino)phenol and 2-(4-cyclopropyl-2-fluoro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to give an orange solid (1.0 mg, 4.6%). ESI-MS m / z [M+H] + 372.15.

[0505] Example 9: 3-((4-(6-(tert-butyl)pyridin-3-yl)phthalazin-1-yl)amino)phenol

[0506] [ka]

[0507] The title compound was prepared similarly to Example 2 using 3-((4-chlorophthalazin-1-yl)amino)phenol and 2-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to give a yellow solid (3.0 mg, 13.8%). ESI-MS m / z [M+H] + 371.2.

[0508] Example 10: 3-((4-(3-cyclopropylphenyl)phthalazin-1-yl)amino)phenol

[0509] [ka]

[0510] The title compound was prepared as in Example 2 using 3-((4-chlorophthalazin-1-yl)amino)phenol and 2-(3-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as an orange solid (2.1 mg, 10.1%). ESI-MS m / z [M+H] + 354.2.

[0511] Example 11: 4-(4-fluorophenyl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine

[0512] [ka]

[0513] The title compound was prepared similarly to Example 2 using 4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine and 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and obtained as a yellow solid (25.7 mg, 98%). ESI-MS m / z [M+H] + 337.2.

[0514] Example 12: N-(1-methylpiperidin-3-yl)-4-(o-tolyl)phthalazin-1-amine

[0515] [ka]

[0516] The title compound was prepared in the same manner as in Example 2 using 4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine and o-tolylboronic acid, and obtained as an orange solid (8.7 mg, 38.9%). ESI-MS m / z [M+H] + 333.2.

[0517] Example 13: N-(1-methylpiperidin-3-yl)-4-(4-(trifluoromethyl)phenyl)phthalazin-1-amine

[0518] [ka]

[0519] The title compound was prepared similarly to Example 2 using 4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine and (4-(trifluoromethyl)phenyl)boronic acid and obtained as a yellow solid (25.6 mg, 98.4%). 1 H NMR(400MHz,CD3OD)δppm1.84-2.13(m,2H),2.16-2.43(m,2H),2.92-3.05(m,3H),3.05-3.21(m,2H),3.64(br d,J=10.54Hz,1H),3.86-4.02(m,1H),4.57-4.75(m,1H),7.95-8.00(m,2H),8.00-8.0 5(m,2H),8.08-8.13(m,1H),8.19(td,J=7.72,1.13Hz,1H),8.23-8.30(m,1H),8.71(br d,J=7.53Hz,1H);ESI-MS m / z [M+H] + 387.2.

[0520] Example 14: 4-(2-chlorophenyl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine

[0521] [ka]

[0522] The title compound was prepared in the same manner as in Example 2 using 4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine and (2-chlorophenyl)boronic acid, and obtained as a pale yellow solid (4.5 mg, 19%). ESI-MS m / z [M+H] + 353.15.

[0523] Example 15: N-(1-methylpiperidin-3-yl)-4-(p-tolyl)phthalazin-1-amine

[0524] [ka]

[0525] The title compound was prepared similarly to Example 2 using 4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine and p-tolylboronic acid and obtained as a yellow solid (19 mg, 85%). 1 H NMR(400MHz,CD3OD)δppm1.82-2.10(m,2H),2.15-2.42(m,2H),2.55(s,3H),2.91-3.13(m,2H),3.00(s,3H),3.56-3.6 8(m,1H),3.90-4.05(m,1H),4.58-4.72(m,1H),7.56-7.60(m,2H),7.67(d,J=8.16Hz,2H),8.16-8.24(m,2H),8.31(br t,J=7.22Hz,1H),8.65(brd,J=8.03Hz,1H);ESI-MS m / z [M+H] + 333.2.

[0526] Example 16: 4-(4-cyclopropylphenyl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine

[0527] [ka]

[0528] The title compound was prepared similarly to Example 2 using 4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine and (4-cyclopropylphenyl)boronic acid and obtained as an orange solid (24.5 mg, 100%). 1 H NMR(400MHz,CD3OD)δppm0.85-0.92(m,2H),1.10-1.20(m,2H),1.88(td,J=12.30,2.38Hz, 1H),1.95-2.08(m,1H),2.08-2.16(m,1H),2.17-2.26(m,1H),2.32-2.40(m,1H),2.87-3.1 4(m,2H),3.00(s,3H),3.62(brd,J=11.17Hz,1H),3.91-4.04(m,1H),4.58-4.75(m,1H),7. 44(m,J=8.28Hz,2H),7.66(m,J=8.16Hz,2H),8.16-8.26(m,2H),8.26-8.37(m,1H),8.65(br d,J=8.16Hz,1H);ESI-MS m / z [M+H] + 359.2.

[0529] Example 17: 4-(3-chlorophenyl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine

[0530] [ka]

[0531] The title compound was prepared in the same manner as in Example 2 using 4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine and (3-chlorophenyl)boronic acid, and obtained as a pale yellow solid (1.0 mg, 4.2%). ESI-MS m / z [M+H] + 353.2.

[0532] Example 18: N-(1-methylpiperidin-3-yl)-4-(m-tolyl)phthalazin-1-amine

[0533] [ka]

[0534] The title compound was prepared in the same manner as in Example 2 using 4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine and m-tolylboronic acid, and obtained as a white solid (8.0 mg, 36%). ESI-MS m / z [M+H] + 333.2.

[0535] Example 19: 3-((4-(4-cyclopropylphenyl)phthalazin-1-yl)amino)phenol

[0536] [ka]

[0537] The title compound was prepared similarly to Example 2 using 3-((4-chlorophthalazin-1-yl)amino)phenol and (4-cyclopropylphenyl)boronic acid and obtained as an orange solid (3.4 mg, 9.7%). 1 H NMR(400MHz,CD3OD)δppm0.78-0.86(m,2H),1.07-1.13(m,2H),2.02-2.09(m,1H),6.90(d,J=7.53Hz,1H),7.09(d,J=7 ESI-MS m / z [M+H] + 354.2.

[0538] Example 20: 4-(6-(tert-butyl)pyridin-3-yl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine

[0539] [ka]

[0540] The title compound was prepared similarly to Example 2 using 4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine and 2-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and obtained as a solid (28 mg, 100%). 1 H NMR(400MHz,CD3OD)δppm1.36-1.40(m,9H),1.55-1.75(m,2H),1.76-1.85(m, 1H),1.93-2.03(m,1H),2.14-2.28(m,2H),2.15-2.29(m,5H),2.57-2.67(m,1 H),2.97-3.09(m,1H),4.48-4.57(m,1H),7.58-7.62(m,1H),7.74-7.82(m,2H ),7.81-7.89(m,1H),7.92-7.97(m,1H),8.26-8.31(m,1H),8.63-8.68(m,1H).

[0541] Example 21: 4-(4-(difluoromethyl)phenyl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine

[0542] [ka]

[0543] The title compound was prepared similarly to Example 2 using 4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine and 2-(4-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. ESI-MS m / z [M+H] + 369.2.

[0544] Example 22: N-(1-methylpiperidin-3-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)phthalazin-1-amine

[0545] [ka]

[0546] The title compound was prepared similarly to Example 2 using 4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine and 2-tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. ESI-MS m / z [M+H] + 388.1.

[0547] Example 23: (R)-4-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol

[0548] [ka]

[0549] The title compound was prepared similarly to Example 2 using (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (25 mg, 0.090 mmol) and (4-hydroxyphenyl)boronic acid (19 mg, 0.14 mmol) and obtained as a solid (3.6 mg, 11%). 1 H NMR(400MHz,CD3OD)δppm1.62-1.81(m,2H),1.82-1.92(m,1H),2.03-2.12(m,1H),2.25-2.36(m,5H),2.64-2.76(m,1H),3.06-3.1 7(m,1H),4.56-4.65(m,1H),6.95-7.00(m,2H),7.45-7.51(m,2H),7.77-7.80(m,1H),8.85-8.89(m,1H),9.66-9.71(m,1H);ESI-MS m / z [M+H] + 336.1.

[0550] Example 24: (R)-5-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-2-(trifluoromethoxy)benzonitrile

[0551] [ka]

[0552] The title compound was prepared similarly to Example 2 using (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (25 mg, 0.090 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)benzonitrile (42 mg, 0.14 mmol) and obtained as a solid (10 mg, 25%). 1 H NMR(400MHz,CD3OD),δppm1.61-1.81(m,2H),1.83-1.93(m,1H),2.02-2.12(m,1 H),2.26-2.39(m,5H),2.63-2.76(m,1H),3.04-3.17(m,1H),4.59-4.68(m,1H), 7.71-7.74(m,1H),7.75-7.80(m,1H),8.07-8.14(m,1H),8.18-8.24(m,1H),8.1 8-8.23(m,1H),8.18-8.24(m,1H),8.89-8.95(m,1H),9.70-9.78(m,1H);ESI-MS m / z [M+H] + 429.2.

[0553] Example 25: (R)-1-(3-fluoro-4-methoxyphenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0554] [ka]

[0555] The title compound was prepared similarly to Example 2 using (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and (3-fluoro-4-methoxyphenyl)boronic acid. ESI-MS m / z [M+H] + 368.1.

[0556] Example 26: (R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0557] [ka]

[0558] The title compound was prepared similarly to Example 2 using (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid. ESI-MS m / z [M+H] + 378.1.

[0559] Example 27: (R)-1-(4-(difluoromethoxy)phenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0560] [ka]

[0561] The title compound was prepared similarly to Example 2 using (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and (4-(difluoromethoxy)phenyl)boronic acid. ESI-MS m / z [M+H] + 386.1.

