1-amino-4-phenyl phthalazine derivatives useful for treatment of neurodegenerative diseases

Abstract

Disclosed are compounds of Formula (1), # imgabs0, and pharmaceutically acceptable salts thereof, wherein alpha, beta, m, R5, R6, R7, R9, R10, R11, Ra, Rb, X1, X2, X3, X4, and X8 are as defined in the specification. The present disclosure also relates to materials and methods for preparing compounds of Formula (1), pharmaceutical compositions containing said compounds of Formula (1), and their use for treating diseases, disorders and conditions associated with NLRP3.

Description

Technical Field

[0001] The present invention relates to 1-amino-4-phenylphthalazine derivatives that are NLRP3 inflammasome inhibitors, pharmaceutical compositions containing the 1-amino-4-phenylphthalazine derivatives, and their use in treating diseases, disorders, and conditions associated with NLRP3, including neurodegenerative diseases such as Parkinson's disease. Background Art

[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 in the coming decades, particularly affecting countries with aging populations. See I. Fernández-Cruz and E. Reynaud, "Proteasome Subunits Involved in Neurodegenerative Diseases", Arch Med Res. 52(1): 1-14 (2021).

[0003] One of the pathological characteristics of neurodegenerative diseases is the aggregation of certain proteins into oligomers or fibrils. These conformational changes cause neurotoxicity, leading to inflammation and neurodegeneration. Although the clinical manifestations of these diseases vary, they generally share common underlying mechanisms and pathophysiology. See BD Dugger and D W Dickson, “Pathology of Neurodegenerative Diseases”, Cold Spring Harbor Perspect Biol 9(7): a028035 (2017). In fact, systemic activation of the innate immune system is the host's first line of defense against pathogens and tissue damage, and subsequent neuroinflammation plays a key role in the onset and development of these diseases. See S. Amor, F. Puentes, D. Baker et al., “Inflamm ation in neurodegenerative diseases”, Immunology 129(2): 154-69 (2010). Neuroinflammation is a physiological response to exogenous and endogenous damage targeting the central nervous system (CNS) and represents a protective response in the brain. However, excessive inflammatory responses are harmful to the CNS. See LILabzin, MTHeneka, and E. Latz, "Innate Imm unity and Neurodegeneration," Annu Rev Med 69:437-449 (2018).

[0004] Microglia are myeloid cells of the CNS that play an important role in the innate immune response of the CNS. They express pattern recognition receptors (PRRs) that enable the host to recognize pathogen-associated molecular patterns (PAMPS) and host-derived or environmentally derived danger-associated molecular patterns (DAMPS). See R.M. Ransohoff, M.A. Brown, “Innate immune unity 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 VM Dixit, “Inflammasomes: mechanism of assembly, regulation and signaling”, Nat Rev Immunol 16(7):407-20(2016). The participation of PRRs activates multiple inflammatory signaling pathways to eliminate infection and repair damaged tissues. The persistent inflammation seen in a variety of neurodegenerative diseases can be maintained by the innate immune sensor of danger signals, the inflammasome. There are several different inflammasomes, all defined by the PRRs they contain. Among the PRRs from the NLR family, NLRs (NLRP1, NLRP3, 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-containing domain 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: the pattern recognition receptor (PRR) protein, NLRP3; apoptosis-associated speck-like protein (ASC) containing a caspase activation and recruitment domain (CARD), which acts as a central adaptor protein; and the inflammatory caspase, caspase-1. See Kelley et al. (2019). NLRP3 consists of three domains: the amino-terminal pyrin domain (PYD); the central NACHT domain, which has ATPase activity essential for NLRP3 self-association and oligomerization; and the carboxyl-terminal LLR domain. See Broz and Dixit (2016).

[0006] The activation of the NLRP3 inflammasome involves a two-step process. The first "start" signal is generated by detecting PAMPs or DAMPs via TLRs. This start signal leads to NF-κB-dependent transcriptional upregulation of NLRP3 and pro-IL-1, but also controls the post-translational modification of NLRP3. See J. Yang, Z. Liu and T. S. Xiao, "Post-translational regulation of inflammasomes", Cell Mol Immunol 14(1): 65-79(2017). The initial trigger is followed by a second "activation" signal (β-amyloid protein, α-synuclein and other protein damage, ATP, crystals, nucleic acids, toxins), which induces conformational changes in various inflammasome components, followed by assembly of monomeric NLRP3 and oligomerization into nuclei, leading to the formation and activation of the NLRP3 inflammasome. See A. Lu, VG Magupalli, J. Ruan et al., “Unified polymerization mechanism for the assembly of ASC-dependent inflam masomes”, Cell 156(6):1193-1206 (2014). This large multimeric protein works by cleaving several proteins, including pro-interleukin (pro-IL)-18 and pro-IL-1β, into their mature inflammatory cytokines IL-18 and IL-1β through caspase-1-dependent proteolytic cleavage. See Kelley et al. (2019). Caspase-1 can also cleave gasdermin D (GSD MD), thereby helping GSDMD insert into the cell membrane to form pores, thereby initiating a specific type of cell death called pyroptosis, which releases a soluble intracellular portion, thereby driving the inflammatory response. See SLFink and BT Cookson, "Caspase-1-dependent poreformation during pyroptosis leads to osmotic lysis of infected hostmacrophages", Cell Microbiol 8(11):1812-25 (2006).

[0007] In addition to this "classic" NLRP3 inflammasome activation pathway, an "atypical" NLRP3 activation pathway has been described in the literature. The atypical pathway involves activation of caspase-4 / 5 (or its mouse ortholog, caspase-11) by cytosolic LPS, inducing pyroptosis through cleavage of GSDMD and releasing high-mobility group box 1 protein (HMGB1), leading to the production of IL-1β. See M. Lamkanfi and VM 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 bioactive forms of the proinflammatory cytokines IL-1β and IL-18, which trigger an inflammatory signaling cascade that promotes neuroinflammation, neuronal damage, and cell death. See SM Allan, PJ Tyrrell, and NJ 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 disease called cryopyrin-associated periodic syndrome (CAPS). See L.M. Booshehri and H.M. Hoffman, “CAPS and NLRP3”, J Clin Immunol 39(3):277-286 (2019). This is a rare, inherited autoinflammatory disease characterized by inflammation of the systemic, skin, musculoskeletal, and central nervous systems, affecting an estimated 1 to 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); Ann Rheum Dis 71(7):1264 (2012). Clinicians classify CAPS disorders based on the severity of their symptoms. The most severe form of CAPS is called 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 low temperatures. See Booshehri and Hoffman (2019). Current anti-IL-1 therapies (anakinra, rilonacept, canakinumab) have been shown to successfully treat CAPS, but clinical experience over the past decade has shown that some CAPS patients respond less well over time and require higher or more frequent dosing or a change in therapy.See R. Caorsi, L. Lepore, F. Zulian, et al., “The schedule of administration of canakinumab in cryopyrin-associated periodic syndrome is driven by the phenotype severity rather than the age”, Arthritis Res Ther 15(1):R33 (2013); S. Urien, C. Bardin, B. Bader-Meunier, et al., “Anakinra pharmacokinetics 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 can block the NLRP3 inflammasome pathway have recently been reported. These small molecule inhibitors include the prototype NLRP3 inhibitor MCC-950. See RC Coll, JRHill, CJ Day et al., “MCC950 directly targets the NLRP 3 ATP-hydrolysis motif for inflammasome inhibition”, Nat Chem Biol 15(6):556-559 (2019); RC Coll, AA Robertson, JJ 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 as a pharmacological tool in many studies to demonstrate that the NLRP3 inflammasome is a viable drug target for developing therapeutics for human diseases. See S. Corcoran, R. Halai and M. A. 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 treating neurodegenerative diseases, including Parkinson's disease, and in treating CAPS disorders associated with heterozygous gain-of-function mutations in the NLRP3 gene. Summary of the Invention

[0011] The present invention provides 1-amino-4-phenylphthalazine derivatives and pharmaceutically acceptable salts thereof. The present invention also provides pharmaceutical compositions containing 1-amino-4-phenylphthalazine derivatives and their use for treating diseases, disorders, and conditions associated with NLRP3, including Parkinson's disease and other neurodegenerative disorders.

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

[0013]

[0014] or a pharmaceutically acceptable salt thereof, wherein:

[0015] α is a single bond and β is a single bond; and

[0016] (i)X 1 is CH2, CH(CH3) or X C ;

[0017] X 2 O and X 3 CH2 or X C ,or

[0018] X 2 CH2 or X C And X 3 is 0; and

[0019] X 4 is a bond, CH2, CH2CH2 or X C ;

[0020] where X C Selected from C 3-6 Cycloalkylene and C 3-5 Oxacycloalkylene, each of which is substituted with 0 to 4 substituents independently selected from halo, and wherein X 1 、X 2 、X 3 and X 4 One and no more than one of the C ;or

[0021] (ii)X 1 C(HR 1 );

[0022] X 2 is O;

[0023] X 3 C(HR 3 );and

[0024] X 4 is CH2;

[0025] where R 1 and R 3 Together they represent bridge R 1 and R 2 The carbon atom to which it is attached 1-3 alkanediyl; or

[0026] (iii)X 1 is CH2;

[0027] X 2 C(HR 2 );

[0028] X 3 is O;

[0029] And X 4 C(HR 4 );

[0030] where R 2 and R 4 Together they represent bridge R 2 and R 4 The carbon atom to which it is attached 1-3 alkanediyl; or

[0031] (iv)X 1 C(HR 1 );

[0032] X 2 O and X 3 for CH2, or

[0033] X 2 is CH2 and X 3 is 0; and

[0034] X 4 C(HR 4 );

[0035] where R 1 and R 4 Together means C 1-3 alkanediyl; or

[0036] (v)X 1 C(HR 1 );

[0037] X 2 is CH2;

[0038] X 3 C(HR 3 );and

[0039] X 4 is CH2;

[0040] where R1 and R 3 Together they represent bridge R 1 and R 3 The carbon atom to which it is attached 1-2 alkanediyloxy or O; or

[0041] (vi)X 1 C(HR 1 );

[0042] X 2 is CH2;

[0043] X 3 is CH2; and

[0044] X 4 C(HR 4 );

[0045] where R 1 and R 4 Together they represent bridge R 1 and R 4 The carbon atom to which it is attached 1-2 Alkanediyloxy or O;

[0046] m is selected from 0, 1 and 2;

[0047] Each R a and R b independently selected from hydrogen and C 1-4 Alkyl, or R a and R b With R a and R b The carbon atoms are connected together to form C 3-6 Cycloalkylene, provided that if m is 2, not more than one R a and R b With R a and R b The carbon atoms connected together form C 3-6 cycloalkylene;

[0048] R 5 Selected from:

[0049] (a)C 3-8 Cycloalkyl substituted with 0 to 5 substituents independently selected from:

[0050] (i) halo, hydroxy, cyano and oxo;

[0051] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0052] (iii)C1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0053] (b)C 3-8 Heterocyclyl wherein up to 3 carbon ring atoms are each independently substituted with 0 to 2 substituents independently selected from:

[0054] (i) halo, hydroxy, cyano and oxo;

[0055] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0056] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0057] and wherein the nitrogen ring atom, if present, is unsubstituted or substituted with a substituent selected from:

[0058] (i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0059] (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is substituted with 0 to 3 independently selected halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and

[0060] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0061] Among them C 3-8 The heterocyclyl group has only one ring heteroatom selected from nitrogen, oxygen and sulfur; and

[0062] n is selected from 0 and 1;

[0063] The conditions are:

[0064] If m is 0, X 1 C(HR 1 ), X 2 CH2, X 3 CH2, X 4 C(HR 4 ), X 8 is CH, α and β are both single bonds, R 1 and R 4 Together they represent bridge R 1 and R 4 The carbon atom to which the ethane-1,2-diyl radical is attached, R 6 、R 10 and R 11 Each is hydrogen, R 7 is a hydroxyl group, and R 9 is cyano, methyl or cyclopropyl, then R 5 is not 1-methylpiperidin-3-yl; and

[0065] If m is 0, X 1 C(HR 1 ), X 2 CH2, X 3 CH2, X 4 C(HR 4 ), X 8 is CH, α and β are both single bonds, R 1 and R 4 Together they represent bridge R 1 and R 4 The carbon atom to which the compound is attached is a 1,1-diyl group or O, R 6 、R 10 and R 11 Each is hydrogen, R 7 is a hydroxyl group, and R 9 is cyano, methyl or cyclopropyl, then R 5 Not 1-methylpiperidin-3-yl;

[0066] (c) phenyl, which is independently selected from halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Alkoxy is substituted by substituents, provided that at least one of the substituents is a hydroxyl group;

[0067] R 6 Selected from hydrogen and C 1-4 alkyl;

[0068] X 8 Selected from N and CR 8 ;

[0069] R 7 、R8 and R 11 Each independently selected from:

[0070] (i) hydrogen, halo, hydroxy and cyano;

[0071] (ii)C 1-4 Alkyl and C 1-4 alkoxy groups, each of which is substituted with 0 to 3 substituents independently selected from halo; and

[0072] (iii)C 3-8 Cycloalkyl, which is independently selected from halo, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted with a substituent; and

[0073] R 9 and R 10 Each independently selected from:

[0074] (i) hydrogen, halo, hydroxy and cyano;

[0075] (ii)C 1-4 Alkyl and C 1-4 alkoxy groups, each of which is substituted with 0 to 3 substituents independently selected from halo; and

[0076] (iii)C 3-8 Cycloalkyl, which is independently selected from halo, C 1-4 Alkyl and C 1-4 Substitution of the alkoxy group; or

[0077] R 9 and R 10 An ethane-1,2-dioxy moiety is formed bridging the carbon atom to which it is attached.

[0078] Another aspect of the present invention provides a compound selected from the group consisting of the compounds described in the Examples and pharmaceutically acceptable salts thereof.

[0079] Another aspect of the present invention provides a compound or a pharmaceutically acceptable salt as defined in the preceding paragraph for use as a medicament.

[0080] Another 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.

[0081] Another aspect of the present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, for use in treating diseases, disorders or conditions associated with NLRP3, including diseases, disorders or conditions associated with heterozygous gain-of-function mutations in the NLRP3 gene, such as cryptopyrin-associated periodic syndrome (CAPS).

[0082] Another aspect of the present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any 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 a heterozygous gain-of-function mutation in the NLRP3 gene, such as cryptopyrin-associated periodic syndrome (CAPS)).

[0083] Another aspect of the present invention provides a method for treating a disease, condition or disorder associated with NLRP3, including a disease, condition or disorder associated with a heterozygous gain-of-function mutation in the NLRP3 gene, such as cryptopyrin-associated periodic syndrome (CAPS), comprising administering to a subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph.

[0084] Another aspect of the present invention provides a method for treating cryopyrin-associated periodic syndromes (CAPS), including neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Mueller-Weiss 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.

[0085] Another aspect of the present invention provides a method of treating a disease, condition or disorder 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 of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, wherein the disease, condition or disorder is a neurodegenerative disease, condition or disorder.

[0086] Another 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 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.

[0087] Another aspect of the present invention provides an effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof, or any of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph; and at least one additional pharmacologically active agent. DETAILED DESCRIPTION

[0088] Unless otherwise indicated, this disclosure uses the definitions provided below.

[0089] "Substituted" refers to the presence of a chemical substituent or moiety (e.g., C 1-6 When used in conjunction with alkyl) means that one or more hydrogen atoms of the substituent or moiety have been replaced with one or more non-hydrogen atoms or groups, provided that valence requirements are met and the substitution results in a chemically stable compound.

[0090] "About" or "approximately" when used in connection with a measurable numerical variable refers to the indicated value of the variable and all values ​​of the variable that are within the experimental error of the indicated value or within ±10% of the indicated value, whichever is greater.

[0091] "Alkyl" refers to straight-chain and branched saturated hydrocarbon groups generally having the specified number of carbon atoms (e.g., C 1-4 Alkyl refers to an alkyl group having 1 to 4 (ie, 1, 2, 3, or 4) carbon atoms, C 1-6 Alkyl refers to an alkyl group having 1 to 6 carbon atoms, and so on. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentan-1-yl, pentan-2-yl, pentan-3-yl, 3-methylbutan-1-yl, 3-methylbutan-2-yl, 2-methylbutan-2-yl, 2,2,2-trimethylethan-1-yl, n-hexyl, and the like.

[0092] "Alkanediyl" refers to a divalent alkyl group where alkyl is defined above and generally has the specified number of carbon atoms (e.g., C 1-4 Alkanediyl refers to an alkanediyl group having 1 to 4 (ie, 1, 2, 3 or 4) carbon atoms, C 1-6 Alkanediyl refers to an alkanediyl group having 1 to 6 carbon atoms, and so on. 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.

[0093] "Alkenyl" refers to straight and branched hydrocarbon groups having one or more carbon-carbon double bonds and generally having the 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.

[0094] "Alkynyl" refers to a straight or branched hydrocarbon group having one or more carbon-carbon triple bonds and generally having the 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.

[0095] "Alkoxy" refers to straight-chain and branched saturated hydrocarbon groups, generally having the specified number of carbon atoms (e.g., C 1-4 Alkoxy refers to an alkoxy group having 1 to 4 (ie, 1, 2, 3 or 4) carbon atoms, C 1-6 Alkoxy refers to an alkoxy group having 1 to 6 carbon atoms, and so on. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-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-hexyloxy, and the like.

[0096] "Alkyldiyloxy" refers to a divalent alkoxy group, wherein alkoxy is defined above and generally has the specified number of carbon atoms (e.g., C 1-3 Alkanediyloxy refers to an alkanediyl group having 1 to 3 (ie, 1, 2, or 3) carbon atoms, C 1-2 Alkanediyl refers to an alkanediyl group having 1 or 2 carbon atoms, etc.). Examples of alkanediyl groups include methane-1,1-diyloxy, ethane-1,2-diyloxy, ethane-1,1-diyloxy, propane-1,3-diyloxy, propane-1,2-diyloxy, propane-1,1-diyloxy, propane-2,2-diyloxy, and the like.

[0097] "Alkylcarbonyl" and "alkylsulfonyl" refer to an alkyl group as defined above attached through a carbonyl (C(O)) or sulfonyl (SO2) group, respectively, and generally having the indicated number of carbon atoms, including the carbonyl carbon atom. For example, C(O) 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, C1-6 Alkylsulfonyl refers to an alkylsulfonyl group having 1 to 6 carbon atoms, and so on. Examples of alkylcarbonyl groups include carbonyl (formyl), methylcarbonyl (acetyl), ethylcarbonyl, isopropylcarbonyl, n-propylcarbonyl, and the like. Examples of alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-propylsulfonyl, and the like.

[0098] "Halo," "halogen," and "halo" are used interchangeably and refer to fluoro, chloro, bromo, and iodo.

[0099] "Haloalkyl," "haloalkenyl," and "haloalkynyl" refer to alkyl, alkenyl, and alkynyl, respectively, substituted with one or more halogen atoms, wherein alkyl, alkenyl, and alkynyl are defined above and generally have the specified number of carbon atoms. Examples of haloalkyl 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.

[0100] "Cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon groups (e.g., C 3-8 Cycloalkyl refers to a cycloalkyl group having 3 to 8 carbon atoms as ring members. Bicyclic hydrocarbon groups can include isolated rings (two rings share no carbon atoms), spiro rings (two rings share one carbon atom), fused rings (two rings share two carbon atoms and a bond between the two shared carbon atoms), and bridged rings (two rings share two carbon atoms but no shared bond). Cycloalkyl groups can be attached via any ring atom, unless such attachment would violate valence requirements, and, where specified, can optionally include one or more non-hydrogen substituents, unless such substitution would violate valence requirements.

[0101] 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, etc. 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 isolated bicyclic cycloalkyls include those derived from bis(cyclobutane), cyclobutanecyclopentane, bis(cyclopentane), cyclobutanecyclohexane, cyclopentanecyclohexane, bis(cyclohexane), and the like.

[0102] "Cycloalkanediyl" refers to a divalent cycloalkyl group, wherein cycloalkyl is defined above and generally has the specified number of carbon atoms (e.g., C 3-5 Cycloalkanediyl refers to a cycloalkanediyl group having 3 to 5 (ie, 3, 4 or 5) carbon atoms, C 3-6 Cycloalkanediyl refers to a cycloalkanediyl group having 3 to 6 carbon atoms, and so on. Examples of cycloalkanediyl groups include cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and the like.

[0103] "Cycloalkylene" refers to a divalent monocyclic cycloalkyl group, wherein the cycloalkyl group is as defined above, which is attached through a single carbon atom of the group and generally has the specified number of carbon atoms forming the ring (e.g., C 3-6 Cycloalkylene refers to a cycloalkylene group having 3 to 6 carbon atoms as ring members. Examples include cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene.

[0104] "Oxacycloalkylene" refers to a divalent cycloalkyl group as defined above in which one carbon atom is replaced by an oxygen atom, which is attached through a single carbon atom of the group, and generally has a specified number of carbon atoms forming the ring (e.g., C 3-5Oxacycloalkylene refers to a cycloalkylene group having 3 to 5 carbon atoms and one oxygen atom as ring members. Examples include 2-oxacyclobutylene, 3-oxacyclobutylene, 2-oxacyclopentylene, 3-oxacyclopentylene, 2-oxacyclohexylene, 3-oxacyclohexylene, and 4-oxacyclohexylene.

[0105] "Cycloalkenyl" refers to partially unsaturated monocyclic and bicyclic hydrocarbon radicals, typically having a specified number of carbon atoms constituting one or more rings. Like cycloalkyls, bicyclic cycloalkenyls can include isolated rings, spirocycles, fused rings, or bridged rings. Similarly, cycloalkenyls can be attached via any ring atom and, where specified, can optionally include one or more non-hydrogen substituents, unless such attachment or substitution would violate valence requirements. Examples of cycloalkenyls include partially unsaturated analogs of the above-mentioned cycloalkyls, such as cyclobutenyl (i.e., cyclobuten-1-yl and cyclobuten-3-yl), cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, and the like.

[0106] "Aryl" refers to fully unsaturated monocyclic aromatic hydrocarbons and polycyclic aromatic hydrocarbons having at least one aromatic ring. Both monocyclic and polycyclic aromatic groups generally have a specific number of carbon atoms (e.g., C 6-14 Aryl refers to an aromatic group having 6 to 14 carbon atoms as ring members. The group may be attached via any ring atom and, where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements. Examples of aryl groups include phenyl, biphenyl, cyclobutabenzenyl, indenyl, naphthyl, benzocycloheptyl, biphenylene, fluorenyl, groups derived from cycloheptatrienyl cations, and the like.

[0107] "Arylene" refers to a divalent aromatic radical, wherein aryl is defined above. Examples of arylene radicals include o-phenylene (ie, benzene-1,2-diyl).

[0108] "Heterocycle" and "heterocyclyl" are used interchangeably and refer to a saturated or partially unsaturated monocyclic or bicyclic group having ring atoms consisting of carbon atoms and one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Both monocyclic and bicyclic groups typically have a specified number of carbon atoms in one or more of their rings (e.g., C 2-6Heterocyclyl refers to a heterocyclyl group having 2 to 6 carbon atoms and 1 to 4 heteroatoms as ring members. As with bicyclic cycloalkyl groups, bicyclic heterocyclyl groups may include isolated, spiro, fused, and bridged rings. The heterocyclyl group may be attached via any ring atom and, where specified, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound. Examples of heterocyclic groups include oxirane, thiirane, azirane (e.g., aziridan-1-yl and aziridan-2-yl), oxetanyl, thiirane, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1,4-dioxanyl, heterocycloheptyl, 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.

[0109] "Heterocycle-diyl" refers to a heterocycle group linked through two ring atoms of the group, wherein heterocycle is defined above. A heterocycle-diyl group generally has the specified number of carbon atoms in one or more of its rings (e.g., C 2-6 Heterocycle-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-mentioned heterocycle groups, such as morpholine-3,4-diyl, pyrrolidine-1,2-diyl, 1-pyrrolidinyl-2-ylidene, 1-pyridyl-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.

[0110] "Heteroaromatic" and "heteroaryl" are used interchangeably and refer to unsaturated monocyclic aromatic groups and polycyclic groups having at least one aromatic ring, each group having ring atoms consisting 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 a heteroaryl group having 1 to 9 carbon atoms and, for example, 1 to 4 heteroatoms as ring members), and may include any of the monocyclic heterocycles listed above fused to any bicyclic group of a benzene ring. The heteroaryl group may be attached via any ring atom (or ring atoms of a fused ring) and, where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would 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), furyl, 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.

[0111] Examples of heteroaryl groups also include bicyclic groups such as benzofuranyl, isobenzofuranyl, benzothienyl, benzo[c]thienyl, 1H-indolyl, 3H-indolyl, isoindolyl, 1H-isoindolyl, indolinyl, isoindololinyl, 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, 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[1,2-c]pyrimidinyl, [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, 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-pyrrole [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.

[0112] "Heteroarylene" refers to a heteroaryl group linked through two ring atoms of a group, wherein heteroaryl is defined above. Heteroarylene groups generally have a specified number of carbon atoms in one or more of their rings (e.g., C3-5 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 above-mentioned heteroaryl groups, such as pyridine-2,3-diyl, pyridine-3,4-diyl, pyrazole-4,5-diyl, pyrazole-3,4-diyl, and the like.

[0113] "Oxo" refers to a double-bonded oxygen (=0).

[0114] "Leaving group" refers to any group that leaves a molecule during a fragmentation process, including substitution reactions, elimination reactions, and addition-elimination reactions. A leaving group can be nuclear free, in which the group leaves with a pair of electrons that originally served as a bond between the leaving group and the molecule; or it can be ionized, in which the group leaves without a pair of electrons. The ability of a nuclear free leaving group to leave depends on the strength of its base, with the strongest base being the weakest leaving group. Common nuclear free leaving groups include nitrogen (e.g., from diazonium salts); sulfonates, including alkyl sulfonates (e.g., methanesulfonates), fluoroalkyl sulfonates (e.g., trifluoromethanesulfonates, hexafluoropropanesulfonates, nonafluorobutanesulfonates, and trifluoroethanesulfonates), and aryl sulfonates (e.g., toluenesulfonates, bromobenzenesulfonates, chlorobenzenesulfonates, and nitrobenzenesulfonates). Others include carbonates, halides, carboxylate anions, phenolates, and alkoxides. Some stronger bases, such as NH2 - and OH - , can be treated with acid to become a better leaving group. Common ionizing leaving groups include protons, CO2 and metals.

[0115] "Opposite enantiomer" refers to a molecule that is a non-superimposable mirror image of a reference molecule, which can be obtained by inverting all stereogenic centers of the reference molecule. For example, if the reference molecule has an absolute stereochemistry of S, the opposite enantiomer has an absolute stereochemistry of R. Similarly, if the reference molecule has an absolute stereochemistry of S,S, the opposite enantiomer has an R,R stereochemistry, and so on.

[0116] "Stereoisomers" and "stereoisomers" of a compound having a given stereochemical configuration refer to the opposite enantiomer and any diastereomers of the compound, including geometric isomers (Z / E) of the compound. For example, if a compound has an S,R,Z stereochemical configuration, its stereoisomers would include its opposite enantiomer having an R,S,Z configuration, and its diastereomers having S,S,Z configuration, R,R,Z configuration, S,R,E configuration, R,S,E configuration, S,S,E configuration, and R,R,E configuration. If the stereochemical configuration of a compound is not specified, "stereoisomer" refers to any one of the possible stereochemical configurations of the compound.

[0117] "Substantially pure stereoisomer" and variations thereof refers to a sample containing a compound having a particular stereochemical configuration, with that compound constituting at least about 95% of the sample.

[0118] "Pure stereoisomers" and variations thereof refer to a sample containing a compound having a specific stereochemical configuration, with that compound constituting at least about 99.5% of the sample.

[0119] "Subject" refers to mammals, including humans.

[0120] "Pharmaceutically acceptable" substances refer to those substances that are suitable for administration to a subject.

[0121] "Treat," "treat," "treat," or "treating" means to reverse, alleviate, inhibit the progress of, or prevent the disease, condition, or disorder to which such term applies, or to reverse, alleviate, inhibit the progress of, or prevent one or more symptoms of, such disease, condition, or disorder.

[0122] "Treatment" refers to the act of treating as defined immediately above.

[0123] "Drug," "drug substance," "active pharmaceutical ingredient," etc., refers to a compound (e.g., a compound of Formula 1, including subclasses and compounds specifically named herein) that can be used to treat a subject in need of treatment.

[0124] An "effective amount" of a drug, a "therapeutically effective amount" of a drug, and the like, refers to the amount of the drug that can be used to treat a subject and may depend on, among other things, the weight and age of the subject and the route of administration.

[0125] "Excipient" refers to any diluent or vehicle for a drug.

[0126] A "pharmaceutical composition" refers to a combination of one or more drug substances and one or more excipients.

[0127] "Drug", "pharmaceutical dosage form", "dosage form", "final dosage form", etc. refer to a pharmaceutical composition suitable for treating a subject in need of treatment and generally in the form of a tablet, capsule, sachet containing powder or granules, liquid solution or suspension, patch, film, etc.

[0128] "NLRP3-associated disorder" and similar language refers to a disease, condition, or disorder in a subject for which inhibition of the NLRP3 inflammasome pathway may provide a therapeutic or prophylactic benefit.

[0129] The following abbreviations may be used in this specification: Ac (acetyl); Ac2O (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-butyloxycarbonyl); 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)]methanesulfonate palladium(II)); Cbz (benzyloxycarbonyl); DAST (N,N-diethyl-S,S,S-trifluoro-λ 4 thiamine); 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, Hünig's Base); DMA (N,N-dimethylacetamide); DMAP (4-dimethylaminopyridine); DME (1,2-dimethoxyethane); DMF (N,N-dimethylformamide); DMP (Dess-Martin periodinane). periodinane); DMSO (dimethyl sulfoxide); dppf (1,1'-bis(diphenylphosphino)ferrocene); DTT (dithiothreitol); EC 50 (effective concentration at half-maximal response); EDA (ethoxylated dodecanol, ); EDC (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide); EDTA (ethylenediaminetetraacetic acid); ee (enantiomeric excess); ELS (evaporative light scattering); eq (equivalent); Et (ethyl); Et3N (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)hexahydropyrazine-1-ethanesulfonic acid); HOAc (acetic acid); HOBt (1H-benzo[d][1,2,3]triazol-1-ol); IC 50(concentration at 50% inhibition); IPA (isopropyl alcohol); IPAc (isopropyl acetate); IPE (isopropyl ether); LDA (lithium diisopropylamide); LiHMDS (lithium bis(trimethylsilyl)amide); mCPBA (m-chloroperbenzoic acid); Me (methyl); MeOH (methanol); MOMO (methoxymethoxy); MTBE (tert-butyl methyl ether); mp (melting point); NaOt-Bu (sodium tert-butoxide); NMM (N-methylmorpholine); NMP (1-methylpyrrolidin-2-one); OTBS (tert-butyldimethylsilyl ether); OTf (trifluoromethanesulfonate); PE (petroleum ether); Ph (phenyl); pEC 50 (-log 10 (EC 50 ), where EC 50 Given in molar concentration (M); pIC 50 (-log 10 (IC 50 ), where IC 50 Given as molar concentration (M); Pr (propyl); c-Pr (cyclopropyl), i-Pr (isopropyl); PTFE (polytetrafluoroethylene); PyBOP ((benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate); (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-trioxatriphosphaninane 2,4,6-trioxide); TBAF (N,N,N-tributylbutane-1-fluoride); TBSOTf (tert-butyldimethylsilyl trifluoromethanesulfonate) ); TCEP (tris(2-carboxyethyl)phosphine); TFA (trifluoroacetic acid); TFAA (2,2,2-trifluoroacetic anhydride); THF (tetrahydrofuran); TMEDA (N,N,N',N'-tetramethylethane-1,2-diamine); TMS (trimethylsilyl); TMSOTf (trimethylsilyl trifluoromethanesulfonate); 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)).

[0130] As described below, the present disclosure relates to compounds of Formula 1 and pharmaceutically acceptable salts thereof. The present disclosure also relates to materials and methods for preparing compounds of Formula 1, pharmaceutical compositions containing the compounds of Formula 1, and uses of compounds of Formula 1 and pharmaceutically acceptable salts thereof (optionally in combination with other pharmacologically active agents) for treating CNS diseases, disorders, or conditions, including neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and other diseases, disorders, or conditions associated with NLRP3.

[0131] Compounds of Formula 1 and pharmaceutically acceptable salts thereof include those compounds wherein:

[0132] (1) α is a single bond and β is a single bond; and

[0133] (i)X 1 is CH2, CH(CH3) or X C ;

[0134] X 2 O and X 3 CH2 or X C ,or

[0135] X 2 CH2 or X C And X 3 is 0; and

[0136] X 4 is a bond, CH2, CH2CH2 or X C ;

[0137] where X C Selected from C 3-6 Cycloalkylene and C 3-5 Oxacycloalkylene, each of which is substituted with 0 to 4 substituents independently selected from halo, and wherein X 1 、X 2 、X 3 and X 4 One and no more than one of the C ;or

[0138] (ii)X 1 C(HR 1 );

[0139] X 2 is O;

[0140] X 3 C(HR 3 );and

[0141] X 4 is CH2;

[0142] where R1 and R 3 Together they represent bridge R 1 and R 2 The carbon atom to which it is attached 1-3 alkanediyl; or

[0143] (iii)X 1 is CH2;

[0144] X 2 C(HR 2 );

[0145] X 3 is O;

[0146] And X 4 C(HR 4 );

[0147] where R 2 and R 4 Together they represent bridge R 2 and R 4 The carbon atom to which it is attached 1-3 alkanediyl; or

[0148] (iv)X 1 C(HR 1 );

[0149] X 2 O and X 3 for CH2, or

[0150] X 2 is CH2 and X 3 is 0; and

[0151] X 4 C(HR 4 );

[0152] where R 1 and R 4 Together means C 1-3 alkanediyl; or

[0153] (v)X 1 C(HR 1 );

[0154] X 2 is CH2;

[0155] X 3 C(HR 3 );and

[0156] X 4 is CH2;

[0157] where R1 and R 3 Together they represent bridge R 1 and R 3 The carbon atom to which it is attached 1-2 alkanediyloxy or O; or

[0158] (vi)X 1 C(HR 1 );

[0159] X 2 is CH2;

[0160] X 3 is CH2; and

[0161] X 4 C(HR 4 );

[0162] where R 1 and R 4 Together they represent bridge R 1 and R 4 The carbon atom to which it is attached 1-2 Alkanediyloxy or O;

[0163] m is selected from 0, 1 and 2;

[0164] Each R a and R b independently selected from hydrogen and C 1-4 Alkyl, or R a and R b With R a and R b The carbon atoms are connected together to form C 3-6 Cycloalkylene, provided that if m is 2, not more than one R a and R b With R a and R b The carbon atoms connected together form C 3-6 cycloalkylene;

[0165] R 5 Selected from:

[0166] (a)C 3-8 Cycloalkyl, substituted with 0 to 5 substituents independently selected from the following:

[0167] (i) halo, hydroxy, cyano and oxo;

[0168] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0169] (iii)C1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0170] (b)C 3-8 Heterocyclyl wherein up to 3 carbon ring atoms are each independently substituted with 0 to 2 substituents independently selected from:

[0171] (i) halo, hydroxy, cyano and oxo;

[0172] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0173] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0174] and wherein the nitrogen ring atom, if present, is unsubstituted or substituted with a substituent selected from:

[0175] (i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0176] (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is substituted with 0 to 3 independently selected halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and

[0177] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0178] Among them C 3-8 The heterocyclyl group has only one ring heteroatom selected from nitrogen, oxygen and sulfur; and

[0179] n is selected from 0 and 1;

[0180] The conditions are:

[0181] If m is 0, X 1 C(HR 1 ), X 2 CH2, X 3 CH2, X 4 C(HR 4 ), X 8 is CH, α and β are both single bonds, R 1 and R 4 Together they represent bridge R 1 and R 4 The carbon atom to which the ethane-1,2-diyl radical is attached, R 6 、R 10 and R 11 Each is hydrogen, R 7 is a hydroxyl group, and R 9 is cyano, methyl or cyclopropyl, then R 5 is not 1-methylpiperidin-3-yl; and

[0182] If m is 0, X 1 C(HR 1 ), X 2 CH2, X 3 CH2, X 4 C(HR 4 ), X 8 is CH, α and β are both single bonds, R 1 and R 4 Together they represent bridge R 1 and R 4 The carbon atom to which the compound is attached is a 1,1-diyl group or O, R 6 、R 10 and R 11 Each is hydrogen, R 7 is a hydroxyl group, and R 9 is cyano, methyl or cyclopropyl, then R 5 Not 1-methylpiperidin-3-yl;

[0183] (c) phenyl, which is independently selected from halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Alkoxy is substituted by substituents, provided that at least one of the substituents is a hydroxyl group;

[0184] R 6 Selected from hydrogen and C 1-4 alkyl;

[0185] X 8 Selected from N and CR 8 ;

[0186] R 7 、R8 and R 11 Each independently selected from:

[0187] (i) hydrogen, halo, hydroxy and cyano;

[0188] (ii)C 1-4 Alkyl and C 1-4 alkoxy groups, each of which is substituted with 0 to 3 substituents independently selected from halo; and

[0189] (iii)C 3-8 Cycloalkyl, which is independently selected from halo, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted with a substituent; and

[0190] R 9 and R 10 Each independently selected from:

[0191] (i) hydrogen, halo, hydroxy and cyano;

[0192] (ii)C 1-4 Alkyl and C 1-4 alkoxy groups, each of which is substituted with 0 to 3 substituents independently selected from halo; and

[0193] (iii)C 3-8 Cycloalkyl, which is independently selected from halo, C 1-4 Alkyl and C 1-4 Substitution of the alkoxy group; or

[0194] R 9 and R 10 An ethane-1,2-dioxy moiety is formed bridging the carbon atom to which it is attached.

