1-Amino-4-phenylphthalazine derivatives useful for the treatment of neurodegenerative diseases

Abstract

A compound of formula (1), [Formula 1] JPEG2026503702000374.jpg74158 and pharmaceutically acceptable salts thereof (wherein α, β, m, R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R a , R b , X 1 , X 2 , X 3 , X 4 and X 8 (wherein is defined herein) is disclosed. The disclosure also relates to materials and methods for preparing compounds of formula (1), pharmaceutical compositions containing them, 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 inhibitors of the NLRP3 inflammasome, pharmaceutical compositions containing them, and their use for treating diseases, disorders, and conditions associated with NLRP3, including neurodegenerative diseases such as Parkinson's disease. [Background technology]

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

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

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

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

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

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

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

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

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

[0011] The present invention provides 1-amino-4-phenylphthalazine derivatives and pharmaceutically acceptable salts thereof. The present invention also provides pharmaceutical compositions containing the 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 is a compound of formula 1: [ka] or a pharmaceutically acceptable salt thereof, α is a single bond, β is a single bond, (i)X 1 is CH2, CH(CH3), or X C and X 2 is O and X 3 is CH2 or X C or X 2 is CH2 or X C and X 3 is O, X 4 is a bond, CH2, CH2CH2, or X C and X C is C 3-6 Cycloalkylidene and C 3-5 oxacycloalkylidene, each substituted with 0 to 4 substituents independently selected from halo; 1 , X 2 , X 3 , and X 4 One and less than one of X C or (ii) X 1 is C(HR 1 ) and X 2 is O, X 3 is C(HR 3 ) and X 4 is CH2, R 1 and R 3 Together, R 1 and R 2 C bridging the carbon atoms to which 1-3 represents an alkanediyl, or (iii)X 1 is CH2, X 2 is C(HR 2 ) and X 3 is O, X 4 is C(HR 4 ) and R 2 and R 4 Together, R 2 and R 4 C bridging the carbon atoms to which 1-3 represents an alkanediyl, or (iv) X 1 is C(HR 1 ) and X 2 is O and X 3 is CH2, or X 2 is CH2 and X 3 is O, X 4 is C(HR 4 ) and R 1 and R 4 Together, C 1-3 represents an alkanediyl, or (v)X 1 is C(HR 1 ) and X 2 is CH2, X 3 is C(HR 3 ) and X 4 is CH2, R 1 and R 3 Together, R 1 and R 3 C bridging the carbon atoms to which 1-2 alkanediyloxy or O, or (vi)X 1 is C(HR 1 ) and X 2 is CH2, X 3 is CH2, X 4 is C(HR 4 ) and R 1 and R 4 Together, R 1 and R 4 C bridging the carbon atoms to which 1-2 represents alkanediyloxy or O, m is selected from 0, 1, and 2; R a and R b are hydrogen and C, respectively. 1-4 alkyl, or R a and R b is R a and R b together with the carbon atom to which it is attached, C 3-6 Forms a cycloalkylidene, with the proviso that if m is 2, then R a and R b At most one of the R a and R b together with the carbon atom to which it is attached, C 3-6 forming a cycloalkylidene, R 5 is the following: (a)C 3-8 Cycloalkyl (substituted with 0 to 5 substituents independently selected from: (i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (b)C 3-8 Heterocyclyl (up to 3 carbon ring atoms are each independently substituted with 0-2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); Nitrogen ring atoms, when present, are unsubstituted or substituted with substituents selected from the following: (I C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C1-4 substituted with 0 to 3 substituents independently selected from alkoxy; The C 3-8 heterocyclyl has only one ring heteroatom selected from nitrogen, oxygen, and sulfur; n is selected from 0 and 1; however, m is 0 and X 1 C(HR 1 ) and X 2 is CH2 and X 3 is CH2 and X 4 C(HR 4 ) and X 8 is CH, α and β are both single bonds, and R 1 and R 4 Together, R 1 and R 4 represents ethane-1,2-diyl bridging the carbon atoms to which R is attached, 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 is cyano, methyl, or cyclopropyl, R 5 is not 1-methylpiperidin-3-yl, m is 0 and X 1 C(HR 1 ) and X 2 is CH2 and X 3 is CH2 and X 4 C(HR 4 ) and X 8 is CH, α and β are both single bonds, and R 1 and R 4 Together, R 1 and R 4 represents methane-1,1-diyl or O bridging the carbon atoms to which R is bonded, 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 is cyano, methyl, or cyclopropyl, R5 is not 1-methylpiperidin-3-yl), (c) Phenyl (halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy, provided that at least one of the substituents is hydroxy; is selected from R 6 is hydrogen and C 1-4 alkyl, X 8 N and CR 8 is selected from R 7 , R 8 and R 11 are respectively: (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo), and (iii)C 3-8 Cycloalkyl (halo, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy are independently selected from R 9 and R 10 are respectively: (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo), and (iii)C 3-8 Cycloalkyl (halo, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy are independently selected from, or R 9 and R 10form an ethane-1,2-dioxy moiety bridging the carbon atoms to which they are attached).

[0013] Another aspect of the present invention provides a compound selected from the group of compounds described in the Examples and pharmaceutically acceptable salts thereof.

[0014] A further aspect of the invention provides a compound or a pharmaceutically acceptable salt as defined in the preceding paragraph for use as a pharmaceutical.

[0015] An additional aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, and a pharmaceutically acceptable excipient.

[0016] Another aspect of the present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, for treating a disease, disorder, or condition associated with NLRP3, including a disease, disorder, or condition associated with heterozygous gain-of-function mutations in the NLRP3 gene, such as cryopyrin-associated periodic fever syndrome (CAPS).

[0017] A further aspect of the invention provides the use of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, for the manufacture of a medicament for treating a disease, disorder, or condition associated with NLRP3, including a disease, disorder, or condition associated with heterozygous gain-of-function mutations in the NLRP3 gene, such as cryopyrin-associated periodic fever syndrome (CAPS).

[0018] An additional aspect of the present invention provides a method for treating a disease, disorder, or condition associated with NLRP3, including a disease, disorder, or condition associated with a heterozygous gain-of-function mutation in the NLRP3 gene, such as cryopyrin-associated periodic fever syndrome (CAPS), comprising administering to a subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph.

[0019] Another aspect of the invention provides a method of treating cryopyrin-associated periodic fever syndromes (CAPS), including neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS), comprising administering to a subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph.

[0020] A further aspect of the present invention provides a method of treating a disease, disorder, or condition in a subject, comprising administering to the subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, wherein the disease, disorder, or condition is a neurodegenerative disease, disorder, or condition.

[0021] An additional aspect of the present invention provides a method of treating a disease, disorder, or condition in a subject comprising administering to the subject an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, wherein the disease, disorder, or condition is selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion disease.

[0022] Another aspect of the present invention provides an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, or any one of the compounds or pharmaceutically acceptable salts defined in the preceding paragraph, and at least one additional pharmacologically active agent. DETAILED DESCRIPTION OF THE INVENTION

[0023] Unless otherwise indicated, this disclosure uses the definitions set forth below.

[0024] "Substituted" refers to a chemical substituent or moiety (e.g., C 1-6 When used in connection with an alkyl group, it means that one or more hydrogen atoms of that substituent or moiety are replaced with one or more non-hydrogen atoms or groups, provided that valency requirements are met and the substitution results in a chemically stable compound.

[0025] "About" or "approximately," when used in connection with a measurable, numerical variable, refers to the indicated value of that variable and all values ​​of that variable within experimental error of the indicated value or within ±10 percent of the indicated value, whichever is greater.

[0026] "Alkyl" refers to straight-chain and branched saturated hydrocarbon groups generally having a specified number of carbon atoms (e.g., C 1-4 Alkyl refers to an alkyl group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms, C 1-6 (Alkyl refers to an alkyl group having 1 to 6 carbon atoms, etc.) Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, n-hexyl, and the like.

[0027] "Alkanediyl" refers to a divalent alkyl group, where alkyl is defined above, generally having a specified number of carbon atoms (e.g., C1-4 Alkanediyl refers to an alkanediyl group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms, C 1-6 (Alkanediyl refers to an alkanediyl group having 1 to 6 carbon atoms, etc.) Examples of alkanediyl groups include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, propane-2,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, butane-1,1-diyl, isobutane-1,3-diyl, isobutane-1,1-diyl, isobutane-1,2-diyl, and the like.

[0028] "Alkenyl" refers to straight-chain and branched hydrocarbon groups having one or more carbon-carbon double bonds and generally having a specified number of carbon atoms. Examples of alkenyl groups include ethenyl, 1-propen-1-yl, 1-propen-2-yl, 2-propen-1-yl, 1-buten-1-yl, 1-buten-2-yl, 3-buten-1-yl, 3-buten-2-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methyl-1-propen-1-yl, 2-methyl-2-propen-1-yl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, and the like.

[0029] "Alkynyl" refers to a straight or branched chain hydrocarbon group having one or more carbon-carbon triple bonds and generally having a specified number of carbon atoms. Examples of alkynyl groups include ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, 3-butyn-1-yl, 3-butyn-2-yl, 2-butyn-1-yl, and the like.

[0030] "Alkoxy" refers to straight and branched chain saturated hydrocarbon groups attached through an oxygen atom, generally having the specified number of carbon atoms (e.g., C 1-4 Alkoxy refers to an alkoxy group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms, C 1-6(Alkoxy refers to an alkoxy group having 1 to 6 carbon atoms, etc.) Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, t-butoxy, pent-1-yloxy, pent-2-yloxy, pent-3-yloxy, 3-methylbut-1-yloxy, 3-methylbut-2-yloxy, 2-methylbut-2-yloxy, 2,2,2-trimethyleth-1-yloxy, n-hexoxy, and the like.

[0031] "Alkanediyloxy" refers to a divalent alkoxy group, where alkoxy is defined above, generally having the specified number of carbon atoms (e.g., C 1-3 Alkanediyloxy refers to an alkanediyl group having 1 to 3 (i.e., 1, 2, or 3) carbon atoms, C 1-2 Alkanediyl refers to alkanediyl groups 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.

[0032] "Alkylcarbonyl" and "alkylsulfonyl" refer to an alkyl group, as defined above, attached through a carbonyl (C(O)) or sulfonyl (SO) group, respectively, and generally having a specified number of carbon atoms, including the carbon atom of the carbonyl group. For example, C 1-4 Alkylcarbonyl refers to an alkylcarbonyl group having 1 to 4 (i.e., 1, 2, 3, or 4) carbon atoms, including the carbonyl portion; C 1-6Alkylsulfonyl refers to an alkylsulfonyl group having 1 to 6 carbon atoms, etc. Examples of alkylcarbonyl groups include carbonyl (formyl), methylcarbonyl (acetyl), ethylcarbonyl, i-propylcarbonyl, n-propylcarbonyl, etc. Examples of alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, i-propylsulfonyl, n-propylsulfonyl, etc.

[0033] "Halo," "halogen," and "halogeno" may be used interchangeably and refer to fluoro, chloro, bromo, and iodo.

[0034] "Haloalkyl," "haloalkenyl," and "haloalkynyl" refer to alkyl, alkenyl, and alkynyl groups (where alkyl, alkenyl, and alkynyl are defined above) substituted with one or more halogen atoms and generally having a specified number of carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1-chloroethyl, 1,1-dichloroethyl, 1-fluoro-1-methylethyl, 1-chloro-1-methylethyl, and the like.

[0035] "Cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon groups, generally having a specified number of carbon atoms comprising the ring(s) (e.g., C 3-8Cycloalkyl refers to a cycloalkyl group having 3 to 8 carbon atoms as ring members. Bicyclic hydrocarbon groups may include separated rings (two rings with no carbon atoms in common), spiro rings (two rings with one carbon atom in common), fused rings (two rings with two carbon atoms in common and a bond between two common carbon atoms), and bridged rings (two rings with two carbon atoms in common but no common bond). Cycloalkyl groups may be bonded through any ring atom, provided such bonding does not violate valence requirements, and, where indicated, may optionally contain one or more non-hydrogen substituents, provided such substitution does not violate valence requirements.

[0036] Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 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, and the like. Examples of bridged cycloalkyl groups include bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[4.1.1]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[4.2.1]nonanyl, bicyclo[3.3.2]decanyl, bicyclo[4.2.2]decanyl, bicyclo[4.3.1]decanyl, bicyclo[3.3.3]undecanyl, bicyclo[4.3.2]undecanyl, bicyclo[4.3.3]dodecanyl, and the like. Examples of spirocycloalkyl groups include spiro[3.3]heptanyl, spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, etc. Examples of split bicyclic cycloalkyl groups include those derived from bi(cyclobutane), cyclobutanecyclopentane, bi(cyclopentane), cyclobutanecyclohexane, cyclopentanecyclohexane, bi(cyclohexane), etc.

[0037] "Cycloalkanediyl" refers to a divalent cycloalkyl group, where cycloalkyl is defined above, generally having a specified number of carbon atoms (e.g., C 3-5 Cycloalkanediyl refers to a cycloalkanediyl group having 3 to 5 (i.e., 3, 4, or 5) carbon atoms, C 3-6Cycloalkanediyl refers to a cycloalkanediyl group having 3 to 6 carbon atoms, etc.) Examples of cycloalkanediyl groups include cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and the like.

[0038] "Cycloalkylidene" refers to a divalent monocyclic cycloalkyl group (cycloalkyl is defined above) attached through a single carbon atom of the group and generally having a specified number of carbon atoms comprising the ring (e.g., C 3-6 Cycloalkylidene refers to a cycloalkylidene group having 3 to 6 carbon atoms as ring members.) Examples include cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene.

[0039] "Oxacycloalkylidene" refers to a divalent cycloalkyl group (as defined above), generally having a specified number of carbon atoms that comprise the ring, attached through a single carbon atom in the group, in which one of the carbon atoms is replaced by an oxygen atom (e.g., C 3-5 Oxacycloalkylidene refers to a cycloalkylidene group having 3 to 5 carbon atoms and 1 oxygen atom as ring members.) Examples include 2-oxacyclobutylidene, 3-oxacyclobutylidene, 2-oxacyclopentylidene, 3-oxacyclopentylidene, 2-oxacyclohexylidene, 3-oxacyclohexylidene, and 4-oxacyclohexylidene.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0066] Compounds of Formula I, and pharmaceutically acceptable salts thereof, include those which are: (1) α is a single bond and β is a single bond; (i)X 1 is CH2, CH(CH3), or X C and X 2 is O and X 3 is CH2 or X C or X 2 is CH2 or X C and X 3 is O, X 4 is a bond, CH2, CH2CH2, or X C and X C is C 3-6 Cycloalkylidene and C 3-5 oxacycloalkylidene, each substituted with 0 to 4 substituents independently selected from halo; 1 , X 2 , X 3 , and X 4 One and less than one of X C and (ii) X 1 is C(HR 1 ) and X 2 is O, X 3 is C(HR 3 ) and X 4is CH2, R 1 and R 3 Together, R 1 and R 2 C bridging the carbon atoms to which 1-3 represents an alkanediyl, or (iii)X 1 is CH2, X 2 is C(HR 2 ) and X 3 is O, X 4 is C(HR 4 ) and R 2 and R 4 Together, R 2 and R 4 C bridging the carbon atoms to which 1-3 represents an alkanediyl, or (iv) X 1 is C(HR 1 ) and X 2 is O and X 3 is CH2, or X 2 is CH2 and X 3 is O, X 4 is C(HR 4 ) and R 1 and R 4 Together, C 1-3 represents an alkanediyl, or (v)X 1 is C(HR 1 ) and X 2 is CH2, X 3 is C(HR 3 ) and X 4 is CH2, R 1 and R 3 Together, R 1 and R 3C bridging the carbon atoms to which 1-2 alkanediyloxy or O, or (vi)X 1 is C(HR 1 ) and X 2 is CH2, X 3 is CH2, X 4 is C(HR 4 ) and R 1 and R 4 Together, R 1 and R 4 C bridging the carbon atoms to which 1-2 represents alkanediyloxy or O, m is selected from 0, 1, and 2; R a and R b are hydrogen and C, respectively. 1-4 alkyl, or R a and R b is R a and R b together with the carbon atoms to which both are attached, 3-6 Forms a cycloalkylidene, with the proviso that if m is 2, then R a and R b At most one of the R a and R b together with the carbon atom to which it is attached, C 3-6 forming a cycloalkylidene, R 5 is the following: (a)C 3-8 Cycloalkyl (substituted with 0 to 5 substituents independently selected from: (i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4alkoxy (each substituted with 0-3 substituents independently selected from halo); (b)C 3-8 Heterocyclyl (up to 3 carbon ring atoms are each independently substituted with 0-2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); Nitrogen ring atoms, when present, are unsubstituted or substituted with substituents selected from the following: (I C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; The C 3-8 heterocyclyl has only one ring heteroatom selected from nitrogen, oxygen, and sulfur; n is selected from 0 and 1; however, m is 0 and X 1 C(HR 1 ) and X 2 is CH2 and X 3 is CH2 and X 4 C(HR 4 ) and X 8 is CH, α and β are both single bonds, and R 1 and R 4 Together, R 1 and R 4 represents ethane-1,2-diyl bridging the carbon atoms to which R is attached, 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 is cyano, methyl, or cyclopropyl, R 5 is not 1-methylpiperidin-3-yl, m is 0 and X 1 C(HR 1 ) and X 2 is CH2 and X 3 is CH2 and X 4 C(HR 4 ) and X 8 is CH, α and β are both single bonds, and R 1 and R 4 Together, R 1 and R 4 represents methane-1,1-diyl or O bridging the carbon atoms to which R is bonded, 6 , R 10 and R 11 are each hydrogen, and R 7 is hydroxy and R 9 is cyano, methyl, or cyclopropyl, R 5 is not 1-methylpiperidin-3-yl), (c) Phenyl (halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 and 0 to 3 substituents independently selected from alkoxy, provided that at least one of the substituents is hydroxy. is selected from R 6 is hydrogen and C 1-4 alkyl, X 8 N and CR 8 is selected from R 7 , R 8 and R 11 are respectively: (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo), and (iii)C 3-8 Cycloalkyl (halo, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy are independently selected from R 9 and R 10 are respectively: (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo), and (iii)C 3-8 Cycloalkyl (halo, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy are independently selected from, or R 9 and R 10 are independently selected from:

[0067] In addition to embodiment (1) above, compounds of Formula 1 include those in which: (61) α is a single bond, β is a single bond, (i)X1 is CH2, CH(CH3), or X C and X 2 is O and X 3 is CH2 or X C or X 2 is CH2 or X C and X 3 is O, X 4 is a bond, CH2, CH2CH2, or X C and X C is C 3-6 Cycloalkylidene and C 3-5 oxacycloalkylidene, each substituted with 0 to 4 substituents independently selected from halo; 1 , X 2 , X 3 , and X 4 One and less than one of X C or (ii) X 1 is C(HR 1 ) and X 2 is O, X 3 is C(HR 3 ) and X 4 is CH2, R 1 and R 3 Together, R 1 and R 2 C bridging the carbon atoms to which 1-3 represents an alkanediyl, or (iii)X 1 is CH2, X 2 is C(HR 2 ) and X 3 is O, X 4 is C(HR 4 ) and R 2 and R 4Together, R 2 and R 4 C bridging the carbon atoms to which 1-3 represents an alkanediyl, or (iv) X 1 is C(HR 1 ) and X 2 is O and X 3 is CH2, or X 2 is CH2 and X 3 is O, X 4 is C(HR 4 ) and R 1 and R 4 Together, C 1-3 represents an alkanediyl, or (v)X 1 is C(HR 1 ) and X 2 is CH2, X 3 is C(HR 3 ) and X 4 is CH2, R 1 and R 3 Together, R 1 and R 3 C bridging the carbon atoms to which 1-2 alkanediyloxy or O, or (vi)X 1 is C(HR 1 ) and X 2 is CH2, X 3 is CH2, X 4 is C(HR 4 ) and R 1 and R 4 Together, R 1 and R 4 C bridging the carbon atoms to which 1-2It represents alkanediyloxy or O.

[0068] In addition to embodiment (61) of the preceding paragraph, compounds of Formula 1 include those in which: (62)X 1 is CH2, CH(CH3), or X C and X 2 is O and X 3 is CH2 or X C or X 2 is CH2 or X C and X 3 is O, X 4 is a bond, CH2, CH2CH2, or X C and X C is C 3-6 Cycloalkylidene and C 3-5 oxacycloalkylidene, each substituted with 0 to 4 substituents independently selected from halo; 1 , X 2 , X 3 , and X 4 One and less than one of X C is.

[0069] In addition to embodiment (62) of the preceding paragraph, compounds of Formula 1 include those in which: (63)X C is C 3-4 Cycloalkylidene and C 3-5 oxacycloalkylidene, each substituted with 0 to 4 substituents independently selected from halo; (64)X C is C 3-4 cycloalkylidene (substituted with 0-4 substituents independently selected from halo); (65)X C is cyclopropylidene (substituted with 0-4 substituents independently selected from halo); (66)X Cis cyclobutylidene (substituted with 0 to 4 substituents independently selected from halo); (67)X C is C 3-5 oxacycloalkylidene (substituted with 0 to 4 substituents independently selected from halo); (68)X C is oxacyclobutylidene (substituted with 0 to 4 substituents independently selected from halo); (69)X C is 3-oxacyclobutylidene (substituted with 0 to 4 substituents independently selected from halo); (70)X C is oxacyclopentylidene (substituted with 0 to 4 substituents independently selected from halo); (71)X C is 3-oxacyclopentylidene (substituted with 0 to 4 substituents independently selected from halo); (72)X C is oxacyclohexylidene (substituted with 0 to 4 substituents independently selected from halo); (73)X C is 4-oxacyclohexylidene (substituted with 0 to 4 substituents independently selected from halo).

[0070] In addition to embodiments (62)-(73) of the preceding paragraph, compounds of Formula 1 include those in which: (74)X 1 is CH2 or X C and X 2 is O and X 3 is CH2 or X C or X 2 is CH2 or X C and X 3 is O, X 4 is CH2 or X C and (75)X 1is CH2 or X C and X 2 is O and X 3 is CH2 or X C or X 2 is CH2 or X C and X 3 is O, X 4 is a bond, (76)X 1 is CH2 or X C and X 2 is O and X 3 is CH2 or X C and X 4 is a bond, (77)X 1 is X C and X 2 is O and X 3 is CH2, or X 2 is CH2 and X 3 is O, X 4 is a bond, (78)X 1 is X C and X 2 is O and X 3 is CH2, X 4 is a bond, (79)X 1 is CH2 or X C and X 2 is O and X 3 is CH2 or X C or X 2 is CH2 or X C and X 3 is O, X 4 is CH2CH2, or (80)X 1 is X C and X 2 is O and X 3 is CH2, or X 2 is CH2 and X 3 is O, X 4 is CH2CH2.

[0071] In addition to embodiments (62) through (80) of the preceding paragraph, compounds of Formula 1 include those in which: (81)X C is substituted with 0 to 3 substituents independently selected from halo; (82)X C is substituted with 0 to 2 substituents independently selected from halo; (83)X C is substituted with 0 to 1 substituents independently selected from halo, or (84)X C is non-substituted.

[0072] In addition to embodiments (62)-(80) above, compounds of Formula 1 include those in which: (85)X C is substituted with 0 to 4 fluoro; (86)X C is substituted with 0 to 3 fluoro groups, (87)X C is substituted with 0 to 2 fluoro, or (88)X C is substituted with 0 to 1 fluoro.

[0073] In addition to the above embodiment (61), the compound of formula 1 may also be X 1 C(HR 1 ) and X 2 is O and X 3 C(HR 3 ) and X 4 is CH2, and R 1 and R 3together represent: (89)R 1 and R 3 C bridging the carbon atoms to which 1-3 Alkanediyl, (90)R 1 and R 3 C bridging the carbon atoms to which 1-2 Alkanediyl, (91)R 1 and R 3 methane-1,1-diyl bridging the carbon atoms to which (92)R 1 and R 3 ethane-1,2-diyl bridging the carbon atoms to which it is attached.

[0074] In addition to the above embodiment (61), the compound of formula 1 may also be X 1 is CH2 and X 2 C(HR 2 ) and X 3 is O and X 4 C(HR 4 ), including those where R 2 and R 4 together represent: (93)R 2 and R 4 C bridging the carbon atoms to which 1-3 Alkanediyl, (94)R 2 and R 4 C bridging the carbon atoms to which 1-2 Alkanediyl, (95)R 2 and R 4 methane-1,1-diyl bridging the carbon atoms to which (96)R 2 and R 4 ethane-1,2-diyl bridging the carbon atoms to which it is attached.

[0075] In addition to embodiment (61) above, compounds of Formula 1 include those in which: (97)X 1 is C(HR 1 ) and X 2 is O and X 3 is CH2, or X 2 is CH2 and X 3 is O, X 4 is C(HR 4 ) and R 1 and R 4 Together, C 1-3 represents alkanediyl, (98)X 1 is C(HR 1 ) and X 2 is O, X 3 is CH2, X 4 is C(HR 4 ) and R 1 and R 4 Together, C 1-3 represents an alkanediyl, or (99)X 1 is C(HR 1 ) and X 2 is CH2, X 3 is O, X 4 is C(HR 4 ) and R 1 and R 4 Together, C 1-3 Represents alkanediyl.

[0076] In addition to embodiments (97)-(99) of the preceding paragraph, compounds of Formula 1 may also be R 1 and R 4 together represent: (100)R 1 and R 4 C bridging the carbon atoms to which 1-2 Alkanediyl, (101)R 1 and R 4methane-1,1-diyl bridging the carbon atoms to which (102)R 1 and R 4 ethane-1,2-diyl bridging the carbon atoms to which it is attached.

[0077] In addition to embodiment (61) above, compounds of Formula 1 include those in which: (103)X 1 is C(HR 1 ) and X 2 is CH2, X 3 is C(HR 3 ) and X 4 is CH2, R 1 and R 3 Together, R 1 and R 3 C bridging the carbon atoms to which 1-2 It represents alkanediyloxy or O.

[0078] In addition to embodiment (103) of the preceding paragraph, the compound of Formula 1 may further comprise R 1 and R 3 together represent: (104)R 1 and R 3 C bridging the carbon atoms to which 1-2 alkanediyloxy, (105)R 1 and R 3 methane-1,1-diyloxy bridging the carbon atom to which is attached; (106)R 1 and R 3 ethane-1,2-diyloxy bridging the carbon atom to which is attached, or (107)O.

[0079] In addition to embodiment (61) above, compounds of Formula 1 include those in which: (108)X 1 is C(HR 1 ) and X 2 is CH2, X 3 is CH2, X 4 is C(HR 4 ) and R 1 and R 4 Together, R 1 and R 4 C bridging the carbon atoms to which 1-2 It represents alkanediyloxy or O.

[0080] In addition to embodiment (108) of the preceding paragraph, the compound of Formula 1 may further comprise R 1 and R 4 together represent: (109)R 1 and R 4 C bridging the carbon atoms to which 1-2 alkanediyloxy, (110)R 1 and R 4 methane-1,1-diyloxy bridging the carbon atom to which is attached; (111)R 1 and R 4 ethane-1,2-diyloxy bridging the carbon atom to which is attached, or (112)O.

[0081] In addition to any one of the above embodiments (1) through (112), compounds of Formula 1 include those where m is: (116)0, or (117)1 or 2.

[0082] In addition to embodiment (117) of the preceding paragraph, compounds of Formula 1 include those in which: (118)R a and R b are hydrogen and C, respectively. 1-4 independently selected from alkyl, (119)R a and R b are hydrogen and C, respectively.1-3 independently selected from alkyl, (120)R a and R b are each independently selected from hydrogen and methyl; (121)R a are each methyl, and R b are each hydrogen, (122)R a are each methyl, and R b are each methyl, (123)R a are each hydrogen, and R b are each hydrogen, (124)R a and R b are hydrogen and C, respectively. 1-4 alkyl, or R a and R b is R a and R b together with the carbon atom to which they are attached form a cyclopropylidene or cyclobutylidene, provided that if m is 2, then R a and R b At most one of the R a and R b together with the carbon atom to which it is attached to form a cyclopropylidene or cyclobutylidene, (125)R a and R b are hydrogen and C, respectively. 1-4 alkyl, or R a and R b is R a and R b together with the carbon atom to which they are attached form a cyclopropylidene, provided that if m is 2, then R a and R b At most one of the R a and R b together with the carbon atom to which it is attached to form a cyclopropylidene, (126)R a and R b are hydrogen and C, respectively.1-3 alkyl, or R a and R b is R a and R b together with the carbon atom to which they are attached form a cyclopropylidene, provided that if m is 2, then R a and R b At most one of the R a and R b together with the carbon atom to which it is attached to form a cyclopropylidene. (127)R a and R b are each independently selected from hydrogen and methyl, or R a and R b is R a and R b together with the carbon atom to which they are attached form a cyclopropylidene, provided that if m is 2, then R a and R b At most one of the R a and R b together with the carbon atom to which it is attached to form a cyclopropylidene, or (128)R a and R b are each hydrogen or R a and R b is R a and R b together with the carbon atom to which they are attached form a cyclopropylidene, provided that if m is 2, then R a and R b At most one of the R a and R b together with the carbon atom to which it is attached to form a cyclopropylidene.