[0562] Example 28: (R)-2-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol

[0563] [ka]

[0564] The title compound was prepared in the same manner as in Example 2, using (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and (2-hydroxyphenyl)boronic acid as the reaction substrates. ESI-MS m / z [M+H] + 336.1.

[0565] Example 29: (R)-2-fluoro-4-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol

[0566] [ka]

[0567] The title compound was prepared similarly to Example 2 using (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and (3-fluoro-4-hydroxyphenyl)boronic acid. ESI-MS m / z [M+H] + 354.2.

[0568] Example 30: (R)—N-(1-methylpiperidin-3-yl)-1-(p-tolyl)pyrido[3,4-d]pyridazin-4-amine

[0569] [ka]

[0570] The title compound was prepared similarly to Example 2 using (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and p-tolylboronic acid. ESI-MS m / z [M+H] + 334.2.

[0571] Example 31: (R)-1-(4-chloro-2-methylphenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0572] [ka]

[0573] The title compound was prepared similarly to Example 2 using (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and (4-chloro-2-methyl-phenyl)boronic acid. 1 H NMR(400MHz,CD3OD)δppm1.77-2.07(m,2H),2.11-2.15(m,3H),2.16-2.25(m,1H),2.30-2.41(m,1H),2.85-3.11(m,5H),3.53-3.66(m,1H), 3.93-4.11(m,1H),4.63-4.74(m,1H),7.33-7.38(m,1H),7.39-7.46(m ,2H),7.48-7.54(m,1H),8.94-9.03(m,1H),9.75-9.99(m,1H);ESI-MS m / z [M+H] + 368.1.

[0574] Example 32: (R)—N-(1-methylpiperidin-3-yl)-1-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyridazin-4-amine

[0575] [ka]

[0576] The title compound was prepared similarly to Example 2 using (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and (4-(trifluoromethoxy)phenyl)boronic acid. 1H NMR(400MHz,CD3OD)δppm1.77-2.09(m,2H),2.14-2.39(m,2H),2.86-3.09(m,5H),3.52-3.65(m,1H),3.93-4.0 8(m,1H),4.63-4.76(m,1H),7.49-7.58(m,2H),7.75-7.86(m,3H),8.98-9.05(m,1H),9.74-9.91(m,1H);ESI-MS m / z [M+H] + 404.1.

[0577] Example 33: (R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0578] [ka]

[0579] The title compound was prepared similarly to Example 2 using (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and (2-fluoro-4-(trifluoromethyl)phenyl)boronic acid. 1 H NMR(400MHz,CD3OD)δppm1.79-2.08(m,2H),2.16-2.38(m,2H),2.86-3.08(m,5H),3.55-3.64(m,1H),3.98-4.10(m,1H), 4.69-4.79(m,1H),7.47-7.57(m,1H),7.73-7.80(m,2H),7.80-7.86(m,1H),8.91-8.99(m,1H),9.71-9.85(m,1H);ESI-MS m / z [M+H] + 406.1.

[0580] Example 34: (R)—N-(1-methylpiperidin-3-yl)-1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-amine

[0581] [ka]

[0582] The title compound was prepared similarly to Example 2 using (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and (4-(trifluoromethyl)phenyl)boronic acid. ESI-MS m / z [M+H] + 388.1.

[0583] Example 35: (R)-1-(4-methoxyphenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0584] [ka]

[0585] The title compound was prepared similarly to Example 2 using (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and (4-methoxyphenyl)boronic acid. ESI-MS m / z [M+H] + 350.2.

[0586] Example 36: (R)-5-Methoxy-2-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol

[0587] [ka]

[0588] The title compound was prepared similarly to Example 2 using (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and (2-hydroxy-4-methoxyphenyl)boronic acid. ESI-MS m / z [M+H] + 366.1.

[0589] Example 37: (R)-1-(4-(difluoromethyl)phenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0590] [ka]

[0591] The title compound was prepared similarly to Example 2 using (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and (4-(difluoromethyl)phenyl)boronic acid. ESI-MS m / z [M+H] + 370.1.

[0592] Example 38: 3-((4-(p-tolyl)phthalazin-1-yl)amino)phenol

[0593] [ka]

[0594] To a solution of 3-((4-chlorophthalazin-1-yl)amino)phenol (400 mg, 1.47 mmol) and p-tolylboronic acid (300.23 mg, 2.21 mmol) in toluene (0.5 mL), EtOH (0.1 mL), and HO (0.1 mL) at 25 °C, Pd(PPh) (510.37 mg, 441.66 μmol) and NaCO (468.11 mg, 4.42 mmol) were added. The reaction mixture was stirred at 90 °C for 1 h under a N atmosphere and then concentrated under reduced pressure. The resulting residue was diluted with saturated aqueous NaHCO (30 mL), extracted with DCM (40 mL), and filtered through a Celite® pad. The filtrate was concentrated under reduced pressure and purified by preparative HPLC (Method B) to give the formate salt of the title compound as a yellow solid (151.1 mg, 42.82% yield, 96.98% purity). 1H NMR(400MHz,DMSO-d6)δppm2.43(s,3H),6.46(br d,J=8.03Hz,1H),7.13(t,J=8.16Hz,1H),7.26-7.42(m,3H),7.51-7.66(m,3H),7 .85-8.04(m,3H),8.14(s,1H),8.65(d,J=8.28Hz,1H),8.94-9.64(m,2H);ESI-MS m / z [M+H] + 328.1.

[0595] Example 39: 2-((4-(4-methoxyphenyl)phthalazin-1-yl)amino)phenol

[0596] [ka]

[0597] The title compound was prepared similarly to Example 38 using 2-((4-chlorophthalazin-1-yl)amino)phenol (300 mg, 883.32 μmol, 80% purity) and (4-methoxyphenyl)boronic acid (201.34 mg, 1.32 mmol) and obtained as a yellow solid (17.5 mg, 14.6%). 1 H NMR(400MHz,CD3Cl)δppm3.91(s,3H),6.87-6.96(m,1H),7.07(d,J=8.6Hz,2H),7.15(d,J=3.7Hz ,2H),7.19(d,J=7.7Hz,1H),7.61(d,J=8.6Hz,2H),7.82-7.88(m,1H),7.89-7.95(m,1H),8.02(br d,J=7.5Hz,1H),8.17(br s,1H). ESI-MS m / z [M+H] + 344.2.

[0598] Example 40: 3-((1-(4-methoxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)phenol

[0599] [ka]

[0600] Example 41: 3-((4-(4-methoxyphenyl)pyrido[3,4-d]pyridazin-1-yl)amino)phenol

[0601] [ka]

[0602] The title compound was prepared in a similar manner to Example 38 using a mixture of 3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)phenol and 3-((4-chloropyrido[3,4-d]pyridazin-1-yl)amino)phenol (53.3 mg, 195.46 μmol) and (4-methoxyphenyl)boronic acid (29.70 mg, 195.46 μmol). The title compound of Example 40 was obtained as a yellow solid (18 mg, 27%). 1 H NMR (400 MHz, DMSO-d) δ ppm 3.80 (s, 3H), 6.40-6.47 (m, 1H), 7.05-7.13 (m, 3H), 7.23-7.29 (m, 1H), 7.53 (t, J = 2.13 Hz, 1H), 7.58-7.62 (m, 2H), 7.69 (dd, J = 5.69, 0.69 Hz, 1H), 8.93 (d, J = 5.63 Hz, 1H), 9.36 (s, 1H), 9.42-9.48 (m, 1H), 9.91-9.96 (m, 1H); ESI-MS m / z [M+H]+ 345.1. The title compound of Example 41 was obtained as a yellow solid (18 mg, 27%). 1 H NMR (400 MHz, DMSO-d 6 )δppm3.88(s,3H),6.46-6.52(m,1H),7.12-7.20(m,4H),7.32-7.36(m,1H),7.61-7.65(m,2H),7.69-7 .75(m,2H),8.52-8.57(m,1H),9.06-9.12(m,1H),9.28(s,1H),9.32(s,1H),9.40-9.45(m,1H);ESI-MS m / z [M+H] + 345.1.

[0603] Example 42: N-(1-methylpiperidin-3-yl)-4-phenylphthalazin-1-amine

[0604] [ka]

[0605] A mixture of 4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine (25 mg, 0.0903 mmol), 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (18 mg, 0.0903 mmol), and Pd(dppf)Cl (6.4 mg, 0.00903 mmol) in 1,4-dioxane (0.4 mL) and 3 M KCO (0.15 mL, 0.452 mmol) was stirred at 60 °C for 22 h using a heating block to give a yellow-orange solution. The reaction mixture was concentrated by rotary evaporation, dissolved in DMF (1 mL), filtered through a 0.45 μm nylon membrane filter (VWR), rinsed with DMF (0.5 mL), and purified by preparative HPLC (Method B). Pure fractions were combined and concentrated by rotary evaporation at 45 °C. The resulting mixture was dried in vacuo to give the title compound as a white solid (16 mg, 56%). 1 H NMR(400MHz,DMSO-d6)δppm1.47(qd,J=11.71,3.76Hz,1H),1.54-1.69(m,1H),1.86-2.05(m,3H),2.23(s,3H),2.68-2.79(m,1H),3.10(br d,J=8.28Hz,1H),4.38-4.50(m,1H),7.10(br d,J=7.53Hz,1H),7.47-7.58(m,3H),7.58-7.63(m,2H),7.75-7.80(m,1H),7. 84(td,J=7.53,1.25Hz,1H),7.87-7.94(m,1H),8.43(d,J=8.03Hz,1H);ESI-MS m / z [M+H] + 319.1.

