NLRP3 inflammasome inhibitors

Abstract

This specification generally describes a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof, 1 , R 2A , R 2B , R 2 , R 2D , W, X, Y, and Z have the meanings defined in the specification. Such compounds are useful for inhibiting NLRP3 inflammasome activity and may be useful as therapeutic agents. The present specification also relates to the use of such compounds for treating or preventing diseases or conditions in which NLRP3 inflammasome activity is involved. The present specification further relates to compositions comprising such compounds.

Description

[Technical field]

[0001] Field Described herein are compounds (including salts thereof) that are inhibitors of the NLRP3 inflammasome, uses of such compounds, and compositions containing such compounds. [Background technology]

[0002] background The NLRP3 inflammasome is a multiprotein complex consisting of NLR family pyrin domain-containing 3 (NLRP3) proteins, PYD and CARD domain-containing (ASC, also known as PYCARD), and caspase 1 (CASP1), a stress-sensing pathway that leads to inflammatory responses (Swanson KV et al. Nat Rev Immunol. 2019 Aug;19(8):477-489). Upon activation, these three proteins aggregate into a large multiprotein complex called a speck.

[0003] The NLRP3 protein consists of three domains: PYD, NACHT, and LRR (Sharif H et al. Nature. 2019 Jun;570(7761):338-343). The amino-terminal PYD domain is thought to be important for binding between NLRP3 and the PYD domain of ASC, and the NACHT domain has ATPase activity. This suggests that the LRR domain may regulate oligomerization through conformational changes, and the LRR domain is thought to induce autoinhibition by folding into the NACHT domain. The activity of the NLRP3 protein is further regulated by many post-translational modifications, including phosphorylation and ubiquitination.

[0004] Many cellular stressors, such as pathogen-associated molecular patterns (PAMPs), endogenous danger signals (DAMPs) and environmental irritants, have been shown to aggregate inflammasomes into specks. Inflammasome activation is thought to require two steps (McKee CM et al. J Leukoc Biol. 2020 Sep;108(3):937-952). The first priming step serves to increase the levels of inflammasome components and can be initiated, for example, by lipopolysaccharide (LPS, a common PAMP). LPS is detected through toll-like receptors and NF-kB mediated transcription of NLRP3 and IL1B. A secondary stimulus initiates rapid oligomerization of inflammasome components into specks and produces activated caspase-1.

[0005] In addition to this two-step process, there is evidence that the very high induction of NLRP3 transcription typically promotes inflammasome activation in a single step upon prolonged LPS exposure.

[0006] The downstream effects of activated NLRP3 inflammasome are further expanded by caspase-1 mediated cleavage, thus activating GSDMD. Upon activation, GSDMD forms large pores, resulting in a controlled form of lytic cell death called pyroptosis (Kovacs SB et al. Trends Cell Biol. 2017 Sep;27(9):673-684). In effect, pyroptosis amplifies inflammation by releasing cellular contents, resulting in the recruitment and influx of additional immune cells.

[0007] Dysregulated inflammasome drive, even at low levels, can result in tissue damage and chronic disease over the course of years, as demonstrated for cryopyrin-associated periodic syndromes 1, 2, and 3, where a causative genetic lesion in NLRP3 has been identified (Kacar M et al. Rheumatology (Oxford). 2019 Nov 1;58(Suppl 6):vi31-vi43).

[0008] Activation of the NLRP3 inflammasome is often associated with multiple indications (discussed herein) where its presence or activity in diseased tissues has been demonstrated, and thus inhibiting the NLRP3 inflammasome would resolve unwanted inflammation.

[0009] The NLRP3 inflammasome may modulate both acute kidney injury (AKI) and chronic kidney disease (CKD). Mice lacking NLRP3 inflammasome components and their downstream mediators may be protected from renal injury in experimental models of both AKI and CKD (Hutton HL et al. Nephrology. 2016 21(9):736-744). Inflammation plays a key role in the development of AKI. After an initial ischemia, sepsis, or nephrotoxicity trigger, the release of inflammatory cytokines and chemokines by renal endothelial cells and tubular epithelium may lead to leukocyte recruitment and subsequent kidney injury. The role of the inflammasome in this process is evident in both biomarker studies and experimental models of AKI (Andersen K et al. Kidney Int. 2014 Nov;86(5):965-78). Clinical and experimental studies are demonstrating that both systemic and local renal inflammation play important roles in the development and progression of diabetic kidney disease (DKD) (Tang SCW et al. Nat Rev Nephrol. 2020 Apr;16(4):206-222). Specifically, the NLRP3 inflammasome links the sensing of metabolic stress in the diabetic kidney to the activation of a proinflammatory cascade via induction of IL-1β and IL-18, which leads to chronic injury and renal function decline in CKD / DKD (Shahzad K et al. J Am Soc Nephrol. 2016 Aug;27(8):2270-5).

[0010] There are studies that NLRP3 inflammasome is involved in cardiovascular disease (An N et al. Front Immunol. 2019 Jul 10;10:1592). The relationship between NLRP3 inflammasome and coronary atherosclerotic heart disease via cholesterol crystals / monosodium glutamate and downstream factors and vascular injury has been well described (Jin Y et al. J Am Heart Assoc. 2019 Jun 18;8(12):e012219). In addition, NLRP3 inflammasome may also be involved in the pathological mechanisms of cardiomyopathies, including myocardial infarction (MI), cardiac remodeling, and cardiac hypertrophy (An N et al. Front Immunol. 2019 Jul 10;10:1592).

[0011] Nonalcoholic fatty liver disease (NAFLD) is defined as excess hepatic fat accumulation (steatosis) of more than 5% induced by causes other than alcohol intake. Fatty liver progresses to nonalcoholic steatohepatitis (NASH) with or without fibrosis in a variable percentage of individuals, ultimately resulting in cirrhosis, liver failure and hepatocellular carcinoma in susceptible individuals (Friedman et al Nat Med. 2018 Jul;24(7):908-922). Inflammation involving the NLRP3 inflammasome is involved in the pathology of most acute and chronic liver diseases, including NAFLD, NASH, alcoholic steatohepatitis, chronic hepatitis C virus (HCV) infection, ischemia-reperfusion injury and paracetamol-induced liver injury (Szabo et al Nat Rev Gastroenterol Hepatol 2015; 12:387-400). Hepatic NLRP3 and downstream target mRNA levels are elevated in NASH and correlate with hepatic collagen expression levels in humans. In addition, inducible activation of NLRP3 increases liver fibrosis in mice, and NLRP3 knockout mice are protected from experimentally induced NASH, including hepatitis and fibrosis (Wree et al J Mol Med, 2014, DOI: 10.1007 / s00109-014-1170-1). Inhibition of the NLRP3 inflammasome using a small molecule inhibitor (MCC950) reduced liver inflammation and fibrosis in experimental models of NASH in which mice were fed a high-fat or methionine- and choline-deficient diet (Mridha et al Journal of Hepatology, 2017, DOI: 10.1016 / j.jhep.2017.01.022). Thus, NLRP3 inflammasome inhibition can protect against liver diseases, including NAFLD and NASH.

[0012] Several hyperactivating mutations in NLRP3 are associated with autoinflammatory diseases that result in inappropriate release of inflammatory cytokines, including IL-1β, and inflammatory symptoms. Cryopyrin-associated periodic syndromes (CAPS) include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous arthritis (CINCA) syndrome, or neonatal-onset multisystem inflammatory disease (NOMID) (Booshehri ML et al. J Clin Immunol. 2019 Apr;39(3):277-286).

[0013] The NLRP3 inflammasome has also been implicated in gout and pseudogout, as both monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD), crystals found in gout, are activators of the NLRP3 inflammasome (Martinon F et al. Nature 440: 237-241, 2006). In sarcoidosis, the NLRP3 inflammasome has been identified as one of the key intracellular pathways (Riteau N et al. Eur Respir J. 2020; 55(3):2000149), and increased activity has been demonstrated in the lungs of sarcoid patients.

[0014] Inflammasomes play a role in autoimmune diseases, and evidence suggests that inhibition of the NLRP3 inflammasome may have positive effects in rheumatoid arthritis (RA), multiple sclerosis (MS), Addison's disease, celiac disease, systemic lupus erythematosus (SLE), and vitiligo (Shaw PJ et al. Trends Mol Med. 2011 Feb;17(2):57-64).

[0015] In inflammatory skin diseases, activation of the NLRP3 inflammasome has been demonstrated in acne vulgaris (Li ZJ et al. J Invest Dermatol. 2014 Nov;134(11):2747-2756) and hidradenitis suppurativa (Kelly G et al. Br J Dermatol. 2015 Dec;173(6):1431-9).

[0016] Emerging evidence suggests that persistent activation of NLRP3 may be involved in the progression of several chronic lung diseases, including idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and asthma (De Nardo D. et al. Am J Pathol. 2014 Jan;184(1):42-54).

[0017] In inflammatory bowel disease (IBD), evidence suggests that inflammasome-driven IL-Ιβ and IL-18 play a role in IBD pathology, and NLRP3 inflammasome inhibitors may be effective in ulcerative colitis (UC) and Crohn's disease (Zhen Y et al. Front Immunol. 2019 Feb 28;10:276).

[0018] Therefore, inhibitors of the NLRP3 inflammasome may be useful in treating the diseases and conditions described herein that are associated with the activation of the NLRP3 inflammasome. However, to date, no small molecule synthetic inhibitors of the NLRP3 inflammasome have been approved for medical use.

[0019] Small molecule inhibitors of the NLRP3 inflammasome have been previously discussed, for example, in WO 2020 / 234715; however, notwithstanding the foregoing, there remains a need for additional compounds that are inhibitors of the NLRP3 inflammasome and may be particularly promising for development as therapeutic agents. The compounds disclosed herein may also exhibit improved inhibition of the NLRP3 inflammasome (in vitro and in vivo) compared to other known NLRP3 inflammasome inhibitors. The compounds disclosed herein may also exhibit favorable toxicological profiles (e.g., reduced hERG inhibition), favorable pharmacokinetic profiles, and / or advantageous physical properties (e.g., higher water solubility) compared to other known NLRP3 inflammasome inhibitors. Thus, such compounds may be particularly useful for treating disease conditions in which inhibition of the NLRP3 inflammasome is beneficial. Summary of the Invention

[0020] overview Briefly, this specification describes, in part, a compound of formula (I): [ka] [In the formula, R 1 teeth, [ka] is selected from Each R 3 -H and -C 1-3 independently selected from alkyl, R 4 -H and -C 1-3 alkyl, R 2A , R 2B , R 2C and R 2D are each independently -H, -F, -Cl, -C which is unsubstituted or substituted with 1 to 3 -F substituents; 1-3selected from alkyl, cyclopropyl, -OCF3 and -SO2Me; W, X, Y and Z are each independently CR 5 and N, where none of W, X, Y and Z is N, or one of W, X, Y and Z is N, and the rest of W, X, Y and Z are CR 5 and Each R 5 are independently selected from -H, -Me, and -F. or a pharma- ceutically acceptable salt thereof is described.

[0021] Also described herein, in part, is a pharmaceutical composition comprising a compound according to Formula (I), or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0022] Also described herein, in part, are compounds of Formula (I), or a pharma- ceutically acceptable salt thereof, for use in therapy.

[0023] Also described herein, in part, is a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, for use in treating a subject having a disease or condition in which NLRP3 inflammasome activity is implicated.

[0024] Also described herein, in part, is a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use in the treatment of a disease or condition selected from renal disease, cardiovascular disease, hepatic disease, inflammatory disease, inflammatory skin disease, inflammatory bowel disease, autoimmune disease, and respiratory disease.

[0025] Also described herein, in part, is the use of a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or condition involving NLRP3 inflammasome activity.

[0026] Also described herein, in part, is the use of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or condition selected from renal disease, cardiovascular disease, hepatic disease, inflammatory disease, inflammatory skin disease, inflammatory bowel disease, autoimmune disease, and respiratory disease.

[0027] Also described herein, in part, is a method for treating a disease or condition in which NLRP3 inflammasome activity is implicated in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharma- ceutical acceptable salt thereof.

[0028] Also described herein, in part, is a method for treating a disease or condition selected from renal disease, cardiovascular disease, liver disease, inflammatory disease, inflammatory skin disease, inflammatory bowel disease, autoimmune disease, and respiratory disease in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharma- ceutical acceptable salt thereof.

[0029] Further aspects of the present disclosure will be apparent to those skilled in the art upon reading this specification. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] Description of Exemplary Implementations Many embodiments are detailed throughout this specification and will be apparent to those of skill in the art, and this specification is not to be construed as being limited in any way to the specific embodiments described herein.

[0031] In one embodiment, a compound of formula (I): [ka] [In the formula, R 1 teeth, [ka] is selected from Each R 3 -H and -C 1-3 independently selected from alkyl, R 4 -H and -C 1-3 alkyl, R 2A , R 2B , R 2C and R 2D are each independently -H, -F, -Cl, -C which is unsubstituted or substituted with 1 to 3 -F substituents; 1-3 selected from alkyl, cyclopropyl, -OCF3 and -SO2Me; W, X, Y and Z are each independently CR 5 and N, where none of W, X, Y, and Z is N or one of them is N, and the remainder of W, X, Y, and Z is CR 5 and Each R 5 are independently selected from -H, -Me, and -F. or a pharma- ceutically acceptable salt thereof.

[0032] Part R of the following embodiment 1 , R 2A , R 2B , R 2C , R 2D , R 3 , R 4 , R 5 , W, X, Y, Z, either alone or in combination, may be applied to the description of compounds of formula (I) provided herein.

[0033] In one embodiment, R 1 teeth, [ka] is selected from.

[0034] In one embodiment, R 1 teeth, [ka] is selected from.

[0035] In one embodiment, R 1 teeth, [ka] is selected from.

[0036] In one embodiment, R 1 teeth, [ka] is selected from.

[0037] In one embodiment, R 1 teeth, [ka] is selected from.

[0038] In one embodiment, R 1 teeth, [ka] is selected from.

[0039] In one embodiment, R 1 teeth, [ka] is selected from.

[0040] In one embodiment, R 1 teeth, [ka] It is.

[0041] In one embodiment, R 1 teeth, [ka] It is.

[0042] In one embodiment, each R 3 -H and -C 1-3 alkyl.

[0043] In one embodiment, each R 3 is independently selected from -H and -Me.

[0044] In one embodiment, each R 3 is -H.

[0045] In one embodiment, each R 3 is -Me.

[0046] In one embodiment, R 4 -H and -C 1-3 is selected from alkyl.

[0047] In one embodiment, R 4 is selected from -H and -Me

[0048] In one embodiment, R 4 is -H.

[0049] In one embodiment, R 4 is -Me.

[0050] In one embodiment, R 2A , R 2B , R 2C and R 2D are each independently -H, -F, -Cl, -C which is unsubstituted or substituted with 1 to 3 -F substituents; 1-3It is selected from alkyl, cyclopropyl, -OCF3 and -SO2Me.

[0051] In one embodiment, R 2A , R 2B , R 2C and R 2D are each independently selected from -H, -F, -Cl, -Me, -Et, -n-Pr, -i-Pr, -CH2F, -CHF2, -CF3, cyclopropyl, -OCF3, and -SO2Me.

[0052] In one embodiment, R 2A , R 2B , R 2C and R 2D are each independently selected from -H, -F, -Cl, -Me, -Et, cyclopropyl, -CF3, -OCF3, and -SO2Me.

[0053] In one embodiment, R 2A , R 2B , R 2C and R 2D Two, three or four of R are -H; 2A , R 2B , R 2C and R 2D The remainder is not -H.

[0054] In one embodiment, R 2A , R 2B , R 2C and R 2D Two or three of R are -H; 2A , R 2B , R 2C and R 2D The remainder is not -H.

[0055] In one embodiment, R 2A , R 2B , R 2C and R 2D Two of them are -H and R 2A , R 2B , R 2C and R 2D Two of them are not -H.

[0056] In one embodiment, R 2A , R 2B , R 2C and R 2D Three of them are -H and R 2A , R 2B , R 2C and R 2D One of them is not -H.

[0057] In one embodiment, R 2A is -H, -F, -Cl, -C which is unsubstituted or substituted with 1 to 3 -F substituents 1-3 It is selected from alkyl, cyclopropyl, -OCF3 and -SO2Me.

[0058] In one embodiment, R 2A is selected from -H, -F, -Cl, -Me, -Et, cyclopropyl, -CF3, -OCF3 and -SO2Me.

[0059] In one embodiment, R 2A is selected from -H and -F.

[0060] In one embodiment, R 2A is -H.

[0061] In one embodiment, R 2B is -H, -F, -Cl, -C which is unsubstituted or substituted with 1 to 3 -F substituents 1-3 It is selected from alkyl, cyclopropyl, -OCF3 and -SO2Me.

[0062] In one embodiment, R 2B is selected from -H, -F, -Cl, -Me, -Et, cyclopropyl, -CF3, -OCF3 and -SO2Me.

[0063] In one embodiment, R 2B is selected from -H, -F, -CF3 and -SO2Me.

[0064] In one embodiment, R 2B is selected from -F, -CF3 and -SO2Me.

[0065] In one embodiment, R 2B is -H.

[0066] In one embodiment, R 2B is not -H.

[0067] In one embodiment, R 2B is -F.

[0068] In one embodiment, R 2B is -CF3.

[0069] In one embodiment, R 2B is -SO2Me.

[0070] In one embodiment, R 2C is -H, -F, -Cl, -C which is unsubstituted or substituted with 1 to 3 -F substituents 1-3 It is selected from alkyl, cyclopropyl, -OCF3 and -SO2Me.

[0071] In one embodiment, R 2C is selected from -H, -F, -Cl, -Me, -Et, cyclopropyl, -CF3, -OCF3 and -SO2Me.

[0072] In one embodiment, R 2C is selected from -H and -F.

[0073] In one embodiment, R 2C is -H.

[0074] In one embodiment, R 2D is -H, -F, -Cl, -C which is unsubstituted or substituted with 1 to 3 -F substituents 1-3 It is selected from alkyl, cyclopropyl, -OCF3 and -SO2Me.

[0075] In one embodiment, R 2D is selected from -H, -F, -Cl, -Me, -Et, cyclopropyl, -CF3, -OCF3 and -SO2Me.

[0076] In one embodiment, R 2D is selected from -H and -F.

[0077] In one embodiment, R 2D is -H.

[0078] In one embodiment, R 2D is -F.

[0079] In one embodiment, R 2A and R 2C is -H.

[0080] In one embodiment, R 2A is -H, R 2B is selected from -H, -F, -CF3 and -SO2Me, R 2C is -H, R 2D is -H.

[0081] In one embodiment, R 2A is -H, R 2B is selected from -F, -CF3 and -SO2Me, R 2C is -H, R 2D is -H.

[0082] In one embodiment, R 2A is -H, R 2B is -F, R 2C is -H, R 2D is -H.

[0083] In one embodiment, R 2A is -H, R 2B is -CF3, R 2C is -H, R 2D is -H.

[0084] In one embodiment, R 2A is -H, R 2B is -SO2Me, R 2C is -H, R 2D is -H.

[0085] In one embodiment, R 2A is -H, R 2B is selected from -H or -Cl, R 2C is -H, R 2D is -F.

[0086] In one embodiment, W, X, Y and Z are each independently CR 5 and N, where one of W, X, Y and Z is not N or one of them is N, and the remainder of W, X, Y and Z are selected from CR 5 It is.

[0087] In one embodiment, W, X and Z are each CR 5 and Y is CR 5 Or N.

[0088] In one embodiment, W, X, Y and Z are each CR 5 It is.

[0089] In one embodiment, W, X and Z are each CR 5 and Y is N.

[0090] In one embodiment, one of W, X, Y and Z is CR 5 and one of W, X, Y and Z is not N or one of them is N and the remainder of W, X, Y and Z are CH.

[0091] In one embodiment, each R 5 is independently selected from -H, -Me, and -F.

[0092] In one embodiment, each R 5 is -H.

[0093] In one embodiment, W, X, Y and Z are each CH.

[0094] In one embodiment, W, X and Z are each CH and Y is N.

[0095] In one embodiment, R 1 teeth, [ka] is selected from Each R 3 is independently selected from -H and -Me, and optionally each R 3 is -H, R 4 is selected from -H and -Me, and optionally R 4 is -H, R 2A and R 2C are -H, R 2B is selected from -H, -F, -CF3 and -SO2Me, and optionally R 2B is -CF3, R 2D is selected from -H and -F, and optionally R 2D is -H, One of W, X, Y, and Z is CR 5 and one of W, X, Y and Z is not N or one of them is N, and the remainder of W, X, Y and Z are CH; R 5 is selected from H, -Me and -F.

[0096] In one embodiment, R 1 teeth, [ka] is selected from Each R 3 is independently selected from -H and -Me, and optionally each R 3 is -H, R 4 is selected from -H and -Me, and optionally R 4 is -H, R 2A and R 2C are -H, R 2B is selected from -H, -F, -CF3 and -SO2Me, and optionally R 2B is -CF3, R 2D is selected from -H and -F, and optionally R 2D is -H, One of W, X, Y, and Z is CR 5 and one of W, X, Y and Z is not N or one of them is N, and the remainder of W, X, Y and Z are CH; R 5 is selected from -H, -Me and -F.

[0097] In one embodiment, R 1 teeth, [ka] is selected from Each R 3 is independently selected from -H and -Me, and optionally each R 3 is -H, R 4 is selected from -H and -Me, and optionally R 4 is -H, R 2A and R 2C are -H, R 2B is selected from -H, -F, -CF3 and -SO2Me, and optionally R 2B is -CF3, R 2D is selected from -H and -F, and optionally R2D is -H, W, X and Z are each CH; Y is CH or N.

[0098] In one embodiment, the following: 3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]propane-1,2-diol; 3-[[4-(4-chloro-3-fluoro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; 3-[[4-(4,5-difluoro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; 3-[[4-(2-fluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; 3-[[4-(4-chloro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; 3-[[4-[2-hydroxy-4-(trifluoromethoxy)phenyl]phthalazin-1-yl]amino]propane-1,2-diol; 3-[[4-[2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]propane-1,2-diol; 3-[[4-(2,4-difluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; 3-[[4-(4-chloro-2-fluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; 3-[[4-(2-chloro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; 3-[[4-(2-hydroxy-4-methyl-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; 3-[[4-(2-hydroxy-5-methyl-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; 3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]-7-methyl-phthalazin-1-yl]amino]propane-1,2-diol; 3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]-6-methyl-phthalazin-1-yl]amino]propane-1,2-diol; 2-[4-[[3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-methylsulfonyl-phenol; 2-[4-[[2-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[2-hydroxycyclohexyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]cycloheptanol; 2-(4-((3-hydroxycyclohexyl)amino)phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-((3-hydroxycyclobutyl)amino)phthalazin-1-yl)-5-(trifluoromethyl)phenol; 3-Fluoro-2-(4-((3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)phenol; 2-(4-((3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-[4-[[3-hydroxy-3-methyl-cyclopentyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[1-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol; 5-Chloro-2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 3-Fluoro-2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 5-Chloro-3-fluoro-2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 3-Fluoro-2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethoxy)phenol; 2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-3-(trifluoromethyl)phenol; 5-Ethyl-2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Cyclopropyl-2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 4-Fluoro-2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 4-Fluoro-2-[4-[[2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 3-Fluoro-2-[4-[[2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethoxy)phenol; 5-Chloro-3-fluoro-2-[4-[[2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Chloro-2-[4-[[2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 2-[4-[[3-hydroxy-3-methyl-cyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-(4-((3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol; 3-Fluoro-2-(4-((3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3-Chloro-2-fluoro-6-(4-((3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 4,5-Difluoro-2-(4-((3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3-Fluoro-2-(4-((3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5-Chloro-2-(4-((3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3,5-Difluoro-2-(4-((3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 2-[4-[(2-hydroxy-2-methyl-propyl)amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 5-Chloro-2-[4-[(2-hydroxy-2-methyl-propyl)amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 2-[4-[(2-hydroxy-2-methyl-propyl)amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethoxy)phenol; 5-Chloro-3-fluoro-2-[4-[(2-hydroxy-2-methyl-propyl)amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 3-Fluoro-2-[4-[(2-hydroxy-2-methyl-propyl)amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 5-Fluoro-2-(4-((2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3-Fluoro-2-(4-((2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3-Fluoro-2-(1-((2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol; 5-Fluoro-2-(1-((2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol; 2-[4-[[2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[3-hydroxycyclopentyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-(4-((3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5-Fluoro-2-(4-((3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3-Fluoro-2-(1-((3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol; 3-[[1-[2-hydroxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]amino]propane-1,2-diol; 2-[8-[[3-hydroxycyclohexyl]amino]pyrido[2,3-d]pyridazin-5-yl]-5-(trifluoromethyl)phenol; 3-Fluoro-2-(8-((3-hydroxy-3-methylcyclobutyl)amino)pyrido[2,3-d]pyridazin-5-yl)phenol; 2-[8-[[3-hydroxycyclohexyl]amino]-2-methyl-pyrido[2,3-d]pyridazin-5-yl]-5-(trifluoromethyl)phenol; and 3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]-2-methyl-propane-1,2-diol; or a pharma- ceutically acceptable salt thereof.