[0195] In addition to the above embodiment (1), compounds of formula 1 include those compounds wherein:

[0196] (61)α is a single bond and β is a single bond; and

[0197] (i)X 1 is CH2, CH(CH3) or X C ;

[0198] X 2 O and X 3 CH2 or X C ,or

[0199] X 2 CH2 or X C And X 3 is 0; and

[0200] X 4 is a bond, CH2, CH2CH2 or X C ;

[0201] where X C Selected from C 3-6 Cycloalkylene and C 3-5 Oxacycloalkylene, each of which is substituted with 0 to 4 substituents independently selected from halo, and wherein X 1 、X 2 、X 3 and X 4 One and no more than one of the C ;or

[0202] (ii)X 1 C(HR 1 );

[0203] X 2 is O;

[0204] X 3 C(HR 3 );and

[0205] X 4 is CH2;

[0206] where R 1 and R 3 Together they represent bridge R 1 and R 2 The carbon atom to which it is attached 1-3 alkanediyl; or

[0207] (iii)X 1 is CH2;

[0208] X 2 C(HR 2 );

[0209] X 3 is O;

[0210] And X 4 C(HR 4 );

[0211] where R 2 and R 4 Together they represent bridge R 2 and R 4 The carbon atom to which it is attached 1-3 alkanediyl; or

[0212] (iv)X 1 C(HR 1 );

[0213] X2 O and X 3 for CH2, or

[0214] X 2 is CH2 and X 3 is 0; and

[0215] X 4 C(HR 4 );

[0216] where R 1 and R 4 Together means C 1-3 alkanediyl; or

[0217] (v)X 1 C(HR 1 );

[0218] X 2 is CH2;

[0219] X 3 C(HR 3 );and

[0220] X 4 is CH2;

[0221] where R 1 and R 3 Together they represent bridge R 1 and R 3 The carbon atom to which it is attached 1-2 alkanediyloxy or O; or

[0222] (vi)X 1 C(HR 1 );

[0223] X 2 is CH2;

[0224] X 3 is CH2; and

[0225] X 4 C(HR 4 );

[0226] where R 1 and R 4 Together they represent bridge R 1 and R 4 The carbon atom to which it is attached 1-2 Alkanediyloxy or O.

[0227] In addition to embodiment (61) in the preceding paragraph, compounds of Formula 1 include those wherein:

[0228] (62)X 1 is CH2, CH(CH3) or X C ;

[0229] X 2 O and X 3 CH2 or X C ,or

[0230] X 2 CH2 or X C And X 3 is 0; and

[0231] X 4 is a bond, CH2, CH2CH2 or X C ;

[0232] where X C Selected from C 3-6 Cycloalkylene and C 3-5 Oxacycloalkylene, each of which is substituted with 0 to 4 substituents independently selected from halo, and wherein X 1 、X 2 、X 3 and X 4 One and no more than one of the C .

[0233] In addition to embodiment (62) in the preceding paragraph, compounds of Formula 1 include those wherein:

[0234] (63)X C Selected from C 3-4 Cycloalkylene and C 3-5 Oxacycloalkylene, each substituted with 0 to 4 substituents independently selected from halo;

[0235] (64)X C C 3-4 Cycloalkylene, substituted with 0 to 4 substituents independently selected from halo;

[0236] (65)X C is cyclopropylene, which is substituted with 0 to 4 substituents independently selected from halo;

[0237] (66)X C is cyclobutylene, which is substituted with 0 to 4 substituents independently selected from halo;

[0238] (67)X C C 3-5 Oxacycloalkylene substituted with 0 to 4 substituents independently selected from halo;

[0239] (68)X Cis oxacyclobutylene, which is substituted with 0 to 4 substituents independently selected from halo;

[0240] (69)X C is 3-oxacyclobutylene, substituted with 0 to 4 substituents independently selected from halo;

[0241] (70)X C is oxacyclopentylene, which is substituted with 0 to 4 substituents independently selected from halo;

[0242] (71)X C is 3-oxacyclopentylene, which is substituted with 0 to 4 substituents independently selected from halo;

[0243] (72)X C is oxacyclohexylene substituted with 0 to 4 substituents independently selected from halo; or

[0244] (73)X C is 4-oxacyclohexylene substituted with 0 to 4 substituents independently selected from halo.

[0245] In addition to embodiments (62) to (73) in the preceding paragraph, compounds of Formula 1 include those wherein:

[0246] (74)X 1 CH2 or X C ;

[0247] X 2 O and X 3 CH2 or X C ,or

[0248] X 2 CH2 or X C And X 3 is 0; and

[0249] X 4 CH2 or X C ;

[0250] (75)X 1 CH2 or X C ;

[0251] X 2 O and X 3 CH2 or X C ,or

[0252] X 2 CH2 or X C And X 3 is 0; and

[0253] X4 is the key;

[0254] (76)X 1 CH2 or X C ;

[0255] X 2 O and X 3 CH2 or X C ;and

[0256] X 4 is the key;

[0257] (77)X 1 For X C ;

[0258] X 2 O and X 3 for CH2, or

[0259] X 2 is CH2 and X 3 is 0; and

[0260] X 4 is the key;

[0261] (78)X 1 For X C ;

[0262] X 2 O and X 3 is CH2; and

[0263] X 4 is the key;

[0264] (79)X 1 CH2 or X C ;

[0265] X 2 O and X 3 CH2 or X C ,or

[0266] X 2 CH2 or X C And X 3 is 0; and

[0267] X 4 is CH2CH2; or

[0268] (80)X 1 For X C ;

[0269] X 2 O and X 3 for CH2, or

[0270] X 2 is CH2 and X 3 is 0; and

[0271] X 4 is CH2CH2.

[0272] In addition to embodiments (62) to (80) in the preceding paragraph, compounds of Formula 1 include those wherein:

[0273] (81)X C substituted with 0 to 3 substituents independently selected from halo;

[0274] (82)X C substituted with 0 to 2 substituents independently selected from halo;

[0275] (83)X C substituted with 0 to 1 substituents independently selected from halo; or

[0276] (84)X C Not replaced.

[0277] In addition to the above embodiments (62) to (80), compounds of Formula 1 include those wherein:

[0278] (85)X C substituted with 0 to 4 fluorines;

[0279] (86)X C substituted with 0 to 3 fluorines;

[0280] (87)X C substituted with 0 to 2 fluorine; or

[0281] (88)X C Substituted with 0 to 1 fluorine.

[0282] In addition to the above embodiment (61), compounds of Formula 1 include those wherein X 1 C(HR 1 ), X 2 O, X 3 C(HR 3 ) and X 4 is CH2, where R 1 and R 3 Together we say:

[0283] (89) Bridge R 1 and R 3 The carbon atom to which it is attached 1-3 Alkanediyl;

[0284] (90) Bridge R1 and R 3 The carbon atom to which it is attached 1-2 Alkanediyl;

[0285] (91) Bridge R 1 and R 3 The carbon atom to which the methane-1,1-diyl radical is attached; or

[0286] (92) Bridge R 1 and R 3 The attached carbon atom is ethane-1,2-diyl.

[0287] In addition to the above embodiment (61), compounds of Formula 1 include those wherein X 1 CH2, X 2 C(HR 2 ), X 3 O and X 4 C(HR 4 ), where R 2 and R 4 Together we say:

[0288] (93) Bridge R 2 and R 4 The carbon atom to which it is attached 1-3 Alkanediyl;

[0289] (94) Bridge R 2 and R 4 The carbon atom to which it is attached 1-2 Alkanediyl;

[0290] (95) Bridge R 2 and R 4 The carbon atom to which the methane-1,1-diyl radical is attached; or

[0291] (96) Bridge R 2 and R 4 The attached carbon atom is ethane-1,2-diyl.

[0292] In addition to the above embodiment (61), compounds of Formula 1 include those wherein:

[0293] (97)X 1 C(HR 1 );

[0294] X 2 O and X 3 for CH2, or

[0295] X 2 is CH2 and X 3 is 0; and

[0296] X 4 C(HR 4 );

[0297] where R 1 and R 4 Together means C 1-3 Alkanediyl;

[0298] (98)X 1 C(HR 1 );

[0299] X 2 is O;

[0300] X 3 is CH2, and

[0301] X 4 C(HR 4 );

[0302] where R 1 and R 4 Together means C 1-3 alkanediyl; or

[0303] (99)X 1 C(HR 1 );

[0304] X 2 is CH2;

[0305] X 3 is 0; and

[0306] X 4 C(HR 4 );

[0307] where R 1 and R 4 Together means C 1-3 Alkanediyl.

[0308] In addition to embodiments (97) to (99) in the preceding paragraph, compounds of Formula 1 include those wherein R 1 and R 4 Together we say:

[0309] (100) Bridge R 1 and R 4 The carbon atom to which it is attached 1-2 Alkanediyl;

[0310] (101) Bridge R 1 and R 4 The carbon atom to which the methane-1,1-diyl radical is attached; or

[0311] (102) Bridge R 1 and R 4 The attached carbon atom is ethane-1,2-diyl.

[0312] In addition to the above embodiment (61), compounds of Formula 1 include those wherein:

[0313] (103)X 1 C(HR 1 );

[0314] X 2 is CH2;

[0315] X 3 C(HR 3 );and

[0316] X 4 is CH2;

[0317] where R 1 and R 3 Together they represent bridge R 1 and R 3 The carbon atom to which it is attached 1-2 Alkanediyloxy or O.

[0318] In addition to embodiment (103) in the preceding paragraph, compounds of Formula 1 include those wherein R 1 and R 3 Together we say:

[0319] (104) Bridge R 1 and R 3 The carbon atom to which it is attached 1-2 Alkanediyloxy;

[0320] (105) Bridge R 1 and R 3 methane-1,1-diyloxy to the carbon atom to which it is attached;

[0321] (106) Bridge R 1 and R 3 ethane-1,2-diyloxy to the carbon atom to which it is attached; or

[0322] (107)O.

[0323] In addition to the above embodiment (61), compounds of Formula 1 include those wherein:

[0324] (108)X 1 C(HR 1 );

[0325] X2 is CH2;

[0326] X 3 is CH2; and

[0327] X 4 C(HR 4 );

[0328] where R 1 and R 4 Together they represent bridge R 1 and R 4 The carbon atom to which it is attached 1-2 Alkanediyloxy or O.

[0329] In addition to embodiment (108) in the preceding paragraph, compounds of Formula 1 include those wherein R 1 and R 4 Together we say:

[0330] (109) Bridge R 1 and R 4 The carbon atom to which it is attached 1-2 Alkanediyloxy;

[0331] (110) Bridge R 1 and R 4 methane-1,1-diyloxy to the carbon atom to which it is attached;

[0332] (111) Bridge R 1 and R 4 ethane-1,2-diyloxy to the carbon atom to which it is attached; or

[0333] (112)O.

[0334] In addition to any one of the above embodiments (1) to (112), compounds of Formula 1 include those wherein m is:

[0335] (116)0; or

[0336] (117)1 or 2.

[0337] In addition to embodiment (117) in the preceding paragraph, compounds of Formula 1 include those wherein:

[0338] (118) Each R a and R b independently selected from hydrogen and C 1-4 alkyl;

[0339] (119) Each R a and R b independently selected from hydrogen and C 1-3alkyl;

[0340] (120) Each R a and R b independently selected from hydrogen and methyl;

[0341] (121) Each R a is methyl and each R b is hydrogen;

[0342] (122) Each R a is methyl and each R b is methyl;

[0343] (123) Each R a is hydrogen and each R b is hydrogen;

[0344] (124) Each R a and R b independently selected from hydrogen and C 1-4 Alkyl, or R a and R b With R a and R b The carbon atoms to which they are attached together form a cyclopropylene or cyclobutylene group, provided that if m is 2, not more than one R a and R b With R a and R b The attached carbon atoms together form a cyclopropylene or cyclobutylene group;

[0345] (125) Each R a and R b independently selected from hydrogen and C 1-4 Alkyl, or R a and R b With R a and R b The carbon atoms to which they are attached together form a cyclopropylene group, provided that if m is 2, not more than one R a and R b With R a and R b The attached carbon atoms together form a cyclopropylene group;

[0346] (126) Each R a and R b independently selected from hydrogen and C 1-3 Alkyl, or R a and R b With R a and R b The carbon atoms to which they are attached together form a cyclopropylene group, provided that if m is 2, not more than one R a and R bWith R a and R b The attached carbon atoms together form a cyclopropylene group;

[0347] (127) Each R a and R b are independently selected from hydrogen and methyl, or R a and R b With R a and R b The carbon atoms to which they are attached together form a cyclopropylene group, provided that if m is 2, not more than one R a and R b With R a and R b The carbon atoms to which they are attached together form a cyclopropylene group; or

[0348] (128) Each R a and R b is hydrogen, or R a and R b With R a and R b The carbon atoms to which they are attached together form a cyclopropylene group, provided that if m is 2, not more than one R a and R b With R a and R b The attached carbon atoms together form a cyclopropylene group.

[0349] In addition to any one of the above embodiments (1) to (128), compounds of Formula 1 include those wherein R 5 for:

[0350] (129)C 3-8 Cycloalkyl substituted with 0 to 5 substituents independently selected from:

[0351] (i) halo, hydroxy, cyano and oxo;

[0352] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0353] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0354] (130)C 4-7 Cycloalkyl substituted with 0 to 5 substituents independently selected from:

[0355] (i) halo, hydroxy, cyano and oxo;

[0356] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0357] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0358] (131) Cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]hept-1-yl, and spiro[3.3]hept-2-yl, each of which is substituted with 0 to 5 substituents independently selected from the group consisting of:

[0359] (i) halo, hydroxy, cyano and oxo;

[0360] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0361] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0362] (132) Cycloalkyl selected from cyclobutyl, cyclohexyl, bicyclo[2.2.1]hept-1-yl, and spiro[3.3]hept-2-yl, each of which is substituted with 0 to 5 substituents independently selected from the group consisting of:

[0363] (i) halo, hydroxy, cyano and oxo;

[0364] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0365] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0366] (133) Cycloalkyl selected from cyclobutyl, cyclohexyl, and bicyclo[2.2.1]hept-1-yl, each of which is substituted with 0 to 5 substituents independently selected from the group consisting of:

[0367] (i) halo, hydroxy, cyano and oxo;

[0368] (ii) amino, which is independently selected from C 1-4Substitution of the alkyl group with a substituent; and

[0369] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0370] (134) Cycloalkyl, which is cyclobutyl substituted with 0 to 5 substituents independently selected from the group consisting of:

[0371] (i) halo, hydroxy, cyano and oxo;

[0372] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0373] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0374] (135) Cycloalkyl, which is a cyclohexyl group substituted with 0 to 5 substituents independently selected from the group consisting of:

[0375] (i) halo, hydroxy, cyano and oxo;

[0376] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0377] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo; or

[0378] (136) Cycloalkyl, which is bicyclo[2.2.1]hept-1-yl substituted with 0 to 5 substituents independently selected from:

[0379] (i) halo, hydroxy, cyano and oxo;

[0380] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0381] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 Alkoxy groups, each of which is substituted with 0 to 3 substituents independently selected from halo.

[0382] In addition to any one of embodiments (129) to (136) in the preceding paragraph, compounds of Formula 1 include those wherein R 5 The cycloalkyl group is substituted with 0 to 5 substituents independently selected from:

[0383] (137) (i) halo, hydroxy and oxo;

[0384] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0385] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0386] (138) (i) halo and hydroxy;

[0387] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0388] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0389] (139)(i) hydroxyl and fluorine;

[0390] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0391] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0392] (140)(i) hydroxyl group;

[0393] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0394] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0395] (141)(i) halo, hydroxy, cyano and oxo;

[0396] (ii) amino, which is independently selected from C 1-3 Substitution of the alkyl group with a substituent; and

[0397] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0398] (142) (i) halo, hydroxy, cyano and oxo;

[0399] (ii) amino substituted with 0 to 2 substituents independently selected from methyl; and

[0400] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0401] (143) (i) halo, hydroxy, cyano and oxo;

[0402] (ii) amino groups, which are unsubstituted; and

[0403] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0404] (144) (i) halo, hydroxy, cyano and oxo;

[0405] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0406] (iii)C 1-3 Alkyl, C 1-3 Alkylcarbonyl and C 1-3 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0407] (145) (i) halo, hydroxy, cyano and oxo;

[0408] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0409] (iii) methyl, methylcarbonyl, ethylcarbonyl, methoxy and ethoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0410] (146) (i) halo, hydroxy, cyano and oxo;

[0411] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0412] (iii) methyl and methoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0413] (147)(i) hydroxyl group;

[0414] (ii) amino substituted with 0 to 2 substituents independently selected from methyl; and

[0415] (iii) methyl and methoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0416] (148)(i) hydroxyl group;

[0417] (ii) amino substituted with 0 to 2 substituents independently selected from methyl; and

[0418] (iii) methyl and methoxy, each of which is substituted with 0 to 3 substituents independently selected from fluorine; or

[0419] (149) Hydroxyl, dimethylamino, methyl, trifluoromethyl and methoxy.

[0420] In addition to any one of the preceding embodiments (129) to (149), compounds of Formula 1 include those wherein R 5 Cycloalkyl:

[0421] (150) substituted with 0 to 4 substituents;

[0422] (151) substituted with 0 to 3 substituents;

[0423] (152) substituted with 0 to 2 substituents;

[0424] (153) substituted with 0 to 1 substituents; or

[0425] (154) Unsubstituted.

[0426] In addition to any one of the above embodiments (1) to (128), compounds of Formula 1 include those wherein R 5 for:

[0427] (155)C 3-8 Heterocyclyl wherein up to 3 carbon ring atoms are each independently substituted with 0 to 2 substituents independently selected from:

[0428] (i) halo, hydroxy, cyano and oxo;

[0429] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0430] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0431] and wherein the nitrogen ring atom, if present, is unsubstituted or substituted with a substituent selected from:

[0432] (i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0433] (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is substituted with 0 to 3 independently selected halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and

[0434] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0435] (156)C 3-8 Heterocyclyl, wherein the ring heteroatoms are selected from nitrogen and oxygen and up to 3 carbon ring atoms are each independently substituted with 0 to 2 substituents independently selected from:

[0436] (i) halo, hydroxy, cyano and oxo;

[0437] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0438] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0439] and wherein the nitrogen ring atom, if present, is unsubstituted or substituted with a substituent selected from:

[0440] (i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0441] (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is substituted with 0 to 3 independently selected halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and

[0442] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0443] (157)C 3-8 Heterocyclyl wherein the ring heteroatom is nitrogen and up to 3 carbon ring atoms are each independently substituted with 0 to 2 substituents independently selected from:

[0444] (i) halo, hydroxy, cyano and oxo;

[0445] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0446] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0447] and wherein the nitrogen ring atom is unsubstituted or substituted with a substituent selected from:

[0448] (i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0449] (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is substituted with 0 to 3 independently selected halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and

[0450] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0451] (158) Heterocyclyl selected from azetidinyl, piperidinyl, 1-azabicyclo[2.2.1]heptyl, quinuclidinyl, pyrrolidinyl, 3-azabicyclo[3.1.0]hexan-1-yl and 2-oxabicyclo[2.2.1]hept-4-yl, wherein R 5 Up to 3 carbon ring atoms of the heterocyclyl group are each independently substituted with 0 to 2 substituents independently selected from:

[0452] (i) halo, hydroxy, cyano and oxo;

[0453] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0454] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0455] And where R 5 The nitrogen ring atom of the heterocyclyl group, if present, is unsubstituted or substituted with a substituent selected from:

[0456] (i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0457] (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is substituted with 0 to 3 independently selected halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C1-4 Alkoxy and oxo groups are substituted with substituents; and

[0458] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of the alkoxy group; or

[0459] (159) a heterocyclyl group selected from azetidin-1-yl, piperidin-2-yl, piperidin-3-yl, 1-azabicyclo[2.2.1]hept-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]hept-4-yl, wherein R 5 Up to 3 carbon ring atoms of the heterocyclyl group are each independently substituted with 0 to 2 substituents independently selected from:

[0460] (i) halo, hydroxy, cyano and oxo;

[0461] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0462] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0463] And where R 5 The nitrogen ring atom of the heterocyclyl group, if present, is unsubstituted or substituted with a substituent selected from:

[0464] (i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0465] (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is substituted with 0 to 3 independently selected halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and

[0466] (iii) Phenyl-(CH2) nand pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 The substituents of the alkoxy group are substituted.

[0467] In addition to any one of the preceding embodiments (155) to (159), compounds of Formula 1 include those wherein R 5 Up to 3 carbon ring atoms of the heterocyclyl group are each independently substituted with 0 to 2 substituents independently selected from:

[0468] (160)(i) halo, hydroxy and oxo;

[0469] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0470] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0471] (161)(i) halo and oxo;

[0472] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0473] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0474] (162) (i) halo;

[0475] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0476] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0477] (163) (i) halo, hydroxy, cyano and oxo;

[0478] (ii) amino, which is independently selected from C 1-3 Substitution of the alkyl group with a substituent; and

[0479] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0480] (164) (i) halo, hydroxy, cyano and oxo;

[0481] (ii) amino substituted with 0 to 2 substituents independently selected from methyl; and

[0482] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0483] (165) (i) halo, hydroxy, cyano and oxo;

[0484] (ii) amino groups, which are unsubstituted; and

[0485] (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0486] (166) (i) halo, hydroxy, cyano and oxo;

[0487] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0488] (iii)C 1-3 Alkyl, C 1-3 Alkylcarbonyl and C 1-3 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0489] (167) (i) halo, hydroxy, cyano and oxo;

[0490] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0491] (iii) methyl, methylcarbonyl, ethylcarbonyl, methoxy and ethoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0492] (168) (i) halo, hydroxy, cyano and oxo;

[0493] (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and

[0494] (iii) methyl and methoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0495] (169) (i) halo and oxo;

[0496] (ii) amino substituted with 0 to 2 substituents independently selected from methyl; and

[0497] (iii) methyl and methoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0498] (170)(i) halo and oxo;

[0499] (ii) amino substituted with 0 to 2 substituents independently selected from methyl; and

[0500] (iii) methyl and methoxy, each of which is substituted with 0 to 3 substituents independently selected from fluorine;

[0501] (171) halo, oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy and isopropoxy;

[0502] (172) halo, oxo, methyl, ethyl, propyl and isopropyl; or

[0503] (173) Fluoro, oxo, methyl, ethyl, propyl and isopropyl.

[0504] In addition to any one of embodiments (155) to (173) of the preceding paragraph, compounds of Formula 1 include those wherein:

[0505] (174)R 5 Up to two carbon ring atoms of the heterocyclyl group are each substituted;

[0506] (175)R 5 Up to one carbon ring atom of the heterocyclyl group is substituted; or

[0507] (176)R 5 None of the carbon ring atoms of the heterocyclyl group is substituted.

[0508] In addition to any one of the preceding embodiments (155) to (176), compounds of Formula 1 include those wherein R 5 C 3-8 Heterocyclyl, wherein the nitrogen ring atom (if present) is unsubstituted or substituted with a substituent selected from:

[0509] (177)(i)C 1-3 Alkyl, C 1-3 Alkylcarbonyl and C 1-3 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0510] (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is independently selected from halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and

[0511] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0512] (178)(i)C 1-3 alkyl, methylcarbonyl, ethylcarbonyl, methylsulfonyl and ethylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0513] (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is independently selected from halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and

[0514] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0515] (179) (i) methyl, ethyl, isopropyl, methylcarbonyl and methylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0516] (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8The cycloalkyl moiety is independently selected from halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and

[0517] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0518] (180) (i) methyl, ethyl, isopropyl, methylcarbonyl, methylsulfonyl, each of which is substituted with 0 to 3 substituents selected from fluorine;

[0519] (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is independently selected from halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and

[0520] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0521] (181)(i) methyl, ethyl, isopropyl, methylcarbonyl, methylsulfonyl, each of which is unsubstituted;

[0522] (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is independently selected from halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and

[0523] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0524] (182)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0525] (ii)C 3-5 Cycloalkyl-(CH2) n , the C 3-5 The cycloalkyl moiety is independently selected from halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and

[0526] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0527] (183)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0528] (ii)C 3-5 Cycloalkyl-(CH2) n , the C 3-5 The cycloalkyl moiety is independently selected from halo, C 1-3 Alkyl, C 1-3 Alkylcarbonyl, C 1-3 Alkoxy and oxo groups are substituted with substituents; and

[0529] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0530] (184)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0531] (ii)C3-5 Cycloalkyl-(CH2) n , the C 3-5 The cycloalkyl moiety is independently selected from halo, C 1-3 Alkyl and C 1-3 Substitution of the alkoxy group with a substituent; and

[0532] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0533] (185)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0534] (ii)C 3-5 Cycloalkyl-(CH2) n , the C 3-5 The cycloalkyl moiety is independently selected from C 1-3 Alkyl and C 1-3 Substitution of the alkoxy group with a substituent; and

[0535] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0536] (186)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0537] (ii)C 3-5 Cycloalkyl-(CH2) n , the C 3-5 The cycloalkyl moiety is substituted with 0 to 3 substituents independently selected from halo, methyl, and methoxy; and

[0538] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0539] (187)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0540] (ii)C 3-5 Cycloalkyl-(CH2) n , the C 3-5 The cycloalkyl moiety is substituted with 0 to 3 substituents independently selected from fluoro, methyl and methoxy; and

[0541] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0542] (188)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0543] (ii)C 3-5 Cycloalkyl-(CH2) n , the C 3-5 The cycloalkyl moiety is substituted with 0 to 3 substituents independently selected from methyl and methoxy; and

[0544] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0545] (189)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0546] (ii)C 3-5 Cycloalkyl-(CH2) n , the C 3-5 The cycloalkyl moiety is unsubstituted; and

[0547] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0548] (190)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0549] (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is independently selected from halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and

[0550] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-3 Alkyl and C 1-3 Substitution of alkoxy groups;

[0551] (191)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0552] (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is independently selected from halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and

[0553] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 substituents independently selected from halo, hydroxy, cyano, methyl and methoxy;

[0554] (192)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0555] (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is independently selected from halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and

[0556] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 substituents independently selected from halo, hydroxy, methyl and methoxy;

[0557] (193)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0558] (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is independently selected from halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and

[0559] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 substituents independently selected from fluoro, chloro, hydroxy, methyl and methoxy;

[0560] (194)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0561] (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is independently selected from halo, C 1-4 Alkyl, C1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and

[0562] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 substituents independently selected from fluoro, hydroxy, methyl and methoxy;

[0563] (195)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0564] (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is independently selected from halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and

[0565] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are unsubstituted;

[0566] (196) (i) methyl, ethyl, isopropyl, methylcarbonyl, methylsulfonyl, each of which is substituted with 0 to 3 substituents selected from fluorine;

[0567] (ii)C 3-5 Cycloalkyl-(CH2) n , the C 3-5 The cycloalkyl moiety is substituted with 0 to 3 substituents independently selected from fluoro, methyl and methoxy; and

[0568] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 substituents independently selected from fluoro, hydroxy, methyl and methoxy;

[0569] (197) (i) methyl, ethyl, isopropyl, methylcarbonyl, methylsulfonyl, each of which is substituted with 0 to 3 substituents selected from fluorine;

[0570] (ii)C 3-5 Cycloalkyl-(CH2) n , the C 3-5The cycloalkyl moiety is substituted with 0 to 3 substituents independently selected from methyl and methoxy; and

[0571] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 substituents independently selected from fluoro, hydroxy, methyl and methoxy; or

[0572] (198) (i) methyl, ethyl, isopropyl, methylcarbonyl, methylsulfonyl, each of which is substituted with 0 to 3 substituents selected from fluorine;

[0573] (ii)C 3-5 Cycloalkyl-(CH2) n , the C 3-5 The cycloalkyl moiety is substituted with 0 to 3 substituents independently selected from methyl and methoxy; and

[0574] (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are unsubstituted.

[0575] In addition to any one of the preceding embodiments (155) to (198), compounds of Formula 1 include those wherein:

[0576] (199)R 5 C 3-8 heterocyclyl and n is 0; or

[0577] (200)R 5 C 3-8 heterocyclic group and n is 1.

[0578] In addition to any one of the above embodiments (1) to (128), compounds of Formula 1 include those wherein R 5 is a phenyl group, wherein:

[0579] (201) is independently selected from 0 to 3 halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Alkoxy is substituted by substituents, provided that at least one of the substituents is a hydroxyl group;

[0580] (202) is independently selected from 0 to 3 halo, hydroxy, cyano, C 1-3 Alkyl and C 1-3 Alkoxy is substituted by substituents, provided that at least one of the substituents is a hydroxyl group;

[0581] (203) is 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;

[0582] (204) is 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;

[0583] (205) unsubstituted or substituted with hydroxyl; or

[0584] (206) Unsubstituted.

[0585] In addition to any one of the preceding embodiments (1) to (206), compounds of Formula 1 include those wherein R 6 Selected from:

[0586] (207) Hydrogen and C 1-3 alkyl;

[0587] (208) Hydrogen and methyl;

[0588] (209) methyl; or

[0589] (210) Hydrogen.

[0590] In addition to any one of the preceding embodiments (1) to (210), compounds of Formula 1 include those wherein:

[0591] (211)X 8 CR 8 .

[0592] In addition to any one of the preceding embodiments (1) to (211), compounds of Formula 1 include those wherein R 7 、R 8 and R 11 Each independently selected from:

[0593] (212) (i) hydrogen, halo and hydroxy;

[0594] (ii)C 1-4 Alkyl and C 1-4 alkoxy groups, each of which is substituted with 0 to 3 substituents independently selected from halo; and

[0595] (iii)C 3-8 Cycloalkyl, which is independently selected from halo, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0596] (213)(i) hydrogen, halo and hydroxy; and

[0597] (ii)C 1-4 Alkyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0598] (214)(i) hydrogen, halo and hydroxy; and

[0599] (ii)C 1-3 Alkyl and C 1-3 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0600] (215)(i) hydrogen, halo and hydroxy; and

[0601] (ii) methyl and methoxy, each of which is substituted with 0 to 3 substituents independently selected from halo; or

[0602] (216)(i) hydrogen, halo and hydroxy; and

[0603] (ii) methyl and methoxy, each of which is substituted with 0 to 3 fluorine groups.

[0604] In addition to any one of the above embodiments (1) to (211), compounds of Formula 1 include those wherein R 7 and R 8 are all hydrogen, and R 11 Selected from:

[0605] (217)(i) hydrogen, halo and hydroxy; and

[0606] (ii)C 1-3 Alkyl and C 1-3 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo;

[0607] (218)(i) hydrogen, halo and hydroxy; and

[0608] (ii) methyl and methoxy, each of which is substituted with 0 to 3 substituents independently selected from halo; or

[0609] (219)(i) hydrogen, halo and hydroxy; and

[0610] (ii) methyl and methoxy, each of which is substituted with 0 to 3 fluorine groups.

[0611] In addition to any one of the preceding embodiments (1) to (219), compounds of Formula 1 include those wherein R 9 and R 10 Each independently selected from:

[0612] (220)(i) hydrogen, halo, hydroxy and cyano;

[0613] (ii)C 1-4 Alkyl and C 1-4 alkoxy groups, each of which is substituted with 0 to 3 substituents independently selected from halo; and

[0614] (iii)C 3-8 Cycloalkyl, which is independently selected from halo, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0615] (221)(i) Hydrogen, halo, hydroxy and cyano;

[0616] (ii)C 1-4 Alkyl and C 1-3 alkoxy groups, each of which is substituted with 0 to 3 substituents independently selected from halo; and

[0617] (iii)C 3-8 Cycloalkyl, which is independently selected from halo, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0618] (222)(i) Hydrogen, halo, hydroxy and cyano;

[0619] (ii)C 1-4 alkyl and methoxy, each of which is substituted with 0 to 3 substituents independently selected from halo; and

[0620] (iii)C 3-8 Cycloalkyl, which is independently selected from halo, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0621] (223) (i) hydrogen, halo, hydroxy and cyano;

[0622] (ii)C 1-4 Alkyl and methoxy, each substituted with 0 to 3 fluorines; and

[0623] (iii)C 3-8 Cycloalkyl, which is independently selected from halo, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0624] (224) (i) hydrogen, halo, hydroxy and cyano;

[0625] (ii)C 1-4 Alkyl and C 1-4alkoxy groups, each of which is substituted with 0 to 3 substituents independently selected from halo; and

[0626] (iii)C 3-5 Cycloalkyl, which is independently selected from halo, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0627] (225)(i) hydrogen, halo, hydroxy and cyano;

[0628] (ii)C 1-4 Alkyl and C 1-4 alkoxy groups, each of which is substituted with 0 to 3 substituents independently selected from halo; and

[0629] (iii)C 3-5 Cycloalkyl, which is independently selected from C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups;

[0630] (226) (i) hydrogen, halo, hydroxy and cyano;

[0631] (ii)C 1-4 Alkyl and C 1-4 alkoxy groups, each of which is substituted with 0 to 3 substituents independently selected from halo; and

[0632] (iii)C 3-5 Cycloalkyl, which is independently selected from C 1-3 Alkyl and C 1-3 Substitution of alkoxy groups;

[0633] (227) (i) hydrogen, halo, hydroxy and cyano;

[0634] (ii)C 1-4 Alkyl and C 1-4 alkoxy groups, each of which is substituted with 0 to 3 substituents independently selected from halo; and

[0635] (iii)C 3-5 cycloalkyl substituted with 0 to 3 substituents independently selected from methyl and methoxy;

[0636] (228) (i) hydrogen, halo, hydroxy and cyano;

[0637] (ii)C 1-4 Alkyl and C 1-4 alkoxy groups, each of which is substituted with 0 to 3 substituents independently selected from halo; and

[0638] (iii) cyclopropyl and cyclobutyl, each of which is substituted with 0 to 3 substituents independently selected from methyl and methoxy;

[0639] (229) (i) hydrogen, halo, hydroxy and cyano;

[0640] (ii)C 1-4 Alkyl and C 1-3 alkoxy groups, each of which is substituted with 0 to 3 substituents independently selected from halo; and

[0641] (iii)C 3-5 Cycloalkyl, which is independently selected from C 1-3 Alkyl and C 1-3 Substitution of alkoxy groups;

[0642] (230)(i) hydrogen, halo, hydroxy and cyano;

[0643] (ii)C 1-4 Alkyl and C 1-3 alkoxy groups, each of which is substituted with 0 to 3 fluorine groups; and

[0644] (iii)C 3-5 Cycloalkyl, which is independently selected from C 1-3 Alkyl and C 1-3 Substitution of the alkoxy group; or

[0645] (231)(i) Hydrogen, halo, hydroxy and cyano;

[0646] (ii)C 1-4 Alkyl and C 1-3 alkoxy groups, each of which is substituted with 0 to 3 fluorine groups; and

[0647] (iii)C 3-5 Cycloalkyl substituted with 0 to 3 substituents independently selected from methyl and methoxy.

[0648] The compounds of Formula 1, including those specifically named in the embodiments (1) to (231) and examples described in the preceding paragraph, may exist in the form of salts, complexes, solvates, hydrates, and liquid crystals. Similarly, salts of the compounds of Formula 1 may exist in the form of complexes, solvates, hydrates, and liquid crystals.