[0606] Example 43: 4-(4-chloro-2-fluorophenyl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine

[0607] [ka]

[0608] A mixture of 4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine (100 mg, 309.80 μmol, formate), (4-chloro-2-fluorophenyl)boronic acid (81.03 mg, 464.70 μmol), Pd(dppf)Cl.CHCl (50.60 mg, 61.96 μmol), and CsCO (302.82 mg, 929.40 μmol) in dioxane (5 mL) and HO (1 mL) was stirred at 100° C. for 15 h under N. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (Method B). The title compound was obtained as a brown solid (49.1 mg, 37.3%). 1 H NMR(400MHz,DMSO-d6)δppm1.43-1.70(m,2H),1.74-1.84(m,1H),1.94-2.12(m,3H),2.29(s,3H),2.79(br d,J=11.1Hz,1H),4.46(br s,1H),7.31(br d,J=6.4Hz,1H),7.44-7.52(m,2H),7.55-7.68(m,2H),7.79-7.95(m,2H),8.20(s,1H),8.45(d,J=8.1Hz,1H). ESI-MS m / z [M+H] + 371.

[0609] Example 44: 4-(4-chloro-3-fluorophenyl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine

[0610] [ka]

[0611] The title compound was prepared in the same manner as in Example 43 using 4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine (100 mg, 309.80 μmol, formate salt) and (4-chloro-3-fluorophenyl)boronic acid (64.82 mg, 371.76 μmol) and obtained as a yellow solid (10.6 mg, 9.13% yield, 99% purity). 1 H NMR(400MHz,DMSO-d6)δppm1.37-1.50(m,1H),1.52-1.66(m,1H),1.69-1.78(m,1H),1.88-2.01(m,3H),2.21(s,3H),2.72(br d,J=11.5Hz,1H),3.07(br d,J=8.6Hz,1H),4.41(br s,1H),7.21(br d,J=7.3Hz,1H),7.46(d,J=8.4Hz,1H),7.65(dd,J=10.1,1.8Hz,1H),7.70-7.80(m,2H) ),7.83(t,J=7.5Hz,1H),7.86-7.94(m,1H),8.17(s,1H),8.42(d,J=8.2Hz,1H);ESI-MS m / z [M+H] + 371.3.

[0612] Example 45: 4-(4-methoxyphenyl)-N-methyl-N-(1-methylpiperidin-3-yl)phthalazin-1-amine

[0613] [ka]

[0614] The title compound was prepared in the same manner as in Example 43 using 4-chloro-N-methyl-N-(1-methylpiperidin-3-yl)phthalazin-1-amine (14.7 mg, 0.051 mmol) and (4-methoxyphenyl)boronic acid (11.5 mg, 0.076 mmol) and obtained as a pale yellow film (1.4 mg, 6.9% yield, approximately 90% purity). 1H NMR(400MHz,CD3OD)δppm1.57-1.71(m,1H),1.76-1.94(m,2H),1.98-2.09(m,2H),2.35(s,3H),2.45(t,J=10.9Hz,1H),2.85(br d,J=10.8Hz,1H),3.11-3.23(m,4H),3.92(s,3H),3.97-4.09(m,1H),7.11-7.21(m,2H) ,7.58-7.68(m,2H),7.85-7.93(m,1H),7.94-8.05(m,2H),8.21(d,J=8.2Hz,1H);ESI-MS m / z [M+H] + 363.20.

[0615] Example 46: 4-(4-chloro-2-methylphenyl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine

[0616] [ka]

[0617] A mixture of 4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine (0.083 g, 0.3 mmol), (4-chloro-2-methylphenyl)boronic acid (0.051 g, 0.300 mmol), Pd(PPh3)4 (0.035 g, 0.030 mmol), and K2CO3 (0.124 g, 0.900 mmol) in toluene (1.042 mL) and water (0.208 mL) was degassed and purged with N2 (3x). The mixture was stirred at 90 °C for 1 h under a N2 atmosphere and then concentrated under reduced pressure. DMF (2 mL) was added. The mixture was filtered, and the filtrate was purified by preparative HPLC. The title compound was obtained as an off-white solid (3.8 mg, 3.5%). 1H NMR(400MHz,CD3OD)δppm0.64-0.71(m,1H),0.91-0.99(m,1H),1.15-1.21(m,1H),1.53-1.58 (m,1H),1.70-1.79(m,1H),1.83-1.89(m,1H),2.04-2.06(m,3H),2.32-2.36(m,3H),2.60-2.7 6(m,1H),3.05-3.20(m,1H),4.53-4.61(m,1H),7.13-7.21(m,1H),7.25-7.29(m,1H),7.33-7 .35(m,1H),7.41-7.44(m,1H),7.78-7.81(m,1H),7.88(s,1H),8.32(d,J=8.28Hz,1H);ESI-MS m / z [M+H] + 367.4.

[0618] Example 47: 1-(4-chloro-2-methoxyphenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0619] [ka]

[0620] Example 48: 4-(4-chloro-2-methoxyphenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0621] [ka]

[0622] The title compound was prepared in the same manner as in Example 46 using a mixture of 1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (0.056 g, 0.2 mmol), and (4-chloro-2-methoxyphenyl)boronic acid (0.037 g, 0.200 mmol). The title compound of Example 47 was obtained as an off-white solid (11.8 mg, 15.4%). 1 H NMR(400MHz,CD3OD)δppm1.74-1.90(m,1H),1.91-2.01(m,1H),2.09-2.21(m,1H),2.25-2 .36(m,1H),2.79-2.97(m,4H),2.98-3.06(m,1H),3.50-3.61(m,1H),3.73(s,3H),3.84-4 .03(m,1H),4.54-4.66(m,1H),7.20(dd,J=8.09,1.82Hz,1H),7.30(d,J=1.76Hz,1H),7.4 2(d,J=8.16Hz,1H),7.56(d,J=5.52Hz,1H),9.02(d,J=5.52Hz,1H),9.84(brs,1H);ESI-MS m / z [M+H] + 384.2. The title compound of Example 48 was obtained as an off-white solid (3.9 mg, 5.1%). 1 H NMR(400MHz,CD3OD)δppm1.76-2.05(m,2H),2.12-2.22(m,1H),2.26-2.35(m,1H),2 .82-2.91(m,1H),2.91-2.96(m,3H),2.97-3.06(m,1H),3.53-3.62(m,1H),3.75-3.8 1(m,3H),3.88-4.03(m,1H),4.57-4.69(m,1H),7.23-7.29(m,1H),7.34-7.38(m,1H) ,7.46-7.54(m,1H),8.29-8.54(m,1H),9.02-9.08(m,1H),9.09-9.15(m,1H);ESI-MS m / z [M+H] + 384.2.

[0623] Example 49: 1-(4-chloro-2-methylphenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0624] [ka]

[0625] Example 50: 4-(4-chloro-2-methylphenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0626] [ka]

[0627] The title compound was prepared in the same manner as in Example 46 using a mixture of 1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine (0.056 g, 0.2 mmol), and (4-chloro-2-methoxyphenyl)boronic acid (0.034 g, 0.200 mmol). The title compound of Example 49 was obtained as an off-white solid (11.5 mg, 15.6%). 1 H NMR(400MHz,CD3OD)δppm1.76-1.93(m,1H),1.93-2.03(m,1H),2.10-2.13(m,3H),2.13-2.23(m,1H),2.26-2.39(m,1H),2.80-3.08(m,5H),3.5 0-3.63(m,1H),3.86-4.05(m,1H),4.58-4.72(m,1H),7.31-7.37(m,1H) ,7.40-7.47(m,2H),7.48-7.52(m,1H),9.02(d,J=5.52Hz,1H),9.85(br s,1H);ESI-MS m / z [M+H] + 368.2. The title compound of Example 50 was obtained as an off-white solid (2.7 mg, 3.7%). 1H NMR(400MHz,CD3OD)δppm1.78-2.05(m,2H),2.13-2.16(m,3H),2.16-2.23(m,1H),2 .27-2.36(m,1H),2.83-2.91(m,1H),2.92-2.97(m,3H),2.97-3.07(m,1H),3.54-3.6 2(m,1H),3.93-4.04(m,1H),4.59-4.71(m,1H),7.39-7.43(m,1H),7.44-7.49(m,1H) ,7.52-7.57(m,1H),8.28-8.54(m,1H),8.88-8.95(m,1H),9.08-9.14(m,1H);ESI-MS m / z [M+H] + 368.2.

[0628] Example 51: 1-(2,4-dichlorophenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0629] [ka]

[0630] Example 52: 4-(2,4-dichlorophenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0631] [ka]

[0632] The title compound was prepared in the same manner as in Example 46 using a mixture of 1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine (0.056 g, 0.2 mmol) and (2,4-dichlorophenyl)boronic acid (0.038 g, 0.200 mmol). The title compound of Example 51 was obtained as an off-white solid (1.7 mg, 2.2%). 1H NMR(400MHz,CD3OD)δppm1.79-2.02(m,2H),2.14-2.23(m,1H),2.28-2.36(m,1 H),2.86-2.92(m,1H),2.92-2.98(m,3H),2.98-3.07(m,1H),3.53-3.63(m,1H), 3.96-4.05(m,1H),4.67-4.76(m,1H),7.35-7.41(m,1H),7.50-7.55(m,1H),7.5 6-7.62(m,1H),7.73-7.77(m,1H),8.90-8.94(m,1H),9.69-9.85(m,1H);ESI-MS m / z [M+H] + 388.2. The title compound of Example 52 was obtained as an off-white solid (1 mg, 1%). 1 H NMR(400MHz,CD3OD)δppm1.84-2.03(m,2H),2.15-2.22(m,1H),2.27-2.34 (m,1H),2.83-2.89(m,1H),2.91-2.98(m,3H),2.98-3.06(m,1H),3.56-3.6 0(m,1H),3.99-4.05(m,1H),4.64-4.72(m,1H),7.55-7.64(m,2H),7.75-7. 79(m,1H),8.19-8.25(m,1H),8.83-8.88(m,1H),8.98-9.04(m,1H);ESI-MS m / z [M+H] + 388.2.