[0099] In one embodiment, the following: (2S)-3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-(4-chloro-3-fluoro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-(4-chloro-3-fluoro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-(4,5-difluoro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-(4,5-difluoro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-(2-fluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-(2-fluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-(4-chloro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-(4-chloro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-[2-hydroxy-4-(trifluoromethoxy)phenyl]phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-[2-hydroxy-4-(trifluoromethoxy)phenyl]phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-[2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-[2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-(2,4-difluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-(2,4-difluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-(4-chloro-2-fluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-(4-chloro-2-fluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-(2-chloro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-(2-chloro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-(2-hydroxy-4-methyl-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-(2-hydroxy-4-methyl-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-(2-hydroxy-5-methyl-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-(2-hydroxy-5-methyl-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]-7-methyl-phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]-7-methyl-phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]-6-methyl-phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]-6-methyl-phthalazin-1-yl]amino]propane-1,2-diol; 2-[4-[[(1R,3R)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,3S)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,3S)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,3R)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,3R)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-methylsulfonyl-phenol; 2-[4-[[(1S,3S)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-methylsulfonyl-phenol; 2-[4-[[(1R,3S)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-methylsulfonyl-phenol; 2-[4-[[(1S,3R)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-methylsulfonyl-phenol; 2-[4-[[(1R,2S)-2-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,2R)-2-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,2R)-2-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,2S)-2-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,2S)-2-hydroxycyclohexyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,2R)-2-hydroxycyclohexyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,2R)-2-hydroxycyclohexyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,2S)-2-hydroxycyclohexyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; (1R,2R)-2-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]cycloheptanol; (1S,2S)-2-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]cycloheptanol; (1R,2S)-2-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]cycloheptanol; (1S,2R)-2-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]cycloheptanol; 2-(4-(((1R,3R)-3-hydroxycyclohexyl)amino)phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-(((1S,3S)-3-hydroxycyclohexyl)amino)phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-[4-[[(1S,3R)-3-hydroxycyclohexyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-(4-(((1r,3r)-3-hydroxycyclobutyl)amino)phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-[4-[[(1s,3s)-3-hydroxycyclobutyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 3-Fluoro-2-(4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)phenol; 3-Fluoro-2-(4-(((1r,3r)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)phenol; 2-(4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-(((1r,3r)-3-hydroxy-3-methylcyclobutyl)amino)phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-[4-[[(1R,3R)-3-hydroxy-3-methyl-cyclopentyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,3S)-3-hydroxy-3-methyl-cyclopentyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,3S)-3-hydroxy-3-methyl-cyclopentyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,3R)-3-hydroxy-3-methyl-cyclopentyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[1-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol; 2-[1-[[(1S,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol; 2-[1-[[(1R,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol; 2-[1-[[(1S,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol; 5-Chloro-2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Chloro-2-[4-[[(1S,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Chloro-2-[4-[[(1R,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Chloro-2-[4-[[(1S,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 3-Fluoro-2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 3-Fluoro-2-[4-[[(1S,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 3-Fluoro-2-[4-[[(1R,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 3-Fluoro-2-[4-[[(1S,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 5-Chloro-3-fluoro-2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Chloro-3-fluoro-2-[4-[[(1S,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Chloro-3-fluoro-2-[4-[[(1R,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Chloro-3-fluoro-2-[4-[[(1S,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 3-Fluoro-2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 3-Fluoro-2-[4-[[(1S,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 3-Fluoro-2-[4-[[(1R,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 3-Fluoro-2-[4-[[(1S,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethoxy)phenol; 2-[4-[[(1S,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethoxy)phenol; 2-[4-[[(1R,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethoxy)phenol; 2-[4-[[(1S,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethoxy)phenol; 2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-3-(trifluoromethyl)phenol; 2-[4-[[(1S,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-3-(trifluoromethyl)phenol; 2-[4-[[(1R,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-3-(trifluoromethyl)phenol; 2-[4-[[(1S,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-3-(trifluoromethyl)phenol; 5-Ethyl-2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Ethyl-2-[4-[[(1S,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Ethyl-2-[4-[[(1R,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Ethyl-2-[4-[[(1S,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Cyclopropyl-2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Cyclopropyl-2-[4-[[(1S,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Cyclopropyl-2-[4-[[(1R,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Cyclopropyl-2-[4-[[(1S,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 4-Fluoro-2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 4-Fluoro-2-[4-[[(1S,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 4-Fluoro-2-[4-[[(1R,3R)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 4-Fluoro-2-[4-[[(1S,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 4-Fluoro-2-[4-[[(1R,2R)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 4-Fluoro-2-[4-[[(1S,2R)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 4-Fluoro-2-[4-[[(1R,2S)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 4-Fluoro-2-[4-[[(1S,2S)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 3-Fluoro-2-[4-[[(1R,2R)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 3-Fluoro-2-[4-[[(1R,2S)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 3-Fluoro-2-[4-[[(1S,2R)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 3-Fluoro-2-[4-[[(1S,2S)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,2R)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethoxy)phenol; 2-[4-[[(1S,2S)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethoxy)phenol; 2-[4-[[(1R,2S)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethoxy)phenol; 2-[4-[[(1S,2R)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethoxy)phenol; 5-Chloro-3-fluoro-2-[4-[[(1R,2R)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Chloro-3-fluoro-2-[4-[[(1S,2S)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Chloro-3-fluoro-2-[4-[[(1R,2S)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Chloro-3-fluoro-2-[4-[[(1S,2R)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Chloro-2-[4-[[(1R,2R)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Chloro-2-[4-[[(1S,2S)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Chloro-2-[4-[[(1R,2S)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-Chloro-2-[4-[[(1S,2R)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 2-(4-(((1R,3R)-3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-(((1R,3S)-3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-(((1S,3R)-3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-(((1S,3S)-3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-[4-[[(1R,3R)-3-hydroxy-3-methyl-cyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,3S)-3-hydroxy-3-methyl-cyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,3R)-3-hydroxy-3-methyl-cyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,3S)-3-hydroxy-3-methyl-cyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-(4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol; 2-(4-(((1r,3r)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol; 3-Fluoro-2-(4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3-Fluoro-2-(4-(((1r,3r)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3-Chloro-2-fluoro-6-(4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3-Chloro-2-fluoro-6-(4-(((1r,3r)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 4,5-Difluoro-2-(4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 4,5-Difluoro-2-(4-(((1r,3r)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3-Fluoro-2-(4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 3-Fluoro-2-(4-(((1r,3r)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5-Chloro-2-(4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 5-Chloro-2-(4-(((1r,3r)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3,5-Difluoro-2-(4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3,5-Difluoro-2-(4-(((1r,3r)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 2-[4-[(2-hydroxy-2-methyl-propyl)amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 5-Chloro-2-[4-[(2-hydroxy-2-methyl-propyl)amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 2-[4-[(2-hydroxy-2-methyl-propyl)amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethoxy)phenol; 5-Chloro-3-fluoro-2-[4-[(2-hydroxy-2-methyl-propyl)amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 3-Fluoro-2-[4-[(2-hydroxy-2-methyl-propyl)amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 5-Fluoro-2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 5-Fluoro-2-(4-(((1S,2S)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 5-Fluoro-2-(4-(((1S,2R)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 5-Fluoro-2-(4-(((1R,2S)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3-Fluoro-2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3-Fluoro-2-(4-(((1S,2S)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3-Fluoro-2-(4-(((1S,2R)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3-Fluoro-2-(4-(((1R,2S)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3-Fluoro-2-(1-(((1R,2R)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol; 3-Fluoro-2-(1-(((1S,2S)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol; 3-Fluoro-2-(1-(((1S,2R)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol; 3-Fluoro-2-(1-(((1R,2S)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol; 5-Fluoro-2-(1-(((1R,2R)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol; 5-Fluoro-2-(1-(((1S,2S)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol; 5-Fluoro-2-(1-(((1R,2S)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol; 5-Fluoro-2-(1-(((1S,2R)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol; 2-[4-[[(1S,2R)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,2S)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,2S)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,2R)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-(4-(((1r,3r)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5-Fluoro-2-(4-(((1R,3R)-3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 5-Fluoro-2-(4-(((1S,3S)-3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 5-Fluoro-2-(4-(((1R,3S)-3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 5-Fluoro-2-(4-(((1S,3R)-3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; 3-Fluoro-2-(1-(((1R,3R)-3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol; 3-Fluoro-2-(1-(((1R,3S)-3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol; 3-Fluoro-2-(1-(((1S,3R)-3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol; 3-Fluoro-2-(1-(((1S,3S)-3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol; (2S)-3-[[1-[2-hydroxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]amino]propane-1,2-diol; (2R)-3-[[1-[2-hydroxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]amino]propane-1,2-diol; 2-[8-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[2,3-d]pyridazin-5-yl]-5-(trifluoromethyl)phenol; 2-[8-[[(1S,3R)-3-hydroxycyclohexyl]amino]pyrido[2,3-d]pyridazin-5-yl]-5-(trifluoromethyl)phenol; 2-[8-[[(1R,3R)-3-hydroxycyclohexyl]amino]pyrido[2,3-d]pyridazin-5-yl]-5-(trifluoromethyl)phenol; 2-[8-[[(1S,3S)-3-hydroxycyclohexyl]amino]pyrido[2,3-d]pyridazin-5-yl]-5-(trifluoromethyl)phenol; 3-Fluoro-2-(8-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[2,3-d]pyridazin-5-yl)phenol; 3-Fluoro-2-(8-(((1r,3r)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[2,3-d]pyridazin-5-yl)phenol; 2-[8-[[(1R,3S)-3-hydroxycyclohexyl]amino]-2-methyl-pyrido[2,3-d]pyridazin-5-yl]-5-(trifluoromethyl)phenol; 2-[8-[[(1S,3R)-3-hydroxycyclohexyl]amino]-2-methyl-pyrido[2,3-d]pyridazin-5-yl]-5-(trifluoromethyl)phenol; 2-[8-[[(1R,3R)-3-hydroxycyclohexyl]amino]-2-methyl-pyrido[2,3-d]pyridazin-5-yl]-5-(trifluoromethyl)phenol; 2-[8-[[(1S,3S)-3-hydroxycyclohexyl]amino]-2-methyl-pyrido[2,3-d]pyridazin-5-yl]-5-(trifluoromethyl)phenol; (S)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)-2-methylpropane-1,2-diol; and (R)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)-2-methylpropane-1,2-diol; or a pharma- ceutically acceptable salt thereof.

[0100] In one embodiment, the following: [ka] or a pharma- ceutically acceptable salt thereof.

[0101] In one embodiment, the following: [ka] or a pharma- ceutically acceptable salt thereof.

[0102] In one embodiment, the following: [ka] or a pharma- ceutically acceptable salt thereof.

[0103] Terms not specifically defined herein should be understood to have the meaning that would be given to them by one of ordinary skill in the art in light of this disclosure and context. However, as used herein, unless otherwise indicated, the following terms have the indicated meanings and the following conventions will be observed. In the groups defined below, the number of carbon atoms is often specified before the group, e.g., C 1-3 Alkyl means an alkyl group or radical having 1 to 3 carbon atoms.

[0104] "Alkyl" means a saturated aliphatic branched or straight chain hydrocarbon group having the specified number of carbon atoms. For example, C 1-3 Alkyl means a group having 1 to 3 carbon atoms arranged in a linear or branched manner, for example, -CH2CH2CH3 or -CH(CH3)2.

[0105] "Halogen" means a fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo) radical.

[0106] The chemical names of the compounds described herein were generated using ChemDraw Professional version 19.0.0.22 or Biovia Draw 2020 EE from PerkinElmer®. Those skilled in the art will appreciate that different chemical naming software may generate different chemical names for a particular compound. Where compounds described herein are presented in the form of a chemical name and a chemical formula, in the event of any discrepancy, the formula shall prevail.

[0107] In substituents such as --OH and --CN, the "-" refers to the point of attachment of the substituent to the remainder of the molecule.

[0108] [ka] In fragments such as [ka] specifies the point of attachment of the fragment to the rest of the molecule.

[0109] The term "pharmaceutical acceptable" is used to specify that an object (e.g., a salt, a dosage form, or an excipient) is suitable for use in patients. An exemplary list of pharmaceutical acceptable salts can be found in Handbook of Pharmaceutical Salts: Properties, Selection and Use, PH Stahl and CG Wermuth, editors, Weinheim / Zurich:Wiley-VCH / VHCA, 2002. Suitable pharmaceutical acceptable salts of the compound of formula (I) are, for example, acid addition salts or base addition salts. The acid addition salts of the compound of formula (I) can be formed by contacting the compound with a suitable inorganic or organic acid under conditions known to those skilled in the art. The acid addition salts can be formed, for example, using an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Acid addition salts may also be formed using organic acids selected from the group consisting of trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid, and para-toluenesulfonic acid.

[0110] Thus, in one embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein the pharma- ceutically acceptable salt is a salt of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid or para-toluenesulfonic acid.

[0111] The compounds described herein may form base addition salts. The base addition salts of the compounds of formula (I) can be formed by contacting the compounds with a suitable inorganic or organic base under conditions known to those skilled in the art. For example, it may be possible to prepare an alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., calcium) salt by treating the compounds with an alkali metal or alkaline earth metal hydroxide or alkoxide (e.g., ethoxide or methoxide) or a suitable basic organic amine (e.g., choline or meglumine) in an aqueous medium. Thus, in one embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein the pharma- ceutically acceptable salt is a sodium, potassium, lithium, calcium, choline or meglumine salt.

[0112] In one embodiment, there is provided a compound according to formula (I) or a pharma- ceutically acceptable salt thereof.

[0113] In one embodiment, there is provided a compound according to formula (I):

[0114] In one embodiment, there is provided a pharma- ceutically acceptable salt of a compound of formula (I).

[0115] The compounds and salts described herein may exist in solvated and unsolvated forms.For example, the solvated forms may be hydrated forms, such as hemihydrate, monohydrate, dihydrate, trihydrate or alternative amounts thereof.All such solvated and unsolvated forms of the compounds of formula (I) are included herein.

[0116] Atoms of the compounds and salts described herein may exist as their isotopes. Compounds of formula (I) in which an atom is replaced by one or more of its isotopes (e.g., compounds in which one or more carbon atoms are 11 C or 13 C carbon isotope or one or more hydrogen atoms of the compound of formula (I) 2 H or3 All compounds of formula (I) in which the H isotope is included herein.

[0117] The compounds of the present application may exist in one or more geometric, optical, enantiomeric and diastereomeric forms, including, but not limited to, cis and trans, E and Z, and R, S and meso forms. Unless otherwise specified, reference to a particular compound includes all such isomers, including racemic and other mixtures. Where appropriate, such isomers can be separated from their mixtures by application or adaptation of known methods, such as chromatographic and recrystallization techniques.

[0118] Compounds of formula (I) may contain one or more chiral centers. Unless a structure or chemical name herein indicates chirality, the structure or name is intended to encompass any single stereoisomer and any mixture of stereoisomers (e.g., racemates) corresponding to the structure or name. Structures herein are represented by solid or dashed wedges (i.e., [ka] When a bond is depicted as a solid or dashed wedge, the solid or dashed wedge is intended to indicate the absolute configuration of the chiral center, unless an "or" or "&" chiral flag is present at the chiral center. A group of related chiral flags are indicated with the same integer, e.g., "or1", "&1", "or2", "&2", etc. One of ordinary skill in the art will understand the meaning of the chiral flag at the chiral center. For example, the structure [ka] indicates that the compound is a single stereoisomer with a defined absolute configuration. [ka] indicates that the compound is a single stereoisomer with a defined relative configuration at the flagged chiral centers, but the absolute configuration at the flagged chiral centers is unknown. [ka] indicates that the compound is a mixture of stereoisomers with defined relative configurations at the flagged chiral centers.

[0119] It is well known in the art how such optically active forms can be separated. For example, a single stereoisomer can be obtained by isolation from a mixture of isomers (e.g., a racemate) using, for example, chiral chromatographic separation. In other embodiments, a single stereoisomer can be obtained by, for example, direct synthesis from chiral starting materials.

[0120] According to one embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof, which is a single enantiomer present in enantiomeric excess (%ee) of 95% or more, 98% or more, or 99% or more. Advantageously, the single enantiomer is present in enantiomeric excess of 99% or more.

[0121] According to one embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof, which is a single enantiomer having an enantiomeric excess (%ee) in the range of 95-100%.

[0122] According to one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, in association with a pharma- ceutically acceptable diluent or carrier, the single enantiomer being present in enantiomeric excess (%ee) of 95% or more, 98% or more, or 99% or more. Advantageously, the single enantiomer is present in enantiomeric excess of 99% or more.

[0123] According to one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, in single enantiomer in enantiomeric excess (% ee) in the range of 95-100%, in association with a pharma- ceutically acceptable diluent or carrier.

[0124] The compounds of the present application may exist in one or more tautomeric forms, including, but not limited to, keto and enol forms. Reference to a particular compound includes all tautomeric forms, including mixtures thereof. Thus, a structure shown in this specification as one tautomer is intended to include the other tautomeric forms as well.

[0125] The compounds of formula (I) can be administered in the form of prodrugs. Prodrugs are compounds that are broken down in the human or animal body to release the compounds of formula (I). Such pharma-ceutically acceptable prodrugs of the compounds of formula (I) also form an embodiment. Various forms of prodrugs are known in the art. For example, a) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985) b)A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991) c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992) d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988) and e) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984) Please refer to.

[0126] In one embodiment, there is provided a prodrug of a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof.

[0127] In one embodiment, there is provided an N-oxide of a compound or prodrug of formula (I) as defined herein, or a pharma- ceutically acceptable salt thereof.

[0128] As a result of their NLRP3 inflammasome inhibitory activity, the compounds of formula (I) and their pharma- ceutically acceptable salts are expected to be useful in therapy.

[0129] The term "treatment" is intended to have its ordinary meaning of dealing with a disease or condition to completely or partially alleviate one, some or all of its symptoms or to correct or compensate for the underlying pathology. The term "treatment" also includes "prophylaxis" unless otherwise indicated. The terms "therapeutic" and "therapeutically" should be construed accordingly.

[0130] The term "prevention" is intended to have its ordinary meaning, and includes primary prevention, to prevent the onset of a disease or condition, and secondary prevention, where a disease or condition has already occurred and the patient is protected, either temporarily or permanently, from progression or worsening of the disease or condition or from the onset of new symptoms associated with the disease or condition.

[0131] The term "treatment" is used synonymously with "therapy." Similarly, the term "treating" can be considered as "applying therapy," as "treatment" is defined herein.

[0132] Thus, the compounds or pharmaceutical compositions described herein can be used therapeutically, e.g., to treat a disease or disorder. Also provided is a method of treating a disease or disorder comprising administering a therapeutically effective amount of a compound described herein to a subject or patient in need thereof.

[0133] In one embodiment, there is provided a method for treating a disease or condition in which NLRP3 inflammasome activity is implicated in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof.

[0134] In one embodiment, the present invention relates to a renal disease, such as acute kidney injury, chronic kidney disease and diabetic kidney disease; a cardiovascular disease, such as coronary atherosclerotic heart disease, cardiomyopathy, myocardial infarction, cardiac hypertrophy and ischemia-reperfusion injury; a liver disease, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic steatohepatitis, chronic hepatitis C virus infection and paracetamol-induced liver injury; an inflammatory disease, such as autoinflammatory disorders, cryopyrin-associated periodic syndrome, familial common cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous arthritis (CINCA) syndrome and neonatal-onset multisystem inflammatory disease (NOMID); an inflammatory skin disease, such as inflammatory inflammatory disorders ... A method is provided for treating a disease or condition selected from skin diseases, such as acne vulgaris and hidradenitis suppurativa; inflammatory bowel diseases, such as ulcerative colitis (UC) and Crohn's disease; autoimmune diseases, such as gout, pseudogout, rheumatoid arthritis (RA), multiple sclerosis (MS), Addison's disease, celiac disease, systemic lupus erythematosus (SLE) and vitiligo, and respiratory diseases, such as chronic lung disease, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma, in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof.

[0135] In one embodiment, the present invention is directed to a method for treating acute kidney injury, chronic kidney disease, diabetic kidney disease, coronary atherosclerotic heart disease, cardiomyopathy, myocardial infarction, cardiac hypertrophy, ischemia-reperfusion injury, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic steatohepatitis, chronic hepatitis C virus infection, paracetamol-induced liver injury, autoinflammatory disorders, cryopyrin-associated periodic syndrome, familial common cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous arthritis (CINCA) syndrome, neonatal-onset multisystem inflammatory disease (NOMID), Methods are provided for treating a disease or condition selected from acne vulgaris, hidradenitis suppurativa, ulcerative colitis (UC), Crohn's disease, gout, pseudogout, rheumatoid arthritis (RA), multiple sclerosis (MS), Addison's disease, celiac disease, systemic lupus erythematosus (SLE), vitiligo, chronic lung disease, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0136] In one embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in therapy.

[0137] In one embodiment, there is provided a compound of Formula (I) or a pharma- ceutically acceptable salt thereof for use in treating a subject having a disease or condition in which NLRP3 inflammasome activity is implicated.

[0138] In one embodiment, the present invention relates to a method for treating renal diseases, such as acute kidney injury, chronic kidney disease and diabetic kidney disease; cardiovascular diseases, such as coronary atherosclerotic heart disease, cardiomyopathy, myocardial infarction, cardiac hypertrophy and ischemia-reperfusion injury; liver diseases, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic steatohepatitis, chronic hepatitis C virus infection and paracetamol-induced liver injury; inflammatory diseases, such as autoinflammatory disorders, cryopyrin-associated periodic syndrome, familial common cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous arthritis (CINCA) syndrome and There is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment of a disease or condition selected from neonatal onset multisystem inflammatory disease (NOMID); inflammatory skin diseases such as acne vulgaris and hidradenitis suppurativa; inflammatory bowel diseases such as ulcerative colitis (UC) and Crohn's disease; autoimmune diseases such as gout, pseudogout, rheumatoid arthritis (RA), multiple sclerosis (MS), Addison's disease, celiac disease, systemic lupus erythematosus (SLE) and vitiligo and respiratory diseases such as chronic lung disease, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma.

[0139] In one embodiment, the present invention is directed to a method for treating acute kidney injury, chronic kidney disease, diabetic kidney disease, coronary atherosclerotic heart disease, cardiomyopathy, myocardial infarction, cardiac hypertrophy, ischemia-reperfusion injury, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic steatohepatitis, chronic hepatitis C virus infection, paracetamol-induced liver injury, autoinflammatory disorders, cryopyrin-associated periodic syndrome, familial common cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous arthritis (CINCA). In one embodiment, a compound of formula (I) or a pharmacologic acceptable salt thereof is provided for use in the treatment of a disease or condition selected from: chronic obstructive pulmonary disease (COPD), neonatal onset multisystem inflammatory disease (NOMID), acne vulgaris, hidradenitis suppurativa, ulcerative colitis (UC), Crohn's disease, gout, pseudogout, rheumatoid arthritis (RA), multiple sclerosis (MS), Addison's disease, celiac disease, systemic lupus erythematosus (SLE), vitiligo, chronic lung disease, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma.

[0140] In one embodiment, there is provided the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or condition involving NLRP3 inflammasome activity.

[0141] In one embodiment, the present invention relates to a method for treating renal diseases, such as acute kidney injury, chronic kidney disease and diabetic kidney disease; cardiovascular diseases, such as coronary atherosclerotic heart disease, cardiomyopathy, myocardial infarction, cardiac hypertrophy and ischemia-reperfusion injury; liver diseases, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic steatohepatitis, chronic hepatitis C virus infection and paracetamol-induced liver injury; inflammatory diseases, such as autoinflammatory disorders, cryopyrin-associated periodic syndrome, familial common cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous arthritis (CINCA) syndrome and neonatal There is provided the use of a compound of formula (I) or a pharmacologic acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or condition selected from non-onset multisystem inflammatory disease (NOMID); inflammatory skin diseases such as acne vulgaris and hidradenitis suppurativa; inflammatory bowel disease such as ulcerative colitis (UC) and Crohn's disease; autoimmune diseases such as gout, pseudogout, rheumatoid arthritis (RA), multiple sclerosis (MS), Addison's disease, celiac disease, systemic lupus erythematosus (SLE) and vitiligo and respiratory diseases such as chronic lung disease, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma.

[0142] In one embodiment, the present invention is directed to a method for treating acute kidney injury, chronic kidney disease, diabetic kidney disease, coronary atherosclerotic heart disease, cardiomyopathy, myocardial infarction, cardiac hypertrophy, ischemia-reperfusion injury, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic steatohepatitis, chronic hepatitis C virus infection, paracetamol-induced liver injury, autoinflammatory disorders, cryopyrin-associated periodic syndrome, familial common cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous arthropathy (CINCA) syndrome, There is provided the use of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or condition selected from neonatal-onset multisystem inflammatory disease (NOMID), acne vulgaris, hidradenitis suppurativa, ulcerative colitis (UC), Crohn's disease, gout, pseudogout, rheumatoid arthritis (RA), multiple sclerosis (MS), Addison's disease, celiac disease, systemic lupus erythematosus (SLE), vitiligo, chronic lung disease, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma.

[0143] The term "therapeutically effective amount" refers to an amount of a compound of formula (I) described in any of the embodiments herein that is effective to provide a "therapy" in a subject or to "treat" a disease or condition in a subject. A therapeutically effective amount may cause any observable or measurable change in a subject, as described in the definitions of "therapy", "treatment" and "prevention" above. As will be appreciated by those skilled in the art, an effective amount may vary depending on the route of administration, the use of excipients, and the combination with other agents. For example, when a combination therapy is used, the amount of a compound of formula (I) or a pharma- ceutically acceptable salt described herein and the amount of another pharma- ceutical active agent, when combined, are collectively effective to treat a targeted disorder or condition in a subject. In this context, the combined amount is a "therapeutically effective amount" if, when combined, they are sufficient to reduce the symptoms of a disease or condition that responds to inhibition of the NLRP3 inflammasome as described above. Typically, such amounts can be determined by one of ordinary skill in the art from, for example, the dosage ranges set forth herein for the compounds of Formula (I) or their pharma- ceutically acceptable salts and approved or otherwise published dosage ranges for other pharma- ceutically active compounds.

[0144] A "subject" includes, for example, mammals, such as humans.

[0145] The compounds of formula (I) and their pharma- ceutically acceptable salts may be administered as pharmaceutical compositions containing one or more pharma- ceutically acceptable excipients.

[0146] Thus, in one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

[0147] The excipients selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition provided. Suitable pharma-ceutically acceptable excipients are well known to those skilled in the art and are described, for example, in Handbook of Pharmaceutical Excipients, Sixth edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients may function, for example, as adjuvants, diluents, carriers, stabilizers, flavorings, colorings, fillers, binders, disintegrants, lubricants, glidants, thickeners and coatings. As those skilled in the art will understand, a particular pharma-ceutically acceptable excipient may perform one or more functions, or may perform alternative functions, depending on how much of the excipient is present in the composition and what other excipients are present in the composition.