[0083] In addition to any one of the above embodiments (1) to (128), the compound of Formula 1 may further comprise R 5 but includes: (129)C 3-8 Cycloalkyl (substituted with 0 to 5 substituents independently selected from: (i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (130)C 4-7 Cycloalkyl (substituted with 0 to 5 substituents independently selected from: (i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (131) Cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptan-1-yl, and spiro[3.3]heptan-2-yl, each of which is substituted with 0 to 5 substituents independently selected from: (i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (132) Cycloalkyl selected from cyclobutyl, cyclohexyl, bicyclo[2.2.1]heptan-1-yl, and spiro[3.3]heptan-2-yl, each of which is substituted with 0 to 5 substituents independently selected from: (i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (133) Cycloalkyl selected from cyclobutyl, cyclohexyl, and bicyclo[2.2.1]heptan-1-yl, each of which is substituted with 0 to 5 substituents independently selected from: (i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (134) Cycloalkyl, which is cyclobutyl substituted with 0 to 5 substituents independently selected from the following: (i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (135) Cycloalkyl, which is cyclohexyl substituted with 0 to 5 substituents independently selected from the following: (i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo), or (136) Cycloalkyl is bicyclo[2.2.1]heptan-1-yl substituted with 0 to 5 substituents independently selected from the following: (i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo);

[0084] In addition to any one of embodiments (129)-(136) of the preceding paragraph, the compound of Formula 1 may further comprise R 5 Cycloalkyls include those substituted with 0 to 5 substituents independently selected from: (137)(i) halo, hydroxy, and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (138)(i) halo and hydroxy, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (139)(i) hydroxy and fluoro, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (140)(i) hydroxy, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (141) (i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-3 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (142) (i) halo, hydroxy, cyano and oxo, (ii) amino (substituted with 0 to 2 substituents independently selected from methyl), and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (143) (i) halo, hydroxy, cyano and oxo, (ii) unsubstituted amino, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (144)(i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-3 Alkyl, C 1-3 Alkylcarbonyl, and C 1-3 alkoxy (each substituted with 0-3 substituents independently selected from halo); (145)(i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii) methyl, methylcarbonyl, ethylcarbonyl, methoxy, and ethoxy, each substituted with 0 to 3 substituents independently selected from halo; (146)(i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii) methyl and methoxy, each substituted with 0 to 3 substituents independently selected from halo; (147)(i) hydroxy, (ii) amino (substituted with 0 to 2 substituents independently selected from methyl), and (iii) methyl and methoxy, each substituted with 0 to 3 substituents independently selected from halo; (148)(i) hydroxy, (ii) amino (substituted with 0 to 2 substituents independently selected from methyl), and (iii) methyl and methoxy, each substituted with 0 to 3 substituents independently selected from fluoro; or (149) Hydroxy, dimethylamino, methyl, trifluoromethyl, and methoxy.

[0085] In addition to any one of embodiments (129)-(149) of the preceding paragraph, the compound of Formula 1 may further comprise R 5 Included are those where cycloalkyl is: (150) Substituted with 0 to 4 substituents, (151) Substituted with 0 to 3 substituents; (152) Substituted with 0 to 2 substituents; (153) Substituted with 0 to 1 substituents, or (154) Unsubstituted.

[0086] In addition to any one of the above embodiments (1) to (128), the compound of Formula 1 may further comprise R 5 but includes: (155)C 3-8 Heterocyclyl (up to 3 carbon ring atoms are each independently substituted with 0-2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); Nitrogen ring atoms, when present, are unsubstituted or substituted with substituents selected from the following: (I C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy); (156)C 3-8 Heterocyclyl (the ring heteroatoms are selected from nitrogen and oxygen, and up to three carbon ring atoms are each independently substituted with 0-2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); Nitrogen ring atoms, when present, are unsubstituted or substituted with substituents selected from the following: (I C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n(Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy); (157)C 3-8 Heterocyclyl (wherein the ring heteroatom is nitrogen and up to three carbon ring atoms are each independently substituted with 0-2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); The nitrogen ring atom is unsubstituted or substituted with a substituent selected from the following: (I C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy); (158) Heterocyclyl (R) selected from azetidinyl, piperidinyl, 1-azabicyclo[2.2.1]heptanyl, quinuclidinyl, pyrrolidinyl, 3-azabicyclo[3.1.0]hexan-1-yl, and 2-oxabicyclo[2.2.1]heptan-4-yl 5 Up to three carbon ring atoms of a heterocyclyl are each independently substituted with 0 to 2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); R 5 The nitrogen ring atom of a heterocyclyl, if present, is unsubstituted or substituted with a substituent selected from: (I C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy); (159) Heterocyclyl (R) selected from azetidin-1-yl, piperidin-2-yl, piperidin-3-yl, 1-azabicyclo[2.2.1]heptan-3-yl, quinuclidin-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 3-azabicyclo[3.1.0]hexan-1-yl, and 2-oxabicyclo[2.2.1]heptan-4-yl 5 Up to three carbon ring atoms of a heterocyclyl are each independently substituted with 0 to 2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); R 5 The nitrogen ring atom of a heterocyclyl, if present, is unsubstituted or substituted with a substituent selected from: (I C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4substituted with 0 to 3 substituents independently selected from alkoxy);

[0087] In addition to any one of embodiments (155)-(159) of the preceding paragraph, the compound of Formula 1 may further comprise R 5 Heterocyclyl includes those in which up to three carbon ring atoms are each independently substituted with 0-2 substituents independently selected from: (160)(i) halo, hydroxy, and oxo; (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (161)(i) halo and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (162)(i) Halo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (163)(i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-3 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-4 Alkyl, C1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (164)(i) halo, hydroxy, cyano and oxo, (ii) amino (substituted with 0 to 2 substituents independently selected from methyl), and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (165)(i) halo, hydroxy, cyano and oxo, (ii) unsubstituted amino, and (iii)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (166)(i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii)C 1-3 Alkyl, C 1-3 Alkylcarbonyl, and C 1-3 alkoxy (each substituted with 0-3 substituents independently selected from halo); (167)(i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4 substituted with 0 to 2 substituents independently selected from alkyl, and (iii) methyl, methylcarbonyl, ethylcarbonyl, methoxy, and ethoxy, each substituted with 0 to 3 substituents independently selected from halo; (168)(i) halo, hydroxy, cyano and oxo, (ii) Amino (C 1-4substituted with 0 to 2 substituents independently selected from alkyl, and (iii) methyl and methoxy, each substituted with 0 to 3 substituents independently selected from halo; (169)(i) halo and oxo, (ii) amino (substituted with 0 to 2 substituents independently selected from methyl), and (iii) methyl and methoxy, each substituted with 0 to 3 substituents independently selected from halo; (170)(i) halo and oxo, (ii) amino (substituted with 0 to 2 substituents independently selected from methyl), and (iii) methyl and methoxy, each substituted with 0 to 3 substituents independently selected from fluoro; (171) Halo, oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy; (172) halo, oxo, methyl, ethyl, propyl, and isopropyl, or (173) Fluoro, oxo, methyl, ethyl, propyl, and isopropyl.

[0088] In addition to any one of embodiments (155)-(173) of the preceding paragraph, compounds of Formula 1 include those in which: (174)R 5 up to two carbon ring atoms of a heterocyclyl are each substituted; (175)R 5 At most one carbon ring atom of the heterocyclyl is substituted, or (176)R 5 None of the carbon ring atoms of a heterocyclyl is substituted.

[0089] In addition to any one of embodiments (155)-(176) of the preceding paragraph, the compound of Formula 1 may further comprise R 5 C 3-8Included are heterocyclyls in which the nitrogen ring atom, if present, is unsubstituted or substituted with a substituent selected from: (177)(i)C 1-3 Alkyl, C 1-3 Alkylcarbonyl, and C 1-3 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (178)(i)C 1-3 alkyl, methylcarbonyl, ethylcarbonyl, methylsulfonyl, and ethylsulfonyl, each substituted with 0 to 3 substituents independently selected from halo; (ii) C 3-8 Cycloalkyl-(CH2) n (C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (179) (i) methyl, ethyl, isopropyl, methylcarbonyl, and methylsulfonyl, each substituted with 0 to 3 substituents independently selected from halo; (ii) C 3-8 Cycloalkyl-(CH2) n (C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (180) (i) methyl, ethyl, isopropyl, methylcarbonyl, methylsulfonyl (each substituted with 0 to 3 substituents selected from fluoro); (ii) C 3-8 Cycloalkyl-(CH2) n (C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (181) (i) Methyl, ethyl, isopropyl, methylcarbonyl, methylsulfonyl (each unsubstituted), (ii) C 3-8 Cycloalkyl-(CH2) n (C3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (182)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-5 Cycloalkyl-(CH2) n (C 3-5 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (183)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-5 Cycloalkyl-(CH2) n (C 3-5 The cycloalkyl moiety can be halo, C 1-3 Alkyl, C1-3 Alkyl carbonyl, C 1-3 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (184)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-5 Cycloalkyl-(CH2) n (C 3-5 The cycloalkyl moiety can be halo, C 1-3 Alkyl, and C 1-3 substituted with 0 to 3 substituents independently selected from alkoxy, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (185)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-5 Cycloalkyl-(CH2) n (C 3-5 The cycloalkyl moiety is C 1-3 Alkyl, and C 1-3 substituted with 0 to 3 substituents independently selected from alkoxy, and (iii) phenyl-(CH2)n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (186)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-5 Cycloalkyl-(CH2) n (C 3-5 the cycloalkyl moiety is substituted with 0-3 substituents independently selected from halo, methyl, and methoxy; and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (187)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-5 Cycloalkyl-(CH2) n (C 3-5 the cycloalkyl moiety is substituted with 0-3 substituents independently selected from fluoro, methyl, and methoxy; and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (188)(i)C1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-5 Cycloalkyl-(CH2) n (C 3-5 the cycloalkyl moiety is substituted with 0-3 substituents independently selected from methyl and methoxy, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (189)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-5 Cycloalkyl-(CH2) n (C 3-5 the cycloalkyl portion is unsubstituted), and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (190)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (Phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C 1-3 Alkyl, and C 1-3 substituted with 0 to 3 substituents independently selected from alkoxy; (191)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n wherein the phenyl and pyridinyl moieties are substituted with 0-3 substituents independently selected from halo, hydroxy, cyano, methyl, and methoxy; (192)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n wherein the phenyl and pyridinyl moieties are substituted with 0-3 substituents independently selected from halo, hydroxy, methyl, and methoxy; (193)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n wherein the phenyl and pyridinyl moieties are substituted with 0-3 substituents independently selected from fluoro, chloro, hydroxy, methyl, and methoxy; (194)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) nwherein the phenyl and pyridinyl moieties are substituted with 0-3 substituents independently selected from fluoro, hydroxy, methyl, and methoxy; (195)(i)C 1-4 Alkyl, C 1-4 Alkylcarbonyl, and C 1-4 alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C 3-8 Cycloalkyl-(CH2) n (C 3-8 The cycloalkyl moiety can be halo, C 1-4 Alkyl, C 1-4 Alkyl carbonyl, C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy and oxo, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (the phenyl and pyridinyl moieties are unsubstituted), (196) (i) methyl, ethyl, isopropyl, methylcarbonyl, methylsulfonyl (each substituted with 0 to 3 substituents selected from fluoro); (ii) C 3-5 Cycloalkyl-(CH2) n (C 3-5 the cycloalkyl moiety is substituted with 0-3 substituents independently selected from fluoro, methyl, and methoxy; and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n wherein the phenyl and pyridinyl moieties are substituted with 0-3 substituents independently selected from fluoro, hydroxy, methyl, and methoxy; (197) (i) methyl, ethyl, isopropyl, methylcarbonyl, methylsulfonyl (each substituted with 0 to 3 substituents selected from fluoro); (ii) C 3-5 Cycloalkyl-(CH2) n (C 3-5the cycloalkyl moiety is substituted with 0-3 substituents independently selected from methyl and methoxy, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n wherein the phenyl and pyridinyl moieties are substituted with 0-3 substituents independently selected from fluoro, hydroxy, methyl, and methoxy; (198) (i) methyl, ethyl, isopropyl, methylcarbonyl, methylsulfonyl (each substituted with 0 to 3 substituents selected from fluoro); (ii) C 3-5 Cycloalkyl-(CH2) n (C 3-5 the cycloalkyl moiety is substituted with 0-3 substituents independently selected from methyl and methoxy, and (iii) phenyl-(CH2) n and pyridinyl-(CH2) n (The phenyl and pyridinyl moieties are unsubstituted).

[0090] In addition to any one of embodiments (155) through (198) of the preceding paragraph, compounds of Formula 1 include those in which: (199)R 5 is C 3-8 heterocyclyl and n is 0, or (200)R 5 is C 3-8 heterocyclyl, and n is 1.

[0091] In addition to any one of the above embodiments (1) to (128), the compound of Formula 1 may further comprise R 5 However, the following phenyl groups are included: (201) Halo, Hydroxy, Cyano, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy, provided that at least one of the substituents is hydroxy; (202) Halo, hydroxy, cyano, C 1-3Alkyl, and C 1-3 substituted with 0 to 3 substituents independently selected from alkoxy, provided that at least one of the substituents is hydroxy; (203) 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; (204) 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; (205) unsubstituted or hydroxy-substituted, or (206) Unsubstituted.

[0092] In addition to any one of embodiments (1) through (206) of the preceding paragraph, the compound of Formula 1 may further comprise R 6 is selected from the following: (207) Hydrogen and C 1-3 Alkyl, (208) Hydrogen and methyl, (209) Methyl, or (210) Hydrogen.

[0093] In addition to any one of embodiments (1) through (210) of the preceding paragraph, the compound of Formula 1 includes those where: (211)X 8 is CR 8 is.

[0094] In addition to any one of embodiments (1) through (211) of the preceding paragraph, the compound of Formula 1 may further comprise R 7 , R 8 and R 11 each of which is independently selected from the following: (212) (i) hydrogen, halo, and hydroxy; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo), and (iii)C 3-8 Cycloalkyl (halo, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (213) (i) hydrogen, halo, and hydroxy, and (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo); (214)(i) hydrogen, halo, and hydroxy; and (ii) C 1-3 Alkyl and C 1-3 alkoxy (each substituted with 0-3 substituents independently selected from halo); (215)(i) hydrogen, halo, and hydroxy; and (ii) methyl and methoxy, each substituted with 0 to 3 substituents independently selected from halo; (216) (i) hydrogen, halo, and hydroxy; and (ii) methyl and methoxy (each substituted with 0 to 3 fluoro).

[0095] In addition to any one of the above embodiments (1) to (211), the compound of Formula 1 may further comprise R 7 and R 8 are both hydrogen, and R 11 is selected from the following: (217) (i) hydrogen, halo, and hydroxy, and (ii) C 1-3 Alkyl and C 1-3 alkoxy (each substituted with 0-3 substituents independently selected from halo); (218)(i) hydrogen, halo, and hydroxy, and (ii) methyl and methoxy, each substituted with 0 to 3 substituents independently selected from halo, or (219)(i) hydrogen, halo, and hydroxy; and (ii) methyl and methoxy (each substituted with 0 to 3 fluoro).

[0096] In addition to any one of embodiments (1) through (219) of the preceding paragraph, the compound of Formula 1 may further comprise R 9 and R 10 each of which is independently selected from the following: (220) (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo), and (iii)C 3-8 Cycloalkyl (halo, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (221) (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-3 alkoxy (each substituted with 0-3 substituents independently selected from halo); (iii)C 3-8 Cycloalkyl (halo, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (222) (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 alkyl and methoxy, each substituted with 0-3 substituents independently selected from halo; (iii)C 3-8 Cycloalkyl (halo, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (223) (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 alkyl and methoxy (each substituted with 0-3 fluoro), and (iii)C 3-8 Cycloalkyl (halo, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (224) (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo), and (iii)C 3-5 Cycloalkyl (halo, C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (225) (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo), and (iii)C 3-5 Cycloalkyl(C 1-4 Alkyl, and C 1-4 substituted with 0 to 3 substituents independently selected from alkoxy; (226) (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo), and (iii)C 3-5 Cycloalkyl(C 1-3 Alkyl, and C 1-3 substituted with 0 to 3 substituents independently selected from alkoxy; (227) (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo), and (iii)C 3-5cycloalkyl (substituted with 0 to 3 substituents independently selected from methyl and methoxy); (228) (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-4 alkoxy (each substituted with 0-3 substituents independently selected from halo), and (iii) cyclopropyl, and cyclobutyl (each substituted with 0 to 3 substituents independently selected from methyl and methoxy); (229) (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-3 alkoxy (each substituted with 0-3 substituents independently selected from halo); (iii)C 3-5 Cycloalkyl(C 1-3 Alkyl, and C 1-3 substituted with 0 to 3 substituents independently selected from alkoxy; (230) (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-3 alkoxy (each substituted with 0-3 fluoro), and (iii)C 3-5 Cycloalkyl(C 1-3 Alkyl, and C 1-3 substituted with 0 to 3 substituents independently selected from alkoxy; (231) (i) hydrogen, halo, hydroxy, and cyano; (ii) C 1-4 Alkyl and C 1-3 alkoxy (each substituted with 0-3 fluoro), and (iii)C 3-5 cycloalkyl (substituted with 0-3 substituents independently selected from methyl and methoxy);

[0097] Compounds of Formula 1 include those compounds specifically named in the Examples and in the embodiments (1) through (231) described in the preceding paragraphs, and may exist as salts, complexes, solvates, hydrates, and liquid crystals. Similarly, compounds of Formula 1 that are salts may exist as complexes, solvates, hydrates, and liquid crystals.

[0098] The compounds of Formula 1 can form pharmaceutically acceptable complexes, salts, solvates, and hydrates. These salts include acid addition salts (including diacids) and base salts. Pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid, as well as non-toxic salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfuric acids. Such salts include acetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, and isethionate. Salts include phosphate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate salts.

[0099] Pharmaceutically acceptable base salts include salts derived from bases containing metal cations, such as alkali metal cations or alkaline earth metal cations, and amines. Examples of suitable metal cations include sodium, potassium, magnesium, calcium, zinc, and aluminum. Examples of suitable amines include arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine, lysine, N-methylglucamine, olamine, 2-amino-2-hydroxymethyl-propane-1,3-diol, and procaine. For a discussion of useful acid addition salts and base salts, see S.M. Berge et al., J. Pharm. Sci. (1977) 66:1-19. See also Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (2002).

[0100] Pharmaceutically acceptable salts can be prepared using various methods. For example, a compound of Formula 1 can be reacted with an appropriate acid or base to obtain the desired salt. Alternatively, a precursor of the compound of Formula 1 can be reacted with an acid or base to remove acid- or base-labile protecting groups or to open the lactone or lactam group of the precursor. In addition, a salt of the compound of Formula 1 can be converted to another salt (or free form) by treating it with an appropriate acid or base or by contacting it with an ion exchange resin. If the salt precipitates from solution after the reaction, it can be recovered by filtration or by isolating the salt by evaporation. The degree of ionization of the salt can vary from completely ionized to almost non-ionized.

[0101] Compounds of Formula 1 can exist in a range of solid states, from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a substance lacks long-range order at the molecular level and can exhibit the physical properties of either a solid or a liquid, depending on temperature. Typically, such substances do not produce distinctive X-ray diffraction patterns and are more formally described as liquids, although they exhibit the properties of a solid. Upon heating, a change from solid to liquid properties occurs, characterized by a change of state, typically second-order ("glass transition"). The term "crystalline" refers to a solid phase in which a substance has an internal structure with regular order at the molecular level and produces a distinctive X-ray diffraction pattern with distinct peaks. Such substances, when heated sufficiently, also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase transition, typically first-order ("melting point").

[0102] The compound of formula 1 can exist in unsolvated and solvated forms. The term "solvate" describes a molecular complex containing a compound and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" refers to a solvate in which the solvent is water. Pharmaceutically acceptable solvates include those in which the solvent may be isotopically substituted (e.g., DO, acetone-d6, DMSO-d6).

[0103] A currently accepted classification system for solvates and hydrates of organic compounds distinguishes between isolated site, channel, and metal ion-coordinated solvates and hydrates. See, for example, KR Morris (HGBrittain ed.) Polymorphism in Pharmaceutical Solids (1995). Isolated site solvates and hydrates are those in which the solvent (e.g., water) molecules are isolated from direct contact with each other by intervening molecules of the organic compound. In channel solvates, the solvent molecules reside in lattice channels where they are next to other solvent molecules. In metal ion-coordinated solvates, the solvent molecules are bound to the metal ion.

[0104] When the solvent or water is tightly bound, the complex has a well-defined stoichiometry independent of humidity. However, when the solvent or water is weakly bound, as in the case of channel solvates and hygroscopic compounds, the water or solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will typically be observed.

[0105] The compounds of Formula 1 may also exist as multicomponent complexes (other than salts and solvates) in which the compound (drug) and at least one other component are present in stoichiometric or non-stoichiometric amounts. This type of complex includes inclusion complexes (drug-host inclusion complexes) and cocrystals. The latter is typically defined as a crystalline complex of neutral molecular constituents bound together through non-covalent interactions, but can also be a complex of a neutral molecule and a salt. Cocrystals can be prepared by melt crystallization, recrystallization from a solvent, or by physically grinding the components together. See, for example, O. Almarsson and MJ Zaworotko, Chem. Commun. (2004) 17:1889-1896. For a review of multicomponent complexes, see JK Haleblian, J. Pharm. Sci. (1975) 64(8):1269-88.

[0106] Compounds of Formula 1 can exist in a mesomorphic state (mesophase or liquid crystal) when subjected to appropriate conditions. The mesomorphic state is between the true crystalline state and the true liquid state (either melt or dissolve). Mesomorphs that arise as a result of a change in temperature are described as "thermotropic," while mesomorphs that result from the addition of a second component, such as water or another solvent, are described as "lyotropic." Compounds that have the potential to form lyotropic mesophases are described as "amphiphilic," and contain polar ionic moieties (e.g., -COO - Na + , -COO - K + , -SO3 - Na + ) or polar nonionic moiety (-N - N +(CH3)3, etc. See, for example, N.H. Hartshorne and A. Stuart, Crystals and the Polarizing Microscope (4th ed., 1970).

[0107] Each compound of Formula 1 may exist as a polymorph, stereoisomer, tautomer, or some combination thereof, may be isotopically labeled, may result from administration of a prodrug, or may form a metabolite following administration.

[0108] A "prodrug" refers to a compound that has little or no pharmacological activity but can be converted into a compound with the desired pharmacological activity when metabolized in vivo. Prodrugs can be prepared by replacing appropriate functional groups present in a pharmacologically active compound with a "promoiety," as described, for example, in H. Bundgaar, Design of Prodrugs (1985). Examples of prodrugs include ester, ether, or amide derivatives of the compounds of Formula 1 that contain carboxylic acid, hydroxy, or amino functional groups, respectively. For a detailed discussion of prodrugs, see, for example, T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," ACS Symposium Series 14 (1975) and EB Roche ed., Bioreversible Carriers in Drug Design (1987).

[0109] "Metabolite" refers to a compound formed in vivo upon administration of a pharmacologically active compound. Examples include hydroxymethyl, hydroxy, secondary amino, primary amino, phenol, and carboxylic acid derivatives of compounds of Formula 1 bearing methyl, alkoxy, tertiary amino, secondary amino, phenyl, and amido groups, respectively.

[0110] The compounds of Formula 1 can exist as stereoisomers resulting from the presence of one or more asymmetric centers, one or more double bonds, or both. The stereoisomers can be pure, substantially pure, or mixtures. Such stereoisomers can also result from acid addition or base salts in which the counterion is optically active (e.g., when the counterion is D-lactate or L-lysine).

[0111] Compounds of Formula 1 can exist as tautomers, which are isomers resulting from tautomerization. Tautomeric isomerism includes, for example, imine-enamine, keto-enol, oxime-nitroso, and amide-imidic acid tautomerism.

[0112] Compounds of formula 1 may exhibit more than one type of isomerism.

[0113] Geometric (cis / trans) isomers may be separated by conventional techniques such as chromatography or fractional crystallization.

[0114] Conventional techniques for preparing or isolating compounds of a specific stereochemical configuration include chiral synthesis from appropriate optically pure precursors or resolution of the racemate (or racemate of a salt or derivative), for example, using chiral high-pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) can be reacted with an appropriate optically active compound, for example, an alcohol, or, if the compound of Formula 1 contains an acidic or basic moiety, with an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereoisomeric mixture can be separated by chromatography, fractional crystallization, or the like, and the appropriate diastereoisomer can be converted to a compound with the required stereochemical configuration. For a further discussion of techniques for separating stereoisomers, see E.L. Eliel and S.H. Wilen, Stereochemistry of Organic Compounds (1994).

[0115] Compounds of Formula 1 may have isotopic variations in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Suitable isotopes for inclusion in compounds of Formula 1 include, for example, isotopes of hydrogen, such as 2 H and 3 H; isotopes of carbon, e.g., 11 C. 13 C, and 14 C; isotopes of nitrogen, e.g., 13 N and 15 N; isotopes of oxygen, e.g., 15 O. 17 O, and 18 O; isotopes of sulfur, e.g., 35 S; isotopes of fluorine, e.g., 18 F; isotopes of chlorine, e.g., 36 Cl; as well as isotopes of iodine, e.g., 123 I and 125 Isotopic variants (e.g., deuterium, 2 The use of H) can provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) due to increased metabolic stability. Additionally, certain isotopic variations of the disclosed compounds may be substituted with radioactive isotopes (e.g., tritium, 3 H, or 14 C) can be incorporated, which can be useful for drug and / or substrate tissue distribution studies. 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds can be prepared by processes analogous to those described elsewhere in this disclosure, using the appropriate isotopically labeled reagent in place of an unlabeled reagent.

[0116] Compounds of Formula 1 can be prepared using the techniques described below. Some of the methods and examples may omit details of common reactions, including oxidations, reductions, and the like, separation techniques (extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like), and analytical procedures, which are known to those skilled in the art of organic chemistry. Details of such reactions and techniques can be found in several treatises, including Richard Larock's Comprehensive Organic Transformations (1999) and the multi-volume series, Compendium of Organic Synthetic Methods (since 1974), edited by Michael B. Smith et al. Starting materials and reagents can be obtained from commercial sources or prepared using literature methods. Some of the reaction schemes may exclude by-products resulting from chemical transformations (e.g., alcohols from the hydrolysis of esters, CO from the decarboxylation of diacids, and the like). Additionally, in some cases, reaction intermediates may be used in subsequent steps without isolation or purification (i.e., in situ).

[0117] In the methods and examples that follow, certain compounds can be prepared using protecting groups that prevent undesired chemical reactions outside of the reactive site. Protecting groups can also be used to enhance the solubility of the compound or to otherwise modify its physical properties. For a discussion of protecting group strategies, a description of materials and methods for installing and removing protecting groups, and a summary of useful protecting groups for common functional groups such as amines, carboxylic acids, alcohols, ketones, and aldehydes, see T.W. Greene and P.G. Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000).

[0118] Generally, chemical transformations described throughout this specification can be carried out using substantially stoichiometric amounts of reactants, although certain reactions can benefit from using an excess of one or more reactants. Additionally, although many of the reactions disclosed throughout this specification can be carried out at about room temperature (RT) and ambient pressure, some reactions can be carried out at elevated pressures or higher temperatures (e.g., reflux conditions) or lower temperatures (e.g., −78° C. to 0° C.) can be used, depending on reaction kinetics, yield, etc. Any reference within this disclosure and claims to a stoichiometric range, temperature range, pH range, etc., includes the indicated endpoints, whether or not explicitly using the word “range.”

[0119] Many chemical transformations may also employ one or more compatible solvents, which can affect the reaction rate and yield. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, nonpolar solvents, or some combination. Representative solvents include saturated aliphatic hydrocarbons (e.g., n-pentane, n-hexane, n-heptane, n-octane, cyclohexane, methylcyclohexane); aromatic hydrocarbons (e.g., benzene, toluene, xylene); halogenated hydrocarbons (e.g., methylene chloride, chloroform, carbon tetrachloride); aliphatic alcohols (e.g., methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, 2-methyl-propan-1-ol, butan-2-ol, 2-methyl-propan-2-ol, pentan-1-ol, 3-methyl-butan-1-ol, hexane-1-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol, 2-(2-methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol, 2-(2 ethers (e.g., diethyl ether, diisopropyl ether, dibutyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, 1-methoxy-2-(2-methoxy-ethoxy)-ethane, 1-ethoxy-2-(2-ethoxy-ethoxy)-ethane, tetrahydrofuran, 1,4-dioxane); ketones (e.g., acetone, methyl ethyl ketone); esters (methyl acetate, ethyl acetate); nitrogen-containing solvents (e.g., formamide, N,N-dimethylformamide, acetonitrile, N-methyl-pyrrolidone, pyridine, quinoline, nitrobenzene); sulfur-containing solvents (e.g., carbon disulfide, dimethyl sulfoxide, tetrahydro-thiophene-1,1-dioxide); and phosphorus-containing solvents (e.g., hexamethylphosphoric acid triamide).

[0120] In the following schemes, substituent identifiers (e.g., α, β, m, R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , Ra , R b , X 1 , X 2 , X 3 , X 4 and X 8 ) are as defined above for Formula 1. As noted above, some of the starting materials and intermediates may contain protecting groups, which are removed prior to the formation of the final product. In such cases, the substituent identifiers refer to the moieties defined in Formula 1 and those moieties bearing the appropriate protecting groups. For example, a starting material or intermediate in a synthetic method may contain a potentially reactive (secondary) amine. In such cases, the amine may include moieties with or without, for example, a Boc or Cbz group attached to the amine.

[0121] Schemes A and B show general methods for preparing compounds of Formula 1. According to Scheme A, a 1,4-dihalophthalazine derivative or analog (A1, where X is Cl) is reacted with an amine (A2) in the presence of a base (e.g., DIPEA, K2CO3, etc.) and a solvent (e.g., ACN, DMSO, NMP, etc.) at elevated temperatures (e.g., 80°C to 150°C) to provide a halophthalazine amine (A3). The amine (A3) can then be converted to a diboronic acid or ester (A4, e.g., each R 12 is H or C 1-4 alkyl) to give compounds of formula 1 directly or indirectly, for example after removal of protecting groups, further elaboration of functional groups, separation of stereoisomers or positional isomers, etc.