[0633] Example 53: (R)-4-(2-fluoro-4-methoxyphenyl)-N-(1-methylpiperidin-3-yl)phthalazin-1-amine

[0634] [ka]

[0635] To a solution of (R)-4-chloro-N-(1-methylpiperidin-3-yl)phthalazin-1-amine (100 mg, 361 μmol), (2-fluoro-4-methoxyphenyl)boronic acid (79.83 mg, 469.71 μmol), and CsCO (235.45 mg, 722.64 μmol) in dioxane (2 mL) and HO (0.4 mL) was added Pd(dppf)Cl (13.22 mg, 18.07 μmol, 0.05 eq). The mixture was stirred at 100 °C for 12 h under N. LC-MS showed one main peak with the desired m / z. The mixture was filtered, and the filtrate was purified by preparative HPLC (Method B). The title compound was obtained as a yellow solid (52 mg, 34% yield, 96% purity). 1 H NMR(400MHz,DMSO-d6)δppm1.41-1.69(m,2H),1.73-1.83(m,1H),1.94-2.08(m,3H),2.27(s,3H),2.77(br d,J=11.1Hz,1H),3.13(br d,J=7.8Hz,1H),3.87(s,3H),4.44(br s,1H),6.93-7.06(m,2H),7.18(br d,J=6.1Hz,1H),7.40-7.52(m,2H),7.78-7.93(m,2H),8.19(s,1H),8.42(d,J=8.1Hz,1H);ESI-MS m / z [M+H] + 367.

[0636] Example 54: 4-(4-chlorophenyl)-N-((3R,5R)-1-cyclopropyl-5-fluoropiperidin-3-yl)phthalazin-1-amine

[0637] [ka]

[0638] Nitrogen was bubbled through a solution of 4-chloro-N-((3R,5R)-1-cyclopropyl-5-fluoropiperidin-3-yl)phthalazin-1-amine (39.7 mg, 0.124 mmol) and 2-(4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (36.9 mg, 0.155 mmol) in dioxane (1.24 mL) in a 40 mL vial equipped with a stir bar for 5 min. To the mixture was added aqueous KCO (2 M, 186 μL, 0.371 mmol), followed by PdCl(dppf) (9.06 mg, 0.012 mmol). The reaction mixture was stirred overnight at 90 °C under a nitrogen atmosphere using a heating block, then diluted with water and extracted with EtOAc (3x). The organic layers were combined, washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was taken up in DMF (1 mL) and MeOH (1 mL) and filtered through a hydrophilic PTFE 0.45 μm syringe filter (VWR®). The filtrate was purified by preparative HPLC (Method A). The product-containing fractions were evaporated and dried in vacuo to give the TFA salt of the title compound as a yellow film (7.0 mg, 11%). ESI-MS m / z [M+H] + 397.2.

[0639] Example 55: N-((3R,5R)-1-cyclopropyl-5-fluoropiperidin-3-yl)-4-(4-methoxyphenyl)phthalazin-1-amine

[0640] [ka]

[0641] The title compound was prepared in the same manner as in Example 54 using 4-chloro-N-((3R,5R)-1-cyclopropyl-5-fluoropiperidin-3-yl)phthalazin-1-amine (81 mg, 0.252 mmol) and (4-methoxyphenyl)boronic acid (48.0 mg, 0.316 mmol) and obtained as a white solid (2.8 mg, 2.8%). 1H NMR(400MHz,DMSO-d6)δppm0.26-0.54(m,4H),1.65-1.95(m,2H),2.28(brt,J=10.2Hz,2H),2.42(br d,J=13.2Hz,1H),3.01-3.18(m,1H),3.28(br d,J=4.3Hz,1H),3.86(s,3H),4.59-4.77(m,1H),4.89-5.11(m,1H),7.05-7.1 6(m,3H),7.48-7.61(m,2H),7.77-7.97(m,3H),8.39(d,J=7.8Hz,1H);ESI-MS m / z [M+H] + 393.20.

[0642] Example 56: (R)-4-(4-methoxyphenyl)-8-methyl-N-(1-methylpiperidin-3-yl)phthalazin-1-amine

[0643] [ka]

[0644] A mixture of (R)-4-chloro-8-methyl-N-(1-methylpiperidin-3-yl)phthalazin-1-amine and (R)-4-chloro-5-methyl-N-(1-methylpiperidin)-3-yl)phthalazin-1-amine (50 mg), (4-methoxyphenyl)boronic acid (31.35 mg, 206.34 μmol), Pd(dppf)Cl.CHCl (28.08 mg, 34.39 μmol), and CsCO (112.05 mg, 343.90 μmol) in dioxane (2 mL) and HO (0.3 mL) was stirred at 100° C. for 12 h under N. LC-MS showed one main peak with the desired m / z. The mixture was diluted with 1M aqueous HCl (2 mL), extracted with EtOAc (3 mL x 2), and the aqueous layer was concentrated and purified by preparative HPLC (Method C) to give the title compound as a yellow solid (25 mg, 40%). 1H NMR(400MHz,DMSO-d6)δppm1.51-1.91(m,4H),2.34(s,3H),2.39-2.50(m,2H),2.53-2.58(m,1H),2.96(s,4H),3.85(s,3H),4.46(br s,1H),6.23(br s,1H),7.09(d,J=8.6Hz,2H),7.49(d,J=8.6Hz,2H),7.59-7.73(m,3H),8.23(s,1H);ESI-MS m / z [M+H] + 363.2.

[0645] Example 57: (R)-1-(2-fluoro-4-methoxyphenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0646] [ka]

[0647] To a solution of (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (75 mg, 270.03 μmol), (2-fluoro-4-methoxyphenyl)boronic acid (59.66 mg, 351.03 μmol), and CsCO (175.96 mg, 540.05 μmol) in dioxane (2 mL) and HO (0.4 mL) was added Pd(dppf)Cl (9.88 mg, 13.50 μmol). The mixture was stirred at 100 °C for 12 h under N. LC-MS showed one main peak with the desired m / z. The mixture was filtered, and the filtrate was purified by preparative HPLC (Method B) to give the formate salt of the title compound as a yellow solid (21.5 mg, 18.6% yield, 96.7% purity). 1H NMR(400MHz,DMSO-d6)δppm1.41-1.53(m,1H),1.55-1.68(m,1H),1.77(br d,J=13.0Hz,1H),1.90-2.05(m,3H),2.23(s,3H),2.74(br d,J=10.9Hz,1H),3.11(br d,J=8.1Hz,1H),3.87(s,3H),4.47(br d,J=5.9Hz,1H),6.99(dd,J=8.5,2.4Hz,1H),7.04(dd,J=12.1,2.4Hz,1H),7.33(dd,J=5.5,3.1Hz,1H) ,7.50(t,J=8.6Hz,1H),7.68(d,J=7.4Hz,1H),8.19(s,1H),8.89(d,J=5.6Hz,1H),9.81(s,1H);ESI-MS m / z [M+H] + 368.

[0648] Example 58: (R)—N-(1-(2-fluoroethyl)piperidin-3-yl)-4-(4-methoxyphenyl)phthalazin-1-amine

[0649] [ka]

[0650] The title compound was prepared in a similar manner to Example 57 using (R)-4-chloro-N-(1-(2-fluoroethyl)piperidin-3-yl)phthalazin-1-amine (150 mg, 485.78 μmol) and (4-methoxyphenyl)boronic acid (147.63 mg, 971.56 μmol) and obtained as a gray solid (24.1 mg, 13.4%). 1H NMR(400MHz,DMSO-d6)δppm1.39-1.68(m,2H),1.69-1.82(m,1H),1.93-2.14(m,3H),2.64(t,J=4.88Hz,1H),2.71(t,J=4.94Hz,1H),2.86(br d,J=11.01Hz,1H),3.16-3.25(m,1H),3.85(s,3H),4.35-4.47(m,1H),4.49(t,J=4.88Hz,1H),4.61(t,J=4.94Hz,1H),7 .05(d,J=7.75Hz,1H),7.10(d,J=8.76Hz,2H),7.54(d,J=8.63Hz,2H),7.77-7.92(m,3H),8.40(d,J=8.00Hz,1H);ESI-MS m / z [M+H] + 381.

[0651] Example 59: (R)-5-chloro-2-(4-((1-(2-fluoroethyl)piperidin-3-yl)amino)phthalazin-1-yl)phenol

[0652] [ka]

[0653] The title compound was prepared in the same manner as in Example 57 using (R)-4-chloro-N-(1-(2-fluoroethyl)piperidin-3-yl)phthalazin-1-amine (200 mg, 647.71 μmol) and (4-chloro-2-hydroxyphenyl)boronic acid (133.98 mg, 777.25 μmol) and obtained as a yellow solid (37.3 mg, 20.4%). 1H NMR(400MHz,DMSO-d6)δppm1.41-1.67(m,2H),1.70-1.80(m,1H),1.94-2.13(m,3H),2.61-2.67(m,1H),2.71(t,J=4.89Hz,1H),2.86(br d,J=11.04Hz,1H),3.21(br d,J=7.03Hz,1H),4.35-4.47(m,1H),4.49(t,J=5.02Hz,1H),4.61(t,J=4.89Hz,1H),6.95-7.05(m,2H),7.09(d,J=7.78Hz, 1H),7.30(d,J=8.28Hz,1H),7.46(d,J=7.78Hz,1H),7.73-7.80(m,1H),7.81-7.89(m,1H),8.37(d,J=8.28Hz,1H),10.17(br s,1H); 19 F NMR(376MHz,DMSO-d6)δppm-216.54(br s,1F);ESI-MS m / z [M+H] + 401.2.