[0148] In one embodiment, a pharmaceutical composition is provided comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient, wherein the amount of the pharma- ceutically acceptable excipient in the composition is 1 mg or more. In a further embodiment, the amount of the pharma- ceutically acceptable excipient in the composition is 10 mg or more. In a further embodiment, the amount of the pharma- ceutically acceptable excipient in the composition is 100 mg or more.

[0149] The pharmaceutical composition may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), inhalation (e.g., as fine powders or liquid aerosols), insufflation (e.g., as fine powders) or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular or intramuscular administration, or as suppositories for rectal administration). The composition may be obtained by conventional techniques well known in the art. Compositions intended for oral use may contain additional ingredients, such as one or more colorants, sweeteners, flavors and / or preservatives.

[0150] The compound represented by formula (I) is usually administered at a concentration of 2.5 to 5000 mg / m 2 The subject will be administered a unit dose in the range of about 0.05-100 mg / kg or body surface area of ​​the subject. This will usually provide a therapeutically effective dose. A unit dosage form, such as a tablet or capsule, may contain, for example, 0.1-400 mg active ingredient. The daily dosage will necessarily vary depending on the host being treated, the particular route of administration, any concurrent therapy, and the severity of the disease or condition being treated.

[0151] The pharmaceutical compositions described herein comprise a compound of formula (I) or a pharma- ceutically acceptable salt thereof and are therefore expected to be useful in therapy.

[0152] Thus, in one embodiment, there is provided a pharmaceutical composition as disclosed herein for use in therapy.

[0153] In one embodiment, there is provided a pharmaceutical composition disclosed herein for use in treating a subject having a disease or condition in which NLRP3 inflammasome activity is implicated.

[0154] In one embodiment, the present invention is directed to renal diseases, such as acute kidney injury, chronic kidney disease and diabetic kidney disease; cardiovascular diseases, such as coronary atherosclerotic heart disease, cardiomyopathy, myocardial infarction, cardiac hypertrophy and ischemia-reperfusion injury; liver diseases, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic steatohepatitis, chronic hepatitis C virus infection and paracetamol-induced liver injury; inflammatory diseases, such as autoinflammatory disorders, cryopyrin-associated periodic syndrome, familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous arthritis (CINCA). In one embodiment, the pharmaceutical compositions disclosed herein are for use in the treatment of a disease or condition selected from: chronic pulmonary disease, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and asthma.

[0155] In one embodiment, the present invention relates to a method for treating acute kidney injury, chronic kidney disease, diabetic kidney disease, coronary atherosclerotic heart disease, cardiomyopathy, myocardial infarction, cardiac hypertrophy, ischemia-reperfusion injury, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic steatohepatitis, chronic hepatitis C virus infection, paracetamol-induced liver injury, autoinflammatory disorders, cryopyrin-associated periodic syndrome, familial common cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous arthritis (CARD), chronic inflammatory bowel disease (CIDR), chronic inflammatory bowel disease (CICD ... In one embodiment, a pharmaceutical composition as disclosed herein is provided for use in treating a disease or condition selected from: myeloma, myeloadenitis, pulmonary fibrosis (MYC), myeloadenitis purulenta (MYC), myeloadenitis purulenta (MYC), myeloadenitis purulenta (MYC), myeloadenitis cerebral fibrosis ...

[0156] Synthesis method The compounds of formula (I) can be prepared by following the procedures of the following schemes using appropriate materials, and are further illustrated by the specific examples provided herein. Furthermore, by utilizing the procedures described herein, those skilled in the art can easily prepare additional compounds that fall within the scope of the claims. The examples further illustrate the details for preparing the compounds disclosed herein. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparation procedures can be used to prepare these compounds.

[0157] The compounds exemplified herein can also be isolated in the form of pharma- ceutically acceptable salts, such as those described herein above.

[0158] Reactive functional groups (e.g., hydroxy) in intermediates used in the preparation of compounds of formula (I) may need to be protected to avoid undesired participation in the reaction leading to the formation of the compound. Conventional protecting groups can be used, such as those described in PGM Wuts in "Greene's Protective Groups in Organic Synthesis", Fifth Edition., John Wiley & Sons Inc., 2014. For example, if a phenolic hydroxy group is protected as a methyl ether, the protecting group can be removed by using BBr3 in dichloromethane. Benzyl protecting groups can be removed by hydrogenation over a palladium catalyst, and para-methoxybenzyl groups can be removed using HCl in alcohol. Acetal protecting groups of diols can be removed by treatment with acid (e.g., AcOH / H2O or HCl in 1,4-dioxane).

[0159] [ka] Compound 6 can be prepared by the process shown in Scheme 1. Compound 1 can be reacted with amino alcohol (2) in the presence of a base (e.g., DIPEA) in a polar solvent (e.g., NMP) to give compound 3. R 5 When is not -H, the resulting regioisomers can be separated using a suitable separation technique, for example, chromatography. Compound 3 can be reacted with an optionally protected aryl boronic acid / boronic ester (4) in the presence of a suitable transition metal catalyst in a Suzuki cross-coupling reaction to give compound 5. PG 1 is a suitable phenolic hydroxy protecting group, such as methyl, benzyl, or 4-methoxybenzyl. Compound 6 can be converted to PG using appropriate conditions. 1 This is provided by removing protecting groups (if present).

[0160] [ka] Compound 10 can be prepared by the process shown in Scheme 2. Compound 1 can be reacted with an optionally protected aminodiol (7) in the presence of a base (e.g., DIPEA) in a polar solvent (e.g., NMP) to give compound 8. PG 2 is a suitable protecting group for a diol, e.g., an acetal. 5 When is not -H, the resulting regioisomers can be separated using a suitable separation technique, for example, chromatography. Compound 8 can be reacted with an optionally protected aryl boronic acid / boronic ester (4) in the presence of a suitable transition metal catalyst in a Suzuki cross-coupling reaction to give compound 9. PG 1 is a suitable phenolic hydroxy protecting group, such as methyl, benzyl, or 4-methoxybenzyl. Compound 10 can be converted to PG using appropriate conditions. 1 and P.G. 2Alternatively, an unprotected aminodiol can be used in the first step and the protecting group PG is removed prior to the Suzuki cross-coupling reaction. 2 can be introduced.

[0161] The aza derivatives of compounds 6 and 10 can be prepared using the processes depicted in Schemes 1 and 2, substituting compounds 11 and 12 for compound 1, and separating the resulting regioisomers using an appropriate separation technique, e.g., chromatography. [ka]

[0162] [ka] Compound 17 can be prepared by the process shown in Scheme 3. Compound 14 is provided by lithium-halogen exchange of compound 13 with an alkyllithium (e.g., n-BuLi) in a solvent such as THF, followed by addition to 3-(tert-butyl) 4-methylpyridine-3,4-dicarboxylate and reaction with hydrazine. PG 1 is a suitable phenolic hydroxy protecting group, e.g., methyl, benzyl, or 4-methoxybenzyl. Compound 16 can be chlorinated with a chlorinating agent, e.g., phosphoryl trichloride, in the presence of a base (e.g., pyridine) and a solvent (e.g., 1,4-dioxane), followed by reaction with amino alcohol 15 in the presence of a base (e.g., triethylamine) and a polar solvent (e.g., MeCN). Alternatively, compound 16 can be coupled with amino alcohol 15 in the presence of a coupling reagent (e.g., BOP) and a base (e.g., DBU) in the presence of a polar solvent (e.g., DMF) to give compound 17. Compound 17 can be prepared by the conversion of PG from compound 16 using appropriate conditions. 1 This is provided by removing the protecting group.

[0163] In the above schemes 1 to 3, [ka] is R as described herein. 1 Represents. EXAMPLES

[0164] Working Example The compounds described herein are further illustrated in the following examples, which are offered by way of illustration only and are not limiting.

[0165] In the examples, high-resolution mass spectra were recorded on a Micromass LCT mass spectrometer equipped with an electrospray interface (LC-HRMS).

[0166] 1 H NMR measurements were performed on Bruker Avance III 300, 400, 500 and 600 spectrometers at 300, 400, 500 and 600 MHz, respectively. 1 H frequency. Experiments were typically recorded at 25° C. Chemical shifts are given in ppm using the solvent as internal standard. Protons on heteroatoms, e.g., NH and OH protons, when detected by NMR, are reported only and may be missing. The following abbreviations (and derivatives thereof, e.g., dd, doublet of doublet, etc.) have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet.

[0167] Flash chromatography was performed using either normal phase silica FLASH+® (40M, 25M or 12M), Biotage® SNAP Cartridges KP-Sil (340, 100, 50 or 10), Biotage® SNAP Cartridges KP-NH (340, 100, 50 or 10) or Agela® Flash Column Silica-CS Cartridges (330, 180, 120, 80) unless otherwise stated.

[0168] Reverse phase flash chromatography was performed using Agela® C-18 spherical 20-35 μM 100A cartridges unless otherwise stated.

[0169] Purification was performed by preparative HPLC, preparative SFC or reverse phase flash chromatography on standard equipment using MS or UV triggered fraction collection and using the conditions specified.

[0170] Generally, all solvents used were of commercial analytical grade. Anhydrous solvents were always used for reactions.

[0171] Microwave reactions were carried out in a Biotage® Initator+ using a suitable glass reactor.

[0172] The intermediates and examples named below were named using ChemDraw Professional version 19.0.0.22 from PerkinElmer or Biovia Draw 2020 EE. One of skill in the art will appreciate that different chemical naming software may generate different chemical names for a particular compound.

[0173] List of abbreviations AcOH = acetic acid aq.=aqueous solution BOP = (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate d=day DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene DCM = dichloromethane DIPEA = N,N-diisopropylethylamine DMAP = dimethylaminopyridine DME = dimethoxyethane DMF = Dimethylformamide DMSO = dimethyl sulfoxide DMSO-d6 = Hexadeuterodimethyl sulfoxide Et2O = diethyl ether EtOAc = ethyl acetate EtOH = ethanol h=time HPLC = High Performance Liquid Chromatography IPA = 2-propanol IPE = Isopropyl Ether iPrOAc = isopropyl acetate KOAc = Potassium Acetate LCMS = Liquid Chromatography Mass Spectrometry MeCN = acetonitrile MeLi = methyllithium MeOH = methanol min=minutes MS(ESI) / HRMS(ESI) = Mass spectrometry (electrospray ionization) / High-resolution mass spectrometry MTBE = tert-butyl methyl ether NaOAc = Sodium Acetate n-BuLi = 1-Butyl lithium n-BuNH2 = 1-butylamine NMP = N-methyl-2-pyrrolidone Pd / C = palladium supported on carbon PdCl2(Amphos)2 = Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) Pd(dppf)Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl2·CH2Cl2=[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane Pd(PPh3)4 = Tetrakis(triphenylphosphine)palladium(0) PMBCl = 4-Methoxybenzyl chloride rt=room temperature RT=retention time sat.=saturated SFC = Supercritical Fluid Chromatography SPhos Pd G3 = (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = Thin Layer Chromatography Xphos Pd G3 = (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0174] Intermediates Intermediate 1 Step 1: Intermediate 2: tert-Butyl 4-[2-methoxy-4-(trifluoromethyl)benzoyl]pyridine-3-carboxylate [ka] To a solution of 1-bromo-2-methoxy-4-(trifluoromethyl)benzene (37.7 g, 148.0 mmol, 1.0 equiv.) in THF (100 mL) was added n-BuLi (100 mL, 158.0 mmol, 1.1 equiv.) (1.6 M in hexanes) at -78 °C and the solution was stirred at -78 °C. After 10 min, O3-tert-butyl O4-methyl pyridine-3,4-dicarboxylate (35.1 g, 148.0 mmol, 1.0 equiv.) in THF (20 mL) was added dropwise via syringe over 20 min and the reaction mixture was stirred at -78 °C for 2 h. To the mixture was added AcOH (9.1 mL) in 350 mL H2O at -78 °C and the reaction mixture was brought to room temperature. EtOAc was added to the mixture, the two phases were separated and the aqueous phase was extracted with EtOAc. The organic phase was dried over Na2SO4 and evaporated to give the title compound (57.5 g, 62%) as a brown oil. MS (ESI): m / z [M+H] + :382.2.

[0175] Step 2: Intermediate 3: 1-[2-Methoxy-4-(trifluoromethyl)phenyl]-3H-pyrido[3,4-d]pyridazin-4-one [ka] Intermediate 2 (57.4 g, 91.8 mmol, 61 wt% purity) was dissolved in EtOH (306 mL), hydrazine monohydrate (26.8 mL, 551.1 mmol, 6.0 equiv) was added, the mixture was stirred for 10 min, then 4.0 M aqueous NaOH (92.0 mL, 367.4 mmol, 6.0 equiv) was added. The reaction mixture was stirred at room temperature for 2 h. AcOH (31.5 mL, 551.1 mmol, 6.0 equiv) was added to the mixture and the product started to precipitate. The reaction mixture was filtered and the solid was washed with EtOH / H2O (1:1, 400 mL) and dried to give the title compound (21.7 g, 68%) as a pale yellow solid. MS (ESI): m / z [M+H] + :322.1. 1H NMR (400 MHz, DMSO-d6) δ 3.81 (s, 3H), 7.21 (dd, 1H), 7.47 - 7.54 (m, 2H), 7.63 (d, 1H), 8.94 (d, 1H), 9.51 (d, 1H), 13.24 (br s, 1H).

[0176] Step 3: Intermediate 1: 4-chloro-1-[2-methoxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazine [ka] To a suspension of intermediate 3 (32 g, 100 mmol) and phosphoryl trichloride (200 g, 1304 mmol) in 1,4-dioxane (100 mL) was added pyridine (12 mL, 149.6 mmol) at room temperature. The mixture was heated to 110 °C and stirred for 1 h. The mixture was concentrated under vacuum, then the residue was azeotroped with toluene. The residue was dissolved in CHCl3 (amylene added) and brine, and the layers were separated. The aqueous layer was extracted with EtOAc, the combined organic layers were dried over Na2SO4, and concentrated under vacuum. The residue was azeotroped with toluene, then the crude mixture was triturated with hexane / EtOAc (8:2) and filtered to give intermediate 1 (22.3 g, 66%) as a brown solid. MS (ESI): m / z [M+H] + :340.1 / 342.1. 1 H NMR (400 MHz, CDCl3) δ 3.78 (s, 3H), 7.31 (s, 1H), 7.43 (dd, 1H), 7.45 - 7.49 (m, 1H), 7.63 (dd, 1H), 9.04 (d, 1H), 9.82 (d, 1H).

[0177] Intermediates 4 and 5 Step 1: Intermediate 6: tert-Butyl N-[(1R,3S)-3-hydroxycyclopentyl]carbamate [ka] To a solution of (1S,3R)-3-aminocyclopentanol hydrochloride (3.0 g, 21.8 mmol) and TEA (6.1 mL, 43.6 mmol) in THF (50 mL) was added di-tert-butyl dicarbonate (5.7 g, 26.2 mmol) at room temperature. The mixture was heated to 60 °C and stirred for 16 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a gradient of 40-100% EtOAc in hexanes as the mobile phase to give the title compound (4.3 g, 97%) as a colorless syrup. MS (ESI): m / z [M+H] + :202.0. 1 H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 1.57 - 1.67 (m, 1H), 1.70 - 1.83 (m, 2H), 1.87 - 2.12 (m, 2H), 2.31 - 2.52 (m, 1H), 3.96 - 4.09 (m, 1H), 4.31 - 4.42 (m, 1H), 5.05 - 5.33 (m, 1H).

[0178] Step 2: Intermediate 7: tert-Butyl N-[(1R)-3-oxocyclopentyl]carbamate [ka] To a solution of intermediate 6 (4.3 g, 21.1 mmol) in CH2Cl2 (100 mL) was added (1,1-diacetoxy-3-oxo-1λ 5 ,2-Benzoiodoxol-1-yl)acetate (13.5 g, 31.8 mmol) was added slowly at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and stirred for 20 min, then saturated aqueous Na2S2O3 was added to the mixture and stirred for 20 min. The mixture was extracted with CHCl3. The organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography using a gradient of 10-60% EtOAc in hexane as mobile phase to give the title compound (3.8 g, 90%) as a colorless powder.1 H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 1.78 - 1.91 (m, 1H), 2.07 - 2.16 (m, 1H), 2.17 - 2.29 (m, 1H), 2.30 - 2.43 (m, 2H), 2.62 (dd, 1H), 4.23 (br d, 1H), 4.64 (br s, 1H).

[0179] Step 3: Intermediate 4: tert-Butyl N-[(1R,3S)-3-hydroxy-3-methyl-cyclopentyl]carbamate and intermediate 5: tert-butyl N-[(1R,3R)-3-hydroxy-3-methyl-cyclopentyl]carbamate [ka] To a solution of intermediate 7 (3.8 g, 19.0 mmol) in THF (160 mL) was added MeLi (24.5 mL, 3.1 mol / L in Et2O, 76 mmol) dropwise at -78 °C, and the mixture was stirred at -78 °C. After 1 h, MeLi (24.5 mL, 3.1 mol / L in Et2O, 76 mmol) was added dropwise to the reaction mixture at -78 °C, and the mixture was stirred at -78 °C for 1 h. Saturated aqueous NH4Cl was added to the mixture, and the mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography using a gradient of 20-70% EtOAc in hexanes as the mobile phase to give intermediate 4 (926 mg, 23%) as a colorless liquid, and intermediate 5 (779 mg, 19%) as a colorless liquid. Intermediate 4: 1H NMR (400 MHz, CDCl3) δ 1.36 (s, 3H), 1.43 (s, 9H), 1.54 - 1.62 (m, 1H), 1.63 - 1.70 (m, 1H), 1.73 - 1.86 (m, 2H), 1.87 - 1.97 (m, 1H), 2.06 - 2.16 (m, 1H), 2.44 (br s, 1H), 3.96 - 4.16 (m, 1H), 5.30 (br s, 1H). Intermediate 5: 1 H NMR (400 MHz, CDCl3) δ 1.37 (s, 3H), 1.44 (s, 11H), 1.66 - 1.84 (m, 2H), 1.95 - 2.04 (m, 1H), 2.11 - 2.20 (m, 1H), 2.21 - 2.33 (m, 1H), 4.11 - 4.30 (m, 1H), 4.55 (br s, 1H).

[0180] Intermediate 8: 3-(tert-butyl)4-methyl pyridine-3,4-dicarboxylate [ka] Tert-butanol (200 mL) was added to 4-(methoxycarbonyl)nicotinic acid (25.0 g, 138 mmol), followed by di-tert-butyl dicarbonate (60.2 g, 276 mmol) and pyridine (25 mL). DMAP (100 mg, catalytic) was added and the reaction was stirred at 35° C. overnight. Water and iPrOAc were added and the two phases were separated. The organic extract was washed with two portions of water, evaporated, and the residue was evaporated with toluene twice. The residue was filtered through a silica column using 40% MTBE in heptane as the mobile phase to give the title compound (27.7 g, 84%) as a pale yellow oil. 1 H NMR (500 MHz, DMSO-d6) δ 1.52 (s, 9H), 3.88 (s, 3H), 7.65 (dd, 1H), 8.87 (d, 1H), 8.96 (d, 1H).

[0181] Intermediate 9: 2-[2-fluoro-6-methoxy-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a solution of 1-fluoro-3-methoxy-5-(trifluoromethyl)benzene (2.00 g, 10.3 mmol) in THF (20 mL) was added n-BuLi (6.5 mL, 10.3 mmol) at -78 °C and the mixture was stirred at -78 °C. After 1 h, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.3 mL, 11.0 mmol) was added to the reaction mixture at -78 °C and the mixture was stirred at -78 °C for 2 h. To the mixture was added 10% aqueous citric acid and EtOAc, the mixture was warmed to room temperature, extracted with EtOAc, washed with brine, dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure. The crude mixture was triturated with IPE and filtered to give the title compound (1055 mg, 32%) as a colorless powder. The solvent was evaporated under reduced pressure and the crude mixture was purified by silica gel column chromatography using a gradient of 20-50% EtOAc in hexanes as the mobile phase to give the title compound (1814 mg, 55%) as a colorless powder. MS (ESI): m / z [M- CH 11 ] - 237.0. 1 H NMR (400 MHz, CDCl3) δ 1.39 (s, 12H), 3.85 (s, 3H), 6.83 (s, 1H), 6.91 (dd, 1H).

[0182] Intermediate 10: [2-Fluoro-6-hydroxy-4-(trifluoromethyl)phenyl]boronic acid [ka] To a solution of intermediate 9 (614.6 mg, 1.9 mmol) in CH2Cl2 (4 mL) at 0 °C, BBr3 (6.0 mL, 6.0 mmol, 1 M in CH2Cl2) was added and stirred at 0 °C for 1 h. The reaction mixture was poured into ice water and extracted with CHCl3. The organic layer was separated and concentrated under vacuum. The residue was triturated with hexane and filtered to give the title compound (285 mg, 50%) as a pink powder. MS (ESI): m / z [MH] - 222.9. 1 H NMR (400 MHz, CDCl3) δ 5.87 (br d, 2H), 6.83 (dd, 1H), 7.00 (s, 1H), 9.07 (s, 1H).

[0183] Intermediate 11: (4-Chloro-2-fluoro-6-hydroxy-phenyl)boronic acid [ka] The title compound (2.2 g, 77%) as a white powder was prepared analogously to Intermediate 10 using (4-chloro-2-fluoro-6-methoxy-phenyl)boronic acid (3.0 g, 14.7 mmol). MS (ESI): m / z [MH] - 188.9 / 190.9. 1 H NMR (400 MHz, CD3OD) δ 3.37 (s, 1H), 6.59 - 6.66 (m, 2H).

[0184] Intermediate 12: 1-Bromo-4-cyclopropyl-2-methoxy-benzene [ka] To a suspension of 1-bromo-4-iodo-2-methoxy-benzene (2.0 g, 6.4 mmol) and potassium;cyclopropyl(trifluoro)borane (1.4 g, 9.7 mmol) in toluene (12 mL) and H2O (6 mL) was added Cs2CO3 (6.3 g, 19.3 mmol), butyldi-1-adamantylphosphine (230 mg, 0.64 mmol) and diacetoxypalladium (74 mg, 0.33 mmol) at room temperature. The mixture was heated at 100 °C and stirred for 6 h. The reaction mixture was cooled to room temperature, H2O was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography using a gradient of 0-10% EtOAc in hexanes as mobile phase to give the title compound (992.7 mg, 48%) as a brown liquid. MS(ESI):m / z [MH] - Not detected. 1 H NMR (400 MHz, CDCl3) δ 0.65 - 0.71 (m, 2H), 0.95 - 1.01 (m, 2H), 1.82 - 1.92 (m, 1H), 3.88 (s, 3H), 6.53 (dd, 1H), 6.65 (d, 1H), 7.38 (d, 1H).

[0185] Intermediate 13: 2-(4-cyclopropyl-2-methoxy-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] The title compound (371 mg, 43%) was prepared as a brown solid similarly to intermediate 9 using intermediate 12 (987.2 mg, 3.1 mmol). MS (ESI): m / z [M+H] + 275.1. 1H NMR (400 MHz, CDCl3) δ 0.70 - 0.75 (m, 2H), 0.93 - 1.00 (m, 2H), 1.33 (s, 12H), 1.88 (tt, 1H), 3.82 (s, 3H), 6.59 (d, 1H), 6.62 (dd, 1H), 7.57 (d, 1H).

[0186] Intermediate 14: 2-[5-Fluoro-2-methoxy-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a solution of 1-fluoro-5-iodo-4-methoxy-2-(trifluoromethyl)benzene (2.8 g, 8.8 mmol) in 1,4-dioxane (30 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.8 g, 11.0 mmol), KOAc (2.5 g, 25.4 mmol) and Pd(dppf)Cl2·CH2Cl2 (689 mg, 0.84 mmol) at room temperature. The mixture was heated at 100 °C and stirred for 4 h. The reaction mixture was cooled to room temperature, H2O was added and the mixture was filtered. The filtrate was extracted with EtOAc (2 times). The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 10-40% EtOAc in hexanes as the mobile phase to give a brown gum. The residue was triturated with EtOAc and filtered. The filtrate was concentrated under vacuum to give the title compound (459.7 mg, 16%) as a black gum. MS(ESI): m / z [MH] - Not detected. 1 H NMR (400 MHz, CDCl3) δ 1.36 (s, 12H), 3.85 (s, 3H), 6.99 (d, 1H), 7.46 (d, 1H).

[0187] Intermediate 15 Step 1: Intermediate 16: 2-benzyloxy-1-bromo-4-methylsulfonyl-benzene [ka] To a suspension of sodium hydride (60% in mineral oil, 1.9 g, 48.0 mmol, 1.1 equiv) in DMF (80 mL, 0.5 M) was added benzyl alcohol (5.0 mL, 48.0 mmol, 1.1 equiv) at 0 °C and the solution was stirred for 5 min. Then, 2-bromo-5-methylsulfonylphenol (11.1 g, 43.9 mmol, 1.0 equiv) was added to the mixture at 0 °C. The mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was cooled to 0 °C and then H2O (100 mL) was added slowly. The precipitate was collected by filtration and washed with H2O (100 mL). The precipitate was washed with hexane / EtOAc = 48 / 2 (300 mL) to give the title compound (16.3 g, 47.7 mmol, quant.) as a white solid. MS (ESI): m / z [M+H] + 338.7 / 340.9.