[0649] The compound of formula 1 can form pharmaceutically acceptable complexes, salts, solvates and hydrates. These salts include acid addition salts (including diacids) and basic 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, and non-toxic salts derived from organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamates, edisylate, ethanesulfonate, formate, fumarate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogenphosphate, dihydrogenphosphate, pyroglutamate, glucarate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, and xinofoate.

[0650] 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-methylglucosamine, ethanolamine, 2-amino-2-hydroxymethyl-propane-1,3-diol, and procaine. For a discussion of useful acid addition salts and base salts, see SM Berge et al., J. Pharm. Sci. (1977) 66: 1-19; see also Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (2002).

[0651] Pharmaceutically acceptable salts can be prepared using various methods. For example, the compound of formula 1 can be reacted with a suitable acid or base to obtain the desired salt. Alternatively, the precursor of the compound of formula 1 can be reacted with an acid or base to remove a protective group that is unstable to the acid or base or to open the lactone or lactam group of the precursor. In addition, the salt of the compound of formula 1 can be converted into another salt (or free form) by treating with a suitable acid or base or by contacting with an ion exchange resin. After the reaction, if the salt precipitates out from the solution, it can be filtered, or the salt can be separated by evaporation to reclaim the salt. The degree of ionization of the salt can vary between completely ionized to almost unionized.

[0652] Formula 1 compound can exist in a continuous solid form within the range of completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and may exhibit the physical properties of a solid or liquid depending on temperature. Typically, such materials do not produce unique X-ray diffraction patterns, and although they exhibit the properties of a solid, they are more formally described as liquids. After heating, a change from solid to liquid properties occurs, characterized by a change in state, typically secondary ("glass transition"). The term "crystallization" refers to a solid phase in which a material has a regular, ordered internal structure at the molecular level and produces a unique X-ray diffraction pattern with a specified peak. Such materials will also exhibit the properties of a liquid when fully heated, but the change from solid to liquid is characterized by a phase transition, typically primary ("melting point").

[0653] The compound of formula 1 may also exist in unsolvated and solvated forms. The term "solvate" describes a molecular complex comprising a compound and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" is a solvate in which the solvent is water. Pharmaceutically acceptable solvates include those in which the solvent may be isotopically substituted (e.g., D2O, acetone-d6, DMSO-d6).

[0654] The currently recognized classification system for solvates and hydrates of organic compounds is a system for distinguishing solvates and hydrates of isolated sites, channels and metal ion coordination. See, for example, KR Morris (HG Rittain, ed.) Polymorphism in Pharmaceutical Solids (1995). Isolated site solvates and hydrates are solvates and hydrates in which solvent (e.g., water) molecules are isolated by intervening molecules of organic compounds to avoid direct contact with each other. In channel solvates, solvent molecules are located in lattice channels adjacent to other solvent molecules. In metal ion coordinated solvates, solvent molecules are bonded to the metal ion.

[0655] When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry, regardless of humidity. However, when the solvent or water is weakly bound (such as in channel solvates and hygroscopic compounds), the water or solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry is typically observed.

[0656] Formula 1 compound can also exist as a multi-component complex (except salt and solvate), wherein the compound (drug) and at least one other component are present in a stoichiometric or non-stoichiometric amount. This type of complex includes clathrate (drug-main inclusion complex) and co-crystal. The latter is typically defined as a crystalline complex of neutral molecular components combined together by non-covalent interactions, but may also be a complex of neutral molecules and salts. Co-crystals can be prepared by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together. See, for example, O.Almarsson and MJZaworotko, Chem.Commun. (2004) 17: 1889-1896. For a general review of multi-component complexes, see JKHaleblian, J.Pharm.Sci. (1975) 64 (8): 1269-88.

[0657] When subjected to appropriate conditions, the compounds of Formula 1 can exist in a mesomorphic state (a mesophase or liquid crystal). The mesomorphic state is between a true crystalline state and a true liquid state (melt or solution). Mesomorphism due to temperature changes is described as "thermotropic", and mesomorphism due to the addition of a second component such as water or another solvent is described as "lyotropic". Compounds that may form lyotropic mesophases are described as "amphiphilic" and include compounds with polar ionic moieties (e.g., -COOˉNa + 、-COOˉK + 、-SO3ˉNa + ) or polar nonionic moieties (such as -NˉN + (CH3)3) molecules. See, for example, NH Hartshorne and A. Stuart, Crystals and the Polarizing Microscope (4th ed., 1970).

[0658] Each compound of Formula 1 may exist as polymorphs, stereoisomers, tautomers, or some combination thereof, may be isotopically labeled, may result from administration of a prodrug, or may form a metabolite following administration.

[0659] "Prodrug" refers to a compound with little or no pharmacological activity that can be converted into a compound with the desired pharmacological activity when metabolized in vivo. Prodrugs can be prepared by replacing the appropriate functional groups present in the pharmacologically active compound with "pro-moieties" such as those described in H.Bundgaar, Design of Prodrugs (1985). Examples of prodrugs include ester, ether or amide derivatives of compounds of formula 1 having carboxylic acid, hydroxyl or amino functional groups, respectively. For further discussion of prodrugs, see, for example, T.Higuchi and V.Stella "Pro-drugs as Novel Delivery Systems", ACS Symposium Series 14 (1975) and E.B.Roche, ed., Bioreversible Carriers in Drug Design (1987).

[0660] "Metabolites" refer to compounds formed in vivo upon administration of a pharmacologically active compound. Examples include hydroxymethyl, hydroxyl, secondary amino, primary amino, phenol, and carboxylic acid derivatives of compounds of Formula 1 having methyl, alkoxy, tertiary amino, secondary amino, phenyl, and amide groups, respectively.

[0661] The compounds of Formula 1 may exist as stereoisomers, which are formed by the presence of one or more stereogenic centers, one or more double bonds, or both. Stereoisomers may be pure, substantially pure, or mixtures. Such stereoisomers may also be formed by acid addition salts or base salts where the counterion is optically active, such as, for example, when the counterion is D-lactate or L-lysine.

[0662] The compounds of Formula 1 may exist as tautomers, which are isomers resulting from tautomerization. Tautomerism includes, for example, imine-enamine, keto-enol, oxime-nitroso, and amide-imidic acid tautomerism.

[0663] Compounds of Formula 1 may exhibit more than one type of isomerism.

[0664] Geometric (cis / trans) isomers may be separated by conventional techniques such as chromatography and fractional crystallization.

[0665] Conventional techniques for preparing or separating compounds with specific stereochemical configurations include synthesizing from suitable optically pure precursor chirality or using, for example, chiral high pressure liquid chromatography (HPLC) to split racemate (or the racemate of salt or derivative). Alternatively, racemate (or racemic precursor) can be reacted with suitable optically active compounds, such as alcohol, or when Formula 1 compound contains acidic or basic moieties, with acid or alkali (such as tartaric acid or 1-phenylethylamine). Gained diastereomeric mixtures can be separated by chromatography, fractional crystallization, and suitable diastereomers can be converted into compounds with desired stereochemical configurations. For further discussion of the technology for separating stereoisomers, see E.L. Eliel and S.H. Wilen, Stereochemistry of Organic Compounds (1994).

[0666] The 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 the compounds of Formula 1 include, for example, isotopes of hydrogen, such as 2 H and 3 H; isotopes of carbon, such as 11 C. 13 C and 14 C; isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O. 17 O and 18 O; isotopes of sulfur, such as 35 S; isotopes of fluorine, such as 18 F; isotopes of chlorine, such as 36 Cl; and isotopes of iodine, such as 123 I and 125 I. Isotopic variation (e.g., deuterium 2 The use of H) may provide certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. In addition, certain isotopic variations of the disclosed compounds may contain radioactive isotopes (e.g., tritium, 3 H or 14 C), which can be used for drug and / or substrate tissue distribution studies. Using positron emitting isotopes, such as 11 C. 18 F. 15 O and 13 N substitution is useful in positron emission tomography (PET) studies to examine substrate receptor occupancy.Isotopically labeled compounds can be prepared by methods analogous to those described elsewhere in this disclosure using an appropriate isotopically labeled reagent in place of the unlabeled reagent.

[0667] Formula 1 compound can be prepared using the technology described below.Some methods and examples can omit the details of common reactions (including oxidation, reduction, etc.), separation techniques (extraction, evaporation, precipitation, chromatography, filtration, wet grinding, crystallization, etc.) and analytical procedures, which are known to those of ordinary skill in the field of organic chemistry. The details of such reactions and techniques can be found in several papers, including Richard Larock, Comprehensive Organic Transformations (1999), and the multi-volume series edited by Michael B.Smith et al., Compendium of Organic Synthetic Methods (1974 and subsequent). Starting materials and reagents can be obtained from commercial sources or can be prepared using literature methods. Some reaction processes can omit the minor products obtained by chemical conversion (for example, alcohol obtained from ester hydrolysis, CO obtained from diacid decarboxylation, etc.). In addition, in some cases, the reaction intermediates can be used in subsequent steps (that is, in situ) without being separated or purified.

[0668] In the methods and examples below, some compounds can be prepared using protecting groups that prevent undesirable chemical reactions from occurring at other reaction sites. Protecting groups can also be used to enhance solubility or otherwise change the physical properties of compounds. For discussion of protecting group strategies, for arranging and removing the description of the materials and methods of protecting groups and for the compilation of useful protecting groups for common functional groups (including amine, carboxylic acid, alcohol, ketone, aldehyde etc.), see TW Greene and P.G Wuts, Protecting Groups in Organic Chemistry (1999) and P.Kocienski, Protective Groups (2000).

[0669] In general, the chemical transformations described throughout this specification can be carried out using substantially stoichiometric amounts of reactants, although certain reactions may benefit from using an excess of one or more reactants. In addition, many reactions disclosed throughout this specification can be carried out at approximately room temperature (RT) and ambient pressure, but some reactions may be carried out at elevated pressures or employ higher temperatures (e.g., reflux conditions) or lower temperatures (e.g., -78°C to 0°C) depending on reaction kinetics, yields, etc. Any reference to stoichiometric ranges, temperature ranges, pH ranges, etc. in this disclosure and claims, whether or not the word "range" is explicitly used, also includes the indicated endpoints.

[0670] Many chemical transformations may also employ one or more compatible solvents, which may affect 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, non-polar 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., dichloromethane, 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, hexan-1-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol, 2-(2-methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol, 2-(2-butoxy-ethoxy)-ethanol); ethers (e.g., diethyl ether, diisopropyl ether, dibutyl ether, 1,2-dimethoxy-ethane, 1,2-diethoxy-ethane, 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 triamide).

[0671] In the schemes below, substituent identifiers (e.g., 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 ) as defined above for Formula 1. However, as mentioned earlier, some starting materials and intermediates may include protecting groups that are removed prior to the final product. In such cases, the substituent identifier refers to the moiety defined in Formula 1 and those moieties having appropriate protecting groups. For example, the starting material or intermediate in the synthetic method may include a potentially reactive (secondary) amine. In such cases, the amine will include moieties with or without a Boc or Cbz group attached to the amine.

[0672] 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, wherein, for example, X is Cl) is reacted with an amine (A2) at elevated temperature (e.g., 80° C. to 150° C.) in the presence of a base (e.g., DIPEA, K2CO3, etc.) and a solvent (e.g., ACN, DMSO, NMP, etc.) to give a halophthalazineamine (A3). Subsequently, after, for example, removal of protecting groups, further purification of functional groups, separation of stereoisomers or regioisomers, etc., the amine (A3) is reacted with a diboronic acid or ester (A4, wherein, for example, each R is a hydroxyl group, a hydroxyl group, or a hydroxyl group) at elevated temperature (e.g., 50-110° C.) in the presence of a palladium catalyst (e.g., Pd(PPH3)4, Pd(dppf)Cl2, Pd(dppf)Cl2.CH2Cl2, AmPhosPdCl2, XPhosPdCl2, etc.), a base (e.g., Na2CO3, K2CO3, Cs2CO3, KF, etc.) and one or more solvents (e.g., 1,4-dioxane, DMF, ACN, EtOH, H2O, etc.). 12 H or C 1-4 alkyl) to react directly or indirectly to obtain a compound of formula 1.

[0673] Alternatively, as shown in Scheme B, a 1,4-dihalogenophthalazine derivative or analog (A1) can be first reacted with a diboronic acid or ester (A4) in the presence of a palladium catalyst, a base, and a solvent as described in Scheme A. Then, the resulting aromatic substituted halophthalazine (B1) is reacted with an amine (A2) directly in the presence of a base and a solvent as described in Scheme A at elevated temperature, or after removing the protecting group, further refining the functional groups, separating stereoisomers or regioisomers, etc., to obtain a compound of Formula 1.

[0674] The methods depicted in the schemes can be varied as desired. For example, protecting groups can be added or removed, and the product can be further refined by, for example, alkylation, acylation, hydrolysis, oxidation, reduction, amidation, sulfonation, alkynylation, etc., to obtain the desired final product. In addition, any intermediate or final product comprising a mixture of stereoisomers can be optionally purified by chiral column chromatography (e.g., supercritical fluid chromatography) or by derivatization with an optically pure reagent as described above to obtain the desired stereoisomer.

[0675]

[0676]

[0677] The biopharmaceutical properties of the compounds of Formula 1 (including the compounds named above) and their pharmaceutically acceptable complexes, salts, solvates and hydrates, such as solubility and solution stability across pH values, permeability, etc., should be evaluated to select an appropriate dosage form and route of administration. The compounds intended for pharmaceutical use can be administered as crystalline or amorphous products and can be obtained, for example, in the form of solid plugs, powders or films by methods such as precipitation, crystallization, freeze drying, spray drying, evaporative drying, microwave drying or radio frequency drying.

[0678] The compounds of formula 1 can be administered alone or in combination with one another or with one or more pharmacologically active compounds other than the compounds of formula 1. Generally, one or more of these compounds are administered in association with one or more pharmaceutically acceptable excipients as a pharmaceutical composition (formulation). The choice of excipient depends 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 edition, 2000).

[0679] The compound of Formula 1 can be administered orally. Oral administration may involve swallowing, in which case the compound enters the bloodstream via the gastrointestinal tract. Alternatively or additionally, oral administration may involve mucosal administration (e.g., buccal, sublingual, supralingual administration), such that the compound enters the bloodstream via the oral mucosa.

[0680] Formulations suitable for oral administration include solid, semisolid, and liquid systems, such as tablets; soft or hard capsules containing multi- or nanoparticles, liquids, or powders; lozenges that can be filled with liquids; chewables; gels; rapidly dispersing dosage forms; films; ovule preparations; sprays; and buccal or mucosal adhesive patches. Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations can be used as fillers in soft or hard capsules (e.g., made of gelatin or hydroxypropylmethylcellulose) and typically contain a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil) and one or more emulsifiers, suspending agents, or both. Liquid formulations can also be prepared by reconstitution of a solid (e.g., from a sachet).

[0681] 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.

[0682] For tablet dosage forms, the active pharmaceutical ingredient (API) may comprise from about 1 wt% to about 80 wt% or more typically from about 5 wt% to about 60 wt% of the dosage form, depending on the dose. In addition to the API, the tablet may include 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, polyvinyl pyrrolidone, methylcellulose, microcrystalline cellulose, C 1-6 Alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant will comprise from about 1 wt % to about 25 wt % or from about 5 wt % to about 20 wt % of the dosage form.

[0683] Binders are generally used to impart cohesiveness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, 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.

[0684] The tablet may also include a surfactant, such as sodium lauryl sulfate and polysorbate 80; and a glidant, such as silicon dioxide and talc. When present, the surfactant may comprise from about 0.2 wt% to about 5 wt% of the tablet, and the glidant may comprise from about 0.2 wt% to about 1 wt% of the tablet.

[0685] The tablet may also contain a lubricant such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. The lubricant may comprise from about 0.25 wt % to about 10 wt % or from about 0.5 wt % to about 3 wt % of the tablet.

[0686] Tablet blends can be compressed directly or by roller compaction to form tablets. Alternatively, the tablet blend or portions of the blend can be wet, dry, or melt granulated, melt-congealed, or extruded before tableting. If desired, one or more components can be graded by screening or grinding or both before blending. The final dosage form can comprise one or more layers and can be coated, uncoated, or encapsulated. Exemplary tablets can 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, granulation, milling, screening, tableting, 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. (eds.), Pharmaceutical Dosage Forms: Tablets, Vol. 1-3 (2nd ed., 1990); and D.K. Parikh and C.K. Parikh, Handbook of Pharmaceutical Granulation Technology, Vol. 81 (1997).

[0687] Consumable oral films for humans or animals are flexible, water-soluble or water-swellable film formulations that can dissolve quickly or adhere to the mucosa. In addition to the API, typical films also include one or more film-forming polymers, adhesives, solvents, wetting agents, plasticizers, stabilizers or emulsifiers, viscosity modifiers, and solvents. Other film ingredients may include antioxidants, colorants, flavorings and flavor enhancers, preservatives, saliva stimulants, cooling agents, cosolvents (including oils), emollients, bulking agents, defoamers, surfactants, and taste masking agents. Certain components in the formulation may perform more than one function.

[0688] In addition to dosage requirements, the amount of API in the film can also depend on its solubility. If water-soluble, the API will typically comprise from about 1 wt% to about 80 wt% of the non-solvent component (solute) in the film, or from about 20 wt% to 50 wt% of the solute in the film. Less soluble APIs can comprise a larger proportion of the composition, typically comprising about 88 wt% of the non-solvent component in the film.

[0689] 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.

[0690] Film dosage forms are typically prepared by evaporative drying of an aqueous film coated onto a peelable backing or paper, which can be carried out in a drying oven or drying tunnel (e.g., in a combined coater-dryer device), in a freeze drying apparatus, or in a vacuum oven.

[0691] Useful solid formulations for oral administration may include immediate release formulations and sustained release formulations. Sustained release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. For a general description of suitable sustained 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.

[0692] The compound of Formula 1 can also be administered directly into the bloodstream, muscle, or internal organs of a subject. Suitable techniques for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration. Suitable devices for parenteral administration include needle injectors, including microneedle injectors, needle-free injectors, and infusion devices.

[0693] Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (e.g., at a pH of about 3 to about 9). However, for some applications, the compound of Formula 1 may be more suitably formulated as a sterile non-aqueous solution or dry form for use in combination with a suitable vehicle such as sterile, pyrogen-free water. Preparation of parenteral formulations under aseptic conditions (e.g., by freeze drying) can be readily accomplished using standard pharmaceutical techniques.

[0694] The solubility of the compound for preparing parenteral solution can be increased by appropriate formulation technology, such as being combined with a solubility enhancer. Preparations for parenteral administration can be formulated for immediate release or sustained release. Sustained release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release. Therefore, Formula 1 compound can be formulated as a suspension, solid, semisolid or thixotropic liquid, and administered as an implant reservoir for providing sustained release of the active compound. Examples of such preparations include drug-coated stents and semisolid and suspensions comprising drug-loaded poly (DL-lactic acid-co-glycolic acid) (PGLA) microspheres.

[0695] The compound of Formula 1 can also be applied topically, intradermally, or transdermally to the skin or mucous membranes. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical carriers can include ethanol, water, mineral oil, liquid paraffin, white paraffin, glycerol, polyethylene glycol, and propylene glycol. Topical formulations can also contain penetration enhancers. See, for example, Finnin and Morgan, J. Pharm. Sci. 88(10):955-958 (1999).

[0696] Other local administration methods include electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free (e.g., Powderject TM and Bioject TM ) injection for delivery. Formulations for topical administration may be formulated for immediate or sustained release as described above.

[0697] Formula 1 compound can also be administered intranasally or by inhalation, typically in the form of dry powder, aerosol spray or nasal drops. Inhalers can be used to administer dry powders, which only contain API, API and a powder blend of a diluent (such as lactose), or mixed component particles including API and phospholipids (such as phosphatidylcholine). For intranasal use, the powder can include a bioadhesive, for example, chitosan or cyclodextrin. Pressurized containers, pumps, sprayers, atomizers or nebulizers can be used to produce aerosol sprays from a solution or suspension containing the API, one or more agents for dispersing, solubilizing or prolonging the release of the API (for example, EtOH with or without water), one or more solvents used as propellants (for example, 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane), and optional surfactants, such as sorbitan trioleate, oleic acid or oligolactic acid. A sprayer using electrohydrodynamics can be used to produce a fine mist.

[0698] Prior to use in a dry powder or suspension formulation, the drug product is typically comminuted to a particle size suitable for delivery by inhalation (typically, 90% of the particles by volume have a maximum dimension less than 5 microns). This can be achieved by any suitable size reduction method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing, high pressure homogenization, or spray drying.

[0699] Capsules, blisters, and cartridges (made, for example, of gelatin or hydroxypropylmethylcellulose) for use in an inhaler or insufflator may be formulated to contain a powder mix of the active compound, a suitable powder base such as lactose or starch, and a potency modifier such as L-leucine, mannitol, or magnesium stearate. Lactose may be anhydrous or monohydrated. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0700] Suitable solution formulations for use in nebulizers that use electrohydrodynamics to generate a fine mist can contain from about 1 μg to about 20 mg of API per actuation, and the actuation volume can vary from about 1 μL to about 100 μL. A typical formulation can include one or more compounds of Formula 1, propylene glycol, sterile water, EtOH, and NaCl. Alternative solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol.

[0701] Formulations for inhaled administration, intranasal administration, or both can be formulated for immediate or sustained release using, for example, PGLA. Suitable flavorings (such as menthol and levomenthol) or sweeteners (such as saccharin or saccharin sodium) can be added to formulations intended for inhaled / intranasal administration.

[0702] In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve that delivers a metered dose. The unit is typically arranged to administer a metered dose or "bolus" containing from about 10 μg to about 1000 μg of the API. The total daily dose will typically be in the range of from about 100 μg to about 10 mg, which can be administered in a single dose or, more usually, in divided doses throughout the day.

[0703] The active compound can be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. Formulations for rectal or vaginal administration can be formulated as immediate or sustained release, as described above.

[0704] Formula 1 compound can also be directly applied to eyes or ears, typically in the form of micronized suspension or solution drops in isotonic sterile saline with adjusted pH value. Other preparations suitable for eye and ear administration include ointments, gels, biodegradable implants (such as absorbable gel sponges, collagen), non-biodegradable implants (such as silicones), wafers, lenses and microparticles or vesicle systems, such as lipid vesicles (niosomes) or liposomes. Preparations can include one or more polymers and preservatives, such as benzalkonium chloride. Typical polymers include cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (for example, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose) and heteropolysaccharide polymers (for example, gellan gum). Such preparations can also be delivered by iontophoresis. Preparations for eye or ear administration can be formulated as described above to carry out quick release or sustained release.

[0705] In order to improve the solubility, dissolution rate, taste masking, bioavailability or stability of the compound of formula 1, the compound can be combined with a soluble macromolecular entity, including cyclodextrin and its derivatives and polymers containing polyethylene glycol. For example, API-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. Both inclusion complexes and non-inclusion complexes can be used. As an alternative to direct compounding with the API, cyclodextrin can be used as an auxiliary additive, i.e., as a carrier, diluent or solubilizer. Alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin are commonly used to achieve these purposes. See, for example, WO 91 / 11172, WO 94 / 02518 and WO 98 / 55148.

[0706] As described above, one or more compounds of Formula 1, including the compounds 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, disorders, and conditions. In such cases, the active compounds can be combined into a single dosage form as described above, or can be provided in the form of a kit suitable for co-administration of the composition. The kit comprises (1) two or more different pharmaceutical compositions, at least one of which contains a compound of Formula 1; and (2) a device for separately retaining the two pharmaceutical compositions, such as a separate bottle or a separate foil packet. An example of such a kit is the familiar blister pack for packaging tablets or capsules. The kit is suitable for administering different types of dosage forms (e.g., oral and parenteral) or administering different pharmaceutical compositions at independent dosing intervals, or for adjusting different pharmaceutical compositions to each other. To help patient compliance, the kit typically includes instructions for administration and can provide a memory aid.

[0707] For administration to human patients, the total daily dose of the claimed and disclosed compounds is typically in the range of 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 doses may only require a total daily dose of about 0.1 mg to about 300 mg. The total daily dose can be administered in single or divided doses and may be outside the typical range given above at the discretion of the physician. Although these doses are based on an average human subject having a mass of about 60 kg to about 70 kg, the physician will be able to determine the appropriate dose for a patient (e.g., an infant) having a mass outside this weight range.

[0708] As described above, the compounds of Formula 1 can be used to treat diseases, conditions, and disorders for which inhibition of the NLRP3 inflammasome pathway is indicated, including diseases, conditions, or disorders associated with heterozygous gain-of-function mutations in the NLRP3 gene, such as cryopyrin-associated periodic syndromes (CAPS). These may include neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Mueller-Weiss syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

[0709] The compounds of formula 1 can be used to treat neurodegenerative diseases, disorders and conditions associated with NLRP3. These diseases, disorders and conditions may include Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion diseases, Alzheimer's disease and other forms of dementia associated with one or more medical conditions (i.e., severe or mild neurocognitive disorders), including frontotemporal lobar degeneration, Lewy body disease, vascular disease, traumatic brain injury, substance or drug use, HIV infection, prion disease, Parkinson's disease and Huntington's disease. The compounds of formula 1 can also be used to treat severe or mild neurocognitive disorders associated with depression, schizophrenia, bipolar disorder and autism.

[0710] The claimed and disclosed compounds can be combined with one or more other pharmacologically active compounds or therapies to treat one or more conditions, diseases, or disorders for which inhibition of the NLRP3 inflammasome pathway is indicated. Such combinations may provide significant therapeutic advantages, including minimal side effects, improved ability to treat underserved patient populations, or synergistic activity. For example, compounds of Formula 1 (including the compounds specifically named above) and pharmaceutically acceptable complexes, salts, solvates, and hydrates thereof can be administered simultaneously, sequentially, or separately with a combination of one or more compounds or therapies for treating Alzheimer's disease, including β-secretase inhibitors, γ-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs, such as azapropazone, aspirin, celecoxib, diclofenac (with and without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid sodium, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, choline and magnesium salicylate, bissalate, and sulindac), vitamin E, and anti-amyloid antibodies. Specific examples of compounds useful in treating Alzheimer's disease include donepezil, rivastigmine, memantine, and galantamine.

[0711] In addition to drugs for improving cognition, the compounds of Formula 1 can be combined with sedatives, hypnotics, anxiolytics, antipsychotics, tranquilizers, and other drugs used to treat Alzheimer's disease. For example, the compounds of Formula 1 can be combined with one or more agents used to treat depression (antidepressants) and / or schizophrenia (atypical or typical antipsychotics), including amitriptyline, amoxapine, aripiprazole, asenapine, bupropion, chlordiazepoxide, chlordiazepoxide, chlorpromazine ... Citalopram, chlorpromazine, clozapine, desipramine, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, fluphenazine, fluphenazine, haloperidol, iloperidone, imipramine, isocarboxazid, lamotrigine, levmilnacipran, lurasidone, mirtazapine, nefazodone, nortriptyline, olanzapine, paliperidone, paroxetine, perphenazine, phenelzine, protriptyline, quetiapine, risperidone, selegiline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, vilazodone, and vortioxetine and ziprasidone.

[0712] Likewise, the compounds of Formula 1 may be combined with one or more agents used to treat anxiety (anxiolytics), including benzodiazepines (alprazolam, chlordiazepoxide, clobazepam, clonazepam, clorazepam, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, prazepam, quazepam, temazepam, and triazolam), antihistamines (hydroxyzine), nonbenzodiazepines (eszopiclone, zaleplon, zolpidem, and zopiclone), and buspirone.

[0713] The compounds of Formula 1 can also be combined with one or more agents used to treat epilepsy (antiepileptics or anticonvulsants), 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, vilgabaine, and zonisamide.

[0714] Biological activity

[0715] The biological activity of the compounds of Formula 1 against NLRP3 can be determined using the following in vitro method.

[0716] IL-1β analysis (reported as IC 50 )

[0717] According to the supplier's instructions, monocytic THP-1 cells (ATCC: TIB-202) were maintained in RPMI medium (Life Technologies, catalog number A10491-01); RPMI was supplemented with 10% heat-inactivated fetal bovine serum (Hyclone catalog number SH30396.03). Cells were differentiated into macrophages by adding 25 ng / mL IFN-γ (PeproTech, catalog number 300-02-100UG) at 37°C / 5% CO2 for 24 hours. The medium was replaced with fresh medium without FBS, and the cells were 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 was replaced with fresh medium without FBS. Cells were plated at 40,000 cells per well in 384-well flat-bottom cell culture plates (Costar 3764) containing compounds serially diluted 1:3.16 in DMSO (added at 1:1000) and incubated at 37°C / 5% CO2 for 30 minutes. NLRP3 inflammasomes were activated by adding 2.5 mM ATP (Sigma catalog number A3377) 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 ELISA (human IL-1β ELISA, R&D systems, catalog number DY201) according to the manufacturer's instructions.

[0718] Description of TNF-α assay (reported as IC 50 )

[0719] According to the supplier's instructions, monocytic THP-1 cells (ATCC: TIB-202) were maintained in RPMI medium (Life Technologies, catalog number A10491-01); RPMI was supplemented with 10% heat-inactivated fetal bovine serum (Hyclone catalog number SH30396.03). Cells were differentiated into macrophages by adding 25 ng / mL IFN-γ at 37°C / 5% CO2 for 24 hours. The medium was replaced with fresh medium without FBS. Cells were plated at 40,000 cells per well in 384-well flat-bottom cell culture plates (Costar 3764) containing compounds serially diluted 1:3.16 in DMSO (added at 1:1000) and incubated at 37°C / 5% CO2 for 30 minutes. The NF-κB pathway was activated by adding 50 ng / mL LPS and the cells were incubated at 37°C / 5% CO2 for 3 hours. At the end of the incubation period, the supernatant (40 μL) was removed and IL-1β levels were monitored using ELISA (Human TNF-α ELISA, R&D systems, cat. no. DY210) according to the manufacturer's instructions.

[0720] Data interpretation

[0721] IC 50 The values ​​were calculated by fitting a logistic curve to the plot of percent inhibition versus inhibitor concentration: Y = [bottom + (top - bottom)] / (1 + 10^[(Log IC 50 =[0-X)·Hill Slope], where Y is the % inhibition at the inhibitor concentration, X, "Bottom" is the lowest inhibition value (0%), "Top" is the maximum inhibition value (100%), and "Hill Slope" describes the slope of the sigmoidal curve between the "Bottom" and "Top" values. Curve fitting was performed using in-house developed software.

[0722] 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.

[0723] MDCK-MDR1 assay (reported as apparent permeability and efflux ratio)

[0724] Madine-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 P-gp inducer colchicine (200 nM) (Sigma catalog number C9754). Cells were plated at 6.25 x 10 cells per well. 3 The cells were seeded at a density of 100 cells per well on the apical side of an HTS-Transwell-96 plate (0.4 μm pore size, Corning catalog number 3381) using 75 μL and 250 μL DMEM medium in the apical and basolateral wells, respectively, and incubated at 37°C / 5% CO2. After 72 hours, fresh DMEM medium was replaced in the apical and basolateral compartments, and the cells were allowed to grow into a monolayer for 144 hours before starting the experimental incubation. Incubation was performed in Han's balanced salt solution (HBSS, Fisher Scientific catalog number 14025134) at pH 7.4 containing 1% bovine serum albumin (Sigma, catalog number A9418) and 10 mM HEPES (Fisher Scientific, catalog number 15630080). The DMEM medium was removed and the cells were rinsed with warm (37°C) HBSS. The HBSS of the test compound with 1 μM substrate concentration (0.1%v / v DMSO) is added to top or basolateral compartment (being respectively 75 μ L or 250 μ L), and blank HBSS buffer solution is added in duplicate to the compartment lacking test compound.Cells are incubated at 37 ℃ / 5%CO2 for 60 minutes.When the incubation period ends, 50 μ L samples are taken out from each receiving compartment and are diluted to 150 μ L acetonitrile (Fisher Scientific, catalog number (Cat. No.) A996SK4)+0.1% formic acid (Sigma, catalog number (Cat. No.) F0507).Sample is centrifuged at 4 ℃ for 10 minutes with 2000rcf, and afterwards 100 μ L supernatant is transferred in new microplate and diluted with 100 μ L HPLC grade water (Fisher Scientific, catalog number (Cat. No.) W64). Samples were analyzed using a triple quadrupole mass spectrometer API-5500QTrap (ABSciex, serial number AU23291006) and associated autosampler and HPLC pump instrument optimized for flow cytometry via a Kinetix 2.1 x 50 mm C18 The test products were detected using a Phenomenex column (Phenomenex, catalog number 00B-4605-AN).

[0725] The apparent permeability (P) was calculated using the following equation: app ) value and outflow ratio:

[0726]

[0727] Among them, P app A-B is the apparent permeability from the apical pore to the basolateral pore; P app B-A is the apparent permeability from the basolateral pore to the apical pore; concentration BL is the basolateral pore concentration; AP is the top pore concentration; A is the pore surface area (cm 2 ), which is 0.143 cm for the above measurement 2 ; t is the incubation time (seconds), which is 3600 seconds for the above assay; and ER is the P-gp-mediated efflux ratio.

[0728] Example

[0729] The following examples are intended to be illustrative and non-limiting, and represent specific embodiments of the invention.

[0730] In the following examples, a number of compounds were obtained 1 H nuclear magnetic resonance (NMR) spectroscopy. Characteristic chemical shifts (δ) are given in parts per million downfield from tetramethylsilane, using conventional abbreviations for designating major peaks, 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).

[0731] Where indicated, intermediate preparations and example compounds were purified by HPLC. Tables 1 to 3 list the columns, mobile phases and gradients used for certain HPLC separations.

[0732] Table 1: HPLC Method A

[0733]

[0734] Table 2: HPLC Method B

[0735]

[0736] Table 3: HPLC Method C

[0737]

[0738] Preparation and Examples Supercritical fluid chromatography (SFC) can be used to separate enantiomers. Table 4 lists the equipment, materials and conditions for certain SFC separations.

[0739] Table 4: SFC method

[0740]

[0741] In addition to HPLC, some preparations and examples may employ flash chromatography or preparative thin layer chromatography (TLC). 254 Preparative TLC was performed on the plate.

[0742] After separation by chromatography, the solvent was removed and the mixture was evaporated by centrifugal evaporation (e.g. GeneVac TM ), rotary evaporator, vacuum flask, etc. to obtain the product. The reaction is typically carried out at a pressure of about 1 atmosphere (14.7 psi) in an inert (e.g., nitrogen) or reactive (e.g., H2) atmosphere.

[0743] Preparation 1: 5,5-difluoro-1-methyl-piperidin-3-amine

[0744]

[0745] Step 1: tert-Butyl (5,5-difluoro-1-methylpiperidin-3-yl)carbamate

[0746]

[0747] 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 hour. Formic acid (203.34 mg, 4.23 mmol) was added dropwise and the mixture was stirred at 70 ° C for 1 hour. The reaction mixture was quenched with NH 3.H 2 O (5 mL) and concentrated under reduced pressure. The product was purified by flash chromatography ( 12 g silica gel column) and the residue was purified using a 0 to 20% DCM in MeOH gradient (35 mL / min) to give the title compound (310 mg, crude). ESI-MS m / z [M+H] + 251.1.

[0748] Step 2: 5,5-Difluoro-1-methyl-piperidin-3-amine

[0749] 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

[0750] Preparation 2: 1-cyclopropylpiperidin-3-amine

[0751]

[0752] Step 1: tert-Butyl (1-cyclopropylpiperidin-3-yl)carbamate

[0753]

[0754] 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 molecular sieves To the product of 4-nitro-1-oxo-2-nitropropane (3 g) and (1-ethoxycyclopropyloxy)trimethylsilane (7.83 g, 44.94 mmol, 9.03 mL) was added acetic acid (10.79 g, 179.75 mmol, 10.28 mL) and NaBH3CN (2.82 g, 44.94 mmol). The mixture was stirred at 65 ° C for 16 hours. The resulting suspension was filtered and concentrated. The crude product was diluted with NaHCO3 aqueous solution (50 mL) and extracted with DCM (100 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (DCM / MeOH=1: 0 to 10: 1). The title compound (6.5 g, 90%) was obtained as a colorless oil. 1 H NMR (400MHz, CD3Cl) δppm 4.92-5.27(m,1H),3.73(br s,1H),2.49-2.81(m,4H),1.67(brs,4H),1.55(br s,1H),1.45(s,9H),0.47(br d,J=6.27Hz,4H).