[0122] Alternatively, as shown in Scheme B, 1,4-dihalophthalazine derivatives or analogs (A1) can first be reacted with a diboronic acid or ester (A4) in the presence of a palladium catalyst, a base, and a solvent as shown in Scheme A. The resulting aromatic-substituted halophthalazine (B1) is then reacted with an amine (A2) in the presence of a base and a solvent at elevated temperature as described for Scheme A to afford either directly or after removal of protecting groups, further elaboration of functional groups, separation of stereoisomers or regioisomers, etc.

[0123] The methods shown in these schemes can be modified as desired. For example, protecting groups can be added or removed, and the products can be further elaborated, for example, via alkylation, acylation, hydrolysis, oxidation, reduction, amidation, sulfonation, alkynation, etc., to obtain the desired final product. Furthermore, any intermediates or final products that contain a mixture of stereoisomers can optionally be purified to obtain the desired stereoisomer by chiral column chromatography (e.g., supercritical fluid chromatography) or by derivatization with optically pure reagents, as described above. [ka] [ka]

[0124] The compounds of Formula 1 (including the compounds named above, as well as pharmaceutically acceptable complexes, salts, solvates, and hydrates thereof) should be evaluated for biopharmaceutical properties such as solubility and solution stability versus pH, permeability, etc. to select an appropriate dosage form and route of administration. Compounds intended for pharmaceutical use may be administered as crystalline or amorphous products, and may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, lyophilization, spray drying, evaporative drying, microwave drying, or radio frequency drying.

[0125] The compounds of formula 1 can be administered alone, in combination with each other, or in combination with one or more pharmacologically active compounds different from the compounds of formula 1. Generally, one or more of these compounds are administered as a pharmaceutical composition (formulation) in combination with one or more pharmaceutically acceptable excipients. The choice of excipient depends, inter alia, on the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Useful pharmaceutical compositions and methods for their preparation can be found, for example, in A. R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000).

[0126] The compound of formula 1 can be orally administered.Oral administration can include swallowing, in which case the compound enters the bloodstream through the gastrointestinal tract.Alternatively or additionally, oral administration can include mucosal administration (e.g., buccal, sublingual, supragingual administration), in which case the compound enters the bloodstream through the oral mucosa.

[0127] Preparations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multiparticulates or nanoparticles, liquids, or powders; lozenges that can be filled with liquid; chewable tablets; gels; fast-dispersing dosage forms; films; vaginal suppositories; sprays; and buccal or mucoadhesive patches.Liquid preparations include suspensions, solutions, syrups, and elixirs.Such preparations can be used as fillers in soft or hard capsules (for example, made from gelatin or hydroxypropylmethylcellulose), and typically contain carriers (for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or suitable oils), and one or more emulsifiers, suspending agents, or both.Liquid preparations can also be prepared by reconstituting solids (for example, from sachets).

[0128] 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.

[0129] For tablet dosage forms, depending on the dosage, the active pharmaceutical ingredient (API) may comprise from about 1 wt% to about 80 wt% of the dosage form, or more typically from about 5 wt% to about 60 wt% of the dosage form. In addition to the API, tablets may contain one or more disintegrants, binders, diluents, surfactants, glidants, lubricants, antioxidants, colorants, flavorings, preservatives, and taste-masking agents. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, C 1-6 Included are alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, disintegrants comprise from about 1 wt% to about 25 wt%, or from about 5 wt% to about 20 wt% of the dosage form.

[0130] Binders are generally used to give tablet formulations cohesion.Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and calcium hydrogen phosphate dihydrate.

[0131] Tablets may also include surfactants, such as sodium lauryl sulfate and polysorbate 80, and glidants, such as silicon dioxide and talc. When present, the surfactants may comprise from about 0.2 wt% to about 5 wt% of the tablet, and the glidants may comprise from about 0.2 wt% to about 1 wt% of the tablet.

[0132] Tablets may also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants may comprise from about 0.25 wt% to about 10 wt%, or from about 0.5 wt% to about 3 wt% of the tablet.

[0133] Tablet blends may be compressed directly or by roller compaction to form tablets. Tablet blends, or portions of the blends, may alternatively be wet-, dry-, or melt-granulated, melt-congealed, or extruded prior to tableting. If desired, one or more of the components may be sized by sieving or milling, or both, prior to blending. The final dosage form may comprise one or more layers, may be coated or uncoated, or may be encapsulated. An exemplary tablet may contain up to about 80 wt% API, about 10 wt% to about 90 wt% binder, about 0 wt% to about 85 wt% diluent, about 2 wt% to about 10 wt% disintegrant, and about 0.25 wt% to about 10 wt% lubricant. For a discussion of blending, granulating, milling, sieving, tabletting, coating, and descriptions of alternative techniques for preparing drug products, see A.R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000); H.A. Lieberman et al. (ed.), Pharmaceutical Dosage Forms: Tablets, Vol. 1-3 (2nd ed., 1990); and D.K. Parikh & C.K. Parikh, Handbook of Pharmaceutical Granulation Technology, Vol. 81 (1997).

[0134] Consumable oral films for human or veterinary use are flexible, water-soluble or water-swellable thin film dosage forms that can be fast-dissolving or mucoadhesive. In addition to the API, typical films contain one or more film-forming polymers, binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity modifiers, and solvents. Other film ingredients can include antioxidants, colorants, flavors and flavor enhancers, preservatives, saliva stimulants, cooling agents, cosolvents (including oils), emollients, bulking agents, antifoaming agents, surfactants, and taste masking agents. Some components of the formulation can perform more than one function.

[0135] In addition to dosage requirements, the amount of API in the film can depend on its solubility. If water-soluble, the API will typically comprise about 1 wt% to about 80 wt% of the non-solvent components (solutes) in the film, or about 20 wt% to about 50 wt% of the solutes in the film. Less soluble APIs may comprise a larger proportion of the composition, typically up to about 88 wt% of the non-solvent components in the film.

[0136] The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids, and typically comprises from about 0.01 wt% to about 99 wt% or from about 30 wt% to about 80 wt% of the film formulation.

[0137] Film dosage forms are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper, which may be carried out in a drying oven or tunnel (e.g., in a combined coating and drying apparatus), a freeze-drying machine, or a vacuum oven.

[0138] Solid formulations useful for oral administration can include immediate-release formulations and modified-release formulations. Modified-release formulations include delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, and programmed-release. For a general description of suitable modified-release formulations, see U.S. Patent No. 6,106,864. For details of other useful release technologies, such as high-energy dispersions and osmotic and coated particles, see Verma et al., Pharmaceutical Technology Online (2001) 25(2):1-14.

[0139] The compound of formula 1 can also be directly administered into the bloodstream, muscle or internal organs of the subject.The techniques suitable for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.The device suitable for parenteral administration includes needle-type (including microneedle) injector, needle-free injector and infusion device.

[0140] Parenteral formulations are typically aqueous solutions, which may contain excipients such as salts, carbohydrates, and buffers (e.g., pH of about 3 to about 9). However, for some applications, the compounds of Formula 1 may be more suitably formulated as sterile, non-aqueous solutions or as a dry form for use with a suitable vehicle, such as sterile, pyrogen-free water. Preparation of parenteral formulations under sterile conditions (e.g., by lyophilization) can be readily accomplished using standard pharmaceutical techniques.

[0141] The solubility of compounds used in the preparation of parenteral solutions can be increased by appropriate formulation techniques, such as the incorporation of solubility enhancers. Formulations for parenteral administration can be formulated for immediate or modified release. Modified release formulations include delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, and programmed-release. Thus, the compound of Formula 1 can be formulated as a suspension, solid, semisolid, or thixotropic liquid for administration as an implanted depot that provides modified release of the active compound. Examples of such formulations include drug-coated stents and semisolids and suspensions containing drug-loaded poly(DL-lactic-co-glycolic acid) (PGLA) microspheres.

[0142] The compounds of Formula 1 may also be administered topically, intradermally, or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Topical formulations may also include penetration enhancers. See, for example, Finnin and Morgan, J. Pharm. Sci. 88(10):955-958 (1999).

[0143] Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free (e.g., Powderject™ and Bioject™) injection. Formulations for topical administration may be formulated to be immediate or modified release, as described above.

[0144] The compounds of Formula 1 may also be administered intranasally or by inhalation, typically in the form of a dry powder, aerosol spray, or nasal drops. An inhaler may be used to administer the dry powder, which may include the API alone, a powder blend of the API with a diluent such as lactose, or mixed-component particles containing the API and a phospholipid such as phosphatidylcholine. For intranasal use, the powder may contain a bioadhesive agent, such as chitosan or cyclodextrin. A pressurized container, pump, sprayer, atomizer, or nebulizer may be used to generate an aerosol spray from a solution or suspension containing the API, one or more agents for dispersing, solubilizing, or extending the release of the API (e.g., EtOH, with or without water), one or more solvents that function as propellants (e.g., 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane), and an optional surfactant, such as sorbitan trioleate, oleic acid, or oligolactic acid. Electrohydrodynamic atomizers can be used to generate a fine mist.

[0145] Prior to use in a dry powder or suspension formulation, the drug product is usually milled to a particle size suitable for delivery by inhalation (typically 90% of the particles by volume have a largest dimension less than 5 microns). This can be achieved by any suitable milling method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing, high pressure homogenization, or spray drying.

[0146] Capsules, blisters, and cartridges for use in an inhaler or insufflator (made, for example, from gelatin or hydroxypropylmethylcellulose) can be formulated containing a powder mix of the active compound, a suitable powder base such as lactose or starch, and a performance modifier such as L-leucine, mannitol, or magnesium stearate. Lactose can be anhydrous or monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0147] Solution formulations suitable for use in atomizers that use electrohydrodynamics to generate a fine mist may contain about 1 μg to about 20 mg of API per actuation, and actuation volumes may vary from about 1 μL to about 100 μL. A typical formulation may include one or more compounds of Formula 1, propylene glycol, sterile water, EtOH, and NaCl. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

[0148] Formulations for inhaled administration, intranasal administration, or both, can be formulated to be immediate or modified release, using, for example, PGLA. Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to formulations intended for inhaled / intranasal administration.

[0149] For dry powder inhalers and aerosols, the dosage unit is determined by utilizing a valve that delivers a metered amount. The unit is typically designed to administer a metered dose or "puff" containing from about 10 μg to about 1000 μg of API. The total daily dose typically ranges from about 100 μg to about 10 mg, which may be administered in a single dose or, more usually, in divided doses throughout the day.

[0150] Active compound can be administered rectally or vaginally, for example, in the form of suppository, pessary or enema.Cocoa butter is a conventional suppository base, but various alternatives can be used if appropriate.The preparation for rectal or vaginal administration can be formulated as described above to be immediate release or modified release.

[0151] The compound of Formula 1 may be administered directly to the eye or ear, typically in the form of droplets of a micronized suspension or solution in pH-adjusted, isotonic, sterile saline. Other formulations suitable for ocular and otic administration include ointments, gels, biodegradable implants (e.g., absorbent gel sponges, collagen), non-biodegradable implants (e.g., silicone), wafers, lenses, and microparticle or vesicular systems such as niosomes or liposomes. The formulation may contain one or more polymers and preservatives, such as benzalkonium chloride. Typical polymers include cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose), and heteropolysaccharide polymers (e.g., gellan gum). Such formulations may also be delivered by iontophoresis. Formulations for ocular or otic administration may be formulated for immediate or modified release, as described above.

[0152] The compounds of Formula 1 may be combined with soluble macromolecular entities, such as cyclodextrin and its derivatives, and polyethylene glycol-containing polymers, to improve their solubility, dissolution rate, taste-masking, bioavailability, or stability. For example, API-cyclodextrin complexes are generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the API, cyclodextrins may be used as auxiliary additives, i.e., carriers, diluents, or solubilizers. Alpha-, beta-, and gamma-cyclodextrins are commonly used for these purposes. See, for example, WO91 / 11172, WO94 / 02518, and WO98 / 55148.

[0153] As noted above, one or more compounds of Formula 1, including those specifically named above, and their pharmaceutically active complexes, salts, solvates, and hydrates, can be combined with each other or with one or more other active pharmaceutically active compounds to treat various diseases, conditions, and disorders. In such cases, the active compounds may be combined in a single dosage form, as described above, or provided in the form of a kit suitable for simultaneous administration of the compositions. A kit includes (1) two or more different pharmaceutical compositions, at least one of which contains a compound of Formula 1, and (2) a device for separately holding the two pharmaceutical compositions (e.g., a divided bottle or a divided foil packet). An example of such a kit is a common blister pack used for packaging tablets or capsules. The kit is suitable for administering different types of dosage forms (e.g., oral and parenteral), or for administering different pharmaceutical compositions at different dosing intervals, or for titrating different pharmaceutical compositions relative to one another. To aid patient compliance, the kit typically includes instructions for administration and may provide a memory aid.

[0154] When administered to a human patient, the total daily dose of the claimed and disclosed compounds typically ranges from about 0.1 mg to about 3000 mg, depending on the route of administration. For example, oral administration may require a total daily dose of about 1 mg to about 3000 mg, while intravenous administration may require a total daily dose of only about 0.1 mg to about 300 mg. The total daily dose may be administered in a single dose or in divided doses and, at the physician's discretion, may fall outside the typical ranges set forth above. These dosages are based on an average human subject weighing about 60 kg to about 70 kg, although a physician would be able to determine the appropriate dose for patients (e.g., infants) weighing outside this weight range.

[0155] As described above, the compounds of Formula 1 can be used to treat diseases, disorders, and conditions in which inhibition of the NLRP3 inflammasome pathway is indicated, including diseases, disorders, or conditions associated with heterozygous gain-of-function mutations in the NLRP3 gene, such as cryopyrin-associated periodic fever syndrome (CAPS), which may include neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

[0156] The compounds of Formula 1 can be used to treat neurodegenerative diseases, disorders, and conditions associated with NLRP3. These can include frontotemporal lobar degeneration, Lewy body disease, vascular disease, traumatic brain injury, substance or drug use, HIV infection, prion diseases, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion diseases, Alzheimer's disease, and other forms of dementia (i.e., severe or mild neurocognitive disorders) associated with one or more medical conditions. The compounds of Formula 1 can also be used to treat severe or mild neurocognitive disorders associated with depression, schizophrenia, bipolar disorder, and autism.

[0157] The claimed and disclosed compounds may be combined with one or more other pharmacologically active compounds or therapies for treating one or more disorders, diseases, or conditions for which inhibition of the NLRP3 inflammasome pathway is indicated. Such combinations may provide significant therapeutic benefits, including reduced side effects, improved treatment capabilities for underserved patient populations, or synergistic activity. For example, the compounds of Formula 1, including the compounds specifically named above, and their pharmaceutically acceptable complexes, salts, solvates, and hydrates, may be administered simultaneously, sequentially, or separately in combination with one or more compounds or therapies for treating Alzheimer's disease. Such compounds or therapies include beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., apazone, aspirin, celecoxib, diclofenac (with or without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, choline and magnesium salicylate, salsalate, and sulindac), vitamin E, and anti-amyloid antibodies. Specific examples of compounds used to treat Alzheimer's disease include donepezil, rivastigmine, memantine, and galantamine.

[0158] In addition to drugs used to improve cognition, the compounds of Formula 1 may be combined with sedatives, hypnotics, anxiolytics, antipsychotics, tranquilizers, and other medications used to treat Alzheimer's disease. For example, the compounds of Formula 1 may be combined with one or more drugs for treating depression and / or schizophrenia (antidepressants and / or atypical or typical antipsychotics), including amitriptyline, amoxapine, aripiprazole, asenapine, bupropion, chlordiazepoxide, citalopram, chlorpromazine, clozapine, desipramine, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, fluphenazine ... azide, haloperidol, iloperidone, imipramine, isocarboxazid, lamotrigine, levomilnacipran, lurasidone, mirtazapine, nefazodone, nortriptyline, olanzapine, paliperidone, paroxetine, perphenazine, phenelzine, protriptyline, quetiapine, risperidone, selegiline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, vilazodone, and vortioxetine, and ziprasidone.

[0159] Similarly, the compounds of Formula 1 may be combined with one or more agents for treating anxiety (antianxiety medications), including benzodiazepines (alprazolam, chlordiazepoxide, clobazepam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, prazepam, quazepam, temazepam, and triazolam), antihistamines (hydroxyzine), non-benzodiazepines (eszopiclone, zaleplon, zolpidem, and zopiclone), and buspirone.

[0160] The compounds of Formula 1 may also be combined with one or more agents for treating epilepsy (antiepileptic or anticonvulsant drugs), including acetazolamide, carbamazepine, clobazam, clonazepam, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide.

[0161] biological activity

[0162] The biological activity of the compounds of formula 1 with respect to NLRP3 can be determined using the following in vitro method.

[0163] IL-1β assay (IC 50 (reported as

[0164] Monocytic THP-1 cells (ATCC: TIB-202) were maintained in RPMI medium (Life Technologies, catalog number A10491-01) according to the manufacturer's instructions. 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) for 24 hours at 37°C / 5% CO2. 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 seeded at 40,000 cells per well into 384-well flat-bottom cell culture plates (Costar 3764) containing compounds (added at 1:1000) in a 1:3.16 serial dilution series in DMSO and incubated at 37°C / 5% CO2 for 30 minutes. 2.5 mM ATP (Sigma catalog no. A3377) was added to activate the NLRP3 inflammasome, and the cells were incubated at 37°C / 5% CO2 for 2 hours. At the end of the incubation period, 40 μL of supernatant was removed and IL-1β levels were monitored using an ELISA (human IL-1β ELISA, R&D systems, catalog no. DY201) according to the manufacturer's instructions.

[0165] TNF-α Assay Description (IC 50 (reported as

[0166] Monocytic THP-1 cells (ATCC:TIB-202) are maintained in RPMI medium (Life Technologies, catalog number A10491-01) according to the supplier's instructions. RPMI is supplemented with 10% heat-inactivated fetal bovine serum (Hyclone catalog number SH30396.03). Cells are differentiated into macrophages by adding 25 ng / mL IFN-γ for 24 hours at 37°C / 5% CO2. The medium is replaced with fresh medium without FBS. Cells are seeded at 40,000 cells per well into 384-well flat-bottom cell culture plates (Costar 3764) containing compounds (added at 1:1000) in a 1:3.16 serial dilution series in DMSO and incubated for 30 minutes at 37°C / 5% CO2. The NF-κB pathway is activated by the addition of 50 ng / mL LPS, and the cells are incubated for 3 hours at 37° C. / 5% CO. At the end of the incubation period, the supernatant (40 μL) is removed and IL-1β levels are monitored using an ELISA (human TNF-α ELISA, R&D systems, catalog number DY210) according to the manufacturer's instructions.

[0167] Data interpretation

[0168] I C 50 The value is Y=[bottom+(top-bottom)] / (1+10^[(LogIC 50 The percentage of inhibition is calculated from a plot of the inhibitor concentration versus the percentage of inhibition by fitting a logistic curve according to [(-X)·Hill slope] (where Y is the % inhibition at inhibitor concentration X, "bottom" is the lowest inhibition value, i.e., 0%, "top" is the maximum inhibition value, i.e., 100%, and "Hill slope" represents the slope of the sigmoidal curve between the "bottom" and "top" values). Curve fitting was performed using internally developed software.

[0169] 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.

[0170] MDCK-MDR1 assay (reported as apparent permeability and efflux ratio)

[0171] Madin-Darby canine kidney (MDCK) cells transfected with multidrug resistance protein 1 (MDR1) were maintained in Dulbecco's modified Eagle's medium (DMEM, Fisher Scientific catalog no. 10569044) according to the supplier's instructions. DMEM was supplemented with 10% heat-inactivated fetal bovine serum (Gibco catalog no. 16000-044), penicillin-streptomycin (100 units / mL) (Gibco catalog no. 15140122), and the P-gp inducer colchicine (200 nM) (Sigma catalog no. C9754). Cells were plated at 6.25 x 10 per well on the apical side of an HTS-Transwell-96 plate (0.4 μm pore size, Corning catalog no. 3381) using 75 μL and 250 μL of DMEM medium for the apical and basolateral wells, respectively. 3Cells are seeded at a density of 1000 μg / well and incubated at 37°C / 5% CO2. After 72 hours, fresh DMEM medium is replaced in the apical and basolateral compartments, and cells are allowed to grow to a monolayer for 144 hours before experimental incubation begins. Incubations are performed in Hank's Balanced Salt Solution (HBSS, Fisher Scientific catalog number 14025134) at pH 7.4 with 1% bovine serum albumin (Sigma, catalog number A9418) and 10 mM HEPES (Fisher Scientific, catalog number 15630080). DMEM medium is removed, and cells are rinsed with warm (37°C) HBSS. HBSS containing test compound at a substrate concentration of 1 μM (0.1% v / v DMSO) is added to either the apical or basolateral compartment (75 μL or 250 μL, respectively), and blank HBSS buffer lacking test compound is added to the compartment in duplicate. The cells are incubated for 60 minutes at 37°C / 5% CO2. At the end of the incubation period, 50 μL of sample is removed from each receiver compartment and diluted in 150 μL of acetonitrile (Fisher Scientific, Catalog No. A996SK4) + 0.1% formic acid (Sigma, Catalog No. F0507). The samples are centrifuged at 2000 rcf for 10 minutes at 4°C, after which 100 μL of supernatant is transferred to a new microplate and diluted with 100 μL of HPLC-grade water (Fisher Scientific, Catalog No. W64). Samples are analyzed using a triple quadrupole mass spectrometer API-5500QTrap (ABSciex, serial number AU23291006) with an attached autosampler and a high performance liquid chromatography pump instrument optimized for detection of the test article via a Kinetix 2.1 x 50 mm C18 100 Å column (Phenomenex, catalog number 00B-4605-AN).

[0172] Apparent permeability (P app ) values ​​and emission ratios are calculated using the following equations:

number

[0173] The following examples are intended to be illustrative and non-limiting and represent specific embodiments of the present invention.

[0174] For many of the compounds in the examples below, 1 H nuclear magnetic resonance (NMR) spectra were obtained. Characteristic chemical shifts (δ) are given in parts per million downfield from tetramethylsilane using conventional abbreviations for major peak designations, including s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). The following abbreviations are used for common solvents: CDCl3 (deuterated chloroform), DMSO-d6 (deuterated dimethyl sulfoxide), CD3OD (deuterated methanol), CD3CN (deuterated acetonitrile), and THF-d8 (deuterated tetrahydrofuran). Mass spectra ([M+H] + m / z for were recorded using electrospray ionization (ESI-MS) or atmospheric pressure chemical ionization (APCI-MS) mass spectrometry.

[0175] Where indicated, intermediate preparations and example compounds are purified by HPLC. Tables 1-3 list the columns, mobile phases, and gradients used for some of the HPLC separations.

[0176] [Table 1]

[0177] [Table 2]

[0178] [Table 3]

[0179] In the preparations and examples, supercritical fluid chromatography (SFC) may be used to separate the enantiomers. Table 4 lists the equipment, materials, and conditions for some SFC separations.

[0180] [Table 4]

[0181] In addition to HPLC, some preparations and examples may use flash chromatography or preparative thin layer chromatography (TLC). Preparative TLC is typically performed on silica gel 60F. 254 Carry out in plates.

[0182] After chromatographic separation, the solvent can be removed and the product dried in a centrifugal evaporator (e.g., GeneVac™), rotary evaporator, vacuum flask, etc. Reactions in an inert (e.g., nitrogen) or reactive (e.g., H) atmosphere are typically carried out at a pressure of about 1 atmosphere (14.7 psi).

[0183] Preparation 1: 5,5-Difluoro-1-methylpiperidin-3-amine [ka]

[0184] Step 1: tert-butyl (5,5-difluoro-1-methylpiperidin-3-yl)carbamate [ka]

[0185] A mixture of tert-butyl (5,5-difluoropiperidin-3-yl)carbamate (500 mg, 2.12 mmol) and aqueous formaldehyde (343.49 mg, 4.23 mmol, 315.12 μL, 37% purity) in THF (1 mL) was stirred at 25° C. for 1 h. Formic acid (203.34 mg, 4.23 mmol) was added dropwise, and the mixture was stirred at 70° C. for 1 h. The reaction mixture was quenched with NH 3 .HO (5 mL) and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® SepaFlash® 12 g silica gel column) using a gradient of 0-20% DCM in MeOH (35 mL / min) to give the title compound (310 mg, crude). ESI-MS m / z [M+H] + 251.1.

[0186] Step 2: 5,5-Difluoro-1-methylpiperidin-3-amine

[0187] 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

[0188] Preparation 2: 1-Cyclopropylpiperidin-3-amine [ka]

[0189] Step 1: tert-butyl (1-cyclopropylpiperidin-3-yl)carbamate [ka]

[0190] 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 4 Å molecular sieves (3 g) and (1-ethoxycyclopropoxy)trimethylsilane (7.83 g, 44.94 mmol, 9.03 mL), followed by acetic acid (10.79 g, 179.75 mmol, 10.28 mL) and NaBHCN (2.82 g, 44.94 mmol). The mixture was stirred at 65 °C for 16 h. The resulting suspension was filtered and concentrated. The crude product was diluted with aqueous NaHCO (50 mL) and extracted with DCM (100 mL × 3). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (DCM / MeOH = 1:0 to 10:1). The title compound was obtained as a colorless oil (6.5 g, 90%). 1 H NMR (400 MHz, CD3Cl) δ ppm 4.92 - 5.27 (m, 1 H), 3.73 (br s, 1 H), 2.49 - 2.81 (m, 4 H), 1.67 (br s, 4 H), 1.55 (br s, 1 H), 1.45 (s, 9 H), 0.47 (br d, J=6.27 Hz, 4H).

[0191] Step 2: 1-Cyclopropylpiperidin-3-amine

[0192] To a mixture of tert-butyl (1-cyclopropylpiperidin-3-yl)carbamate (4.9 g, 20.39 mmol), HCl in dioxane (4 M, 50.97 mL) was added in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 1 h. Excess HCl / dioxane was removed under reduced pressure to give a yellow solid, which was triturated with EtOAc (80 mL). The solid was collected by filtration and dried under vacuum to give the dihydrochloride salt of the title compound as a white solid (2.8 g, 64%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.65 - 0.96 (m, 2 H), 1.02 - 1.24 (m, 2 H), 1.45 - 1.69 (m, 1 H), 1.90 (br d, J=3.26 Hz, 2 H), 2.03 - 2.20 (m, 1 H), 2.84 -3.10 (m, 1 H), 2.89 - 3.00 (m, 1 H), 3.40 - 3.52 (m, 1 H), 3.45 (br d, J=11.80 Hz, 1 H), 3.61 (br d, J=9.03 Hz, 2 H), 8.70 (br s, 3 H), 11.49 (br s, 1 H).

[0193] Preparation 3: (R)-1-Cyclopropylpiperidin-3-amine [ka]

[0194] Step 1: tert-Butyl (R)-(1-cyclopropylpiperidin-3-yl)carbamate [ka]

[0195] To a solution of tert-butyl (R)-piperidin-3-ylcarbamate (3 g, 14.98 mmol) in THF (72 mL) and MeOH (8.1 mL) was added 4Å molecular sieves (3 g, 14.98 mmol), (1-ethoxycyclopropoxy)trimethylsilane (7.83 g, 44.94 mmol, 9.03 mL), acetic acid (10.79 g, 179.75 mmol, 10.28 mL), and NaBHCN (2.82 g, 44.94 mmol). The mixture was stirred at 65 °C for 16 h. LC-MS showed that the desired product was formed as the major component, and TLC (DCM / MeOH = 10:1) showed the reaction was complete (R of the desired product). f =0.43). The suspension was filtered and concentrated. The crude product was diluted with aqueous NaHCO3 (50 mL) and extracted with DCM (100 mL × 3). The 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 (400 MHz, DMSO-d6) δ ppm 0.27 (br s, 2 H), 0.39 (br d, J=3.51 Hz, 2 H), 1.04 - 1.20 (m, 1 H), 1.37 (s, 9 H), 1.52 - 1.72 (m, 3 H), 1.87 - 2.12 (m, 2 H), 2.68 - 2.95 (m, 2 H), 3.21 - 3.32 (m, 1 H), 6.51 - 6.79 (m, 1 H);ESI-MS m / z [M+H] + 241.2.

[0196] Step 2: (R)-1-Cyclopropylpiperidin-3-amine

[0197] 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 (400 MHz, DMSO-d6) δ ppm 0.81 (br d, J=6.48 Hz, 2 H), 1.04 - 1.24 (m, 2 H), 1.46 - 1.67 (m, 1 H), 1.89 (br s, 2 H), 2.00 - 2.14 (m, 1 H), 2.79 - 3.20 (m, 4 H), 3.54 - 3.71 (m, 1 H), 8.59 (br s, 2 H);ESI-MS m / z [M+H] + 141.1.

[0198] Preparation 4: (R)-1-(1-methylcyclopropyl)piperidin-3-amine [ka]

[0199] Step 1: tert-Butyl (R)-(1-acetylpiperidin-3-yl)carbamate [ka]

[0200] To a mixture of tert-butyl (R)-piperidin-3-ylcarbamate (1 g, 4.99 mmol) and DIPEA (1.94 g, 14.98 mmol, 2.61 mL) in DCM (15 mL) was added AcO (560.71 mg, 5.49 mmol, 514.42 μL). The mixture was stirred at 20° C. for 12 h. TLC (DCM / MeOH=10:1) showed that the starting material was completely consumed (R f =0.25), one new main spot was formed (Rf =0.53). The mixture was washed with HO (20 mL), concentrated in vacuo, and the resulting residue was purified by flash chromatography (ISCO® SepaFlash® 24 g silica gel column) using a gradient of 0-3% MeOH in DCM (35 mL / min). The title compound was obtained as a white solid (1 g, 83%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (m, 11 H), 1.59 - 1.83 (m, 2 H), 1.90 - 2.02 (m, 3 H), 2.42 (dd, J=12.1, 10.2 Hz, 1 H), 2.89 - 3.09 (m, 1 H), 3.18 - 3.30 (m, 1 H), 3.59 (br t, J=13.3 Hz, 1 H), 3.71 - 4.17 (m, 1 H), 6.75 - 7.06 (m, 1 H).