[0188] Step 2: Intermediate 15: 2-(2-benzyloxy-4-methylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a solution of intermediate 16 (13.9 g, 40.6 mmol, 1.0 equiv) in 1,4-dioxane (135 mL) was added bis(pinacolato)diboron (15.5 g, 60.9 mmol, 1.5 equiv), KOAc (10.0 g, 102.0 mmol, 2.5 equiv) and Pd(dppf)Cl2·CH2Cl2 (1.7 g, 2.0 mmol, 0.05 equiv) at room temperature. The mixture was heated to 110 °C and stirred for 26 h. The reaction mixture was cooled to room temperature and filtered through Celite®. The insoluble material was washed with EtOAc (300 mL). The filtrate was washed with H2O (100 mL) and brine (30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 20-40% EtOAc in hexane as the mobile phase to give a pale yellow syrup. The resulting syrup was then crystallized with hexane to give the title compound (11.0 g, 69%) as a white powder; MS (ESI): m / z [M+H] + 389.3.

[0189] Working Example Example 1 : Step 1: Intermediate 17: 4-chloro-N-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]phthalazin-1-amine [ka] To a solution of 1,4-dichlorophthalazine (177 g, 889 mmol, 1.0 equiv) in anhydrous NMP (450 mL) were added DIPEA (310 mL, 1.78 mmol, 2.0 equiv) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (123 g, 938 mmol, 1.05 equiv) at room temperature, and the mixture was stirred at 110 °C for 5 h. The reaction mixture was cooled to room temperature and poured into H2O. The mixture was extracted with EtOAc / Hexane = 1:1 and washed with H2O. The organic layer was evaporated under reduced pressure. The residue was triturated with IPE and filtered to give the title compound (212 g, 81%) as a pale yellow powder. MS (ESI): m / z 294.1 / 296.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 1.28 (s, 3H), 1.38 (s, 3H), 3.50 - 3.77 (m, 3H), 4.00 - 4.20 (m, 1H), 4.40 - 4.48 (m, 1H), 7.83 - 7.91 (m, 1H), 7.97 - 8.04 (m, 2H), 8.05 - 8.11 (m, 1H), 8.35 - 8.41 (m, 1H).

[0190] Step 2: Intermediate 18: 2-[4-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methylamino]phthalazin-1-yl]-5-(trifluoromethyl)phenol [ka] To a suspension of intermediate 17 (203 g, 691 mmol, 1.0 equiv.) and (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (213 g, 1.03 mol, 1.5 equiv.) in 1,4-dioxane (1.7 L) and 2.0 M aqueous Na2CO3 (1.04 L, 2.08 mol, 3.0 equiv.), Pd(dppf)Cl2·CH2Cl2 (11.3 g, 13.8 mmol, 0.02 equiv.) was added and the mixture was stirred and refluxed under argon for 6 h. To the reaction mixture was added (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (28.5 g, 138 mmol) and Pd(dppf)Cl2·CH2Cl2 (11.3 g, 13.8 mmol, 0.02 equiv.). After 3 h, the mixture was cooled to room temperature and poured into H2O and EtOAc. Activated charcoal was added to the solvent, the mixture was stirred and filtered through Celite®. The filtrate was extracted with EtOAc and the organic layer was evaporated under reduced pressure. The crude mixture was purified by flash chromatography (silica; CHCl3 / MeOH=100 / 0-19 / 1-8 / 2). The collected fractions were further purified by flash chromatography (NH silica; CHCl3 / MeOH=100 / 0-39 / 1-8 / 2) to give the title compound (112 g, 39%) as a brown solid. MS (ESI) m / z 420.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 1.29 (s, 3H), 1.40 (s, 3H), 3.60 - 3.73 (m, 1H), 3.76 - 3.87 (m, 2H), 4.01 - 4.10 (m, 1H), 4.46 - 4.55 (m, 1H), 7.25 - 7.33 (m, 2H), 7.41 - 7.57 (m, 2H), 7.69 - 7.91 (m, 3H) 8.32 - 8.38 (m, 1H), 10.3 (br s, 1H).

[0191] Step 3: Example 1: (2S)-3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]propane-1,2-diol [ka] To a suspension of intermediate 18 (112 g, 267 mmol) in AcOH (240 mL) was added H2O (80 mL) and the mixture was stirred at 80 °C for 5 h. The mixture was cooled to room temperature and evaporated under reduced pressure. The crude mixture was purified by flash chromatography (silica; CHCl3 / MeOH = 100 / 0-90 / 10-80 / 20) to give the title compound (65.3 g, 57%) as a colorless solid. The residue (65.3 g + 7.51 g (residue from previous batch)) was triturated with MeOH and filtered. EtOH was added to the resulting solid and the solvent was evaporated under reduced pressure to give the title compound (62.7 g, 86%) as a colorless solid. MS (ESI): m / z 380.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 3.39 - 3.49 (m, 2H), 3.51 - 3.61 (m, 1H), 3.70 - 3.80 (m, 1H), 3.82 - 3.91 (m, 1H), 4.80 - 4.90 (m, 1H), 5.21 - 5.29 (m, 1H), 7.26 - 7.32 (m, 2H), 7.43 - 7.48 (m, 1H), 7.49 - 7.54 (m, 1H), 7.71 (br s, 1H), 7.77 - 7.83 (m, 1H), 7.85 - 7.92 (m, 1H), 8.32 - 8.41 (m, 1H), 10.37 (br s, 1H).

[0192] Examples 2-11 in Table 1 below were synthesized from intermediate 17 using the specific boronic acids listed below similarly to the procedure for Example 1. Example 12 was synthesized using the R-enantiomer of intermediate 17 similarly to the preparation of Example 1. [Table 1] TIFF2024523623000051.tif236169 TIFF2024523623000052.tif100169

[0193] Example 13: Step 1: Intermediate 19: 2-Bromo-1-[(4-methoxyphenyl)methoxy]-4-methyl-benzene [ka] To a suspension of 2-bromo-4-methyl-phenol (1.0 g, 5.3 mmol) and K2CO3 (2.2 g, 16 mmol) in DMF (9 mL) was added PMBCl (1.0 g, 6.4 mmol) at room temperature and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into H2O and extracted with EtOAc. The organic layer was washed with H2O and evaporated under reduced pressure. The crude mixture was purified by flash chromatography (Normal silica; Hexane / EtOAc=95 / 5-80 / 20) to give the title compound (1.7 g, quant.) as a colorless oil. MS (ESI): not detected.

[0194] Step 2: Intermediate 20: 2-[2-[(4-methoxyphenyl)methoxy]-5-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To a suspension of intermediate 19 (1.7 g, 5.5 mmol), NaOAc (1.1 g, 11 mmol) and bis(pinacolate)diboron (1.7 g, 6.7 mmol) in 1,4-dioxane (14 mL), PdCl2(dppf)·CH2Cl2 (0.45 g, 0.55 mmol) was added and the mixture was heated to 100 °C and stirred for 4 h. The mixture was cooled to room temperature, poured into H2O and filtered through Celite®. The solvent was extracted with EtOAc and evaporated under reduced pressure. The crude mixture was purified by flash chromatography (silica; hexane / EtOAc = 100 / 0-80 / 20) to give the title compound (1.73 g, 88%) as a yellow oil. MS (ESI): m / z 355.0 [M+H] + .

[0195] Step 3: Intermediate 21: N-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-4-[2-[(4-methoxyphenyl)methoxy]-5-methyl-phenyl]phthalazin-1-amine [ka]

[0196] To a suspension of intermediate 20 (271 mg, 0.766 mmol), intermediate 17 (150 mg, 0.511 mmol) and Na2CO3 (162 mg, 1.53 mmol) in 1,4-dioxane (2.6 mL) and H2O (0.5 mL) was added SPhos Pd G3 (40 mg, 0.051 mmol). The vial was sealed and the reaction was heated in a microwave reactor at 120 °C for 1 h. The reaction mixture was poured into brine and extracted with CHCl3. The organic layer was evaporated under reduced pressure. The crude mixture was purified by flash chromatography (silica; CHCl3 / MeOH = 100 / 0-93 / 7). The collected fractions were further purified by flash chromatography (NH silica; CHCl3 / MeOH = 100 / 0-90 / 10) to give the title compound (182 mg, 73%) as a yellow amorphous. MS(ESI): m / z 484.4 [MH] -

[0197] Step 4: Example 13: (2S)-3-[[4-(2-hydroxy-5-methyl-phenyl)phthalazin-1-yl]amino]propane-1,2-diol [ka] To a suspension of intermediate 21 (180 mg) in MeOH (1 mL) was added 2M HCl in 1,4-dioxane (1 mL) and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure. The crude mixture was purified by flash chromatography (silica; 100 / 0-85 / 15) and reversed-phase flash chromatography on a C18 column using a gradient of 20-50% MeCN (10 mM, aq.) in (NH4)2CO3 as the mobile phase to give the title compound (55 mg, 46%) as a pale yellow amorphous. MS (ESI): m / z 326.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 2.27 (s, 3H), 3.39 - 3.47 (m, 2H), 3.50 - 3.60 (m, 1H), 3.68 - 3.77 (m, 1H), 3.80 - 3.89 (m, 1H), 4.84 - 4.91 (m, 1H), 5.30 - 5.38 (m, 1H), 6.85 - 6.90 (m, 1H), 6.95 - 7.16 (m, 2H), 7.48 - 7.59 (m, 2H), 7.75 - 7.90 (m, 2H), 8.30 - 8.35 (m, 1H), 9.30 - 9.45 (m, 1H).

[0198] Examples 14 and 15: Step 1: Intermediate 22: 6-Methyl-2,3-dihydrophthalazine-1,4-dione [ka] To a solution of 5-methylisobenzofuran-1,3-dione (5.0 g, 31 mmol) in AcOH (15 mL) was added hydrazine monohydrate (4.9 mL, 0.10 mol) at room temperature and the mixture was stirred at room temperature for 16 h and heated to 110 °C. After 1 h, the mixture was cooled to room temperature and IPE and EtOH were added to the mixture. The precipitate was filtered and poured into H2O. The precipitate was filtered and dried to give the title compound (4.97 g, 91%) as a colorless powder. MS (ESI): m / z 177.1 [M+H] + .

[0199] Step 2: Intermediate 23: 1,4-Dichloro-6-methyl-phthalazine [ka] To a solution of intermediate 22 (4.97 g, 28.2 mmol) in toluene (1.0 mL) and pyridine (4.5 mL) was added phosphoryl trichloride (13.2 mL) at room temperature and the mixture was stirred at 100° C. for 2 h. The mixture was cooled to room temperature and evaporated under reduced pressure. The crude mixture was poured into H2O at 0° C. and stirred at room temperature. The precipitate was filtered and dried to give the title compound (5.10 g, 83%) as a pale yellow powder. MS (ESI): m / z 213.1 / 215.1 [M+H] + .

[0200] Step 3: Intermediate 24: 4-chloro-N-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-7-methyl-phthalazin-1-amine [ka] and intermediate 25: 4-chloro-N-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl]-6-methyl-phthalazin-1-amine [ka] To a solution of intermediate 23 (2.10 g, 9.86 mmol) in anhydrous NMP (10 mL) were added DIPEA (4.11 mL, 29.6 mmol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (1.40 g, 10.7 mmol) at room temperature, and the mixture was stirred at 100° C. for 4 h. The reaction mixture was cooled to room temperature and poured into H2O. The mixture was extracted with EtOAc, and the organic layer was evaporated under reduced pressure. The crude mixture was purified by flash chromatography (silica, hexane / EtOAc=100 / 0-20 / 80) to give a 1:1 mixture of intermediates 22 and 23 (0.898 g, 30%) as a slightly yellow amorphous solid. MS (ESI): m / z 308.1 / 310.1 [M+H] +

[0201] Step 4: Intermediate 26: 2-[4-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methylamino]-6-methyl-phthalazin-1-yl]-5-(trifluoromethyl)phenol [ka] and intermediate 27: 2-[4-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methylamino]-7-methyl-phthalazin-1-yl]-5-(trifluoromethyl)phenol [ka] To a suspension of a 1:1 mixture of intermediate 24 and intermediate 25 (400 mg, 1.30 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (401 mg, 1.95 mmol) and Na2CO3 (413 mg, 3.90 mmol) in 1,4-dioxane (3.2 mL) and H2O (1 mL) was added SPhos Pd G3 (101 mg, 0.130 mmol). The vial was sealed and the reaction was heated at 120 °C in a microwave reactor for 30 min. The reaction mixture was poured into H2O and extracted with CHCl3. The organic layer was evaporated under reduced pressure. The crude mixture was purified by column chromatography (silica, CHCl3 / MeOH = 100 / 0-95 / 5). The collected fractions were further purified by column chromatography (NH silica, CHCl3 / MeOH=100 / 0-95 / 5) to give the title compound (180 mg, 32%) as a yellow amorphous solid. The isolated material had a 6-methyl / 7-methyl ratio of 1:1. MS(ESI): m / z 434.2 [M+H] +

[0202] Step 5: Example 14: (2S)-3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]-7-methyl-phthalazin-1-yl]amino]propane-1,2-diol [ka] and Example 15: (2S)-3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]-6-methyl-phthalazin-1-yl]amino]propane-1,2-diol [ka] To a suspension of a 1:1 mixture of intermediate 26 and intermediate 27 (179 mg, 0.41 mmol) in MeOH (1 mL) was added 2M HCl in 1,4-dioxane (4 mL) and the reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure. The crude mixture was purified by flash chromatography (normal silica; CHCl3 / MeOH=100 / 0-80 / 20) to give Example 14 (24 mg, 15%) as a pale yellow amorphous and Example 15 (64 mg, 39%) as a pale yellow amorphous. Example 14: 1 H NMR (400 MHz, DMSO-d6) δ 2.47 (s, 3H), 3.38 - 3.78 (m, 4H), 3.85 - 3.93 (m, 1H), 7.29 - 7.37 (m, 3H), 7.52 - 7.57 (m, 1H), 7.80 - 7.91 (m, 1H), 8.45 - 8.60 (m, 1H). MS(ESI):m / z 394.1 [M+H] + . Example 15: 1 H NMR (400 MHz, DMSO-d6) δ 2.47 (s, 3H), 3.41 - 3.52 (m, 2H), 3.57 - 3.68 (m, 1H), 3.72 - 3.81 (m, 1H), 3.87 - 3.93 (m, 1H), 7.30 - 7.36 (m, 2H), 7.37 - 7.42 (m, 1H), 7.52 - 7.56 (m, 1H), 7.82 - 7.88 (m, 1H), 8.60 - 8.67 (m, 1H). MS(ESI):m / z 394.1 [M+H] + .

[0203] Example 16 Step 1: Intermediate 28: (1R,3R)-3-[(4-chlorophthalazin-1-yl)amino]cyclopentanol [ka] To a solution of 1,4-dichlorophthalazine (1.40 g, 7.0 mmol) in NMP (9 mL), (1R,3R)-3-aminocyclopentanol; hydrochloride (0.97 g, 7.0 mmol, 1.0 equiv.) and DIPEA (6.1 mL, 35 mmol, 5.0 equiv.) were added at room temperature, and the reaction mixture was heated at 110° C. for 22 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHCO3, and extracted with CHCl3. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude material. The crude compound was purified by column chromatography (silica, CHCl3 / MeOH=100:0-90:10) to give the title compound (1.37 g, 74%) as a brown powder. MS (ESI): m / z 264.1 / 266.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 1.52 - 1.54 (m, 1H), 1.57 - 1.67 (m, 1H), 1.70 - 1.80 (m, 1H), 1.81 - 1.91 (m, 1H), 2.10 - 2.20 (m, 1H), 2.34 - 2.42 (m, 1H), 2.48 - 2.58 (m, 1H), 4.48 - 4.55 (m, 1H), 4.83 - 4.92 (m, 1H), 5.00 - 5.07 (m, 1H), 7.72 - 7.75 (m, 1H), 7.82 - 7.89 (m, 2H), 8.17 - 8.20 (m, 1H).

[0204] Step 2: Example 16: 2-[4-[[(1R,3R)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol [ka] To a solution of intermediate 28 (400 mg, 27.0 mmol, 1.1 equiv) and [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (310 mg, 1.5 mmol, 1.0 equiv) in DME (5.0 mL) was added Pd(dppf)Cl2·CH2Cl2 (124 mg, 0.15 mmol, 0.1 equiv) and 2M aqueous Na2CO3 (2.3 mL, 3.0 equiv) at room temperature. The mixture was heated at 85 °C and stirred for 5 h. The reaction mixture was cooled to room temperature, H2O was added, and then the mixture was extracted with CHCl3 (3 times). The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (NH silica, CHCl3 / MeOH=100:0-80:20). The collected fractions were further purified by column chromatography (silica gel, CHCl3 / MeOH=100:0-90:10) to give the title compound (217 mg, 37%) as a yellow powder. MS(ESI): m / z 390.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 1.51 -1.68 (m, 2H), 1.80 - 1.88 (m, 1H), 1.96 - 2.10 (m, 2H), 2.21 - 2.31 (m, 1H), 4.27 - 4.35 (m, 1H), 4.53 (d, 1H), 4.77 - 4.88 (m, 1H), 7.22 - 7.30 (m, 3H), 7.44 (d, 1H), 7.52 (d, 1H), 7.76 (td, 1H), 7.84 (td, 1H), 8.39 (d, 1H), 10.0 - 10.6 (m, 1H).

[0205] Example 17 Step 1: Intermediate 29: (1S,3S)-3-[(4-chlorophthalazin-1-yl)amino]cyclopentanol [ka] The title compound was prepared using the same procedure as Intermediate 28, starting with (1S,3S)-3-aminocyclopentanol hydrochloride. The compound was isolated as a brown solid. MS (ESI): m / z 264.1 / 266.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 1.50 - 1.54 (m, 1H), 1.57 - 1.66 (m, 1H), 1.70 - 1.80 (m, 1H), 1.81 - 1.91 (m, 1H), 2.10 - 2.20 (m, 1H), 2.34 - 2.42 (m, 1H), 2.48 - 2.58 (m, 1H), 4.48 - 4.55 (m, 1H), 4.83 - 4.92 (m, 1H), 5.00 - 5.07 (m, 1H), 7.72 - 7.75 (m, 1H), 7.82 - 7.89 (m, 2H), 8.17 - 8.20 (m, 1H).

[0206] Step 2: Example 17: 2-[4-[[(1S,3S)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol [ka] The title compound was prepared using the same procedure as in Example 16, with Intermediate 29 as the starting material. The compound was isolated as a brown solid. MS(ESI): m / z 390.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 1.50 - 1.69 (m, 2H), 1.80 - 1.89 (m, 1H), 1.94 - 2.12 (m, 2H), 2.21 - 2.31 (m, 1H), 4.26 - 4.36 (m, 1H), 4.52 (d, 1H), 4.77 - 4.88 (m, 1H), 7.23 - 7.33 (m, 3H), 7.44 (d, 1H), 7.52 (d, 1H), 7.76 (td, 1H), 7.84 (td, 1H), 8.39 (d, 1H), 10.0 - 10.6 (m, 1H).

[0207] Example 18 Step 1: Intermediate 30: (1R,3R)-3-[[4-(2-benzyloxy-4-methylsulfonyl-phenyl)phthalazin-1-yl]amino]cyclopentanol [ka] To a solution of intermediate 28 (70 mg, 0.265 mmol, 1.0 equiv) and intermediate 15 (104 mg, 0.268 mmol, 1.0 equiv) in DME (0.5 mL) was added Pd(dppf)Cl2·CH2Cl2 (22 mg, 0.0265 mmol, 0.1 equiv) and 2M aqueous Na2CO3 (0.8 mL, 3.0 equiv) at room temperature. The mixture was heated at 90 °C and stirred for 3 h. The reaction mixture was cooled to room temperature, H2O was added, and then the mixture was extracted with EtOAc (3 times). The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (silica, EtOAc / MeOH=100:0-93:7) to give the title compound (34.3 mg, 26%) as an orange solid. MS (ESI): m / z 490.3 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 1.50 - 1.70 (m, 2H), 1.70 - 1.83 (m, 1H), 1.85 - 1.98 (m, 1H), 2.12 - 2.15 (m, 1H), 2.53 - 2.63 (m, 1H), 3.09 (s, 3H), 4.51 - 4.58 (m, 1H), 4.95 - 5.05 (m, 1H), 5.05 - 5.18 (m, 3H), 6.97 - 7.03 (m, 2H), 7.13 - 7.20 (m, 3H), 7.53 (d, 1H), 7.63 (d, 1H), 7.65 - 7.72 (m, 2H), 7.75 (s, 1H), 7.76 - 7.79 (m, 2H).

[0208] Step 2: Example 18: 2-[4-[[(1R,3R)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-methylsulfonyl-phenol [ka] To a solution of intermediate 30 (34.3 mg, 0.070 mmol, 1.0 equiv) in EtOH (2 mL) was added Pd / C (26.0 mg, 5% wet) under nitrogen atmosphere. The nitrogen was then replaced with 1 atm of hydrogen and the reaction mixture was stirred at room temperature for 7 h. The mixture was filtered through a Celite® pad. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography using a gradient of 5-10% MeOH in EtOAc as the mobile phase to give the title compound (24.7 mg, 88%) as a yellowish powder. MS (ESI): m / z 400.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 1.50 - 1.69 (m, 2H), 1.80 - 1.89 (m, 1H), 1.95 - 2.10 (m, 2H), 2.21 - 2.31 (m, 1H), 3.26 (s, 3H), 4.27 - 4.33 (m, 1H), 4.52 (d, 1H), 4.78 - 4.90 (m, 1H), 7.25 (d, 1H), 7.44 (d, 1H), 7.47 - 7.52 (m, 2H), 7.56 (d, 1H), 7.77 (td, 1H), 7.85 (td, 1H), 8.39 (d, 1H), 10.2 - 10.7 (m, 1H).

[0209] Examples 19-37 in Table 2 were all prepared following the procedure of Example 17 using the appropriate amino alcohol. [Table 2] TIFF2024523623000072.tif201169 TIFF2024523623000073.tif219169 TIFF2024523623000074.tif221169 TIFF2024523623000075.tif146169

[0210] Example 38 Step 1: Intermediate 31: (1R,3R)-3-[[1-[2-methoxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]amino]-1-methyl-cyclopentanol [ka] To a solution of intermediate 5 (149.8 mg, 0.70 mmol) in CH2Cl2 (2 mL) was added TFA (1.0 mL, 13.1 mmol) at room temperature. The mixture was stirred at room temperature for 40 min and the reaction mixture was concentrated. The residue was azeotroped with toluene. To a solution of the residue in MeCN (1.2 mL) was added TEA (0.49 mL, 3.50 mmol) and the mixture was stirred at room temperature for 10 min. To the mixture was added intermediate 1 (199.3 mg, 0.59 mmol) and the vial was sealed. The reaction was heated in a microwave reactor at 130 °C for 2.5 h. The reaction mixture was concentrated and the residue was purified by NH silica gel column chromatography using a gradient of 0-10% MeOH in EtOAc as mobile phase to give the title compound (195 mg, 74%) as a brown powder. MS (ESI): m / z [M+H] + :419.1. 1 H NMR (400 MHz, CDCl3) δ 1.47 (s, 3H), 1.67 - 1.80 (m, 2H), 1.83 - 2.02 (m, 2H), 2.52 - 2.72 (m, 2H), 3.76 (s, 3H), 4.99 - 5.15 (m, 1H), 5.50 (br d, 1H), 7.23 - 7.29 (m, 2H), 7.41 (dd, 1H), 7.63 (d, 1H), 8.83 (d, 1H), 9.32 (s, 1H).

[0211] Step 2: Example 38: 2-[4-[[(1R,3R)-3-hydroxy-3-methyl-cyclopentyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol [ka] To a solution of intermediate 31 (195 mg, 0.44 mmol) in 2,4,6-trimethylpyridine (5 mL) was added LiI (626.9 mg, 4.68 mmol) at room temperature. The mixture was stirred at 160 °C in the dark for 4 h. The reaction mixture was cooled to room temperature and H2O was added. The mixture was extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by NH column chromatography using a gradient of 10-30% MeOH in EtOAc as the mobile phase to give a red gum. The residue was purified by flash column chromatography using a gradient of 0-20% MeOH in EtOAc as the mobile phase to give the title compound (102.6 mg, 56%) as a yellow powder. MS (ESI): m / z [M+H] + 405.0. 1 H NMR (400 MHz, DMSO-d6) δ 1.33 (s, 3H), 1.64 - 1.86 (m, 4H), 2.22 (dd, 1H), 2.28 - 2.41 (m, 1H), 4.41 (s, 1H), 4.86 - 5.01 (m, 1H), 7.24 - 7.30 (m, 2H), 7.32 (d, 1H), 7.56 (d, 1H), 7.80 (d, 1H), 8.84 (d, 1H), 9.78 (d, 1H), 10.44 (br s, 1H).

[0212] Example 39: 2-[4-[[(1R,3S)-3-hydroxy-3-methyl-cyclopentyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol [ka] The title compound was prepared similarly to Example 38 using Intermediate 4 instead of Intermediate 5. MS (ESI): m / z [M+H] + 405.2. 1H NMR (400 MHz, DMSO-d6) δ 1.30 (s, 3H), 1.51 - 1.67 (m, 1H), 1.74 - 1.91 (m, 2H), 1.93 - 2.08 (m, 1H), 2.10 - 2.25 (m, 2H), 4.59 - 4.80 (m, 2H), 7.22 - 7.36 (m, 3H), 7.56 (d, 1H), 7.90 (br d, 1H), 8.84 (d, 1H), 9.78 (s, 1H).

[0213] Example 40 Step 1: Intermediate 32: 1-Bromo-2-((4-methoxybenzyl)oxy)-4-(trifluoromethyl)benzene [ka] 2-Bromo-5-(trifluoromethyl)phenol (3.0 g, 12.45 mmol) and 1-(bromomethyl)-4-methoxybenzene (2.53 g, 12.57 mmol) were dissolved in MeCN (30 mL) and potassium carbonate (1.892 g, 13.69 mmol) was added in one portion (no or very weak exotherm). The reaction mixture turned yellow. The reaction mixture was stirred at room temperature overnight. The reaction was complete after 16 h by NMR. Water and EtOAc were added and the phases were separated. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine and evaporated. This gave a slightly orange oil that did not crystallize from IPA (ca. 15 mL). Instead the oil was purified by column chromatography (silica gel, heptane / EtOAc:20 / 1 as eluent) to yield 3.58 g (80%) of the title compound as a colorless oil that crystallized on standing. 1 H NMR (500 MHz, DMSO-d6) δ 3.76 (s, 3H), 5.23 (s, 2H), 6.95 - 7.00 (m, 2H), 7.22 - 7.28 (m, 1H), 7.42 (d, 2H), 7.51 (d, 1H), 7.80 - 7.86 (m, 1H).