[0755] Step 2: 1-Cyclopropylpiperidin-3-amine

[0756] To a mixture of tert-butyl (1-cyclopropylpiperidin-3-yl)carbamate (4.9 g, 20.39 mmol) was added HCl (4 M, 50.97 mL) in dioxane at 25 ° C. under N 2 in one portion. The mixture was stirred at 25 ° C. for 1 hour. 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)δppm 0.65-0.96(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(brd,J=11.80Hz,1H),3.61(br d, J=9.03Hz, 2H), 8.70 (br s, 3H), 11.49 (br s, 1H).

[0757] Preparation 3: (R)-1-cyclopropylpiperidin-3-amine

[0758]

[0759] Step 1: tert-Butyl (R)-(1-cyclopropylpiperidin-3-yl)carbamate

[0760]

[0761] To tert-butyl (R)-piperidin-3-ylcarbamate (3 g, 14.98 mmol) in THF (72 mL) and MeOH (8.1 mL) was added molecular sieves (3 g, 14.98 mmol), (1-ethoxycyclopropyloxy)trimethylsilane (7.83 g, 44.94 mmol, 9.03 mL), acetic acid (10.79 g, 179.75 mmol, 10.28 mL) and NaBH3CN (2.82 g, 44.94 mmol). The mixture was stirred at 65 ° C for 16 hours. LC-MS showed that the desired product was formed as the main component, and TLC (DCM / MeOH=10:1) showed that the reaction was complete (R of the desired product f=0.43). The suspension was filtered and concentrated. The crude material was diluted with aqueous NaHCO3 (50 mL) and extracted with DCM (100 mL x 3). The organic layers were combined, 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)δppm 0.27(br s,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.

[0762] Step 2: (R)-1-cyclopropylpiperidin-3-amine

[0763] 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. 1 H NMR (400MHz, DMSO-d6) δppm 0.81 (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.

[0764] Preparation 4: (R)-1-(1-methyl-cyclopropyl)piperidin-3-amine

[0765]

[0766] Step 1: tert-Butyl (R)-(1-acetylpiperidin-3-yl)carbamate

[0767]

[0768] To a mixture of (R)-tert-butyl 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 hours. TLC (DCM / MeOH = 10: 1) indicated that the starting material was completely consumed (R f = 0.25) and a major new spot is formed (R f =0.53). The mixture was washed with H2O (20 mL) and concentrated in vacuo and purified by flash chromatography ( The resulting residue was purified on a 24 g silica gel column) using a 0 to 3% MeOH gradient in DCM (35 mL / min). The title compound was obtained as a white solid (1 g, 83%). 1 H NMR(400MHz,DMSO-d6)δppm 1.38(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).

[0769] Step 2: (R)-tert-Butyl(1-(1-methyl-cyclopropyl)piperidin-3-yl)carbamate

[0770]

[0771] To a solution of tert-butyl (R)-(1-acetylpiperidin-3-yl)carbamate (900 mg, 3.71 mmol) and Ti(i-PrO)4 (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 hours. TLC (EtOAc / MeOH = 20:1) indicated that approximately 40% of the starting material remained (R f = 0.68) and a major new spot was detected (R f =0.66). The reaction mixture was quenched with H2O (2 mL) and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography ( 20 g silica gel column) and the resulting residue was purified using a 0 to 5% MeOH gradient in DCM (35 mL / min). The title compound was obtained as a colorless gum (160 mg, 16.9%).1 HNMR(400MHz,DMSO-d6)δppm 0.29(br s,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).

[0772] Step 3: (R)-1-(1-Methyl-cyclopropyl)piperidin-3-amine

[0773] A mixture of (R)-tert-butyl(1-(1-methyl-cyclopropyl)piperidin-3-yl)carbamate (160 mg, 629.01 μmol) in HCl / dioxane (4 M, 5 mL) was stirred at 20° C. for 12 hours. TLC (EtOAc / MeOH=20:1) indicated 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)δppm 0.72-0.82(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).

[0774] Preparation 5: (3R,5R)-1-cyclopropyl-5-fluoropiperidin-3-amine

[0775]

[0776] Step 1: tert-Butyl ((3R,5R)-1-cyclopropyl-5-fluoropiperidin-3-yl)carbamate

[0777]

[0778] 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-ethoxycyclopropyloxy)trimethylsilane (0.523 g, 3.00 mmol) and subsequently with sodium cyanoborohydride (0.283 g, 4.50 mmol). The reaction mixture was stirred at 60 ° C overnight and then partitioned between EtOAc and saturated NaHCO3 aqueous solution. The aqueous phase was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography ( RediSep The resulting residue was purified using a 40 g silica gel column) using a 0 to 100% EtOAc gradient in heptane. The product-containing fractions were evaporated to afford the title compound as a white solid (0.333 g, 86%). ESI-MS m / z [M+H] + 259.0.

[0779] Step 2: (3R,5R)-1-cyclopropyl-5-fluoropiperidin-3-amine

[0780] 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 a homogeneous mixture. The reaction mixture was concentrated to dryness in vacuo to give the dihydrochloride salt of the title compound (351.5 mg crude, 298 mg theoretical, assumed quantitative and 84% purity), which was used without additional purification. ESI-MS m / z [M+H] + 159.2.

[0781] Preparation 22: (R)-1-(2-fluoroethyl)piperidin-3-amine

[0782]

[0783] Step 1: (R)-tert-Butyl(1-(2-fluoroethyl)piperidin-3-yl)carbamate

[0784]

[0785] To a mixture of (R)-piperidin-3-ylcarbamic acid tert-butyl ester (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 KCO (51.76 g, 374.48 mmol). The mixture was stirred at 15 ° C for 12 hours, then diluted with H O (150 mL) and extracted with EtOAc (200 mL x 2). The organic layers were combined, washed with brine (200 mL), dried over NaSO, filtered and concentrated under reduced pressure. The product was purified by flash chromatography ( The residue was purified using a 220 g silica gel column) using a 0 to 100% EtOAc in PE gradient (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.

[0786] Step 2: (R)-1-(2-fluoroethyl)piperidin-3-amine

[0787] A mixture of (R)-tert-butyl(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 h 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.

[0788] Preparation 56: 1',4'-dichloro-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine]

[0789]

[0790] Step 1: Methyl 1-(2-(1,3-dioxolan-2-yl)ethoxy)cyclopropane-1-carboxylate

[0791]

[0792] At 0 ° C, to a solution of NaH (2.07g, 51.67mmol, 60% purity) in DMF (100mL) was added 1-hydroxycyclopropane-1-carboxylic acid methyl ester (5g, 43.06mmol). The mixture was stirred at 0 ° C for 0.5 hours. Then, 2-(2-bromoethyl)-1,3-dioxolane (19.49g, 107.65mmol, 12.91mL) was added and the mixture was stirred at 25 ° C for 16 hours. TLC (PE / EtOAc=5:1, Rf=0.3 of the desired product) showed a new spot. The reaction mixture was quenched with water (100mL) and extracted with EtOAc (100mL). The organic phase was washed with water (150mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using a 0 to 20% EtOAc gradient in PE. The pure fractions were collected and the solvent was evaporated in vacuo to afford the title compound as a yellow oil (3.5 g). 1 HNMR(400MHz,CDCl3)δppm 4.96(t,J=4.8Hz,1H),3.98-3.93(m,2H),3.87-3.82(m,2H),3.75-3.71( m,5H),1.93(dt,J=5.2,6.8Hz,2H),1.29-1.26(m,2H),1.18-1.14(m,2H).

[0793] Step 2: Methyl 1-(3-oxopropoxy)cyclopropane-1-carboxylate

[0794]

[0795] At 25 ° C, to a solution of 1- (2- (1,3-dioxolane-2-yl) ethoxy) cyclopropane-1-carboxylic acid methyl ester (2 g, 9.25 mmol) in THF (10 mL) was added aqueous HCl (1M, 27.75 mL). The mixture was stirred at 25 ° C for 16 hours. TLC (PE / EtOAc = 5: 1, Rf = 0.2 of the desired product) showed a new spot. The reaction mixture was adjusted to a pH greater than 7 and then extracted with EtOAc (15 mL). The organic phase was washed with water (15 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain the title compound (crude) as a yellow oil (1.4 g, 88%). 1H NMR (400MHz, CDCl3) δppm 9.79(t,J=1.6Hz,1H),3.93(t,J=6.0Hz,2H),3.73(s,3H),2.66(dt,J=1.6,6.0Hz,2H),1.29(t,J=3.6Hz,2H),1.20-1.16(m,2H).

[0796] Step 3: Methyl 1-(but-3-yn-1-yloxy)cyclopropane-1-carboxylate

[0797]

[0798] To a solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (2.68 g, 13.94 mmol) in MeOH (3 mL) was added K2CO3 (963.23 mg, 6.97 mmol) at 0 ° C. The mixture was stirred at 0 ° C for 0.5 hours. Then, a solution of 1-(3-oxopropoxy)cyclopropane-1-carboxylate (1.2 g, 6.97 mmol) in MeOH (2 mL) was added and the mixture was stirred at 25 ° C for 2 hours. TLC (PE / EtOAc=5:1, Rf=0.6 of the desired product) showed a new spot. The mixture was diluted with DCM (15 mL) and the organic phase was washed with water (15 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using a 0 to 20% EtOAc gradient in PE. The pure fractions were collected and the solvent was evaporated in vacuo to afford the title compound as a yellow oil (300 mg). 1 H NMR (400MHz, CDCl3) δppm 3.76-3.72 (m, 5H), 2.47 (dt, J = 2.4, 6.8Hz, 2H), 1.98 (t, J = 2.4Hz, 1H), 1.35-1.29 (m, 2H), 1.23-1.18 (m, 2H).

[0799] Step 4: 1-(But-3-yn-1-yloxy)cyclopropane-1-carboxylic acid

[0800]

[0801] At 25 ° C, to a solution of 1- (but-3-yn-1-yloxy) cyclopropane-1-carboxylic acid methyl ester (100 mg, 594.57 μmol) in MeOH (2 mL) was added LiOH.HO (99.80 mg, 2.38 mmol) and HO (1 mL). The mixture was stirred at 25 ° C for 12 hours. TLC (PE / EtOAc = 5: 1, Rf = 0.2 of the desired product) showed a new spot. The mixture was adjusted to pH < 6 with 1N HCl aqueous solution, and then extracted with DCM (5 mL). The organic phase was washed with water (5 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain the title compound (crude) (60 mg, 65%) as a yellow oil. 1 HNMR (400MHz, CDCl3) δppm 3.75 (t, J = 6.8 Hz, 2H), 2.48 (dt, J = 2.4, 6.8 Hz, 2H), 2.01 (t, J = 2.4 Hz, 1H), 1.43-1.38 (m, 2H), 1.32-1.27 (m, 2H).

[0802] Step 5: 1-(2-(3,6-dichloropyridazin-4-yl)ethoxy)cyclopropane-1-carboxylic acid

[0803]

[0804] To a solution of 1-(but-3-yn-1-yloxy)cyclopropane-1-carboxylic acid (60 mg, 389.20 μmol) in toluene (1 mL) was added 3,6-dichloro-1,2,4,5-tetrazine (70.50 mg, 467.04 μmol) at 25 ° C. The mixture was stirred at 100 ° C for 2 hours. TLC (PE / EtOAc=3:1, Rf=0.2 of the desired product) showed a new spot. The mixture was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography using a 0 to 40% EtOAc gradient in PE. The pure fractions were collected and the solvent was evaporated under vacuum to obtain the title compound (40 mg) as a red oil. 1 H NMR (400MHz, CDCl3) δppm7.85 (s, 1H), 3.97 (t, J = 5.6Hz, 2H), 2.99 (t, J = 5.6Hz, 2H), 1.45-1.39 (m, 2H), 1.22-1.15 (m, 2H).

[0805] Step 6: 1',4'-dichloro-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine]

[0806] At 25 ° C, to a solution of 1- (2- (3,6-dichloropyridazin-4-yl) ethoxy) cyclopropane-1-carboxylic acid (120 mg, 433.05 μmol) in H2O (5 mL) and acetone (5 mL) was added AgNO3 (100 mg, 588.67 μmol), ammonium peroxodisulfate (1.6 M, 541.31 μL) and TFA (1 M, 108.26 μL). The mixture was stirred at 50 ° C for 2 hours. TLC (PE / EtOAc = 3: 1, Rf = 0.4 of the desired product) showed a new spot. The mixture was cooled to room temperature (25 ° C), poured into an ice-cold saturated NaHCO3 aqueous solution (100 mL), and then extracted with EtOAc (80 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to afford a brown gum which was purified by silica gel column chromatography using a 0 to 30% PE gradient in EtOAc. The pure fractions were collected and the solvent was evaporated under vacuum to afford the title compound (17 mg) as a light yellow solid. 1 H NMR (400MHz, CDCl3) δppm 4.00(t,J=5.6Hz,2H),2.98(t,J=5.6Hz,2H),2.17-2.10(m,2H),1.31-1.24(m,2H); ESI-MS m / z[M+H] + 230.8.

[0807] Preparation 57: 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[0808]

[0809] Step 1: ((4-oxaspiro[2.5]oct-6-en-7-yl)oxy)(tert-butyl)dimethylsilane

[0810]

[0811] A mixture of 4-oxaspiro [2.5] octan-7-one (2.1 g, 16.65 mmol), TBSOTf (5.46 g, 20.66 mmol, 4.75 mL) and DIPEA (4.30 g, 33.29 mmol, 5.80 mL) in DCM (30 mL) was degassed and purged with N2 (3 ×), and then stirred at 25 ° C for 3 hours. TLC (PE / EtOAc = 3: 1, by I2 staining) indicates that the starting material is consumed and shows a new major spot with lower polarity. The mixture was diluted with water (50 mL) and DCM (100 mL). The aqueous phase and the organic phase were separated. The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to obtain a dark brown oily crude product (5.0 g). The crude product was purified by flash chromatography (20 g silica gel column) using a 0 to 20% EtOAc gradient in PE. The title compound was obtained as a light yellow oil (3.6 g, 90%). 1 H NMR (400MHz, CDCl3) δppm 4.27-4.81(m,1H),3.70-3.97(m,2H),1.97-2.10(m,2H),0.77(d,J=1.2Hz,9H),0.61-0.71(m,2H),0.27-0.42(m,2H),0.00(d,J=2.8Hz,6H).

[0812] Step 2: 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[0813] At 25 ° C, the reactants ((4-oxaspiro [2.5] oct-6-ene-7-yl) oxygen base) (tert-butyl) dimethylsilane (1.8g, 7.49mmol) and 3,6-dichloro-1,2,4,5-tetrazine (1.36g, 8.98mmol) were combined in toluene (40mL) with stirring. The mixture was stirred and heated to 105 ° C and kept for 2 hours. LC-MS indicated that the desired product was obtained. The mixture was concentrated to obtain a red solid (3.0g). The product was purified by chromatography (SiO2 column) using a 0 to 30% EtOAc gradient in PE. The first batch of products (0.8g) was combined with the second batch (790mg) and the third batch (820mg) and purified by SFC (DAICEL Further purification was performed using a column (AD-10 μm, 30 mm×250 mm) with a mobile phase of CO 2 and 35% Neu-ACN to obtain the title compound (1.8 g, 69%) as a light yellow solid. 1H NMR (400MHz, CDCl3) δppm 4.47-4.86(m,2H),2.86(s,2H),1.00-1.14(m,2H),0.56-0.76(m,2H); ESI-MS m / z[M+H] + 230.6.

[0814] Preparation 58: 4'-chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine]

[0815]

[0816] Preparation 59: 1'-chloro-4'-(2-(methoxymethoxy)-4-methylphenyl)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine]

[0817]

[0818] To a mixture of 1', 4'-dichloro-7', 8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine] (200 mg, 865.51 μmol) and 2-(2-(methoxymethoxy)-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (312.96 mg, 1.13 mmol) in dioxane (3 mL) and H2O (0.75 mL) was added Cs2CO3 (1.13 g, 3.46 mmol) and Pd(dppf)Cl2 (70.68 mg, 86.55 μmol) at one time. The mixture was stirred at 100 ° C for 1 hour. LC-MS showed that the desired product was obtained. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography ( The resulting residue was purified on a 12 g silica gel column using a 0 to 30% EtOAc in PE gradient (25 mL / min). The title compound of Preparation 58 was obtained as a white solid (42 mg, 14% yield, 96.99% purity). 1H NMR (400MHz, DMSO-d6) δppm 1.15-1.28(m,2H),2.05(br s,1H),2.23-2.33(m,1H),2.42(s,3H),2.53(br d,J=17.73Hz,1H),2.92-3.08(m,1H),3.38(s,3H),3.78-4.00(m,2H),5.11(br d,J=4.89Hz,2H),6.97(d,J=7.70Hz,1H),7.07(s,1H),7.18(d,J=7.58Hz,1H); ESI-MS m / z[M+H] + 347.0. The title compound of Preparation 59 was obtained as a yellow oil (55 mg, 16% yield, 85% purity). 1 HNMR(400MHz,DMSO-d6)δppm 0.88-1.06(m,4H),2.40(s,3H),2.99-3.08(m,2H),3.38(s,3H),4.06(q,J=6.2 8Hz,2H),5.02-5.14(m,2H),6.87(d,J=7.70Hz,1H),6.98-7.04(m,2H); ESI-MS m / z[M+H] + 347.0.

[0819] Preparations 60 and 61: 4'-chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] and 1'-chloro-4'-(2-(methoxymethoxy)-4-methylphenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[0820]

[0821] To a solution of 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine](500mg, 2.16mmol) and 2-(2-(methoxymethoxy)-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (782.41mg, 2.81mmol) in dioxane (5mL) and H2O (1mL) was added Cs2CO3 (2.82g, 8.66mmol) and Pd(dppf)Cl2.CH2Cl2 (176.70mg, 216.38μmol). The mixture was stirred at 80°C under N2 for 1 hour. LC-MS showed that the desired product was obtained. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography ( The resulting residue was purified on a 24 g silica column using a 0 to 30% EtOAc in PE gradient (35 mL / min). A mixture of the title compounds was obtained as a yellow oil (416 mg). 1 H NMR (400MHz, CDCl3) δppm 0.40-0.60(m,1H),0.65-0.77(m,1H),0.84-1.08(m,2H),2.23-2.38(m,1H),2.4 3(s,3H),2.79-3.11(m,1H),3.39(d,J=10.0Hz,3H),4.28-4.52(m,1H),4.77(br d,J=2.3Hz,1H),5.11(d,J=5.6Hz,2H),6.99(d,J=7.5Hz,1H),7.08(s,1H),7.23(d,J=7.6Hz,1H).

[0822] Preparation 62: 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine

[0823]

[0824] To a flask filled with toluene (100 mL) was added 8-oxabicyclo[3.2.1]octan-3-one (2500 mg, 19.8 mmol), 4-methylbenzenesulfonic acid monohydrate (38 mg, 0.198 mmol) and pyrrolidine (1.6 mL, 19.8 mmol). The mixture was stirred at room temperature for 0.5 hours. The solvent was removed by rotary evaporation and the mixture was transferred to a flask filled with 3,6-dichloro-1,2,4,5-tetrazine (2991 mg, 19.8 mmol) and toluene (100 mL). The reaction mixture was heated to 120 ° C and stirred for 0.5 hours. The reaction mixture was concentrated and then purified by flash chromatography ( The resulting product was purified on a 80 g silica gel column using 100% DCM eluent (24 mL / min) to afford the title compound.

[0825] Preparation 63: 5-chloro-2-(4-chloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol

[0826]

[0827] Preparation 64: 5-chloro-2-(1-chloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)phenol

[0828]

[0829] A mixture of 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (1500 mg, 6.5 mmol), Cs2CO3 (4.2 g, 13.0 mmol), Pd(dppf)Cl2.CH2Cl2 (530 mg, 0.65 mmol) and (4-chloro-2-hydroxyphenyl)boronic acid (1.12 g, 6.5 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was stirred in a sealed tube on a metal heating block at 100°C for 30 minutes. The product was purified by flash chromatography ( The reaction mixture was purified on a 40 g silica gel column using 50% EtOAc in heptane as eluent (24 mL / min) to afford the two title compounds.

[0830] Preparation 65: rac-4'-chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)-4,5,5',8'-tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazine]

[0831]

[0832] Preparation 66: rac-1'-chloro-4'-(2-(methoxymethoxy)-4-methylphenyl)-4,5,5',8'-tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazine]

[0833]

[0834] Step 1: tert-Butyl-(2,6-dioxaspiro[4.5]dec-8-en-9-yloxy)dimethylsilane

[0835]

[0836] To a mixture of 2,6-dioxaspiro[4.5]dec-9-one (1.00 g, 6.40 mmol) and triethylamine (13 mL, 12.8 mmol) in DCM (16 mL) cooled to 0 ° C was added tert-butyldimethylsilyl trifluoromethanesulfonate (1.5 mL, 6.72 mmol) dropwise. The mixture was stirred at room temperature overnight and then treated with water and extracted with DCM. The organic layer was washed with water and brine, dried over MgSO4, and concentrated to obtain the title compound as a brown oil (crude). 14 H 26 ESI-MS of O3Si[M+H] + Calculated value 270.17; experimental value 271.28.

[0837] Step 2: 1',4'-dichloro-4,5,5',8'-tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazine]

[0838]

[0839] A mixture of 3,6-dichloro-1,2,4,5-tetrazine (0.83 g, 5.47 mmol) in toluene (8 mL) was cooled to 0 ° C. A solution of tert-butyl-(2,6-dioxaspiro[4.5]dec-8-en-9-yloxy)dimethylsilane (1.48 g, 5.47 mmol) in toluene (3 mL) was added dropwise. The mixture was heated at 120 ° C overnight and then filtered. The filtrate was concentrated and purified by normal phase silica gel column chromatography (40 g), eluting with a heptane / EtOAc gradient (5: 1 to 0: 1). The combined fractions were concentrated to obtain the title compound (0.604 g, 42%). 10 H 10 ESI-MS of Cl2N2O2[M+H] + Calculated value 260.01; experimental value 261.1.

[0840] Step 3: rac-4'-chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)-4,5,5',8'-tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazine] and rac-1'-chloro-4'-(2-(methoxymethoxy)-4-methylphenyl)-4,5,5',8'-tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazine]

[0841] By 1,4-dichlorospiro [5,8-dihydropyrano [3,4-d] pyridazine -7,3 '- tetrahydrofuran] (374mg, 1.43mmol), Cs2CO3 (898mg, 2.75mmol), 2- (2- (methoxymethoxy) -4- methylphenyl) -4,4,5,5- tetramethyl -1,3,2- dioxaborolane (306mg, 1.10mmol), Pd (dppf) Cl2 (90mg, 0.110mmol) and 1,4- dioxane (6mL) and water (1.5mL) mixture was purged with nitrogen for 5 minutes, and then heated at 90 DEG C under nitrogen for 4 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by normal phase silica gel column (80g) using heptane / EtOAc gradient (20% to 70%). The product-containing fractions were concentrated to afford the two title compounds. Preparation 65 (123 mg, 29%), C 19 H 21 ESI-MS of ClN2O4[M+H]+ Calculated value 376.12; Found value 377.3; and Preparation 66 (17 mg, 4%), C 19 H 21 ESI-MS of ClN2O4[M+H] + Calculated value 376.12; experimental value 377.3.

[0842] Preparation 68: 4'-Chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-1'-amine and 1'-Chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-amine

[0843]

[0844] To a solution of 1', 4'-dichloro-5', 8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (550 mg, 2.38 mmol), (3R, 5R)-5-fluoro-1-methyl-piperidin-3-amine (1.95 g, 9.52 mmol, 2HCl) in DMSO (10 mL) was added K3PO4 (3.03 g, 14.28 mmol) and BTMPO (300.07 mg, 714.04 μmol), CuI (181.32 mg, 952.06 μmol). The mixture was stirred at 120 ° C under N2 for 48 hours. LC-MS showed that 52% of the expected mass was detected. The reactant was filtered and evaporated to dryness. The residue was purified by preparative HPLC (Xtimate C18-10 μm, 40 mm×150 mm column) using a 0 to 26% ACN gradient in water (containing formic acid) to afford a mixture of the title compounds as a black solid (420 mg, crude product). 15 H 20 ESI-MS[M+H] of ClFN4O + Calculated value 326.13; experimental value 327.1.

[0845] Preparation 69: 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine

[0846]

[0847] Toluene (100 mL) was added to a flask containing 8-oxabicyclo[3.2.1]octan-3-one (2500 mg, 19.8 mmol), p-toluenesulfonic acid monohydrate (38 mg, 0.198 mmol) and pyrrolidine (1.6 mL, 19.8 mmol). The mixture was stirred at room temperature for half an hour. The solvent was removed by rotary evaporation and the mixture was then transferred to a flask filled with 3,6-dichloro-1,2,4,5-tetrazine (2991 mg, 19.8 mmol) and toluene (100 mL). The reactants were heated to 120 ° C and stirred for half an hour. The reaction mixture was concentrated and purified by flash chromatography ( The resulting mixture was purified on a 80 g silica gel column eluting with DCM (24 mL / min) to afford the title compound.

[0848] Preparation 70: 4-Chloro-1-(2-(methoxymethoxy)-4-methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine

[0849]

[0850] Preparation 71: 1-Chloro-4-(2-(methoxymethoxy)-4-methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine

[0851]

[0852] A mixture of 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (600 mg, 2.6 mmol), Cs2CO3 (1.69 g, 5.19 mmol), Pd(dppf)Cl2.CH2Cl2 (212 mg, 0.26 mmol) and [2-(methoxymethoxy)-4-methyl-phenyl]boronic acid (0.509 g, 2.6 mmol) in 1,4-dioxane (13.6 mL) and water (3.4 mL) was stirred in a sealed tube on a metal heating block at 100°C for 1 hour. The product was purified by flash chromatography ( The reaction mixture was purified on a silica gel column eluting with 50% EtOAc in heptane (24 mL / min) to afford the two title compounds.

[0853] Preparation 72: (5R,8S)-1,4-dichloro-5,7,8,9-tetrahydro-5,8-epoxyoxepino[3,4-d]pyridazine

[0854]

[0855] Toluene (100 mL) was added to a flask containing dihydro-levulinone (2536 mg, 19.8 mmol), p-toluenesulfonic acid monohydrate (38 mg, 0.198 mmol) and pyrrolidine (1.6 mL, 19.8 mmol). The mixture was stirred at room temperature for half an hour. The solvent was removed by rotary evaporation and the mixture was transferred to a flask filled with 3,6-dichloro-1,2,4,5-tetrazine (2991 mg, 19.8 mmol) and toluene (100 mL). The reactants were heated to 120 ° C and stirred for half an hour. The reaction mixture was concentrated and purified by flash chromatography ( 80g The obtained product was purified on a silica gel column (eluted with DCM (24 mL / min) to afford the title compound.

[0856] Preparation 73: 2-((5R,8S)-4-chloro-5,7,8,9-tetrahydro-5,8-epoxyoxepino[3,4-d]pyridazin-1-yl)-5-methylphenol

[0857]

[0858] Preparation 74: 2-((5R,8S)-1-chloro-5,7,8,9-tetrahydro-5,8-epoxyoxepino[3,4-d]pyridazin-4-yl)-5-methylphenol

[0859]

[0860] A mixture of 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (900 mg, 3.9 mmol), Cs2CO3 (3.1 g, 9.65 mmol), Pd(dppf)Cl2.CH2Cl2 (315 mg, 0.39 mmol) and (2-hydroxy-4-methyl-phenyl)boronic acid (0.587 g, 3.9 mmol) in 1,4-dioxane (13.6 mL) and water (3.4 mL) was stirred in a sealed tube on a metal heating block at 100°C for 1 hour. The product was purified by flash chromatography ( 40g The reaction mixture was purified on a silica gel column eluting with 50% EtOAc in heptane (24 mL / min) to afford the two title compounds.

[0861] Preparation 75: 4-Chloro-1-(2-fluoro-6-(methoxymethoxy)-4-methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine

[0862]

[0863] Preparation 76: 1-Chloro-4-(2-fluoro-6-(methoxymethoxy)-4-methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine

[0864]

[0865] A mixture of 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (100 mg, 0.43 mmol), XPhos Palladacycle G4 (56 mg, 0.065 mmol) and 2-(2-fluoro-6-(methoxymethoxy)-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.128 g, 0.43 mmol) in THF (2.26 mL) and 0.5 M K 3 PO 4 (0.56 mL) was stirred in a sealed tube on a metal heating block at 100° C. for 1 hour. The product was purified by flash chromatography ( 40g The reaction mixture was purified on a silica gel column eluting with 50% EtOAc in heptane (24 mL / min) to afford the two title compounds.

[0866] Preparation 77: 1,4-dichloro-5,6,7,8-tetrahydro-5,8-epoxyphthalazine

[0867]

[0868] A solution of racemic-(1S,4R)-7-oxabicyclo[2.2.1]heptan-2-one (200 mg, 1.78 mmol) in toluene (8.9182 mL) was treated with pyrrolidine (0.15 mL, 1.78 mmol) and p-toluenesulfonic acid monohydrate (3.4 mg, 0.0178 mmol) and stirred at room temperature for 30 minutes. 3,6-dichloro-1,2,4,5-tetrazine (296 mg, 1.96 mmol) was then added in small portions. The reaction mixture was stirred at 120 ° C for 2 hours and then concentrated under reduced pressure. The product was purified by flash column chromatography ( 24g The residue was purified by HPLC-MS / MS (FastFilm® Gold column) using a 0-100% EtOAc in heptane gradient to afford the title compound (25 mg, 6.5%) as an off-white solid.

[0869] Preparation 78: 2-(4-chloro-5,6,7,8-tetrahydro-5,8-epoxyphthalazin-1-yl)-5-methylphenol

[0870]

[0871] A mixture of 1,4-dichloro-5,6,7,8-tetrahydro-5,8-epoxyphthalazine (21.6 mg, 0.1 mmol), Cs2CO3 (65 mg, 0.2 mmol), Pd(dppf)Cl2.CH2Cl2 (8.1 mg, 0.01 mmol) and (2-hydroxy-4-methyl-phenyl)boronic acid (0.015 g, 0.1 mmol) in 1,4-dioxane (0.5 mL) and water (0.13 mL) was stirred in a sealed tube on a metal heating block at 100°C for 1 hour. The product was purified by flash chromatography ( 40g The reaction mixture was purified on a silica gel column eluting with 50% EtOAc in heptane (24 mL / min) to afford the title compound.

[0872] Preparation 79: 1,4-Dichlorospiro[5,7-dihydropyrano[3,4-d]pyridazine-8,1'-cyclopropane]

[0873]

[0874] Step 1: Methyl 1-((prop-2-yn-1-yloxy)methyl)cyclopropane-1-carboxylate

[0875]

[0876] To a mixture of methyl 1-(hydroxymethyl)cyclopropanecarboxylate (5 g, 38.42 mmol) and 3-bromoprop-1-yne (5.48 g, 46.10 mmol, 3.97 mL) in THF (50 mL) was added NaH (1.84 g, 46.10 mmol, 60% purity) at 0°C. The mixture was stirred at 0°C for 30 minutes and then at 60°C for 5 hours. TLC (PE / EtOAc = 3:1, R of the desired product) was obtained. f =0.6) indicated that the starting alcohol was completely consumed. The mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography ( 40g The residue was purified on a silica gel column) using a 0 to 20% EtOAc in PE gradient (45 mL / min) to afford the title compound (3.6 g, 56%) as a white solid. 1 H NMR (400MHz, CDCl3) δppm 0.89-0.97 (m, 2H), 1.25-1.32 (m, 2H), 2.42 (t, J = 2.32Hz, 1H), 3.65-3.70 (m, 5H), 4.19 (d, J = 2.32Hz, 2H).

[0877] Step 2: 1-((prop-2-yn-1-yloxy)methyl)cyclopropane-1-carboxylic acid

[0878]

[0879] To a solution of ethyl 1-(prop-2-ynyloxymethyl)cyclopropanecarboxylate (10 g, 54.88 mmol) in MeOH (80 mL) was added LiOH.HO (9.21 g, 219.52 mmol) and HO (40 mL). The mixture was stirred at 25 ° C for 12 hours. TLC (PE / EtOAc=3:1, Rf=0.3 of the desired product) indicated that the starting ester was completely consumed. The reaction mixture was acidified to pH=5-6 with 2M HCl at 0 ° C and extracted with EtOAc (30 × 5 mL). The combined organic layers were dried over NaSO, filtered and concentrated under reduced pressure to obtain the title compound (8.4 g, 89% yield, 90% purity) as a colorless oil. 1 H NMR (400MHz, CDCl3) δppm 0.83-0.88 (m, 2H), 1.05-1.09 (m, 2H), 3.38-3.44 (m, 1H), 3.54 (s, 2H), 4.11 (d, J = 2.20Hz, 2H), 12.16 (br s, 1H).

[0880] Step 3: 1-[(3,6-dichloropyridazin-4-yl)methoxymethyl]cyclopropanecarboxylic acid

[0881]

[0882] To a solution of 1-(prop-2-ynyloxymethyl)cyclopropanecarboxylic acid (1 g, 6.49 mmol) in toluene (20 mL) was added 3,6-dichloro-1,2,4,5-tetrazine (1.47 g, 9.73 mmol). The mixture was stirred at 120 ° C for 2 hours. TLC (PE / EtOAc=1:1, Rf=0.4 of the desired product) indicated that the starting acid was completely consumed. The mixture was concentrated in vacuo. The product was purified by flash chromatography ( 20g The residue was purified on a silica gel column eluting with a 0 to 50% EtOAc in PE gradient (40 mL / min) to afford the title compound as a red solid (500 mg, 27.8%). 1 H NMR (400MHz, CDCl3) δppm0.99-1.13(m,2H),1.38-1.54(m,2H),3.77(s,2H),4.60(s,2H),7.82(s,1H).

[0883] Step 4: 1,4-Dichlorospiro[5,7-dihydropyrano[3,4-d]pyridazine-8,1'-cyclopropane]

[0884]

[0885] At 25 ° C, to a solution of 1- [(3,6-dichloropyridazine-4-yl) methoxymethyl] cyclopropanecarboxylic acid (2 g, 7.22 mmol) in ACN (80 mL) and H2O (80 mL) was added silver nitrate (4.11 g, 24.19 mmol). Ammonium sulfate (1M, 21.65 mL) and ammonium peroxodisulfate (1.6 M, 13.53 mL) were added. The mixture was stirred at 70 ° C for 2 hours. LC-MS showed that the expected mass was detected. The mixture was cooled to room temperature, poured into an ice-cold saturated NaHCO3 aqueous solution (50 mL), filtered, and then extracted with DCM (50 mL × 3). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography ( 20g The residue was purified on a silica gel column) using a 0-10% EtOAc in PE gradient (45 mL / min) to afford the title compound (290 mg, 17.4%) as a white solid. 1 H NMR (400MHz, CDCl3) δppm 0.90-1.00 (m, 2H), 2.16-2.24 (m, 2H), 3.63 (s, 2H), 4.82 (s, 2H).

[0886] Preparation 80: (1R,2R)-2-((4'-chloro-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[3,4-d]pyridazin-1'-yl)amino)cyclohexan-1-ol

[0887]

[0888] Preparation 81: (1R,2R)-2-((1'-chloro-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[3,4-d]pyridazin-4'-yl)amino)cyclohexan-1-ol

[0889]

[0890] The starting material 1 ', 4'-dichloro-5'H, 7'H-spiro [cyclopropane-1,8'-pyrano [3,4-d] pyridazine] (200 mg, 865.51 μmol), (1R, 2R) -2-aminocyclohexan-1-ol (249.21 mg, 2.16 mmol) and NaI (389.20 mg, 2.60 mmol) were absorbed in NMP (5 mL) in a microwave tube. The sealed tube was heated at 180 ° C for 3 hours in a microwave reactor. LC-MS showed that the expected mass was detected. The mixture was purified by preparative HPLC (Boston Green ODS-5 μm, 30 mm × 150 mm column) using a 21% to 61% ACN gradient in water (containing formic acid). The product was purified by flash chromatography ( 10g The crude product was purified on a silica gel column using a 0 to 10% EtOAc in PE gradient (30 mL / min). The title compound of Preparation 80 was obtained as a yellow solid (70 mg). 1 H NMR (400MHz, CDCl3) δppm 0.88-0.97(m,2H),1.16-1.58(m,4H),1.65-1.87(m,4H),2.06-2.25(m,2H),3.37-3.47(m,1 H),3.59(q,J=11.78Hz,2H),3.97-4.12(m,1H),4.20-4.31(m,1H),4.72-4.76(m,2H); ESI-MS m / z[M+H] + 310.1. The title compound of Preparation 81 was obtained as a yellow solid (70 mg). 1 H NMR (400MHz, CDCl3) δppm 0.74-0.92(m,2H),1.21-1.51(m,4H),1.70-1.81(m,2H),2.01-2.19(m ,4H),3.48-3.53(m,2H),3.56-3.68(m,1H),3.94-4.10(m,1H),4.33(br d,J=5.26Hz,1H),4.53-4.76(m,2H); ESI-MS m / z[M+H] + 310.1.