[0201] Step 2: tert-butyl (R)-(1-(1-methylcyclopropyl)piperidin-3-yl)carbamate [ka]

[0202] To a solution of tert-butyl (R)-(1-acetylpiperidin-3-yl)carbamate (900 mg, 3.71 mmol) and Ti(i-PrO) (2.11 g, 7.43 mmol, 2.19 mL) in THF (15 mL) was added EtMgBr (3 M, 6.19 mL) dropwise at 0 °C. The mixture was stirred at 20 °C for 12 h. TLC (EtOAc / MeOH = 20:1) showed that approximately 40% of the starting material remained (R f =0.68), and one new main spot was detected (R f=0.66). The reaction mixture was quenched with HO (2 mL) and filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash chromatography (ISCO® SepaFlash® 20 g silica gel column) using a gradient of 0-5% MeOH in DCM (35 mL / min). The title compound was obtained as a colorless gum (160 mg, 16.9%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.29 (br s, 2 H), 0.41 (br s, 2 H), 0.97 (s, 3 H), 1.03 - 1.23 (m, 2 H), 1.37 (s, 9 H), 1.48 - 1.74 (m, 2 H), 2.02 - 2.14 (m, 1 H), 2.18 - 2.29 (m, 1 H), 2.59 (br d, J=11.3 Hz, 1 H), 2.75 (br d, J=6.9 Hz, 1 H), 3.25 (br s, 1 H), 6.60 (br d, J=7.1 Hz, 1 H).

[0203] Step 3: (R)-1-(1-methylcyclopropyl)piperidin-3-amine

[0204] A mixture of tert-butyl (R)-(1-(1-methylcyclopropyl)piperidin-3-yl)carbamate (160 mg, 629.01 μmol) in HCl / dioxane (4 M, 5 mL) was stirred at 20° C. for 12 hours. TLC (EtOAc / MeOH=20:1) showed that the starting material was completely consumed (R f =0.66). The mixture was concentrated in vacuo to give the HCl salt of the title compound as a yellow solid (120 mg, crude), which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.72 - 0.82 (m, 2 H), 1.31 (s, 5 H), 1.51 - 1.66 (m, 1 H), 1.74 - 2.14 (m, 3 H), 3.06 - 3.33 (m, 3 H), 3.40 - 3.50 (m, 1 H), 3.62 - 3.94 (m, 1 H), 8.53 (br s, 2 H), 11.27 (br s, 1 H).

[0205] Preparation 5: (3R,5R)-1-Cyclopropyl-5-fluoropiperidin-3-amine [ka]

[0206] Step 1: tert-butyl ((3R,5R)-1-cyclopropyl-5-fluoropiperidin-3-yl)carbamate [ka]

[0207] A solution of tert-butyl ((3R,5R)-5-fluoropiperidin-3-yl)carbamate (0.327 g, 1.50 mmol) in THF (5 mL), MeOH (5 mL), and acetic acid (1.0 mL) was treated with (1-ethoxycyclopropoxy)trimethylsilane (0.523 g, 3.00 mmol), followed by sodium cyanoborohydride (0.283 g, 4.50 mmol). The reaction mixture was stirred at 60 °C overnight and then partitioned between EtOAc and saturated aqueous NaHCO. The aqueous phase was extracted with EtOAc. The organic layers were combined, dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography (ISCO® RediSep Rf Gold® 40 g silica gel column) with ELS detection using a gradient of 0–100% EtOAc in heptane. Evaporation of product-containing fractions gave the title compound as a white solid (0.333 g, 86%). ESI-MS m / z [M+H]+ 259.0.

[0208] Step 2: (3R,5R)-1-Cyclopropyl-5-fluoropiperidin-3-amine A solution of tert-butyl ((3R,5R)-1-cyclopropyl-5-fluoropiperidin-3-yl)carbamate (0.333 g, 1.29 mmol) in dioxane (6.45 mL) was treated with HCl (4 M in dioxane, 1.61 mL, 6.45 mmol). The reaction mixture was stirred at room temperature over the weekend. A small amount of MeOH was added to ensure the mixture was homogeneous. The reaction mixture was concentrated to dryness in vacuo to give the dihydrochloride salt of the title compound (crude 351.5 mg, assumed quantitative theoretical 298 mg, purity 84%), which was used without further purification. ESI-MS m / z [M+H] + 159.2.

[0209] Preparation 22: (R)-1-(2-fluoroethyl)piperidin-3-amine [ka]

[0210] Step 1: tert-butyl (R)-(1-(2-fluoroethyl)piperidin-3-yl)carbamate [ka]

[0211] To a mixture of tert-butyl (R)-piperidin-3-ylcarbamate (15 g, 74.90 mmol) and 1-bromo-2-fluoroethane (19.02 g, 149.79 mmol) in ACN (80 mL) was added NaI (5.61 g, 37.45 mmol) and K2CO3 (51.76 g, 374.48 mmol). The mixture was stirred at 15 °C for 12 h, then diluted with HO (150 mL) and extracted with EtOAc (200 mL × 2). The organic layers were combined, washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® SepaFlash® 220 g silica gel column) using a gradient of 0 to 100% EtOAc in PE (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.

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

[0213] A mixture of tert-butyl (R)-(1-(2-fluoroethyl)piperidin-3-yl)carbamate (7 g, 28.42 mmol) in HCl / dioxane (4 M, 20 mL) was stirred at 18 °C for 12 hours and then concentrated under reduced pressure to give the dihydrochloride salt of the title compound as a white solid (6.1 g, 98% yield, 100% purity). ELSD-MS m / z [M+H] + 147.1.

[0214] Preparation 56: 1',4'-Dichloro-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine] [ka]

[0215] Step 1: Methyl 1-(2-(1,3-dioxolan-2-yl)ethoxy)cyclopropane-1-carboxylate [ka]

[0216] To a solution of NaH (2.07 g, 51.67 mmol, 60% purity) in DMF (100 mL) was added methyl 1-hydroxycyclopropane-1-carboxylate (5 g, 43.06 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Next, 2-(2-bromoethyl)-1,3-dioxolane (19.49 g, 107.65 mmol, 12.91 mL) was added, and the mixture was stirred at 25 °C for 16 h. TLC (PE / EtOAc = 5:1, Rf = 0.3 for the desired product) showed one new spot. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL). The combined organic phases were washed with water (150 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 gradient of 0 to 20% EtOAc in PE. The pure fractions were collected and the solvent was evaporated in vacuo to give the title compound as a yellow oil (3.5 g). 1 H NMR (400MHz, CDCl3) δ ppm 4.96 (t, J=4.8 Hz, 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, 6.8 Hz, 2H), 1.29 - 1.26 (m, 2H), 1.18 - 1.14 (m, 2H).

[0217] Step 2: Methyl 1-(3-oxopropoxy)cyclopropane-1-carboxylate [ka]

[0218] To a solution of methyl 1-(2-(1,3-dioxolan-2-yl)ethoxy)cyclopropane-1-carboxylate (2 g, 9.25 mmol) in THF (10 mL) was added aqueous HCl (1 M, 27.75 mL) at 25° C. The mixture was stirred at 25° C. for 16 h. TLC (PE / EtOAc=5:1, Rf=0.2 for the desired product) showed one new spot. The reaction mixture was adjusted to pH >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 give the title compound (crude) as a yellow oil (1.4 g, 88%). 1 H NMR (400MHz, CDCl3) δ ppm 9.79 (t, J=1.6 Hz, 1H), 3.93 (t, J=6.0 Hz, 2H), 3.73 (s, 3H), 2.66 (dt, J=1.6, 6.0 Hz, 2H), 1.29 (t, J=3.6 Hz, 2H), 1.20 - 1.16 (m, 2H).

[0219] Step 3: Methyl 1-(but-3-yn-1-yloxy)cyclopropane-1-carboxylate [ka]

[0220] To a solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (2.68 g, 13.94 mmol) in MeOH (3 mL) was added KCO (963.23 mg, 6.97 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Next, a solution of methyl 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 h. TLC (PE / EtOAc = 5:1, Rf = 0.6 for the desired product) showed one 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 gradient of 0 to 20% EtOAc in PE. The pure fractions were collected and the solvent was evaporated in vacuo to give the title compound as a yellow oil (300 mg). 1 H NMR (400 MHz, CDCl3) δ ppm 3.76 - 3.72 (m, 5H), 2.47 (dt, J=2.4, 6.8 Hz, 2H), 1.98 (t, J=2.4 Hz, 1H), 1.35 - 1.29 (m, 2H), 1.23 - 1.18 (m, 2H).

[0221] Step 4: 1-(but-3-yn-1-yloxy)cyclopropane-1-carboxylic acid [ka]

[0222] To a solution of methyl 1-(but-3-yn-1-yloxy)cyclopropane-1-carboxylate (100 mg, 594.57 μmol) in MeOH (2 mL) was added LiOH.HO (99.80 mg, 2.38 mmol) and HO (1 mL) at 25 °C. The mixture was stirred at 25 °C for 12 h. TLC (PE / EtOAc = 5:1, Rf = 0.2 for the desired product) showed one new spot. The mixture was adjusted to pH < 6 with 1 N aqueous HCl 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 give the title compound (crude) as a yellow oil (60 mg, 65%). 1 H NMR (400 MHz, CDCl3) δ ppm 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).

[0223] Step 5: 1-(2-(3,6-dichloropyridazin-4-yl)ethoxy)cyclopropane-1-carboxylic acid [ka]

[0224] 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 h. TLC (PE / EtOAc = 3:1, Rf = 0.2 for the desired product) showed one new spot. The mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient of 0 to 40% EtOAc in PE. Pure fractions were collected, and the solvent was evaporated in vacuo to give the title compound (40 mg) as a red oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.85 (s, 1H), 3.97 (t, J=5.6 Hz, 2H), 2.99 (t, J=5.6 Hz, 2H), 1.45 - 1.39 (m, 2H), 1.22 - 1.15 (m, 2H).

[0225] Step 6: 1',4'-Dichloro-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine]

[0226] To a solution of 1-(2-(3,6-dichloropyridazin-4-yl)ethoxy)cyclopropane-1-carboxylic acid (120 mg, 433.05 μmol) in HO (5 mL) and acetone (5 mL) was added AgNO (100 mg, 588.67 μmol), ammonium peroxydisulfate (1.6 M, 541.31 μL), and TFA (1 M, 108.26 μL) at 25 °C. The mixture was stirred at 50 °C for 2 h. TLC (PE / EtOAc = 3:1, Rf = 0.4 for the desired product) showed one new spot. The mixture was cooled to room temperature (25 °C) and poured into ice-cold saturated aqueous NaHCO (100 mL), followed by extraction with EtOAc (80 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give a brown gum, which was purified by silica gel column chromatography using a gradient of 0-30% PE in EtOAc. Pure fractions were collected and the solvent was evaporated in vacuo to give the title compound (17 mg) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ ppm 4.00 (t, J=5.6 Hz, 2H), 2.98 (t, J=5.6 Hz, 2H), 2.17 - 2.10 (m, 2H), 1.31 - 1.24 (m, 2H);ESI-MS m / z [M+H] + 230.8.

[0227] Preparation 57: 1',4'-Dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] [ka]

[0228] Step 1: ((4-oxaspiro[2.5]oct-6-en-7-yl)oxy)(tert-butyl)dimethylsilane [ka]

[0229] 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 N (3x), then stirred at 25 °C for 3 h. TLC (PE / EtOAc = 3:1, stained with I) indicated that the starting material had been consumed and one new major spot with low polarity was present. The mixture was diluted with water (50 mL) and DCM (100 mL). The aqueous and organic phases were separated. The organic layer was washed with brine (50 mL), dried over NaSO, filtered, and concentrated to give the crude product as a dark brown oil (5.0 g). The crude product was purified by flash chromatography (20 g silica gel column) using a gradient of 0-20% EtOAc in PE to give the title compound as a pale yellow oil (3.6 g, 90%). 1 H NMR (400 MHz, CDCl3) δ ppm 4.27-4.81 (m, 1H), 3.70-3.97 (m, 2H), 1.97-2.10 (m, 2H), 0.77 (d, J=1.2 Hz, 9H), 0.61-0.71 (m, 2H), 0.27-0.42 (m, 2H), 0.00 (d, J=2.8 Hz, 6H).

[0230] Step 2: 1',4'-Dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]

[0231] The reactants ((4-oxaspiro[2.5]oct-6-en-7-yl)oxy)(tert-butyl)dimethylsilane (1.8 g, 7.49 mmol) and 3,6-dichloro-1,2,4,5-tetrazine (1.36 g, 8.98 mmol) were combined in toluene (40 mL) with stirring at 25 °C. The mixture was stirred and heated to 105 °C for 2 h. LC-MS showed that the desired product had been obtained. The mixture was concentrated to give a red solid (3.0 g). The product was purified by chromatography (SiO column) using a gradient of 0-30% EtOAc in PE. The first batch of product (0.8 g) was combined with the second (790 mg) and third batches (820 mg) and further purified by SFC (DAICEL CHIRALPAK AD-10 μm, 30 mm × 250 mm column) using a mobile phase of CO and 35% Neu-ACN to give the title compound as a pale yellow solid (1.8 g, 69%). 1 H NMR (400 MHz, CDCl3) δ ppm 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.

[0232] Preparation 58: 4'-chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine] [ka]

[0233] Preparation 59: 1'-chloro-4'-(2-(methoxymethoxy)-4-methylphenyl)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine] [ka]

[0234] 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 HO (0.75 mL) was added CsCO (1.13 g, 3.46 mmol) and Pd(dppf)Cl (70.68 mg, 86.55 μmol) in one portion. The mixture was stirred at 100 °C for 1 h. LC-MS indicated that the desired product had been obtained. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (ISCO® SepaFlash® 12 g silica gel column) using a gradient of 0 to 30% EtOAc in PE (25 mL / min). The title compound of Preparation 58 was obtained as a white solid (42 mg, 14% yield, 96.99% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.15 - 1.28 (m, 2 H), 2.05 (br s, 1 H), 2.23 - 2.33 (m, 1 H), 2.42 (s, 3 H), 2.53 (br d, J=17.73 Hz, 1 H), 2.92 - 3.08 (m, 1 H), 3.38 (s, 3 H), 3.78 - 4.00 (m, 2 H), 5.11 (br d, J=4.89 Hz, 2 H), 6.97 (d, J=7.70 Hz, 1 H), 7.07 (s, 1 H), 7.18 (d, J=7.58 Hz, 1 H);ESI-MS m / z [M+H] + 347.0. Obtain the title compound of Preparation 59 as a yellow oil (55 mg, 16% yield, 85% purity). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 - 1.06 (m, 4 H), 2.40 (s, 3 H), 2.99 - 3.08 (m, 2 H), 3.38 (s, 3 H), 4.06 (q, J=6.28 Hz, 2 H), 5.02 - 5.14 (m, 2 H), 6.87 (d, J=7.70 Hz, 1 H), 6.98 - 7.04 (m, 2 H);ESI-MS m / z [M+H] + 347.0.

[0235] 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] [ka]

[0236] 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-(2-(methoxymethoxy)-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (782.41 mg, 2.81 mmol) in dioxane (5 mL) and HO (1 mL) was added CsCO (2.82 g, 8.66 mmol) and Pd(dppf)Cl.CHCl (176.70 mg, 216.38 μmol). The mixture was stirred at 80 °C for 1 h under N. LC-MS indicated that the desired product had been obtained. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (ISCO® SepaFlash® 24 g silica gel column) using a gradient of 0-30% EtOAc in PE (35 mL / min) to give a mixture of the title compounds as a yellow oil (416 mg). 1H NMR (400 MHz, CDCl3) δ ppm 0.40 - 0.60 (m, 1 H), 0.65 - 0.77 (m, 1 H), 0.84 - 1.08 (m, 2 H), 2.23 - 2.38 (m, 1 H), 2.43 (s, 3 H), 2.79 - 3.11(m, 1 H), 3.39 (d, J=10.0 Hz, 3 H), 4.28 - 4.52 (m, 1 H), 4.77 (br d, J=2.3 Hz, 1 H), 5.11 (d, J=5.6 Hz, 2 H), 6.99 (d, J=7.5 Hz, 1 H), 7.08 (s, 1 H), 7.23 (d, J=7.6 Hz, 1 H).

[0237] Preparation 62: 1,4-Dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine [ka]

[0238] To a flask charged with toluene (100 mL) were 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 h. The solvent was removed by rotary evaporation, and the mixture was transferred to a flask charged 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 h. The reaction mixture was concentrated and then purified by flash chromatography (ISCO® SepaFlash® 80 g silica gel column) using an eluent of 100% DCM (24 mL / min) to provide the title compound.

[0239] Preparation 63: 5-chloro-2-(4-chloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)phenol [ka]

[0240] Preparation 64: 5-chloro-2-(1-chloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)phenol [ka]

[0241] A mixture of 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (1500 mg, 6.5 mmol), CsCO (4.2 g, 13.0 mmol), Pd(dppf)Cl.CHCl (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 at 100 °C in a sealed tube on a metal heating block for 30 min. The reaction mixture was purified by flash chromatography (ISCO SepaFlash 40 g silica gel column) using an eluent of 50% EtOAc in heptane (24 mL / min) to give the two title compounds.

[0242] 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] [ka]

[0243] Preparation 66: rac-1'-chloro-4'-(2-(methoxymethoxy)-4-methoxyphenyl)-4,5,5',8'-tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazine] [ka]

[0244] Step 1: tert-butyl-(2,6-dioxaspiro[4.5]dec-8-en-9-yloxy)dimethylsilane [ka]

[0245] To a mixture of 2,6-dioxaspiro[4.5]decan-9-one (1.00 g, 6.40 mmol) and triethylamine (13 mL, 12.8 mmol) in DCM (16 mL) cooled to 0 °C, tert-butyldimethylsilyl trifluoromethanesulfonate (1.5 mL, 6.72 mmol) was added dropwise. The mixture was stirred at room temperature overnight, then treated with water and extracted with DCM. The organic phase was washed with water and brine, dried over MgSO4, and concentrated to give the title compound as a brown oil (crude). ESI-MS [M+H] + C 14 H 26 Calculated value for O3Si: 270.17, measured value: 271.28.

[0246] Step 2: 1',4'-Dichloro-4,5,5',8'-tetrahydro-2H-spiro[furan-3,7'-pyrano[3,4-d]pyridazine] [ka]

[0247] 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 give the title compound (0.604 g, 42%). ESI-MS [M+H] + C 10 H 10 Calculated value for Cl2N2O2: 260.01, found value: 261.1.

[0248] 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]

[0249] A mixture of 1,4-dichlorospiro[5,8-dihydropyrano[3,4-d]pyridazine-7,3'-tetrahydrofuran] (374 mg, 1.43 mmol), CsCO (898 mg, 2.75 mmol), 2-(2-(methoxymethoxy)-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (306 mg, 1.10 mmol), Pd(dppf)Cl (90 mg, 0.110 mmol), 1,4-dioxane (6 mL), and water (1.5 mL) was purged with nitrogen for 5 minutes and then heated at 90 °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 MgSO, and concentrated. The residue was purified on a normal-phase silica gel column (80 g) using a heptane / EtOAc gradient (20% to 70%). Concentration of the product-containing fractions gave the two title compounds. Preparation 65 (123 mg, 29%), ESI-MS [M+H] + C 19 H 21 Calculated for ClN2O4 376.12, found 377.3, and preparation 66 (17 mg, 4%), ESI-MS [M+H] + C 19 H 21 Calculated for ClN2O4: 376.12, found: 377.3.

[0250] 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 [ka]

[0251] 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 KPO (3.03 g, 14.28 mmol), BTMPO (300.07 mg, 714.04 μmol), and CuI (181.32 mg, 952.06 μmol). The mixture was stirred at 120 °C for 48 h under N. LC-MS showed that 52% of the desired mass was detected. The reaction was filtered and evaporated to dryness. The residue was purified by preparative HPLC (Xtimate C18-10 μm, 40 mm × 150 mm column) using a gradient of 0-26% ACN in water (containing formic acid) to give the mixture of title compounds as a black solid (420 mg, crude). ESI-MS [M+H] + C 15 H 20 Calculated for ClFN4O: 326.13, measured: 327.1.

[0252] Preparation 69: 1,4-Dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine [ka]

[0253] 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 30 minutes. The solvent was removed by rotary evaporation, and the mixture was then transferred to a flask charged with 3,6-dichloro-1,2,4,5-tetrazine (2991 mg, 19.8 mmol) and toluene (100 mL). The reaction was heated to 120° C. and stirred for 30 minutes. The reaction mixture was concentrated and purified by flash chromatography (ISCO® SepaFlash® 80 g silica gel column) eluting with DCM (24 mL / min) to provide the title compound.

[0254] Preparation 70: 4-chloro-1-(2-(methoxymethoxy)-4-(methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine [ka]

[0255] Preparation 71: 1-chloro-4-(2-(methoxymethoxy)-4-(methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine [ka]

[0256] A mixture of 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (600 mg, 2.6 mmol), CsCO (1.69 g, 5.19 mmol), Pd(dppf)Cl.CHCl (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 at 100 °C in a sealed tube on a metal heating block for 1 h. The reaction mixture was purified by flash chromatography (ISCO® 40 g SepaFlash® silica gel column) eluting with 50% EtOAc in heptane (24 mL / min) to give the two title compounds.

[0257] Preparation 72: (5R,8S)-1,4-Dichloro-5,7,8,9-tetrahydro-5,8-epoxyoxepino[3,4-d]pyridazine [ka]

[0258] Toluene (100 mL) was added to a flask containing dihydrolevoglucosenone (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 30 minutes. The solvent was removed by rotary evaporation, and the mixture was transferred to a flask charged with 3,6-dichloro-1,2,4,5-tetrazine (2991 mg, 19.8 mmol) and toluene (100 mL). The reaction was heated to 120° C. and stirred for 30 minutes. The reaction mixture was concentrated and purified by flash chromatography (ISCO® 80 g SepaFlash® silica gel column) eluting with DCM (24 mL / min) to provide the title compound.

[0259] Preparation 73: 2-((5R,8S)-4-chloro-5,7,8,9-tetrahydro-5,8-epoxyoxepino[3,4-d]pyridazin-1-yl)-5-methylphenol [ka]

[0260] Preparation 74: 2-((5R,8S)-1-chloro-5,7,8,9-tetrahydro-5,8-epoxyoxepino[3,4-d]pyridazin-4-yl)-5-methylphenol [ka]

[0261] A mixture of 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (900 mg, 3.9 mmol), CsCO (3.1 g, 9.65 mmol), Pd(dppf)Cl.CHCl (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 at 100 °C in a sealed tube on a metal heating block for 1 h. The reaction mixture was purified by flash chromatography (ISCO® 40 g SepaFlash® silica gel column) eluting with 50% EtOAc in heptane (24 mL / min) to give the two title compounds.

[0262] Preparation 75: 4-chloro-1-(2-fluoro-6-(methoxymethoxy)-4-(methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine [ka]

[0263] Preparation 76: 1-chloro-4-(2-fluoro-6-(methoxymethoxy)-4-(methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine [ka]

[0264] 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 KPO (0.56 mL) was stirred at 100 °C for 1 h in a sealed tube on a metal heating block. The reaction mixture was purified by flash chromatography (ISCO® 40 g SepaFlash® silica gel column) eluting with 50% EtOAc in heptane (24 mL / min) to give the two title compounds.

[0265] Preparation: 77: 1,4-Dichloro-5,6,7,8-tetrahydro-5,8-epoxyphthalazine [ka]

[0266] A solution of rac-(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. Next, 3,6-dichloro-1,2,4,5-tetrazine (296 mg, 1.96 mmol) was added in small portions. The reaction mixture was stirred at 120 °C for 2 hours and then concentrated under reduced pressure. The residue was purified by flash column chromatography (ISCO® 24 g RediSep® Gold column) using a gradient of 0 to 100% EtOAc in heptane to give the title compound (25 mg, 6.5%) as an off-white solid.

[0267] Preparation: 78: 2-(4-chloro-5,6,7,8-tetrahydro-5,8-epoxyphthalazin-1-yl)-5-methylphenol [ka]

[0268] A mixture of 1,4-dichloro-5,6,7,8-tetrahydro-5,8-epoxyphthalazine (21.6 mg, 0.1 mmol), CsCO (65 mg, 0.2 mmol), Pd(dppf)Cl.CHCl (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 at 100 °C in a sealed tube on a metal heating block for 1 h. The reaction mixture was purified by flash chromatography (ISCO® 40 g SepaFlash® silica gel column) eluting with 50% EtOAc in heptane (24 mL / min) to give the two title compounds.

[0269] Preparation 79: 1,4-Dichlorospiro[5,7-dihydropyrano[3,4-d]pyridazine-8,1'-cyclopropane] [ka]

[0270] Step 1: Methyl 1-((prop-2-yn-1-yloxy)methyl)cyclopropane-1-carboxylate [ka]

[0271] 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 min and then at 60° C. for 5 h. TLC (PE / EtOAc = 3:1, R f = 0.6 for the desired product), indicating complete consumption of the starting alcohol. The mixture was quenched with HO (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (ISCO® 40 g SepaFlash® silica gel column) using a gradient of 0-20% EtOAc in PE (45 mL / min) to afford the title compound as a white solid (3.6 g, 56%). 1 H NMR (400 MHz, CDCl3) δ ppm 0.89 - 0.97 (m, 2 H), 1.25 - 1.32 (m, 2 H), 2.42 (t, J=2.32 Hz, 1 H), 3.65 - 3.70 (m, 5 H), 4.19 (d, J=2.32 Hz, 2 H).

[0272] Step 2: 1-((prop-2-yn-1-yloxy)methyl)cyclopropane-1-carboxylic acid [ka]

[0273] To a solution of ethyl 1-(prop-2-ynoxymethyl)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 h. TLC (PE / EtOAc = 3:1, Rf = 0.3 for the desired product) indicated complete consumption of the starting ester. The reaction mixture was acidified with 2 M HCl at 0 °C to pH = 5-6 and extracted with EtOAc (30 × 5 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound as a colorless oil (8.4 g, 89% yield, 90% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 0.83 - 0.88 (m, 2 H), 1.05 - 1.09 (m, 2 H), 3.38 - 3.44 (m, 1 H), 3.54 (s, 2 H), 4.11 (d, J=2.20 Hz, 2 H), 12.16 (br s, 1 H).

[0274] Step 3: 1-[(3,6-dichloropyridazin-4-yl)methoxymethyl]cyclopropanecarboxylic acid [ka]

[0275] To a solution of 1-(prop-2-ynoxymethyl)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 h. TLC (PE / EtOAc = 1:1, Rf = 0.4 for the desired product) indicated complete consumption of the starting acid. The mixture was concentrated in vacuo. The residue was purified by flash chromatography (ISCO® 20 g SepaFlash® silica gel column) eluting with a gradient of 0 to 50% EtOAc in PE (40 mL / min) to give the title compound as a red solid (500 mg, 27.8%). 1H NMR (400 MHz, CDCl3) δ ppm 0.99 - 1.13 (m, 2 H), 1.38 - 1.54 (m, 2 H), 3.77 (s, 2 H), 4.60 (s, 2 H), 7.82 (s, 1 H).

[0276] Step 4: 1,4-Dichlorospiro[5,7-dihydropyrano[3,4-d]pyridazine-8,1'-cyclopropane] [ka]

[0277] To a solution of 1-[(3,6-dichloropyridazin-4-yl)methoxymethyl]cyclopropanecarboxylic acid (2 g, 7.22 mmol) in ACN (80 mL) and HO (80 mL) was added silver nitrate (4.11 g, 24.19 mmol) at 25 °C. Sulfuric acid (1 M, 21.65 mL) and peroxydisulfuric acid, ammonium salt (1.6 M, 13.53 mL) were added. The mixture was stirred at 70 °C for 2 h. LC-MS showed that the desired mass was detected. The mixture was cooled to room temperature, poured into ice-cold saturated aqueous NaHCO (50 mL), filtered, and then extracted with DCM (50 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (ISCO® 20 g SepaFlash® silica gel column) using a gradient of 0-10% EtOAc in PE (45 mL / min) to afford the title compound as a white solid (290 mg, 17.4%). 1 H NMR (400 MHz, CDCl3) δ ppm 0.90 - 1.00 (m, 2 H), 2.16 - 2.24 (m, 2 H), 3.63 (s, 2 H), 4.82 (s, 2 H).

[0278] 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 [ka]

[0279] 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 [ka]

[0280] The starting materials 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 placed in a microwave tube in NMP (5 mL). The sealed tube was heated in a microwave reactor at 180 °C for 3 h. LC-MS showed that the desired mass was detected. The mixture was purified by preparative HPLC (Boston Green ODS-5 μm, 30 mm × 150 mm column) using a gradient of 21–61% ACN in water (with formic acid). The crude product was purified by flash chromatography (ISCO® 10 g SepaFlash® silica gel column) using a gradient of 0-10% EtOAc in PE (30 mL / min) to give the title compound of Preparation 80 as a yellow solid (70 mg). 1 H NMR (400 MHz, CDCl3) δ ppm 0.88 - 0.97 (m, 2 H), 1.16 - 1.58 (m, 4 H), 1.65 - 1.87 (m, 4 H), 2.06 - 2.25 (m, 2 H), 3.37 - 3.47 (m, 1 H), 3.59 (q, J=11.78 Hz, 2 H), 3.97 - 4.12 (m, 1 H), 4.20 - 4.31 (m, 1 H), 4.72 - 4.76 (m, 2 H);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 (400 MHz, CDCl3) δ ppm 0.74 - 0.92 (m, 2 H), 1.21 - 1.51 (m, 4 H), 1.70 - 1.81 (m, 2H), 2.01 - 2.19 (m, 4H), 3.48 - 3.53 (m, 2H), 3.56 - 3.68 (m, 1 H), 3.94 - 4.10 (m, 1 H), 4.33 (br d, J=5.26 Hz, 1 H), 4.53 - 4.76 (m, 2 H);ESI-MS m / z [M+H] + 310.1.