[0214] Step 2: Intermediate 33: tert-Butyl 4-[2-[(4-methoxyphenyl)methoxy]-4-(trifluoromethyl)benzoyl]pyridine-3-carboxylate [ka] Intermediate 8 (7.0 g, 29.6 mmol) was dissolved in THF (50 mL) and cooled to -78 °C. In a separate flask, intermediate 32 (10.7 g, 29.6 mmol) was dissolved in THF (50 mL) and n-BuLi (19.4 mL, 31.1 mmol, 1.6 M in hexanes) was added at -78 °C. The pale yellow solution was stirred at -78 °C for 15 seconds and then added dropwise via cannula to the first solution. The reaction mixture was stirred at -78 °C for 10 minutes, then AcOH (1.9 mL in 100 mL water) was added, followed by EtOAc. The reaction mixture was allowed to reach room temperature and the two phases were separated. The organic extract was washed with water and evaporated to give the title compound (14.4 g, quantitative) as an orange oil. Used in the next step without further purification. MS (ESI): m / z [M+H] + 488.3.

[0215] Step 3: Intermediate 34: 1-[2-[(4-methoxyphenyl)methoxy]-4-(trifluoromethyl)phenyl]-3H-pyrido[3,4-d]pyridazin-4-one [ka] Intermediate 33 (41.4 g, 84.9 mmol) was dissolved in THF (300 mL), hydrazine monohydrate (21.1 mL, 340 mmol, 50% in water) was added and the reaction mixture was stirred at 60° C. for 16 h. Water (100 mL) was added and the mixture was stirred at room temperature and then poured into water (600 mL). The solid was filtered off and washed with water and MTBE. The product was slurried in refluxing EtOAc (1 L). Cooled to room temperature and filtered to give the title compound (17.3 g, 48%) as an off-white solid. MS (ESI): m / z [M+H] + 428.2. 1H NMR (500 MHz, DMSO-d6) δ 3.68 (s, 3H), 5.15 (s, 2H), 6.75 (d, 2H), 7.02 (d, 2H), 7.27 (d, 1H), 7.51 (d, 1H), 7.65 (d, 2H), 8.93 (d, 1H), 9.48 (s, 1H), 13.23 (s, 1H).

[0216] Step 4: Intermediate 35: 4-chloro-1-[2-[(4-methoxyphenyl)methoxy]-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazine [ka] Intermediate 34 (6.0 g, 14.0 mmol) was slurried in 1,4-dioxane (55 mL). Pyridine (9.9 mL, 122 mmol) and phosphoryl trichloride (4.6 mL, 48.9 mmol) were added and the reaction was stirred at 60° C. for 19 h. The mixture was cooled to room temperature and then added to trisodium citrate (180 mL, aq., 1 M). The precipitated product was filtered off, washed with water (2×50 mL) and dried under reduced pressure to give a tan solid. The crude product was slurried in MeCN (80 mL) and heated to 80° C. until dissolved. The mixture was cooled to room temperature and the formed precipitate was filtered off, washed with MeCN (2×15 mL) and dried to give the title compound (2.57 g, 41%) as a tan solid. MS (ESI): m / z [M+H] + 446.3. 1 H NMR (500 MHz, DMSO-d6) δ 3.66 (s, 3H), 5.15 (s, 2H), 6.73 (d, 2H), 6.99 (d, 2H), 7.58 (d, 1H), 7.65 (dd, 1H), 7.72 (d, 2H), 9.10 (d, 1H), 9.69 - 9.82 (m, 1H).

[0217] Step 5: Intermediate 36: (1R,2R)-2-[[1-[2-[(4-methoxyphenyl)methoxy]-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]amino]cyclohexanol [ka] Intermediate 35 (2.6 g, 5.7 mmol), (1R,2R)-2-aminocyclohexan-1-ol (1.1 g, 9.2 mmol) and NaHCO3 (2.4 g, 28.7 mmol) were mixed in IPA (22 mL) and stirred at 80 °C for 3 days. The reaction mixture was poured into water (100 mL) and stirred at room temperature for 2 h. The solid was filtered off, washed with water and dried under reduced pressure at 40 °C to give the title compound (2.9 g, 96%) as a tan solid. MS (ESI): m / z [M+H] + 535.6. 1 H NMR (500 MHz, DMSO-d6) δ 1.30 (s, 4H), 1.69 (d, 2H), 1.97 (d, 1H), 2.12 (s, 1H), 3.61 (d, 1H), 3.66 (s, 3H), 4.19 (s, 1H), 4.83 (s, 1H), 5.11 (s, 2H), 6.74 (d, 2H), 7.03 (d, 2H), 7.26 (d, 1H), 7.48 (d, 1H), 7.60 (s, 2H), 7.67 (d, 1H), 8.81 (d, 1H), 9.76 (s, 1H).

[0218] Step 6: Example 40: 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol [ka] Intermediate 36 (2.9 g, 5.5 mmol) was slurried in anhydrous EtOH (99.5%, 7 mL), HCl (4 M in 1,4-dioxane, 20.7 mL, 82.9 mmol) was added, and the reaction was stirred at room temperature for 2 h. The mixture was added dropwise to Et2O (150 mL) with stirring to give a precipitate, which was filtered off, washed with Et2O, and dried to give a pale yellow solid (HCl salt). The solid was slurried in water (50 mL), basified with saturated aqueous NaHCO3 (pH = 9), and extracted (multiple times) with DCM:MeOH = 9:1. The combined organic extracts were filtered through a phase separator and evaporated to give 1.85 g of an orange semi-solid. The crude product was dissolved in MeCN (20 mL) and IPA (0.5 mL) at 70° C., cooled to room temperature, filtered, washed with MeCN, and dried under reduced pressure at 40° C. to give the title compound (1.25 g, 56%) as a yellow solid. MS (ESI): m / z [M+H] + 405.3. HRMS(ESI):m / z [M+H] + C 20 H 19 Calculated value of F3N4O2: 405.1538, measured value: 405.1538. 1 H NMR (500 MHz, DMSO-d6) δ 1.25 - 1.41 (m, 4H), 1.72 (d, 2H), 1.99 (d, 1H), 2.13 (s, 1H), 3.56 - 3.69 (m, 1H), 4.17 - 4.28 (m, 1H), 7.24 - 7.36 (m, 3H), 7.55 (d, 1H), 7.71 (d, 1H), 8.84 (d, 1H), 9.80 (s, 1H), 10.46 (s, 1H).

[0219] Example 41 Step 1: Intermediate 37: (1S,3R)-3-[(1-chloropyrido[3,4-d]pyridazin-4-yl)amino]cyclohexanol [ka] and intermediate 38: (1S,3R)-3-[(4-chloropyrido[3,4-d]pyridazin-1-yl)amino]cyclohexanol [ka] To a suspension of (1S,3R)-3-aminocyclohexanol hydrochloride (0.93 g, 6.1 mmol, 1.1 equiv) in NMP (12 mL, 0.5 M) was added 1,4-dichloropyrido[3,4-d]pyridazine (1.1 g, 5.7 mmol, 1.0 equiv) and DIPEA (4.0 mL, 23 mmol, 4.1 equiv) at room temperature. The mixture was heated to 90 °C and stirred for 20 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by column chromatography (silica, hexane / EtOAc = 50:50) to give the title compound mixture (intermediate 37 / intermediate 38 = 7:3, 2.1 g, 89%) as a yellow caramel. MS (ESI): m / z 279.1 / 281.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 1.4 - 1.5 (m, 1H), 1.6 - 1.7 (m, 1H), 2.1 - 1.8 (m, 6H), 2.18 (br s, 2H), 4.19 (br s, 1H), 4.5 - 4.6 (m, 0.3H), 4.6 - 4.7 (m, 0.7H), 6.5 - 6.7 (m, 0.3H), 6.9 - 7.1 (m, 0.7H), 7.55 (dd, 0.3H), 7.87 (dd, 0.7H), 8.99 (d, 0.3H), 9.00 (d, 0.7H), 9.28 (d, 0.7H), 9.52 (d, 0.3H).

[0220] Step 2: Intermediate 39: N-[(1R,3S)-3-[tert-butyl(dimethyl)silyl]oxycyclohexyl]-1-chloro-pyrido[3,4-d]pyridazin-4-amine [ka] and intermediate 40: N-[(1R,3S)-3-[tert-butyl(dimethyl)silyl]oxycyclohexyl]-4-chloro-pyrido[3,4-d]pyridazin-1-amine [ka] To a solution of the mixture of intermediate 37 and intermediate 38 from the previous step (1.7 g, 4.1 mmol, 1.0 equiv.) in DMF (25 mL), imidazole (0.34 g, 5.0 mmol, 1.2 equiv.), tert-butyldimethylsilyl chloride (0.68 mg, 4.5 mmol, 1.1 equiv.), and DMAP (0.16 mg, 1.3 mmol, 0.3 equiv.) were added at 0° C., and the mixture was stirred at room temperature for 22 h. The reaction mixture was poured into ice water and extracted with EtOAc (50 mL, 2×). The organic layer was washed with H2O (20 mL, 3×) and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica, hexane / EtOAc=70:30) to give intermediate 39 (798 mg, 50%) as a pale yellow amorphous and intermediate 40 (176 mg, 11%) as a pale yellow powder. Intermediate 39: 1 H NMR (400 MHz, CDCl3) δ 0.18 (s, 3H), 0.21 (s, 3H), 0.96 (s, 9H), 1.4 - 1.5 (m, 1H), 1.6 - 1.8 (m, 3H), 1.8 - 2.0 (m, 3H), 2.0 - 2.1 (m, 1H), 4.1 - 4.2 (m, 1H), 4.6 - 4.7 (m, 1H), 7.00 (br s, 1H), 7.86 (dd, 1H), 9.01 (d, 1H), 9.24 (s, 1H). MS(ESI):m / z 393.2 / 395.2 [M+H]+. Intermediate 40: 1H NMR (400 MHz, CDCl3) δ 0.16 (s, 3H), 0.19 (s, 3H), 0.96 (s, 9H), 1.39 - 1.50 (m, 1H), 1.51 - 1.96 (m, 6H), 1.99 - 2.09 (m, 1H), 4.11 - 4.20 (m, 1H), 4.61 - 4.70 (m, 1H), 6.65 (br s, 1H), 7.53 (d, 1H), 8.98 (d, 1H) 9.53 (s, 1H). MS(ESI):m / z 393.2 / 395.2 [M+H]+.

[0221] Step 3: Intermediate 41: 2-[4-[[(1R,3S)-3-[tert-butyl(dimethyl)silyl]oxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol [ka] To a solution of intermediate 39 from the previous step (201 mg, 0.51 mmol, 1.0 equiv), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (131 mg, 0.63 mmol, 1.2 equiv), and Pd(dppf)Cl2·CHCl2 (45 mg, 0.06 mmol, 0.1 equiv) in 1,4-dioxane (4 mL, 0.1 M) was added 2 M aqueous Na2CO3 (0.80 mL, 1.6 mmol, 3.1 equiv). The mixture was heated at 100 °C and stirred under argon atmosphere for 4 h. The reaction mixture was cooled to room temperature and diluted with H2O and EtOAc. The organic layer was extracted with EtOAc (10 mL, 2 times), washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica, hexane / EtOAc=60:40) then (NH silica, EtOAc / MeOH=95:5) to give the title compound (145 mg, 52%) as a yellow amorphous solid. MS (ESI): m / z 519.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 0.21 (s, 3H), 0.25 (s, 3H), 0.99 (s, 9H), 1.4 - 1.6 (m, 2H), 1.6 - 1.8 (m, 3H), 1.9 - 2.1 (m, 3H), 4.27 (d, 1H), 4.80 (td, 1H), 4.80 (td, 1H), 7.2 - 7.3 (m, 1H), 7.43 (d, 1H), 7.6 - 7.4 (br s, 1H), 7.68 (d, 1H), 7.98 (dd, 1H), 8.98 (d, 1H), 9.36 (s, 1H), 11.63 (br s, 1H).

[0222] Step 4: Example 41: 2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol [ka] To a solution of intermediate 41 (140 mg, 0.26 mmol, 1.0 equiv) in THF (3 mL) was added 1M tetrabutylammonium fluoride solution in THF (0.4 mL, 0.40 mmol, 1.6 equiv) at room temperature. The mixture was stirred at room temperature for 22 h. The resulting mixture was added saturated aqueous NaHCO3 solution and extracted with EtOAc (15 mL, twice). The organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (silica, EtOAc / MeOH=95:5) to give the title compound (96 mg, 89%) as a yellow amorphous. MS (ESI): m / z 405.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 1.5 - 1.6 (m, 1H), 1.7 - 2.1 (m, 6H), 2.1 - 2.2 (m, 1H), 3.7 - 3.8 (m, 1H), 4.2 - 4.3 (m, 1H), 4.7 - 4.8 (m, 1H), 7.25 (m, 1H), 7.2 - 7.3 (m, 1H), 7.43 (d, 1H), 7.68 (d, 1H), 7.98 (d, 1H), 8.98 (d, 1H), 9.37 (s, 1H), 11.4 - 11.7 (m, 1H).

[0223] Example 42 Step 1: Intermediate 42: (1S,3R)-3-[[1-[2-[(4-methoxyphenyl)methoxy]-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]amino]cyclohexanol [ka] Intermediate 35 (1.45 g, 3.3 mmol), (1S,3R)-3-aminocyclohexan-1-ol, HCl (0.54 g, 3.6 mmol) and Na2CO3 (0.72 g, 6.8 mmol) were mixed in sulfolane (14 mL) and the reaction was stirred at 120° C. for 3 h. After the reaction mixture was cooled to room temperature, water and iPrOAc were added and the phases were separated. The aqueous phase was extracted with iPrOAc and the combined organic extracts were washed twice with water and evaporated. The residue was purified by flash chromatography using EtOAc as the mobile phase to give the title compound (1.47 g, 86%) as a pale yellow solid. MS (ESI): m / z [M+H] + 525.5.

[0224] Step 2: Example 42: 2-(4-(((1R,3S)-3-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol dihydrochloride [ka] HCl (15 mL, 60 mmol, 4 M in 1,4-dioxane) was added to intermediate 42 (1.75 g, 3.34 mmol) in anhydrous EtOH (3 mL) to give a clear solution. The reaction was stirred at 40° C. for 15 min and then at room temperature. The reaction mixture was added dropwise to Et2O (100 mL) and the solid was filtered off and washed with Et2O. The solid was redissolved in EtOH and EtOAc was added to precipitate the product. The solid was filtered, washed with two portions of EtOAc and dried to give a yellow solid. The solid was further dissolved in MeCN / water and lyophilized to give the title compound (1.45 g, 91%). MS (ESI): m / z [M+H] + 405.3. HRMS(ESI):m / z [M+H] + C 20 H 19 Calculated value of F3N4O2: 405.1536, measured value: 405.1534. 1 H NMR (500 MHz, DMSO-d6) δ 1.09 - 1.21 (m, 1H), 1.38 (q, 1H), 1.46 - 1.63 (m, 2H), 1.80 (dt, 1H), 1.87 (d, 1H), 1.98 (d, 1H), 2.24 (d, 1H), 3.57 (ddd, 1H), 4.15 (dt, 1H), 7.39 (d, 1H), 7.43 (s, 1H), 7.51 (d, 1H), 7.58 (d, 1H), 9.11 (d, 1H), 10.24 (s, 1H), 11.02 (s, 1H).

[0225] Example 43: 2-[1-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol [ka] The title compound was prepared similarly to Example 41 using Intermediate 40 instead of Intermediate 39. MS(ESI): m / z 405.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 1.10 - 1.20 (m, 1H), 1.20 - 1.45 (m, 3H), 1.72 - 1.82 (m, 1H), 1.82 - 1.93 (m, 1H), 1.98 - 2.08 (m, 1H), 2.23 - 2.33 (m, 1H), 3.50 - 3.63 (m, 1H), 4.22 - 4.35 (m, 1H), 4.65 - 4.75 (m, 1H), 7.15 - 7.30 (m, 2H), 7.45 - 7.60 (m, 2H), 8.25 (d, 1H), 8.85 (s, 1H), 8.90 (d, 1H).

[0226] Example 44 Step 1: Intermediate 43: 2-[4-[[(1R,3S)-3-[tert-butyl(dimethyl)silyl]oxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-chloro-phenol [ka] To a solution of intermediate 39 (1.1 g, 2.8 mmol), 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.0 g, 3.9 mmol), and Pd(dppf)Cl2·CH2Cl2 (231 mg, 0.283 mmol, 0.1 equiv) in 1,4-dioxane (4 mL) was added 2M aqueous Na2CO3 (4.2 mL, 8.4 mmol, 3.0 equiv). The mixture was heated at 100 °C and stirred under argon atmosphere for 2.5 h. The reaction mixture was cooled to room temperature and diluted with H2O. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography using a gradient of 20-50% EtOAc in hexanes as the mobile phase. The collected fractions were further purified by NH silica gel column chromatography using a gradient of 50-100% EtOAc in hexanes as the mobile phase to give the title compound (774.7 mg, 55%) as a yellow amorphous. MS (ESI): m / z [M+H] + 485.2 / 487.1. 1 H NMR (400 MHz, CDCl3) δ0.20 (s, 3H), 0.24 (s, 3H), 0.99 (s, 9H), 1.45 - 1.62 (m, 1H), 1.63 - 1.83 (m, 3H), 1.87 - 2.10 (m, 4H), 4.20 - 4.30 (m, 1H), 4.72 - 4.83 (m, 1H), 6.99 (dd, 1H), 7.18 (d, 1H), 7.32 (br s, 1H), 7.50 (d, 1H), 7.97 (dd, 1H), 8.96 (d, 1H), 9.33 - 9.35 (m, 1H), 11.63 (br s, 1H).

[0227] Step 2: Example 44: 5-Chloro-2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol [ka] To a solution of intermediate 43 (174.6 mg, 0.35 mmol, 1.0 equiv) in THF (3 mL) was added 1 M tetrabutylammonium fluoride solution in THF (0.52 mL, 0.52 mmol, 1.5 equiv) at room temperature. The mixture was stirred at room temperature for 21 h. The resulting mixture was added to saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography using a gradient of 0-5% MeOH in EtOAc as the mobile phase to give the title compound (114.5 mg, 81%) as a yellow amorphous. MS (ESI): m / z [M+H] + 371.1 / 373.1. 1 H NMR (400 MHz, DMSO-d6) δ 1.08 - 1.21 (m, 1H), 1.22 - 1.44 (m, 3H), 1.71 - 1.82 (m, 1H), 1.82 - 1.93 (m, 1H), 1.98 - 2.08 (m, 1H), 2.24 - 2.36 (m, 1H), 3.50 - 3.63 (m, 1H), 4.25 - 4.40 (m, 1H), 6.91 (dd, 1H), 6.96 (d, 1H), 7.28 (d, 1H), 7.30 (dd, 1H), 7.67 (d, 1H), 8.82 (d, 1H), 9.74 (d, 1H).

[0228] The examples contained in Table 3 below were synthesized similarly to the two-step procedure of Example 44 using the specified boronic acid and borane. [Table 3]

[0229] Example 49 and Example 50: (R) and (S) atropisomers of 2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-3-(trifluoromethyl)phenol [ka] A solution of intermediate 39 (200 mg, 0.51 mmol, 1.0 equiv), [2-hydroxy-6-(trifluoromethyl)phenyl]boronic acid (125.8 mg, 0.61 mmol), and SPhos Pd G3 (39.8 mg, 0.05 mmol, 0.1 equiv) in 1,4-dioxane (0.77 mL) was added to 2M aqueous Na2CO3 (0.77 mL, 1.5 mmol, 3.0 equiv) and the vial was sealed. The reaction was heated at 150 °C in a microwave reactor for 1 h. The reaction mixture was cooled to room temperature and diluted with H2O and EtOAc. The organic layer was extracted with EtOAc (3 times), washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography using a gradient of 0-10% MeOH in EtOAc, then by NH column chromatography using a gradient of 5-20% MeOH in EtOAc as the mobile phase to give a mixture of products as a pale yellow powder. The residue was dissolved in THF (3 mL) and to the mixture was added 1M tetrabutylammonium fluoride solution in THF (0.6 mL, 0.60 mmol) at room temperature. The mixture was stirred at room temperature for 6 h. To the resulting mixture was added saturated aqueous NaHCO3 solution and extracted with EtOAc (2 times). The organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by reverse-phase flash chromatography on a C18 column using a gradient of 20-50% MeCN (10 mM, aq) in (NH4)2CO3 as the mobile phase to give the first eluting compound Isomer 1 Example 49 (33.3 mg) as a beige powder and the second eluting compound Isomer 2 Example 50 (30.3 mg) as a beige powder. Example 49: MS(ESI):m / z [M+H] + 405.0. 1H NMR (400 MHz, DMSO-d6) δ 1.09 - 1.21 (m, 1H), 1.21 - 1.47 (m, 3H), 1.72 - 1.82 (m, 1H), 1.83 - 1.93 (m, 1H), 2.01 - 2.13 (m, 1H), 2.21 - 2.37 (m, 1H), 3.51 - 3.63 (m, 1H), 4.24 - 4.39 (m, 1H), 4.74 (br d, 1H), 7.02 (dd, 1H), 7.27 (d, 1H), 7.34 (d, 1H), 7.56 (dd, 1H), 7.71 (d, 1H), 8.81 (d, 1H), 9.77 (s, 1H), 10.16 (br s, 1H). Example 50: MS(ESI):m / z [M+H] + 405.0. 1 H NMR (400 MHz, DMSO-d6) δ1.09 - 1.21 (m, 1H), 1.27 - 1.45 (m, 3H), 1.74 - 1.83 (m, 1H), 1.83 - 1.93 (m, 1H), 1.96 - 2.06 (m, 1H), 2.28 - 2.39 (m, 1H), 3.49 - 3.62 (m, 1H), 4.25 - 4.41 (m, 1H), 4.72 (br d, 1H), 7.02 (dd, 1H), 7.28 (d, 1H), 7.34 (d, 1H), 7.56 (dd, 1H), 7.71 (d, 1H), 8.81 (d, 1H), 9.77 (s, 1H), 10.15 (br s, 1H).

[0230] Example 51 Step 1: Intermediate 44: 2-[4-[[(1R,3S)-3-[tert-butyl(dimethyl)silyl]oxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-vinyl-phenol [ka] To a solution of intermediate 43 (185.2 mg, 0.37 mmol) in 1,4-dioxane (1.2 mL) and water (0.8 mL) was added K3PO4 (477.2 mg, 2.2 mmol), potassium;trifluoro(vinyl)borane (149.6 mg, 1.1 mmol) and Xphos Pd G3 (30.0 mg, 0.035 mmol). The vial was sealed and the reaction was heated in a microwave reactor at 120 °C for 30 min. The reaction was then diluted with EtOAc and H2O. The layers were separated, the aqueous layer was extracted with EtOAc and the combined organic layers were washed with saturated aqueous NaHCO3 and brine. The organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash column chromatography using a gradient of 15-70% EtOAc in hexanes as the mobile phase to give the title compound (54.3 mg, 30%) as a brown powder. MS(ESI):m / z [M+H] + 477.2. 1 H NMR (400 MHz, CDCl3) δ0.20 (s, 3H), 0.24 (s, 3H), 0.99 (s, 9H), 1.44 - 1.53 (m, 1H), 1.64 - 1.84 (m, 3H), 1.87 - 2.11 (m, 4H), 4.20 - 4.27 (m, 1H), 4.72 - 4.83 (m, 1H), 5.34 (d, 1H), 5.85 (d, 1H), 6.73 (dd, 1H), 7.06 (dd, 1H), 7.23 (d, 1H), 7.53 (d, 1H), 8.03 (d, 1H), 8.95 (d, 1H), 9.33 (s, 1H).

[0231] Step 2: Intermediate 45: 2-[4-[[(1R,3S)-3-[tert-butyl(dimethyl)silyl]oxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-ethyl-phenol [ka] To a solution of intermediate 44 (52 mg, 0.11 mmol) in EtOAc (2 mL) was added Pd / C (22 mg, 10% wet) under nitrogen atmosphere. The nitrogen was then replaced by 1 atm of hydrogen and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a Celite® pad. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography using a gradient of 10-35% EtOAc in hexanes as the mobile phase to give the title compound (33.4 mg, 66%) as a yellow powder. MS (ESI): m / z [M+H] + 479.2. 1 H NMR (400 MHz, CDCl3) δ0.20 (s, 3H), 0.23 (s, 3H), 0.98 (s, 9H), 1.30 (t, 3H), 1.45 - 1.55 (m, 1H), 1.63 - 1.84 (m, 3H), 1.88 - 2.12 (m, 4H), 2.69 (q, 2H), 4.19 - 4.27 (m, 1H), 4.72 - 4.82 (m, 1H), 6.85 (dd, 1H), 7.03 (d, 1H), 7.48 (d, 1H), 8.05 (dd, 1H), 8.94 (d, 1H), 9.33 (d, 1H), 11.26 (br s, 1H).

[0232] Step 3: Example 51: 5-Ethyl-2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol [ka] The title compound was obtained in the same manner as in Example 44 using Intermediate 45. MS (ESI): m / z [M+H] + 365.2. 1H NMR (400 MHz, CDCl3) δ 1.29 (t, 3H), 1.47 - 1.76 (m, 3H), 1.79 - 2.04 (m, 4H), 2.12 - 2.25 (m, 1H), 2.69 (q, 2H), 4.24 (br s, 1H), 4.61 - 4.79 (m, 1H), 6.86 (dd, 1H), 7.03 (d, 1H), 7.47 (d, 1H), 8.05 (dd, 1H), 8.93 (d, 1H), 9.34 (s, 1H).