[0891] Preparation 82: 4'-Chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[3,4-d]pyridazine] and 1'-Chloro-4'-(2-(methoxymethoxy)-4-methylphenyl)-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[3,4-d]pyridazine]

[0892]

[0893] To a mixture of 1',4'-dichloro-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[3,4-d]pyridazine](310mg, 1.34mmol) in dioxane (4mL) and water (1mL) was added 2-(2-(methoxymethoxy)-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (373.15mg, 1.34mmol), Pd(dppf)Cl2.CH2Cl2 (219.11mg, 268.31μmol) and Cs2CO3 (1.75g, 5.37mmol). The mixture was stirred at 100°C under N2 for 1 hour. LC-MS showed that the expected mass was detected. The mixture was quenched with H2O (10mL) and extracted with EtOAc (10mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. 10g The residue was purified on a silica gel column) using a 0 to 10% EtOAc in PE gradient (30 mL / min) to afford a mixture of two title compounds as yellow solids (280 mg).

[0894] Preparation 83: 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine

[0895]

[0896] Step 1: 1-(8-oxabicyclo[3.2.1]oct-2-en-3-yl)pyrrolidine

[0897]

[0898] To a solution of 8-oxabicyclo[3.2.1]octan-3-one (21 g, 166.45 mmol) in toluene (800 mL) was added TsOH (2.86 g, 16.63 mmol) and pyrrolidine (23.69 g, 332.93 mmol, 27.80 mL). The mixture was stirred at 80 ° C for 0.5 hours and then heated at reflux in a Dess-Martin apparatus for 0.5 hours to remove water. TLC (PE / EtOAc=3:1) indicated that the starting material was completely consumed and a new spot was formed. The reaction mixture was concentrated under reduced pressure to obtain the title compound (28 g, crude) as a red solid.

[0899] Step 2: 1,4-Dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine

[0900] To a solution of 1-(8-oxabicyclo[3.2.1]oct-2-en-3-yl)pyrrolidine (28.0 g, crude) in toluene (800 mL) was added 3,6-dichloro-1,2,4,5-tetrazine (35.30 g, 234.30 mmol). The mixture was stirred at 120 ° C for 1.5 hours. TLC (PE / EtOAc=3:1) indicated that the starting material was completely consumed and the desired product was formed. The reaction mixture was concentrated under reduced pressure to remove the solvent. The product was purified by flash chromatography ( 330g The residue was purified by HPLC (silica gel column) using a 0 to 25% EtOAc gradient in PE (80 mL / min) to afford the crude product (36 g). The crude product was recrystallized from EtOAc (600 mL) and PE (2400 mL) to afford the title compound (21 g, 78% yield, 100% purity) as a white solid. 1 HNMR(400MHz,CDCl3)δppm 1.54-1.80(m,1H),1.94-2.06(m,1H),2.15-2.33(m,2H),2.41(d,J=18.5 1Hz,1H),3.10(m,1H),4.74-4.91(m,1H),5.17(d,J=6.25Hz,1H); ESI-MS m / z[M+H] + 230.0.

[0901] Preparation 84: (1R,2R)-2-(((5S,8R)-1-chloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)cyclohexan-1-ol

[0902]

[0903] Preparation 85: (1R,2R)-2-(((5R,8S)-1-chloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)cyclohexan-1-ol

[0904]

[0905] The starting materials 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (1 g, 4.33 mmol), (1R,2R)-2-aminocyclohexanol (1.25 g, 10.82 mmol), DIPEA (5.59 g, 43.28 mmol, 7.54 mL) and NaI (1.95 g, 12.98 mmol) were absorbed in NMP (8 mL) in a microwave tube. The sealed tube was heated at 180 ° C for 3 hours in a microwave reactor. LC-MS showed that the starting material was completely consumed and a main peak with the expected mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The product was purified by flash chromatography ( 40g The residue was purified by silica gel column using a 0 to 10% MeOH / DCM gradient (35 mL / min) to afford a mixture of stereoisomers as a colorless oil (1.2 g, crude containing NMP). Stereoisomers were separated using a mobile phase of CO2 and 40% iPrOH (containing 0.1% NH3OH) using an AD-10 μm, 30 mm×250 mm column to obtain the title compound of Preparation 84 as a white solid (180 mg, 13.4%). 1 H NMR(400MHz,DMSO-d6)δppm 1.21-1.27(m,3H),1.62-1.72(m,3H),1.89-2.20(m,6H),2.90(m,1H),3.41-3.54(m,2H),3.79-3.90(m,1H),4.55(d,J=5.00Hz,1H),4.74(br t,J=5.82Hz,1H),5.18(d,J=6.13Hz,1H),6.05(d,J=7.50Hz,1H); ESI-MS m / z[M+H] + 309.12. The title compound of Preparation 85 was obtained as a white solid (130 mg, 9.22%). 1 H NMR(400MHz,DMSO-d6)δppm 1.29(br d,J=8.50Hz,3H),1.64-1.79(m,3H),1.83-2.22(m,6H),2.96(m,1H),3.47-3.5 9(m,2H),3.84-3.98(m,1H),4.69-4.83(m,2H),5.23(d,J=6.25Hz,1H),6.15(br d,J=7.63Hz,1H); ESI-MS m / z[M+H] + 309.12.

[0906] Preparation 86: 4-Chloro-1-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine

[0907]

[0908] A mixture of 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (1.5 g, 6.49 mmol), 2-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.97 g, 6.49 mmol), CsCO (8.46 g, 25.97 mmol), Pd(dppf)Cl.CHCl (1.06 g, 1.30 mmol) and H0 (5 mL) in dioxane (20 mL) was degassed and purged with N (3×) and then stirred at 100° C. under N atmosphere for 1 hour. LC-MS showed that the starting material was completely consumed and one major peak with the expected mass was detected. The residue was diluted with H2O (100 mL) and extracted with EtOAc 80 mL (80 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (Xtimate C18-10 μm, 40 mm×150 mm column) using a gradient of 28% to 68% ACN in water (containing NH3H2O+NH4HCO3) over 36 minutes to obtain the title compound (1.3 g, crude) as a white solid. The product was purified by SFC (REGIS (S, S) The crude product was further purified by HPLC (1-5 μm, 30 mm×250 mm column) using a mobile phase of CO 2 and 45% EtOH (containing 0.1% NH 3 OH) to afford the title compound (600 mg, 24.8%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 0.67-0.81(m,2H),0.96-1.10(m,3H),1.51-1.71(m,1H),1.90-2.25(m,5H),3.17-3.24(m,3H),4.6 2-4.78(m,1H),5.07-5.26(m,3H),6.72-6.88(m,1H),6.92-7.02(m,1H),7.11-7.24(m,1H); ESI-MS m / z[M+H] + 372.9.

[0909] Preparation 87: 4-chloro-1-(4-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine

[0910]

[0911] Preparation 88: 1-Chloro-4-(4-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine

[0912]

[0913] The title compound was synthesized as in Preparation 86.

[0914] Preparation 89: 2-(4-chloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol

[0915]

[0916] Preparation 90: 2-(1-chloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)-5-(trifluoromethoxy)phenol

[0917]

[0918] The title compound was synthesized as in Preparation 86.

[0919] Preparation 91: 4'-chloro-1'-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[0920]

[0921] Under nitrogen, 1', 4'-dichloro-5', 8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (300 mg, 1.30 mmol), 2-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (431 mg, 1.30 mmol), Pd(dppf)Cl2.CH2Cl2 (106 mg, 0.130 mmol) and tris(hydrogen phosphate) tripotassium (554 mg, 2.60 mmol) were added to a 20 mL vial. The reactants were heated to 80 ° C and stirred overnight. The reaction mixture was cooled to room temperature and extracted with EtOAc (2 × 20 mL) and water (20 mL). The organics were dried over MgSO 4 and filtered.The solution was concentrated, dissolved in toluene (2 mL) and purified by flash chromatography using a 0 to 50% EtOAc in heptane gradient to afford the title compound as the first eluting compound (120 mg, 23.1%). 1 H NMR(400MHz, CDCl3)δppm 0.46–0.53(m,2H),0.90-1.05(m,2H),2.29(m,1H),2.95(m,1H),3.38(s,3H),4.75(m,2H),5.15(br s,2H),7.38-7.48(m,2H),7.51(s,1H);C 18 H 16 ESI-MS m / z[M+H] of ClF3N2O3 + Calculated value 400.08; experimental value 401.0.

[0922] Preparation 92: 2-(4'-chloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol

[0923]

[0924] Under nitrogen, 1', 4'-dichloro-5', 8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (220 mg, 0.952 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boric acid (196 mg, 0.952 mmol), Pd(dppf)Cl2.CH2Cl2 (78 mg, 0.0952 mmol) and tris(hydrogen phosphate) tripotassium (406 mg, 1.90 mmol) were added to a 20 mL vial of 1,4-dioxane (6.8041 mL) and water (1.701 mL). The reactants were heated to 80 ° C and stirred overnight. The reaction mixture was cooled to room temperature and extracted with EtOAc (2 × 20 mL) and water (20 mL). The organic matter was dried over MgSO4 and filtered. The solution was concentrated using silica gel and purified by flash chromatography using a 0 to 50% EtOAc in heptane gradient to afford the title compound as the first eluting compound (71 mg, 20.9%). 1 H NMR(400MHz,DMSO-d6)δppm C 16 H 12 ESI-MS m / z[M+H] of ClF3N2O2 + Calculated value 356.05; experimental value 357.0.

[0925] Preparation 93: 4'-chloro-1'-(4-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[0926]

[0927] Preparation 94: 1'-chloro-4'-(4-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[0928]

[0929] A microwave vial was charged with 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (178 mg 0.769 mmol), 2-(4-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (234 mg, 0.789 mmol), tripotassium phosphate (328 mg, 1.54 mmol) and Pd(dppf)Cl2.CHCl2 (31.4 mg, 0038 mmol) in 1,4-dioxane / HO (4:1) (15.4 mL, 0.05 M). The vial was capped and a stream of nitrogen was bubbled through the solution for 15 minutes. The reaction mixture was heated to 100 ° C in a microwave reactor and stirred for 3 hours. The reaction was quenched with saturated aqueous NH4Cl solution and the mixture was extracted with DCM. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography ( 120g The residue was purified on a silica gel column using a 0 to 50% EtOAc gradient in heptane (40 mL / min). The title compound of Preparation 93 was obtained as a light yellow oil (97.6 mg, 34%). 20 H 21 ESI-MS m / z[M+H] of ClN2O3 + Calculated value 372.1; found value 373.1. The title compound of Preparation 94 was obtained as a white solid (77.9 mg, 27%). 20 H 21 ESI-MS m / z[M+H] of ClN2O3 + Calculated value 372.1; experimental value 373.1.

[0930] Preparation 95: (1R,2R)-2-((1'-chloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-4'-yl)amino)cyclopentan-1-ol

[0931]

[0932] A mixture of 1', 4'-dichloro-5', 8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (2.00 g, 8.66 mmol), (1R, 2R) -2-aminocyclopentan-1-ol (2.19 g, 21.6 mmol), NaI (6.49 g, 43.3 mmol) and DIPEA (15 mL, 86.6 mmol) in NMP (28.853 mL) was stirred at 180 ° C with high absorbance in a microwave reactor for 1 hour. The reaction mixture was diluted with H2O (200 mL) to provide a brown solution. The crude product was extracted with EtOAc (2 × 200 mL). The organic extracts were combined, dried over Na2SO4, filtered, rinsed with EtOAc, and concentrated by rotary evaporation to provide a brown oily crude product (7.25 g). The crude material was dissolved in toluene (10 mL), concentrated by rotary evaporation, reconstituted in toluene (8 mL) and purified by medium pressure chromatography ( Gold 330g silica gel column) is purified using a 0 to 100% EtOAc gradient in heptane. Early fractions are combined, concentrated by rotary evaporation, and dried in vacuo to provide the title compound (crude) as an orange oil. The oil is dissolved in iPrOAc (5 mL) under reflux and cooled to room temperature. The resulting solid is filtered, rinsed with iPrOAc (3×1 mL), and dried in vacuo to provide the title compound (115.6 mg, 4.5%) as a milky white solid. The filtrate and mixed fractions are combined and purified by medium pressure chromatography using a 1% to 100% EtOAc gradient in heptane. Early fractions are combined, concentrated by rotary evaporation, and dried in vacuo to provide a second batch of the title compound (340.0 mg, 13.3%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.54-0.72 (m, 2H), 0.75-0.93 (m, 2H), 1.40-1.55 (m, 2H), 1.57-1.74 (m, 2H), 1.86 (ddt, J = 12.58, 8.31, 6.37, 6.37 Hz, 1H), 2.11 (dtd, J = 12.99, 7.69, 7.69, 5.52 Hz, 1H), 2.67 (s, 2H), 4.00 (dt, J = 10.42, 5.33 Hz, 1H), 4.09 (quintet, J = 6.40 Hz, 1H), 4.37-4.52 (m, 2H), 4.80-4.87 (m, 1H), 6.01 (d, J = 6.27 Hz, 1H); C 14 H 18 ESI-MS of ClN3O2[M+H] + Calculated value 295.11; experimental value 296.1.

[0933] Preparation 96: 4'-chloro-1'-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazine]

[0934]

[0935] The title compound was synthesized as in Preparation 86.

[0936] Preparation 97: 4'-Chloro-1'-(4-chloro-2-(methoxymethoxy)-6-methylphenyl)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazine]

[0937]

[0938] The title compound was synthesized as in Preparation 86.

[0939] Preparation 98: 2-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0940]

[0941] Step 1: 4-Bromo-3-(methoxymethoxy)benzaldehyde

[0942]

[0943] At 20 ° C, NaH (1.09 g, 27.36 mmol, 60% purity) was added to a solution of 4-bromo-3-hydroxy-benzaldehyde (5 g, 24.87 mmol) in THF (80 mL). After stirring for 15 minutes, bromo(methoxy)methane (3.11 g, 24.87 mmol, 2.03 mL) was added to the reactants at 20 ° C. The mixture was stirred at 20 ° C for 2 hours. TLC (PE / EtOAc=5:1) indicated that the starting material was completely consumed and a new spot was formed. The reaction solution was diluted in NH4Cl aqueous solution (100 mL), stirred for 15 minutes, and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the title compound (6.1 g, 90% yield, 90% purity) as a colorless oil. 1H NMR (400MHz, CDCl3) δppm 3.54 (s, 3H), 5.34 (s, 2H), 7.40 (dd, J = 8.07, 1.31Hz, 1H), 7.64 (d, J = 1.25Hz, 1H), 7.74 (d, J = 8.13Hz, 1H), 9.95 (s, 1H).

[0944] Step 2: 1-Bromo-4-(difluoromethyl)-2-(methoxymethoxy)benzene

[0945]

[0946] To a solution of 4-bromo-3-(methoxymethoxy)benzaldehyde (6.1 g, 24.89 mmol) in DCM (30.5 mL) was added DAST (6.82 g, 42.31 mmol, 5.59 mL) at 0 ° C. The mixture was stirred at 20 ° C for 12 hours. TLC (PE / EtOAc=5: 1) indicated that the starting material was completely consumed and two new spots were formed. The reaction mixture was diluted with NH4Cl (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine (50 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash chromatography ( 120g The residue was purified on a silica gel column using a 0 to 3% EtOAc in PE gradient (70 mL / min). The title compound was obtained as a colorless oil (6.1 g, 91% yield, 90% purity). 1 H NMR (400MHz, CDCl3) δppm 3.53 (s, 3H), 5.28 (s, 2H), 6.38-6.77 (m, 1H), 7.04 (d, J = 7.88Hz, 1H), 7.29 (s, 1H), 7.63 (d, J = 8.25Hz, 1H).

[0947] Step 3: 2-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0948] A mixture of 1-bromo-4-(difluoromethyl)-2-(methoxymethoxy)benzene (700 mg, 2.62 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (865.26 mg, 3.41 mmol), Pd(dppf)Cl (191.79 mg, 262.11 μmol), and KOAc (514.46 mg, 5.24 mmol) in dioxane (18 mL) was degassed and stirred at 100° C. for 2 hours. TLC (PE / EtOAc=10:1) indicated that the limiting reactant was completely consumed and two new spots were formed. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. 12g The residue was purified on a silica gel column) using a 0 to 2% EtOAc in PE gradient (30 mL / min) to afford the title compound as a colorless oil (400 mg, 43.7% yield, 90% purity). 1 H NMR (400MHz, CDCl3) δppm 1.36 (s, 12H), 3.52 (s, 3H), 5.23 (s, 2H), 6.43-6.78 (m, 1H), 7.11-7.19 (m, 2H), 7.76 (d, J = 7.50Hz, 1H).

[0949] Preparation 99: 4'-Chloro-1'-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[0950]

[0951] A mixture of 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (173 mg, 748.66 μmol), 2-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (235.18 mg, 748.66 μmol), Pd(dppf)Cl (109.56 mg, 149.73 μmol), CsCO (975.72 mg, 2.99 mmol) in dioxane (3.5 mL) and H0 (0.9 mL) was degassed and purged with N (3x), and then stirred at 80°C under a N atmosphere for 12 hours. TLC (PE / EtOAc=3:1) indicated that the starting material was completely consumed and two new spots were formed. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash chromatography ( 4g The residue was purified by SFC (DAICEL HPLC) using a 0 to 10% EtOAc in PE gradient (30 mL / min). The HPLC-MS / MS was 1K-10 μm, 50 mm×250 mm column using a mobile phase of CO 2 and 15% MeOH (containing 0.1% NH 3 OH) to obtain the title compound (12 mg, 19% yield, 95% purity) as a white solid. 1 H NMR (400MHz, CDCl3) δppm 0.36-0.65(m,2H),0.96(br d,J=18.76Hz,2H),2.28(br d,J=16.88Hz,1H),2.96(br d,J=17.01Hz,1H),3.37(s,3H),4.75(br d,J=16.13Hz,2H),5.14(br d,J=5.13Hz,2H),6.52-6.83(m,1H),7.29(br d,J=7.88Hz,1H),7.40(s,1H).

[0952] Preparation 100: 2-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0953]

[0954] At 0 ° C under N2, to a mixture of 1-cyclopropyl-3-(methoxymethoxy)benzene (2g, 11.22mmol) and TMEDA (2.74g, 23.57mmol, 3.56mL) in THF (20mL) was added n-BuLi (2.5M in n-hexane) (2.5M, 9.43mL) at one time. The mixture was stirred at 10 ° C for 1 hour, then cooled to -78 ° C, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.59g, 24.69mmol, 5.04mL) was added. The mixture was stirred at 10 ° C for 12 hours. TLC (PE / EtOAc=10: 1) indicated that the starting material was completely consumed and three new spots were formed. The reaction mixture was quenched by adding NH4Cl aqueous solution (100mL) and extracted with EtOAc (100mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. 12g The residue was purified by a silica gel column using a 0 to 5% EtOAc gradient in PE (40 mL / min). The product was further purified by preparative HPLC (Welch Ultimate XB-CN-10 μm, 50 mm × 250 mm) using a 1% to 17% EtOH gradient in hexanes. The title compound was obtained as a colorless oil (1.48 g, 39% yield, 90% purity). 1 H NMR (400MHz, CDCl3) δppm 0.66-0.77(m,2H),0.93-1.03(m,2H),1.34(s,12H),1.84-1.92(m,1H),3.53(s,3H),5.1 9 (s, 2H), 6.70 (dd, J = 7.63, 1.38Hz, 1H), 6.77 (d, J = 1.25Hz, 1H), 7.60 (d, J = 7.63Hz, 1H).

[0955] Preparation 101: 4'-chloro-1'-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[0956]

[0957] To a solution of 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (500 mg, 2.16 mmol) and 2-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (658.19 mg, 2.16 mmol) in dioxane (4 mL) and H2O (1 mL) was added Cs2CO3 (2.82 g, 8.66 mmol) followed by Pd(dppf)Cl2 (316.65 mg, 432.75 μmol). The mixture was stirred at 100 ° C under N2 for 12 hours. LC-MS showed that the starting material was completely consumed and a new peak was detected. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. 4g The residue was purified by SFC (DAICEL HPLC) using a 0 to 20% EtOAc in PE gradient (30 mL / min) to afford the crude product (350 mg). The product was purified by using a mobile phase of CO 2 and 30% EtOH (containing 0.1% NH 3 OH) using a 5 μm, 30 mm×250 mm column (AD-H-5 μm, 30 mm×250 mm column) to obtain the title compound (109 mg, 13.1% yield, 96.7% purity) as a yellow solid. 1 H NMR(400MHz, CDCl3)δppm 0.41-0.58(m,2H),0.76(br d,J=1.4Hz,2H),0.91-1.10(m,4H),1.59-1.76(m,1H),1.88-1.99(m,1H),2.90-3.10(m,1H),3.36(br s,3H),4.74(br d,J=1.8Hz,2H),5.09(br s,2H),6.81(br d,J=7.6Hz,1H),6.99(br s,1H),7.21(br d,J=7.6Hz,1H).

[0958] Preparation 102: 4'-chloro-1'-(2-fluoro-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazine]

[0959]

[0960] Step 1: 2-(4'-chloro-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-3-fluoro-5-(trifluoromethyl)phenol

[0961]

[0962] A mixture of 1',4'-dichloro-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazine] (200 mg, 0.809 mmol), 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (248 mg, 0.809 mmol), Pd(dppf)Cl2.CHCl2 (66 mg, 0.0809 mmol) and tripotassium tris(hydrogen phosphate) (345 mg, 1.62 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL) was purged with nitrogen for 5 minutes and then heated at 100° C. for 40 minutes. The mixture was treated with water and extracted with EtOAc. The organics were washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica column eluting with heptane / EtOAc (9:1 to 0:1). The combined fractions were concentrated to afford the title compound (222 mg, 70%). 16 H 11 ESI-MS m / z[M+H] of ClF4N2O3 + Calculated value 390.0; experimental value 391.2.

[0963] Step 2: 4'-Chloro-1'-(2-fluoro-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazine]

[0964] A solution of 2-(4'-chloro-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin]-1'-yl)-3-fluoro-5-(trifluoromethyl)phenol (222 mg, 0.568 mmol) in THF (8 mL) was cooled to 0 ° C. Sodium hydride (34 mg, 0.852 mmol) was added, and bromomethyl methyl ether (0.070 mL, 0.852 mmol) was added after 30 minutes. The mixture was stirred at room temperature for 10 minutes, and then treated with saturated NH4Cl and extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to obtain the crude product, which was used without purification. 18 H 15 ESI-MS m / z[M+H] of ClF4N2O4 +Calculated value 434.1; experimental value 435.0.

[0965] Preparation 103: 4'-chloro-1'-(2-fluoro-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazine]

[0966]

[0967] Step 1: 1',4'-Dichloro-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazine]

[0968]

[0969] A mixture of 4-oxaspiro [2.4] heptane-6-one (1000 mg, 8.92 mmol), p-toluenesulfonic acid monohydrate (17 mg, 0.0892 mmol) and pyrrolidine (0.74 mL, 8.92 mmol) in toluene (20 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo, and the resulting residue was dissolved in toluene (8 mL) and added to a solution of 3,6-dichloro-1,2,4,5-tetrazine (1178 mg, 7.80 mmol) in toluene (18 mL) at 0 ° C. The mixture was heated at 80 ° C under nitrogen for 1 hour. The mixture was then treated with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column (40 g), eluted with heptane / EtOAc gradient (9: 1 to 0: 1). The combined fractions were concentrated to afford the title compound (0.885 g, 45.7%). 1 H NMR (400MHz, CD3OD) δppm 1.24-1.42(m,2H),1.54-1.72(m,2H),5.23(s,2H); ESI-MS m / z[M+H] of C8H6Cl2N2O + Calculated value 216.0; experimental value 217.0.

[0970] Step 2: 2-(4'-chloro-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazin]-1'-yl)-3-fluoro-5-(trifluoromethyl)phenol

[0971]

[0972] A mixture of 1',4'-dichloro-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazine] (250 mg, 1.15 mmol), 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (353 mg, 1.15 mmol), Pd(dppf)Cl2.CHCl2 (94 mg, 0.115 mmol) and tripotassium tris(hydrogen phosphate) (491 mg, 2.30 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) was purged with nitrogen for 5 minutes and then heated at 100° C. under nitrogen for 35 minutes. The mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column (40 g) eluting with a heptane / EtOAc gradient (4:1 to 0:1). The combined fractions were concentrated to afford the title compound (0.112 g, 26.9%). 15 ESI-MS m / z[M+H] of H9ClF4N2O2 + Calculated value 360.0; experimental value 361.1.

[0973] Step 3: 4'-Chloro-1'-(2-fluoro-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazine]

[0974] A solution of 2-(4'-chloro-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazine]-1'-yl)-3-fluoro-5-(trifluoromethyl)phenol (112 mg, 0.311 mmol) in THF (8 mL) was cooled to 0 ° C. Sodium hydride (19 mg, 0.466 mmol) was added. After stirring for 30 minutes, bromomethyl methyl ether (0.038 mL, 0.466 mmol) was added. The mixture was stirred at room temperature for 10 minutes, and then treated with saturated NH4Cl and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4, and concentrated to obtain the title compound, which was used without purification. 17 H 13 ESI-MS m / z[M+H] of ClF4N2O3 + Calculated value 404.1; experimental value 404.9.

[0975] Preparation 104: 1',4'-dichloro-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[0976]

[0977] Step 1: tert-Butyldimethyl(1-(prop-2-yn-1-yl)cyclopropyloxy)silane

[0978]

[0979] To a solution of 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)acetaldehyde (11.5 g, 53.64 mmol) in MeOH (90 mL) was added 1-diazo-1-dimethoxyphosphoryl-propan-2-one (20.61 g, 107.29 mmol) and K2CO3 (7.41 g, 53.64 mmol). The mixture was stirred at 0 ° C for 10 hours. TLC (PE / EtOAc=10:1) indicated that the starting material was completely consumed and a new spot was formed. The reaction mixture was quenched with NH4Cl aqueous solution (200 mL) and extracted with DCM (200 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by flash chromatography ( 330g The residue was purified on a silica gel column) using a 0 to 1% EtOAc in PE gradient (100 mL / min) to afford the title compound as a colorless oil (5.3 g, 44% yield, 95% purity). 1 H NMR (400MHz, CDCl3) δppm 0.10-0.14 (m, 6H), 0.69-0.72 (m, 2H), 0.73 (br s, 2H), 0.86 (s, 9H), 1.95 (t, J = 2.44Hz, 1H), 2.59 (d, J = 2.50Hz, 2H).

[0980] Step 2: 5-(1-((tert-Butyldimethylsilyl)oxy)cyclopropyl)pent-3-yn-2-one

[0981]

[0982] A 50 mL flame-dried flask was charged with tert-butyldimethyl(1-(prop-2-yn-1-yl)cyclopropyloxy)silane (15.7 g, 74.62 mmol) and THF (40 mL). The solution was cooled to -78 ° C and n-BuLi (2.5 M in hexane, 32.83 mL) was added dropwise. The solution was stirred at -78 ° C for 30 minutes, then N-methoxy-N-methyl-acetamide (8.46 g, 82.09 mmol, 8.73 mL) was added dropwise. The reaction was warmed to 0 ° C and stirred for an additional 3 hours. TLC (PE / EtOAc = 20: 1) indicated that the starting material was completely consumed and a new spot was formed. The reaction mixture was poured into a saturated NH4Cl aqueous solution (100 mL) in an ice bath. The phases were separated and the aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. 220g The residue was purified on a silica gel column) using a 0-4% EtOAc in PE gradient (100 mL / min) to afford the title compound as a colorless oil (15.24 g, 80.89% yield, 90% purity). 1 H NMR (400MHz, CDCl3) δppm 0.14 (s, 6H), 0.68 (s, 2H), 0.80 (s, 2H), 0.87 (s, 9H), 2.33 (s, 3H), 2.73 (s, 2H).

[0983] Step 3: 5-(1-((tert-Butyldimethylsilyl)oxy)cyclopropyl)pent-3-yn-2-ol

[0984]

[0985] To a solution of 5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pent-3-yn-2-one (15.24 g, 60.37 mmol) and trichlorocerium (19.35 g, 78.49 mmol, 4.93 mL) in MeOH (50 mL) was added NaBH4 (3.05 g, 80.62 mmol) at 25 ° C. The reaction mixture was stirred for 0.5 hours. TLC (PE / EtOAc=20:1) indicated that the starting material was completely consumed and a new spot was formed. The mixture was poured into a saturated NH4Cl aqueous solution (100 mL) in an ice bath. The phases were separated and the aqueous layer was extracted with EtOAc (100×3 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography ( 80g The residue was purified on a silica gel column) using a 0 to 5% EtOAc in PE gradient (75 mL / min) to afford the title compound as a colorless oil (12.8 g, 85.3% yield, 90% purity). 1 H NMR (400MHz, CDCl3) δppm 0.12(s,6H),0.62-0.69(m,2H),0.70-0.76(m,2H),0.86(s,9H),1.42(d,J=6.50Hz,3H),2.60(s,2H),4.50(q,J=6.50Hz,1H).

[0986] Step 4: 1-(5-((1-((tert-Butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6-dichloropyridazin-4-yl)ethan-1-ol

[0987]

[0988] A mixture of 5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pent-3-yn-2-ol (6.6 g, 25.94 mmol) and 3,6-dichloro-1,2,4,5-tetrazine (5.09 g, 33.72 mmol) in toluene (30 mL) was degassed and purged with N2 (3×), and then stirred at 100°C under N2 atmosphere for 48 hours. TLC (PE / EtOAc=20:1) indicated that the starting material remained and two new spots were formed. The mixture was filtered. The filtrate was evaporated under vacuum to obtain a residue, which was purified by flash chromatography ( 120g The residue was purified on a silica gel column using a 0 to 10% EtOAc in PE gradient (75 mL / min). The title compound was obtained as a brown oil (1.81 g, 18.6% yield, 90% purity). 1 NMR (400MHz, CDCl3) δppm-0.13(s,3H),-0.01(s,3H),0.56-0.66(m,1H),0.74(s,9H),0.83(dt,J=11.16,6.61Hz,1H),0.88- 0.98(m,1H),1.13-1.21(m,1H),1.57(d,J=6.75Hz,3H),2.80(d,J=13.38Hz,1H),4.24-4.33(m,2H),5.44(q,J=6.55Hz,1H).

[0989] Step 5: 1-(5-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6-dichloropyridazin-4-yl)ethyl 4-methylbenzenesulfonate

[0990]

[0991] To a solution of 1-(5-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6-dichloropyridazin-4-yl)ethan-1-ol (5.4 g, 14.31 mmol) in acetone (80 mL) was added K2CO3 (5.93 g, 42.93 mmol) and tosyl chloride (5.46 g, 28.62 mmol). The mixture was stirred at 70 ° C for 18 hours. TLC (PE / EtOAc=5:1) indicated that the starting material remained and two new spots were formed. The mixture was filtered. The filtrate was evaporated under vacuum and purified by flash chromatography ( 40g The resulting residue was purified on a silica gel column) using a 0 to 10% EtOAc in PE gradient (55 mL / min) to afford the title compound as a colorless oil (4.54 g, 59.7% yield, 90% purity). 1 H NMR (400MHz, CDCl3) δppm 0.01-0.09(m,6H),0.36-0.49(m,1H),0.56(br d,J=9.26Hz,1H),0.71(s,9H),0.82-0.94(m,2H),1.85(d,J=6.88Hz,3H),2.39(s,3H),3.06(br d, J=14.51Hz, 1H), 3.67-3.78 (m, 1H), 6.15 (q, J=6.75Hz, 1H), 7.19 (m, J=8.13Hz, 2H), 7.56 (m, J=8.25Hz, 2H).

[0992] Step 6: 1',4'-dichloro-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[0993]

[0994] To a solution of 1-(5-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6-dichloropyridazin-4-yl)ethyl 4-methylbenzenesulfonate (4.45 g, 8.37 mmol) in THF (250 mL) was added TBAF (1 M, 20.93 mL). The mixture was stirred at -20 ° C for 3 hours. TLC (PE / EtOAc = 20: 1) indicated that the starting material was completely consumed and a new spot was formed. The reaction was quenched with aqueous NH4Cl solution (10 mL) and extracted with DCM (10 mL × 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by flash chromatography ( 12g The residue was purified on a silica gel column) using a 0 to 8% EtOAc in PE gradient (35 mL / min) to afford the title compound as a yellow oil (1.06 g, 51.5% yield, 95% purity). 1 H NMR (400MHz, CDCl3) δppm 0.49(dd,J=10.26,6.75Hz,1H),0.79(dt,J=10.32,6.22Hz,1H),0.87-0.95(m,1H),1.10-1.18 (m,1H),1.65(d,J=6.63Hz,3H),2.67-2.75(m,1H),2.96-3.02(m,1H),4.92(q,J=6.63Hz,1H).

[0995] Preparation 105: 4'-chloro-1'-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[0996]

[0997] A mixture of 1',4'-dichloro-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (150 mg, 611.98 μmol), 2-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (203.25 mg, 611.98 μmol), Pd(dppf)Cl2 (89.56 mg, 122.40 μmol) and Cs2CO3 (797.58 mg, 2.45 mmol) in dioxane (3 mL) and H2O (0.75 mL) was degassed and purged with N2 (3×), and then stirred at 100°C under N2 atmosphere for 2 h. TLC (PE / EtOAc=3:1) indicated that the starting material was completely consumed and a new spot was formed. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (5 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash chromatography ( 4g The residue was purified on a silica gel column) using a 0 to 25% EtOAc in PE gradient (30 mL / min) to afford the title compound as a colorless oil (119 mg, 44.5% yield, 95% purity). 1H NMR (400MHz, CDCl3) δppm 0.16-0.41(m,1H),0.62(dt,J=10.29,6.24Hz,1H),0.77-0.94(m,1H),1.00-1.13(m,1H),1.21-1.31(m,1H),1.71(br d,J=6.38Hz,3H),2.59(br s,1H),3.12-3.29(m,1H),3.39(br s,3H),4.99(br s,1H),5.09-5.22(m,2H),7.39-7.54(m,3H)

[0998] Preparation 106: 4'-chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[0999]

[1000] A mixture of 1',4'-dichloro-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (100 mg, 407.99 μmol), 2-(2-(methoxymethoxy)-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (113.48 mg, 407.99 μmol), Pd(dppf)Cl2 (59.71 mg, 81.60 μmol) and Cs2CO3 (531.72 mg, 1.63 mmol) in dioxane (2 mL) and H2O (0.5 mL) was degassed and purged with N2 (3×), and then stirred at 100° C. for 2 hours. LC-MS showed that the starting material was completely consumed, and about 67% of the desired compound was detected. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. 4g The residue was purified on a silica gel column) using a 0 to 20% EtOAc in PE gradient (30 mL / min) to afford the title compound as a colorless oil (110 mg). 1H NMR (400MHz, CDCl3) δppm 0.17-0.41(m,1H),0.61(dt,J=10.2,6.1Hz,1H),0.74-0.93(m,1H),0.99-1.11(m,1H),1.71(d,J=6.5Hz,3H),2.42(s,3H), 2.52-2.77(m,1H),3.36(s,3H),4.95-5.04(m,1H),5.06-5.12(m,2H),6.97(d,J=7.6Hz,1H),7.06(s,1H),7.20-7.26(m,1H)

[1001] Preparation 107: 4'-chloro-1'-(4-chloro-2-(methoxymethoxy)phenyl)-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[1002]

[1003] A mixture of 1',4'-dichloro-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (100 mg, 407.99 μmol), 2-[4-chloro-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (121.81 mg, 407.99 μmol), CsCO (531.72 mg, 1.63 mmol) and Pd(dppf)Cl (59.71 mg, 81.60 μmol) in dioxane (2 mL) and H0 (0.5 mL) was degassed and purged with N (3x), and then stirred at 100°C for 2 hours. TLC (PE / EtOAc=3:1) indicated that the starting material was completely consumed and three new spots were formed. The reaction mixture was diluted with H2O (4 mL) and extracted with EtOAc (4 mL x 3). The combined organic layers were washed with brine (4 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash chromatography ( 4g The residue was purified on a silica gel column) using a 0 to 12% EtOAc in PE gradient (25 mL / min) to afford the title compound as a yellow oil (70 mg, 41% yield, 90% purity). 1H NMR (400MHz, CDCl3) δppm0.14-0.43(m,1H),0.62(dt,J=10.13,6.32Hz,1H),0.74-0.91(m ,1H),1.06(dd,J=11.32,5.69Hz,1H),1.70(d,J=6.50Hz,3H),2.48-2.68(m,1H),3.38(br s,3H),4.88-5.04(m,1H),5.10(br s,2H),7.12-7.16(m,1H),7.28(d,J=1.75Hz,1H).