[0281] 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] [ka]

[0282] To a mixture of 1',4'-dichloro-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[3,4-d]pyridazine] (310 mg, 1.34 mmol) in dioxane (4 mL) and water (1 mL) was added 2-(2-(methoxymethoxy)-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (373.15 mg, 1.34 mmol), Pd(dppf)Cl.CHCl (219.11 mg, 268.31 μmol), and CsCO (1.75 g, 5.37 mmol). The mixture was stirred at 100 °C for 1 h under N. LC-MS showed that the desired mass was detected. The mixture was quenched with HO (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (ISCO® 10 g SepaFlash® silica gel column) using a gradient of 0 to 10% EtOAc in PE (30 mL / min) to give a mixture of the two title compounds as a yellow solid (280 mg).

[0283] Preparation 83: 1,4-Dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine [ka]

[0284] Step 1: 1-(8-oxabicyclo[3.2.1]oct-2-en-3-yl)pyrrolidine [ka]

[0285] To a solution of 8-oxabicyclo[3.2.1]octan-3-one (21 g, 166.45 mmol) in toluene (800 mL) were 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 h and then heated to reflux in a Dean-Stark apparatus for 0.5 h to remove water. TLC (PE / EtOAc = 3:1) showed complete consumption of the starting material and the formation of one new spot. The reaction mixture was concentrated under reduced pressure to give the title compound as a red solid (28 mg, crude).

[0286] Step 2: 1,4-Dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine

[0287] 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 h. TLC (PE / EtOAc = 3:1) indicated complete consumption of the starting material and formation of the desired product. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash chromatography (ISCO®) on a 330 g SepaFlash® silica gel column using a gradient of 0 to 25% EtOAc in PE (80 mL / min) to give the crude product (36 g). The crude product was recrystallized from EtOAc (600 mL) and PE (2400 mL) to give the title compound as a white solid (21 g, 78% yield, 100% purity). 1H NMR (400 MHz, CDCl3) δ ppm 1.54 - 1.80 (m, 1 H), 1.94 - 2.06 (m, 1 H), 2.15 - 2.33 (m, 2 H), 2.41 (d, J=18.51 Hz, 1 H), 3.10 (m, 1 H), 4.74 - 4.91 (m, 1 H), 5.17 (d, J=6.25 Hz, 1 H);ESI-MS m / z [M+H] + 230.0.

[0288] 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 [ka]

[0289] 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 [ka]

[0290] 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 placed in a microwave tube in NMP (8 mL). The sealed tube was heated in a microwave reactor at 180 °C for 3 h. LC-MS showed that the starting material was completely consumed and one main peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash chromatography (ISCO® 40 g SepaFlash® silica gel column) using a gradient of 0-10% MeOH / DCM (35 mL / min) to give a mixture of stereoisomers as a colorless oil (1.2 g, crude with NMP). The stereoisomers were separated by chiral SFC (DAICEL CHIRALPAK® AD-10 μm, 30 mm × 250 mm column) using a mobile phase of CO and 40% iPrOH (with 0.1% NH3OH). The title compound of Preparation 84 was obtained as a white solid (180 mg, 13.4%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.21 - 1.27 (m, 3 H), 1.62 - 1.72 (m, 3 H), 1.89 - 2.20 (m, 6 H), 2.90 (m, 1 H), 3.41 - 3.54 (m, 2 H), 3.79 - 3.90 (m, 1 H), 4.55 (d, J=5.00 Hz, 1 H), 4.74 (br t, J=5.82 Hz, 1 H), 5.18 (d, J=6.13 Hz, 1 H), 6.05 (d, J=7.50 Hz, 1 H);ESI-MS m / z [M+H] + 309.12. Obtain the title compound of Preparation 85 as a white solid (130 mg, 9.22%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (br d, J=8.50 Hz, 3 H), 1.64 - 1.79 (m, 3 H), 1.83 - 2.22 (m, 6 H), 2.96 (m, 1 H), 3.47 - 3.59 (m, 2 H), 3.84 - 3.98 (m, 1 H), 4.69 - 4.83 (m, 2 H), 5.23 (d, J=6.25 Hz, 1 H), 6.15 (br d, J=7.63 Hz, 1 H);ESI-MS m / z [M+H] + 309.12.

[0291] Preparation 86: 4-chloro-1-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine [ka]

[0292] 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 HO (5 mL) in dioxane (20 mL) was degassed and purged with N (3×), then stirred at 100 °C under N atmosphere for 1 h. LC-MS showed complete consumption of the starting material, with one main peak having the desired mass. The residue was diluted with HO (100 mL) and extracted with 80 mL of EtOAc (80 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give 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 NHHO + NHHCO) over 36 min to give the title compound as a white solid (1.3 g, crude). The crude product was further purified by SFC (REGIS(S,S)WHELK-O® 1-5 μm, 30 mm × 250 mm column) using a mobile phase of CO and 45% EtOH (containing 0.1% NHOH) to give the title compound as a white solid (600 mg, 24.8%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.67 - 0.81 (m, 2 H), 0.96 - 1.10 (m, 3 H), 1.51 - 1.71 (m, 1 H), 1.90 - 2.25 (m, 5 H), 3.17 - 3.24 (m, 3 H), 4.62 - 4.78 (m, 1 H), 5.07 - 5.26 (m, 3 H), 6.72 - 6.88 (m, 1 H), 6.92 - 7.02 (m, 1 H), 7.11 - 7.24 (m, 1 H);ESI-MS m / z [M+H] + 372.9.

[0293] 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 [ka]

[0294] 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 [ka]

[0295] The title compound was synthesized analogously to Preparation 86.

[0296] Preparation 89: 2-(4-chloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol [ka]

[0297] Preparation 90: 2-(1-chloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-4-yl)-5-(trifluoromethoxy)phenol [ka]

[0298] The title compound was synthesized analogously to Preparation 86.

[0299] Preparation 91: 4'-chloro-1'-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] [ka]

[0300] To a 20 mL vial was added 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)Cl.CHCl (106 mg, 0.130 mmol), and tripotassium tris(hydrogen phosphate) (554 mg, 2.60 mmol) in 1,4-dioxane (9.2784 mL) and water (2.3196 mL) under nitrogen. The reaction was heated to 80 °C and allowed to stir overnight. The reaction mixture was allowed to cool to room temperature and extracted with EtOAc (2 × 20 mL) and water (20 mL). The organics were dried over MgSO4 and filtered. The solution was concentrated, dissolved in toluene (2 mL), and purified by flash chromatography using a gradient of 0 to 50% EtOAc in heptane to give the title compound (120 mg, 23.1%) as the first eluting compound. 1 H NMR (400 MHz, CDCl3) δ ppm 0.46 - 0.53 (m, 2 H), 0.90 - 1.05 (m, 2 H), 2.29 (m,1 H), 2.95 (m, 1 H), 3.38 (s, 3 H), 4.75 (m, 2 H), 5.15 (br s, 2 H), 7.38 - 7.48 (m, 2 H), 7.51 (s, 1 H);ESI-MS m / z [M+H] + C 18 H 16 Calculated value for ClF3N2O3: 400.08, measured value: 401.0.

[0301] Preparation 92: 2-(4'-chloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-1'-yl)-5-(trifluoromethyl)phenol [ka]

[0302] To a 20 mL vial was added 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (220 mg, 0.952 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (196 mg, 0.952 mmol), Pd(dppf)Cl.CHCl (78 mg, 0.0952 mmol), and tripotassium tris(hydrogen phosphate) (406 mg, 1.90 mmol) in 1,4-dioxane (6.8041 mL) and water (1.701 mL) under nitrogen. The reaction was heated to 80 °C and allowed to stir overnight. The reaction mixture was allowed to cool to room temperature and extracted with EtOAc (2 × 20 mL) and water (20 mL). The organics were dried over MgSO and filtered. The solution was concentrated onto silica gel and purified by flash chromatography using a gradient of 0-50% EtOAc in heptane to give the title compound as the first eluting compound (71 mg, 20.9%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.43 - 0.61 (m, 2 H), 0.78 - 0.91 (m, 2 H), 2.66 (s, 2 H), 4.74 (s, 2 H), 7.18 - 7.36 (m, 2 H), 7.51 (d, J=8.03 Hz, 1 H), 10.73 (s, 1 H);ESI-MS m / z [M+H] + C 16 H 12 Calculated value for ClF3N2O2: 356.05, measured value: 357.0.

[0303] 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] [ka]

[0304] 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] [ka]

[0305] 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), potassium phosphate tripotassium (328 mg, 1.54 mmol), and Pd(dppf)Cl.CHCl (31.4 mg, 0.038 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 min. The reaction mixture was heated to 100 °C in a microwave reactor and stirred for 3 h. The reaction was quenched with saturated aqueous NH4Cl, and the mixture was extracted with DCM. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® 120 g SepaFlash® silica gel column) using a gradient of 0-50% EtOAc in heptane (40 mL / min). The title compound of Preparation 93 was obtained as a pale yellow oil (97.6 mg, 34%). ESI-MS m / z [M+H] + C 20 H 21 Calculated for ClN2O3 372.1, found 373.1. The title compound of Preparation 94 was obtained as a white solid (77.9 mg, 27%). ESI-MS m / z [M+H] + C 20 H 21 Calculated value for ClN2O3: 372.1, measured value: 373.1.

[0306] Preparation 95: (1R,2R)-2-((1'-chloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)amino)cyclopentan-1-ol [ka]

[0307] 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 for 1 h on high absorption in a microwave reactor. The reaction mixture was diluted with HO (200 mL) to give a brown solution. The crude product was extracted with EtOAc (2 × 200 mL). The organic extracts were combined, dried over NaSO, filtered, rinsed with EtOAc, and concentrated by rotary evaporation to give the crude product as a brown oil (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 (RediSep® Rf Gold 330 g silica gel column) using a gradient of 0 to 100% EtOAc in heptane. The initial fractions were combined, concentrated by rotary evaporation, and dried in vacuo to give the title compound as a yellow-orange oil (crude). The oil was dissolved in iPrOAc (5 mL) under reflux and cooled to room temperature. The resulting solid was filtered, rinsed with iPrOAc (3 × 1 mL), and dried in vacuo to give the title compound as an off-white solid (115.6 mg, 4.5%). The filtrate and mixed fractions were combined and purified by medium-pressure chromatography using a gradient of 1 to 100% EtOAc in heptane. The initial fractions were combined, concentrated by rotary evaporation, and dried in vacuo to give a second crop of the title compound as a white solid (340.0 mg, 13.3%). 1H NMR (400 MHz,DMSO-d6) δ ppm 0.54 - 0.72 (m,2 H),0.75 - 0.93 (m,2 H),1.40 - 1.55 (m,2 H),1.57 - 1.74 (m, 2 H), 1.86 (ddt. (quintet, J=6.40 Hz,1 H),4.37 - 4.52 (m,2 H),4.80 - 4.87 (m,1 H),6.01 (d, J=6.27Hz, 1H), ESI-MS [M+H] + C 14 H 18 Calculated value for ClN3O2: 295.11, found value: 296.1.

[0308] 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] [ka]

[0309] The title compound was synthesized analogously to Preparation 86.

[0310] 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] [ka]

[0311] The title compound was synthesized analogously to Preparation 86.

[0312] Preparation 98: 2-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0313] Step 1: 4-Bromo-3-(methoxymethoxy)benzaldehyde [ka]

[0314] To a solution of 4-bromo-3-hydroxy-benzaldehyde (5 g, 24.87 mmol) in THF (80 mL) was added NaH (1.09 g, 27.36 mmol, 60% purity) at 20 °C. After stirring for 15 min, bromo(methoxy)methane (3.11 g, 24.87 mmol, 2.03 mL) was added to the reaction at 20 °C. The mixture was stirred at 20 °C for 2 h. TLC (PE / EtOAc = 5:1) showed that the starting material was completely consumed and one new spot was formed. The reaction solution was diluted with aqueous NH Cl (100 mL), stirred for 15 min, and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure to give the title compound as a colorless oil (6.1 g, 90% yield, 90% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 3.54 (s,3 H),5.34 (s,2 H),7.40 (dd,J=8.07,1.31 Hz,1 H),7.64 (d,J =1.25Hz,1H),7.74(d,J=8.13Hz,1H),9.95(s,1H).

[0315] Step 2: 1-Bromo-4-(difluoromethyl)-2-(methoxymethoxy)benzene [ka]

[0316] 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 h. TLC (PE / EtOAc = 5:1) showed complete consumption of the starting material and the formation of two new spots. The reaction mixture was diluted with NH4Cl (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® 120 g SepaFlash® silica gel column) using a gradient of 0 to 3% EtOAc in PE (70 mL / min). The title compound was obtained as a colorless oil (6.1 g, 91% yield, 90% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 3.53 (s, 3 H), 5.28 (s, 2 H), 6.38 - 6.77 (m, 1 H), 7.04 (d, J=7.88 Hz, 1 H), 7.29 (s, 1 H), 7.63 (d, J=8.25 Hz, 1 H).

[0317] Step 3: 2-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0318] 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-dioxaborolane (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 h. TLC (PE / EtOAc = 10:1) showed complete consumption of the limited reactant and the formation of two new spots. 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 × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® 12 g SepaFlash® silica gel column) using a gradient of 0 to 2% EtOAc in PE (30 mL / min) to give the title compound as a colorless oil (400 mg, 43.7% yield, 90% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 1.36 (s, 12 H), 3.52 (s, 3 H), 5.23 (s, 2 H), 6.43 - 6.78 (m, 1 H), 7.11 - 7.19 (m, 2 H), 7.76 (d, J=7.50 Hz, 1 H).

[0319] Preparation 99: 4'-chloro-1'-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] [ka]

[0320] 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 HO (0.9 mL) was degassed and purged with N (3×), then stirred at 80 °C for 12 h under a N atmosphere. TLC (PE / EtOAc = 3:1) showed complete consumption of the starting material and the formation of two new spots. The reaction mixture was diluted with HO (5 mL) and extracted with DCM (5 mL × 3). The combined organic layers were washed with brine (5 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® 4 g SepaFlash® silica gel column) using a gradient of 0–10% EtOAc in PE (30 mL / min), followed by SFC (DAICEL CHIRALPAK® IK-10 μm, 50 mm × 250 mm column) using a mobile phase of CO and 15% MeOH (containing 0.1% NH3OH). The title compound was obtained as a white solid (12 mg, 19% yield, 95% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 0.36 - 0.65 (m, 2 H), 0.96 (br d, J=18.76 Hz, 2 H), 2.28 (br d, J=16.88 Hz, 1 H), 2.96 (br d, J=17.01 Hz, 1 H), 3.37 (s, 3 H), 4.75 (br d, J=16.13 Hz, 2 H), 5.14 (br d, J=5.13 Hz, 2 H), 6.52 - 6.83 (m, 1 H), 7.29 (br d, J=7.88 Hz, 1 H), 7.40 (s, 1 H).

[0321] Preparation 100: 2-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0322] To a mixture of 1-cyclopropyl-3-(methoxymethoxy)benzene (2 g, 11.22 mmol) and TMEDA (2.74 g, 23.57 mmol, 3.56 mL) in THF (20 mL) was added n-BuLi (2.5 M in n-hexane) (2.5 M, 9.43 mL) in one portion at 0 °C under N. The mixture was stirred at 10 °C for 1 h, then cooled to -78 °C, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.59 g, 24.69 mmol, 5.04 mL) was added. The mixture was stirred at 10 °C for 12 h. TLC (PE / EtOAc = 10:1) showed complete consumption of the starting material and the formation of three new spots. The reaction mixture was quenched with aqueous NH4Cl (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® 12 g SepaFlash® silica gel column) using a gradient of 0-5% EtOAc 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 gradient of 1-17% EtOH in hexanes. The title compound was obtained as a colorless oil (1.48 g, 39% yield, 90% purity). 1H NMR (400 MHz, CDCl3) δ ppm 0.66 - 0.77 (m, 2 H), 0.93 - 1.03 (m, 2 H), 1.34 (s, 12 H), 1.84 - 1.92 (m, 1 H), 3.53 (s, 3 H), 5.19 (s, 2 H), 6.70 (dd, J=7.63, 1.38 Hz, 1 H), 6.77 (d, J=1.25 Hz, 1 H), 7.60 (d, J=7.63 Hz, 1 H).

[0323] Preparation 101: 4'-chloro-1'-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] [ka]

[0324] 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 HO (1 mL) was added CsCO (2.82 g, 8.66 mmol), followed by Pd(dppf)Cl (316.65 mg, 432.75 μmol). The mixture was stirred at 100 °C under N for 12 h. LC-MS showed complete consumption of the starting material and the detection of a new peak. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® 4 g SepaFlash® silica gel column) using a gradient of 0 to 20% EtOAc in PE (30 mL / min) to give the crude product (350 mg). The product was purified by SFC (DAICEL CHIRALPAK® AD-H-5 μm, 30 mm × 250 mm column) using a mobile phase of CO2 and 30% EtOH (containing 0.1% NH3OH). The title compound was obtained as a yellow solid (109 mg, 13.1% yield, 96.7% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 0.41 - 0.58 (m, 2 H), 0.76 (br d, J=1.4 Hz, 2 H), 0.91 - 1.10 (m, 4 H), 1.59 - 1.76 (m, 1 H), 1.88 - 1.99 (m, 1 H), 2.90 - 3.10 (m, 1 H), 3.36 (br s, 3 H), 4.74 (br d, J=1.8 Hz, 2 H), 5.09 (br s, 2 H), 6.81 (br d, J=7.6 Hz, 1 H), 6.99 (br s, 1 H), 7.21 (br d, J=7.6 Hz, 1 H).

[0325] 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] [ka]

[0326] 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 [ka]

[0327] 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)Cl.CHCl (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 MgSO, and concentrated. The residue was purified by silica column eluting with heptane / EtOAc (9:1 to 0:1). The combined fractions were concentrated to give the title compound (222 mg, 70%). ESI-MS m / z [M+H] + C 16 H 11 Calculated value for ClF4N2O3: 390.0, measured value: 391.2.

[0328] 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]

[0329] 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 after 30 min, bromomethyl methyl ether (0.070 mL, 0.852 mmol) was added. The mixture was stirred at room temperature for 10 min, then treated with saturated NH4Cl and extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to give the crude compound, which was used without purification. ESI-MS m / z [M+H] + C 18 H 15 Calculated value for ClF4N2O4: 434.1, measured value: 435.0.

[0330] Preparation 103: 4'-chloro-1'-(2-fluoro-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazine] [ka]

[0331] Step 1: 1',4'-Dichloro-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazine] [ka]

[0332] A mixture of 4-oxaspiro[2.4]heptan-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). A solution of 3,6-dichloro-1,2,4,5-tetrazine (1178 mg, 7.80 mmol) in toluene (18 mL) was added 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 layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified on a 40 g silica gel column eluted with a heptane / EtOAc gradient (9:1 to 0:1). The combined fractions were concentrated to give the title compound (0.885 g, 45.7%). 1 H NMR (400 MHz,CD3OD) δ ppm 1.24 - 1.42 (m,2 H),1.54 - 1.72 (m,2 H),5.23 (s,2 H), ESI-MS m / z [M+H] + Calculated value for C8H6Cl2N2O: 216.0, found value: 217.0.

[0333] Step 2: 2-(4'-chloro-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazin]-1'-yl)-3-fluoro-5-(trifluoromethyl)phenol [ka]

[0334] 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)Cl.CHCl (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 MgSO, and concentrated. The residue was purified on a silica gel column (40 g) eluting with a heptane / EtOAc gradient (4:1 to 0:1). The combined fractions were concentrated to give the title compound (0.112 g, 26.9%). ESI-MS m / z [M+H] + C 15 Calculated value for H9ClF4N2O2: 360.0, found value: 361.1.

[0335] Step 3: 4'-chloro-1'-(2-fluoro-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazine]

[0336] A solution of 2-(4'-chloro-7'H-spiro[cyclopropane-1,5'-furo[3,4-d]pyridazin]-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, then treated with saturated NH4Cl and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4, and concentrated to give the title compound, which was used without further purification. ESI-MS m / z [M+H] + C17 H 13 Calculated value for ClF4N2O3: 404.1, measured value: 404.9.

[0337] Preparation 104: 1',4'-Dichloro-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] [ka]

[0338] Step 1: tert-butyldimethyl(1-(prop-2-yn-1-yl)cyclopropoxy)silane [ka]

[0339] To a solution of 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)acetaldehyde (11.5 g, 53.64 mmol) in MeOH (90 mL) were 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 h. TLC (PE / EtOAc = 10:1) showed that the starting material was completely consumed and one new spot was formed. The reaction mixture was quenched with aqueous NH4Cl (200 mL) and extracted with DCM (200 mL × 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® 330 g SepaFlash® silica gel column) using a gradient of 0 to 1% EtOAc in PE (100 mL / min) to afford the title compound as a colorless oil (5.3 mg, 44% yield, 95% purity). 1H NMR (400 MHz, CDCl3) δ ppm 0.10 - 0.14 (m, 6 H), 0.69 - 0.72 (m, 2 H), 0.73 (br s, 2 H), 0.86 (s, 9 H), 1.95 (t, J=2.44 Hz, 1 H), 2.59 (d, J=2.50Hz, 2H).

[0340] Step 2: 5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pent-3-yn-2-one [ka]

[0341] A 50 mL flame-dried flask was charged with tert-butyldimethyl(1-(prop-2-yn-1-yl)cyclopropoxy)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. After stirring the solution at -78 °C for 30 min, 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 h. TLC (PE / EtOAc = 20:1) showed complete consumption of the starting material and the formation of one new spot. The reaction mixture was poured into saturated aqueous NH4Cl (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 NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (ISCO® 220 g SepaFlash® silica gel column) using a gradient of 0 to 4% EtOAc in PE (100 mL / min) to afford the title compound as a colorless oil (15.24 g, 80.89% yield, 90% purity). 1H NMR (400 MHz, CDCl3) δ ppm 0.14 (s, 6 H), 0.68 (s, 2 H), 0.80 (s, 2 H), 0.87 (s, 9 H), 2.33 (s, 3 H), 2.73 (s, 2 H).

[0342] Step 3: 5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pent-3-yn-2-ol [ka]

[0343] To a solution of 5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pent-3-yn-2-one (15.24 g, 60.37 mmol) and cerium trichloride (19.35 g, 78.49 mmol, 4.93 mL) in MeOH (50 mL) at 25 °C was added NaBH (3.05 g, 80.62 mmol). The reaction mixture was stirred for 0.5 h. TLC (PE / EtOAc = 20:1) showed complete consumption of the starting material and the formation of one new spot. The mixture was poured into saturated aqueous NH Cl (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 Na SO , filtered, and concentrated in vacuo. The residue was purified by flash chromatography (ISCO® 80 g SepaFlash® silica gel column) using a gradient of 0 to 5% EtOAc in PE (75 mL / min) to afford the title compound as a colorless oil (12.8 g, 85.3% yield, 90% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 0.12 (s, 6 H), 0.62 - 0.69 (m, 2 H), 0.70 - 0.76 (m, 2 H), 0.86 (s, 9 H), 1.42 (d, J=6.50 Hz, 3 H), 2.60 (s, 2 H), 4.50 (q, J=6.50 Hz, 1H).

[0344] Step 4: 1-(5-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6-dichloropyridazin-4-yl)ethan-1-ol [ka]

[0345] 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 N (3x), then stirred at 100 °C under N atmosphere for 48 h. TLC (PE / EtOAc = 20:1) showed that starting material remained and two new spots had formed. The mixture was filtered. The filtrate was evaporated in vacuo to give a residue that was purified by flash chromatography (ISCO® 120 g SepaFlash® silica gel column) using a gradient of 0-10% EtOAc in PE (75 mL / min). The title compound was obtained as a brown oil (1.81 g, 18.6% yield, 90% purity). 1 NMR (400 MHz, CDCl3) δ ppm -0.13 (s, 3 H), -0.01 (s, 3 H), 0.56 - 0.66 (m, 1 H), 0.74 (s, 9 H), 0.83 (dt, J=11.16, 6.61 Hz, 1 H), 0.88 - 0.98 (m, 1 H), 1.13 - 1.21 (m, 1 H), 1.57 (d, J=6.75 Hz, 3 H), 2.80 (d, J=13.38 Hz, 1 H), 4.24 - 4.33 (m, 2 H), 5.44 (q, J=6.55 Hz, 1 H).

[0346] Step 5: 1-(5-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6-dichloropyridazin-4-yl)ethyl 4-methylbenzenesulfonate [ka]

[0347] 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 toluenesulfonyl chloride (5.46 g, 28.62 mmol). The mixture was stirred at 70 °C for 18 h. TLC (PE / EtOAc = 5:1) showed that starting material remained and two new spots had formed. The mixture was filtered. The filtrate was evaporated in vacuo, and the resulting residue was purified by flash chromatography (ISCO® 40 g SepaFlash® silica gel column) using a gradient of 0 to 10% EtOAc in PE (55 mL / min) to give the title compound as a colorless oil (4.54 g, 59.7% yield, 90% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 0.01 - 0.09 (m, 6 H), 0.36 - 0.49 (m, 1 H), 0.56 (br d, J=9.26 Hz, 1 H), 0.71 (s, 9 H), 0.82 - 0.94 (m, 2 H), 1.85 (d, J=6.88 Hz, 3 H), 2.39 (s, 3 H), 3.06 (br d, J=14.51 Hz, 1 H), 3.67 - 3.78 (m, 1 H), 6.15 (q, J=6.75 Hz, 1 H), 7.19 (m, J=8.13 Hz, 2 H), 7.56 (m, J=8.25 Hz, 2H).

[0348] Step 6: 1',4'-Dichloro-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] [ka]

[0349] 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 h. TLC (PE / EtOAc=20:1) showed that the starting material was completely consumed and one new spot was formed. The reaction was quenched with aqueous NH4Cl (10 mL) and extracted with DCM (10 mL × 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® 12 g SepaFlash® silica gel column) using a gradient of 0 to 8% EtOAc in PE (35 mL / min) to afford the title compound as a yellow oil (1.06 g, 51.5% yield, 95% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 0.49 (dd, J=10.26, 6.75 Hz, 1 H), 0.79 (dt, J=10.32, 6.22 Hz, 1 H), 0.87 - 0.95 (m, 1 H), 1.10 - 1.18 (m, 1 H), 1.65 (d, J=6.63 Hz, 3 H), 2.67 - 2.75 (m, 1 H), 2.96 - 3.02 (m, 1 H), 4.92 (q, J=6.63 Hz, 1 H).

[0350] Preparation 105: 4'-chloro-1'-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] [ka]

[0351] 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)Cl (89.56 mg, 122.40 μmol), and CsCO (797.58 mg, 2.45 mmol) in dioxane (3 mL) and HO (0.75 mL) was degassed and purged with N (3x), then stirred at 100 °C for 2 h under a N atmosphere. TLC (PE / EtOAc = 3:1) showed complete consumption of the starting material and the formation of one new spot. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® 4 g SepaFlash® silica gel column) using a gradient of 0 to 25% EtOAc in PE (30 mL / min) to give the title compound as a colorless oil (119 g, 44.5% yield, 95% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 0.16 - 0.41 (m, 1 H), 0.62 (dt, J=10.29, 6.24 Hz, 1 H), 0.77 - 0.94 (m, 1 H), 1.00 - 1.13 (m, 1 H), 1.21 - 1.31 (m, 1 H), 1.71 (br d, J=6.38 Hz, 3 H), 2.59 (br s, 1 H), 3.12 - 3.29 (m, 1 H), 3.39 (br s, 3 H), 4.99 (br s, 1 H), 5.09 - 5.22 (m, 2 H), 7.39 - 7.54 (m, 3H)

[0352] Preparation 106: 4'-chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] [ka]

[0353] 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)Cl (59.71 mg, 81.60 μmol), and CsCO (531.72 mg, 1.63 mmol) in dioxane (2 mL) and HO (0.5 mL) was degassed and purged with N (3×), then stirred at 100 °C for 2 h. LC-MS showed complete consumption of the starting material, with approximately 67% of the desired compound detected. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® 4 g SepaFlash® silica gel column) using a gradient of 0 to 20% EtOAc in PE (30 mL / min) to give the title compound (110 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.17 - 0.41 (m, 1 H), 0.61 (dt, J=10.2, 6.1 Hz, 1 H), 0.74 - 0.93 (m, 1 H), 0.99 -1.11 (m, 1 H), 1.71 (d, J=6.5 Hz, 3 H), 2.42 (s, 3 H), 2.52 - 2.77 (m, 1 H), 3.36 (s, 3 H), 4.95 - 5.04 (m, 1 H), 5.06 - 5.12 (m, 2 H), 6.97 (d, J=7.6 Hz, 1 H), 7.06 (s, 1 H), 7.20 - 7.26 (m, 1 H)

[0354] Preparation 107: 4'-chloro-1'-(4-chloro-2-(methoxymethoxy)phenyl)-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] [ka]

[0355] 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 HO (0.5 mL) was degassed and purged with N (3×), then stirred at 100 °C for 2 h. TLC (PE / EtOAc = 3:1) showed complete consumption of the starting material and the formation of three new spots. The reaction mixture was diluted with HO (4 mL) and extracted with EtOAc (4 mL × 3). The combined organic layers were washed with brine (4 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® 4 g SepaFlash® silica gel column) using a gradient of 0 to 12% EtOAc in PE (25 mL / min) to give the title compound as a yellow oil (70 mg, 41% yield, 90% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 0.14 - 0.43 (m, 1 H), 0.62 (dt, J=10.13, 6.32 Hz, 1 H), 0.74 - 0.91 (m, 1 H), 1.06 (dd, J=11.32, 5.69 Hz, 1 H), 1.70 (d, J=6.50 Hz, 3 H), 2.48 - 2.68 (m, 1 H), 3.38 (br s, 3 H), 4.88 - 5.04 (m, 1 H), 5.10 (br s, 2 H), 7.12 - 7.16 (m, 1 H), 7.28 (d, J=1.75Hz, 1H)

[0356] Preparation 108: 4'-chloro-1'-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] [ka]

[0357] 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)Cl (417.98 mg, 571.23 μmol), and CsCO (3.72 g, 11.42 mmol) in dioxane (18 mL) and HO (4.5 mL) was degassed and purged with N (3×), then stirred at 80 °C for 12 h. TLC (PE / EtOAc = 3:1) showed complete consumption of the starting material and the formation of two new spots. The reaction mixture was diluted with HO (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® 12 g SepaFlash® silica gel column) using a gradient of 0 to 10% EtOAc in PE (40 mL / min). The desired compound and its regioisomer were obtained as a white solid (455 mg, mixture). The mixture was purified by SFC (DAICEL CHIRALPAK® IK-10 μm, 50 mm × 250 mm column) using a mobile phase of CO and 15% MeOH (containing 0.1% NH3OH). The title compound (retention time: 4.189 min) was obtained as a white solid (131 mg, 50.9% yield, 99% purity). 1H NMR (400 MHz, CDCl3) δ ppm 0.36 - 0.65 (m, 2 H), 0.96 (br d, J=18.76 Hz, 2 H), 2.28 (br d, J=16.88 Hz, 1 H), 2.96 (br d, J=17.01 Hz, 1 H), 3.37 (s, 3 H), 4.75 (br d, J=16.13 Hz, 2 H), 5.14 (br d, J=5.13 Hz, 2 H), 6.52 - 6.83 (m, 1 H), 7.29 (br d, J=7.88 Hz, 1 H), 7.40 (s, 1 H). The regioisomer 1'-chloro-4'-(4-(difluoromethyl)-2-(methoxymethoxy)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (retention time: 4.496 min) was obtained as a white solid (138 mg, 52.5% yield, 97% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.71 (br s, 2 H), 0.86 (br s, 2 H), 2.94 (s, 2 H), 3.27 - 3.30 (m, 3 H), 4.19 - 4.59 (m, 2 H), 5.24 (br s, 2 H), 6.94 - 7.29 (m, 1 H), 7.37 (d, J=7.75 Hz, 1 H), 7.44 - 7.56 (m, 2 H).

