BRILL ZACHARY (US)
FRADERA XAVIER (US)
SILIPHAIVANH PHIENG (US)
SU JING (US)
RICO DUQUE JENNY LORENA (US)
BRILL ZACHARY G (US)
FRADERA XAVIER (US)
SILIPHAIVANH PHIENG (US)
SU JING (US)
| WO2020103884A1 | 2020-05-28 |
| US20120122889A1 | 2012-05-17 | |||
| US20050119484A1 | 2005-06-02 |
| What is claimed is: 1. A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: R1 is aryl, C3-C10cycloalkyl or heteroaryl, wherein the aryl, C3-C10cycloalkyl or heteroaryl is unsubstituted or substituted with one to three substituents selected from the group consisting of halogen, C1-C6alkyl, CN, OH, alkoxy, -N(R3)2, -SC1-C6alkyl and C3-C6cycloalkyl; Each occurrence of R2 is selected from the group consisting of hydrogen, OH, C1-C6alkylOH, CN, C1-C6alkylCN, C1-C6alkyl, haloC1-C6alkyl, halogen, alkoxy, C1-C6alkylOC1-C6alkyl, aryl, heteroaryl, cycloheteroalkyl, C3-C10cycloalkyl, -O-aryl, -O-heteroaryl, -O-cycloheteroalkyl, -OC3-C10cycloalkyl, C1-C6alkylaryl, C1-C6alkylheteroaryl, C1-C6alkyl-cycloheteroalkyl, C1-C6alkylC3-C10cycloalkyl, haloC1-C6alkylaryl, haloC1-C6alkylheteroaryl, haloC1-C6alkyl-cycloheteroalkyl, haloC1-C6alkylC3-C10cycloalkyl, -CO-aryl, -OC1-C6alkylaryl, -OC1-C6alkylheteroaryl, -OC1-C6alkyl-cycloheteroalkyl, -OC1-C6alkylC3-C6cycloalkyl, -SO2C1-C6alkyl, -SO2aryl, -S-aryl, -SC1-C6alkyl, -N(R3)2, and C1-C6alkylN(R3)2, wherein any aryl, heteroaryl, cycloalkyl or cycloheteroalkyl is unsubstituted or substituted with one to three substituents selected from the group consisting of OH, haloC1-C6alkyl, aryl, heteroaryl, N(R3)2, SO2C1-C6alkyl, alkoxy, CN, halogen, C1-C6alkyl, -SC1-C6alkyl, C1-C6alkyl- cycloheteroalkyl, C1-C6alkylheteroaryl and C1-C6alkylOH; R3 is hydrogen, C1-C6alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of CN, C1- C6alkyl, haloC1-C6alkyl and alkoxy; and n is 1, 2, 3, 4, 5 or 6, wherein, when n is 2, 3, 4, 5 or 6, two R2 substituents can be taken together to form a cycloheteroalkyl or C3-C10cycloalkyl, wherein the cycloheteroalkyl or C3- C10cycloalkyl is unsubstituted or substituted with one to four substituents selected from the group consisting of halogen, C1-C6alkyl, aryl, alkoxy, -O-aryl, -O-heteroaryl, N(R3)2, CN, - SO2C1-C6alkyl, C1-C6alkylOH, heteroaryl, C(O)OC1-C6alkyl, and C1-C6alkyl-cycloheteroalkyl. 2. A compound of claim 1, wherein n is 2 or 3. 3. A compound of claim 1 or 2, wherein each occurrence of R2 is independently selected from the group consisting of methyl, OH, fluorine, CN, methoxy, chlorine, ethoxy, difluoromethyl, trifluoromethyl, -SO2CH3, isopropyl, cyclopropyl, 4. The compound of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein n is at least 2, and wherein the two R2 substituents can be taken together to form: 5. A compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein: R1 is aryl, C3-C10cycloalkyl or heteroaryl, wherein the aryl, C3-C10cycloalkyl or heteroaryl is unsubstituted or substituted with one to three substituents selected from the group consisting of halogen, C1-C6alkyl, CN, OH, alkoxy, -N(R3)2, -SC1-C6alkyl and C3-C6cycloalkyl; R2a is hydrogen, halogen, CN, OH, C1-C6alkyl, alkoxy, C3-C6cycloalkyl, C1-C6alkylOH, C1-C6alkylOC1-C6alkyl, N(R3)2 or haloC1-C6alkyl, or taken with R2b forms a cycloheteroalkyl or C3-C10cycloalkyl, wherein the cycloheteroalkyl or C3-C10cycloalkyl is unsubstituted or substituted with one to four substituents selected from the group consisting -SO2C1-C6alkyl, C1- C6alkylOH, heteroaryl, C(O)OC1-C6alkyl, halogen, C1-C6alkyl, aryl, alkoxy, -O-aryl, -O- heteroaryl, N(R3)2, CN and C1-C6alkyl-cycloheteroalkyl; R2b is hydrogen, OH, C1-C6alkylOH, CN, C1-C6alkylCN, C1-C6alkyl, haloC1-C6alkyl, halogen, alkoxy, C1-C6alkylOC1-C6alkyl, aryl, heteroaryl, cycloheteroalkyl, C3-C10cycloalkyl, - O-aryl, -O-heteroaryl, -O-cycloheteroalkyl, -OC3-C10cycloalkyl, C1-C6alkylaryl, C1- C6alkylheteroaryl, C1-C6alkyl-cycloheteroalkyl, C1-C6alkylC3-C10cycloalkyl, haloC1- C6alkylaryl, haloC1-C6alkylheteroaryl, haloC1-C6alkyl-cycloheteroalkyl, haloC1-C6alkylC3- C10cycloalkyl, -CO-aryl, -OC1-C6alkylaryl, -OC1-C6alkylheteroaryl, -OC1-C6alkyl- cycloheteroalkyl, -OC1-C6alkylC3-C6cycloalkyl, -SO2C1-C6alkyl, -SO2aryl, -S-aryl, -SC1- C6alkyl, -N(R3)2 or C1-C6alkylN(R3)2, wherein any aryl, heteroaryl, cycloalkyl or cycloheteroalkyl is unsubstituted or substituted with one to three substituents selected from the group consisting of