[1004] Preparation 108: 4'-chloro-1'-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[1005]

[1006] A mixture of 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (660 mg, 2.86 mmol), 2-[4-(difluoromethyl)-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (897.22 mg, 2.86 mmol), Pd(dppf)Cl2 (417.98 mg, 571.23 μmol) and Cs2CO3 (3.72 g, 11.42 mmol) in dioxane (18 mL) and H2O (4.5 mL) was degassed and purged with N2 (3×), and then stirred at 80° C. for 12 hours. TLC (PE / EtOAc=3:1) indicated that the starting material was completely consumed and two new spots were formed. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash chromatography ( 12g The residue was purified by SFC (DAICEL HPLC) using a 0 to 10% EtOAc gradient in PE (40 mL / min). A mixture of the desired compound and its regioisomers was obtained as a white solid (455 mg, mixture). The mixture was purified using a 1K-10 μm, 50 mm×250 mm column) using a mobile phase of CO 2 and 15% MeOH (containing 0.1% NH 3 OH) to obtain the title compound as a white solid (131 mg, 50.9% yield, 99% purity) (retention time: 4.189 min). 1H NMR (400MHz, CDCl3) δppm0.36-0.65(m,2H),0.96(br d,J=18.76Hz,2H),2.28(br d,J=16.88Hz,1H),2.96(br d,J=17.01Hz,1H),3.37(s,3H),4.75(br d,J=16.13Hz,2H),5.14(br d,J=5.13Hz,2H),6.52-6.83(m,1H),7.29(br d,J=7.88Hz,1H),7.40(s,1H). The regioisomer 1'-chloro-4'-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] was obtained as a white solid (138 mg, 52.5% yield, 97% purity) (retention time: 4.496 min). 1 H NMR(400MHz,DMSO-d6)δppm 0.71(br s,2H),0.86(br s,2H),2.94(s,2H),3.27-3.30(m,3H),4.19-4.59(m,2H),5.24(br s,2H),6.94-7.29(m,1H),7.37(d,J=7.75Hz,1H),7.44-7.56(m,2H).

[1007] Preparation 109: 4'-chloro-1'-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[1008]

[1009] To a solution of 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (500 mg, 2.16 mmol) and 2-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (658.19 mg, 2.16 mmol) in dioxane (4 mL) and H2O (1 mL) was added Cs2CO3 (2.82 g, 8.66 mmol) followed by Pd(dppf)Cl2 (316.65 mg, 432.75 μmol). The mixture was stirred at 100 ° C under N2 for 12 hours. LC-MS showed that the starting material was completely consumed and approximately 42% of the desired compound was detected. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. 4g The residue was purified by SFC (DAICEL HPLC ... The mixture was purified using a 5 μm, 30 mm×250 mm column (AD-H-5 μm, 30 mm×250 mm column) using a mobile phase of CO 2 and 30% EtOH (containing 0.1% NH 3 OH) to obtain the title compound as a yellow solid (109 mg, 13.1% yield, 96.7% purity) (retention time: 6.793 min). 1 H NMR (400MHz, CDCl3) δppm0.41-0.58(m,2H),0.76(br d,J=1.4Hz,2H),0.91-1.10(m,4H),1.59-1.76(m,1H),1.88-1.99(m,1H),2.90-3.10(m,1H),3.36(br s,3H),4.74(br d,J=1.8Hz,2H),5.09(br s,2H),6.81(br d,J=7.6Hz,1H),6.99(br s,1H),7.21(br d,J=7.6Hz,1H). The regioisomer 1'-chloro-4'-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] was obtained as a red solid (90 mg, 10% yield, 91% purity) (retention time: 7.772 min). 1 H NMR (400MHz, CDCl3) δ = 7.21 (d, J = 7.8Hz, 1H), 6.98 (s, 1H), 6.85-6.79 (m, 1H), 5.10 (s, 2H), 4.73-4.28 (m, 2H), 3.38 (s, 3H), 2.90(brs,2H),2.02(s,1H),1.99-1.90(m,1H),1.06-1.00(m,2H),0.99-0.93(m,2H),0.79-0.73(m,2H),0.71-0.65(m,2H).

[1010] Preparation 110: 4'-Chloro-1'-(4-cyclopropyl-2,6-difluorophenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] and 1'-Chloro-4'-(4-cyclopropyl-2,6-difluorophenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[1011]

[1012] To a 20 mL vial was added 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (500 mg, 2.16 mmol), 2-(4-cyclopropyl-2,6-difluoro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.61 g, 2.16 mmol), Xantphos Palladacycle G3 (205 mg, 0.216 mmol) and potassium tris(hydrogen phosphate) (1.38 g, 6.49 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL). The vial was filled with nitrogen and the reaction mixture was heated to 90 ° C overnight with stirring. The reaction mixture was cooled to room temperature and then extracted with EtOAc (2×20 mL) and brine (20 mL). The organic matter was dried over MgSO4 and filtered. The solution was concentrated and purified by flash chromatography using a 0 to 50% EtOAc in heptane gradient to afford a mixture of the title compounds (54 mg, 0.0774 mmol, 3.58%). 18 H 15 ESI-MS m / z[M+H] of ClF2N2O + Calculated value 348.1; experimental value 349.1.

[1013] Preparation 111: 4'-Chloro-1'-(4-cyclopropyl-2-fluorophenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] and 1'-Chloro-4'-(4-cyclopropyl-2-fluorophenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[1014]

[1015] To a 20 mL vial equipped with a stir bar was added 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (500 mg, 2.16 mmol), 2-(4-cyclopropyl-2-fluoro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (567 mg, 2.16 mmol), Pd(dppf)Cl2.CH2Cl2 (177 mg, 0.216 mmol) and potassium tris(hydrogen phosphate) (0.92 g, 4.33 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL). The vial was filled with nitrogen and the reaction mixture was heated to 80 ° C overnight with stirring. The reaction mixture was cooled to room temperature and extracted with EtOAc (2×10 mL) and brine (10 mL). The organic matter was dried over MgSO4 and filtered. The solution was concentrated and purified by flash chromatography using a 0 to 50% EtOAc in heptane gradient to afford a mixture of the title compounds (338 mg, 0.511 mmol, 23.61%). 18 H 16 ESI-MS m / z[M+H] of ClFN2O + Calculated value 330.1; experimental value 331.1.

[1016] Preparation 112: 4-chloro-1-(2-(methoxymethoxy)-4-methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine

[1017]

[1018] A mixture of 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (460 mg, 2.0 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd(dppf)Cl2.CH2Cl2 (146 mg, 0.2 mmol) and 2-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.61 g, 2.0 mmol) in THF (10.4 mL) and 0.5 M K3PO4 (2.6 mL) was stirred in a sealed tube on a metal heating block at 100° C. for 30 minutes. The product was purified by flash chromatography ( 40g The reaction mixture was purified on a silica gel column using 33% EtOAc in heptane (24 mL / min) to afford the title compound.

[1019] Preparation 113: 4-chloro-1-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine

[1020]

[1021] A mixture of 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (231 mg, 1.00 mmol), 2-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (298 mg, 1.00 mmol), Xantphos Palladacycle G4 (96 mg, 0.100 mmol), tripotassium phosphate (637 mg, 3.00 mmol), toluene (10 mL) and water (2.5 mL) was evacuated and backfilled with nitrogen (3×), and then heated to 60° C. and stirred for 4 hours. The mixture was diluted with saturated NH4Cl (50 mL) and extracted with DCM (50 mL×3). The organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated to obtain a mixture of regioisomers, which was purified by flash chromatography ( The mixture was separated using heptane / dioxane (4:1) using 80 g x 2 stacked silica columns. The first eluting isomer was designated as the title compound (75 mg, 20.45%). 1 H NMR(400MHz,CD3OD)δppm 1.10-1.18(m,2H),1.48-1.66(m,3H),2.02-2.28(m,4H),2.95-3.06(m,1H),4.70-4.79(m,1H),5.23-5.32(m,1H),6.84-6.97(m,2H).

[1022] Preparation 114: 1',4'-dichloro-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[1023]

[1024] Step 1: 1-(2,2-dimethoxyethyl)cyclopropan-1-ol

[1025]

[1026] To a solution of methyl 3,3-dimethoxypropanoate (60g, 404.98mmol, 57.42mL) in THF (800mL) was added tetraisopropoxytitanium solution (23.02g, 81.00mmol, 23.90mL) at 0°C, and then bromo(ethyl)magnesium (3M in Et2O, 337.48mL) was added dropwise at 0°C over a period of 1 hour. The reaction mixture was stirred at 0°C for 2 hours. TLC (PE / EtOAc=5:1) indicated that the starting material was completely consumed and two new spots were formed. The reaction mixture was diluted with THF (500mL) and quenched with NH4Cl aqueous solution (2000mL). The resulting white precipitate was filtered off and the filtrate was extracted with EtOAc (1000mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by flash chromatography ( 330g The residue was purified on a silica gel column) using a 0 to 15% EtOAc in PE gradient (100 mL / min) to afford the title compound as a yellow oil (30 g, 51% yield, 90% purity). 1 HNMR (400MHz, CDCl3) δppm 0.42-0.48 (m, 2H), 0.74-0.80 (m, 2H), 1.88 (d, J = 5.75Hz, 2H), 3.39 (s, 6H), 4.68 (t, J = 5.75Hz, 1H).

[1027] Step 2: 2-(1-((tert-Butyldimethylsilyl)oxy)cyclopropyl)acetaldehyde

[1028]

[1029] A mixture of 1-(2,2-dimethoxyethyl)cyclopropanol (15g, 102.61mmol), 2,6-lutidine (54.97g, 513.05mmol, 59.75mL), TBSOTf (29.84g, 112.87mmol, 25.92mL) and TMSOTf (34.21g, 153.92mmol, 27.81mL) in DCM (100mL) was degassed and purged with N2 (3×), and then stirred at 25°C under N2 atmosphere for 10 hours. TLC (PE / EtOAc=10:1) indicated that the starting material was completely consumed and two new spots were formed. The reaction mixture was quenched with NH4Cl aqueous solution (100mL) and extracted with DCM (100mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by flash chromatography ( 330g The residue was purified on a silica gel column using a 0 to 5% EtOAc in PE gradient (100 mL / min). The title compound was obtained as a yellow oil (12 g, 49% yield, 90% purity). 1 H NMR (400MHz, CDCl3) δppm 0.09 (s, 6H), 0.58-0.64 (m, 2H), 0.83 (s, 9H), 0.84-0.86 (m, 2H), 2.46 (d, J = 2.75Hz, 2H), 9.94 (t, J = 2.81Hz, 1H).

[1030] Step 3: tert-Butyl-dimethyl-(1-prop-2-ynylcyclopropyloxy)silane

[1031]

[1032] To a solution of 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)acetaldehyde (11.5 g, 53.64 mmol) in MeOH (90 mL) was added 1-diazo-1-dimethoxyphosphoryl-propan-2-one (20.61 g, 107.29 mmol) and K2CO3 (7.41 g, 53.64 mmol). The mixture was stirred at 0 ° C for 10 hours. TLC (PE / EtOAc=10:1) indicated that the starting material was completely consumed and a new spot was formed. The reaction mixture was quenched with NH4Cl aqueous solution (200 mL) and extracted with DCM (200 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by flash chromatography ( 330g The residue was purified on a silica gel column using a 0 to 1% EtOAc in PE gradient (100 mL / min). The title compound was obtained as a colorless oil (5.3 g, 44% yield, 95% purity). 1 H NMR (400MHz, CDCl3) δppm0.10-0.14(m,6H),0.69-0.72(m,2H),0.73(br s,2H),0.86(s,9H),1.95(t,J=2.44Hz,1H),2.59(d,J=2.50Hz,2H).

[1033] Step 4: 5-(1-((tert-Butyldimethylsilyl)oxy)cyclopropyl)pent-3-yn-2-one

[1034]

[1035] A 50 mL flame-dried flask was charged with tert-butyl-dimethyl-(1-prop-2-ynylcyclopropyloxy)silane (15.7 g, 74.62 mmol) and THF (40 mL). The solution was cooled to -78 ° C and n-BuLi (2.5 M in hexane, 32.83 mL) was added dropwise. The solution was stirred at -78 ° C for 30 minutes, then N-methoxy-N-methyl-acetamide (8.46 g, 82.09 mmol, 8.73 mL) was added dropwise. The reaction mixture was warmed to 0 ° C and stirred for 3 hours. TLC (PE / EtOAc = 20: 1) indicated that the starting material was completely consumed and a new spot was formed. The reaction mixture was poured into a saturated NH4Cl aqueous solution (100 mL) in an ice bath and the phases were separated. The aqueous layer was extracted with EtOAc (100 mL x 3) and the combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. 220g The residue was purified on a silica gel column using a 0 to 4% EtOAc in PE gradient (100 mL / min). The title compound was obtained as a colorless oil (15.24 g, 80.89% yield, 90% purity). 1 H NMR (400MHz, CDCl3) δppm 0.14 (s, 6H), 0.68 (s, 2H), 0.80 (s, 2H), 0.87 (s, 9H), 2.33 (s, 3H), 2.73 (s, 2H).

[1036] Step 5: 5-(1-((tert-Butyldimethylsilyl)oxy)cyclopropyl)pent-3-yn-2-ol

[1037]

[1038] To a solution of 5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pent-3-yn-2-one (15.24 g, 60.37 mmol) and trichlorocerium (19.35 g, 78.49 mmol, 4.93 mL) in MeOH (50 mL) was added NaBH4 (3.05 g, 80.62 mmol) at 25 ° C. The reaction mixture was stirred for 0.5 hours. TLC (PE / EtOAc=20:1) indicated that the starting material was completely consumed and a new spot was formed. The mixture was poured into a saturated NH4Cl aqueous solution (100 mL) in an ice bath and the phases were separated. The aqueous layer was extracted with EtOAc (100×3 mL) and the combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography ( 80g The residue was purified on a silica gel column using a 0 to 5% EtOAc in PE gradient (75 mL / min). The title compound was obtained as a colorless oil (12.8 g, 85.3% yield, 90% purity). 1 H NMR (400MHz, CDCl3) δppm 0.12(s,6H),0.62-0.69(m,2H),0.70-0.76(m,2H),0.86(s,9H),1.42(d,J=6.50Hz,3H),2.60(s,2H),4.50(q,J=6.50Hz,1H).

[1039] Step 6: 1-(5-((1-((tert-Butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6-dichloropyridazin-4-yl)ethan-1-ol

[1040]

[1041] A mixture of 5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pent-3-yn-2-ol (6.6 g, 25.94 mmol) and 3,6-dichloro-1,2,4,5-tetrazine (5.09 g, 33.72 mmol) in toluene (30 mL) was degassed and purged with N2 (3×), and then stirred at 100° C. under N2 atmosphere for 48 hours. TLC (PE / EtOAc=20:1) indicated that some starting material remained and two new spots were formed. The mixture was filtered. The filtrate was evaporated under vacuum and purified by flash chromatography ( 120g The residue was purified on a silica gel column using a 0 to 10% EtOAc in PE gradient (75 mL / min). The title compound was obtained as a brown oil (1.81 g, 18.6% yield, 90% purity). 1 H NMR (400MHz, CDCl3) δppm-0.13(s,3H),-0.01(s,3H),0.56-0.66(m,1H),0.74(s,9H),0.83(dt,J=11.16,6.61Hz,1H),0.88- 0.98(m,1H),1.13-1.21(m,1H),1.57(d,J=6.75Hz,3H),2.80(d,J=13.38Hz,1H),4.24-4.33(m,2H),5.44(q,J=6.55Hz,1H).

[1042] Step 7: 1-(5-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6-dichloropyridazin-4-yl)ethyl 4-methylbenzenesulfonate

[1043]

[1044] To a solution of 1-(5-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6-dichloropyridazin-4-yl)ethan-1-ol (5.4 g, 14.31 mmol) in acetone (80 mL) was added K2CO3 (5.93 g, 42.93 mmol) and TsCl (5.46 g, 28.62 mmol). The mixture was stirred at 70 ° C for 18 hours. TLC (PE / EtOAc=5:1) indicated that some starting material remained and two new spots were formed. The mixture was filtered. The filtrate was evaporated under vacuum to obtain a residue, which was purified by flash chromatography ( 40g The residue was purified on a silica gel column using a 0 to 10% EtOAc in PE gradient (55 mL / min). The title compound was obtained as a colorless oil (4.54 g, 59.7% yield, 90% purity). 1 H NMR (400MHz, CDCl3) δppm0.01-0.09(m,6H),0.36-0.49(m,1H),0.56(br d,J=9.26Hz,1H),0.71(s,9H),0.82-0.94(m,2H),1.85(d,J=6.88Hz,3H),2.39(s,3H),3.06(br d, J=14.51Hz, 1H), 3.67-3.78 (m, 1H), 6.15 (q, J=6.75Hz, 1H), 7.19 (m, J=8.13Hz, 2H), 7.56 (m, J=8.25Hz, 2H).

[1045] Step 8: 1',4'-dichloro-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[1046]

[1047] To a solution of 1-(5-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6-dichloropyridazin-4-yl)ethyl 4-methylbenzenesulfonate (4.45 g, 8.37 mmol) in THF (250 mL) was added TBAF (1 M, 20.93 mL). The mixture was stirred at -20 ° C for 3 hours. TLC (PE / EtOAc=20:1) indicated that the starting material was completely consumed and a new spot was formed. The reaction mixture was quenched with aqueous NH4Cl solution (10 mL) and extracted with DCM (10 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by flash chromatography ( 12g The residue was purified on a silica gel column using a 0 to 8% EtOAc in PE gradient (35 mL / min). The title compound was obtained as a yellow oil (1.06 g, 51.5% yield, 95% purity). 1 H NMR (400MHz, CDCl3) δppm 0.49(dd,J=10.26,6.75Hz,1H),0.79(dt,J=10.32,6.22Hz,1H),0.87-0.95(m,1H),1.10-1.18 (m,1H),1.65(d,J=6.63Hz,3H),2.67-2.75(m,1H),2.96-3.02(m,1H),4.92(q,J=6.63Hz,1H).

[1048] Preparation 115 and Preparation 116: (1R,2R)-2-(((5R,8S)-1-chloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)cyclopentan-1-ol and (1R,2R)-2-(((5S,8R)-1-chloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)cyclopentan-1-ol

[1049]

[1050] The title compound was synthesized as in Preparations 84 and 85.

[1051] Preparation 117: 1'-Chloro-N-((1R,2R)-2-methoxycyclopentyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-amine

[1052]

[1053] A mixture of 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (0.20 g, 0.844 mmol), (1R,2R)-2-methoxycyclopentan-1-amine hydrochloride (0.32 g, 2.11 mmol), sodium iodide (0.63 g, 4.22 mmol) and DIPEA (1.5 mL, 8.44 mmol) in NMP (3 mL) was stirred at high absorbance at 180 ° C in a microwave reactor for 1 hour. The reaction mixture was transferred to a 100 mL separatory funnel and the layers were separated. The bottom layer was diluted with H2O (20 mL) to provide a brown solution. The crude product was extracted with EtOAc (2 × 20 mL). The organic extracts were combined, dried over Na2SO4, filtered, rinsed with EtOAc, and concentrated by rotary evaporation to provide a brown oily crude product (0.864 g). The crude material was dissolved in toluene (3 mL), concentrated by rotary evaporation, reconstituted in toluene (3 mL) and purified by medium pressure chromatography ( Gold 80g silica gel column) was purified using a 0 to 100% EtOAc in heptane gradient. Early fractions were combined, concentrated by rotary evaporation, and dried in vacuo to afford the title compound as an oil (29.3 mg, 11.2%). 1 H NMR (400MHz, CDCl3) δppm 0.57-0.69(m,2H),0.91-1.02(m,2H),1.43-1.53(m,1H),1.65-1.79(m,2H),1.80-1.90(m,1H),1.90-2.00(m ,1H),2.40(td,J=13.55,8.03Hz,1H),2.67-2.80(m,2H),3.46(s,3H),3.68-3.82(m,2H),4.33-4.50(m,2H); 15 H 20 ESI-MS m / z[M+H] of ClN3O2 + Calculated value 309.12; experimental value 310.1.

[1054] Preparation 118: 1'-Chloro-N-((1R,2R)-2-methoxycyclobutyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-amine

[1055]

[1056] 1', 4'-dichloro-5', 8'-dihydrospiro [cyclopropane-1,7'-pyrans [3,4-d] pyridazine] (330 mg, 1.43 mmol), DIPEA (2.5 mL, 14.3 mmol) and (1R, 2R) -2-methoxycyclobutylamine (361 mg, 3.57 mmol) in NMP (7.5 mL) were added to a 20 mL microwave vial and heated at 180 ° C for 1 hour in a Biotage microwave reactor. The reaction mixture was extracted with EtOAc (2 × 50 mL) and brine (50 mL). The organic matter was combined, dried over MgSO4, and concentrated under reduced pressure to obtain an oil. The crude product was purified by flash chromatography using a 0 to 100% EtOAc gradient in heptane to obtain the title compound as the first eluting peak (33 mg, 7.8%). 1 H NMR (400MHz, CDCl3) δppm 0.54-0.66(m,2H),0.94-1.02(m,2H),1.45(br t,J=9.79Hz,1H),1.67(tdd,J=10.85,10.85,9.29,8.41Hz,1H),2.08-2.22(m,1H),2.31-2.43(m,1H) ,2.67-2.78(m,2H),3.34(s,3H),3.84(q,J=7.36Hz,1H),4.45(d,J=1.51Hz,2H),4.50-4.63(m,1H);C 14 H 18 ESI-MS m / z[M+H] of ClN3O2 + Calculated value 295.1; experimental value 296.1.

[1057] Preparation 119: 1'-Chloro-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-amine

[1058]

[1059] To a 20mL microwave vial equipped with a stirring bar, (3S, 4R) -3-methoxytetrahydro -2H- pyran -4- amine (710mg, 5.41mmol), 1', 4'- dichloro -5', 8'- dihydrospiro [cyclopropane -1,7'- pyrans [3,4-d] pyridazine] (500mg, 2.16mmol), DIPEA (3.8mL, 21.6mmol) and sodium iodide (1622mg, 10.8mmol) were added to NMP (11mL). The reaction mixture was stirred at 180 ° C for 1 hour in a Biotage microwave reactor and then extracted with EtOAc (2 × 50mL) and brine (50mL). Organic matter was separated and dried over MgSO4. The solution was filtered, concentrated under reduced pressure, and purified by flash chromatography using a gradient of 20% to 80% EtOAc in heptane to afford the title compound as the first eluting peak (21 mg, 2.98%).

[1060] 1 H NMR (400MHz, CDCl3) δppm 0.57-0.68(m,2H),0.97–0.99(m,2H),1.53-1.56(m,1H),2.58-2.81(m,3H),3.26-3.46(m,5H),3.5 5(td,J=11.60,2.29Hz,1H),3.88(dt,J=11.74,3.58Hz,1H),4.08-4.26(m,2H),4.38-4.49(m,2H); C 15 H 20 ESI-MS m / z[M+H] of ClN3O3 + Calculated value 325.1; experimental value 326.1.

[1061] Preparation 120: (1R,2R)-2-((1'-chloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-4'-yl)amino)cyclobutan-1-ol

[1062]

[1063] 1', 4'-dichloro-5', 8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (600mg, 2.60mmol), DIPEA (4.5mL, 26.0mmol), (1R, 2R)-2-aminocyclobutan-1-ol (566mg, 6.49mmol) and sodium iodide (1946mg, 13.0mmol) in NMP (10mL) were added to a 20mL microwave vial. The reaction mixture was heated at 180 ° C for 1 hour in a Biotage microwave reactor and then extracted with EtOAc (2×50mL) and brine (50mL). The organic matter was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting oil was purified by flash chromatography, eluting with a 0 to 100% EtOAc gradient in heptane to obtain the title compound as the first elution peak (91mg, 11%). 1 H NMR (400MHz, CDCl3) δppm 0.59-0.66(m,2H),0.90-1.03(m,2H),1.46-1.63(m,1H),1.71-1.85(m,1H),2.14-2.28(m ,2H),2.73-2.74(s,2H),3.52-3.65(m,1H),3.90-4.06(m,2H),4.43-4.44(s,2H),4.78(br s,1H);C 13 H 16 ESI-MS m / z[M+H] of ClN3O2 + Calculated value 281.1; experimental value 282.0.

[1064] Example 233: 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine]-1'-yl)-5-methylphenol

[1065]

[1066] Step 1: N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-1'-(2-(methoxymethoxy)-4-methylphenyl)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine]-4'-amine

[1067]

[1068] Under N2, to a mixture of 4'-chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)-7', 8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine](60mg, 173.01μmol) and (3R, 5R)-5-fluoro-1-methylpiperidin-3-amine (141.94mg, 692.03μmol, 2HCl) in toluene (1mL) was added Cs2CO3(225.48mg, 692.03μmol), BINAP(21.55mg, 34.60μmol) and Pd(OAc)2(3.88mg, 17.30μmol). The mixture was stirred at 100°C for 12 hours. LC-MS showed that the desired product was obtained. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography ( The residue was purified using a 4 g silica gel column) using a 0 to 5% MeOH gradient in DCM (20 mL / min). The title compound was obtained as a yellow oil (74.3 mg, 75.5% yield, 77.8% purity). ESI-MS m / z [M+H] + 443.1.

[1069] Step 2: 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazin-1'-yl)-5-methylphenol

[1070] A mixture of N-((3R, 5R)-5-fluoro-1-methylpiperidin-3-yl)-1'-(2-(methoxymethoxy)-4-methylphenyl)-7', 8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine]-4'-amine (65 mg, 146.88 μmol) in DCM (3 mL) and TFA (0.6 mL) was stirred at 28 ° C for 2 hours. LC-MS showed that the desired product was obtained. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Boston Prime C18-5 μm, 30 mm × 150 mm column) using a 5% to 30% ACN gradient in water (containing FA). The formate salt of the title compound was obtained as a yellow solid (20.6 mg, 29.3% yield, 98.4% purity). 1H NMR(400MHz,DMSO-d6)δppm 0.98-1.12(m,2H),1.69-1.84(m,2H),1.85-2.11(m,2H),2.27(d,J=6.82Hz,7H),2.44-2.49(m,1 H),2.53-2.60(m,3H),2.65-2.77(m,1H),3.78(t,J=5.72Hz,2H),4.32(d,J=7.70Hz,1H),4.48(br s,1H),4.72-4.95(m,1H),6.71(d,J=7.70Hz,1H),6.74(s,1H),7.03(d,J=7.48Hz,1H),9.57(br s,1H);ESI-MS m / z[M+H] + 399.1.

[1071] Example 234: 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine]-4'-yl)-5-methylphenol

[1072]

[1073] Step 1: N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-4'-(2-(methoxymethoxy)-4-methylphenyl)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine]-1'-amine

[1074]

[1075] Under N2, to a mixture of 1'-chloro-4'-(2-(methoxymethoxy)-4-methylphenyl)-7', 8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine](76mg, 219.14μmol) and (3R, 5R)-5-fluoro-1-methylpiperidin-3-amine (179.78mg, 876.57μmol, 2HCl) in toluene (1mL) was added Cs2CO3(285.60mg, 876.57μmol), BINAP(27.29mg, 43.83μmol) and Pd(OAc)2(4.92mg, 21.91μmol). The mixture was stirred at 100°C for 12 hours. LC-MS showed that the desired product was obtained. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography ( The resulting residue was purified using a 4 g silica gel column) using a 0 to 5% MeOH gradient in DCM (20 mL / min). The title compound was obtained as a yellow oil (59.4 mg, 61.3%). ESI-MS m / z [M+H] + 443.3.

[1076] Step 2: 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine]-4'-yl)-5-methylphenol

[1077] A mixture of N-((3R, 5R)-5-fluoro-1-methylpiperidin-3-yl)-4'-(2-(methoxymethoxy)-4-methylphenyl)-7', 8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine]-1'-amine (59 mg, 133.33 μmol) in DCM (3 mL) and TFA (0.6 mL) was stirred at 28 ° C for 2 hours. LC-MS showed that the desired product was obtained. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Boston Prime C18-5 μm, 30 mm × 150 mm column) using a 5% to 30% ACN gradient in water (containing FA). The formate salt of the title compound was obtained as a white solid (10 mg, 18% yield, 97.7% purity). 1 H NMR(400MHz,DMSO-d6)δppm 0.59-1.03(m,4H),1.67-1.88(m,1H),1.96(br t,J=9.90Hz,1H),2.02-2.18(m,2H),2.24(d,J=18.93Hz,6H),2.53-2.60(m,2H),2.80-3.02(m,2H),3.92(br t,J=5.83Hz,2H),4.55(br s,1H),4.84-5.06(m,1H),5.68(d,J=8.14Hz,1H),6.62(d,J=7.48Hz,1H),6.66(s,1H),6.84(br d,J=6.38Hz,1H),9.34(brs,1H); ESI-MS m / z[M+H] + 399.1.

[1078] Example 235: 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-yl)-5-methylphenol

[1079]

[1080] Example 236: 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-1'-yl)-5-methylphenol

[1081]

[1082] Step 1: N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-1'-(2-(methoxymethoxy)-4-methylphenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-amine and N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-4'-(2-(methoxymethoxy)-4-methylphenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-1'-amine

[1083]

[1084] A mixture of 4'-chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] and 1'-chloro-4'-(2-(methoxymethoxy)-4-methylphenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (170 mg), (3R,5R)-5-fluoro-1-methylpiperidin-3-amine (402.15 mg, 1.96 mmol, 2HCl), Pd(OAc)2 (22.01 mg, 98.04 μmol), BINAP (122.09 mg, 196.07 μmol) and Cs2CO3 (958.27 mg, 2.94 mmol) in toluene (10 mL) was stirred at 100 °C for 12 h. LC-MS showed that the starting material was consumed and the desired product was obtained. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by flash chromatography ( The crude product was purified on a 20 g silica gel column using a 0 to 3% MeOH gradient in DCM (35 mL / min). A mixture of the title compounds was obtained as a brown oil (171 mg, 95% purity). 1H NMR (400MHz, CDCl3) δppm0.44(s,1H),0.66(s,1H),0.82-1.01(m,2H),2.20- 2.82(m,2H),2.36-2.47(m,5H),3.07(s,1H),3.41(d,J=9.7Hz,3H),4.53(br d,J=4.8Hz,1H),4.75-4.99(m,2H),5.10(br d,J=7.0Hz,2H),5.32(s,2H),6.94(d,J=7.7Hz,1H),7.04(d,J=3.5Hz,1H),7.23(d,J=7.3Hz,1H).

[1085] Step 2: 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)-5-methylphenol and 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-methylphenol

[1086] At 20 ° C, to a mixture of N- ((3R, 5R) -5- fluoro-1-methylpiperidin-3-yl) -1'- (2- (methoxymethoxy) -4-methylphenyl) -5', 8'- dihydrospiro [cyclopropane -1,7'- pyranos [3,4-d] pyridazine] -4'- amine and N- ((3R, 5R) -5- fluoro-1-methylpiperidin-3-yl) -4'- (2- (methoxymethoxy) -4-methylphenyl) -5', 8'- dihydrospiro [cyclopropane -1,7'- pyranos [3,4-d] pyridazine] -1'- amine (171 mg) in DCM (15 mL) was added TFA (4.62 g, 40.52 mmol, 3 mL). The reaction mixture was stirred at 20 ° C for 12 hours. LC-MS showed that the starting material was converted to the desired product. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC (Method C) to obtain a mixture of two isomers (63 mg), which was purified by SFC (DAICEL The mixture was further purified using a 1G-10 μm, 30 mm×250 mm column) using a mobile phase of CO 2 and 60% EtOH (containing 0.1% NH 3 H 2 O). The title compound of Example 235 was obtained as a white solid (18.2 mg, 100% purity). 1H NMR (400MHz, CDCl3) δppm 0.68-0.78(m,2H),1.06-1.14(m,2H),1.69-1.86(m,2H),2.22-2.33(m,1H),2.36-2.38(m,3H),2.42(br s,3H),2.48-2.64(m,4H),2.65-2.85(m,1H),2.96-3.23(m,1H),4.67-4.9 7(m,5H),6.74(d,J=8.1Hz,1H),6.96(s,1H),7.05(d,J=7.9Hz,1H); ESI-MS m / z[M+H] + 399.1. The title compound of Example 236 was obtained as a white solid (15.8 mg, 100% purity). 1 H NMR (400MHz, CDCl3) δppm 0.48-0.59(m,2H),0.88(s,1H),0.91-0.98(m,2H),1.70-1.90(m,1H),2.31-2.38(m,4H),2.38-2.48(m,2H),2.48-2.62(m,2H),2.70(br s,1H),2.96(s,2H),3.08(br s,1H),4.54(br s,3H),4.80(br s,2H),6.75(d,J=8.1Hz,1H),6.95(s,1H),7.30(br s,1H); ESI-MS m / z[M+H] + 399.1.

[1087] Example 237: 5-Chloro-2-((5R,8S)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol

[1088]

[1089] Example 238: 5-Chloro-2-((5S,8R)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol

[1090]

[1091] A mixture of 5-chloro-2-(4-chloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol (160 mg, 0.50 mmol), CsCO (484 mg, 1.49 mmol), Pd(dba) (45 mg, 0.0495 mmol), R-BINAP (62 mg, 0.0990 mmol) and (3R,5R)-5-fluoro-1-methylpiperidin-3-amine (112 mg, 0.545 mmol, 2HCl) in toluene (5 mL) was stirred in a sealed tube on a metal heating block at 100° C. for 16 hours. The reaction mixture was concentrated under vacuum to give a crude product mixture, which was purified by preparative HPLC (Method A) using a 10% to 30% ACN (0.035% TFA) gradient in water (0.005% TFA). The TFA salt of the title compound of Example 237 was obtained as a colorless oil (5.5 mg, 2.1%). 1 H NMR(400MHz,CD3OD)δppm 1.69-1.82(m,1H),1.98-2.18(m,2H),2.23-2.32(m,2H),2.36(d,J=18.34Hz,1H),2.54-2.66(m,1H),2.99(s ,3H),3.01-3.10(m,1H),3.11-3.19(m,1H),3.32-3.45(m,1H),3.76-3.89(m,2H),4.74-4.82(m,2H),5.31(br d,J=6.60Hz,2H),7.03-7.13(m,2H),7.33(d,J=8.25Hz,1H); ESI-MS m / z[M+H] + 419.2. The title compound of Example 238 was obtained as a pink oil as a TFA salt (9.5 mg, 3.6%). 1 H NMR(400MHz,CD3OD)δppm 1.72-1.81(m,1H),2.05-2.12(m,1H),2.11-2.32(m,3H),2.33-2.40(m ,1H),2.50-2.65(m,1H),3.00(s,3H),3.03-3.11(m,1H),3.12-3.19(m ,1H),3.35-3.47(m,1H),3.76-3.87(m,2H),4.75-4.81(m,2H),5.20-5 .39(m,2H),7.04-7.10(m,2H),7.34(d,J=8.07Hz,1H); ESI-MSm / z[M+H] + 419.2.

[1092] Example 239: 5-Chloro-2-((5S,8R)-1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)phenol

[1093]

[1094] Example 240: 5-Chloro-2-((5R,8S)-1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)phenol

[1095]

[1096] A mixture of 5-chloro-2-(1-chloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)phenol (160 mg, 0.50 mmol), CsCO (484 mg, 1.49 mmol), Pd(dba) (45 mg, 0.0495 mmol), R-BINAP (62 mg, 0.0990 mmol) and (3R,5R)-5-fluoro-1-methylpiperidin-3-amine (112 mg, 0.545 mmol, 2HCl) in toluene (5 mL) was stirred in a sealed tube on a metal heating block at 100° C. for 16 hours. The reaction mixture was concentrated under vacuum to give a crude product mixture, which was purified by preparative HPLC (Method A) using a 10% to 30% ACN (0.035% TFA) gradient in water (0.005% TFA). The title compound of Example 239 was obtained as a pink oil as a TFA salt (19 mg, 7.2%). 1 H NMR(400MHz,CD3OD)δppm 1.78-1.92(m,1H),2.00-2.18(m,3H),2.22-2.33(m,1H),2.47-2.61(m,2H),2.99(s,3H),3.04-3.19(m,2H),3.34-3.48(m,1 ESI-MS m / z[M+H] + 419.2. The title compound of Example 240 was obtained as a pink oil as a TFA salt (16 mg, 6.0%). 1H NMR(400MHz,CD3OD)δppm 1.79-1.89(m,1H),1.94-2.21(m,3H),2.21-2.36(m,1H),2.45-2.61(m,2H),2.99(s,3H),3.00-3.17(m,2H),3.32- 3.47(m,1H),3.76-3.86(m,2H),4.74-4.87(m,3H),5.21-5.39(m,1H),7.06-7.17(m,2H),7.30-7.39(m,1H); ESI-MS m / z[M+H] + 419.2.