[0358] Preparation 109: 4'-chloro-1'-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] [ka]

[0359] 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 HO (1 mL) was added CsCO (2.82 g, 8.66 mmol), followed by Pd(dppf)Cl (316.65 mg, 432.75 μmol). The mixture was stirred at 100 °C for 12 h under N. LC-MS showed complete consumption of the starting material, with approximately 42% of the desired compound detected. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® 4 g SepaFlash® silica gel column) using a gradient of 0 to 20% EtOAc in PE (30 mL / min). The title compound and its regioisomers were obtained as a white solid (350 mg total), which was purified by SFC (DAICEL CHIRALPAK® AD-H-5 μm, 30 mm × 250 mm column) using a mobile phase of CO and 30% EtOH (containing 0.1% NH3OH). The title compound (retention time: 6.793 min) was obtained as a yellow solid (109 mg, 13.1% yield, 96.7% purity). 1H NMR (400 MHz, CDCl3) δ ppm 0.41 - 0.58 (m, 2 H), 0.76 (br d, J=1.4 Hz, 2 H), 0.91 - 1.10 (m, 4 H), 1.59 - 1.76 (m, 1 H), 1.88 - 1.99 (m, 1 H), 2.90 - 3.10 (m, 1 H), 3.36 (br s, 3 H), 4.74 (br d, J=1.8 Hz, 2 H), 5.09 (br s, 2 H), 6.81 (br d, J=7.6 Hz, 1 H), 6.99 (br s, 1 H), 7.21 (br d, J=7.6 Hz, 1 H). The regioisomer 1'-chloro-4'-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (retention time: 7.772 min) was obtained as a red solid (90 mg, 10% yield, 91% purity). 1 H NMR (400 MHz, CDCl3) δ = 7.21 (d, J=7.8 Hz, 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 (br s, 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).

[0360] 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] [ka]

[0361] 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-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.61 g, 2.16 mmol), Xantphos Palladacycle G3 (205 mg, 0.216 mmol), and tripotassium tris(hydrogen phosphate) (1.38 g, 6.49 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL). The vial was flushed with nitrogen, and the reaction mixture was heated and stirred at 90 °C overnight. The reaction mixture was allowed to cool to room temperature and then extracted with EtOAc (2 × 20 mL) and brine (20 mL). The organics were dried over MgSO4 and filtered. The solution was concentrated and purified by flash chromatography using a gradient of 0-50% EtOAc in heptane to give the mixture of title compounds (54 mg, 0.0774 mmol, 3.58%). ESI-MS m / z [M+H] + C 18 H 15 Calculated value for ClF2N2O: 348.1; measured value: 349.1.

[0362] 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] [ka]

[0363] 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-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (567 mg, 2.16 mmol), Pd(dppf)Cl.CHCl (177 mg, 0.216 mmol), and tripotassium tris(hydrogen phosphate) (0.92 g, 4.33 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL). The vial was flushed with nitrogen, and the reaction mixture was heated and stirred at 80 °C overnight. The reaction mixture was allowed to cool to room temperature and extracted with EtOAc (2 × 10 mL) and brine (10 mL). The organics were dried over MgSO4 and filtered. The solution was concentrated and purified by flash chromatography using a gradient of 0-50% EtOAc in heptane to give the mixture of title compounds (338 mg, 0.511 mmol, 23.61%). ESI-MS m / z [M+H] + C 18 H 16 Calculated value for ClFN2O: 330.1; measured value: 331.1.

[0364] Preparation 112: 4-chloro-1-(2-(methoxymethoxy)-4-(methylphenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine [ka]

[0365] A mixture of 1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine (460 mg, 2.0 mmol), CsCO (1.3 g, 4.0 mmol), Pd(dppf)Cl.CHCl (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 KPO (2.6 mL) was stirred in a sealed tube on a metal heating block at 100 °C for 30 min. The reaction mixture was purified by flash chromatography (ISCO® 40 g SepaFlash® silica gel column) using 33% EtOAc in heptane (24 mL / min) to give the title compound.

[0366] Preparation 113: 4-chloro-1-(2,6-difluoro-4-(1-fluorocyclopropyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazine [ka]

[0367] 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), potassium phosphate tribasic (637 mg, 3.00 mmol), toluene (10 mL), and water (2.5 mL) was evacuated and backfilled with nitrogen (3x), then heated to 60 °C and stirred for 4 h. The mixture was diluted with saturated NH4Cl (50 mL) and extracted with DCM (3x 50 mL). The organic layer was washed with brine (50 mL), dried over NaSO, and concentrated to give a mixture of regioisomers, which were separated by flash chromatography (ISCO® 80 g × 2 stacked silica columns) using heptane / dioxane (4:1). The first-eluting isomer was assigned as the title compound (75 mg, 20.45%). 1 H NMR (400 MHz, CD3OD) δ ppm 1.10 - 1.18 (m, 2 H), 1.48 - 1.66 (m, 3 H), 2.02 - 2.28 (m, 4 H), 2.95 - 3.06 (m, 1 H), 4.70 - 4.79 (m, 1 H), 5.23 - 5.32 (m, 1H), 6.84 - 6.97 (m, 2H).

[0368] Preparation 114: 1',4'-Dichloro-5'-methyl-5',8'-dichlorospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] [ka]

[0369] Step 1: 1-(2,2-dimethoxyethyl)cyclopropan-1-ol [ka]

[0370] To a solution of methyl 3,3-dimethoxypropanoate (60 g, 404.98 mmol, 57.42 mL) in THF (800 mL) was added a solution of tetraisopropoxytitanium (23.02 g, 81.00 mmol, 23.90 mL) at 0 °C, followed by the dropwise addition of bromo(ethyl)magnesium (3 M in EtO, 337.48 mL) over 1 h at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. TLC (PE / EtOAc = 5:1) showed complete consumption of the starting material and the formation of two new spots. The reaction mixture was diluted with THF (500 mL) and quenched with aqueous NH Cl (2000 mL). The resulting white precipitate was filtered off, and the filtrate was extracted with EtOAc (1000 mL × 3). The combined organic phase was dried over anhydrous Na SO and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® 330 g SepaFlash® silica gel column) using a gradient of 0 to 15% EtOAc in PE (100 mL / min) to afford the title compound as a yellow oil (30 g, 51% yield, 90% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 0.42 - 0.48 (m, 2 H), 0.74 - 0.80 (m, 2 H), 1.88 (d, J=5.75 Hz, 2 H), 3.39 (s, 6 H), 4.68 (t, J=5.75 Hz, 1 H).

[0371] Step 2: 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)acetaldehyde [ka]

[0372] A mixture of 1-(2,2-dimethoxyethyl)cyclopropanol (15 g, 102.61 mmol), 2,6-dimethylpyridine (54.97 g, 513.05 mmol, 59.75 mL), TBSOTf (29.84 g, 112.87 mmol, 25.92 mL), and TMSOTf (34.21 g, 153.92 mmol, 27.81 mL) in DCM (100 mL) was degassed and purged with N (3x), then stirred under N atmosphere at 25 °C for 10 h. TLC (PE / EtOAc = 10:1) showed complete consumption of the starting material and the formation of two new spots. The reaction mixture was quenched with aqueous NH4Cl (100 mL) and extracted with DCM (100 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® 330 g SepaFlash® silica gel column) using a gradient of 0-5% EtOAc in PE (100 mL / min) to give the title compound as a yellow oil (12 g, 49% yield, 90% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 0.09 (s, 6 H), 0.58 - 0.64 (m, 2 H), 0.83 (s, 9 H), 0.84 - 0.86 (m, 2 H), 2.46 (d, J=2.75 Hz, 2 H), 9.94 (t, J=2.81 Hz, 1 H).

[0373] Step 3: tert-butyl-dimethyl-(1-prop-2-ynylcyclopropoxy)silane [ka]

[0374] To a solution of 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)acetaldehyde (11.5 g, 53.64 mmol) in MeOH (90 mL) were 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 h. TLC (PE / EtOAc = 10:1) showed that the starting material was completely consumed and one new spot was formed. The reaction mixture was quenched with aqueous NH4Cl (200 mL) and extracted with DCM (200 mL × 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® 330 g SepaFlash® silica gel column) using a gradient of 0 to 1% EtOAc in PE (100 mL / min). The title compound was obtained as a colorless oil (5.3 g, 44% yield, 95% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 0.10 - 0.14 (m, 6 H), 0.69 - 0.72 (m, 2 H), 0.73 (br s, 2 H), 0.86 (s, 9 H), 1.95 (t, J=2.44 Hz, 1 H), 2.59 (d, J=2.50Hz, 2H).

[0375] Step 4: 5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pent-3-yn-2-one [ka]

[0376] A 50 mL flame-dried flask was charged with tert-butyl-dimethyl-(1-(prop-2-ynylcyclopropoxy)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 min, after which 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 h. TLC ( A 20:1 PE / EtOAc (20:1) analysis showed complete consumption of the starting material and the formation of one new spot. The reaction mixture was poured into saturated aqueous NH4Cl (100 mL) in an ice bath, and the phases were separated. The aqueous layer was extracted with EtOAc (100 mL × 3), and the combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (ISCO® 220 g SepaFlash® silica gel column) using a gradient of 0–4% EtOAc in PE (100 mL / min). The title compound was obtained as a colorless oil (15.24 g, 80.89% yield, 90% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 0.14 (s, 6 H), 0.68 (s, 2 H), 0.80 (s, 2 H), 0.87 (s, 9 H), 2.33 (s, 3 H), 2.73 (s, 2 H).

[0377] Step 5: 5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pent-3-yn-2-ol [ka]

[0378] To a solution of 5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pent-3-yn-2-one (15.24 g, 60.37 mmol) and cerium trichloride (19.35 g, 78.49 mmol, 4.93 mL) in MeOH (50 mL) at 25 °C was added NaBH (3.05 g, 80.62 mmol). The reaction mixture was stirred for 0.5 h. TLC (PE / EtOAc = 20:1) showed complete consumption of the starting material and the formation of one new spot. The mixture was poured into saturated aqueous NH Cl (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 Na SO , filtered, and concentrated in vacuo. The residue was purified by flash chromatography (ISCO® 80 g SepaFlash® silica gel column) using a gradient of 0-5% EtOAc in PE (75 mL / min) to give the title compound as a colorless oil (12.8 g, 85.3% yield, 90% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 0.12 (s, 6 H), 0.62 - 0.69 (m, 2 H), 0.70 - 0.76 (m, 2 H), 0.86 (s, 9 H), 1.42 (d, J=6.50 Hz, 3 H), 2.60 (s, 2 H), 4.50 (q, J=6.50 Hz, 1H).

[0379] Step 6: 1-(5-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6-dichloropyridazin-4-yl)ethan-1-ol [ka]

[0380] 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 N (3×), then stirred at 100°C under N atmosphere for 48 h. TLC (PE / EtOAc = 20:1) showed some starting material remained and two new spots had formed. The mixture was filtered. The filtrate was evaporated in vacuo, and the residue was purified by flash chromatography (ISCO® 120 g SepaFlash® silica gel column) using a gradient of 0-10% EtOAc in PE (75 mL / min). The title compound was obtained as a brown oil (1.81 g, 18.6% yield, 90% purity). 1 H NMR (400 MHz, CDCl3) δ ppm -0.13 (s, 3 H), -0.01 (s, 3 H), 0.56 - 0.66 (m, 1 H), 0.74 (s, 9 H), 0.83 (dt, J=11.16, 6.61 Hz, 1 H), 0.88 - 0.98 (m, 1 H), 1.13 - 1.21 (m, 1 H), 1.57 (d, J=6.75 Hz, 3 H), 2.80 (d, J=13.38 Hz, 1 H), 4.24 - 4.33 (m, 2 H), 5.44 (q, J=6.55 Hz, 1 H).

[0381] Step 7: 1-(5-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)-3,6-dichloropyridazin-4-yl)ethyl 4-methylbenzenesulfonate [ka]

[0382] 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 h. TLC (PE / EtOAc = 5:1) showed that some starting material remained and two new spots had formed. The mixture was filtered. The filtrate was evaporated in vacuo to give a residue that was purified by flash chromatography (ISCO® 40 g SepaFlash® silica gel column) using a gradient of 0 to 10% EtOAc in PE (55 mL / min). The title compound was obtained as a colorless oil (4.54 g, 59.7% yield, 90% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 0.01 - 0.09 (m, 6 H), 0.36 - 0.49 (m, 1 H), 0.56 (br d, J=9.26 Hz, 1 H), 0.71 (s, 9 H), 0.82 - 0.94 (m, 2 H), 1.85 (d, J=6.88 Hz, 3 H), 2.39 (s, 3 H), 3.06 (br d, J=14.51 Hz, 1 H), 3.67 - 3.78 (m, 1 H), 6.15 (q, J=6.75 Hz, 1 H), 7.19 (m, J=8.13 Hz, 2 H), 7.56 (m, J=8.25 Hz, 2H).

[0383] Step 8: 1',4'-Dichloro-5'-methyl-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] [ka]

[0384] 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 h. TLC (PE / EtOAc = 20:1) showed complete consumption of the starting material and the formation of one new spot. The reaction mixture was quenched with aqueous NH4Cl (10 mL) and extracted with DCM (10 mL × 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® 12 g SepaFlash® silica gel column) using a gradient of 0–8% EtOAc in PE (35 mL / min). The title compound was obtained as a yellow oil (1.06 g, 51.5% yield, 95% purity). 1 H NMR (400 MHz, CDCl3) δ ppm 0.49 (dd, J=10.26, 6.75 Hz, 1 H), 0.79 (dt, J=10.32, 6.22 Hz, 1 H), 0.87 - 0.95 (m, 1 H), 1.10 - 1.18 (m, 1 H), 1.65 (d, J=6.63 Hz, 3 H), 2.67 - 2.75 (m, 1 H), 2.96 - 3.02 (m, 1 H), 4.92 (q, J=6.63 Hz, 1 H).

[0385] 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 [ka]

[0386] The title compound was synthesized analogously to preparations 84 and 85.

[0387] Preparation 117: 1'-chloro-N-((1R,2R)-2-methoxycyclopentyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-amine [ka]

[0388] 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 180 °C for 1 h on high absorption in a microwave reactor. The reaction mixture was transferred to a 100 mL separatory funnel, and the layers were separated. The lower layer was diluted with HO (20 mL) to give 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 give the crude product as a brown oil (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 (RediSep® Rf Gold 80 g silica gel column) using a gradient of 0 to 100% EtOAc in heptane. The initial fractions were combined, concentrated by rotary evaporation, and dried in vacuo to give the title compound as an oil (29.3 mg, 11.2%). 1H NMR (400 MHz, CDCl3) δ ppm 0.57 - 0.69 (m, 2 H), 0.91 - 1.02 (m, 2 H), 1.43 - 1.53 (m, 1 H), 1.65 - 1.79 (m, 2 H), 1.80 - 1.90 (m, 1 H), 1.90 - 2.00 (m, 1 H), 2.40 (td, J=13.55, 8.03 Hz, 1 H), 2.67 - 2.80 (m, 2 H), 3.46 (s, 3 H), 3.68 - 3.82 (m, 2 H), 4.33 - 4.50 (m, 2 H);ESI-MS m / z [M+H] + C 15 H 20 Calculated value for ClN3O2: 309.12, found value: 310.1.

[0389] Preparation 118: 1'-chloro-N-((1R,2R)-2-methoxycyclobutyl)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine]-4'-amine [ka]

[0390] A 20 mL microwave vial containing 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (330 mg, 1.43 mmol), DIPEA (2.5 mL, 14.3 mmol), and (1R,2R)-2-methoxycyclobutanamine (361 mg, 3.57 mmol) in NMP (7.5 mL) was heated at 180 °C for 1 h in a Biotage microwave reactor. The reaction mixture was extracted with EtOAc (2 × 50 mL) and brine (50 mL). The organic layers were combined, dried over MgSO and concentrated under reduced pressure to give an oil. The crude product was purified by flash chromatography using a gradient of 0 to 100% EtOAc in heptane to give the title compound (33 mg, 7.8%) as the first eluting peak. 1H NMR (400 MHz, CDCl3) δ ppm 0.54 - 0.66 (m, 2 H), 0.94 - 1.02 (m, 2 H), 1.45 (br t, J=9.79 Hz, 1 H), 1.67 (tdd, J=10.85, 10.85, 9.29, 8.41 Hz, 1 H), 2.08 - 2.22 (m, 1 H), 2.31 - 2.43 (m, 1 H), 2.67 - 2.78 (m, 2 H), 3.34 (s, 3 H), 3.84 (q, J=7.36 Hz, 1 H), 4.45 (d, J=1.51 Hz, 2 H), 4.50 - 4.63 (m, 1 H); ESI-MS m / z [M+H] + C 14 H 18 Calculated value for ClN3O2: 295.1, found value: 296.1.

[0391] 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 [ka]

[0392] To a 20 mL microwave vial equipped with a stir bar was added (3S,4R)-3-methoxytetrahydro-2H-pyran-4-amine (710 mg, 5.41 mmol), 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (500 mg, 2.16 mmol), DIPEA (3.8 mL, 21.6 mmol), and sodium iodide (1622 mg, 10.8 mmol) in NMP (11 mL). The reaction mixture was stirred at 180 °C in a Biotage microwave reactor for 1 h and then extracted with EtOAc (2 × 50 mL) and brine (50 mL). The organics were separated and dried over MgSO. The solution was filtered, concentrated under reduced pressure and purified by flash chromatography using a gradient of 20-80% EtOAc in heptane to give the title compound as the first eluting peak (21 mg, 2.98%). 1 H NMR (400 MHz, CDCl3) δ ppm 0.57 - 0.68 (m, 2 H), 0.97 - 0.99 (m, 2 H), 1.53 - 1.56 (m, 1 H), 2.58 - 2.81 (m, 3 H), 3.26 - 3.46 (m, 5 H), 3.55 (td, J=11.60, 2.29 Hz, 1 H), 3.88 (dt, J=11.74, 3.58 Hz, 1 H), 4.08 - 4.26 (m, 2 H), 4.38 - 4.49 (m, 2 H);ESI-MS m / z [M+H] + C 15 H 20 Calculated value for ClN3O3: 325.1, found value: 326.1.

[0393] Preparation 120: (1R,2R)-2-((1'-chloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)amino)cyclobutan-1-ol [ka]

[0394] To a 20 mL microwave vial was added 1',4'-dichloro-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazine] (600 mg, 2.60 mmol), DIPEA (4.5 mL, 26.0 mmol), (1R,2R)-2-aminocyclobutan-1-ol (566 mg, 6.49 mmol), and sodium iodide (1946 mg, 13.0 mmol) in NMP (10 mL). The reaction mixture was heated at 180 °C in a Biotage microwave reactor for 1 h and then extracted with EtOAc (2 × 50 mL) and brine (50 mL). The organics were separated, dried over MgSO, filtered, and concentrated under reduced pressure. The resulting oil was purified by flash chromatography, eluting with a gradient of 0 to 100% EtOAc in heptane to give the title compound as the first eluting peak (91 mg, 11%). 1 H NMR (400 MHz, CDCl3) δ ppm 0.59 - 0.66 (m, 2 H), 0.90 - 1.03 (m, 2 H), 1.46 - 1.63 (m, 1 H), 1.71 - 1.85 (m, 1 H), 2.14 - 2.28 (m, 2 H), 2.73 - 2.74 (s, 2 H), 3.52 - 3.65 (m, 1 H), 3.90 - 4.06 (m, 2 H), 4.43 - 4.44 (s, 2 H), 4.78 (br s, 1 H);ESI-MS m / z [M+H] + C 13 H 16 Calculated value for ClN3O2: 281.1, measured value: 282.0.

[0395] Example 233: 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 [ka]

[0396] 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 [ka]

[0397] To a mixture of 4'-chloro-1'-(2-(methoxymethoxy)-4-methylphenyl)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine] (60 mg, 173.01 μmol) and (3R,5R)-5-fluoro-1-methylpiperidin-3-amine (141.94 mg, 692.03 μmol, 2HCl) in toluene (1 mL) 、 Cs2CO3 (225.48 mg, 692.03 μmol), BINAP (21.55 mg, 34.60 μmol), and Pd(OAc)2 (3.88 mg, 17.30 μmol) were added in one portion under N2. The mixture was stirred at 100 °C for 12 h. LC-MS showed that the desired product was obtained. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (ISCO® SepaFlash® 4 g silica gel column) using a gradient of 0-5% MeOH 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.

[0398] 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-methylpheno

[0399] 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 h. 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 gradient of 5 to 30% ACN 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). 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.98 - 1.12 (m, 2 H), 1.69 - 1.84 (m, 2 H), 1.85 - 2.11 (m, 2 H), 2.27 (d, J=6.82 Hz, 7 H), 2.44 - 2.49 (m, 1 H), 2.53 - 2.60 (m, 3 H), 2.65 - 2.77 (m, 1 H), 3.78 (t, J=5.72 Hz, 2 H), 4.32 (d, J=7.70 Hz, 1 H), 4.48 (br s, 1 H), 4.72 - 4.95 (m, 1 H), 6.71 (d, J=7.70 Hz, 1 H), 6.74 (s, 1 H), 7.03 (d, J=7.48 Hz, 1 H), 9.57 (br s, 1 H);ESI-MS m / z [M+H] + 399.1.

[0400] Example 234: 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 [ka]

[0401] 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 [ka]

[0402] To a mixture of 1'-chloro-4'-(2-(methoxymethoxy)-4-methoxyphenyl)-7',8'-dihydrospiro[cyclopropane-1,5'-pyrano[3,4-d]pyridazine] (76 mg, 219.14 μmol) and (3R,5R)-5-fluoro-1-methylpiperidin-3-amine (179.78 mg, 876.57 μmol, 2HCl) in toluene (1 mL) was added CsCO (285.60 mg, 876.57 μmol), BINAP (27.29 mg, 43.83 μmol), and Pd(OAc) (4.92 mg, 21.91 μmol) in one portion under N. The mixture was stirred at 100 °C for 12 h. LC-MS showed that the desired product was obtained. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (ISCO® SepaFlash® 4 g silica gel column) using a gradient of 0-5% MeOH 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.

[0403] Step 2: 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

[0404] 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 h. 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 gradient of 5 to 30% ACN 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 (400 MHz, DMSO-d6) δ ppm 0.59 - 1.03 (m, 4 H), 1.67 - 1.88 (m, 1 H), 1.96 (br t, J=9.90 Hz, 1 H), 2.02 - 2.18 (m, 2 H), 2.24 (d, J=18.93 Hz, 6 H), 2.53 - 2.60 (m, 2 H), 2.80 - 3.02 (m, 2 H), 3.92 (br t, J=5.83 Hz, 2 H), 4.55 (br s, 1 H), 4.84 - 5.06 (m, 1 H), 5.68 (d, J=8.14 Hz, 1 H), 6.62 (d, J=7.48 ESI-MS m / z [M+H] + 399.1.

[0405] Example 235: 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 [ka]

[0406] Example 236: 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 [ka]

[0407] 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 [ka]

[0408] 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), (3 A mixture of (R,5R)-5-fluoro-1-methylpiperidin-3-amine (402.15 mg, 1.96 mmol, 2HCl), Pd(OAc) (22.01 mg, 98.04 μmol), BINAP (122.09 mg, 196.07 μmol), and CsCO (958.27 mg, 2.94 mmol) in toluene (10 mL) was stirred at 100 °C for 12 h. LC-MS indicated that the starting material had been consumed and the desired product had been obtained. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (ISCO SepaFlash 20 g silica gel column) using a gradient of 0–3% MeOH in DCM (35 mL / min). The title compound mixture was obtained as a brown oil (171 mg, 95% pure). 1 H NMR (400 MHz, CDCl3) δ ppm 0.44 (s, 1 H), 0.66 (s, 1 H), 0.82 - 1.01 (m, 2 H), 2.20 - 2.82 (m, 2 H), 2.36 - 2.47 (m, 5 H), 3.07 (s, 1 H), 3.41(d, J=9.7 Hz, 3 H), 4.53 (br d, J=4.8 Hz, 1 H), 4.75 - 4.99 (m, 2 H), 5.10 (br d, J=7.0 Hz, 2 H), 5.32 (s, 2 H), 6.94 (d, J=7.7 Hz, 1 H), 7.04 (d, J=3.5 Hz, 1 H), 7.23 (d, J=7.3 Hz, 1 H).

[0409] 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

[0410] To a mixture of 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 (171 mg) in DCM (15 mL) was added TFA (4.62 g, 40.52 mmol, 3 mL) at 20°C. 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 give a mixture of two isomers (63 mg), which was further purified by SFC (DAICEL CHIRALPAK® IG-10 μm, 30 mm × 250 mm column) using a mobile phase of CO and 60% EtOH (containing 0.1% NH HO) to give the title compound of Example 235 as a white solid (18.2 mg, 100% pure). 1H NMR (400 MHz, CDCl3) δ ppm 0.68 - 0.78 (m, 2 H), 1.06 - 1.14 (m, 2 H), 1.69 - 1.86 (m, 2 H), 2.22 - 2.33 (m, 1 H), 2.36 - 2.38 (m, 3 H), 2.42 (br s, 3 H), 2.48 - 2.64 (m, 4 H), 2.65 - 2.85 (m, 1 H), 2.96 - 3.23 (m, 1 H), 4.67 - 4.97 (m, 5 H), 6.74 (d, J=8.1 Hz, 1 H), 6.96 (s, 1 H), 7.05 (d, J=7.9 Hz, 1 H); 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 (400 MHz, CDCl3) δ ppm 0.48 - 0.59 (m, 2 H), 0.88 (s, 1 H), 0.91 - 0.98 (m, 2 H), 1.70 - 1.90 (m, 1 H), 2.31 - 2.38 (m, 4 H), 2.38 - 2.48 (m, 2 H), 2.48 - 2.62 (m, 2 H), 2.70 (br s, 1 H), 2.96 (s, 2 H), 3.08 (br s, 1 H), 4.54 (br s, 3 H), 4.80 (br s, 2 H), 6.75 (d, J=8.1 Hz, 1 H), 6.95 (s, 1 H), 7.30 (br s, 1H);ESI-MS m / z [M+H] + 399.1.