OH, haloC1-C6alkyl, aryl, heteroaryl, N(R3)2, SO2C1-C6alkyl, alkoxy, CN, halogen, C1-C6alkyl, -SC1-C6alkyl, C1-C6alkyl-cycloheteroalkyl, C1-C6alkylheteroaryl and C1- C6alkylOH or, when taken with R2a forms a cycloheteroalkyl or C3-C10cycloalkyl, wherein the cycloheteroalkyl or C3-C10cycloalkyl is unsubstituted or substituted with one to four substituents selected from the group consisting halogen, C1-C6alkyl, aryl, alkoxy, -O-aryl, -O-heteroaryl, N(R3)2, CN, -SO2C1-C6alkyl, C1-C6alkylOH, heteroaryl, C(O)OC1-C6alkyl, and C1-C6alkyl- cycloheteroalkyl; R2c is hydrogen, C1-C6alkyl, C1-C6alkylOH, C3-C10cycloalkyl, heteroaryl, C1- C6alkylOC1-C6alkyl, C1-C6alkylO-heteroaryl, C1-C6alkylheteroaryl, aryl or C1-C6alkylaryl, wherein the aryl, heteroaryl, C3-C6cycloalkyl, C1-C6alkylheteroaryl or C1-C6alkylaryl is unsubstituted or substituted with one to four substituents selected from the group consisting of halogen C1-C6alkyl, CN, OH and alkoxy; and R3 is hydrogen, C1-C6alkyl, aryl or heteroaryl, wherein the aryl and heteroaryl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of CN, C1- C6alkyl, haloC1-C6alkyl and alkoxy. 6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1 is aryl. 7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R1 is phenyl. 8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R1 is unsubstituted or substituted with one or two halogens selected from the group consisting of fluorine and chlorine. 9. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1 is C3-C10cycloalkyl. 10. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1 is : . 11. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1 is heteroaryl. 12. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1 is : , wherein R1 is unsubstituted or substituted with one or two substituents selected from the group consisting of methyl, fluorine, and CN. 13. The compound of any one of claims 5-12, or a pharmaceutically acceptable salt thereof, wherein R2c is hydrogen, methyl, 14. The compound of any one of claims 5-13, or a pharmaceutically acceptable salt thereof, wherein R2a is hydrogen, methyl, OH, fluorine, CN, or methoxy. 15. The compound of any one of claims 5-13, or a pharmaceutically acceptable salt thereof, wherein R2a is taken with R2b and forms: 16. The compound of any one of claims 5-14, or a pharmaceutically acceptable salt thereof, wherein R2b is hydrogen, OH, chlorine, fluorine, CN, methoxy, ethoxy, methyl, difluoromethyl, trifluoromethyl, -SO2CH3, isopropyl, cyclopropyl, , , , , , , , , 17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, and R3 is hydrogen, methyl, or phenyl. 18. A compound of Formula III: or a pharmaceutically acceptable salt thereof, wherein: R2a is hydrogen, halogen, CN, OH, C1-C6alkyl, alkoxy or haloC1-C6alkyl, or taken with R2b forms a cycloheteroalkyl or C3-C10cycloalkyl, wherein the cycloheteroalkyl or C3- C10cycloalkyl is unsubstituted or substituted with one to four substituents selected from the group consisting -SO2C1-C6alkyl, C1-C6alkylOH, heteroaryl, C(O)OC1-C6alkyl, and C1-C6alkyl- cycloheteroalkyl; R2b is hydrogen, -O-aryl, -O-heteroaryl, C1-C6alkylaryl, OH, -CO-aryl, -OC3- C10cycloalkyl, heteroaryl, alkoxy, -OC1-C6alkylaryl, haloC1-C6alkyl, C1-C6alkyl, halogen, C3- C10cycloalkyl, C1-C6alkylOC1-C6alkyl, aryl, -OC1-C6alkyl-cycloheteroalkyl, -SO2C1-C6alkyl, cycloheteroalkyl, -S-aryl, -SO2aryl, -N(R3)2, C1-C6alkylheteroaryl, haloC1-C6alkylheteroaryl, C1- C6alkylC3-C10cycloalkyl, -O-cycloheteroalkyl, C1-C6alkyl-cycloheteroalkyl, -OC1- C6alkylheteroaryl or CN, wherein the -O-heteroaryl, -O-aryl, C1-C6alkylaryl, -OC1-C6alkyl- cycloheteroalkyl, cycloheteroalkyl, -S-aryl, -SO2aryl, heteroaryl, -OC1-C6alkylheteroaryl or -O- cycloheteroalkyl is unsubstituted or substituted with one to three substituents selected from the group consisting of alkoxy, CN, halogen, C1-C6alkyl, -SC1-C6alkyl, C1-C6alkyl- cycloheteroalkyl, C1-C6alkylheteroaryl and C1-C6alkylOH or, when taken with R2a forms a cycloheteroalkyl or C3-C10cycloalkyl, wherein the cycloheteroalkyl or C3-C10cycloalkyl is unsubstituted or substituted with one to four substituents selected from the group consisting - SO2C1-C6alkyl, C1-C6alkylOH, heteroaryl, C(O)OC1-C6alkyl, and C1-C6alkyl-cycloheteroalkyl; R2c is hydrogen, C1-C6alkyl, aryl or C1-C6alkylaryl, wherein the aryl or C1-C6alkylaryl is unsubstituted or substituted with one to four halogen substituents; and R3 is hydrogen, C1-C6alkyl or aryl. 19. A compound of Formula I, or a pharmaceutically acceptable salt thereof, having the structure: 20. A method for treating RIPK1 dependent inflammation and cell death that occurs in inherited and sporadic diseases including Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease, chronic traumatic encephalopathy, rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease, psoriasis as well as acute tissue injury caused by stroke, traumatic brain injury, encephalitis comprising administering to a patient in need thereof a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-19. 