[1097] Example 241: (R)-5-methyl-2-(1-((1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)phenol

[1098]

[1099] A mixture of 1-chloro-4-(2-(methoxymethoxy)-4-methylphenyl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazine (60 mg, 0.187 mmol), (R)-1-methylpiperidin-3-amine (26 mg, 0.224 mmol), Pd(dba) (17 mg, 0.0187 mmol), R-BINAP (23 mg, 0.0374 mmol) and CsCO (183 mg, 0.561 mmol) in toluene (4.8 mL) was purged with nitrogen for 5 minutes and then heated at 100 ° C under nitrogen overnight. The mixture was treated with water, extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated. The resulting residue was dissolved in dioxane (2 mL). Hydrogen chloride (0.19 mL, 0.748 mmol) in dioxane was added. The mixture was stirred at room temperature for 4 hours and then purified by preparative HPLC (Phenomenex Gemini C18, 5 μm, 30 mm ID×150 mm column) using a 10% to 100% ACN (0.035% TFA) gradient in water (0.05% TFA), slowly increasing ACN from 10% to 60%. Product-containing fractions were evaporated to provide the title compound (9.3 mg, 11%) as a clear oil. 1HNMR(400MHz,CD3OD)δppm 1.70-2.01(m,2H),2.08-2.27(m,2H),2.37(s,3H),2.77(br s,2H),2.86-3.02(m,5H),3.56(br c 20 H 26 ESI-MS of N4O2[M+H] + Calculated value 354.21; experimental value 355.4.

[1100] Example 242: (R)-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[1101]

[1102] Example 243: (R)-2-(1-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol

[1103]

[1104] To a mixture of (R)-2-(3-((1-chloro-7,8-dihydro-5H-pyranos[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)ethan-1-ol and (R)-2-(3-((4-chloro-7,8-dihydro-5H-pyranos[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)ethan-1-ol (170 mg, 0.54 mmol in total) in THF (2 mL) was added (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (224 mg, 1.08 mmol), K PO .HO (0.5 M, 4 mL) and Xphos Pd G (92 mg, 0.108 mmol). The mixture was degassed and purged with N (3×) and then stirred at 60° C. under an N atmosphere for 12 hours. LC-MS showed two peaks with the desired MS. The reaction mixture was evaporated and then partitioned between DCM / H2O (5 mL / 1 mL). The layers were separated and the aqueous phase was extracted with DCM (4 mL x 2). The combined organic layers were collected, dried, and concentrated to give a residue, which was purified by preparative HPLC (C18-1, 5 μm, 30 mm ID x 150 mm) using a gradient of 10% to 50% ACN in water (containing NH4OH) over 9 minutes. The title compound of Example 242 (27 mg, 24%) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 7.40(d,J=7.70Hz,1H),7.18-7.26(m,2H),5.64(d,J=7.92Hz,1H),4.46(s,2H),4.21-4.40(m,2H),3.76(t,J=5.39Hz,2H),3.49(br t,J=6.16Hz,2H),2.97-3.07(m,1H),2.70-2.80(m,1H),2.36-2.45(m,4H),1.93-2.06 (m,2H),1.83-1.91(m,1H),1.63-1.74(m,1H),1.47-1.56(m,1H),1.33-1.43(m,1H); C 21 H 25 ESI-MS m / z[M+H] of F3N4O3 + Calculated value 438.19; found value 439.1. The title compound of Example 243 was obtained as a white solid (30 mg, 26%). 1H NMR (400MHz, DMSO-d6) δppm 7.37 (d, J = 7.70Hz, 1H), 7.18-7.26 (m, 2H), 5.84 (d, J = 8.14Hz, 1H), 4.20-4.47 (m, 4H), 3.92 (t, J = 5.61Hz, 2H), 3.50 (br t,J=6.16Hz,2H),2.96-3.04(m,1H),2.68-2.78(m,1H),2.48(br s,4H),2.06(br t,J=10.01Hz,2H),1.81-1.91(m,1H),1.68(br s,1H),1.55(br s,2H);C 21 H 25 [M+H] of F3N4O3 + Calculated value 438.19; experimental value 439.1.

[1105] Example 244: (R)-2-(4-((1-(2-methoxyethyl)piperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-methylphenol

[1106]

[1107] A mixture of 4-chloro-1-[2-(methoxymethoxy)-4-methyl-phenyl]-7,8-dihydro-5H-pyrano[3,4-d]pyridazine (61 mg, 0.190 mmol), (R)-1-(2-methoxyethyl)piperidin-3-amine dihydrochloride (44 mg, 0.190 mmol), Pd(dba) (17 mg, 0.0190 mmol), R-BINAP (24 mg, 0.0380 mmol) and CsCO (248 mg, 0.761 mmol) in toluene (6 mL) was purged with nitrogen for 5 minutes and then heated at 120 ° C overnight. The mixture was treated with water and extracted with EtOAc. The extracted layer was washed with brine, dried over MgSO4, and concentrated. The resulting residue was dissolved in dioxane (2 mL). Hydrogen chloride (0.38 mL, 0.761 mmol) in dioxane was added. The mixture was stirred at room temperature for 3 hours and purified by preparative HPLC (Phenomenex Gemini C18, 5 μm, 30 mm ID×150 mm column) using a 10% to 100% ACN (containing 0.079% ammonium bicarbonate) gradient in water (containing 0.079% ammonium), slowly increasing ACN from 10% to 60%. Product-containing fractions were evaporated to provide the title compound (0.8 mg, 0.71%) as a clear oil. 1H NMR (400MHz, CD3OD) δppm1.51-1.72(m,2H),1.73-1.96(m,2H),2.32(s,5H),2.54-2.70(m,5H),2.96-3.05(m,1H),3.34(s C 22 H 30 ESI-MS of N4O3[M+H] + Calculated value 398.23; experimental value 399.1.

[1108] Example 245: 2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[1109]

[1110] By 1- chloro-N- ((3R, 5R) -5- fluoro-1-methylpiperidin-3-yl) -7,8- dihydro -5H- pyrano [3,4-d] pyridazine -4- amine (50mg, 166.25μmol), (2- hydroxy -4- (trifluoromethyl) phenyl) boronic acid (51.35mg, 249.37μmol), Pd (dppf) Cl .CH Cl (13.58mg, 16.62μmol) and Cs CO (216.66mg, 664.98μmol) in a mixture of dioxane (2mL) and H O (0.5mL) degassed and purged with N (3×), and then stirred at 100°C under N atmosphere for 2 hours. LC-MS showed that 56% expected mass was detected. The reaction mixture was evaporated and partitioned between DCM / H O (5mL / 1mL). The layers were separated and the aqueous phase was extracted with DCM (4 mL x 2). The combined organic layers were collected, dried, and concentrated to a residue that was purified by preparative HPLC (Xtimate C18, 5 μm, 30 mm ID x 150 mm column) using a 0-30% ACN in water (containing FA) gradient over 25 minutes. The formate salt of the title compound was obtained as a white solid (37.9 mg, 52% yield, 98% purity). 1HNMR(400MHz,DMSO-d6)δppm 1.56-1.82(m,1H),1.86-1.98(m,1H),2.03-2.28(m,5H),2.36-2.46(m,2H),2.84-2.95(m,1H),2.96-3.05(m,1H),3.78(br C 20 H 22 ESI-MS of F4N4O2[M+H] + Calculated value 426.17; experimental value 427.2.

[1111] Example 246: 2-((5R,8S)-1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5,7,8,9-tetrahydro-5,8-epoxyoxepino[3,4-d]pyridazin-4-yl)-5-methylphenol

[1112]

[1113] A mixture of 2-((5R,8S)-1-chloro-5,7,8,9-tetrahydro-5,8-epoxyoxepino[3,4-d]pyridazin-4-yl)-5-methylphenol (40 mg, 0.131 mmol), Cs2CO3 (128 mg, 0.4 mmol), Pd2(dba)3 (12 mg, 0.0131 mmol), R-BINAP (16 mg, 0.0263 mmol) and (3R,5R)-5-fluoro-1-methylpiperidin-3-amine dihydrochloride (54 mg, 0.263 mmol) in toluene (5 mL) was stirred in a sealed tube on a metal heating block at 100° C. for 16 hours. The reaction mixture was then concentrated under vacuum to obtain a crude product mixture, which was purified by preparative HPLC (Phenomenex The crude product mixture was purified by C18 column using a 10% to 100% ACN gradient in water (10 mM NH4HCO3, pH = 9.5-10) to obtain the title compound as a yellow oil (14 mg, 27%). 1H NMR (400MHz, CD3OD) δppm1.64-1.84(m,1H),2.09-2.22(m,2H),2.23(s,3H),2.28(s,3H),2.30-2.44(m,2H),2.84-3.00(m,2H),3.05-3.1 4(m,1H),3.57-3.67(m,1H),3.84-3.90(m,1H),4.56-4.65(m,1H),4. 81-4.94(m,2H),5.80(s,1H),6.63-6.72(m,2H),7.09-7.16(m,1H); C 21 H 25 ESI-MS of FN4O3[M+H] + Calculated value 400.19; experimental value 401.2.

[1114] Example 247: 2-((5R,8S)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5,7,8,9-tetrahydro-5,8-epoxyoxepino[3,4-d]pyridazin-1-yl)-5-methylphenol

[1115]

[1116] A mixture of 2-((5R,8S)-4-chloro-5,7,8,9-tetrahydro-5,8-epoxyoxepino[3,4-d]pyridazin-1-yl)-5-methylphenol (40 mg, 0.131 mmol), Cs2CO3 (128 mg, 0.4 mmol), Pd2(dba)3 (12 mg, 0.0131 mmol), R-BINAP (16 mg, 0.0263 mmol) and (3R,5R)-5-fluoro-1-methylpiperidin-3-amine dihydrochloride (54 mg, 0.263 mmol) in toluene (5 mL) was stirred in a sealed tube on a metal heating block at 100° C. for 16 hours. The reaction mixture was then concentrated under vacuum to obtain a crude product mixture, which was purified by preparative HPLC (Phenomenex The crude product mixture was purified using a C18 column) using a 10% to 100% ACN gradient in water (10 mM NH4HCO3, pH = 9.5-10) to obtain the title compound (3.0 mg, 6%) as an orange oil. 1H NMR(400MHz,CD3OD)δppm1.84(s,2H),2.04-2.11(m,1H),2.21-2.22(m,3H), 2.23(s,3H),2.29(dd,J=18.07,0.75Hz,2H),2.78-2.88(m,1H),2.93-3.09(m ,2H),3.51-3.57(m,1H),3.85-3.92(m,1H),4.58-4.68(m,1H),4.77-4.92(m ,2H),6.22(s,1H),6.61-6.64(m,1H),6.65-6.69(m,1H),6.95-7.00(m,1H); C 21 H 25 ESI-MS of FN4O3[M+H] + Calculated value 400.19; experimental value 401.2.

[1117] Example 248: 2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol

[1118] Example 249: 2-((5R,8S)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol

[1119] Example 250: 2-((5S,8R)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol

[1120]

[1121] A mixture of 4-chloro-1-(2-(methoxymethoxy)-4-methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (300 mg, 0.865 mmol), Cs2CO3 (846 mg, 2.6 mmol), Pd2(dba)3 (79 mg, 0.0865 mmol), R-BINAP (108 mg, 0.173 mmol) and (3R, 5R)-5-fluoro-1-methylpiperidin-3-amine dihydrochloride (266 mg, 1.298 mmol) in toluene (5 mL) was stirred in a sealed tube on a metal heating block at 100 ° C for 16 hours. The reaction mixture was added to a solution of TFA (2 mL) in DCM (10 mL), stirred at 60 ° C for 1 hour, and then concentrated under vacuum to obtain a crude product mixture. The product was purified by preparative HPLC (Phenomenex The product mixture was purified by a C18 column using a 10% to 30% ACN (0.035% TFA) gradient in water (0.005% TFA) to obtain the title compound of Example 248 as a mixture of diastereomers. The diastereomers were separated by preparative SFC (Waters, ChiralTech IC, 5 μm, 21 mm ID x 150 mm column) using a 40% to 50% MeOH (containing 0.1% NH OH) gradient in CO 2 . The first product was the title compound of Example 249, which was obtained as a yellow semi-solid (31 mg, 9.0%). 1 H NMR(400MHz,CD3OD)δppm 1.62-1.74(m,1H),1.74-1.90(m,1H),1.96-2.05(m,1H),2.11-2.28(m ,5H),2.30(s,3H),2.32(s,3H),2.33-2.48(m,1H),2.88-2.97(m,1H),2 .98-3.05(m,1H),3.10-3.20(m,1H),4.66-4.78(m,2H),4.90-5.02(m,1 H),5.15(d,J=5.77Hz,1H),6.70-6.76(m,2H),7.04(d,J=7.53Hz,1H); C 22 H 27 ESI-MS of FN4O2[M+H] + Calculated value: 398.21; found: 399.2. The second product was the title compound of Example 250, which was obtained as a yellow semisolid (37 mg, 11%). 1H NMR(400MHz,CD3OD)δppm 1.62-1.89(m,2H),1.95-2.04(m,1H),2.27(br s,5H),2.30(s,3H),2.31(s,3H),2.32-2.39(m,1H),2.86-3.06(m,2H),3.08-3.18(m,1H),4.63 -4.78(m,2H),4.91-5.01(m,1H),5.11-5.17(m,1H),6.69-6.76(m,2H),7.04(d,J=7.53Hz,1H); C 22 H 27 ESI-MS of FN4O2[M+H] + Calculated value 398.21; experimental value 399.2.

[1122] Example 251: 2-(1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)-5-methylphenol

[1123]

[1124] Example 252: 2-((5S,8R)-1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)-5-methylphenol

[1125]

[1126] A mixture of 1-chloro-4-(2-(methoxymethoxy)-4-methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (300 mg, 0.865 mmol), Cs2CO3 (846 mg, 2.6 mmol), Pd2(dba)3 (79 mg, 0.0865 mmol), R-BINAP (108 mg, 0.173 mmol) and (3R, 5R)-5-fluoro-1-methylpiperidin-3-amine dihydrochloride (266 mg, 1.298 mmol) in toluene (5 mL) was stirred in a sealed tube on a metal heating block at 100 ° C for 16 hours. The reaction mixture was added to a solution of TFA (2 mL) in DCM (10 mL), stirred at 60 ° C for 1 hour, and then concentrated under vacuum to obtain a crude product mixture. The product was purified by preparative HPLC (Phenomenex The product mixture was purified using a C18 column) using a gradient of 10% to 30% ACN (0.035% TFA) in water (0.005% TFA). The TFA salt of the title compound of Example 251 was obtained as a light yellow semisolid (55 mg, 12.4%). 1 HNMR(400MHz,CD3OD)δppm 1.82-1.91(m,1H),2.04-2.33(m,4H),2.40(s,3H),2.50-2.66(m,2H),3.01(d,J=2.38Hz,3H),3.04-3.20(m,2H),3.34-3 C 22 H 27 ESI-MS of FN4O2[M+H] + Calculated value 398.21; found value 399.2. The diastereomers were separated by preparative SFC (Waters, Phenomenex Amylose-1 column) using a 25% to 50% MeOH (containing 0.1% NH4OH) gradient in CO2 to obtain the title compound of Example 252.

[1127] Example 253: 5-Chloro-2-(1-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)phenol

[1128]

[1129] A mixture of 5-chloro-2-(1-chloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)phenol (100 mg, 0.309 mmol), Cs2CO3 (302 mg, 0.93 mmol), Pd2(dba)3 (28 mg, 0.0309 mmol), R-BINAP (108 mg, 0.173 mmol) (39 mg, 0.062 mmol) and (1R,2R)-2-aminocyclohexanol (39.1 mg, 0.34 mmol) in toluene (1 mL) was stirred in a sealed tube on a metal heating block at 100° C. for 16 hours. The mixture was then concentrated under vacuum to obtain a crude product mixture, which was purified by preparative HPLC (Phenomenex The crude product mixture was purified using a C18 column) using a gradient of 10% to 30% ACN (0.035% TFA) in water (0.005% TFA). The title compound was obtained as a light yellow semisolid (6 mg, 5%). 1 H NMR(400MHz,CD3OD)δppm 1.22-1.54(m,4H),1.60-2.20(m,9H),2.27-2.41(m,1H),2.89-3.07(m,1H),3.46-3.58( m,1H),3.65-3.75(m,1H),4.72-4.74(m,1H),6.90-6.97(m,2H),7.15(d,J=8.03Hz,1H); C 21 H 24 ESI-MS of ClN3O3[M+H] + Calculated value 401.15; experimental value 402.2.

[1130] Example 254: 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-4,5,5',8'-tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazine]-1'-yl)-5-methylphenol

[1131]

[1132] A mixture of rac-4'-chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)-4,5,5',8'-tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazine] (17 mg, 0.0451 mmol), (3R,5R)-5-fluoro-1-methylpiperidin-3-amine dihydrochloride (11 mg, 0.0541 mmol), Pd2(dba)3 (4.1 mg, 0.00451 mmol), R-BINAP (5.6 mg, 0.00902 mmol) and Cs2CO3 (59 mg, 0.180 mmol) in toluene (3 mL) was purged with nitrogen for 5 minutes. The vial was sealed and heated at 110 ° C overnight. The mixture was treated with water, extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated. The residue was dissolved in dioxane (2 mL) and HCl in dioxane (0.045 mL, 0.180 mmol) was added. The mixture was stirred at room temperature for 3 hours and purified by preparative HPLC (Phenomenex Gemini C18, 5 μm, 30 mm ID×150 mm column) using a 10% to 100% ACN (0.035% TFA) gradient in water (0.05% TFA), slowly increasing ACN from 10% to 60%, to obtain the title compound. 1H NMR(400MHz,CD3OD)δppm 1.91-2.20(m,2H),2.24-2.33(m,1H),2.38(s,3H),2.53-2.63(m,1H),2.88-2.91(m,2H),3.0 0(s,3H),3.03-3.14(m,1H),3.65-3.70(m,1H),3.78-3.88(m,2H),3.93-4.04(m,3H),4.72(br d,J=6.90Hz,3H),5.23-5.39(m,1H),6.88(s,1H),6.89-6.93(m,1H),7.22-7.27(m,1H); C 23 H 29 ESI-MS of FN4O3[M+H] + Calculated value 428.22; experimental value 429.54.

[1133] Example 255: 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-4,5,5',8'-tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazine]-4'-yl)-5-methylphenol

[1134]

[1135] A mixture of rac-1'-chloro-4'-(2-(methoxymethoxy)-4-methylphenyl)-4,5,5',8'-tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazine](80 mg, 0.212 mmol), (3R,5R)-5-fluoro-1-methylpiperidin-3-amine dihydrochloride (52 mg, 0.255 mmol), Pd(dba)(19 mg, 0.0212 mmol), R-BINAP(26 mg, 0.0425 mmol) and CsCO(277 mg, 0.849 mmol) in toluene (6 mL) was purged with nitrogen for 5 minutes. The vial was sealed, heated at 110 °C overnight, and then filtered. The filtrate was concentrated and the residue was dissolved in dioxane (2 mL) and treated with HCl (0.21 mL, 0.849 mmol). The mixture was stirred at RT for 3 h and purified by preparative HPLC (Phenomenex Gemini C18, 5 μm, 30 mm ID×150 mm column) using a 10% to 100% ACN (0.035% TFA) gradient in water (0.05% TFA), slowly increasing ACN from 10% to 60%, to give the title compound. 1HNMR (400 MHz, CD3OD) δppm 1.78-1.88(m,1H),1.95-2.15(m,2H),2.17-2.26(m,1H),2.38(s,3H),2. 53-2.64(m,1H),2.77-2.90(m,2H),2.99(s,4H),3.33-3.45(m,1H),3.51- 3.56(m,1H),3.78-3.93(m,5H),3.96-4.03(m,1H),4.76-4.82(m,1H),5.2 1-5.39(m,1H),6.85-6.88(m,1H),6.90-6.95(m,1H),7.21-7.27(m,1H); C 23 H 29 ESI-MS of FN4O3[M+H] + Calculated value 428.22; experimental value 429.54.

[1136] Example 256: 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-2,3,5,5',6,8'-hexahydrospiro[pyran-4,7'-pyrano[3,4-d]pyridazine]-1'-yl)-5-methylphenol

[1137]

[1138] The title compound was synthesized using a procedure similar to Example 254 from the starting material 1,9-dioxaspiro[5.5]undecan-4-one. 1 H NMR(400MHz,CD3OD)δppm 1.78-1.83(m,3H),2.01-2.22(m,1H),2.38(s,3H),2.53-2.64(m,1H),2.68-2.72(m,2H),3.00(s,3H),3.05-3.15(m,1H),3.67(br d,J=1.25Hz,2H),3.73-3.84(m,6H),4.65(s,2H),4.76-4.85(m,1H),5.2 2-5.38(m,1H),6.87-6.89(m,1H),6.89-6.93(m,1H),7.23-7.26(m,1H); C 24 H 31 ESI-MS of FN4O3[M+H] + Calculated value 442.24; experimental value 443.48.

[1139] Example 257: 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-1'-yl)-5-(trifluoromethyl)phenol

[1140]

[1141] Example 258: 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-yl)-5-(trifluoromethyl)phenol

[1142]

[1143] To a mixture of 4'-chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-1'-amine and 1'-chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-amine To a stirred solution of the product (100 mg, 0.31 mmol) in dioxane (2 mL) and H2O (0.5 mL) was added (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (125 mg, 0.61 mmol), Cs2CO3 (403 mg, 1.24 mmol) and Pd(dppf)Cl2.CH2Cl2 (25 mg, 0.031 μmol). The mixture was stirred at 100 ° C under N2 for 2 hours. LC-MS showed that 48% of the expected mass was detected. The reaction mixture was evaporated and then distributed between DCM / H2O (5 mL / 5 mL). The layers were separated and the aqueous phase was extracted with DCM (4 mL×2). The combined organic layers were collected, dried, and concentrated to obtain a residue. The product was purified by flash chromatography ( 4g The residue was purified by silica gel column) using a 0 to 15% DCM in MeOH gradient (30 mL / min) to afford the crude product (70 mg), which was purified by preparative SFC (DAICEL The crude product was further purified by HPLC (IG-10 μm, 30 mm ID×250 mm column) using a mobile phase of CO 2 and 35% MeOH (containing 0.1% NH 3 OH) to obtain the title compound of Example 258 as a white solid (12 mg, 57%). 1HNMR(400MHz,CD3OD)δppm 0.58-0.76(m,2H),0.86-0.98(m,2H),1.71-1.98(m,1H),2.23-2.40(m,2H),2.42-2.48(m,3H),2.49-2.58(m,1H),2.58-2.66(m,2H), C 22 H 24 ESI-MS of F4N4O2[M+H] + Calculated value 452.18; found value 452.9. The title compound of Example 257 was obtained as a white solid (8 mg, 38%). 1 H NMR(400MHz,CD3OD)δppm 0.33-0.62(m,2H),0.76-0.97(m,2H),1.74-1.99(m,1H),2.30-2.45(m,2H),2.47-2.54(m,3H),2.55-2.70(m,3H),3.10-3.2 4(m,2H),4.55-4.58(m,2H),4.74-4.80(m,2H),4.99-5.09(m,1H),7.12-7.27(m,2H),7.35-7.44(m,1H),8.38-8.45(m,1H). C 22 H 24 ESI-MS of F4N4O2[M+H] + Calculated value 452.18; experimental value 453.0.

[1144] Example 259: 6-((4-(4-chloro-2-hydroxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)amino)spiro[3.3]heptan-2-ol

[1145]

[1146] By 5- chloro- 2- (1- chloro- 6,7,8,9- tetrahydro -5H- 5,8- epoxycycloheptane [d] pyridazine -4- base) phenol (100mg, 0.309mmol), Cs2CO3 (302mg, 0.93mmol), Pd2(dba)3 (28mg, 0.0309mmol), R-BINAP (39mg, 0.062mmol) and 6- aminospiro [3.3] heptane -2- alcohol (43.2mg, 0.34mmol) in toluene (1mL) mixture was stirred at 100 DEG C on a metal heating block in a sealed tube for 16 hours. The reaction mixture was then concentrated under vacuum to obtain a crude product mixture. The crude product mixture was purified by preparative HPLC (Phenomenex The product mixture was purified using a C18 column) using a gradient of 10% to 30% ACN (0.035% TFA) in water (0.005% TFA). The title compound was obtained as a yellow semisolid (25 mg, 19.6%). 1 H NMR(400MHz,CD3OD)δppm 1.55-1.69(m,1H),1.93(s,7H),2.03-2.22(m,3H),2.29-2.47(m,3H),2.72-2.82(m,1H),3.97- 4.06(m,1H),4.34-4.42(m,1H),4.64-4.73(m,2H),6.80-6.87(m,2H),7.04(d,J=8.78Hz,1H); C 22 H 24 ESI-MS of ClN3O3[M+H] + Calculated value 413.15; experimental value 414.2.

[1147] Example 260: 2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-epoxyphthalazin-1-yl)-5-methylphenol

[1148]

[1149] A mixture of 2-(4-chloro-5,6,7,8-tetrahydro-5,8-epoxyphthalazin-1-yl)-5-methylphenol (10 mg, 0.0346 mmol), Cs2CO3 (34 mg, 0.104 mmol), Pd2(dba)3 (3.2 mg, 0.00346 mmol), R-BINAP (4.3 mg, 0.0069 mmol) and (3R, 5R)-5-fluoro-1-methylpiperidin-3-amine dihydrochloride (10.6 mg, 0.052 mmol) in toluene (1 mL) was stirred in a sealed tube on a metal heating block at 100 ° C for 16 hours. The reaction mixture was then concentrated under vacuum to obtain a crude product mixture. The crude product mixture was purified by preparative HPLC (Phenomenex

[1150] The product mixture was purified by C18 column using a 10% to 100% ACN gradient in water (10 mM NH4HCO3, pH = 9.5-10) to obtain the title compound as a yellow oil (1.0 mg, 7.5%). 1 HNMR(400MHz,CD3OD)δppm 1.42-1.49(m,1H),1.57-1.64(m,1H),1.72-1.85(m,1H),2.05-2.30(m,2H),2.05-2 .29(m,1H),2.30-2.30(m,1H),2.31-2.40(m,6H),2.40-2.49(m,1H),2.94-3.02(m, 1H),3.12-3.24(m,1H),4.64-4.71(m,1H),4.98-5.07(m,1H),5.61-5.69(m,1H),5. 77(d,J=5.02Hz,1H),6.76-6.88(m,1H),6.79-6.87(m,1H),7.33(d,J=8.53Hz,1H); C 21 H 25 ESI-MS of FN4O2[M+H] + Calculated value 384.20; experimental value 385.2.

[1151] Example 262: 4-Fluoro-2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-1'-yl)-5-methylphenol

[1152]

[1153] Example 263: 4-Fluoro-2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-yl)-5-methylphenol

[1154]

[1155] To a mixture of 4'-chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-amine and 1'-chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-amine (70 mg, 214 μmol) in THF (1 mL) were added 2-[5-fluoro-2-(methoxymethoxy)-4-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (317.17 mg, 1.07 mmol), Xphos Pd G4 (18.43 mg, 21.42 μmol) and K 3 PO 4 (0.5 M, 2 mL) were added. The mixture was stirred at 50° C. under N 2 for 3 hr. LC-MS showed that 63% of the expected mass was detected. The reaction mixture was evaporated and then partitioned between DCM / H 2 O (5 mL / 5 mL). The layers were separated and the aqueous layer was extracted with DCM (4 mL×2). The combined organic layers were collected, dried, and concentrated to obtain a residue, which was used directly in the next step without further purification. C 24 H 30 ESI-MS of F2N4O3[M+H] + Calculated value 460.23; experimental value 460.8. The residue was taken up in DCM (4 mL) and TFA (1 mL) was added. The mixture was stirred at 25 ° C for 1 hour. LC-MS showed 56% conversion to product with the desired mass. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 1M HCl (3 mL) and extracted with EtOAc (3 mL×2). The organic layer was discarded. The aqueous layer was adjusted to pH 8-9 with NaHCO3 and extracted with dichloromethane / methanol (10 / 1, 10 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash chromatography ( 4g The residue was purified by silica gel column) using a 0 to 10% DCM in MeOH gradient (30 mL / min) to afford the crude product (80 mg), which was purified by preparative SFC (DAICEL The crude product was further purified by 1G-10 μm, 30 mm ID×250 mm column) using a mobile phase of CO 2 and 60% MeOH (containing 0.1% NH 3 OH) to obtain the title compound of Example 262 as a white solid (11 mg, 52%). 1 HNMR(400MHz,CD3OD)δppm 0.35-0.57(m,2H),0.85-0.91(m,2H),1.68-1.94(m,1H),2.13-2.20(m,1H),2.24(d,J=1.38Hz,3H),2.28-2.47(m,5H),2.63(s,2H),2.9 C 22 H 26 ESI-MS of F2N4O2[M+H] + Calculated value 416.20; found value 417.3. The title compound of Example 263 was obtained as a white solid (10 mg, 91%). 1 H NMR (400MHz, CD3OD) δppm 0.59-0.68(m,2H),0.89-0.95(m,2H),1.73-1.92(m,1H),2.13-2.22(m,1H),2.23-2.27(m,3H),2.29(br s,5H),2.56-2.61(m,2H),2.89-3.03(m,1H),3.14-3.23(m,1H),4.44-4.51(m,2 H),4.70-4.80(m,1H),4.93-5.03(m,1H),6.69-6.79(m,1H),6.87-6.93(m,1H); C 22 H 26 ESI-MS of F2N4O2[M+H] + Calculated value 416.20; experimental value 417.3.

[1156] Example 264: 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-1'-yl)phenol

[1157]

[1158] Example 265: 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-yl)phenol

[1159]

[1160] To 4'-chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-1'-amine and 1'-chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-amine ( To a mixture of (70 mg, 214 μmol) in a solution of dioxane (2 mL) and H2O (0.5 mL) was added (2-hydroxyphenyl)boronic acid (88.63 mg, 642.60 μmol), Cs2CO3 (139.58 mg, 428.40 μmol) and Pd(dppf)Cl2.CH2Cl2 (34.98 mg, 42.84 μmol). The mixture was stirred at 100 ° C under N2 for 2 hours. LC-MS showed that 37% of the expected mass was detected. The reaction mixture was evaporated and then distributed between DCM / H2O (5 mL / 5 mL). The layers were separated and the aqueous phase was extracted with DCM (4 mL×2). The combined organic layers were collected, dried and concentrated to obtain a residue, which was purified by flash chromatography ( 4g The residue was purified by preparative SFC (DAICEL 4000). The crude product (40 mg) was further purified by HPLC (IG-10 μm, 30 mm ID×250 mm column) using a mobile phase of CO 2 and 60% EtOH (containing 0.1% NH 3 OH). The title compound of Example 265 (16 mg) was obtained as a white solid. 1 H NMR (400MHz, CD3OD) δppm 0.61-0.67(m,2H),0.89-0.95(m,2H),1.74-1.92(m,1H),2.11-2.22(m,1H),2.26(br s,5H),2.60(s,2H),2.87-3.00(m,1H),3.15(br d,J=9.51Hz,1H),4.41-4.50(m,2H),4.67-4.80(m,1H),4.93-5.01(m,1H),6.85-6.97(m,2H),7.16-7.31(m,2H); C 21 H25 ESI-MS of FN4O2[M+H] + Calculated value 384.20; found value 385.3. The title compound of Example 264 was obtained as a white solid (22 mg). 1 H NMR (400MHz, CD3OD) δppm0.45-0.51(m,2H),0.82-0.88(m,2H),1.70-1.89(m,1H),2.10-2.21(m,1H),2.26-2.45(m,5H),2.58-2.63(m,2H),2.98(br C 21 H 25 ESI-MS of FN4O2[M+H] + Calculated value 384.20; experimental value 385.4.

[1161] Example 266: 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-5-methylphenol

[1162]

[1163] The title compound was prepared using a procedure analogous to Example 254 from the starting material 1,7-dioxaspiro[4.4]nonan-3-one. 1 H NMR(400MHz,CD3OD)δppm 1.89-2.10(m,1H),2.37(s,3H),2.38-2.51(m,2H),2.56-2.68(m,1H),3. 00(d,J=1.51Hz,3H),3.04-3.16(m,1H),3.34-3.42(m,1H),3.77-3.88(m, 2H),3.88-3.95(m,1H),4.00-4.09(m,1H),4.29-4.39(m,2H),4.72-4.83 (m,1H),5.26(dd,J=10.23,0.94Hz,3H),6.88(s,2H),7.26-7.32(m,1H);C 22 H 27 ESI-MS of FN4O3[M+H] +Calculated value 414.21; experimental value 415.7.

[1164] Example 267: 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-5-methylphenol

[1165]

[1166] The title compound was prepared using a procedure analogous to Example 254 from starting materials 1,7-dioxaspiro[4.4]nonan-3-one and (1R,2R)-2-aminocyclohexan-1-ol. 1 H NMR(400MHz,CD3OD)δppm 1.24-1.55(m,4H),1.69-1.84(m,2H),2.02-2.10(m,1H),2.34(s,6H),3.45-3.56(m,1H),3.74-3.81(m,1H), 3.90-4.05(m,2H),4.20-4.40(m,2H),5.35(s,2H),6.73-6.78(m,1H),6.82-6.85(m,1H),7.00-7.05(m,1H); C 22 H 27 ESI-MS of N3O4[M+H] + Calculated value 397.2; experimental value 398.4.

[1167] Example 268: 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol

[1168]

[1169] A mixture of 4-chloro-1-(2-(methoxymethoxy)-4-methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (107 mg, 0.31 mmol), Cs2CO3 (302 mg, 0.93 mmol), Pd2(dba)3 (28 mg, 0.031 mmol), R-BINAP (39 mg, 0.062 mmol) and (1R, 2R)-2-aminocyclohexan-1-ol (71 mg, 0.62 mmol) in toluene (1 mL) was stirred in a sealed tube on a metal heating block at 100 ° C for 16 hours. The reaction mixture was added to a solution of TFA (2 mL) and DCM (10 mL), stirred at 60 ° C for 1 hour, and concentrated under vacuum to obtain a crude product mixture. The product was purified by preparative HPLC (Phenomenex The product mixture was purified by HPLC-MS / MS (HPLC-MS / MS) using a gradient of 10% to 30% ACN (0.035% TFA) in water (0.005% TFA) on a C18 column. The title compound was obtained as a yellow solid (30 mg, 25%). 1 H NMR(400MHz,CD3OD)δppm 1.32-1.52(m,4H)1.59-1.81(m,3H),1.96-2.28(m,6H),2.32(s,3H),3.06(s,1H),3.53-3.62(m,1H ),3.96-4.04(m,1H),4.66-4.74(m,1H),5.17-5.26(m,1H),6.69-6.80(m,2H),7.02-7.08(m,1H); C 22 H 27 ESI-MS of N3O3[M+H] + Calculated value 381.21; experimental value 382.2.

[1170] Example 269: 2-(4-(((1S,3S)-3-hydroxy-3-methylcyclobutyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol

[1171]

[1172] A mixture of 4-chloro-1-(2-(methoxymethoxy)-4-methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (107 mg, 0.31 mmol), CsCO (302 mg, 0.93 mmol), Pd(dba) (28 mg, 0.031 mmol), R-BINAP (39 mg, 0.062 mmol) and (1S, 3S)-3-amino-1-methylcyclobutan-1-ol (31 mg, 0.31 mmol) in toluene (1 mL) was stirred in a sealed tube on a metal heating block at 100 ° C for 16 hours. The reaction mixture was added to a solution of TFA (2 mL) and DCM (10 mL), stirred at 60 ° C for 1 hour, and concentrated under vacuum to obtain a crude product mixture. The product was purified by preparative HPLC (Phenomenex The product mixture was purified by HPLC-MS / MS (HPLC-MS / MS) using a gradient of 10% to 30% ACN (0.035% TFA) in water (0.005% TFA) on a C18 column to obtain the title compound as a yellow oil (50 mg, 44%). 1 HNMR(400MHz,CD3OD)δppm 1.41(s,3H),1.69-1.82(m,1H),2.09-2.39(m,9H),2.57-2.66(m,2H),3.13(dd,J=18.45,5.40Hz,1H) ,3.92-4.02(m,1H),4.72-4.79(m,1H),5.28-5.38(m,1H),6.78-6.88(m,2H),7.15(d,J=7.78Hz,1H);C 21 H 25 ESI-MS of N3O3[M+H] + Calculated value 367.19; experimental value 368.2.