[0411] 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 [ka]

[0412] 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 [ka]

[0413] 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 at 100 °C for 16 h in a sealed tube on a metal heating block. The reaction mixture was concentrated in vacuo to give a crude product mixture that was purified by preparative HPLC (Method A) using a gradient of 10 to 30% ACN (0.035% TFA) in water (0.005% TFA) to give the TFA salt of the title compound of Example 237 as a colorless oil (5.5 mg, 2.1%). 1 H NMR (400 MHz, CD3OD) δ ppm 1.69 - 1.82 (m, 1 H), 1.98 - 2.18 (m, 2 H), 2.23 - 2.32 (m, 2 H), 2.36 (d, J=18.34 Hz, 1 H), 2.54 - 2.66 (m, 1 H), 2.99 (s, 3 H), 3.01 - 3.10 (m, 1 H), 3.11 - 3.19 (m, 1 H), 3.32 - 3.45 (m, 1 H), 3.76 - 3.89 (m, 2 H), 4.74 - 4.82 (m, 2 H), 5.31 (br d, J=6.60Hz, 2H), 7.03 - 7.13 (m, 2 H), 7.33 (d, J=8.25 Hz, 1 H);ESI-MS m / z [M+H]+ 419.2. The TFA salt of the title compound of Example 238 was obtained as a pink oil (9.5 mg, 3.6%). 1 H NMR (400 MHz, CD3OD) δ ppm 1.72 - 1.81 (m, 1 H), 2.05 - 2.12 (m, 1 H), 2.11 - 2.32 (m, 3 H), 2.33 - 2.40 (m, 1 H), 2.50 - 2.65 (m, 1 H), 3.00 (s, 3 H), 3.03 - 3.11 (m, 1 H), 3.12 - 3.19 (m, 1 H), 3.35 - 3.47 (m, 1 H), 3.76 - 3.87 (m, 2 H), 4.75 - 4.81 (m, 2 H), 5.20 - 5.39 (m, 2 H), 7.04 - 7.10 (m, 2 H), 7.34 (d, J=8.07 Hz, 1 H);ESI-MS m / z [M+H] + 419.2.

[0414] 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 [ka]

[0415] 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 [ka]

[0416] 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 at 100 °C for 16 h in a sealed tube on a metal heating block. The reaction mixture was concentrated in vacuo to give a crude product mixture that was purified by preparative HPLC (Method A) using a gradient of 10 to 30% ACN (0.035% TFA) in water (0.005% TFA) to give the TFA salt of the title compound of Example 239 as a pink oil (19 mg, 7.2%). 1 H NMR (400 MHz, CD3OD) δ ppm 1.78 - 1.92 (m, 1 H), 2.00 - 2.18 (m, 3 H), 2.22 - 2.33 (m, 1 H), 2.47 - 2.61 (m, 2 H), 2.99 (s, 3 H), 3.04 - 3.19 (m, 2 H), 3.34 - 3.48 (m, 1 H), 3.73 - 3.90 (m, 2 H), 4.72 - 4.86 (m, 1 H), 4.86 - 4.91 (m, 2 H), 5.18 - 5.38 (m, 1 H), 7.06 - 7.14 (m, 2 H), 7.34 - 7.38 (m, 1 H); ESI-MS m / z [M+H] + 419.2. The TFA salt of the title compound of Example 240 was obtained as a pink oil (16 mg, 6.0%). 1H NMR (400 MHz, CD3OD) δ ppm 1.79 - 1.89 (m, 1 H), 1.94 - 2.21 (m, 3 H), 2.21 - 2.36 (m, 1 H), 2.45 - 2.61 (m, 2 H), 2.99 (s, 3 H), 3.00 - 3.17 (m, 2 H), 3.32 - 3.47 (m, 1 H), 3.76 - 3.86 (m, 2 H), 4.74 - 4.87 (m, 3 H), 5.21 - 5.39 (m, 1 H), 7.06 - 7.17 (m, 2 H), 7.30 - 7.39 (m, 1 H);ESI-MS m / z [M+H] + 419.2.

[0417] Example 241: (R)-5-methyl-2-(1-((1-methylpiperidin-3-yl)amino)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)phenol [ka]

[0418] 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 heated at 100 °C under nitrogen overnight. The mixture was treated with water, extracted with EtOAc, washed with brine, dried over MgSO, and concentrated. The resulting residue was dissolved in dioxane (2 mL). Hydrogen chloride in dioxane (0.19 mL, 0.748 mmol) was added. The mixture was stirred at room temperature for 4 h and then purified by preparative HPLC (Phenomenex Gemini C18, 5 μm, 30 mm ID × 150 mm column) using a gradient of 10 to 100% ACN (0.035% TFA) in water (0.05% TFA) with a slow gradient of 10 to 60% ACN. Evaporation of the product-containing fractions gave the title compound as a clear oil (9.3 mg, 11%). 1 H NMR (400 MHz, CD3OD ) δ ppm 1.70 - 2.01 (m, 2 H), 2.08 - 2.27 (m, 2 H), 2.37 (s, 3 H), 2.77 (br s, 2 H), 2.86 - 3.02 (m, 5 H), 3.56 (br d, J=14.31 Hz, 1 H), 3.76 - 3.86 (m, 1 H), 4.04 - 4.12 (m, 2 H), 4.40 - 4.54 (m, 1 H), 4.56 - 4.62 (m, 2 H), 6.85 - 6.92 (m, 2 H), 7.17 - 7.23 (m, 1 H);ESI-MS [M+H] + C 20 H 26 Calculated value for N4O2: 354.21, measured value: 355.4.

[0419] 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 [ka]

[0420] 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 [ka]

[0421] To a mixture of (R)-2-(3-((1-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-yl)amino)piperidin-1-yl)ethan-1-ol and (R)-2-(3-((4-chloro-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-1-yl)amino)piperidin-1-yl)ethan-1-ol (total 170 mg, 0.54 mmol) in THF (2 mL) was added (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (224 mg, 1.08 mmol), KPO.HO (0.5 M, 4 mL), and Xphos Pd G (92 mg, 0.108 mmol). The mixture was degassed and purged with N (3x), then stirred at 60 °C for 12 h under a N atmosphere. LC-MS showed two peaks with the desired MS. The reaction mixture was evaporated and then partitioned between DCM / HO (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 that was purified by preparative HPLC (C18-1, 5 μm, 30 mm ID x 150 mm) using a gradient of 10-50% ACN in water (with NHOH) over 9 min. The title compound of Example 242 was obtained as a white solid (27 mg, 24%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.40 (d, J=7.70 Hz, 1 H), 7.18 - 7.26 (m, 2 H), 5.64 (d, J=7.92 Hz, 1 H), 4.46 (s, 2 H), 4.21 - 4.40 (m, 2 H), 3.76 (t, J=5.39 Hz, 2 H), 3.49 (br t, J=6.16 Hz, 2 H), 2.97 - 3.07 (m, 1 H), 2.70 - 2.80 (m, 1 H), 2.36 - 2.45 (m, 4 H), 1.93 - 2.06 (m, 2 H), 1.83 - 1.91 (m, 1 H), 1.63 -1.74 (m, 1 H), 1.47 - 1.56 (m, 1 H), 1.33 - 1.43 (m, 1 H);ESI-MS m / z [M+H] + C 21 H 25 The calculated value of F3N4O3 is 438.19, and the measured value is 439.1. The title compound of Example 243 was obtained as a white solid (30 mg, 26%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.37 (d, J=7.70 Hz, 1 H), 7.18 - 7.26 (m, 2 H), 5.84 (d, J=8.14 Hz, 1 H), 4.20 - 4.47 (m, 4 H), 3.92 (t, J=5.61 Hz, 2 H), 3.50 (br t, J=6.16 Hz, 2 H), 2.96 - 3.04 (m, 1 H), 2.68 - 2.78 (m, 1 H), 2.48 (br s, 4 H), 2.06 (br t, J=10.01 Hz, 2 H), 1.81 - 1.91 (m, 1 H), 1.68 (br s, 1 H), 1.55(br s, 2 H);[M+H] + C 21 H 25 The calculated value of F3N4O3 is 438.19, and the measured value is 439.1.

[0422] 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 [ka]

[0423] 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 MgSO, and concentrated. The resulting residue was dissolved in dioxane (2 mL). Hydrogen chloride in dioxane (0.38 mL, 0.761 mmol) was added. The mixture was stirred at room temperature for 3 h and purified by preparative HPLC (Phenomenex Gemini C18, 5 μm, 30 mm ID × 150 mm column) using a gradient of 10 to 100% ACN (containing 0.079% ammonium bicarbonate) in water (containing 0.079% ammonium) followed by a slow gradient of 10 to 60% ACN. Evaporation of the product-containing fractions afforded the title compound as a clear oil (0.8 mg, 0.71%). 1H NMR (400 MHz, CD3OD ) δ ppm 1.51 - 1.72 (m, 2 H), 1.73 - 1.96 (m, 2 H), 2.32 (s, 5 H), 2.54 - 2.70 (m, 5 H), 2.96 - 3.05 (m, 1 H), 3.34 (s, 3 H), 3.52 - 3.58 (m, 2 H), 3.81 - 3.88 (m, 2 H), 4.37 - 4.45 (m, 1 H), 4.54 - 4.59 (m, 2 H), 6.72 - 6.79 (m, 2 H), 7.06 - 7.11 (m, 1 H);ESI-MS [M+H] + C 22 H 30 Calculated value for N4O3: 398.23, measured value: 399.1.

[0424] 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 [ka]

[0425] A mixture of 1-chloro-N-((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)-7,8-dihydro-5H-pyrano[3,4-d]pyridazin-4-amine (50 mg, 166.25 μmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (51.35 mg, 249.37 μmol), Pd(dppf)Cl.CHCl (13.58 mg, 16.62 μmol), and CsCO (216.66 mg, 664.98 μmol) in dioxane (2 mL) and HO (0.5 mL) was degassed and purged with N (3×), then stirred at 100 °C for 2 h under a N atmosphere. LC-MS showed that 56% of the desired mass was detected. The reaction mixture was evaporated and partitioned between DCM / HO (5 mL / 1 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 give a residue that was purified by preparative HPLC (Xtimate C18, 5 μm, 30 mm ID × 150 mm column) using a gradient of 0 to 30% ACN in water (with FA) over 25 min. The formate salt of the title compound was obtained as a white solid (37.9 mg, 52% yield, 98% purity). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.56 - 1.82 (m, 1 H), 1.86 - 1.98 (m, 1 H), 2.03 - 2.28 (m, 5 H), 2.36 - 2.46 (m, 2 H), 2.84 - 2.95 (m, 1 H), 2.96 - 3.05 (m, 1 H), 3.78 (br t, J=5.44 Hz, 2 H), 4.39 - 4.65 (m, 3 H), 4.81 - 5.09 (m, 1 H), 5.63 - 5.85 (m, 1 H), 7.17 - 7.26 (m, 2 H), 7.33 - 7.51 (m, 1 H);ESI-MS [M+H] + C 20 H 22 Calculated value for F4N4O2: 426.17, measured value: 427.2.

[0426] 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 [ka]

[0427] 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) 、 A mixture of 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 at 100 °C for 16 h in a sealed tube on a metal heating block. The reaction mixture was then concentrated in vacuo to give a crude product mixture, which was purified by preparative HPLC (Phenomenex Gemini C18 column) using a 10-100% gradient of ACN in water (10 mM NH4HCO3, pH = 9.5-10). The title compound was obtained as a yellow oil (14 mg, 27%). 1 H NMR (400 MHz, CD3OD) δ ppm 1.64 - 1.84 (m, 1 H), 2.09 - 2.22 (m, 2 H), 2.23 (s, 3 H), 2.28 (s, 3 H), 2.30 - 2.44 (m, 2 H), 2.84 - 3.00 (m, 2 H), 3.05 - 3.14 (m, 1 H), 3.57 - 3.67 (m, 1 H), 3.84 - 3.90 (m, 1 H), 4.56 - 4.65 (m, 1 H), 4.81 - 4.94 (m, 2 H), 5.80 (s, 1 H), 6.63 - 6.72 (m, 2H), 7.09 - 7.16 (m, 1H); ESI-MS [M+H]+ C 21 H 25 Calculated value for FN4O3: 400.19, measured value: 401.2.

[0428] 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 [ka]

[0429] 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), CsCO (128 mg, 0.4 mmol), Pd(dba) (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 at 100 °C for 16 h in a sealed tube on a metal heating block. The reaction mixture was then concentrated in vacuo to give a crude product mixture, which was purified by preparative HPLC (Phenomenex Gemini® C18 column) using a 10-100% gradient of ACN in water (10 mM NH4HCO3, pH = 9.5-10) to give the title compound as an orange oil (3.0 mg, 6%). 1H NMR (400 MHz, CD3OD) δ ppm 1.84 (s, 2 H), 2.04 - 2.11 (m, 1 H), 2.21 - 2.22 (m, 3 H), 2.23 (s, 3 H), 2.29 (dd, J=18.07, 0.75 Hz, 2 H), 2.78 - 2.88 (m, 1 H), 2.93 - 3.09 (m, 2 H), 3.51 - 3.57 (m, 1 H), 3.85 - 3.92 (m, 1 H), 4.58 - 4.68 (m, 1 H), 4.77 - 4.92 (m, 2 H), 6.22 (s, 1 H), 6.61 - 6.64 (m, 1 H), 6.65 - 6.69 (m, 1 H), 6.95 - 7.00 (m, 1 H);ESI-MS [M+H] + C 21 H 25 Calculated value for FN4O3: 400.19, measured value: 401.2.

[0430] 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

[0431] 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

[0432] 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 [ka]

[0433] 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), CsCO (846 mg, 2.6 mmol), Pd(dba) (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 at 100 °C for 16 h in a sealed tube on a metal heating block. The reaction mixture was added to a solution of TFA (2 mL) in DCM (10 mL), stirred at 60 °C for 1 h, and then concentrated in vacuo to give the crude product mixture. The product mixture was purified by preparative HPLC (Phenomenex Gemini® C18 column) using a 10-30% gradient of ACN (0.035% TFA) in water (0.005% TFA) to give 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 × 150 mm column) using a gradient of 40-50% MeOH (with 0.1% NH4OH) in CO2. 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 (400 MHz,CD3OD) δ ppm 1.62 - 1.74 (m,1 H),1.74 - 1.90 (m,1 H),1.96 - 2.05 (m,1 H),2.11 - 2.28 (m,5 H), 2.30 (s, 3 H), 2.32 (s, 3 H), 2.33 - 2.48 (m, 1 H), 2.88 - 2.97 (m, 1 H), 2.98 - 3.05 (m, 1 H), 3.10 - 3.20 (m,1 H),4.66 - 4.78 (m,2 H),4.90 - 5.02 (m,1 H),5.15 (d,J=5.77 Hz,1 H),6.70 - 6.76 (m,2 H), 7.04 (d, J=7.53Hz, 1H);ESI-MS [M+H] + C22 H 27 Calculated for FN4O2 398.21, found 399.2. The second crop was the title compound of Example 250, which was obtained as a yellow semi-solid (37 mg, 11%). 1 H NMR (400 MHz,CD3OD) δ ppm 1.62 - 1.89 (m,2 H),1.95 - 2.04 (m,1 H),2.27 (br s,5 H),2.30 (s,3 H), 2.31 (s, 3 H), 2.32 - 2.39 (m, 1 H), 2.86 - 3.06 (m, 2 H), 3.08 - 3.18 (m, 1 H), 4.63 - 4.78 (m, 2 H), 4.91 - 5.01 (m,1 H),5.11 - 5.17 (m,1 H),6.69 - 6.76 (m,2 H),7.04 (d,J=7.53 Hz,1 H);ESI-MS [M+H] + C 22 H 27 Calculated value for FN4O2: 398.21, measured value: 399.2.

[0434] 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 [ka]

[0435] 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 [ka]

[0436] 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), CsCO (846 mg, 2.6 mmol), Pd(dba) (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 at 100 °C for 16 h in a sealed tube on a metal heating block. The reaction mixture was added to a solution of TFA (2 mL) in DCM (10 mL), stirred at 60 °C for 1 h, and then concentrated in vacuo to give the crude product mixture. The product mixture was purified by preparative HPLC (Phenomenex Gemini® C18 column) using a gradient of 10-30% ACN (0.035% TFA) in water (0.005% TFA) to give the TFA salt of the title compound of Example 251 as a pale yellow semi-solid (55 mg, 12.4%). 1 H NMR (400 MHz, CD3OD) δ ppm 1.82 - 1.91 (m, 1 H), 2.04 - 2.33 (m, 4 H), 2.40 (s, 3 H), 2.50 - 2.66 (m, 2 H), 3.01 (d, J=2.38 Hz, 3 H), 3.04 - 3.20 (m, 2 H), 3.34 - 3.48 (m, 1 H), 3.74 - 3.88 (m, 2 H), 4.76 - 4.85 (m, 1 H), 4.90 - 4.96(range, 2 H) 5.29 - 5.38 (m, 1 H), 6.92 (s, 2 H), 7.22 (s, 1 H);ESI-MS [M+H] + C 22 H 27 Calculated for FN4O2 398.21, found 399.2. The diastereomers were isolated via preparative SFC (Waters, Phenomenex Amylose-1 column) using a gradient of 25-50% MeOH (with 0.1% NH4OH) in CO2 to give the title compound of Example 252.

[0437] 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 [ka]

[0438] 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), CsCO (302 mg, 0.93 mmol), Pd(dba) (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 at 100 °C for 16 h in a sealed tube on a metal heating block. The mixture was then concentrated in vacuo to give a crude product mixture, which was purified by preparative HPLC (Phenomenex Gemini® C18 column) using a 10-30% gradient of ACN (0.035% TFA) in water (0.005% TFA) to give the title compound as a pale yellow semi-solid (6 mg, 5%). 1 H NMR (400 MHz,CD3OD) δ ppm 1.22 - 1.54 (m,4 H),1.60 - 2.20 (m,9 H),2.27 - 2.41 (m,1 H),2.89 - 3.07 (m, 1 H), 3.46 - 3.58 (m, 1 H),3.65 - 3.75 (m,1 H),4.72 - 4.74 (m,1 H),6.90 - 6.97 (m,2 H),7.15 (d, J=8.03 Hz, 1 H);ESI-MS [M+H] + C 21 H 24 Calculated for ClN3O3: 401.15, found: 402.2.

[0439] 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]pyridazin]-1'-yl)-5-methylphenol [ka]

[0440] 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), Pd(dba) (4.1 mg, 0.00451 mmol), R-BINAP (5.6 mg, 0.00902 mmol), and CsCO (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 MgSO, 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 h and purified by preparative HPLC (Phenomenex Gemini C18, 5 μm, 30 mm ID × 150 mm column) using a gradient of 10 to 100% ACN (0.035% TFA) in water (0.05% TFA) slowly ramped to 10 to 60% ACN to give the title compound. 1H NMR (400 MHz,CD3OD) δ ppm 1.91 - 2.20 (m,2 H),2.24 - 2.33 (m,1 H),2.38 (s,3 H),2.53 - 2.63 (m,1 H), 2.88 - 2.91 (m, 2H), 3.00 (s, 3 H), 3.03 - 3.14 (m, 1 H), 3.65 - 3.70 (m, 1 H), 3.78 - 3.88 (m, 2 H), 3.93 - 4.04 (m,3 H),4.72 (br d,J=6.90 Hz,3 H),5.23 - 5.39 (m,1 H),6.88 (s,1 H),6.89 - 6.93 (m,1H) ,7.22-7.27 (m,1H);ESI-MS [M+H] + C 23 H 29 Calculated value for FN4O3: 428.22, measured value: 429.54.

[0441] 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]pyridazin]-4'-yl)-5-methylphenol [ka]

[0442] 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 and heated at 110 °C overnight, 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 room temperature for 3 h and purified by preparative HPLC (Phenomenex Gemini C18, 5 μm, 30 mm ID × 150 mm column) using a gradient of 10 to 100% ACN (0.035% TFA) in water (0.05% TFA) with a slow ramp from 10 to 60% ACN to give the title compound. 1 H NMR (400 MHz,CD3OD) δ ppm 1.78 - 1.88 (m, 1 H), 1.95 - 2.15 (m, 2 H), 2.17 - 2.26 (m, 1 H), 2.38 (s, 3 H), 2.53 - 2.64 (m, 1 H), 2.77 - 2.90 (m, 2 H), 2.99 (s, 4 H), 3.33 - 3.45 (m, 1 H), 3.51 - 3.56 (m, 1 H), 3.78 - 3.93 (m, 5 H), 3.96 - 4.03 (m, 1 H), 4.76 - 4.82 (m, 1 H), 5.21 - 5.39 (m, 1 H), 6.85 - 6.88 (m, 1 H), 6.90 - 6.95 (m, 1 H), 7.21 - 7.27 (m, 1 H);ESI-MS [M+H] + C 23 H 29 Calculated value for FN4O3: 428.22, measured value: 429.54.

[0443] 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]pyridazin]-1'-yl)-5-methylphenol [ka]

[0444] The title compound was synthesized from the starting material 1,9-dioxaspiro[5.5]undecan-4-one using a procedure similar to Example 254. 1 H NMR (400 MHz, CD3OD) δ ppm 1.78-1.83 (m, 3) 2.01 - 2.22 (m,1 H),2.38 (s,3 H),2.53 - 2.64 (m,1 H),2.68 - 2.72 (m,2 H),3.00 (s,3 H),3.05 - 3.15 (m,1 H),3.67 (br d,J=1.25 Hz,2 H),3.73 - 3.84 (m,6 H),4.65 (s,2 H),4.76 - 4.85 (m,1 H),5.22 - 5.38 (m,1 H),6.87 - 6.89 (m,1 H),6.89 - 6.93 (m,1 H), 7.23 - 7.26 (m, 1H); ESI-MS [M+H] + C 24 H 31 Calculated value for FN4O3: 442.24, measured value: 443.48.

[0445] Example 257: 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 [ka]

[0446] Example 258: 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 [ka]

[0447] 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] To a stirred solution of a mixture of [dazin]-4'-amine (100 mg, 0.31 mmol) in dioxane (2 mL) and HO (0.5 mL) was added (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (125 mg, 0.61 mmol), CsCO (403 mg, 1.24 mmol), and Pd(dppf)Cl.CHCl (25 mg, 0.031 μmol). The mixture was stirred at 100 °C for 2 h under N. LC-MS showed that 48% of the desired mass was detected. The reaction mixture was evaporated and then partitioned between DCM / HO (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 give a residue. The residue was purified by flash chromatography (ISCO® 4 g SepaFlash® silica gel column) using a gradient of 0 to 15% DCM in MeOH (30 mL / min) to give the crude product (70 mg), which was further purified by preparative SFC (DAICEL CHIRALPAK® IG-10 μm, 30 mm ID × 250 mm column) using a mobile phase of CO2 and 35% MeOH (containing 0.1% NH3OH) to give the title compound of Example 258 as a white solid (12 mg, 57%). 1H NMR (400 MHz,CD3OD) δ ppm 0.58 - 0.76 (m,2 H),0.86 - 0.98 (m,2 H),1.71 - 1.98 (m,1 H),2.23 - 2.40 (m,2 H),2.42 - 2.48 (m,3 H),2.49 - 2.58 (m, 1 H), 2.58 - 2.66 (m, 2 H), 3.01 - 3.15 (m, 1 H), 4.44 - 4.50 (m, 2 H) H), 4.72 - 4.81 (m, 2H), 4.96 - 5.08 (m, 1H), 7.13 - 7.28 (m, 2H), 7.34 - 7.48 (m, 1H), 8.33 - 8.51 (m, 1H) H);ESI-MS [M+H] + C 22 H 24 Calculated for F4N4O2 452.18, found 452.9. The title compound of Example 257 was obtained as a white solid (8 mg, 38%). 1 H NMR (400 MHz,CD3OD) δ ppm 0.33 - 0.62 (m,2 H),0.76 - 0.97 (m,2 H),1.74 - 1.99 (m,1 H),2.30 - 2.45 (m,2 H),2.47 - 2.54 (m,3 H),2.55 - 2.70 (m,3 H),3.10 - 3.24 (m,2 H),4.55 - 4.58 (m,2 H),4.74 - 4.80 (m,2 H),4.99 - 5.09 (m,1 H),7.12 - 7.27 (m,2 H),7.35 - 7.44 (m,1 H),8.38 - 8.45 (m,1 H). ESI-MS [M+H] + C 22 H 24 Calculated value for F4N4O2: 452.18, measured value: 453.0.

[0448] 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 [ka]

[0449] 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), CsCO (302 mg, 0.93 mmol), Pd(dba) (28 mg, 0.0309 mmol), R-BINAP (39 mg, 0.062 mmol), and 6-aminospiro[3.3]heptan-2-ol (43.2 mg, 0.34 mmol) in toluene (1 mL) was stirred at 100 °C in a sealed tube on a metal heating block for 16 h. The reaction mixture was then concentrated in vacuo to give the crude product mixture. The product mixture was purified by preparative HPLC (Phenomenex Gemini® C18 column) using a gradient of 10-30% ACN (0.035% TFA) in water (0.005% TFA) to give the title compound as a yellow semi-solid (25 mg, 19.6%). 1 H NMR (400 MHz,CD3OD) δ ppm 1.55 - 1.69 (m, 1 H), 1.93 (s, 7 H), 2.03 - 2.22 (m, 3 H), 2.29 - 2.47 (m, 3 H), 2.72 - 2.82 (m, 1 H), 3.97 - 4.06 (m, 1 H), 4.34 - 4.42 (m, 1 H), 4.64 - 4.73 (m, 2 H), 6.80 - 6.87 (m, 2 H), 7.04 (d, J=8.78 Hz, 1 H);ESI-MS [M+H] + C 22 H 24 Calculated value for ClN3O3: 413.15, found value: 414.2.

[0450] 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 [ka]

[0451] A mixture of 2-(4-chloro-5,6,7,8-tetrahydro-5,8-epoxyphthalazin-1-yl)-5-methylphenol (10 mg, 0.0346 mmol), CsCO (34 mg, 0.104 mmol), Pd(dba) (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 at 100 °C in a sealed tube on a metal heating block for 16 h. The reaction mixture was then concentrated in vacuo to give a crude product mixture. The product mixture was purified by preparative HPLC (Phenomenex Gemini® C18 column) using a gradient of 10-100% ACN in water (10 mM NH4HCO3, pH = 9.5-10). The title compound was obtained as a yellow oil (1.0 mg, 7.5%). 1 H NMR (400 MHz,CD3OD) δ ppm 1.42 - 1.49 (m,1 H),1.57 - 1.64 (m,1 H),1.72 - 1.85 (m,1 H),2.05 - 2.30 (m,2 H),2.05 - 2.29 (m,1 H),2.30 - 2.30 (m, 1 H), 2.31 - 2.40 (m, 6 H), 2.40 - 2.49 (m, 1 H), 2.94 - 3.02 (m, 1 H) H), 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=5.02) Hz, 1H), 6.76 - 6.88 (m, 1 H), 6.79 - 6.87 (m, 1 H), 7.33 (d, J=8.53 Hz, 1 H); ESI-MS [M+H] + C 21 H 25 Calculated value for FN4O2: 384.20, measured value: 385.2.

[0452] 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]pyridazin]-1'-yl)-5-methylphenol [ka]

[0453] 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]pyridazin]-4'-yl)-5-methylphenol [ka]

[0454] 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 (70 mg, 214 μmol) in THF (1 mL) was 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 K3PO4 (0.5 M, 2 mL) were added. The mixture was stirred under N2 at 50 °C for 3 h. LC-MS showed that 63% of the desired mass was detected. The reaction mixture was evaporated and partitioned between DCM / H2O (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 give a residue that was used directly in the next step without further purification. ESI-MS [M+H] + C24 H 30 Calculated for F2N4O3: 460.23, found: 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 h. LC-MS showed 56% conversion to the product containing the desired mass. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 1 M HCl (3 mL) and extracted with EtOAc (3 mL x 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 x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO® 4 g SepaFlash® silica gel column) using a gradient of 0–10% DCM in MeOH (30 mL / min) to give the crude product (80 mg), which was further purified by preparative SFC (DAICEL CHIRALPAK® IG-10 μm, 30 mm ID × 250 mm column) using a mobile phase of CO and 60% MeOH (containing 0.1% NH3OH) to give the title compound of Example 262 as a white solid (11 mg, 52%). 1 H NMR (400 MHz,CD3OD) δ ppm 0.35 - 0.57 (m, 2 H), 0.85 - 0.91 (m, 2 H), 1.68 - 1.94 (m, 1 H), 2.13 - 2.20 (m, 1 H), 2.24 (d, J=1.38 Hz, 3 H), 2.28- 2.47 (m, 5 H), 2.63 (s, 2 H), 2.95 - 3.07 (m, 1 H), 3.17 - 3.24 (m, 1 H), 4.39 - 4.59 (m, 2 H), 4.71 - 4.82 (m, 1 H), 4.95 - 5.04 (m, 1 H), 6.72 (d, J=6.50 Hz, 1 H), 6.84 - 6.97 (m, 1 H);ESI-MS [M+H] + C 22 H 26 Calculated for F2N4O2 416.20, found 417.3. The title compound of Example 263 was obtained as a white solid (10 mg, 91%).1 H NMR (400 MHz,CD3OD) δ ppm 0.59 - 0.68 (m, 2 H), 0.89 - 0.95 (m, 2 H), 1.73 - 1.92 (m, 1 H), 2.13 - 2.22 (m, 1 H), 2.23 - 2.27 (m, 3 H), 2.29 (br s, 5 H), 2.56 - 2.61 (m, 2 H), 2.89 - 3.03 (m, 1 H), 3.14 - 3.23 (m, 1 H), 4.44 - 4.51 (m, 2 H), 4.70 - 4.80 (m, 1 H), 4.93 - 5.03 (m, 1 H), 6.69 - 6.79 (m, 1 H), 6.87 - 6.93 (m, 1 H);ESI-MS [M + H] + C 22 H 26 Calculated value for F2N4O2: 416.20, measured value: 417.3.