[0654] Example 60: (R)-2-(4-((1-(2-fluoroethyl)piperidin-3-yl)amino)phthalazin-1-yl)phenol

[0655] [ka]

[0656] The title compound was prepared in the same manner as in Example 57 using (R)-4-chloro-N-(1-(2-fluoroethyl)piperidin-3-yl)phthalazin-1-amine (200 mg, 647.71 μmol) and (2-hydroxyphenyl)boronic acid (178.68 mg, 1.30 mmol) and obtained as a yellow solid (31.5 mg, 15.5%). 1H NMR(400MHz,DMSO-d6)δppm1.42-1.68(m,2H),1.71-1.80(m,1H),1.94-2.13(m,3H),2.65(t,J=4.89Hz,1H),2.72(t,J=4.89Hz,1H),2.86(br d,J=10.79Hz,1H),3.17-3.26(m,1H),4.35-4.47(m,1H),4.50(t,J=4.89Hz,1H),4.62(t,J=4.89Hz,1H),6.88-7.01(m,2H),7.05( d,J=7.78Hz,1H),7.24-7.36(m,2H),7.48(d,J=8.03Hz,1H),7.72-7.80(m,1H),7.81-7.87(m,1H),8.36(d,J=8.28Hz,1H),9.65(br s,1H); 19 F NMR(376MHz,DMSO-d6)δppm-216.55(br s,1F);ESI-MS m / z [M+H] + 367.2.

[0657] Example 61: (R)-4-(2-fluoro-4-methoxyphenyl)-N-(1-(2-fluoroethyl)piperidin-3-yl)phthalazin-1-amine

[0658] [ka]

[0659] The formate salt of the title compound was prepared similarly to Example 57 using (R)-4-chloro-N-(1-(2-fluoroethyl)piperidin-3-yl)phthalazin-1-amine (150 mg, 485.78 μmol) and (2-fluoro-4-methoxyphenyl)boronic acid (165.11 mg, 971.56 μmol) and obtained as a yellow solid (56.1 mg, 26.5%). 1H NMR(400MHz,DMSO-d6)δppm1.41-1.67(m,2H),1.76(br d,J=13.01Hz,1H),1.94-2.14(m,3H),2.65(br t,J=4.88Hz,1H),2.72(br t,J=4.75Hz,1H),2.87(br d,J=10.76Hz,1H),3.21(br d,J=7.88Hz,1H),3.87(s,3H),4.43(br s,1H),4.50(br t,J=4.75Hz,1H),4.62(brt,J=4.75Hz,1H),6.94-7.05(m,2H),7.15(br s,1H),7.40-7.55(m,2H),7.76-7.95(m,2H),8.18(s,1H),8.41(br d,J=8.13Hz,1H);ESI-MS m / z [M+H] + 399.2.

[0660] Example 62: 4-(4-chlorophenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0661] [ka]

[0662] Example 63: 1-(4-chlorophenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0663] [ka]

[0664] The title compound was prepared in the same manner as in Example 57 using a mixture of 1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine (300 mg, 1.08 mmol) and (4-chlorophenyl)boronic acid (337.80 mg, 2.16 mmol). The title compound of Example 62 was obtained as a white solid (18.7 mg, 4.81%). 1 H NMR(400MHz,DMSO-d6)δppm1.35-1.51(m,1H),1.54-1.69(m,1H),1.72-1.84(m,1H),1.85-2.07(m,3H),2.15-2.27(m,3H) ,2.70-2.81(m,1H),3.03-3.14(m,1H),4.32-4.59(m,1H),7.60-7.72(m,6H),8.89-8.96(m,1H),9.74-9.88(m,1H);ESI-MS m / z [M+H] + 354.3. The title compound of Example 63 was obtained as a white solid (23 mg, 5.9%). 1 H NMR(400MHz,DMSO-d6)δppm1.38-1.52(m,1H),1.54-1.69(m,1H),1.73-1.81(m ,1H),1.89-2.05(m,3H),2.19-2.27(m,3H),2.70-2.79(m,1H),3.04-3.14(m,1 H),4.36-4.51(m,1H),7.44-7.50(m,1H),7.61-7.69(m,2H),7.71-7.81(m,2H) ,8.13-8.23(m,1H),8.32-8.40(m,1H),8.97-9.05(m,1H),9.19(s,1H);ESI-MS m / z [M+H] + 354.3.

[0665] Example 64: (R)-1-(4-chlorophenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0666] [ka]

[0667] Example 65: (S)-1-(4-chlorophenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0668] [ka]

[0669] Racemic 1-(4-chlorophenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (22 mg) was resolved by chiral SFC (DAICEL CHIRALPAK® AD-10 μm, 30 mm × 250 mm column) using a mobile phase of CO and 40% IPA (containing 0.1% NH H O). Example 64 was the R-enantiomer and was obtained as a white solid (8.1 mg, 10.6% yield). 1 H NMR(400MHz,DMSO-d6)δppm1.48-1.59(m,1H),1.68(q,J=11.97Hz,1H),1.83(br d,J=13.26Hz,1H),1.96-2.12(m,3H),2.28(s,3H),2.77(br ESI-MS m / z [M+H] + 354.3. Example 65 as the S-enantiomer was obtained as a white solid (3.1 mg, 4.0%). 1H NMR(400MHz,DMSO-d6)δppm1.47-1.59(m,1H),1.62-1.75(m,1H),1.84(br d,J=12.88Hz,1H),1.99-2.12(m,3H),2.29(s,3H),2.81(br s,1H),3.16(br d,J=7.63Hz,1H),4.53(br d,J=6.88Hz,1H),7.66-7.72(m,3H),7.72-7.78(m,3H),8.25(br s,1H),8.97(d,J=5.63Hz,1H),9.88(s,1H);ESI-MS m / z [M+H] + 354.3.

[0670] Example 66: (R)-1-(4-chlorophenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0671] [ka]

[0672] Example 67: (R)-4-(4-chlorophenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0673] [ka]

[0674] The title compound was prepared in the same manner as in Example 57 using a mixture of (R)-4-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine and (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (100.00 mg, 360.03 μmol) and (4-chlorophenyl)boronic acid (112.60 mg, 720.07 μmol). The title compound of Example 66 was obtained as a yellow solid (12.1 mg, 9.5%). 1H NMR(400MHz,DMSO-d6)δppm1.44-1.58(m,1H),1.61-1.72(m,1H),1.75-1.9 0(m,1H),1.95-2.21(m,3H),2.28-2.37(m,3H),2.78-2.97(m,1H),3.21(br s,1H),4.45-4.63(m,1H),7.58-7.80(m,6H),8.87-9.01(m,1H),9.84(s,1H);ESI-MS m / z [M+H] + 354.3. The title compound of Example 67 was obtained as a yellow solid (5.2 mg, 4.1%). 1 H NMR(400MHz,DMSO-d6)δppm1.64-1.82(m,2H),1.84-1.98(m,2H),2.00-2.16(m,2H),2.47-2.67(m,5H),4.51(br s,1H),7.47-7.64(m,4H),8.11-8.19(m,1H),8.85-8.93(m,1H),9.05-9.16(m,1H);ESI-MS m / z [M+H] + 354.3.

[0675] Example 68: 1-(4-chloro-2-fluorophenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0676] [ka]

[0677] Example 69: 4-(4-chloro-2-fluorophenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0678] [ka]

[0679] The title compound was prepared in the same manner as in Example 57 using a mixture of 1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine (120 mg, 0.43 μmol) and (4-chloro-2-fluorophenyl)boronic acid (113.00 mg, 648.06 μmol). The title compound of Example 68 was obtained as a white solid (50 mg, 62%). 1 H NMR(400MHz,DMSO-d6)δppm1.42-1.54(m,1H),1.57-1.70(m,1H),1.74-1.83(m,1H),1.92-2.07(m,3H),2.25(s,3H),2.75(br d,J=11.38Hz,1H),3.12(br d,J=9.38Hz,1H),4.43-4.56(m,1H),7.36(dd,J=5.44,2.69Hz,1H),7.52(dd,J=8.25,1.88Hz ,1H),7.61-7.71(m,2H),7.79(d,J=7.50Hz,1H),8.90(d,J=5.63Hz,1H),9.84(s,1H);ESI-MS m / z [M+H] + 372.1. The title compound of Example 69 was obtained as a white solid (11.4 mg, 12.5%). 1 H NMR(400MHz,DMSO-d6)δppm1.48(br s,1H),1.63(br s,1H),1.79(br s,1H),2.00(br s,3H),2.28(br s,3H),2.79(br s,1H),3.13(br s,1H),4.46(br s,1H),7.54(br s,1H),7.60(br s,1H),7.68(br s,2H),8.29-8.43(m,1H),8.37(br s,1H),8.91(br s,1H),9.01(br s,1H);ESI-MS m / z [M+H] + 372.1.