21. A method of treating amyotrophic lateral sclerosis comprising administering to a patient in need thereof a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-19. 22. The use of a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-19 to treat amyotrophic lateral sclerosis in a patient in need thereof. 23. A pharmaceutical composition comprising a compound of any one of claims 1- 19, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 24. A pharmaceutical composition comprising a compound of any one of claims 1-19 and a pharmaceutically acceptable carrier. |
Also described are the following compounds, or a pharmaceutically acceptable salt thereof:
Also described are the following compounds, or a pharmaceutically acceptable salt thereof:
DEFINITIONS "Alkoxy" means an alkyl-O- group in which the alkyl group encompasses straight alkyl having a carbon number of 1 to 10 and branched alkyl having a carbon number of 3 to 10. Non- limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen. The term “halogen” includes fluorine, chlorine, bromine or iodine. The term “C 1 -C 6 alkyl” encompasses straight alkyl having a carbon number of 1 to 6 and branched alkyl having a carbon number of 3 to 6. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2- dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2- methylpropyl, 1-ethyl-1-methylpropyl, and the like. The term "C3-C6cycloalkyl" encompasses bridged, saturated or unsaturated cycloalkyl groups having 3 to 6 carbons. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "C 3 -C 10 cycloalkyl" encompasses bridged, saturated or unsaturated cycloalkyl groups having 3 to 10 carbons. "Cycloalkyl" also includes non-aromatic rings as well as monocyclic, non-aromatic rings fused to a saturated cycloalkyl group. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl and the like. Examples described by structure include, The term “heteroaryl" means a monocyclic or multicyclic, including bicyclic, aromatic cycloheteroalkyl that contains at least one ring heteroatom selected from O, S and N. Examples of heteroaryl groups include pyridyl (pyridinyl), oxazolyl, azabenzothiazole, benzothiazole, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, isoquinolyl, and the like. The term “cycloheteroalkyl” means mono- or bicyclic or bridged partially unsaturated and saturated rings containing at least one heteroatom selected from N, S and O, each of said rings having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen. Examples include azetidine, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolinyl, benzoxazepinyl, 5,6-dihydroimidazo[2,1- b]thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or n-substituted-(1H, 3H)-pyrimidine-2,4-diones (N-substituted uracils). The term also includes bridged rings such as 5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1]heptyl, 2,5- diazabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.2]octyl, and 3-azabicyclo[3.2.2]nonyl, and azabicyclo[2.2.1]heptanyl. Examples described by structure include, The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, n-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, n-ethylmorpholine, n-ethylpiperidinyl, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidinyl, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. The term “patient” refers to a mammalian patient, preferably a human patient, receiving or about to receive medical treatment. The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of these compounds. Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers. Some of the compounds described herein contain substituted cycloalkanes having cis-and trans-isomers, and unless specified otherwise, are meant to include both cis- and trans- geometric isomers. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. It will be understood that the present invention is meant to include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable, of the compounds described herein, when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations. Solvates, and in particular, the hydrates of the compounds of the structural formulas described herein are included in the present invention as well. Some of the compounds described herein may exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of the present invention. In the compounds described herein, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the formulas described herein. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. A 3 H, 11 C, 18 F labeled compound may be used for PET or SPECT or other imaging studies. Isotopically-enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents or Intermediates. It should be noted that chemically unstable compounds are excluded from the embodiments contained herein. METHODS OF TREATMENT The compounds described herein may be particularly useful for the prevention, treatment or amelioration of RIPK1-mediated diseases or disorders. Such RIPK1-mediated diseases or disorders are likely to be regulated at least in part by programmed necrosis, apoptosis or the production of inflammatory cytokines, particularly inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age-related macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, juvenile idiopathic arthritis (systemic onset juvenile idiopathic arthritis (SoJIA)), psoriatic arthritis), lupus, systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic scleroderma, anti- phospholipid syndrome (APS), vasculitis, osteoarthritis, liver damage/diseases (non-alcohol steatohepatitis (NASH), alcohol steatohepatitis (ASH), autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity), non-alcohol steatohepatitis (NASH), alcohol steatohepatitis (ASH), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFL D), kidney damage/injury (nephritis, renal transplant, surgery, administration of nephrotoxic drugs e.g. cisplatin, acute kidney injury (AKI)), Celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection (rejection of transplant organs, tissues and cells), ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CV A, stroke), myocardial infarction (Ml), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), neonatal brain injury, neonatal hypoxic brain injury, ischemic brain injury, traumatic brain injury allergic diseases (including asthma and atopic dermatitis), peripheral nerve injury, bums, multiple sclerosis, type I diabetes, type II diabetes, obesity, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet' s disease, interleukin- I converting enzyme (ICE, also known as caspase-1) associated fever syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced damage, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), a neoplastic tumor, peridontitis, NEMO-mutations (mutations of NF-kappa-B essential modulator gene (also known as IKK gamma or IKKG)), particularly, NEMO-deficiency syndrome, HOIL-1 deficiency (also known as RBCKl) heme-oxidized IRP 2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial infections and viral infections (such as influenza, staphylococcus, and mycobacterium (tuberculosis)), and Lysosomal storage diseases (particularly, Gaucher disease, and including GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GMl gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs, and Wolman disease), Stevens-Johnson syndrome, toxic epidermal necrolysis, glaucoma, spinal cord injury, fibrosis, complement-mediated cytotoxicity, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, mesothelioma, melanoma, metastasis, breast cancer, non-small cell lung carcinoma (NSCLC), radiation induced necrosis, ischemic kidney damage, ophthalmologic ischemia, intracerebral hemorrhage, subarachnoid hemorrhage, acute liver failure and radiation protection/mitigation, auditory disorders such as noise-induced hearing loss and drugs associated with ototoxicity such as cisplatin, or for the treatment of cells ex vivo to preserve vitality and function. The compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be particularly useful for the treatment of the following RIPK1-mediated diseases