[0455] Example 264: 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 [ka]

[0456] Example 265: 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 [ka]

[0457] 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]-1'-amine To a mixture of [-d]pyridazin]-4'-amine (70 mg, 214 μmol) in dioxane (2 mL) and HO (0.5 mL) was added (2-hydroxyphenyl)boronic acid (88.63 mg, 642.60 μmol), CsCO (139.58 mg, 428.40 μmol), and Pd(dppf)Cl.CHCl (34.98 mg, 42.84 μmol). The mixture was stirred at 100 °C for 2 h under N. LC-MS showed that 37% of the desired mass was detected. The reaction mixture was evaporated and then partitioned between DCM / HO (5 mL / 5 mL). The layers were separated, and the aqueous phase was extracted with DCM (4 mL × 2). The combined organic phases were collected, dried, and concentrated to give a residue that was purified by flash chromatography (ISCO® 4 g SepaFlash® silica gel column) using a gradient of 0 to 15% DCM in MeOH (30 mL / min). The resulting crude product (40 mg) was further purified by preparative SFC (DAICEL CHIRALPAK® IG-10 μm, 30 mm ID × 250 mm column) using a mobile phase of CO2 and 60% EtOH (containing 0.1% NH3OH). The title compound of Example 265 was obtained as a white solid (16 mg). 1H NMR (400 MHz,CD3OD) δ ppm 0.61 - 0.67 (m, 2 H), 0.89 - 0.95 (m, 2 H), 1.74 - 1.92 (m, 1 H), 2.11 - 2.22 (m, 1 H), 2.26 (br s, 5 H), 2.60 (s, 2 H), 2.87 - 3.00 (m, 1 H), 3.15 (br d, J=9.51 Hz, 1 H), 4.41 - 4.50 (m, 2 H), 4.67 - 4.80 (m, 1 H), 4.93 - 5.01 (m, 1 H), 6.85 - 6.97 (m, 2 H), 7.16 - 7.31 (m, 2 H); ESI-MS [M+H] + C 21 H 25 Calculated for FN4O2 384.20, found 385.3. The title compound of Example 264 was obtained as a white solid (22 mg). 1 H NMR (400 MHz,CD3OD) δ ppm 0.45 - 0.51 (m, 2 H), 0.82 - 0.88 (m, 2 H), 1.70 - 1.89 (m, 1 H), 2.10 - 2.21 (m, 1 H), 2.26 - 2.45 (m, 5 H), 2.58 - 2.63 (m, 2 H), 2.98 (br t, J=10.26 Hz, 1 H), 3.11 - 3.24 (m, 1 H), 4.49 - 4.59 (m, 2 H), 4.68 - 4.80 (m, 1 H), 4.94 - 5.01 (m, 1 H), 6.85 - 6.96 (m, 2 H), 7.15 - 7.31 (m, 2H); ESI-MS [M+H] + C 21 H 25 Calculated value for FN4O2: 384.20, measured value: 385.4.

[0458] 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 [ka]

[0459] The title compound was prepared from the starting material 1,7-dioxaspiro[4.4]nonan-3-one using a procedure similar to Example 254. 1 H NMR (400 MHz, CD3OD) δ ppm 1.89 - 2.10 (m, 1 H), 2.37 (s, 3 H), 2.38 - 2.51 (m, 2 H), 2.56 - 2.68 (m, 1 H), 3.00 (d, J=1.51 Hz, 3 H), 3.04 - 3.16 (m, 1 H), 3.34 - 3.42 (m, 1 H), 3.77 - 3.88 (m, 2 H), 3.88 - 3.95 (m, 1 H), 4.00 - 4.09 (m, 1 H), 4.29 - 4.39 (m, 2 H), 4.72 - 4.83 (m, 1 H), 5.26 (dd, J=10.23, 0.94 Hz, 3 H), 6.88 (s, 2 H), 7.26 - 7.32 (m, 1 H);ESI-MS [M+H] + C 22 H 27 Calculated value for FN4O3: 414.21, measured value: 415.7.

[0460] 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 [ka]

[0461] The title compound was prepared from starting materials 1,7-dioxaspiro[4.4]nonan-3-one and (1R,2R)-2-aminocyclohexan-1-ol using a procedure similar to Example 254. 1H NMR (400 MHz,CD3OD) δ ppm 1.24 - 1.55 (m, 4 H), 1.69 - 1.84 (m, 2 H), 2.02 - 2.10 (m, 1 H), 2.34 (s, 6 H), 3.45 - 3.56 (m, 1H), 3.74 - 3.81 (m, 1 H), 3.90 - 4.05 (m, 2 H), 4.20 - 4.40 (m, 2 H), 5.35 (s, 2 H), 6.73 - 6.78 (m, 1H), 6.82 - 6.85 (m, 1H), 7.00 - 7.05 (m, 1H);ESI-MS [M+H] + C 22 H 27 Calculated value for N3O4: 397.2, measured value: 398.4.

[0462] Example 268: 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epoxycyclohepta[d]pyridazin-1-yl)-5-methylphenol [ka]

[0463] 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 (1R,2R)-2-aminocyclohexan-1-ol (71 mg, 0.62 mmol) in toluene (1 mL) was stirred at 100 °C for 16 h in a sealed tube on a metal heating block. The reaction mixture was added to a solution of TFA (2 mL) and DCM (10 mL), stirred at 60 °C for 1 h, and concentrated in vacuo to give the crude product mixture. The product mixture was purified by preparative HPLC (Phenomenex Gemini® C18 column) using a gradient of 10 to 30% ACN (0.035% TFA) in water (0.005% TFA) to give the title compound as a yellow solid (30 mg, 25%). 1 H NMR (400 MHz,CD3OD) δ ppm 1.32 - 1.52 (m, 4 H) 1.59 - 1.81 (m, 3 H), 1.96 - 2.28 (m, 6 H), 2.32 (s, 3 H), 3.06 (s, 1 H), 3.53 - 3.62 (m, 1 ESI-MS [M+H] + C 22 H 27 Calculated value for N3O3: 381.21, measured value: 382.2.

[0464] 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 [ka]

[0465] 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 at 100 °C for 16 h in a sealed tube on a metal heating block. The reaction mixture was added to a solution of TFA (2 mL) and DCM (10 mL), stirred at 60 °C for 1 h, and concentrated in vacuo to give the crude product mixture. The product mixture was purified by preparative HPLC (Phenomenex Gemini® C18 column) using a gradient of 10-30% ACN (0.035% TFA) in water (0.005% TFA) to give the title compound as a yellow oil (50 mg, 44%). 1 H NMR (400 MHz,CD3OD) δ ppm 1.41 (s,3 H),1.69 - 1.82 (m,1 H),2.09 - 2.39 (m,9 H),2.57 - 2.66 (m,2 H), 3.13 (dd, J=18.45, 5.40 Hz, 1 H), 3.92 - 4.02 (m, 1 H), 4.72 - 4.79 (m, 1 H), 5.28 - 5.38 (m, 1 H), 6.78 - 6.88 (m, 1 H), m,2 H),7.15 (d,J=7.78 Hz,1 H);ESI-MS [M+H] + C 21 H 25 Calculated value for N3O3: 367.19, measured value: 368.2.

[0466] 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 [ka]

[0467] 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 (1R,3R)-3-amino-1-methylcyclobutan-1-ol (31 mg, 0.31 mmol) in toluene (1 mL) was stirred at 100 °C for 16 h in a sealed tube on a metal heating block. The reaction mixture was added to a solution of TFA (2 mL) and DCM (10 mL), stirred at 60 °C for 1 h, and concentrated in vacuo to give the crude product mixture. The product mixture was purified by preparative HPLC (Phenomenex Gemini® C18 column) using a gradient of 10-30% ACN (0.035% TFA) in water (0.005% TFA) to give the title compound as a yellow oil (53 mg, 47%). 1 H NMR (400 MHz,CD3OD) δ ppm 1.43 (s, 3 H), 1.71 - 1.81 (m, 1 H), 2.11 - 2.17 (m, 1 H), 2.35 (s, 8 H), 2.53 - 2.62 (m, 2 H), 3.08 - 3.18 (m, 1 ESI-MS [M+H] + C 21 H 25 Calculated value for N3O3: 367.19, measured value: 368.2.

[0468] 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 [ka]

[0469] 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), CsCO (27 mg, 0.082 mmol), Pd(dba) (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 at 100 °C for 16 h in a sealed tube on a metal heating block. The reaction mixture was added to a solution of TFA (2 mL) and DCM (10 mL), stirred at 60 °C for 1 h, and concentrated in vacuo to give the crude product mixture. The product mixture was purified by preparative HPLC (Phenomenex Gemini® C18 column) using a gradient of 10-100% ACN in water (10 mM NH4HCO3, pH = 9.5-10). The title compound was obtained as a colorless oil (2.8 mg, 25%). 1 H NMR (400 MHz,CD3OD) δ ppm 1.66 - 2.32 (m,7 H),2.37 (s,3 H),2.55 - 2.64 (m,1 H),2.95 - 3.02 (m,1 H),2.99 (s, 2 H),3.48 (d, J=1.76 Hz, 1 H),3.80 - 3.88 (m, 2 H),4.76 - 4.82 (m, 2 H),5.24 - 5.37 (m, 2 H),6.66-6.72 (m,2H);ESI-MS [M+H] + C 22 H 26Calculated value for F2N4O2: 416.20, measured value: 417.2.

[0470] 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 [ka]

[0471] 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), CsCO (27 mg, 0.082 mmol), Pd(dba) (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 at 100 °C for 16 h in a sealed tube on a metal heating block. The reaction mixture was added to a solution of TFA (2 mL) and DCM (10 mL), stirred at 60 °C for 1 h, and concentrated in vacuo to give the crude product mixture. The product mixture was purified by preparative HPLC (Phenomenex Gemini® C18 column) using a gradient of 10-100% ACN in water (10 mM NH4HCO3, pH = 9.5-10). The title compound was obtained as a colorless oil (0.8 mg, 7%). 1H NMR (400 MHz,CD3OD) δ ppm 1.69 - 2.35 (m, 7 H), 2.37 - 2.40 (m, 3 H), 2.53 - 2.62 (m, 1 H), 2.98 - 3.01 (m, 3 H), 3.01 - 3.08 (m, 1 H), 3.34 - 3.44 (m, 1 H), 3.76 - 3.89 (m, 2 H), 4.77 - 4.82 (m, 1 H), 4.89 - 4.94 (m, 1 H), 5.20 - 5.40 (m, 1 H), 6.66 - 6.75 (m, 1 H);ESI-MS [M+H] + C 22 H 26 Calculated value for F2N4O2: 416.20, measured value: 417.2.

[0472] Examples 273-300 were prepared in the same manner as the above examples.

[0473] Example 273: (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 [ka]

[0474] 1H NMR (400 MHz,CDCl3) δ ppm 0.46 - 0.53 (m, 2 H), 0.90 - 0.96 (m, 2 H), 1.61 - 1.66 (m, 2 H), 1.74 - 1.78 (m, 1 H), 1.96 - 2.00 (m, 1 H), 2.28 - 2.39 (m, 4 H), 2.62 - 2.72 (m, 2 H), 2.77 - 2.85 (m, 2 H), 2.92 - 2.98 (m, 2 H), 4.49 (dt, J=2.89, 1.57 Hz, 1 H), 4.51 - 4.59 (m, 3 H), 4.60 - 4.64 (m, 1 H), 4.89 - 4.93 (m, 1 H), 6.71 - 6.75 (m, 1 H), 6.92 - 6.94 (m, 1 H), 7.28 - 7.31 (m, 1 H), 11.43 (br s, 1 H);ESI-MS [M+H] + C 23 H 29 Calculated value for FN4O2: 412.23, measured value: 413.2.

[0475] Example 274: (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 [ka]

[0476] 1H NMR (400 MHz,CDCl3) δ ppm 0.69 - 0.75 (m, 2 H), 1.05 - 1.11 (m, 2 H), 1.64 - 1.67 (m, 1 H), 1.72 - 1.79 (m, 1 H), 1.93 - 1.99 (m, 1 H), 2.30 - 2.40 (m, 4 H), 2.55 (d, J=6.78 Hz, 2 H), 2.60 - 2.65 (m, 1 H), 2.66 - 2.77 (m, 2 H), 2.78 - 2.82 (m, 2 H), 4.49 (td, J=4.96, 1.13 Hz, 1 H), 4.53 - 4.58 (m, 1 H), 4.61 (td, J=4.89, 1.51 Hz, 1 H), 4.78 (d, J=1.00 Hz, 2 H), 5.08 - 5.17 (m, 1 H), 6.71 (dd, J=7.91, 1.13 Hz, 1 H), 6.94 (d, J=1.00 Hz, 1 H), 7.03 (d, J=8.03 Hz, 1 H), 11.88 (br s, 1 H);ESI-MS [M+H] + C 23 H 29 Calculated value for FN4O2: 412.23, measured value: 413.2.

[0477] Example 275: 2-(1'-(((1R,2R)-2-hydroxycyclohexyl)amino)-5',8'-dihydrospiro[cyclopropane-1,7'-pyrano[3,4-d]pyridazin]-4'-yl)-5-methylphenol [ka]

[0478] 1H NMR (400 MHz,CDCl3) δ ppm 0.65 - 0.75 (m, 2 H), 1.04 - 1.15 (m, 2 H), 1.26 - 1.38 (m, 2 H), 1.40 - 1.52 (m, 2 H), 1.72 - 1.86 (m, 2 H), 2.11 - 2.26 (m, 2 H), 2.35 (s, 3 H), 2.56 (s, 2 H), 3.44 - 3.55 (m, 1 H), 4.01 - 4.13 (m, 1 H), 4.18 (br d, J=6.53 Hz, 1 H), 4.77 (s, 2 H), 6.72 (dd, J=7.91, 1.13 Hz, 1 H), 6.93 (d, J=0.75 Hz, 1 H), 7.03 (d, J=8.03 Hz, 1 H), 11.53 (s, 1 H);ESI-MS [M+H] + C 22 H 27 Calculated value for N3O3: 381.21, measured value:...

Claims

1. A compound of formula 1, 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, α is a single bond, β is a single bond, (i) X １ is CH ２ , CH(CH ３ ), or X Ｃ and X ２ is O and X ３ is CH ２ Or X Ｃ or X ２ is CH ２ Or X Ｃ and X ３ is O, X ４ is a bond, CH ２ , C.H. ２ CH ２ , or X Ｃ and X Ｃ is C ３－６ Cycloalkylidene and C ３－５ oxacycloalkylidene, each substituted with 0 to 4 substituents independently selected from halo; １ , X ２ , X ３ , and X ４ One or less of X Ｃ or (ii) X １ is C(HR １ ) and X ２ is O, X ３ is C(HR ３ ) and X ４ is CH ２ and R １ and R ３ Together, R １ and R ２ C bridging the carbon atoms to which １－３ represents an alkanediyl, or (iii) X １ is CH ２ and X ２ is C(HR ２ ) and X ３ is O, X ４ is C(HR ４ ) and R ２ and R ４ Together, R ２ and R ４ C bridging the carbon atoms to which １－３ represents an alkanediyl, or (iv) X １ is C(HR １ ) and X ２ is O and X ３ is CH ２ or X ２ is CH ２ and X ３ is O, X ４ is C(HR ４ ) and R １ and R ４ Together, C １－３ represents an alkanediyl, or (v) X １ is C(HR １ ) and X ２ is CH ２ and X ３ is C(HR ３ ) and X ４ is CH ２ and R １ and R ３ Together, R １ and R ３ C bridging the carbon atoms to which １－２ alkanediyloxy or O, or (vi) X １ is C(HR １ ) and X ２ is CH ２ and X ３ is CH ２ and X ４ is C(HR ４ ) and R １ and R ４ Together, R １ and R ４ C bridging the carbon atoms to which １－２ represents alkanediyloxy or O, m is selected from 0, 1, and 2; R ａ and R ｂ are hydrogen and C, respectively. １－４ alkyl, or R ａ and R ｂ is R ａ and R ｂ together with the carbon atoms to which both are attached, ３－６ forms a cycloalkylidene, with the proviso that if m is 2, then R ａ and R ｂ At most one of ａ and R ｂ together with the carbon atom to which it is attached, C ３－６ forming a cycloalkylidene, R ５ Below: (a) C ３－８ Cycloalkyl (substituted with 0 to 5 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) amino (C １－４ substituted with 0 to 2 substituents independently selected from alkyl, and (iii) C １－４ Alkyl, C １－４ Alkylcarbonyl, and C １－４ alkoxy (each substituted with 0-3 substituents independently selected from halo); (b) C ３－８ Heterocyclyl (up to 3 carbon ring atoms are each independently substituted with 0-2 substituents independently selected from: (i) halo, hydroxy, cyano and oxo; (ii) amino (C １－４ substituted with 0 to 2 substituents independently selected from alkyl, and (iii) C １－４ Alkyl, C １－４ Alkylcarbonyl, and C １－４ alkoxy (each substituted with 0-3 substituents independently selected from halo); Nitrogen ring atoms, when present, are unsubstituted or substituted with substituents selected from the following: (i) C １－４ Alkyl, C １－４ Alkylcarbonyl, and C １－４ alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C ３－８ Cycloalkyl-(CH ２ ) ｎ (C ３－８ The cycloalkyl moiety can be halo, C １－４ Alkyl, C １－４ Alkylcarbonyl, C １－４ substituted with 0 to 3 substituents independently selected from alkoxy and oxo; (iii) phenyl-(CH ２ ) ｎ and pyridinyl-(CH ２ ) ｎ (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C １－４ Alkyl, and C １－４ substituted with 0 to 3 substituents independently selected from alkoxy; Said C ３－８ heterocyclyl has only one ring heteroatom selected from nitrogen, oxygen, and sulfur; n is selected from 0 and 1; however, m is 0, and X １ C (HR １ ) and X ２ is CH ２ and X ３ is CH ２ and X ４ C (HR ４ ) and X ８ is CH, α and β are both single bonds, and R １ and R ４ Together, R １ and R ４ represents ethane-1,2-diyl bridging the carbon atoms to which R is bonded; ６ , R １０ and R １１ are each hydrogen, and R ７ is hydroxy, and R ９ is cyano, methyl, or cyclopropyl, R ５ is not 1-methylpiperidin-3-yl, m is 0, and X １ C (HR １ ) and X ２ is CH ２ and X ３ is CH ２ and X ４ C (HR ４ ) and X ８ is CH, α and β are both single bonds, and R １ and R ４ Together, R １ and R ４ represents methane-1,1-diyl or O bridging the carbon atoms to which R is bonded; ６ , R １０ and R １１ are each hydrogen, and R ７ is hydroxy, and R ９ is cyano, methyl, or cyclopropyl, R ５ is not 1-methylpiperidin-3-yl), (c) phenyl (halo, hydroxy, cyano, C １－４ Alkyl, and C １－４ substituted with 0 to 3 substituents independently selected from alkoxy, provided that at least one of said substituents is hydroxy; is selected from R ６ is hydrogen and C １－４ alkyl, X ８ is N and CR ８ is selected from R ７ , R ８ and R １１ are respectively: (i) hydrogen, halo, hydroxy, and cyano; (ii) C １－４ Alkyl and C １－４ alkoxy (each substituted with 0-3 substituents independently selected from halo), and (iii) C ３－８ Cycloalkyl (halo, C １－４ Alkyl, and C １－４ substituted with 0 to 3 substituents independently selected from alkoxy; are independently selected from R ９ and R １０ are respectively: (i) hydrogen, halo, hydroxy, and cyano; (ii) C １－４ Alkyl and C １－４ alkoxy (each substituted with 0-3 substituents independently selected from halo), and (iii) C ３－８ Cycloalkyl (halo, C １－４ Alkyl, and C １－４ substituted with 0 to 3 substituents independently selected from alkoxy; are independently selected from, or R ９ and R １０ form an ethane-1,2-dioxy moiety bridging the carbon atoms to which they are attached).

2. 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, X １ is CH ２ , CH(CH ３ ), or X Ｃ and X ２ is O and X ３ is CH ２ Or X Ｃ and X ２ is CH ２ Or X Ｃ and X ３ is O, X ４ is a bond, CH ２ , C.H. ２ CH ２ , or X Ｃ and X Ｃ is C ３－６ Cycloalkylidene and C ３－５ oxacycloalkylidene, each substituted with 0 to 4 substituents independently selected from halo; １ , X ２ , X ３ , and X ４ One or less of X Ｃ or a pharmaceutically acceptable salt thereof.

3. 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, X １ is CH ２ , (CH (CH ３ ), or X Ｃ and X ２ is O and X ３ is CH ２ Or X Ｃ and X ２ is CH ２ Or X Ｃ and X ３ is O, X ４ is CH ２ Or X Ｃ and X Ｃ is C ３－６ Cycloalkylidene and C ３－５ oxacycloalkylidene, each substituted with 0 to 4 substituents independently selected from halo; １ , X ２ , X ３ , and X ４ One or less of X Ｃ or a pharmaceutically acceptable salt thereof.

4. 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, X １ is C(HR １ ) and X ２ is O, X ３ is C(HR ３ ) and X ４ is CH ２ and R １ and R ３ Together, R １ and R ２ C bridging the carbon atoms to which １－３ The compound or a pharmaceutically acceptable salt thereof, which represents an alkanediyl.

5. 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, X １ is CH ２ and X ２ is C(HR ２ ) and X ３ is O, X ４ is C(HR ４ ) and R ２ and R ４ Together, R ２ and R ４ C bridging the carbon atoms to which １－３ The compound or a pharmaceutically acceptable salt thereof, which represents an alkanediyl.

6. 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, X １ is C(HR １ ) and X ２ is O and X ３ is CH ２ or X ２ is CH ２ and X ３ is O, X ４ is C(HR ４ ) and R １ and R ４ Together, C １－３ The compound or a pharmaceutically acceptable salt thereof, which represents an alkanediyl.

7. 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, X １ is C(HR １ ) and X ２ is CH ２ and X ３ is C(HR ３ ) and X ４ is CH ２ and R １ and R ３ Together, R １ and R ３ C bridging the carbon atoms to which １－２ or a pharmaceutically acceptable salt thereof, wherein R represents alkanediyloxy or O.

8. 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, X １ is C(HR １ ) and X ２ is CH ２ and X ３ is CH ２ and X ４ is C(HR ４ ) and R １ and R ４ Together, R １ and R ４ C bridging the carbon atoms to which １－２ or a pharmaceutically acceptable salt thereof, wherein R represents alkanediyloxy or O.

9. 9. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 8, wherein m is 0.

10. 9. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 8, wherein m is 1 or 2.

11. R ａ and R ｂ are hydrogen and C, respectively. １－４ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, independently selected from alkyl.

12. R ５ teeth, (i) halo, hydroxy, cyano and oxo; (ii) amino (C １－４ substituted with 0 to 2 substituents independently selected from alkyl, and (iii) C １－４ Alkyl, C １－４ Alkylcarbonyl, and C １－４ alkoxy (each substituted with 0-3 substituents independently selected from halo); C substituted with 0 to 5 substituents independently selected from ３－８ 12. The compound or pharmaceutically acceptable salt of any one of claims 1 to 11, which is cycloalkyl.

13. R ５ But C ３－８ Heterocyclyl (having up to three carbon ring atoms: (i) halo, hydroxy, cyano and oxo; (ii) amino (C １－４ substituted with 0 to 2 substituents independently selected from alkyl, and (iii) C １－４ Alkyl, C １－４ Alkylcarbonyl, and C １－４ each independently substituted with 0-2 substituents independently selected from alkoxy, each substituted with 0-3 substituents independently selected from halo; The nitrogen ring atom, if present, is unsubstituted or is one of the following: (i) C １－４ Alkyl, C １－４ Alkylcarbonyl, and C １－４ alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C ３－８ Cycloalkyl-(CH ２ ) ｎ (C ３－８ The cycloalkyl moiety may be halo, C １－４ Alkyl, C １－４ Alkylcarbonyl, C １－４ substituted with 0 to 3 substituents independently selected from alkoxy and oxo; (iii) phenyl-(CH ２ ) ｎ and pyridinyl-(CH ２ ) ｎ (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C １－４ Alkyl, and C １－４ alkoxy) 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein:

14. R ５ But C ３－８ Heterocyclyl, wherein the ring heteroatoms are selected from nitrogen and oxygen and up to three carbon ring atoms are: (i) halo, hydroxy, cyano and oxo; (ii) amino (C １－４ substituted with 0 to 2 substituents independently selected from alkyl, and (iii) C １－４ Alkyl, C １－４ Alkylcarbonyl, and C １－４ alkoxy (each substituted with 0-3 substituents independently selected from halo); each independently substituted with 0 to 2 substituents independently selected from The nitrogen ring atom, if present, is unsubstituted or is one of the following: (i) C １－４ Alkyl, C １－４ Alkylcarbonyl, and C １－４ alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C ３－８ Cycloalkyl-(CH ２ ) ｎ (C ３－８ The cycloalkyl moiety can be halo, C １－４ Alkyl, C １－４ Alkylcarbonyl, C １－４ substituted with 0 to 3 substituents independently selected from alkoxy and oxo; (iii) phenyl-(CH ２ ) ｎ and pyridinyl-(CH ２ ) ｎ (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C １－４ Alkyl, and C １－４ substituted with 0 to 3 substituents independently selected from alkoxy; substituted with a substituent selected from 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein:

15. R ５ But C ３－８ Heterocyclyl, wherein the ring heteroatom is nitrogen and up to three carbon ring atoms are: (i) halo, hydroxy, cyano and oxo; (ii) amino (C １－４ substituted with 0 to 2 substituents independently selected from alkyl, and (iii) C １－４ Alkyl, C １－４ Alkylcarbonyl, and C １－４ alkoxy (each substituted with 0-3 substituents independently selected from halo); each independently substituted with 0 to 2 substituents independently selected from The nitrogen ring atom is unsubstituted or is one of the following: (i) C １－４ Alkyl, C １－４ Alkylcarbonyl, and C １－４ alkylsulfonyl (each substituted with 0-3 substituents independently selected from halo); (ii) C ３－８ Cycloalkyl-(CH ２ ) ｎ (C ３－８ The cycloalkyl moiety can be halo, C １－４ Alkyl, C １－４ Alkylcarbonyl, C １－４ substituted with 0 to 3 substituents independently selected from alkoxy and oxo; (iii) phenyl-(CH ２ ) ｎ and pyridinyl-(CH ２ ) ｎ (The phenyl and pyridinyl moieties may be halo, hydroxy, cyano, C １－４ Alkyl, and C １－４ substituted with 0 to 3 substituents independently selected from alkoxy; substituted with a substituent selected from 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein:

16. R ５ is C ３－８ 16. The compound or pharmaceutically acceptable salt of any one of claims 13 to 15, wherein n is 0;

17. R ５ is phenyl (halo, hydroxy, cyano, C １－４ Alkyl, and C １－４ 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with 0 to 3 substituents independently selected from alkoxy, provided that at least one of said substituents is hydroxy.

18. R ６ 18. The compound or pharmaceutically acceptable salt of any one of claims 1 to 17, wherein is selected from hydrogen and methyl.

19. R ６ 18. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 17, wherein is hydrogen.

20. X ８ is CR ８ 20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein:

21. R ７ and R ８ are both hydrogen, and R １１ Below: (i) hydrogen, halo, and hydroxy, and (ii) C １－３ Alkyl and C １－３ alkoxy (each substituted with 0-3 substituents independently selected from halo); 21. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 20, selected from:

22. R ９ and R １０ are respectively: (i) hydrogen, halo, hydroxy, and cyano; (ii) C １－４ Alkyl and C １－３ alkoxy (each substituted with 0-3 fluoro), and (iii) C ３－５ cycloalkyl (substituted with 0-3 substituents independently selected from methyl and methoxy) 22. The compound or pharmaceutically acceptable salt of any one of claims 1 to 21, independently selected from:

23. The compound of claim 1 selected from the following compounds: 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]pyridazin]-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]pyridazin]-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,3S)-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]pyridazine-5,3′-oxetan]-1-yl)-5-methylphenol, 2-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-7H-spiro[furo[3,4-d]pyridazine-5,3′-oxetan]-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]pyridazin]-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]pyridazin]-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]pyridazin]-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-dihydro-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]heptan-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]heptan-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]pyridazin]-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]pyridazin]-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]pyridazin]-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]pyridazin]-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 foregoing compounds.

24. A compound or a pharmaceutically acceptable salt as defined in any one of claims 1 to 23 for use as a pharmaceutical.

25. A compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 23; and a pharmaceutically acceptable excipient.

26. 24. A compound or a pharmaceutically acceptable salt as defined in any one of claims 1 to 23 for use in the treatment of a disease, disorder, or condition associated with NLRP3.

27. 24. A compound or pharmaceutically acceptable salt as defined in any one of claims 1 to 23 for use in the treatment of a disease, disorder or condition associated with a heterozygous gain-of-function mutation in the NLRP3 gene.

28. 24. A compound or a pharmaceutically acceptable salt as defined in any one of claims 1 to 23 for use in the treatment of cryopyrin-associated periodic fever syndromes (CAPS).

29. 24. A method of treating a disease, disorder, or condition in a subject, comprising administering to the subject a compound or pharmaceutically acceptable salt as defined in any one of claims 1 to 23, wherein the disease, disorder, or condition is associated with NLRP3.

30. 24. A method of treating a disease, disorder, or condition in a subject, comprising administering to the subject a compound or pharmaceutically acceptable salt as defined in 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. 24. A method of treating a disease, disorder, or condition in a subject, comprising administering to the subject a compound or pharmaceutically acceptable salt as defined in any one of claims 1 to 23, wherein the disease, disorder, or condition is cryopyrin-associated periodic fever syndrome (CAPS).

32. 32. The method of claim 31, wherein the cryopyrin-associated periodic fever syndrome is selected from neonatal-onset multisystem inflammatory disease (NOMID / CINCA), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

33. 24. A method of treating a neurodegenerative disease, disorder, or condition in a subject, comprising administering to the subject a compound or pharmaceutically acceptable salt as defined in any one of claims 1 to 23.

34. 24. A method of treating a disease, disorder, or condition in a subject, comprising administering to the subject a compound or pharmaceutically acceptable salt as defined in 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 a pharmaceutically acceptable salt as defined in any one of claims 1 to 23 and at least one additional pharmacologically active agent.

36. 36. The combination of claim 35, wherein the additional pharmacologically active agent is selected from a beta secretase inhibitor, a gamma secretase inhibitor, an HMG-CoA reductase inhibitor, a nonsteroidal anti-inflammatory agent, vitamin E, an anti-amyloid antibody, an antidepressant, an antipsychotic, an anxiolytic, and an anticonvulsant.

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