[0680] Example 70: (S)-1-(4-chloro-2-fluorophenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0681] [ka]

[0682] Example 71: (R)-1-(4-chloro-2-fluorophenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0683] [ka]

[0684] Racemic 1-(4-chlorophenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (20 mg) was resolved by chiral SFC (DAICEL CHIRALCEL® OJ-10 μm, 30 mm × 250 mm column) using a mobile phase of CO and 30% EtOH (containing 0.1% NH₃H₂O). Example 70 was the S-enantiomer and was obtained as a white solid (4.4 mg, 8.7%). 1 H NMR(400MHz,DMSO-d6)δppm1.46-1.54(m,1H),1.60-1.70(m,1H),1.74-1.8 5(m,1H),1.88-2.07(m,3H),2.20-2.31(m,3H),2.72-2.81(m,1H),3.09-3. 17(m,1H),4.46-4.54(m,1H),7.30-7.39(m,1H),7.48-7.56(m,1H),7.62-7 .74(m,2H),7.78-7.85(m,1H),8.86-8.96(m,1H),9.79-9.89(m,1H);ESI-MS m / z [M+H] + 372.1. Example 71 was obtained as the R-enantiomer as a white solid (9.8 mg, 19%). 1H NMR(400MHz,DMSO-d6)δppm1.41-1.54(m,1H),1.55-1.67(m,1H),1.71-1. 83(m,1H),1.87-2.05(m,3H),2.23(s,3H),2.70-2.78(m,1H),3.07-3.13( m,1H),4.43-4.53(m,1H),7.33-7.38(m,1H),7.46-7.57(m,1H),7.61-7.7 1(m,2H),7.76-7.83(m,1H),8.85-8.94(m,1H),9.82-9.87(m,1H);ESI-MS m / z [M+H] + 372.1.

[0685] Example 72: 1-(4-Methoxyphenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0686] [ka]

[0687] Example 73: 4-(4-Methoxyphenyl)-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0688] [ka]

[0689] The title compound was prepared in the same manner as in Example 57 using a mixture of 1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine (200 mg, 0.72 mmol), and (4-methoxyphenyl)boronic acid (218.84 mg, 1.44 mmol). The title compound of Example 73 was obtained as a white solid (6.4 mg, 12.5%). 1H NMR(400MHz,DMSO-d6)δppm1.37-1.52(m,1H),1.53-1.68(m,1H),1.71-1.81(m, 1H),1.84-1.96(m,2H),1.98-2.06(m,1H),2.17-2.26(m,3H),2.65-2.76(m,1H) ,3.03-3.17(m,1H),3.81-3.91(m,3H),4.31-4.59(m,1H),7.10-7.15(m,2H),7. 53-7.62(m,3H),7.63-7.67(m,1H),8.84-8.97(m,1H),9.74-9.86(m,1H);ESI-MS m / z [M+H] + 350.2. The title compound of Example 72 was obtained as a white solid (53.8 mg, 21.2%). 1 H NMR(400MHz,DMSO-d6)δppm1.35-1.51(m,1H),1.53-1.66(m,1H),1.67-1.79(m, 1H),1.83-2.06(m,3H),2.11-2.30(m,3H),2.63-2.81(m,1H),2.97-3.16(m,1H) ,3.78-3.95(m,3H),4.26-4.56(m,1H),6.99-7.22(m,2H),7.26-7.43(m,1H),7. 53-7.80(m,2H),8.22-8.38(m,1H),8.85-9.05(m,1H),9.08-9.30(m,1H);ESI-MS m / z [M+H] + 350.2.

[0690] Example 74: (R)-5-chloro-2-(4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol

[0691] [ka]

[0692] Example 75: (R)-5-chloro-2-(1-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol

[0693] [ka]

[0694] The title compound was prepared in the same manner as in Example 57 using a mixture of (R)-1-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and (R)-4-chloro-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine (300 mg, 1.08 mmol) and (4-chloro-2-hydroxyphenyl)boronic acid (465.45 mg, 2.70 mmol). The title compound of Example 74 was obtained as a yellow solid (64 mg, 16%). 1 H NMR(400MHz,DMSO-d6)δppm1.43-1.56(m,1H),1.59-1.70(m,1H),1.77-1.82(m, 1H),1.98-2.11(m,3H),2.26-2.31(m,3H),2.75-2.83(m,1H),3.12-3.20(m,1H) ,4.41-4.57(m,1H),7.01-7.07(m,2H),7.27-7.32(m,1H),7.32-7.37(m,1H),7. 58-7.67(m,1H),8.15-8.22(m,1H),8.82-8.89(m,1H),9.75-9.81(m,1H);ESI-MS m / z [M+H] + 370.4. The title compound of Example 75 was obtained as a yellow solid (24.5 mg, 5.94% yield, 96.8% purity). 1 H NMR(400MHz,DMSO-d6)δppm1.43-1.57(m,1H),1.58-1.71(m,1H),1.75-1.85(m,1H), 1.96-2.04(m,1H),2.05-2.15(m,2H),2.27-2.34(m,3H),2.76-2.84(m,1H),3.11-3. 20(m,1H),4.39-4.51(m,1H),7.03-7.08(m,2H),7.37-7.42(m,1H),7.42-7.49(m,1H ),8.18-8.23(m,1H),8.29-8.34(m,1H),8.83-8.86(m,1H),8.91-8.96(m,1H);ESI-MS m / z [M+H] +370.3.

[0695] Example 76: 1-(4-chlorophenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0696] [ka]

[0697] Example 77: 4-(4-chlorophenyl)-5-methyl-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0698] [ka]

[0699] The title compound was prepared in the same manner as in Example 57 using a mixture of 1-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine (80 mg) and (4-chlorophenyl)boronic acid (55.55 mg, 355.23 μmol). The title compound of Example 77 was obtained as a white solid (4.1 mg, 4.1%). 1 H NMR(400MHz,CD3OD)δppm1.71-2.01(m,2H),2.06-2.25(m,2H),2.30(s,3H),2.82(s,3H),2.96(br s,2H),3.33-3.38(m,1H),3.71(br dd,J=4.3,1.8Hz,1H),4.64(br s,1H),7.48(br d,J=8.0Hz,2H),7.58(br d,J=8.0Hz,2H),8.08(br d,J=5.3Hz,1H),8.51(br s,1H),8.82(br d,J=5.5Hz,1H);ESI-MS m / z [M+H] + 368.2. The title compound of Example 76 was obtained as a white solid (7 mg, 7%). 1H NMR(400MHz,CD3OD)δppm1.83-2.06(m,2H),2.12(br s,1H),2.25(br s,1H),2.83(s,3H),3.02(br d,J=10.0Hz,2H),3.23(s,4H),3.71(br s,1H),4.71(br s,1H),7.57(br d,J=5.6Hz,1H),7.63(s,4H),8.49(br s,1H),8.73(d,J=5.6Hz,1H);ESI-MS m / z M+H] + 368.2.

[0700] Example 78: (R)-5-Methoxy-2-(5-methyl-4-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol

[0701] [ka]

[0702] Example 79: (R)-5-Methoxy-2-(5-methyl-1-((1-methylpiperidin-3-yl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol

[0703] [ka]

[0704] The title compound was prepared in the same manner as in Example 57 using a mixture of (R)-1-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and (R)-4-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine (45 mg, 154 μmol) and 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (57.86 mg, 231.34 μmol). The title compound of Example 78 was obtained as a yellow solid (5.6 mg, 9.5% yield, 99% purity). 1H NMR(400MHz,DMSO-d6)δppm1.42-1.52(m,1H),1.61(br d,J=12.01Hz,1H),1.76(br d,J=10.88Hz,1H),1.97(br t,J=10.13Hz,3H),2.24(s,3H),2.31(s,3H),2.74(br d,J=10.51Hz,1H),3.09(br d,J=6.25Hz,1H),3.78(s,3H),4.37(br d,J=3.63Hz,1H),6.49(s,1H),6.55(br d,J=8.38Hz,1H),7.13-7.23(m,2H),8.11(d,J=5.63Hz,1H),8.21(s,1H),8.74(d,J=5.63Hz,1H),9.37-9.76(m,1H);ESI-MS m / z [M+H] + 380.4. The title compound of Example 79 was obtained as a yellow solid (9.6 mg, 16% yield, 97% purity). 1 H NMR(400MHz,DMSO-d6)δppm1.53-1.65(m,1H),1.66-1.90(m,3H),2.26(s,3H),2.37-2.45(m,2H),2.79(br d,J=7.38Hz,1H),3.10(s,3H),3.19-3.24(m,1H),3.77-3.84(m,3H),4.38-4.56(m,1H),6.35-6.46(m,1H),6.53-6 .59(m,2H),7.09-7.16(m,1H),7.18-7.24(m,1H),8.11-8.26(m,1H),8.52-8.69(m,1H),9.43-9.98(m,1H);ESI-MS m / z [M+H] + 380.4.

[0705] Example 80: 1-(4-chlorophenyl)-7-methyl-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0706] [ka]

[0707] Example 81: 4-(4-chlorophenyl)-7-methyl-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0708] [ka]

[0709] The title compound was prepared in the same manner as in Example 57 using a mixture of 1-chloro-7-methyl-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-7-methyl-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine (100 mg) and (4-chlorophenyl)boronic acid (80.39 mg, 514.09 μmol). The title compound of Example 80 was obtained as a yellow solid (24.2 mg, 16.6%). 1 H NMR(400MHz,CD3OD)δppm1.77-2.01(m,2H),2.08-2.34(m,2H),2.72(s,3H),2.81(br d,J=2.0Hz,3H),2.95(br d,J=3.4Hz,2H),3.30(br d,J=1.5Hz,1H),3.60-3.81(m,1H),4.70(br s,1H),7.58(s,1H),7.60-7.69(m,4H),8.50(br s,1H),9.63(s,1H);ESI-MS m / z [M+H] + 368.3. The title compound of Example 81 was obtained as a yellow solid (9.9 mg, 6.8%). 1 H NMR(400MHz,CD3OD)δppm1.72-2.03(m,2H),2.08-2.35(m,2H),2.79(s,3H),2.83(s,3H),3.01(br s,2H),3.32-3.39(m,1H),3.70(br d,J=9.4Hz,1H),4.60-4.71(m,1H),7.51-7.75(m,4H),8.12(s,1H),8.48(br s,1H),9.09(s,1H);ESI-MS m / z [M+H] + 368.3.