[0233] Example 52 Step 1: Intermediate 46: (1S,3R)-3-[[1-(4-cyclopropyl-2-methoxy-phenyl)pyrido[3,4-d]pyridazin-4-yl]amino]cyclohexanol [ka] The title compound was obtained in the same manner as in Example 44 using Intermediate 13. MS (ESI): m / z [M+H] + 391.2. 1 H NMR (400 MHz, CDCl3) δ 0.76 - 0.83 (m, 2H), 1.00 - 1.08 (m, 2H), 1.42 - 1.81 (m, 4H), 1.82 - 2.03 (m, 3H), 2.17 - 2.33 (m, 2H), 3.69 (s, 3H), 4.06 - 4.17 (m, 1H), 4.62 - 4.77 (m, 1H), 6.42 - 6.63 (m, 1H), 6.76 (d, 1H), 6.80 (dd, 1H), 7.32 (dd, 1H), 7.37 (d, 1H), 8.77 (d, 1H), 9.28 (s, 1H).

[0234] Step 2: Example 52: 5-Cyclopropyl-2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol [ka] To a solution of intermediate 46 (200 mg, 0.45 mmol) in CHCl (4 mL) was added BBr (3.0 mL, 3.0 mmol, 1 M in CHCl) at -78 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction was quenched with aqueous NaHCO and extracted with CHCl-MeOH (3 times). The organic layer was dried over NaSO and concentrated under vacuum. The residue was purified by flash column chromatography using a gradient of 0-10% MeOH in CHCl as the mobile phase to give a brown gum. The residue was purified by reversed-phase flash chromatography on a C18 column using a gradient of 30-60% MeCN (10 mM, aq) in (NH)CO as the mobile phase to give the title compound (98.7 mg, 50%) as an orange powder. MS (ESI): m / z [M+H] + 377.1. 1 H NMR (400 MHz, DMSO-d6) δ0.65 - 0.74 (m, 2H), 0.95 - 1.03 (m, 2H), 1.08 - 1.21 (m, 1H), 1.23 - 1.45 (m, 3H), 1.72 - 1.82 (m, 1H), 1.83 - 1.97 (m, 2H), 2.03 (br d, 1H), 2.21 - 2.36 (m, 1H), 3.48 - 3.63 (m, 1H), 4.21 - 4.42 (m, 1H), 4.72 (br d, 1H), 6.64 - 6.73 (m, 2H), 7.19 (d, 1H), 7.32 (dd, 1H), 7.64 (d, 1H), 8.83 (d, 1H), 9.66 (br s, 1H), 9.73 (d, 1H).

[0235] Example 53: 4-Fluoro-2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol [ka] Following the two-step procedure described in Example 52, intermediate 14 was used to give the title compound. MS (ESI): m / z [M+H] + 423.0. 1 H NMR (400 MHz, DMSO-d6) δ 1.09 - 1.21 (m, 1H), 1.23 - 1.45 (m, 3H), 1.73 - 1.82 (m, 1H), 1.83 - 1.93 (m, 1H), 1.97 - 2.09 (m, 1H), 2.24 - 2.36 (m, 1H), 3.50 - 3.65 (m, 1H), 4.27 - 4.40 (m, 1H), 4.73 (br s, 1H), 7.25 (d, 1H), 7.32 (dd, 1H), 7.48 (d, 1H), 7.82 (d, 1H), 8.84 (d, 1H), 9.77 (s, 1H).

[0236] Example 54 Step 1: Intermediate 47: (1R,2R)-2-[(1-chloropyrido[3,4-d]pyridazin-4-yl)amino]cyclohexanol [ka] and intermediate 48: (1R,2R)-2-[(4-chloropyrido[3,4-d]pyridazin-1-yl)amino]cyclohexanol [ka] To a suspension of (1R,2R)-2-aminocyclohexanol hydrochloride (3.18 g, 21 mmol, 1.1 equiv) in MeCN (20 mL, 1M) was added 1,4-dichloropyrido[3,4-d]pyridazine (4.0 g, 20 mmol, 1.0 equiv) and DIPEA (10.4 mL, 60 mmol, 3 equiv) at room temperature. The mixture was heated to 100 °C and stirred for 4 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by column chromatography using a gradient of 0-3% MeOH in EtOAc as the mobile phase to give a 3:1 mixture of intermediate 47 and intermediate 48 (4.2 g, 56%) as a pale yellow solid. MS (ESI): m / z [M+H] + 279.1 / 281.1.

[0237] Step 2: Intermediate 49: 1-chloro-N-[(1R,2R)-2-triisopropylsilyloxycyclohexyl]pyrido[3,4-d]pyridazin-4-amine [ka] To a solution of the mixture of intermediate 47 and intermediate 48 from the previous step (3.2 g, 11.5 mmol, 1.0 equiv.) in CHCl (35 mL), 2,6-dimethylpyridine (2.7 mL, 23 mmol, 2 equiv.), triisopropylsilyl trifluoromethanesulfonate (4.63 mL, 17.2 mmol, 1.5 equiv.) were added at 0 °C and the mixture was stirred at the same temperature for 30 min. The reaction mixture was diluted with H0 and the mixture was stirred. The organic layer was separated and concentrated under vacuum. The residue was purified by NH column chromatography using a gradient of 10-30% EtOAc in hexanes as the mobile phase to give the title compound (3.1 g, 61%) as a pale yellow amorphous. MS (ESI): m / z [MH] - 433.3 / 435.3. 1H NMR (400 MHz, CDCl3) δ1.00 - 1.14 (m, 21H), 1.17 - 1.44 (m, 2H), 1.45 - 1.73 (m, 3H), 1.78 - 1.89 (m, 1H), 1.99 - 2.12 (m, 1H), 2.57 - 2.71 (m, 1H), 3.87 - 3.99 (m, 1H), 4.09 - 4.20 (m, 1H), 5.65 (br d, 1H), 7.89 (dd, 1H), 9.02 (d, 1H), 9.21 - 9.24 (m, 1H).

[0238] Step 3: Intermediate 50: 1-[5-fluoro-2-methoxy-4-(trifluoromethyl)phenyl]-N-[(1R,2R)-2-triisopropylsilyloxycyclohexyl]pyrido[3,4-d]pyridazin-4-amine [ka] To a solution of intermediate 49 (150 mg, 0.34 mmol), intermediate 14 (206.9 mg, 0.52 mmol), and PdCl2(Amphos)2 (12.2 mg, 0.02 mmol, 0.05 equiv) in 1,4-dioxane (2 mL) and H2O (0.5 mL) was added Cs2CO3 (337 mg, 1.03 mmol, 3.0 equiv) and the vial was sealed. The reaction was heated in a microwave reactor at 120 °C for 1 h. The reaction mixture was cooled to room temperature and diluted with H2O. The mixture was added to CHCl3 and stirred. The organic layer was separated and concentrated under vacuum. The residue was purified by column chromatography using a gradient of 5-35% EtOAc in hexanes as the mobile phase to give the title compound (126.3 mg, 62%) as a pale yellow amorphous. MS (ESI): m / z [MH] - 591.3. 1H NMR (400 MHz, CDCl3) δ 0.99 - 1.16 (m, 21H), 1.23 - 1.46 (m, 2H), 1.47 - 1.75 (m, 3H), 1.78 - 1.90 (m, 1H), 2.02 - 2.15 (m, 1H), 2.65 - 2.79 (m, 1H), 3.74 (s, 3H), 3.90 - 4.01 (m, 1H), 4.20 - 4.31 (m, 1H), 5.76 (d, 1H), 7.20 (d, 1H), 7.24 - 7.27 (m, 1H), 7.41 (d, 1H), 8.84 (d, 1H), 9.28 (d, 1H).

[0239] Step 4: Intermediate 51: (1R,2R)-2-[[1-[5-fluoro-2-methoxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]amino]cyclohexanol [ka] Starting from intermediate 50, the title compound was prepared similarly to example 44. MS (ESI): m / z [M+H] + 437.0. 1 H NMR (400 MHz, CDCl3) δ1.46 - 1.72 (m, 3H), 1.76 - 2.03 (m, 4H), 2.17 - 2.28 (m, 1H), 3.74 (s, 3H), 4.15 - 4.25 (m, 1H), 4.69 - 4.81 (m, 1H), 6.76 - 6.96 (m, 1H), 7.19 (d, 1H), 7.23 (dd, 1H), 7.40 (d, 1H), 8.83 (d, 1H), 9.30 - 9.33 (m, 1H).

[0240] Step 5: Example 54: 4-Fluoro-2-[4-[[(1R,2R)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol [ka] Starting from intermediate 51, the title compound was prepared in a similar manner to step 2 of example 52. MS (ESI): m / z [M+H] + 422.9. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.22 - 1.43 (m, 4H), 1.63 - 1.78 (m, 2H), 1.92 - 2.06 (m, 1H), 2.06 - 2.19 (m, 1H), 3.57 - 3.68 (m, 1H), 4.18 - 4.30 (m, 1H), 4.81 (br d, 1H), 7.26 (d, 1H), 7.31 (dd, 1H), 7.48 (d, 1H), 7.73 (d, 1H), 8.84 (d, 1H), 9.80 (s, 1H).

[0241] The examples contained in Table 4 below were synthesized similarly to the procedures in Example 54, steps 3 and 4, starting from intermediate 49 and the particular boronic acid as starting materials. [Table 4]

[0242] Example 59 Step 1: Intermediate 52: (1R,3R)-3-[[1-[2-[(4-methoxyphenyl)methoxy]-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]amino]cyclopentanol [ka] Intermediate 35 (2.6 g, 5.8 mmol), (1R,3R)-3-aminocyclopentan-1-ol hydrochloride (0.96 g, 7.0 mmol) and NaHCO3 (2.94 g, 35 mmol) were mixed in IPA (25 mL) and stirred at 80 °C for 20 h. The mixture was poured into water (100 mL), the mixture was cooled to room temperature and the solid product was filtered off, washed with water and dried to give the title compound (2.82 g, 95%) as a beige solid. MS (ESI): m / z [M+H] + 511.5. 1 H NMR (500 MHz, DMSO) δ 1.61 (ddd, 2H), 1.84 (dt, 1H), 1.94 - 2.15 (m, 2H), 2.25 (dd, 1H), 3.67 (s, 3H), 4.20 - 4.39 (m, 1H), 4.57 (d, 1H), 4.84 (h, 1H), 5.11 (s, 2H), 6.73 (d, 2H), 7.02 (d, 2H), 7.28 (d, 1H), 7.50 (d, 1H), 7.56 - 7.69 (m, 2H), 7.76 (d, 1H), 8.83 (d, 1H), 9.75 (s, 1H).

[0243] Step 2: Example 59: 2-(4-(((1R,3R)-3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol [ka] Intermediate 52 (2.7 g, 5.29 mmol) was slurried in anhydrous EtOH (7 mL), HCl (4 M in 1,4-dioxane, 19.8 mL, 79 mmol) was added and the reaction was stirred at room temperature for 2 h before being added dropwise to Et2O (150 mL) with stirring. The precipitate was filtered off and washed with Et2O. The crude solid was dissolved in water (100 mL) and washed with DCM (2 x 50 mL). The aqueous phase was then made basic with NaHCO3 (sat, 50 mL, pH = 9) and the formed slurry was stirred at room temperature for 1 h, the solid was filtered off, washed with water and dried under reduced pressure to give the title compound (1.8 g, 87%) as a tan solid. MS (ESI): m / z [M+H] + 391.3. HRMS(ESI):m / z[M+H] + C 19 H 17 Calculated value of F3N4O2: 391.1382, measured value: 391.1392. 1 H NMR (500 MHz, DMSO-d6) δ 1.51 - 1.70 (m, 2H), 1.85 (dt, 1H), 1.95 - 2.12 (m, 2H), 2.27 (dq, 1H), 4.26 - 4.34 (m, 1H), 4.57 (d, 1H), 4.86 (h, 1H), 7.23 - 7.34 (m, 3H), 7.55 (d, 1H), 7.78 (d, 1H), 8.82 (d, 1H), 9.77 (s, 1H), 10.42 (s, 1H).

[0244] Example 60 Step 1: Intermediate 53: (1S,3R)-3-[[1-[2-[(4-methoxyphenyl)methoxy]-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]amino]cyclopentanol [ka] Intermediate 35 (2.6 g, 5.8 mmol), (1S,3R)-3-aminocyclopentan-1-ol hydrochloride (0.95 g, 6.9 mmol) and NaHCO3 (2.94 g, 35.0 mmol) were mixed in IPA (25 mL) and stirred at 80 °C for 20 h. The mixture was poured into water (100 mL), the mixture was cooled to room temperature and the solid product was filtered off, washed with water and dried to give the title compound (2.87 g, 96%) as a beige solid. MS (ESI): m / z [M+H] + 511.5. 1 H NMR (500 MHz, DMSO-d6) δ 1.58 - 1.95 (m, 4H), 2.07 (d, 1H), 2.32 - 2.45 (m, 1H), 3.67 (s, 3H), 4.18 (s, 1H), 4.58 (h, 1H), 4.74 (d, 1H), 5.11 (s, 2H), 6.74 (d, 2H), 7.01 (d, 2H), 7.28 (d, 1H), 7.49 (d, 1H), 7.58 - 7.66 (m, 2H), 7.86 (d, 1H), 8.83 (d, 1H), 9.76 (s, 1H).

[0245] Step 2: Example 60: 2-(4-(((1R,3S)-3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol [ka] Intermediate 53 (2.8 g, 5.4 mmol) was slurried in anhydrous EtOH (7 mL) and HCl (4 M in 1,4-dioxane, 20.2 mL, 80.8 mmol) was added and the reaction was stirred at room temperature for 2 h before being added dropwise to Et2O (150 mL) with stirring. The precipitate was filtered off and washed with Et2O. The crude solid was slurried in water (130 mL) and washed with DCM (3 x 50 mL). The aqueous phase was then made basic with NaHCO3 (sat, 50 mL, pH = 9) and extracted several times with DCM:MeOH 9:1. The combined organic extracts were evaporated to give an aqueous slurry, which was then stirred for 2 h, the slurry was filtered, the solid was washed with water and dried under reduced pressure at 40 °C to give the title compound (1.45 g, 69%) as a tan solid. MS (ESI): m / z [M+H] + 391.3. HRMS(ESI):m / z[M+H] + C 19 H 17 Calculated value of F3N4O2: 391.1382, measured value: 391.1382. 1H NMR (500 MHz, DMSO-d6) δ 1.67 (ddt, 2H), 1.78 (dq, 1H), 1.87 (dt, 1H), 2.08 (dq, 1H), 2.39 (dt, 1H), 4.18 (p, 1H), 4.59 (h, 1H), 7.19 - 7.31 (m, 3H), 7.53 (d, 1H), 7.86 (d, 1H), 8.82 (d, 1H), 9.78 (s, 1H).

[0246] Example 61 Step 1: Intermediate 54: tert-Butyl N-[(1R)-3-hydroxy-3-methyl-cyclohexyl]carbamate [ka] To a stirred solution of tert-butyl N-[(1R)-3-oxocyclohexyl]carbamate (920 mg, 4.31 mmol) in THF (40 mL) was added methyllithium in Et2O (1.06 mol / L, 16.3 mL, 17.3 mmol) at -78 °C, and the solution was stirred at -78 °C for 1 h. To this solution was added methyllithium in Et2O (1.06 mol / L, 16.3 mL, 17.3 mmol) again at -78 °C, and the solution was stirred at -78 °C for 1 h, quenched with saturated aqueous NH4Cl (50 mL), and extracted with EtOAc. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. Hexane was added to the residue, and the resulting precipitate was collected by filtration to give the title compound (1:4 mixture, 584 mg, 59%) as a colorless amorphous. MS(ESI):m / z [M+H] + 230.2.

[0247] Step 2: Intermediate 55: (3R)-3-amino-1-methyl-cyclohexanol [ka] To a solution of intermediate 54 from the previous step (580 mg, 2.53 mmol) in CH2Cl2 (6 mL) was added TFA (3 mL) and the solution was stirred at room temperature for 2 h. The reaction solution was evaporated under reduced pressure to give the title compound (1176 mg, purity 27.7%, quantitative) as a colorless oil. The material was used in the next step without further purification.

[0248] Step 3: Intermediate 56: (1R,3R)-3-[[1-[2-[(4-methoxyphenyl)methoxy]-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]amino]-1-methyl-cyclohexanol [ka] and intermediate 57: (1S,3R)-3-[[1-[2-[(4-methoxyphenyl)methoxy]-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]amino]-1-methyl-cyclohexanol [ka] To a solution of intermediate 55 (540 mg, 27.7% purity, 1.17 mmol) from the previous step and intermediate 34 (500 mg, 1.17 mmol) in DMF (2 mL) was added DBU (1.31 mL, 8.78 mmol) and BOP (1280 mg, 2.63 mmol) and the solution was stirred at room temperature for 17 h. The reaction solution was poured into saturated aqueous NaHCO3 and the mixture was extracted with CHCl3. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of CHCl3-CHCl3 / MeOH (90 / 10) followed by chiral HPLC (column: CHIRALPAK IE Φ30mm*250mm, solvent: hexane / EtOH / nBuNH2 (35 / 65 / 0.1), flow rate: 20mL / min) to give intermediate 56 (40mg, 6%, MS(ESI): m / z 539.3 [M+H] + ) as a colorless powder and intermediate 57 (49 mg, 8%, MS(ESI): m / z 539.3 [M+H) + ) as a colorless powder.

[0249] Step 4: Example 61: 2-[4-[[(1R,3R)-3-hydroxy-3-methyl-cyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol [ka] To a flask containing intermediate 56 (35 mg, 0.065 mmol) from the previous step, hydrogen chloride in 1,4-dioxane (4 M, 2 mL, 8.0 mmol) was added and the solution was stirred at room temperature for 2 h. The reaction solution was poured into saturated aqueous NaHCO3, and the mixture was extracted with CHCl3. The organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was recrystallized from EtOAc and hexane to give the title compound (22 mg, 81%) as a yellow powder. MS (ESI): m / z 419.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 1.19 (s, 3 H), 1.21 - 1.33 (m, 2 H), 1.47 (t, 1 H), 1.54 - 1.59 (m, 2 H), 1.72 - 1.85 (m, 1 H), 1.94 - 2.00 (m, 1 H), 2.08 - 2.15 (m, 1 H), 4.21 (s, 1 H), 4.64 - 4.75 (m, 1 H), 7.26 - 7.28 (m, 1 H), 7.29 (br s, 1H), 7.32 (d, 1 H), 7.55 (d, 1H), 7.61 (d, 1 H), 8.83 (d, 1 H), 9.77 (s, 1 H), 10.44 (br s, 1 H).

[0250] Example 62: 2-[4-[[(1R,3S)-3-hydroxy-3-methyl-cyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol [ka] The title compound (24 mg, 70%) was prepared as a yellow powder from intermediate 57 (44 mg, 0.082 mmol) in analogy to example 61. MS (ESI): m / z 419.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 1.23 (s, 3 H) 1.36 - 1.53 (m, 3 H) 1.53 - 1.61 (m, 1 H) 1.62 - 1.68 (m, 1 H) 1.69 - 1.81 (m, 1 H) 1.88 - 2.00 (m, 1 H) 4.39 - 4.54 (m, 1 H) 4.69 (s, 1 H) 7.27 - 7.29 (m, 1 H) 7.29 (s, 1 H) 7.30 - 7.35 (m, 1 H) 7.55 (d, 1 H) 7.87 (d, 1 H) 8.84 (d, 1 H) 9.66 (s, 1 H) 10.23 - 10.61 (br, 1 H).

[0251] Example 63 Step 1: Intermediate 58: (1s,3s)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)-1-methylcyclobutan-1-ol [ka] To a suspension of 3-amino-1-methyl-cyclobutanol hydrochloride (1.5 g, 11.0 mmol, 1.1 equiv) in MeCN (10 mL) was added 1,4-dichloropyrido[3,4-d]pyridazine (2.0 g, 10.0 mmol, 1.0 equiv) and DIPEA (5.2 mL, 30.0 mmol, 3.0 equiv) at room temperature. The mixture was heated in a microwave reactor at 130° C. for 0.5 h. The reaction mixture was cooled to room temperature, H2O (50 mL) was added, and the mixture was extracted with EtOAc (30 mL, 3 times). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-5% MeOH in CHCl3 as the mobile phase and reverse-phase flash chromatography on a C18 column using a gradient of 12-17% MeCN (10 mM, aq) in (NH4)2CO3 as the mobile phase to give the title compound (1.1 g, 43%).

[0252] Step 2: Example 63: 2-(4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol [ka] To a solution of intermediate 58 (80.9 mg, 0.28 mmol, 1.0 equiv) and [2-hydroxy-4-(trifluoromethoxy)phenyl]boronic acid (91.6 mg, 0.41 mmol, 1.5 equiv) in 1,4-dioxane (1.8 mL) was added Pd(dppf)Cl2·CHCl2 (22.5 mg, 2.5 mmol, 0.1 equiv) and Na2CO3 (0.41 mL, 0.83 mmol, 2.0 M in H2O) at room temperature. The mixture was heated in a microwave reactor at 100 °C for 0.5 h. The reaction mixture was cooled to room temperature and H2O (10 mL) and CHCl3 (10 mL) were added. The mixture was filtered through a Phase-separator® and the filtrate was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography on a C18 column using a gradient of 30-60% MeCN (10 mM, aq) in (NH4)2CO3 as the mobile phase to give the title compound (10.4 mg, 9%); MS (ESI): m / z [M+H] + 407.1. 1 H NMR (400 MHz, DMSO-d6) δ 1.35 (s, 3H), 2.13 - 2.27 (m, 2H), 2.50 - 2.57 (m, 2H), 4.23 - 4.35 (m, 1H), 5.04 (s, 1H), 6.89 - 6.97 (m, 2H), 7.28 (dd, 1H), 7.39 - 7.47 (m, 1H), 8.06 (d, 1H), 8.84 (d, 1H), 9.78 (s, 1H).

[0253] Example 64: 3-Fluoro-2-(4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol [ka] The title compound was obtained in a similar manner to Example 63 using Intermediate 58, (2-fluoro-6-hydroxy-phenyl)boronic acid and Sphos Pd G3 (79.9 mg, 60%). MS (ESI): m / z [M+H] + 341.1. 1 H NMR (400 MHz, DMSO-d6) δ 1.35 (s, 3H), 2.13 - 2.28 (m, 2H), 2.47 - 2.50 (m, 2H), 4.19 - 4.33 (m, 1H), 5.06 (s, 1H), 6.81 (t, 1H), 6.85 (d, 1H), 7.16 (d, 1H), 7.36 (ddd, 1H), 8.11 (d, 1H), 8.85 (d, 1H), 9.81 (d, 1H), 10.03 (brs, 1H).

[0254] The examples contained in Table 5 below were synthesized similarly to the procedure of Example 63 using the indicated boronic acids. Unless otherwise stated, boronic acids are commercially available. [Table 5] TIFF2024523623000125.tif54169

[0255] Example 70 Step 1: Intermediate 59: 1-[(1-chloropyrido[3,4-d]pyridazin-4-yl)amino]-2-methyl-propan-2-ol [ka] To a solution of 1,4-dichloropyrido[3,4-d]pyridazine (3.0 g, 15 mmol) in MeCN (15 mL) was added TEA (6.3 mL, 45 mmol) and 1-amino-2-methyl-propan-2-ol (1.5 g, 16 mmol) at room temperature and the mixture was stirred at reflux temperature for 1 h. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. To the crude mixture was added CHCl3 and H2O and the two layers were separated. The organic layer was evaporated under reduced pressure. The residue was purified by flash chromatography to give the title compound (1.15 g, 30%) as a yellow amorphous solid. MS (ESI): m / z 253.1 / 255.1 [M+H] + .

[0256] Step 2: Example 70: 2-[4-[(2-hydroxy-2-methyl-propyl)amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol [ka] To a suspension of intermediate 59 (200 mg, 791 mmol, 1.0 equiv), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (261 mg, 1.273 mmol) and Na2CO3 (252 mg, 2.34 mol) in 1,4-dioxane (1 mL) and HO (1 mL) was added SPhos Pd G3 (124 mg, 158 mmol). The vial was sealed and the reaction was heated in a microwave reactor at 120 °C for 1 h. The reaction mixture was poured into HO and extracted with CHCl3. The organic layer was evaporated under reduced pressure. The crude mixture was purified by flash chromatography (silica, CHCl3 / MeOH=100 / 0-85 / 15) and reversed-phase flash chromatography on a C18 column using a gradient of 20-30% MeCN (10 mM, aq) in (NH4)2CO3 as the mobile phase to give the title compound (77 mg, 24%) as a yellow powder. MS (ESI): m / z 379.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 1.23 (s, 6H), 3.65 - 3.75 (m, 2H), 5.00 - 5.12 (m, 1H), 7.22 - 7.34 (m, 3H), 7.51 - 7.60 (m, 2H), 7.82 - 7.93 (m, 1H), 8.81 - 8.90 (m, 1H), 9.77 - 9.84 (m, 1H).

[0257] The examples contained in Table 6 below were synthesized similarly to the procedure of Example 70 using the specified starting materials and Intermediate 59. [Table 6]

[0258] Example 74 Step 1: Intermediate 60: 1-[[1-[2-fluoro-6-methoxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]amino]-2-methyl-propan-2-ol [ka] To a suspension of intermediate 59 (200 mg, 791 mmol), intermediate 9 (226 mg, 950 mmol) and Na2CO3 (252 mg, 2.37 mol) in 1,4-dioxane (2.0 mL) and H2O (1.0 mL) was added SPhos Pd G3 (62 mg, 79 mmol). The vial was sealed and the reaction was heated in a microwave reactor at 120 °C for 1 h. The reaction mixture was poured into H2O and extracted with CHCl3. The organic layer was evaporated under reduced pressure. The crude mixture was purified by flash chromatography (silica, CHCl3 / MeOH = 100 / 0-94 / 6) to give the title compound (342 mg, quant.) as a yellow amorphous. MS (ESI): m / z 409.1 [MH] - .