or disorders: inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age-related macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, systemic onset juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), lupus, systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis, osteoarthritis, liver damage/diseases (non-alcohol steatohepatitis (NASH), alcohol steatohepatitis (ASH) autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), kidney damage/injury (nephritis, renal transplant, surgery, administration of nephrotoxic drugs e.g. cisplatin, acute kidney injury (AKI)), Celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection (rejection of transplant organs, tissues and cells), ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (Ml), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), neonatal brain injury, neonatal hypoxic brain injury, traumatic brain injury, allergic diseases (including asthma and atopic dermatitis), peripheral nerve injury, bums, multiple sclerosis, type I diabetes, type II diabetes, obesity, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-I converting enzyme (ICE, also known as caspase-1) associated fever syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced damage, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), a neoplastic tumor, melanoma, metastasis, breast cancer, non-small cell lung carcinoma (NSCLC), radiation induced necrosis, ischemic kidney damage, ophthalmologic ischemia, intracerebral hemorrhage, subarachnoid hemorrhage, peridontitis, NEMO-mutations (mutations ofNF-kappa-B essential modulator gene (also known as IKK gamma or IKKG)), particularly, NEMO-deficiency syndrome, HOIL-1 deficiency ((also known as RBCKl) heme-oxidized IRP 2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial infections and viral infections (such as influenza, staphylococcus, and mycobacterium (tuberculosis)), and Lysosomal storage diseases (particularly, Gaucher disease, and including GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GMl gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs, and Wolman disease), spinal cord injury, Stevens- Johnson syndrome, fibrosis, complement-mediated cytotoxicity, toxic epidermal necrolysis, and/or for the treatment of cells ex vivo to preserve vitality and function. The compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of glaucoma. The compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be particularly useful for treatment of pancreatic ductal adenocarcinoma, hepatocellular carcinoma, mesothelioma, or melanoma. The compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be particularly useful for the treatment of the following RIPK1-mediated disease or disorder: rheumatoid arthritis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), and psoriasis. The treatment of the above-noted diseases/disorders may concern, more specifically, the amelioration of organ injury or damage sustained as a result of the noted diseases/disorders. For example, the compounds of this invention may be particularly useful for amelioration of brain tissue injury or damage following ischemic brain injury or traumatic brain injury, or for amelioration of heart tissue injury or damage following myocardial infarction, or for amelioration of brain tissue injury or damage associated with Huntington's disease, Alzheimer's disease or Parkinson's disease, or for amelioration of liver tissue injury or damage associated with non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis autoimmune hepatobiliary diseases, or primary sclerosing cholangitis, or overdose of acetaminophen. The compounds of this invention may be particularly useful for the amelioration of organ injury or damage sustained as a result of radiation therapy, or amelioration of spinal tissue injury or damage following spinal cord injury or amelioration of liver tissue injury or damage associated acute liver failure. The compounds of this invention may be particularly useful for amelioration of auditory disorders, such as noise-induced hearing loss or auditory disorders following the administration of ototoxic drugs or substances e.g. cisplatin. The compounds of this invention may be particularly useful for amelioration of solid organ tissue (particularly kidney, liver, and heart and/or lung) injury or damage following transplant or the administration of