[0710] Example 82: 4-(4-chlorophenyl)-7-methoxy-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine

[0711] [ka]

[0712] The title compound was prepared similarly to Example 57 using 4-chloro-7-methoxy-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-1-amine (11 mg, 35.7 μmol) and (4-chlorophenyl)boronic acid (6.71 mg, 42.89 μmol) and obtained as a yellow solid (3.9 mg, 28% yield, 99% purity). 1 H NMR(400MHz,DMSO-d6)δppm1.34-1.51(m,1H),1.53-1.69(m,1H),1.71-1.8 1(m,1H),1.87-2.06(m,3H),2.18-2.27(m,3H),2.73-2.77(m,1H),3.10(br d,J=9.01Hz,1H),3.99-4.06(m,3H),4.33-4.43(m,1H),7.23-7.32(m,1H),7 .59-7.65(m,2H),7.68-7.77(m,1H),8.14-8.21(m,1H),8.88(s,1H);ESI-MS m / z [M+H + 384.3.

[0713] Example 83: 1-(4-chlorophenyl)-7-methoxy-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine

[0714] [ka]

[0715] The title compound was prepared similarly to Example 57 using 1-chloro-7-methoxy-N-(1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (33 mg, 107.22 μmol) and (4-chlorophenyl)boronic acid (20.12 mg, 128.66 μmol) and obtained as a yellow solid (16 mg, 38% yield, 98% purity). 1 H NMR(400MHz,DMSO-d6)δppm1.44-1.56(m,1H),1.59-1.71(m,1H),1.78-1.87(m,1H),1.98-2.2 4(m,3H),2.31-2.37(m,3H),2.81-2.90(m,1H),3.16-3.23(m,1H),3.95-4.02(m,3H),4.49(br s,1H),6.81-6.90(m,1H),7.59-7.64(m,2H),7.66-7.70(m,2H),8.09-8.21(m,1H),9.48-9.58(m,1H);ESI-MS m / z [M+H] + 384.3.

[0716] Example 84: (R)—N-(1-(2-fluoroethyl)piperidin-3-yl)-1-(4-methoxyphenyl)pyrido[3,4-d]pyridazin-4-amine

[0717] [ka]

[0718] The title compound was prepared similarly to Example 57 using (R)-1-chloro-N-(1-(2-fluoroethyl)piperidin-3-yl)pyrido[3,4-d]pyridazin-4-amine (200 mg, 645.64 μmol) and (4-methoxyphenyl)boronic acid (196.22 mg, 1.29 mmol) and obtained as a yellow solid (27.3 mg, 13.4%). 1H NMR(400MHz,DMSO-d6)δppm1.41-1.69(m,2H),1.71-1.84(m,1H),1.96-2.16(m,3H),2.66(t,J=4.88Hz,1H),2.73(t,J=4.88Hz,1H),2.88(br d,J=10.76Hz,1H),3.23(br d,J=7.00Hz,1H),3.85(s,3H),4.39-4.53(m,2H),4.62(t,J=4.88Hz,1H),7.12(d,J=8.63Hz,2H),7 .49-7.61(m,3H),7.64(d,J=5.63Hz,1H),8.15(s,1H),8.90(d,J=5.63Hz,1H),9.79(s,1H);ESI-MS m / z [M+H] + 382.

[0719] Example 85: (R)-5-chloro-2-(4-((1-(2-fluoroethyl)piperidin-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol

[0720] [ka]

[0721] The formate salt of the title compound was prepa...

Claims

1. Compound of formula 1, 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (in the formula, α is a single bond, β is a single bond, X １ CH ２ And, X ２ is O, X ３ CH ２ is, or X ２ CH ２ X ３ It is O, X ４ is CH ２ and m is selected from 0, 1, and 2. R ａ and Ｒｂ These are hydrogen and C, respectively. １－４ Either independently selected from alkyl, or R ａ and R ｂ R ａ and R ｂ Together with the carbon atom to which both are bonded, C ３－６ It forms a cycloalkylidene, however, if m is 2, R ａ and R ｂ One or fewer of these are R ａ and R ｂ Together with the carbon atom to which it is bonded, C ３－６ Forming cycloalkylidenes, R ５ The following can be selected: (a) C ３－８ Cycloalkyl (substituted with 0 to 5 substituents independently selected from the following: (i) Halo, hydroxy, cyano, and oxo; (ii) Amino (C １－４ (substituted with 0 to 2 substituents independently selected from alkyl); and (iii) C １－４ Alkyl, C １－４ Alkylcarbonyl and C １－４ Alkoxy compounds (each substituted with 0 to 3 substituents independently selected from the halo); however, m is 0, X １ , X ２ and X ４ Each CH ２ X ３ O is X ８ CH is, R ６ , R １０ and R １１ Each of them is hydrogen, and R ７ is hydroxyl, R ９ ga CF ３ or OCF ３ If so, R ５ It is not 3-hydroxy-3-methylcyclobutyl, m is 0, X １ , X ３ and X ４ Each CH ２ X ２ O is X ８ CH is, R ６ , R １０ and R １１ Each of them is hydrogen, and R ７ is hydroxyl, R ９ ga CF ３ or OCF ３ If so, R ５ It is not 3-hydroxy-3-methylcyclobutyl, m is 0, X １ , X ２ and X ４ Each CH ２ X ３ O is X ８ CH is, R ６ , R １０ and R １１ Each of them is hydrogen, and R ７ is hydroxyl, R ９ Hydrogen, CF ３ OCF ３ Or if it is cyclobutyl, R ５ It is not 2-hydroxycyclohexyl, m is 0, X １ , X ３ and X ４ Each CH ２ X ２ O is X ８ CH is, R ６ , R １０ and R １１ Each of them is hydrogen, and R ７ is hydroxyl, R ９ Hydrogen, chloro, CF ３ CHF ２ OCF ３ , OCHF ２ , OCH ３ Or if it is cyclobutyl, R ５ It is not 2-hydroxycyclohexyl, m is 0, and X １ , X ２ and X ４ are each CH ２ , X ３ is O, X ８ is CH, R ６ and R １０ are each hydrogen, R ７ is hydroxy, R ９ is methyl, R １１ is fluoro, then R ５ is not 2-hydroxycyclohexyl, m is 0, X １ , X ３ and X ４ Each CH ２ X ２ O is X ８ CH is, R ６ and R １０ Each of them is hydrogen, and R ７ is hydroxyl, R ９ is methyl, R １１ If is fluoro, then R ５ It is not 2-hydroxycyclohexyl, m is 0, X １ , X ３ and X ４ Each CH ２ X ２ O is X ８ CH is, R ６ and R １１ Each of them is hydrogen, and R ７ is hydroxyl, R ９ ga CF ３ And R １０ If is fluoro, then R ５ It is not 2-hydroxycyclohexyl, m is 0, X １ , X ２ and X ４ Each CH ２ X ３ O is X ８ CH is, R ６ , R １０ and R １１ Each of them is hydrogen, and R ７ is hydroxyl, R ９ ga CF ３ If so, R ５ It is not 2-cyanocyclohexyl or 2-aminocyclohexyl, and m is 0, X １ , X ３ and X ４ Each CH ２ X ２ O is X ８ CH is, R ６ , R １０ and R １１ Each of them is hydrogen, and R ７ is hydroxyl, R ９ ga CF ３ If so, R ５ (This is not 2-cyanocyclohexyl.) (b) C ３－８ Heterocyclines (where up to three carbon ring atoms are each independently substituted with 0 to 2 substituents independently selected from the following): (i) Halo, hydroxy, cyano, and oxo; (ii) Amino (C １－４ (substituted with 0 to 2 substituents independently selected from alkyl); and (iii) C １－４ Alkyl, C １－４ Alkylcarbonyl and C １－４ Alkoxy compounds (each substituted with 0 to 3 substituents independently selected from the halo); Here, the nitrogen ring atom, if present, is either unsubstituted or substituted with a substituent selected from the following: (i) C １－４ Alkyl, C １－４ Alkylcarbonyl and C １－４ Alkyl sulfonyl compounds (each substituted with 0 to 3 substituents independently selected from the halo); (ii) C ３－８ Cycloalkyl-(CH ２ ) ｎ (That C ３－８ The cycloalkyl portion is halo, C １－４ Alkyl, C １－４ Alkylcarbonyl, C １－４ (substituted with 0 to 3 substituents independently selected from alkoxy and oxo), and (iii) Phenyl-(CH ２ ) ｎ and pyridinyl-(CH ２ ) ｎ (The phenyl and pyridinyl portions are halo, hydroxy, cyano, C) １－４ Alkyl and C １－４ (Substituted with 0 to 3 substituents independently selected from the alkoxy) Here, C ３－８ A heterocycline has only one ring heteroatom, and the ring heteroatom is selected from nitrogen, oxygen, and sulfur. n is selected from 0 and 1; however, m is 0, X １ , X ２ and X ４ Each CH ２ X ３ O is X ８ CH is, R ６ , R １０ and R １１ Each of them is hydrogen, and R ７ is hydroxyl, R ９ ga CF ３ If so, R ５ It is not piperidine-3-yl or 1-methylpiperidine-3-yl, m is 0, X １ , X ３ and X ４ Each CH ２ X ２ O is X ８ CH is, R ６ , R １０ and R １１ Each of them is hydrogen, and R ７ is hydroxyl, R ９ ga CF ３ If so, R ５ It is not piperidine-3-yl or 1-methylpiperidine-3-yl, m is 0, X １ , X ２ and X ４ Each CH ２ X ３ O is X ８ CH is, R ６ and R １０ Each of them is hydrogen, and R ７ is hydroxyl, R ９ ga CF ３ , methyl or chloro, R １１ If is fluoro, then R ５ It is not 1-methylpiperidine-3-yl, m is 0, X １ , X ２ and X ４ Each CH ２ X ３ O is X ８ CH is, R ６ , R １０ and R １１ Each of them is hydrogen, and R ７ is hydroxyl, R ９ If R is methyl or chloro, ５ (This is not 1-methylpiperidine-3-yl) (c) Phenyl(halo, hydroxy, cyano, C) １－４ Alkyl and C １－４ It is substituted with 0 to 3 substituents independently selected from the alkoxy, provided that at least one of the substituents is hydroxyl. R ６ is hydrogen and C １－４ Selected from alkyl groups, X ８ N and CR ８ Selected from, R ７ , R ８ and R １１ Each of these is independently selected from the following: (i) Hydrogen, halo, hydroxy, and cyano, (ii) C １－４ Alkyl and C １－４ Alkoxy (each substituted with 0 to 3 substituents independently selected from the halo); and (iii) C ３－８ Cycloalkyl (halo, C １－４ Alkyl and C １－４ (Substituted with 0 to 3 substituents independently selected from the alkoxy); R ９ and R １０ Each of these is independently selected from the following: (i) Hydrogen, halo, hydroxy, and cyano, (ii) C １－４ Alkyl and C １－４ Alkoxy (each substituted with 0 to 3 substituents independently selected from the halo); and (iii) C ３－８ Cycloalkyl (halo, C １－４ Alkyl and C １－４ (substituted with 0 to 3 substituents independently selected from the alkoxy); or R ９ and R １０ This forms an ethane-1,2-dioxy moiety that bridges the carbon atoms to which they are bonded.