[0259] Step 2: Example 74: 3-Fluoro-2-[4-[(2-hydroxy-2-methyl-propyl)amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol [ka] To a solution of intermediate 60 (342 mg, 833 mmol) in 2,4,6-trimethylpyridine (1.0 mL) was added LiI (1.12 g, 8.33 mol) and the mixture was heated to 160 °C and stirred. After 0.5 h, the mixture was cooled to room temperature and purified by flash chromatography (silica, CHCl3 / MeOH = 100 / 0-80 / 20) and reversed-phase flash chromatography on a C18 column using a gradient of 20-25% MeCN in H2O as the mobile phase to give the title compound (94 mg, 28%) as a yellow amorphous. MS (ESI): m / z 397.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 1.23 (s, 6H), 3.66 - 3.76 (m, 2H), 4.95 - 5.05 (m, 1H), 7.11 - 7.19 (m, 1H), 7.20 - 7.31 (m, 2H), 7.90 - 7.99 (m, 1H), 8.82 - 8.90 (m, 1H), 9.80 - 9.90 (m, 1H).

[0260] Example 75 Step 1: Intermediate 47: (1R,2R)-2-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclohexan-1-ol [ka] and intermediate 48: (1R,2R)-2-((4-chloropyrido[3,4-d]pyridazin-1-yl)amino)cyclohexan-1-ol [ka] DIPEA (6.46 g, 49.99 mmol) was added to (1R,2R)-2-aminocyclohexan-1-ol (1.267 g, 11.00 mmol), 1,4-dichloropyrido[3,4-d]pyridazine (2 g, 10.00 mmol) in NMP (25 mL) at room temperature. The resulting solution was stirred at 80 °C for 12 h. The solvent was removed under reduced pressure and the crude product was purified by preparative chiral HPLC (column: CHIRAL ART Cellulose-SB, 3*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: IPA (0.5% 2M NH3 in MeOH); 70 mL / min with 50% B at 35 °C). The combined product fractions at a retention time of 6.05 min were lyophilized to give 0.600 g of intermediate 47 (21.5%) as a yellow solid. The combined product fractions with a retention time of 7.67 min were lyophilized to give 0.200 g of intermediate 48 (7.2%) as a yellow solid. Intermediate 47: MS(ESI):m / z [M+H] + 279.10. 1 H NMR (300 MHz, DMSO-d6) δ 1.10 - 1.42 (m, 4 H), 1.67 (s, 2 H), 1.83 - 2.11 (m, 2 H), 3.50 - 3.65 (m, 1 H), 4.10 (s, 1H), 4.75 (m, 1H), 7.70 - 7.85 (m, 2 H), 9.02 (m, 1 H), 9.78 (m, 1 H). Intermediate 48: MS(ESI):m / z [M+H] + 279.05. 1 H NMR (300 MHz, DMSO-d6) δ 1.27 (m, 4 H), 1.65 (m, 2 H), 1.87 - 2.13 (m, 2H), 3.57 (m, 1 H), 4.05 (m, 1 H), 4.69 (m, 1 H), 7.58 (m, 1 H), 8.33 (m, 1 H), 9.07 (m, 1 H), 9.37 (m, 1 H).

[0261] Step 2: Example 75: 5-Fluoro-2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol [ka] Pd(PPh3)4 (20.73 mg, 0.02 mmol) was added to intermediate 47 (100 mg, 0.36 mmol), (4-fluoro-2-hydroxyphenyl)boronic acid (84 mg, 0.54 mmol) and K3PO4 (152 mg, 0.72 mmol) in 1,4-dioxane (5 mL) and water (1 mL) under inert atmosphere. The resulting solution was stirred at 90 °C for 12 h. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (column: YMC-Actus Triart C18 ExRS, 30 mm × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 and 0.1% NH3), mobile phase B: MeCN; 60 mL / min; with a gradient of 10% to 43% B in 7 min). The combined product fractions with a retention time of 6.63 min were lyophilized to give 0.038 g of the title compound (29.9%) as a pale yellow solid. MS (ESI): m / z [M+H] + 355.05. 1 H NMR (300 MHz, DMSO-d6) δ 1.30 (m, 4 H), 1.69 (s, 2 H), 2.04 (m, 2 H), 3.61 (m, 1 H), 4.20 (m, 1 H),4.80 (s, 1 H), 6.68 - 6.87 (m, 2 H), 7.18 - 7.40 (m, 2 H), 7.58 (d, 1 H), 8.82 (d, 1 H), 9.76 (d, 1 H), 10.26 (s, 1 H); 19 F NMR (282 MHz, DMSO-d6) δ -111.322, -111.669(1 F).

[0262] Example 76: 3-Fluoro-2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol [ka] Pd(PPh3)4 (20.73 mg, 0.02 mmol) was added to intermediate 47 (100 mg, 0.36 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (84 mg, 0.54 mmol) and K3PO4 (152 mg, 0.72 mmol) in 1,4-dioxane (5 mL) and water (1 mL) under inert atmosphere. The resulting solution was stirred at 90 °C for 12 h. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 and 0.1% NH3), Mobile phase B: MeCN; 60 mL / min; with a gradient of 10% to 40% B in 8 min). The combined product fractions with a retention time of 7.80 min were lyophilized to give 0.057 g of the title compound (45.1%) as a yellow solid. MS (ESI): m / z [M+H] + 355.15. 1 H NMR (300 MHz, DMSO-d6) δ 1.30 (m, 5 H), 1.70 (m, 2 H), 1.97 (s, 1H), 2.11 (s, 1 H), 3.60 (s, 1 H), 4.21 (s, 1 H), 4.81 (m, 1 H), 6.73 - 6.88 (m, 2 H), 7.13 (m, 1 H), 7.34 (m, 1 H), 7.65 (m, 1 H), 8.82 (m, 1 H), 9.78 (m, 1 H), 10.01 (s, 1 H); 19 F NMR (282 MHz, DMSO-d6) δ -114.433, -114.780 (1 F).

[0263] Example 77: 3-Fluoro-2-(1-(((1R,2R)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol [ka] Pd(PPh3)4 (20.73 mg, 0.02 mmol) was added to intermediate 48 (100 mg, 0.36 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (84 mg, 0.54 mmol) and K3PO4 (152 mg, 0.72 mmol) in 1,4-dioxane (5 mL) under inert atmosphere. The resulting solution was stirred at 90 °C for 12 h. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (column: YMC-Actus Triart C18, 30 mm × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 and 0.1% NH3), mobile phase B: MeCN; 60 mL / min; with a gradient of 12% to 32% B in 10 min). The combined product fractions with a retention time of 9.92 min were lyophilized to give 0.050 g of the title compound (39.3%) as a yellow solid. MS (ESI): m / z [M+H] + 355.00. 1 H NMR (300 MHz, DMSO-d6) δ 1.31 (m, 4 H), 1.69 (m, 2 H), 1.96 (m, 1 H), 2.11 (m, 1 H), 3.60 (m, 1 H), 4.16 (s, 1 H), 4.76 (s, 1 H), 6.76 - 6.90 (m, 2 H), 7.36 (m, 1 H), 7.45 (m, 1 H), 8.32 (m, 1 H), 8.68 (s, 1 H), 8.93 (d, 1 H), 10.08 (s, 1 H); 19 F NMR (282 MHz, DMSO-d6) δ -114.742 (1 F).

[0264] Example 78: 5-fluoro-2-(1-(((1R,2R)-2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol [ka] Pd(PPh3)4 (20.73 mg, 0.02 mmol) was added to intermediate 48 (100 mg, 0.36 mmol), (4-fluoro-2-hydroxyphenyl)boronic acid (84 mg, 0.54 mmol) and K3PO4 (152 mg, 0.72 mmol) in 1,4-dioxane (5 mL) and water (1 mL) under inert atmosphere. The resulting solution was stirred at 90 °C for 12 h. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (column: YMC-Actus Triart C18, 30 mm × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 and 0.1% NH3), mobile phase B: MeCN; 60 mL / min; with a gradient of 16% to 36% B in 10 min). The combined product fractions with a retention time of 7.80 min were lyophilized to give 0.062 g of the title compound (48.5%) as a white solid. MS (ESI): m / z [M+H] + 355.05. 1 H NMR (300 MHz, DMSO-d6) δ 1.29 (m, 5 H), 1.96 (m, 1 H), 2.10 (m, 1 H), 3.59 (s, 1 H), 4.13 (s, 1 H), 4.75 (s, 1 H), 6.65 - 6.98 (m, 2 H), 7.38 (m, 2 H), 8.28 (m, 1 H), 8.80 (s, 1 H), 8.90 (m, 1 H), 10.31 (s, 1 H); 19 F NMR (282 MHz, DMSO-d6) δ -111.459 (1 F).

[0265] The examples included in Table 7 below were synthesized similarly to step 5 of the procedure for making Example 40, but with intermediate 1 instead of intermediate 35, and with the specified amino alcohol instead of (1R,2R)-2-aminocyclohexan-1-ol, followed by deprotection similarly to step 2 of the procedure for making Example 74. [Table 7] TIFF2024523623000138.tif112169

[0266] Example 85 Step 1: Intermediate 61: (1R,3R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclopentan-1-ol [ka] and intermediate 62: (1R,3R)-3-((4-chloropyrido[3,4-d]pyridazin-1-yl)amino)cyclopentan-1-ol [ka] DIPEA (5.04 g, 39.00 mmol) was added to 1,4-dichloropyrido[3,4-d]pyridazine (1.3 g, 6.50 mmol), (1R,3R)-3-aminocyclopentan-1-ol hydrochloride (0.984 g, 7.15 mmol) in NMP (5 mL) at room temperature. The resulting solution was stirred at 80 °C for 12 h. The solvent was removed under reduced pressure and the crude product was purified by preparative chiral HPLC (column: OptiChiral-C9-5, 3*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH (0.5% 2M NH3 in MeOH); 100 mL / min; 50% B at 35 °C). The fractions containing the desired product at a retention time of 2.88 min were dried to yield 1.00 g of intermediate 61 (58.1%) as a yellow solid. The fractions containing the desired product at a retention time of 3.92 min were dried down to yield 0.44 g of intermediate 62 (25.6%) as a yellow solid. Intermediate 61: MS(ESI):m / z [M+H] + 265.05. 1H NMR (300 MHz, DMSO-d6) δ 1.45 - 1.67 (m, 2 H), 1.80 (m, 1 H), 1.88 - 2.09 (m, 2 H), 2.13 - 2.29 (m, 1 H), 4.27 (m, 1 H), 4.44 - 4.80 (m, 2 H), 7.77 - 7.91 (m, 2 H), 9.02 (m, 1 H), 9.76 (m, 1 H). Intermediate 62: MS(ESI):m / z [M+H] + 265.05. 1 H NMR (300 MHz, DMSO-d6) δ 1.56 (m, 2 H), 1.78 (m, 1 H), 1.88 - 2.08 (m, 2 H), 2.12 - 2.28 (m, 1 H), 4.26 (m, 1 H), 4.42 - 4.77 (m, 2 H), 7.69 (m, 1 H), 8.32 (m, 1 H), 9.06 (m, 1 H), 9.37 (m, 1 H).

[0267] Step 2: Example 85: 5-Fluoro-2-(4-(((1R,3R)-3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol [ka] Pd(PPh3)4 (32.7 mg, 0.03 mmol) was added to intermediate 61 (150 mg, 0.57 mmol), (4-fluoro-2-hydroxyphenyl)boronic acid (133 mg, 0.85 mmol) and K3PO4 (241 mg, 1.13 mmol) in 1,4-dioxane (5 mL) and water (0.2 mL) under inert atmosphere. The resulting solution was stirred at 90 °C for 12 h. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 and 0.1% NH3), Mobile phase B: MeCN; 60 mL / min; with gradient 16% to 26% B in 8 min). The combined product fractions with a retention time of 8.75 min were lyophilized to give 0.035 g of the title compound (18.2%) as a grey solid. MS (ESI): m / z [M+H] + 341.15. 1 H NMR (300 MHz, DMSO-d6) δ 1.49 - 1.71 (m, 2 H), 1.78 - 1.90 (m, 1 H), 2.03 (m, 2 H), 2.21 - 2.31 (m, 1 H), 4.30 (s, 1 H), 4.57 (m, 1 H), 4.85 (m, 1 H), 6.72 - 6.86 (m, 2 H), 7.23 - 7.41 (m, 2 H), 7.70 (m, 1 H), 8.83 (m, 1 H), 9.76 (s, 1 H), 10.22 (s, 1 H); 19 F NMR (282 MHz, DMSO-d6) δ-111.625,-111.689,-111.768 (1 F).

[0268] Example 86: 3-Fluoro-2-(1-(((1R,3R)-3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol [ka] Pd(PPh3)4 (21.8 mg, 0.02 mmol) was added to intermediate 62 (100 mg, 0.38 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (70.7 mg, 0.45 mmol) and K3PO4 (241 mg, 1.13 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) under inert atmosphere. The resulting solution was stirred at 90 °C for 16 h. The reaction was quenched by adding water and extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (column: XSelect CSH Fluoro Phenyl, 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: MeCN; 60 mL / min; with a gradient of 2% to 12% B in 7 min). The combined product fractions were lyophilized to give 0.072 g of the title compound (53.3%) as a yellow solid. MS (ESI): m / z [M+H] + 341.00. 1 H NMR (300 MHz, DMSO-d6) δ 1.60 (m, 2 H), 1.82 (m, 1 H), 1.98 (m, 2 H), 2.24 (m, 1 H), 4.29 (s, 1 H), 4.57 (s, 1 H), 4.80 (m, 1 H), 6.83 (m, 2 H), 7.36 (m, 1 H), 7.57 (m, 1 H), 8.30 (m, 1 H), 8.69 (s, 1H), 8.93 (m, 1 H), 10.07 (s, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -114.705, -114.756, -135.688 (1 F).

[0269] Example 87 Step 1: Intermediate 63: (1S,3R)-3-((1-chloropyrido[3,4-d]pyridazin-4-yl)amino)cyclopentan-1-ol [ka] and intermediate 64: (1S,3R)-3-((4-chloropyrido[3,4-d]pyridazin-1-yl)amino)cyclopentan-1-ol [ka] 1,4-Dichloropyrido[3,4-d]pyridazine (1.1 g, 5.50 mmol), (1S,3R)-3-aminocyclopentan-1-ol hydrochloride (0.795 g, 5.77 mmol), and Na2CO3 (1.224 g, 11.55 mmol) were diluted with sulfolane (11 mL) and heated to 80° C. for 3 h with stirring under inert atmosphere. The solid formed was filtered off, the filtrate was washed with DCM and MeOH, and the solvent was removed under reduced pressure. Preparative HPLC was used for regioisomer separation (column: Chiralpak IB N-3, 150*4.6 mm, 3 μm; mobile phase A: CO2, mobile phase B: EtOH (20 mM DEA in EtOH); 3.5 mL / min; 25% B at 40° C.). The fractions with a retention time of 2.63 min were pooled and dried to yield 1.1 g of intermediate 63 (76.0%). The fractions with a retention time of 1.96 min were pooled and dried to yield 347 mg of intermediate 64 (23.8%). Intermediate 63: 1 H NMR (500 MHz, DMSO-d6) δ1.57 - 1.71 (m, 2H), 1.71 - 1.88 (m, 2H), 2.03 - 2.15 (m, 1H), 2.36 (m, 1H), 4.11 - 4.24 (m, 1H), 4.44 (m, 1H), 4.74 (m, 1H), 7.79 (s, 1H), 8.37 (s, 1H), 9.09 (s, 1H), 9.39 (s, 1H). Intermediate 64: 1H NMR (500 MHz, DMSO-d6) δ1.57 - 1.71 (m, 2H), 1.71 - 1.88 (m, 2H), 2.03 - 2.15 (m, 1H), 2.36 (m, 1H), 4.11 - 4.24 (m, 1H), 4.44 (m, 1H), 4.74 (m, 1H), 7.79 (s, 1H), 8.37 (s, 1H), 9.09 (s, 1H), 9.39 (s, 1H).

[0270] Step 2: Example 87: 3-Fluoro-2-(1-(((1R,3S)-3-hydroxycyclopentyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol [ka] A mixture of intermediate 64 (100 mg, 0.38 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (70.7 mg, 0.45 mmol), Pd(PPh3)4 (21.83 mg, 0.02 mmol) and K3PO4 (241 mg, 1.13 mmol) was added in water (1 mL) and 1,4-dioxane (5 mL) at room temperature. The resulting mixture was stirred at 90 °C for 15 h under inert atmosphere. The reaction was quenched by adding water and extracted three times with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (column: XSelect CSH Fluoro Phenyl, 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: MeCN; 60 mL / min; 2% B to 12% B in 7 min). The combined fractions with a retention time of 5.72 min were pooled and lyophilized. The reaction yielded 0.089 g of the title compound (66.6%) as a pale yellow solid. MS (ESI): m / z [M+H] + 341.00. 1H NMR (300 MHz, DMSO-d6) δ 1.65 (m, 2H), 1.82 (m, 2H), 2.07 (m, 1H), 2.37 (m, 1H), 4.17 (m, 1H), 4.54 (m, 1H), 4.76 (s, 1H), 6.83 (m, 2H), 7.36 (m, 1H), 7.67 (m, 1H), 8.32 (m, 1H), 8.69 (s, 1H), 8.93 (m, 1H), 10.07 (s, 1H); 19 F NMR (282 MHz, DMSO-d6) δ -114.714, -114.897 (1 F).

[0271] Example 88 Step 1: Intermediate 65: 2-[4-[[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methylamino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol [ka] To a solution of [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanamine (85.0 mg, 0.65 mmol, 1.1 equiv) in MeCN (2.0 mL) was added DIPEA (0.31 mL, 1.8 mmol, 3.0 equiv) and intermediate 1 (200.0 mg, 0.59 mmol, 1.0 equiv). The mixture was stirred at 100° C. for 44 h. The reaction mixture was concentrated. To the residue was added 2,4,6-trimethylpyridine (12 mL, 89.11 mmol) and LiI (788.0 mg, 5.89 mmol, 10.0 equiv) at room temperature. The mixture was stirred at 160° C. for 5 h in the dark. The reaction mixture was cooled to room temperature. The reaction was quenched by the addition of water and extracted with CHCl3 (3 times). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by reverse-phase flash chromatography on a C18 column using a gradient of 20-50% MeCN (10 mM, aq) in (NH4)2CO3 as the mobile phase to give the title compound as a brown solid (129.3 mg, 50%); MS (ESI): m / z [M+H]+ 421.1.

[0272] Step 2: Example 88: (2S)-3-[[1-[2-hydroxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]amino]propane-1,2-diol [ka] To a suspension of intermediate 65 (124.6 mg, 0.30 mmol, 1.0 equiv) in AcOH (2 mL) was added HO (0.6 mL) and the mixture was stirred at 80 °C for 1 h. The mixture was cooled to room temperature and concentrated. The crude mixture was purified by reverse-phase flash chromatography on a C18 column using a gradient of 20-50% MeCN (10 mM, aq) in (NH4)2CO3 as the mobile phase to give the title compound as a white solid (47.4 mg, 39%). MS (ESI): m / z [M+H] + 381.1. 1 H NMR (400 MHz, DMSO-d6) δ 3.43 - 3.47 (m, 2H), 3.51 - 3.64 (m, 1H), 3.75 - 3.84 (m, 1H), 3.85 - 3.97 (m, 1H), 4.76 (t, 1H), 5.10 (d, 1H), 7.17 - 7.39 (m, 3H), 7.56 (d, 1H), 8.08 - 8.16 (m, 1H), 8.85 (d, 1H), 9.76 (d, 1H), 10.46 (br d, 1H).

[0273] Example 89 Step 1: Intermediate 66: 6,7-Dihydropyrido[2,3-d]pyridazine-5,8-dione [ka] To a suspension of furo[3,4-b]pyridine-5,7-dione (5.00 g, 33.5 mmol) in AcOH (25 mL) was added hydrazine monohydrate (5.3 mL, 110 mmol) at room temperature and the mixture was stirred at reflux for 17 h. The mixture was cooled to room temperature and the precipitate was filtered and washed with H2O to give the title compound (5.15 g, 94%) as a colorless powder. MS (ESI): m / z 164.0 [M+H] + .

[0274] Step 2: Intermediate 67: 5,8-Dichloropyrido[2,3-d]pyridazine [ka] To a solution of intermediate 66 (2.0 g, 12 mmol) in pyridine (1.9 g, 25 mmol) was added phosphoryl trichloride (10 mL) at room temperature and the mixture was stirred at 100° C. for 6 h. The mixture was evaporated under reduced pressure, poured into ice water, extracted with CHCl3, dried over Na2SO4 and filtered. The organic solvent was evaporated under reduced pressure to give the title compound (2.4 g, 98%) as a brown solid. MS (ESI): m / z 200.0 / 202.0 [M+H] + .

[0275] Step 3: Intermediate 68: (1S,3R)-3-[(5-chloropyrido[2,3-d]pyridazin-8-yl)amino]cyclohexanol [ka] To a solution of intermediate 67 (1.20 g, 6.00 mmol) and (1S,3R)-3-aminocyclohexanol hydrochloride in NMP (6.0 mL) was added DIPEA (3.5 mL) and the mixture was stirred at 80° C. for 17 h. The mixture was evaporated under reduced pressure and purified by flash chromatography (NH silica; EtOAc / MeOH=100 / 0-80 / 20) to give the title compound (236 mg, 13%) as a yellow solid. MS (ESI): m / z 279.1 / 281.2 [M+H] + .

[0276] Step 4: Example 89: 2-[8-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[2,3-d]pyridazin-5-yl]-5-(trifluoromethyl)phenol [ka] To a solution of intermediate 68 (236 mg, 0.847 mmol) and (2-fluoro-6-methoxy-phenyl)boronic acid (209 mg, 1.02 mmol) in 1,4-dioxane (5 mL) and 2.0 M aqueous Na2CO3 (2.5 mL) was added Pd(dppf)Cl2·CH2Cl2 (69 mg, 0.085 mmol) and the mixture was stirred at 100 °C for 5 h. The mixture was cooled to room temperature, poured into H2O, extracted with CHCl3, washed with H2O, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude mixture was purified by flash chromatography (NH silica; CHCl3 / MeOH = 100 / 0-90 / 10). The combined product fractions were concentrated and further purified by flash chromatography (silica; CHCl3 / MeOH=100 / 0 to 90 / 10) and then triturated with 10% MeOH in IPE to give the title compound (78 mg, 23%) as a pale yellow powder. MS (ESI): m / z 405.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 1.30 - 1.75 (m, 5H), 1.88 - 2.24 (m, 3H), 2.41 - 2.55 (m, 1H), 3.91 - 4.05 (m, 1H), 4.40 - 4.52 (m, 1H), 7.20 - 7.27 (m, 1H), 7.40 - 7.48 (m, 1H), 7.59 - 7.65 (m, 1H), 7.74 - 7.82 (m, 1H), 8.48 - 8.57 (m, 1H), 9.02 - 9.09 (m, 1H).

[0277] Example 90: 3-Fluoro-2-(8-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)pyrido[2,3-d]pyridazin-5-yl)phenol [ka] The title compound was synthesized similarly to the procedure of Example 63, starting from intermediate 67 and (2-fluoro-6-hydroxy-phenyl)boronic acid. MS (ESI): m / z 341.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 1.33 (s, 3H), 2.16 - 2.27 (m, 2H), 2.45 - 2.55 (m, 2H), 4.31 - 4.42 (m, 1H), 5.01 (br s, 1H), 6.77 - 6.91 (m, 2H), 7.31 - 7.41 (m, 1H), 7.51 - 7.62 (m, 1H), 7.72 - 7.82 (m, 1H), 7.82 - 7.91 (m, 1H), 9.08 - 9.15 (m, 1H).

[0278] Example 91 Step 1: Intermediate 69: 2-Methyl-6,7-dihydropyrido[2,3-d]pyridazine-5,8-dione [ka] To a suspension of 2-methylfuro[3,4-b]pyridine-5,7-dione (5.42 g, 31.6 mmol) in AcOH (24 mL) was added hydrazine monohydrate (5.0 mL, 103 mmol) at room temperature and the mixture was stirred at 125 °C for 40 min. The mixture was cooled to room temperature and the precipitate was filtered, washed with H2O and dried to give the title compound (4.80 g, 86%) as a colorless powder. MS (ESI): m / z 178.0 [M+H] + .

[0279] Step 2: Intermediate 70: 5,8-Dichloro-2-methyl-pyrido[2,3-d]pyridazine [ka] To a solution of intermediate 69 (1.10 g, 6.21 mmol) in pyridine (1.0 mL) was added phosphoryl trichloride (5.0 mL) at room temperature and the mixture was stirred at 100° C. for 5 h under argon atmosphere. The mixture was evaporated under reduced pressure, poured into ice water, extracted with CHCl3, dried over Na2SO4, and filtered. The organic solvent was evaporated under reduced pressure to give the title compound (585 mg, 44%) as a red powder. MS (ESI): m / z 214.0 / 216.0 [M+H] + .

[0280] Step 3: Example 91: 2-[8-[[(1R,3S)-3-hydroxycyclohexyl]amino]-2-methyl-pyrido[2,3-d]pyridazin-5-yl]-5-(trifluoromethyl)phenol [ka] The title compound was synthesized similarly to the procedure of Example 89 starting from Intermediate 70. MS (ESI): m / z 419.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 1.20 - 1.52 (m, 4H), 1.73 - 2.00 (m, 3H), 2.16 - 2.25 (m, 1H), 2.73 (s, 3H), 3.60 - 3.70 (m, 1H), 4.19 - 4.30 (m, 1H), 4.70 - 4.77 (m, 1H), 7.22 - 7.34 (m, 2H), 7.52 - 7.59 (m, 1H), 7.67 - 7.73 (m, 1H), 7.78 - 7.82 (m, 1H).