nephrotoxic drugs or substances e.g. cisplatin. It will be understood that amelioration of such tissue damage may be achieved where possible, by pre-treatment with a compound of the Formulae described herein, or a pharmaceutically acceptable salt thereof; for example, by pre-treatment of a patient prior to administration of cisplatin or pre-treatment of an organ or the organ recipient prior to transplant surgery. Amelioration of such tissue damage may be achieved by treatment with a compound of the Formulae described herein, or a pharmaceutically acceptable salt thereof, during transplant surgery. Amelioration of such tissue damage may also be achieved by short-term treatment of a patient with a compound of the Formulae described herein, or a pharmaceutically acceptable salt thereof, after transplant surgery. In one embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of retinal detachment, macular degeneration, and retinitis pigmentosa. In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of multiple sclerosis. In one embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of traumatic brain injury. In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of Huntington's Disease or Niemann-Pick disease. In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and Alzheimer's disease. In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of age-related macular degeneration. The treatment of retinal detachment, macular degeneration, retinitis pigmentosa, multiple sclerosis, traumatic brain injury, Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease may concern, more specifically, the amelioration of organ injury or damage sustained as a result of these diseases/disorders. For example, the compounds described herein may be particularly useful for amelioration of brain tissue injury or damage following traumatic brain injury, or for amelioration of brain tissue injury or damage associated of Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease. In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of retinal detachment, macular degeneration, and retinitis pigmentosa, and the amelioration of brain tissue injury or damage as a result of multiple sclerosis, traumatic brain injury, Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease. In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of Crohn's disease, ulcerative colitis, psoriasis, rheumatoid arthritis, spondyloarthritis, systemic onset juvenile idiopathic arthritis (SoJIA), and osteoarthritis. In yet another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of psoriasis, rheumatoid arthritis, and ulcerative and colitis. In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of lupus, inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of cerebrovascular accident (CVA, stroke), Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury, multiple sclerosis, Gaucher disease, Niemann-Pick disease, and spinal cord injury. In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of amyotrophic lateral sclerosis (ALS). In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of multiple sclerosis. In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of pancreatic ductal adenocarcinoma (PDAC), metastasis, melanoma, breast cancer, non-small cell lung carcinoma (NSCLC), and radiation induced necrosis. In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of pancreatic ductal adenocarcinoma (PDAC), metastasis, melanoma, breast cancer, and non-small cell lung carcinoma (NSCLC). In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of pancreatic ductal adenocarcinoma (PDAC). In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of intracerebral hemorrhage and subarachnoid hemorrhage. In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of type II diabetes and obesity. In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of atherosclerosis. In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of vasculitis. In another embodiment, the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be useful for the treatment of dependent inflammation and cell death that occurs in inherited and sporadic diseases including Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease, chronic traumatic encephalopathy, rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease, psoriasis as well as acute tissue injury caused by stroke, traumatic