2. A compound or pharmaceutically acceptable salt according to claim 1, wherein m is 0.

3. R ５ However, C is substituted with 0 to 5 substituents independently selected from the following. ３－８ A cycloalkyl compound or pharmaceutically acceptable salt of the compound or pharmaceutically acceptable salt described in claim 1: (i) Halo, hydroxy, cyano, and oxo; (ii) Amino (C １－４ (substituted with 0 to 2 substituents independently selected from alkyl); and (iii) C １－４ Alkyl, C １－４ Alkylcarbonyl and C １－４ Alkoxy compounds (each substituted with 0 to 3 substituents independently selected from the halo).

4. R ５ However, up to three carbon ring atoms are independently substituted with 0 to 2 substituents independently selected from the following: ３－８ A heterocycline compound or pharmaceutically acceptable salt of the compound or pharmaceutically acceptable salt described in claim 1: (i) Halo, hydroxy, cyano, and oxo; (ii) Amino (C １－４ (substituted with 0 to 2 substituents independently selected from alkyl); and (iii) C １－４ Alkyl, C １－４ Alkylcarbonyl and C １－４ Alkoxy compounds (each substituted with 0 to 3 substituents independently selected from the halo); Here, the nitrogen ring atom, if present, is either unsubstituted or substituted with a substituent selected from the following: (i) C １－４ Alkyl, C １－４ Alkylcarbonyl and C １－４ Alkyl sulfonyl compounds (each substituted with 0 to 3 substituents independently selected from the halo); (ii) C ３－８ Cycloalkyl-(CH ２ ) ｎ (That C ３－８ The cycloalkyl portion is halo, C １－４ Alkyl, C １－４ Alkylcarbonyl, C １－４ (substituted with 0 to 3 substituents independently selected from alkoxy and oxo), and (iii) Phenyl-(CH ２ ) ｎ and pyridinyl-(CH ２ ) ｎ (The phenyl and pyridinyl portions are halo, hydroxy, cyano, C) １－４ Alkyl and C １－４ (The alkoxy is substituted with 0 to 3 substituents, which are independently selected.)

5. R ５ However, C selected from piperidine-3-yl, in which up to three carbon ring atoms are independently substituted with 0 to 2 substituents independently selected from the following. ３－８ A heterocycline compound or pharmaceutically acceptable salt of the compound or pharmaceutically acceptable salt described in claim 1: (i) Halo, hydroxy, cyano, and oxo; (ii) Amino (C １－４ (substituted with 0 to 2 substituents independently selected from alkyl); and (iii) C １－４ Alkyl, C １－４ Alkylcarbonyl and C １－４ Alkoxy compounds (each substituted with 0 to 3 substituents independently selected from the halo); Here, the nitrogen ring atom of piperidine-3-yl is either unsubstituted or substituted with a substituent selected from the following: (i) C １－４ Alkyl, C １－４ Alkylcarbonyl and C １－４ Alkyl sulfonyl compounds (each substituted with 0 to 3 substituents independently selected from the halo); (ii) C ３－８ Cycloalkyl-(CH ２ ) ｎ (That C ３－８ The cycloalkyl portion is halo, C １－４ Alkyl, C １－４ Alkylcarbonyl, C １－４ (substituted with 0 to 3 substituents independently selected from alkoxy and oxo), and (iii) Phenyl-(CH ２ ) ｎ and pyridinyl-(CH ２ ) ｎ (The phenyl and pyridinyl portions are halo, hydroxy, cyano, C) １－４ Alkyl and C １－４ (The alkoxy is substituted with 0 to 3 substituents, which are independently selected.)

6. R ８ and R １１ However, both are hydrogen, R ７ However, the compound or pharmaceutically acceptable salt described in claim 1, selected from the following: (i) hydrogen, halo, and hydroxyl; and (ii) C １－３ Alkyl and C １－３ Alkoxy compounds (each substituted with 0 to 3 substituents independently selected from the halo).

7. R ９ and R １０ However, each of the following is independently selected from the following: the compound or pharmaceutically acceptable salt described in claim 1: (i) Hydrogen, halo, hydroxy, and cyano, (ii) C １－４ Alkyl and C １－３ Alkoxy (each substituted with 0 to 3 fluorocarbons); and (iii) C ３－５ Cycloalkyl (substituted with 0 to 3 substituents independently selected from methyl and methoxy).

8. The compound according to claim 1, selected from the following compounds: 5-Chloro-2-(1-(((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)phenol; 2-(1-(((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)-5-methylphenol; 2-(1-(((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)phenol; 5-Fluoro-2-(1-(((3R,5R)-5-Fluoro-1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)phenol; 1-(2-(difluoromethyl)-4-methylphenyl)-N-((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine-4-amine; N-((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)-1-(2-fluoro-4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine-4-amine; 1-(2-(difluoromethyl)-4-methoxyphenyl)-N-((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine-4-amine; 4-(2-(difluoromethyl)-4-methylphenyl)-N-((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine-1-amine; 4-(2-(difluoromethyl)-4-methoxyphenyl)-N-((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine-1-amine; N-((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)-4-(2-fluoro-4-methoxyphenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine-1-amine; N-((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)-4-(4-methoxy-2-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine-1-amine; 4-(4-chloro-2-fluorophenyl)-N-((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine-1-amine; 5-Chloro-2-(4-(((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol; 2-(4-(((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol; N-((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)-4-(2-fluoro-4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine-1-amine; N-((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)-1-(2-fluoro-4-methoxyphenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine-4-amine; N-((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)-1-(4-methoxy-2-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine-4-amine; 1-(4-chloro-2-fluorophenyl)-N-((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine-4-amine; (R)-5-methyl-2-(4-((1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol; 5-Fluoro-2-(4-(((3R,5R)-5-Fluoro-1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol; 2-(4-(((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-methylphenol; (R)-5-methoxy-2-(4-((1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol; (R)-1-(4-methoxyphenyl)-N-(1-methylpiperidine-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine-4-amine; (R)-4-(4-methoxyphenyl)-N-(1-methylpiperidine-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine-1-amine; (R)-5-chloro-2-(4-((1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol; (R)-2-(4-((1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol; (R)-2-(1-((1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)phenol; (R)-N-(1-cyclopropylpiperidine-3-yl)-1-(4-methoxyphenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine-4-amine; 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-methylphenol; 2-(1-(((1R,2R)-2-hydroxycyclohexyl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)-5-methylphenol; 4-((1-(2-hydroxy-4-methylphenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)amino)bicyclo[2.2.1]heptan-1-ol; 4-((4-(2-hydroxy-4-methylphenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)amino)bicyclo[2.2.1]heptan-1-ol; (R)-2-(4-((1-(2-methoxyethyl)piperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-methylphenol; 2-(4-(((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-(((3R,5S)-5-fluoro-1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-methylphenol; 2-(4-(((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol; 2-(4-(((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-methoxyphenol; 5-Cyclopropyl-2-(4-(((3R,5R)-5-Fluoro-1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol; 5-(difluoromethyl)-2-(4-(((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)phenol; and A pharmaceutically acceptable salt of any one of the aforementioned compounds.

9. A compound or pharmaceutically acceptable salt as defined in any one of claims 1 to 8, for use as a pharmaceutical.

10. A compound or pharmaceutically acceptable salt as defined in any one of claims 1 to 8 A pharmaceutical composition comprising pharmaceutically acceptable excipients.

11. A compound or pharmaceutically acceptable salt as defined in any one of claims 1 to 8, for use in the treatment of diseases, disorders, or conditions related to NLRP3.

12. A compound or pharmaceutically acceptable salt as defined in any one of claims 1 to 8, for use in the treatment of a neurodegenerative disease, disorder, or condition.

13. A compound or pharmaceutically acceptable salt as defined in any one of claims 1 to 8, for use in the treatment of a disease, disorder, or condition selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion disease.

14. A combination comprising a compound or pharmaceutically acceptable salt as defined in any one of claims 1 to 8 and at least one additional pharmacologically active agent.

15. The combination according to claim 14, wherein the additional pharmacologically active agent is selected from beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs, vitamin E, anti-amyloid antibodies, antidepressants, antipsychotics, anxiolytics, and anticonvulsants.

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