[0281] Example 92 Step 1: Intermediate 71: 3-[(4-chlorophthalazin-1-yl)amino]-2-methyl-propane-1,2-diol [ka] To a solution of 1,4-dichlorophthalazine (300 mg, 1.51 mmol, 1.0 equiv) in MeCN (2 mL) was added DIPEA (0.78 mL, 4.52 mmol, 3.0 equiv) and 3-amino-2-methyl-propane-1,2-diol (190 mg, 1.81 mmol, 1.2 equiv). The vial was sealed and the reaction was heated at 120 °C in a microwave reactor for 1 h. The reaction mixture was cooled to room temperature and the residual precipitate was triturated with CHCl3 to give the title compound (290 mg, 72%) as a colorless powder. MS (ESI): m / z 268.1 / 270.1 [M+H] + .

[0282] Step 2: Intermediate 72: 4-chloro-N-[(2,2,4-trimethyl-1,3-dioxolan-4-yl)methyl]phthalazin-1-amine [ka] To a mixture of intermediate 71 (200 mg, 0.747 mmol, 1.0 equiv) in DMF (3 mL) and acetone (3 mL), 2,2-dimethoxypropane (3.0 mL, 24.46 mmol, 33 equiv) and para-toluenesulfonic acid monohydrate (28.4 mg, 0.149 mmol, 0.2 equiv) were added, and the mixture was then stirred at room temperature for 12 h. The reaction mixture was concentrated and saturated aqueous NaHCO3 was added. The mixture was extracted with EtOAc, washed with brine, and then the organic layer was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography using a gradient of 25-50% EtOAc in hexanes as the mobile phase to give the title compound (255 mg, 100%) as a colorless gum. MS (ESI) m / z 308.1 / 310.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 1.29 (s, 3H), 1.31 (s, 3H), 1.33 (s, 3H), 3.63 - 3.66 (m, 1H), 3.65 - 3.69 (m, 1H), 3.79 - 3.83 (m, 1H), 4.06 - 4.08 (m 1H), 7.61 - 7.63 (m, 1H), 7.97 - 8.02 (m, 2H), 8.06 - 8.09 (m, 1H), 8.41 - 8.45 (m, 1H).

[0283] Step 3: Intermediate 73: 5-(trifluoromethyl)-2-[4-[(2,2,4-trimethyl-1,3-dioxolan-4-yl)methylamino]phthalazin-1-yl]phenol [ka] To a solution of intermediate 72 (120 mg, 0.35 mmol), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (108 mg, 0.53 mmol) and PdCl2(Amphos)2 (24.9 mg, 0.035 mmol, 0.1 equiv) in DME (2 mL) and H2O (0.5 mL) was added Cs2CO3 (343 mg, 1.05 mmol, 3.0 equiv) and the vial was sealed. The reaction was heated at 120 °C in a microwave reactor for 1 h. The reaction mixture was cooled to room temperature and diluted with H2O. The mixture was added to CHCl3 and stirred. The organic layer was separated and concentrated under vacuum. The residue was purified by column chromatography using a gradient of 0-10% MeOH in CHCl3 as mobile phase to give the title compound (135 mg, 89%) as a pale yellow powder. MS(ESI) m / z 434.2 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 1.34 (s, 3H), 1.35 - 1.36 (m, 6H), 3.68 - 3.71 (m, 1H), 3.73 - 3.76 (m, 1H), 3.89 - 3.94 (m, 1H), 4.13 - 4.15 (m, 1H), 7.27 - 7.30 (m, 2H), 7.44 - 7.47 (m, 2H), 7.51 - 7.54 (m, 1H), 7.77 - 7.81 (m, 1H), 7.86 - 7.88 (m, 1H), 8.38 - 8.40 (m, 1H), 10.36 (br s, 1H).

[0284] Step 4: Example 92: 3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]-2-methyl-propane-1,2-diol [ka] To a solution of intermediate 73 (135 mg, 0.312 mmol) in trifluoroacetic acid (2 mL) was added HO (0.8 mL) and the mixture was stirred at room temperature for 3 h. The mixture was cooled to room temperature and evaporated under reduced pressure. The residue was purified by reversed-phase flash chromatography on a C18 column using a gradient of 30-60% MeCN (10 mM, aq) in (NH4)2CO3 as the mobile phase to give the title compound (84 mg, 68%) as a colorless powder. MS (ESI): m / z 394.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 1.15 (s, 3H), 3.18 - 3.29 (m, 2H), 3.60 - 3.66 (m, 2H), 5.33 - 5.36 (m, 2H), 7.26 - 7.32 (m, 2H), 7.45 - 7.47 (m, 1H), 7.51 - 7.53 (m, 1H), 7.65 - 7.68 (m, 1H), 7.80 - 7.84 (m, 1H), 7.88 - 7.92 (m, 1H), 8.38 - 8.39 (m, 1H), 10.36 (br s, 1H).

[0285] [Table 8] TIFF2024523623000161.tif228169 TIFF2024523623000162.tif236169 TIFF2024523623000163.tif228169 TIFF2024523623000164.tif236169 TIFF2024523623000165.tif242169 TIFF2024523623000166.tif242169

[0286] Biological and physicochemical data Human NLRP3 speckle formation assay (Test A) To profile compounds for NLRP3 antagonist activity with respect to inhibition of nigericin-induced speck formation, ASC-GFP reporter monocytes (InvivoGen #thp-ascgfp) were utilized. The assay is based on NF-kB-dependent expression of an ASC::GFP fusion protein. LPS-primed cells increase expression of ASC::GFP, and nigericin recruits ASC::GFP, procaspase-1, and NLRP3 to form micrometer-sized complexes, ASC-specks, which are quantified by fluorescence microscopy.

[0287] Preparation of assay reagents Assay medium: RPMI 1640 (Gibco #72400-021) supplemented with 10% heat-inactivated FBS (Gibco #10270) Cells: THP-ASC-GFP were cultured (every passage) in RPMI1640 (Gibco #72400-021) supplemented with 10% heat-inactivated FBS (Gibco #10270) and 100 μg / mL Zeocin (Life Technologies #46-0072) to maintain ASC::GFP expression.

[0288] Step-by-step protocol for performing the assay Day 1 1. Cells were counted using CEDEX (Innovartis) and diluted to 375,000 cells / mL in assay medium supplemented with 100 nM phorbol 12-myristate 13-acetate (Sigma #P8139). 2. 20 μl of the above cell mixture was dispensed into a black μclear TC treated (Greiner #781091) 384-well plate using a Multidrop Combi (ThermoFisher). 3. The plates were incubated at 37°C, 5% CO2 for 20 hours. Day 2 1. 10 μl of LPS (Sigma #L2654) was dispensed at 1 μg / mL using a Multidrop Combi (ThermoFisher). 2. The plates were incubated at 37°C, 5% CO2 for 3 hours. 3. 80 nl of test compound in DMSO was prepared from a concentration response curve and diluted in 20 μL of assay medium supplemented with 68 μM ZVAD-FMK (Promega #7231) in a polypropylene 384-well plate (Greiner #781280). 4. 10 μl of the above test compound solution was transferred to the cell plate using a Bravo (Agilent). 5. The plate was incubated at 37°C, 5% CO2 for 30 minutes. 6. 15 μl of 75 μM Nigericin (Sigma #SML1779) was dispensed onto the cell plate using a Certus (Gyger). 7. The plate was incubated at 37°C, 5% CO2 for 1 hour. 8. 15 μl of 17.3% formaldehyde (Sigma #F8775) supplemented with Hoechst nucleic acid stain (Life Technologies #H3570) diluted 1:5000 was added using a Multidrop (ThermoFisher). 9. The plate was incubated at RT for 15 minutes. 10. Plates were washed twice with 40 μl of PBS (Gibco #100100) using a Bluewasher (BlueCatBio). 11. Plates were imaged using ImageXpress (Molecular Devices).

[0289] Image data were processed using Columbus software (Perkin Elmer). Nuclear staining was used to identify cells and spot detection was used to identify ASC-specks within cells. Data were further processed using Screener (Genedata AG). Concentration-response data of speck number per cell were fitted using a four-parameter logistic fit to obtain EC 50 The values ​​are reported in Table 9.

[0290] Nigericin-induced (human NLRP3) IL-1β assay (Test B) Compounds were profiled for NLRP3 antagonist activity with respect to inhibition of nigericin-induced IL-1β release from THP-1 human monocytes. Quantification was performed using a commercially available human IL-1β HTRF detection kit (CisBio, 62HIL1BPEH). The assay uses two anti-IL-1β antibodies in a sandwich assay format; one labeled with a donor fluorophore (Eu cryptate) and the other with an acceptor (XL). An immune complex containing two antibodies bound to the same IL-1β molecule allows fluorescence resonance energy transfer (FRET) between the donor and acceptor after excitation of the donor with a light source, followed by fluorescence at 665 nm from the acceptor. The intensity of the fluorescent signal is proportional to the IL-1β concentration in the sample.

[0291] Preparation of assay reagents Cells: THP human monocytic leukemia cell line. Cells were typically passaged every 2-3 days to maintain a density of 0.2-0.4×10^6 cells / mL. Culture and assay medium: RPMI1640 (Gibco, 72400-021) supplemented with 10% FBS (Sigma, F2442) IL-1β standard: The reconstituted IL-1β standard provided in the CisBio kit was diluted in assay medium to give a final concentration in the assay of 2 ng / mL. HTRF detection reagents: cAMP-d2 and anti-cAMP cryptate were reconstituted according to the CisBio kit instructions. Immediately before use, the reagents were combined using the following ratios: 10 / 24 detection buffer (provided in the kit), 14 / 24 PBS (Gibco, 10010), 1 / 120 IL-1β Eu-cryptate antibody and 1 / 120 IL-1β XL antibody.

[0292] Step-by-step protocol for performing the assay Day 1 1. Test compounds dissolved in DMSO were aquostically dispensed (Labcyte Echo) into white 384-well plates (Greiner; 784075), sealed and stored at rt until assayed. 2. In the Echo dispenser, 20 nL of 50 μM control compound in DMSO (final concentration 250 nM) was added to the 100% inhibition control wells and 20 nL of DMSO was added to the 0% control wells. The control compound can be selected from MCC950 (N-[[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)amino]carbonyl]-4-(1-hydroxy-1-methylethyl)-2-furansulfonamide) or any other compound that acts as a full antagonist in the assay. 3. An aliquot of cells was removed from cells grown in continuous culture and counted on a CEDEX (Innovatis). 4. The number of cells required for the experiment was determined by centrifugation at 250×g for 5 minutes and resuspending the cells at 1.0×10^6 cells / mL in assay medium at 37°C. 5. LPS (Sigma; L2654) was added to a final concentration of 1 μg / mL. 6. Cells were LPS primed in bulk in 50 mL tubes by incubating at 37° C., 5% CO2 and 95% humidity for 3 hours. 7. 4 μL of the 1.0×10^6 cells / mL cell solution was dispensed into a white 384-well small volume plate (Greiner; 784075) using a Multidrop Combi (Thermo Fisher) to give 4000 cells / well. 8. Incubate for 30 minutes at 37°C, 5% CO2 and 95% humidity. 9. 4 μL of 40 μM nigericin in assay medium was added using a Certus (Gyger) to give a final concentration of 20 μM. 10. Incubate at 37°C, 5% CO2 and 95% humidity for 1 hour. 11. 4 μL of HTRF detection reagent was added using a Multidrop Combi. 12. Incubate for 3 hours at rt, protected from light. 13. Homogeneous time-resolved fluorescence (HTRF) signals were detected with an Envision (PerkinElmer) or Pherastar (BMG Labtech) reader (λex=340 nm, λem=665 and 615 nm).

[0293] Using an IL-1β standard curve, the HTRF data was converted to the amount of IL-1β produced in the samples, which was subsequently used to calculate the concentration response. The concentration response data was analyzed using Screener (Genedata) and fitted using a four-parameter logistic fit. The results of the assay are shown in Table 9 as IC 50 Report as (μM).

[0294] I C 50 is defined as the concentration at which inhibitory activity reaches 50% of its maximal level. When assays were performed multiple times for the same compound, geometric mean values ​​are reported. To facilitate comparison of efficacy data, efficacy was normalized to the % inhibitory effect of the test compound compared to the inhibition produced by a saturating concentration of control compound (250 nM).

[0295] BzATP-induced (human NLRP3) IL-1β assay (Test C) In a variation of the IL-1β assay, compounds were tested for their ability to inhibit BzATP (2'(3')-O-(4-benzoylbenzoyl) adenosine 5'-triphosphate)-induced IL-1β release from THP-1 human monocytes. As with the nigericin induction assay, quantification was performed using the Human IL-1β HTRF Detection Kit (CisBio, 62HIL1BPEH).

[0296] There were several differences between the nigericin induction assay (Test B) and the BzATP induction assay. The relevant differences in the conditions in the BzATP induction assay compared to the nigericin induction assay were: - Cell culture medium: RPMI 1640 (Gibco, 11875-119) supplemented with 10% FBS (Sigma, 171012) and penicillin-streptomycin (Thermo Fisher, 15140-122) - Assay medium: RPMI1640 (Gibco, 22400-105) supplemented with 1% FBS (Sigma, 171012) - Cells were primed with LPS (Sigma, L2630) at a final concentration of 2 μg / mL for 24 hours (instead of 1 μg / mL for 3 hours). - IL-1β production was induced by adding BzATP (Sigma, B6396) (instead of nigericin) at a final concentration of 1 mM, followed by incubation for 30 min at 37°C, 5% CO2 and 95% humidity. Includes.

[0297] The results of the assay are shown in Table 9. 50 Report as (μM).

[0298] hERG Assay (Test D) Experiments were performed at rt on a SyncroPatch 384PE (Nanion Technologies) high-throughput patch clamp platform using a medium resistance tip with four patch holes per site. A hERG-expressing Chinese Hamster Ovary K1 (CHO) cell line was used in an assay-ready format and stored in liquid nitrogen until use. Two vials of cells (10 × 10 per vial) were added. 610 mM NaCl, 4 mM KCl, 10 mM HEPES, and 5 mM glucose (pH 7.4). The internal patch clamp solution was 120 mM KF, 20 mM KCl, 10 mM HEPES, 10 mM EGTA, and 25 μM escin (pH 7.2). After the initial sealing process was completed, a seal enhancer solution containing HBSS supplemented with 10 mM CaCl2 and 1 mM MgCl2 was applied to the cells. The external solution was then replaced (4 times) with an external patch clamp solution containing 80 mM NaCl, 4 mM KCl, 10 mM HEPES, 2 mM CaCl2, 1 mM MgCl2, 5 mM glucose, and 60 mM NMDG (pH 7.4). All solutions except escin were stored at rt. Escin was stored at 4°C. All compounds were dispensed into greiner-bio 384-well plates and tested in a 6-point cumulative assay (final DMSO concentration 0.33%). Only wells that passed the pass criteria (seal resistance 30 megaohms, Z prime >0.4 and current size >0.2nA) were used for this analysis. IC of the hERG assay 50 The results (in μM) are reported in Table 9.

[0299] Solubility (Test E) The assay was performed according to the solubility assay described in Wernevik, J. et al., "A Fully Integrated Assay Panel for Early Drug Metabolism and Pharmacokinetics Profiling", Assay and Drug Development Technologies, 2020, 18(4), 157-179, pp. 164-167. Data are reported in Table 9 as solubility (μM). When assays were performed multiple times for the same compound, arithmetic mean values ​​are reported.

[0300] Solubility (Test F) The 20 mM DMSO solutions containing the test compounds were dried and then diluted 100-fold by adding disodium hydrogen phosphate-citrate buffer (diluted McIlvaine buffer, pH 6.5). Under these conditions, the theoretical maximum concentration of the test compounds was 200 μM. The buffers were sonicated, shaken, and kept at 25 °C for 24-72 h. The buffer samples were filtered and the filtrates were diluted with an equal volume of acetonitrile / methanol (1:1, v / v) in a 96-well plate. The 20 mM DMSO solutions containing the test compounds were diluted 100-fold with acetonitrile / methanol (1:1, v / v) and an equal volume of McIlvaine buffer (pH 6.5) was added to use as standard solutions. Standard and test samples were transferred to 384-well plates and analyzed by HPLC. The results of the solubility assay are reported in μg / mL in Table 9.

[0301] [Table 9] TIFF2024523623000168.tif247169 TIFF2024523623000169.tif54169

[0302] LPS / ATP test Male 7-week-old BALB / cAJcl mice were intraperitoneally administered 0.5 mL of 4 μg / mL LPS (Sigma-Aldrich Co. LLC, L2630) solution in PBS (Thermo Fisher Scientific Inc., 10010). One hour later, the test article suspension in 0.5% (w / v) CMC sodium (Nacalai tesque INC., 07326-95) aqueous solution was orally administered at a volume of 10 mL / kg. One hour after test article administration, 0.5 mL of 30 μmol / L ATP (Sigma-Aldrich Co. LLC, A7699) solution in PBS was intraperitoneally administered. Twenty minutes later, the animals were euthanized by cervical dislocation under sevoflurane anesthesia. Immediately after euthanasia, the peritoneal cavity of each animal was washed by intraperitoneal injection of 3 mL of ice-cold PBS. Then, the PBS was collected and the IL-1β concentration was measured using an ELISA kit (R&D Systems Inc., MLB00C). The test results are shown in Table 10.

[0303] [Table 10]

[0304] Those skilled in the art will appreciate that the biological assays described above can be performed using alternative equipment and slight modifications of the protocols without significantly affecting the results.

[0305] The above description of exemplary embodiments is intended only to acquaint those skilled in the art with the applicant's invention, its principles and its practical application, so that they may readily adapt and apply the invention in its numerous forms, as may be best suited to the requirements of a particular use. This description and its specific examples, while showing embodiments of the invention, are for illustrative purposes only. Thus, the invention is not limited to the exemplary embodiments set forth herein, as such may be modified in various ways. In addition, it will be understood that various features of the invention that are described in the context of separate embodiments for reasons of clarity may also be combined to form a single embodiment. Conversely, various features of the invention that are described in the context of a single embodiment for reasons of brevity may also be combined to form subcombinations thereof.

[0306] Any publications disclosed within this specification are hereby incorporated by reference.

Claims

1. Formula (I): 【Chemical 144】 [wherein, R １ is 【Chemical 145】 is, Each R ３ is independently selected from -H and -C １－３ alkyl, R ２Ａ , R ２Ｂ , R ２Ｃ and R ２Ｄ are each independently selected from -H, -F, -Cl, -C １－３ alkyl unsubstituted or substituted by 1 to 3 -F substituents, cyclopropyl, -OCF ３ and -SO ２ Me, W, X, Y, and Z are each independently CR ５ and N, and W, X, Y, and Z are not all N or one of them is N, and the remainder of W, X, Y, and Z are CR ５ and Each R ５ is independently selected from -H, -Me and -F] a compound represented by or a pharmaceutically acceptable salt thereof.

2. R １ is 【Chemical 147】 The compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein is.

3. Each R ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from -H and -Me.

4. Each R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is -H.

5. R １ is 【Chemical 148】 The compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein is.

6. R ２Ａ , R ２Ｂ , R ２ and R ２Ｄ of which two, three or four are -H, and R ２Ａ , R ２Ｂ , R ２Ｃ and R ２Ｄ the remainder of which are not -H, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. R ２Ａ 、R ２Ｂ 、R ２ and R ２Ｄ wherein two or three of R ２Ａ 、R ２Ｂ 、R ２Ｃ and R ２Ｄ are -H and the remainder of R is not -H, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. R ２Ａ and R ２Ｃ is -H, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

9. R ２Ｂ is -H, -F, -CF ３ and -SO ２ Me, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. R ２Ｄ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is selected from -H and -F.

11. R ２Ｂ is selected from -H or -Cl, and R ２Ｄ is -F, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. R ２Ｂ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is not -H.

13. R ２Ａ is -H, and R ２Ｂ is -CF ３ and R ２Ｃ is -H, and R ２Ｄ is -H, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. wherein W, X, Y and Z are each CR ５ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

15. W, X, and Z are each CR ５ wherein Y is N, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. One of W, X, Y, and Z is CR ５ wherein none of W, X, Y, and Z is N or one of W, X, Y, and Z is N and the remainder of W, X, Y, and Z are CH, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

17. Each R ５ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is -H.

18. The compound is as follows: 3 - [[4 - [2 - hydroxy - 4 - (trifluoromethyl)phenyl]phthalazin - 1 - yl]amino]propane - 1,2 - diol; 3 - [[4 - (4 - chloro - 3 - fluoro - 2 - hydroxy - phenyl)phthalazin - 1 - yl]amino]propane - 1,2 - diol; 3 - [[4 - (4,5 - difluoro - 2 - hydroxy - phenyl)phthalazin - 1 - yl]amino]propane - 1,2 - diol; 3 - [[4 - (2 - fluoro - 6 - hydroxy - phenyl)phthalazin - 1 - yl]amino]propane - 1,2 - diol; 3 - [[4 - (4 - chloro - 2 - hydroxy - phenyl)phthalazin - 1 - yl]amino]propane - 1,2 - diol; 3 - [[4 - [2 - hydroxy - 4 - (trifluoromethoxy)phenyl]phthalazin - 1 - yl]amino]propane - 1,2 - diol; 3 - [[4 - [2 - fluoro - 6 - hydroxy - 4 - (trifluoromethyl)phenyl]phthalazin - 1 - yl]amino]propane - 1,2 - diol; 3 - [[4 - (2,4 - difluoro - 6 - hydroxy - phenyl)phthalazin - 1 - yl]amino]propane - 1,2 - diol; 3 - [[4 - (4 - chloro - 2 - fluoro - 6 - hydroxy - phenyl)phthalazin - 1 - yl]amino]propane - 1,2 - diol; 3 - [[4 - (2 - chloro - 6 - hydroxy - phenyl)phthalazin - 1 - yl]amino]propane - 1,2 - diol; 3 - [[4 - (2 - hydroxy - 4 - methyl - phenyl)phthalazin - 1 - yl]amino]propane - 1,2 - diol; 3 - [[4 - (2 - hydroxy - 5 - methyl - phenyl)phthalazin - 1 - yl]amino]propane - 1,2 - diol; 3-[[4-[2-Hydroxy-4-(trifluoromethyl)phenyl]-7-methyl-phthalazin-1-yl]amino]propane-1,2-diol; 3-[[4-[2-Hydroxy-4-(trifluoromethyl)phenyl]-6-methyl-phthalazin-1-yl]amino]propane-1,2-diol; 3-[[1-[2-Hydroxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]amino]propane-1,2-diol; and 3-[[4-[2-Hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]-2-methyl-propane-1,2-diol; The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from 3-[[4-[2-Hydroxy-4-(trifluoromethyl)phenyl]-7-methyl-phthalazin-1-yl]amino]propane-1,2-diol; 3-[[4-[2-Hydroxy-4-(trifluoromethyl)phenyl]-6-methyl-phthalazin-1-yl]amino]propane-1,2-diol; 3-[[1-[2-Hydroxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]amino]propane-1,2-diol; 3-[[4-[2-Hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]-2-methyl-propane-1,2-diol; or a pharmaceutically acceptable salt thereof.

19. The compound is as follows: (2S)-3-[[4-[2-Hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-[2-Hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-(4-Chloro-3-fluoro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-(4-Chloro-3-fluoro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-(4,5-Difluoro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-(4,5-Difluoro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-(2-Fluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-(2-Fluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-(4-Chloro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-(4-Chloro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-[2-Hydroxy-4-(trifluoromethoxy)phenyl]phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-[2-Hydroxy-4-(trifluoromethoxy)phenyl]phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-[2-Fluoro-6-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-[2-Fluoro-6-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-(2,4-Difluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-(2,4-Difluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-(4-Chloro-2-fluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-(4-Chloro-2-fluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-(2-Chloro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-(2-Chloro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-(2-Hydroxy-4-methyl-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-(2-Hydroxy-4-methyl-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-(2-Hydroxy-5-methyl-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-(2-Hydroxy-5-methyl-phenyl)phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-[2-Hydroxy-4-(trifluoromethyl)phenyl]-7-methyl-phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-[2-Hydroxy-4-(trifluoromethyl)phenyl]-7-methyl-phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[4-[2-Hydroxy-4-(trifluoromethyl)phenyl]-6-methyl-phthalazin-1-yl]amino]propane-1,2-diol; (2R)-3-[[4-[2-Hydroxy-4-(trifluoromethyl)phenyl]-6-methyl-phthalazin-1-yl]amino]propane-1,2-diol; (2S)-3-[[1-[2-Hydroxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]amino]propane-1,2-diol; (2R)-3-[[1-[2-Hydroxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]amino]propane-1,2-diol; (S)-3-((4-(2-Hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)-2-methylpropane-1,2-diol; and (R)-3-((4-(2-Hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)amino)-2-methylpropane-1,2-diol; The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from or a pharmaceutically acceptable salt thereof.

20. The compound is 【Chemical 151】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is or a pharmaceutically acceptable salt thereof.

21. The compound is 【Chemical 152】 The compound according to claim 1.

22. Use of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a subject having a disease or condition involving NLRP3 inflammasome activity.

23. Use of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a subject having a disease or condition selected from the group consisting of renal diseases such as acute kidney injury, chronic kidney disease and diabetic kidney disease; cardiovascular diseases such as coronary atherosclerotic heart disease, cardiomyopathy, myocardial infarction, cardiac hypertrophy and ischemia-reperfusion injury; liver diseases such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic steatohepatitis, chronic hepatitis C virus infection and paracetamol-induced liver injury; inflammatory diseases such as autoinflammatory disorders, cryopyrin-associated periodic syndromes, familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous arthritis (CINCA) syndrome and neonatal-onset multisystem inflammatory disease (NOMID); inflammatory skin diseases such as acne vulgaris and hidradenitis suppurativa; inflammatory bowel diseases such as ulcerative colitis (UC) and Crohn's disease; autoimmune diseases such as gout, pseudogout, rheumatoid arthritis (RA), multiple sclerosis (MS), Addison's disease, celiac disease, systemic lupus erythematosus (SLE) and vitiligo; and respiratory diseases such as chronic lung diseases, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma.

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