[1173] Example 270: 2-(4-(((1R,3R)-3-hydroxy-3-methylcyclobutyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol

[1174]

[1175] A mixture of 4-chloro-1-(2-(methoxymethoxy)-4-methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (107 mg, 0.31 mmol), Cs2CO3 (302 mg, 0.93 mmol), Pd2(dba)3 (28 mg, 0.031 mmol), R-BINAP (39 mg, 0.062 mmol) and (1R, 3R)-3-amino-1-methylcyclobutan-1-ol (31 mg, 0.31 mmol) in toluene (1 mL) was stirred in a sealed tube on a metal heating block at 100 ° C for 16 hours. The reaction mixture was added to a solution of TFA (2 mL) and DCM (10 mL), stirred at 60 ° C for 1 hour, and concentrated under vacuum to obtain a crude product mixture. The product was purified by preparative HPLC (Phenomenex The product mixture was purified by HPLC-MS / MS (HPLC-MS / MS) using a gradient of 10% to 30% ACN (0.035% TFA) in water (0.005% TFA) on a C18 column. The title compound was obtained as a yellow oil (53 mg, 47%). 1 HNMR(400MHz,CD3OD)δppm 1.43(s,3H),1.71-1.81(m,1H),2.11-2.17(m,1H),2.35(s,8H),2.53-2 .62(m,2H),3.08-3.18(m,1H),4.51(s,1H),4.75-4.78(m,1H),5.35(br d,J=6.27Hz,1H),6.83-6.87(m,2H),7.15(d,J=7.53Hz,1H); C 21 H 25 ESI-MS of N3O3[M+H] + Calculated value 367.19; experimental value 368.2.

[1176] Example 271: 3-Fluoro-2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol

[1177]

[1178] A mixture of 4-chloro-1-(2-fluoro-6-(methoxymethoxy)-4-methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (10 mg, 0.027 mmol), Cs2CO3 (27 mg, 0.082 mmol), Pd2(dba)3 (2.5 mg, 0.0027 mmol), R-BINAP (3.4 mg, 0.0055 mmol) and (3R, 5R)-5-fluoro-1-methylpiperidin-3-amine dihydrochloride (8.4 mg, 0.04 mmol) in toluene (1 mL) was stirred in a sealed tube on a metal heating block at 100 ° C for 16 hours. The reaction mixture was added to a solution of TFA (2 mL) and DCM (10 mL), stirred at 60 ° C for 1 hour, and concentrated under vacuum to obtain a crude product mixture. The product was purified by preparative HPLC (Phenomenex The product mixture was purified by C18 column using a 10% to 100% ACN gradient in water (10 mM NH4HCO3, pH = 9.5-10) to obtain the title compound (2.8 mg, 25%) as a colorless oil. 1 H NMR(400MHz,CD3OD)δppm 1.66-2.32(m,7H),2.37(s,3H),2.55-2.64(m,1H),2.95-3.02(m,1H),2.99(s,2H),3.48(d, J=1.76Hz,1H),3.80-3.88(m,2H),4.76-4.82(m,2H),5.24-5.37(m,2H),6.66-6.72(m,2H); C 22 H 26 ESI-MS of F2N4O2[M+H] + Calculated value 416.20; experimental value 417.2.

[1179] Example 272: 3-Fluoro-2-(1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)-5-methylphenol

[1180]

[1181] A mixture of 1-chloro-4-(2-fluoro-6-(methoxymethoxy)-4-methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (10 mg, 0.027 mmol), Cs2CO3 (27 mg, 0.082 mmol), Pd2(dba)3 (2.5 mg, 0.0027 mmol), R-BINAP (3.4 mg, 0.0055 mmol) and (3R, 5R)-5-fluoro-1-methylpiperidin-3-amine dihydrochloride (8.4 mg, 0.04 mmol) in toluene (1 mL) was stirred in a sealed tube on a metal heating block at 100 ° C for 16 hours. The reaction mixture was added to a solution of TFA (2 mL) and DCM (10 mL), stirred at 60 ° C for 1 hour, and concentrated under vacuum to obtain a crude product mixture. The product was purified by preparative HPLC (Phenomenex The product mixture was purified by C18 column using a 10% to 100% ACN gradient in water (10 mM NH4HCO3, pH = 9.5-10) to obtain the title compound (0.8 mg, 7%) as a colorless oil. 1 H NMR(400MHz,CD3OD)δppm 1.69-2.35(m,7H),2.37-2.40(m,3H),2.53-2.62(m,1H),2.98-3.01(m,3H),3.01-3.08(m,1H),3.34-3.4 4(m,1H),3.76-3.89(m,2H),4.77-4.82(m,1H),4.89-4.94(m,1H),5.20-5.40(m,1H),6.66-6.75(m,1H); C 22 H 26 ESI-MS of F2N4O2[M+H] + Calculated value 416.20; experimental value 417.2.

[1182] Examples 273 to 300 were prepared as in the above examples.

[1183] Example 273: (R)-2-...

Claims

1. A compound of formula 1, or a pharmaceutically acceptable salt thereof, wherein: α is a single bond and β is a single bond; and (i)X 1 is CH2, CH(CH3) or X C ; X 2 O and X 3 CH2 or X C ,or X 2 CH2 or X C And X 3 is 0; and X 4 is a bond, CH2, CH2CH2 or X C ; where X C Selected from C 3-6 Cycloalkylene and C 3-5 Oxacycloalkylene, each of which is substituted with 0 to 4 substituents independently selected from halo, and wherein X 1 、X 2 、X 3 and X 4 One and no more than one of the C ;or (ii)X 1 C(HR 1 ); X 2 is O; X 3 C(HR 3 );and X 4 is CH2; where R 1 and R 3 Together they represent bridge R 1 and R 2 The carbon atom to which it is attached 1-3 alkanediyl; or (iii)X 1 is CH2; X 2 C(HR 2 ); X 3 is O; And X 4 C(HR 4 ); where R 2 and R 4 Together they represent bridge R 2 and R 4 The carbon atom to which it is attached 1-3 alkanediyl; or (iv)X 1 C(HR 1 ); X 2 O and X 3 for CH2, or X 2 is CH2 and X 3 is 0; and X 4 C(HR 4 ); where R 1 and R 4 Together means C 1-3 alkanediyl; or (v)X 1 C(HR 1 ); X 2 is CH2; X 3 C(HR 3 );and X 4 is CH2; where R 1 and R 3 Together they represent bridge R 1 and R 3 The carbon atom to which it is attached 1-2 alkanediyloxy or O; or (vi)X 1 C(HR 1 ); X 2 is CH2; X 3 is CH2; and X 4 C(HR 4 ); where R 1 and R 4 Together they represent bridge R 1 and R 4 The carbon atom to which it is attached 1-2 Alkanediyloxy or O; m is selected from 0, 1 and 2; Each R a and R b independently selected from hydrogen and C 1-4 Alkyl, or R a and R b With R a and R b The carbon atoms are connected together to form C 3-6 Cycloalkylene, provided that if m is 2, not more than one R a and R b With R a and R b The carbon atoms connected together form C 3-6 cycloalkylene; R 5 Selected from: (a)C 3-8 Cycloalkyl, substituted with 0 to 5 substituents independently selected from the following: (i) halo, hydroxy, cyano and oxo; (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo; (b)C 3-8 Heterocyclyl wherein up to 3 carbon ring atoms are each independently substituted with 0 to 2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo; and 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 of which is substituted with 0 to 3 substituents independently selected from halo; (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is independently selected from halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of alkoxy groups; wherein the C 3-8 The heterocyclyl group has only one ring heteroatom selected from nitrogen, oxygen and sulfur; and n is selected from 0 and 1; The conditions are: If m is 0, X 1 C(HR 1 ), X 2 CH2, X 3 CH2, X 4 C(HR 4 ), X 8 is CH, α and β are both single bonds, R 1 and R 4 Together they represent bridge R 1 and R 4 The carbon atom to which the ethane-1,2-diyl radical is attached, R 6 、R 10 and R 11 Each is hydrogen, R 7 is a hydroxyl group, and R 9 is cyano, methyl or cyclopropyl, then R 5 is not 1-methylpiperidin-3-yl; and If m is 0, X 1 C(HR 1 ), X 2 CH2, X 3 CH2, X 4 C(HR 4 ), X 8 is CH, α and β are both single bonds, R 1 and R 4 Together they represent bridge R 1 and R 4 The carbon atom to which the compound is attached is a 1,1-diyl group or O, R 6 、R 10 and R 11 Each is hydrogen, R 7 is a hydroxyl group, and R 9 is cyano, methyl or cyclopropyl, then R 5 Not 1-methylpiperidin-3-yl; (c) phenyl, which is independently selected from halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Alkoxy is substituted by substituents, provided that at least one of the substituents is a hydroxyl group; R 6 Selected from hydrogen and C 1-4 alkyl; X 8 Selected from N and CR 8 ; R 7 、R 8 and R 11 Each independently selected from: (i) hydrogen, halo, hydroxy and cyano; (ii)C 1-4 Alkyl and C 1-4 alkoxy groups, each of which is substituted with 0 to 3 substituents independently selected from halo; and (iii)C 3-8 Cycloalkyl, which is independently selected from halo, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted with a substituent; and R 9 and R 10 Each independently selected from: (i) hydrogen, halo, hydroxy and cyano; (ii)C 1-4 Alkyl and C 1-4 alkoxy groups, each of which is substituted with 0 to 3 substituents independently selected from halo; and (iii)C 3-8 Cycloalkyl, which is independently selected from halo, C 1-4 Alkyl and C 1-4 Substitution of the alkoxy group; or R 9 and R 10 Together they form an ethane-1,2-dioxy moiety bridging the carbon atoms to which they are attached.

2. The compound or pharmaceutically acceptable salt of claim 1, wherein: X 1 is CH2, CH(CH3) or X C ; X 2 O and X 3 CH2 or X C ,or X 2 CH2 or X C And X 3 is 0; and X 4 is a bond, CH2, CH2CH2 or X C ; where X C Selected from C 3-6 Cycloalkylene and C 3-5 Oxacycloalkylene, each of which is substituted with 0 to 4 substituents independently selected from halo, and wherein X 1 、X 2 、X 3 and X 4 One and no more than one of the C .

3. The compound or pharmaceutically acceptable salt of claim 1, wherein: X 1 is CH2, (CH(CH3) or X C ; X 2 O and X 3 CH2 or X C ,or X 2 CH2 or X C And X 3 is 0; and X 4 CH2 or X C ; where X C Selected from C 3-6 Cycloalkylene and C 3-5 Oxacycloalkylene, each of which is substituted with 0 to 4 substituents independently selected from halo, and wherein X 1 、X 2 、X 3 and X 4 One and no more than one of the C .

4. The compound or pharmaceutically acceptable salt according to claim 1, wherein: X 1 C(HR 1 ); X 2 is O; X 3 C(HR 3 );and X 4 is CH2; where R 1 and R 3 Together they represent bridge R 1 and R 2 The carbon atom to which it is attached 1-3 Alkanediyl.

5. The compound or pharmaceutically acceptable salt according to claim 1, wherein: X 1 is CH2; X 2 C(HR 2 ); X 3 is O; And X 4 C(HR 4 ); where R 2 and R 4 Together they represent bridge R 2 and R 4 The carbon atom to which it is attached 1-3 Alkanediyl.

6. The compound or pharmaceutically acceptable salt of claim 1, wherein: X 1 C(HR 1 ); X 2 O and X 3 for CH2, or X 2 is CH2 and X 3 is 0; and X 4 C(HR 4 ); where R 1 and R 4 Together means C 1-3 Alkanediyl.

7. The compound or pharmaceutically acceptable salt of claim 1, wherein: X 1 C(HR 1 ); X 2 is CH2; X 3 C(HR 3 );and X 4 is CH2; where R 1 and R 3 Together they represent bridge R 1 and R 3 The carbon atom to which it is attached 1-2 Alkanediyloxy or O.

8. The compound or pharmaceutically acceptable salt of claim 1, wherein: X 1 C(HR 1 ); X 2 is CH2; X 3 is CH2; and X 4 C(HR 4 ); where R 1 and R 4 Together they represent bridge R 1 and R 4 The carbon atom to which it is attached 1-2 Alkanediyloxy or O.

9. The compound or pharmaceutically acceptable salt of any one of claims 1 to 8, wherein m is 0. 10 . The compound or pharmaceutically acceptable salt of claim 1 , wherein m is 1 or 2.

11. The compound or pharmaceutically acceptable salt of claim 10, wherein each R a and R b independently selected from hydrogen and C 1-4 alkyl.

12. The compound or pharmaceutically acceptable salt of any one of claims 1 to 11, wherein R 5 C 3-8 Cycloalkyl substituted with 0 to 5 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 Alkoxy groups, each of which is substituted with 0 to 3 substituents independently selected from halo.

13. The compound or pharmaceutically acceptable salt of any one of claims 1 to 11, wherein R 5 C 3-8 Heterocyclyl wherein up to 3 carbon ring atoms are each independently substituted with 0 to 2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo; and 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 of which is substituted with 0 to 3 substituents independently selected from halo; (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is independently selected from halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 The substituents of the alkoxy group are substituted.

14. The compound or pharmaceutically acceptable salt of any one of claims 1 to 11, wherein R 5 C 3-8 Heterocyclyl, wherein the ring heteroatoms are selected from nitrogen and oxygen and up to 3 carbon ring atoms are each independently substituted with 0 to 2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo; and 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 of which is substituted with 0 to 3 substituents independently selected from halo; (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is independently selected from halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 The substituents of the alkoxy group are substituted.

15. The compound or pharmaceutically acceptable salt of any one of claims 1 to 11, wherein R 5 C 3-8 Heterocyclyl, wherein the ring heteroatom is nitrogen and up to 3 carbon ring atoms are each independently substituted with 0 to 2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) amino, which is independently selected from C 1-4 Substitution of the alkyl group with a substituent; and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkoxy, each of which is substituted with 0 to 3 substituents independently selected from halo; and wherein the nitrogen ring atom is unsubstituted or substituted with a substituent selected from the group consisting of: (i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl and C 1-4 alkylsulfonyl, each of which is substituted with 0 to 3 substituents independently selected from halo; (ii)C 3-8 Cycloalkyl-(CH2) n , the C 3-8 The cycloalkyl moiety is independently selected from halo, C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxy and oxo groups are substituted with substituents; and (iii) Phenyl-(CH2) n and pyridyl-(CH2) n , the phenyl and pyridyl moieties are substituted with 0 to 3 independently selected halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 The substituents of the alkoxy group are substituted.

16. The compound or pharmaceutically acceptable salt of any one of claims 13 to 15, wherein R 5 C 3-8 heterocyclic group and n is 0.

17. The compound or pharmaceutically acceptable salt of any one of claims 1 to 11, wherein R 5 is phenyl, which is independently selected from halo, hydroxy, cyano, C 1-4 Alkyl and C 1-4 The substituents of the alkoxy group are substituted, provided that at least one of the substituents is a hydroxy group.

18. The compound or pharmaceutically acceptable salt of any one of claims 1 to 17, wherein R 6 is selected from hydrogen and methyl.

19. The compound or pharmaceutically acceptable salt of any one of claims 1 to 17, wherein R 6 For hydrogen.

20. The compound or pharmaceutically acceptable salt of any one of claims 1 to 19, wherein X 8 CR 8 .

21. A compound or pharmaceutically acceptable salt as claimed in any one of claims 1 to 20, wherein R 7 and R 8 are all hydrogen, and R 11 Selected from: (i) hydrogen, halo and hydroxy; and (ii)C 1-3 Alkyl and C 1-3 Alkoxy groups, each of which is substituted with 0 to 3 substituents independently selected from halo.

22. A compound or pharmaceutically acceptable salt as claimed in any one of claims 1 to 21, wherein R 9 and R 10 Each independently selected from: (i) hydrogen, halo, hydroxy and cyano; (ii)C 1-4 Alkyl and C 1-3 alkoxy groups, each of which is substituted with 0 to 3 fluorine groups; and (iii)C 3-5 Cycloalkyl substituted with 0 to 3 substituents independently selected from methyl and methoxy.

23. The compound of claim 1, selected from the group consisting of: 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazin-1'-yl)-5-methylphenol; 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazin-4'-yl)-5-methylphenol; 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-yl)-5-methylphenol; 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-methylphenol; 5-Chloro-2-((5R,8S)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 5-Chloro-2-((5S,8R)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 5-Chloro-2-((5S,8R)-1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)phenol; 5-Chloro-2-((5R,8S)-1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)phenol; 2-((5R,8S)-1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5,7,8,9-tetrahydro-5,8-epoxyoxepino[3,4-d]pyridazin-4-yl)-5-methylphenol; 2-((5R,8S)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5,7,8,9-tetrahydro-5,8-epoxyoxepino[3,4-d]pyridazin-1-yl)-5-methylphenol; 2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol; 2-((5R,8S)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol; 2-((5S,8R)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol; 2-(1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)-5-methylphenol; 2-((5S,8R)-1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)-5-methylphenol; 5-Chloro-2-(1-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)phenol; 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-4,5,5',8'-tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-methylphenol; 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-4,5,5',8'-tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazin-4'-yl)-5-methylphenol; 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-2,3,5,5',6,8'-hexahydrospiro[pyran-4,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-methylphenol; 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-4'-yl)-5-(trifluoromethyl)phenol; 6-((4-(4-chloro-2-hydroxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)amino)spiro[3.3]heptan-2-ol; 2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-epoxyphthalazin-1-yl)-5-methylphenol; 4-Fluoro-2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-methylphenol; 4-Fluoro-2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-yl)-5-methylphenol; 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)phenol; 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-5-methylphenol; 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-5-methylphenol; 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol; 2-(4-(((1S,3S)-3-hydroxy-3-methylcyclobutyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol; 2-(4-(((1R,3R)-3-hydroxy-3-methylcyclobutyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol; 3-Fluoro-2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol; 3-Fluoro-2-(1-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)-5-methylphenol; (R)-2-(4′-((1-(2-fluoroethyl)piperidin-3-yl)amino)-5′,8′-dihydrospiro[cyclopropane-1,7′-pyrano[3,4-d]pyridazin-1′-yl)-5-methylphenol; (R)-2-(1'-((1-(2-fluoroethyl)piperidin-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)-5-methylphenol; 2-(1'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-4'-yl)-5-methylphenol; 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-methylphenol; 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazin-1'-yl)-5-methylphenol; 2-(4'-(((1R,2R)-2-hydroxy-2-methylcyclohexyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-methylphenol; 2-((R*)-1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-4'-yl)-5-methylphenol; 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-7H-spiro[furo[3,4-d]pyridazin-5,3'-oxetane]-1-yl)-5-methylphenol; 2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7H-spiro[furo[3,4-d]pyridazin-5,3'-oxetane]-1-yl)-5-methylphenol; 5-methyl-2-((5RS,8SR)-4-(((R)-tetrahydrofuran-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 5-Chloro-2-((5R*,8S*)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 5-Chloro-2-((5S*,8R*)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 5-Chloro-2-((5R*,8S*)-4-((((S)-tetrahydrofuran-2-yl)methyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 5-Chloro-2-((5S*,8R*)-4-((((S)-tetrahydrofuran-2-yl)methyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 5-Cyclopropyl-4-fluoro-2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 5-Cyclopropyl-4-fluoro-2-(1-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)phenol; 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'-dihydrospiro[oxetane-3,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-methylphenol; 2-(4'-(((1R,2S)-2-hydroxy-2-methylcyclohexyl)amino)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazin-1'-yl)-5-methylphenol; 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[oxetane-3,7'-pyrano[3,4-d]pyridazine]-4'-yl)-5-methylphenol; 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5',8'-dihydrospiro[oxetane-3,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-methylphenol; 5-Cyclopropyl-4-fluoro-2-(4-(((R)-tetrahydrofuran-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 3-Fluoro-2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5-Cyclopropyl-3-fluoro-2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 5-Cyclopropyl-3-fluoro-2-(1-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)phenol; 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-(((1S,3S)-3-fluoro-5-methylcyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5-Cyclopropyl-2-((5R,8S)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 5-Cyclopropyl-2-((5S,8R)-4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 5-Cyclopropyl-2-((5R,8S)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 5-Cyclopropyl-2-((5S,8R)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 2-(1'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[3,4-d]pyridazin-4'-yl)-5-methylphenol; 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 2-((S*)-4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 2-((R*)-4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 2-(1'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[3,4-d]pyridazine]-4'-yl)-5-methylphenol; 2-(4'-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[3,4-d]pyridazine]-1'-yl)-5-methylphenol; 2-(4-(((R)-tetrahydrofuran-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(1-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)-5-(trifluoromethyl)phenol; 2-(4'-(((1R,2S)-2-hydroxy-2-methylcyclohexyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-methylphenol; 2-(4'-(((1R,2S)-3,3-difluoro-2-hydroxycyclohexyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-methylphenol; 2-(4'-(((1R,2S)-2-hydroxycyclopentyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-methylphenol; 2-(4'-(((1R,3R)-3-hydroxycyclohexyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-methylphenol; 2-(4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-methylphenol; (3R,4S)-4-(((5S,8R)-1-(4-chloro-2-hydroxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)tetrahydrofuran-3-ol; 5-Chloro-2-((5S,8R)-4-((2-methoxy-2-methylpropyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 5-Chloro-2-((5S,8R)-4-((2-hydroxy-2-methylpropyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; (3R,4R)-3-(((5S,8R)-1-(4-chloro-2-hydroxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-4-ol; 4-(((5S,8R)-1-(4-chloro-2-hydroxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)tetrahydrofuran-3-ol; 5-Chloro-2-((5S,8R)-4-(((R)-tetrahydrofuran-3-yl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; (3S,4R)-4-(((5S,8R)-1-(4-chloro-2-hydroxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol; 2-(4'-(((1R,2R)-2-hydroxycyclobutyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; rac-5-(4-(((1R,2R)-2-methoxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-2,3-dihydro-1H-inden-4-ol; rac-5-(1-(((1R,2R)-2-methoxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)-2,3-dihydro-1H-inden-4-ol; 2-(1'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-4'-yl)-5-(trifluoromethyl)phenol; 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-7'H-spiro[cyclobutane-1,5'-furo[3,4-d]pyridazin-1'-yl)-5-methylphenol; 5-chloro-2-(4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; 5-chloro-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; 5-chloro-2-(4'-(((1R,2R)-2-hydroxycyclobutyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazin-1'-yl)-5-methylphenol; 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 2-(4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 5-(4-(((1R,2R)-2-hydroxycyclopentyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-2,3-dihydro-1H-inden-4-ol; 5-(4-(((1R,2R)-2-hydroxycyclobutyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-2,3-dihydro-1H-inden-4-ol; 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol; 2-(1-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)-5-(trifluoromethoxy)phenol; 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; (S)-2-(4'-((tetrahydrofuran-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 2-((5R,8S)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-((5S,8R)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-(((1R,2R)-2-hydroxycyclobutyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; (3S,4R)-4-((1-(2-hydroxy-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)tetrahydro-2H-pyran-3-ol; 5-(1'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)-2,3-dihydro-1H-inden-4-ol; (R)-2-(4'-((tetrahydrofuran-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 5-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-2,3-dihydro-1H-inden-4-ol; 5-(1'-(((1R,2R)-2-hydroxycyclobutyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)-2,3-dihydro-1H-inden-4-ol; 5-(4'-(((1R,2R)-2-hydroxycyclobutyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-2,3-dihydro-1H-inden-4-ol; 5-(4'-(((1R,2R)-2-hydroxycyclohexyl)oxy)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-2,3-dihydro-1H-inden-4-ol; 2-(4-(((1R,2R)-2-hydroxycyclopentyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5-Cyclopropyl-3-fluoro-2-(4-(((1R,2R)-2-hydroxycyclopentyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; rac-2-(4'-(((1R,2S)-3,3-difluoro-2-hydroxycyclopentyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 5-(4′-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro-2H,7′H-spiro[furan-3,5′-furo[3,4-d]pyridazin-1′-yl)-2,3-dihydro-1H-inden-4-ol; 5-cyclopropyl-2-(4'-(((1R,2R)-2-hydroxycyclobutyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; 5-Cyclopropyl-2-(4-(((1R,2R)-2-hydroxycyclobutyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 5-Cyclopropyl-2-(4-(((1R,2R)-2-hydroxycyclopentyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 5-((5R,8S)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-2,3-dihydro-1H-inden-4-ol; 5-((5S,8R)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-2,3-dihydro-1H-inden-4-ol; 5-Cyclopropyl-2-(4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; 5-(4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-2,3-dihydro-1H-inden-4-ol; 5-(Difluoromethyl)-2-((5R,8S)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 5-(Difluoromethyl)-2-((5S,8R)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 2-(4'-(((1S,2R)-2-hydroxycyclopentyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; (R)-5-chloro-2-(4'-((tetrahydrofuran-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; 5-chloro-2-(4'-(((1R,2S)-2-hydroxycyclopentyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; 5-(Difluoromethyl)-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; (R)-5-cyclopropyl-2-(4'-((tetrahydrofuran-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; (1R,2R)-2-(((5R,8S)-1-(4-cyclopropyl-2-fluoro-6-methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)cyclohexan-1-ol; 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-3-methyl-5-(trifluoromethyl)phenol; 5-chloro-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-3-methylphenol; 5-Cyclopropyl-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; 5-((5R,8S)-4-(((1R,2R)-2-hydroxycyclobutyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-2,3-dihydro-1H-inden-4-ol; 5-(Difluoromethyl)-2-(4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; 5-Cyclopropyl-2-(4'-(((1R,2S)-2-hydroxycyclopentyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; 5-Cyclopropyl-4-fluoro-2-(4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; (1R,2R)-2-(((5R,8S)-1-(4-cyclopropyl-2,6-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)cyclohexan-1-ol; 5-(4'-(((1R,2R,3R,4S)-3-hydroxybicyclo[ 2.2.1]hept-2-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-2,3-dihydro-1H-inden-4-ol; 3-Fluoro-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; (3S,4R)-4-((1'-(2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-4'-yl)amino)tetrahydro-2H-pyran-3-ol; rel-5-(4'-(((1R,2R,3R)-2-hydroxy-3-methylcyclohexyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-2,3-dihydro-1H-inden-4-ol; 3-Fluoro-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 5-chloro-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazin-1'-yl)phenol; 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-methylphenol; 5-chloro-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; 4-Fluoro-2-((5R,8S)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 4-Fluoro-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 4-Fluoro-2-(4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 4-Fluoro-2-((5S,8R)-4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5-(4'-(((1R,2S,3S,4S)-3-hydroxybicyclo[ 2.2.1]hept-2-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-2,3-dihydro-1H-inden-4-ol; 2-((R)-4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 5-Chloro-2-((R)-4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; 5-(4'-(((1R,2S)-2-hydroxycyclobutyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-2,3-dihydro-1H-inden-4-ol; 5-(4'-(((1R,2S)-2-hydroxycyclopentyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-2,3-dihydro-1H-inden-4-ol; 3-Fluoro-2-((3R*)-4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 3-Fluoro-2-((3R*)-4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 3-Fluoro-2-(4'-(((R)-tetrahydrofuran-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; (3S,4R)-4-(((3R*)-1′-(2-fluoro-6-hydroxy-4-methylphenyl)-4,5-dihydro-2H,7′H-spiro[furan-3,5′-furo[3,4-d]pyridazin-4′-yl)amino)tetrahydro-2H-pyran-3-ol; (3S,4R)-4-((1'-(2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl)-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazin]-4'-yl)amino)tetrahydro-2H-pyran-3-ol; 2-(4'-(((1R,2R)-2-methoxycyclobutyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 3-Fluoro-2-(4′-(((1R,2R)-2-hydroxycyclohexyl)amino)-7′H-spiro[cyclopropane-1,5′-furo[3,4-d]pyridazin-1′-yl)-5-methylphenol; 3-Fluoro-2-(4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 3-Fluoro-2-((3R*)-4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-5-methylphenol; (R)-2-(4'-((3,3-difluorocyclopentyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; rac-2-(4'-(((3R,4R)-4-methyltetrahydrofuran-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; (1R,2R)-2-(((5S*,8R*)-1-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)cyclopentan-1-ol; 5-chloro-3-fluoro-2-(7'-(((1R,2R)-2-hydroxycyclohexyl)amino)-3'H-spiro[cyclopropane-1,1'-isobenzofuran]-4'-yl)phenol; 2-(4'-(((1R,2R)-2-methoxycyclopentyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 5-(1-Fluorocyclopropyl)-2-((5S*,8R*)-4-(((1R,2R)-2-hydroxycyclopentyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 5-ethyl-3-fluoro-2-(4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazin-1'-yl)phenol; (3S,4R)-4-(((3R*)-1′-(4-ethyl-2-fluoro-6-hydroxyphenyl)-4,5-dihydro-2H,7′H-spiro[furan-3,5′-furo[3,4-d]pyridazin-4′-yl)amino)tetrahydro-2H-pyran-3-ol; (3S,4R)-4-(((3R*)-1′-(4-chloro-2-fluoro-6-hydroxyphenyl)-4,5-dihydro-2H,7′H-spiro[furan-3,5′-furo[3,4-d]pyridazin-4′-yl)amino)tetrahydro-2H-pyran-3-ol; 5-Chloro-3-fluoro-2-((3R*)-4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)phenol; 3-Fluoro-2-(4'-(((1R,2R)-2-methoxycyclohexyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 3-Fluoro-2-(4'-(((1R,2R)-2-methoxycyclopentyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 5-(4'-(cyclobutylamino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-2,3-dihydro-1H-inden-4-ol; 5-(4'-(cyclopentylamino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-2,3-dihydro-1H-inden-4-ol; 5-Cyclopropyl-2-(4-(((1R,2R)-2-methoxycyclopentyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 2-(4'-(cyclopentylamino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; (S)-2-(4'-((3,3-difluorocyclopentyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; (R)-5-(1-fluorocyclopropyl)-2-(4'-((tetrahydrofuran-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; 5-Cyclopropyl-2-((5S*,8R*)-4-(((1R,2R)-2-methoxycyclobutyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 2-((5S*,8R*)-4-(((1R,2R)-2-methoxycyclobutyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; (3S,4R)-4-(((3R*)-1'-(4-(difluoromethyl)-2-fluoro-6-hydroxyphenyl)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-4'-yl)amino)tetrahydro-2H-pyran-3-ol; 5-(Difluoromethyl)-3-fluoro-2-((3R*)-4'-(((1R,2R)-2-hydroxycyclohexyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)phenol; 3-Fluoro-2-((3R*)-4'-(((1R,2R)-2-methoxycyclopentyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-5-methylphenol; 3-Fluoro-2-((3R*)-4'-(((1R,2R)-2-methoxycyclobutyl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-5-methylphenol; 3-Fluoro-2-((3R*)-4'-(((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-5-methylphenol; 3-Fluoro-2-((3R*)-4'-(((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 5-(1,1-difluoroethyl)-3-fluoro-2-((3R*)-4'-(((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)amino)-4,5-dihydro-2H,7'H-spiro[furan-3,5'-furo[3,4-d]pyridazin-1'-yl)phenol; 2-((R*)-4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)-5-(trifluoromethyl)phenol; 2-(4-(((1R,2S)-2-methoxycyclobutyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 1-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-N-((1R,2R)-2-methoxycyclobutyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-amine; 1'-(4-cyclopropyl-2,6-difluorophenyl)-N-((1R,2R)-2-methoxycyclobutyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-amine; 1'-(4-cyclopropyl-2-fluorophenyl)-N-((1R,2R)-2-methoxycyclopentyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-amine; 5-Chloro-2-((S*)-4'-(((1R,2R)-2-hydroxycyclopentyl)amino)-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; (S)-5-methyl-2-(4'-((tetrahydrofuran-3-yl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-1'-yl)phenol; (1R,2R)-2-(((5S*,8R*)-1-(4-cyclopropyl-2,6-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)cyclopentan-1-ol; 2-((5S,8R)-4-(((1R,2R)-2-hydroxycyclopentyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-((5R,8S)-4-(((1R,2R)-2-hydroxycyclopentyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; (1R,2R)-2-(((5S,8R)-1-(2-fluoro-4-(1-fluorocyclopropyl)-6-methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)cyclopentan-1-ol; 5-((5R,8S)-4-(((1R,2R)-2-hydroxycyclopentyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-2,3-dihydro-1H-inden-4-ol; 5-((5S,8R)-4-(((1R,2R)-2-hydroxycyclopentyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-2,3-dihydro-1H-inden-4-ol; 5-Cyclopropyl-2-((5S*,8R*)-4-(((1R,2R)-2-hydroxycyclopentyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol; 3-Fluoro-2-((5S*,8R*)-4-(((1R,2R)-2-hydroxycyclopentyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; (3S,4R)-4-((1'-(2-hydroxy-4-(trifluoromethyl)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-4'-yl)amino)tetrahydro-2H-pyran-3-ol; 1'-(2-Fluoro-4-(1-fluorocyclopropyl)phenyl)-N-((1R,2R)-2-methoxycyclopentyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-amine; 1'-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-N-((1R,2R)-2-methoxycyclopentyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-amine; 1'-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-N-((1R,2R)-2-methoxycyclobutyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-amine; 1'-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-amine; (5R,8S)-1-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-N-((1R,2R)-2-methoxycyclobutyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-amine; (5S,8R)-1-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-N-((1R,2R)-2-methoxycyclobutyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-amine; (1R,2R)-2-(((5R,8S)-1-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)cyclobutan-1-ol; (1R,2R)-2-(((5S,8R)-1-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)amino)cyclobutan-1-ol; 1'-(4-cyclopropyl-2-fluorophenyl)-N-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-amine; and (1R,2R)-2-((1'-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin-4'-yl)amino)cyclobutan-1-ol; or a pharmaceutically acceptable salt of any one of the aforementioned compounds.

24. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 23 for use as a medicament.

25. A pharmaceutical composition comprising: A compound or pharmaceutically acceptable salt according to any one of claims 1 to 23; and Pharmaceutically acceptable excipients.

26. A compound or pharmaceutically acceptable salt of any one of claims 1 to 23 for use in treating a disease, disorder or condition associated with NLRP3.

27. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 23 for use in treating a disease, disorder or condition associated with a heterozygous gain-of-function mutation in the NLRP3 gene.

28. A compound or pharmaceutically acceptable salt as claimed in any one of claims 1 to 23 for use in the treatment of cryopyrin-associated periodic syndromes (CAPS).

29. A method of treating a disease, disorder, or condition in a subject, the method comprising administering to the subject a compound or pharmaceutically acceptable salt of any one of claims 1 to 23, wherein the disease, disorder, or condition is associated with NLRP3.

30. A method of treating a disease, disorder, or condition in a subject, the method comprising administering to the subject a compound or pharmaceutically acceptable salt of any one of claims 1 to 23, wherein the disease, disorder, or condition is associated with a heterozygous gain-of-function mutation in the NLRP3 gene.

31. A method of treating a disease, disorder, or condition in a subject, comprising administering to the subject a compound or pharmaceutically acceptable salt of any one of claims 1 to 23, wherein the disease, disorder, or condition is cryopyrin-associated periodic syndrome (CAPS).

32. The method of claim 31 , wherein the cryopyrin-associated periodic syndrome is selected from the group consisting of neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Mueller-Weiss syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

33. A method of treating a neurodegenerative disease, disorder or condition in a subject, the method comprising administering to the subject a compound or pharmaceutically acceptable salt of any one of claims 1 to 23.

34. A method of treating a disease, disorder or condition in a subject, comprising administering to the subject a compound or pharmaceutically acceptable salt of any one of claims 1 to 23, wherein the disease, disorder or condition is selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion disease.

35. A combination comprising a compound or pharmaceutically acceptable salt as claimed in any one of claims 1 to 23 and at least one additional pharmacologically active agent.

36. The combination of claim 35, wherein the additional pharmacologically active agent is selected from the group consisting of β-secretase inhibitors, γ-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs, vitamin E, anti-amyloid antibodies, antidepressants, antipsychotics, anxiolytics, and anticonvulsants.

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