brain injury, encephalitis. In another embodiment, the compounds of the Formulae described herein, or pharmaceutically acceptable salt thereof, may be useful for the treatment of ischemic kidney damage, ophthalmologic ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage. In another embodiment, the compounds of the Formulae described herein, or pharmaceutically acceptable salt thereof, may be useful for the treatment of non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, and non- alcoholic fatty liver disease (NAFLD). The compounds of the invention, particularly the compounds of the Formulae described herein, or a pharmaceutically acceptable salt thereof, may be particularly useful for the treatment of the RIPK1-mediated, cancer-related diseases or disorders. Gong et al., The role of necroptosis in cancer biology and therapy, Molecular Cancer (2019) 18:100. In one aspect the human has a solid tumor. In one aspect the tumor is selected from head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung carcinoma (NSCLC), prostate cancer, colorectal cancer, ovarian cancer, pancreatic cancer, and pancreatic ductal adenocarcinoma. In one aspect the human has one or more of the following: colorectal cancer (CRC), esophageal cancer, cervical, bladder, breast cancer, head and neck cancer, ovarian cancer, melanoma, renal cell carcinoma (RCC), EC squamous cell carcinoma, non-small cell lung carcinoma, mesothelioma, prostate cancer, and pancreatic ductal adenocarcinoma. In another aspect, the human has a liquid tumor such as diffuse large B cell lymphoma (DLBCL), multiple myeloma, chronic lyphomblastic leukemia (CLL), follicular lymphoma, acute myeloid leukemia and chronic myelogenous leukemia. The present disclosure also relates to a method for treating or lessening the severity of a cancer selected from: brain (gliomas), glioblastomas, astrocytomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, triple negative breast cancer, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer (including squamous cell carcinoma of head and neck), kidney cancer, lung cancer (including lung squamous cell carcinoma, lung adenocarcinoma, lung small cell carcinoma, and non-small cell lung carcinoma), liver cancer (including hepatocellular carcinoma), melanoma, ovarian cancer, pancreatic cancer (including squamous pancreatic cancer), prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic T-cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T- cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, Non- Hodgkin's lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, cancer of the uterus, renal cancer (including kidney clear cell cancer, kidney papillary cancer, renal cell carcinoma), mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer. Specific examples of clinical conditions based on hematologic tumors include leukemias such as chronic myelocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia and acute lymphocytic leukemia; plasma cell malignancies such as multiple myeloma, MGUS and Waldenstrom's macroglobulinemia; lymphomas such as non-Hodgkin's lymphoma, Hodgkin's lymphoma; and the like. The cancer may be any cancer in which an abnormal number of blast cells or unwanted cell proliferation is present or that is diagnosed as a hematological cancer, including both lymphoid and myeloid malignancies. Myeloid malignancies include, but are not limited to, acute myeloid (or myelocytic or myelogenous or myeloblastic) leukemia (undifferentiated or differentiated), acute promyeloid (or promyelocytic or promyelogenous or promyeloblastic) leukemia, acute myelomonocytic (or myelomonoblastic) leukemia, acute monocytic (or monoblastic) leukemia, erythroleukemia and megakaryocytic (or megakaryoblastic) leukemia. These leukemias may be referred together as acute myeloid (or myelocytic or myelogenous) leukemia (AML). Myeloid malignancies also include myeloproliferative disorders (MPD) which include, but are not limited to, chronic myelogenous (or myeloid) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocytosis), and polcythemia vera (PCV). Myeloid malignancies also include myelodysplasia (or myelodysplastic syndrome or MDS), which may be referred to as refractory anemia (RA), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEBT); as well as myelofibrosis (MFS) with or without agnogenic myeloid metaplasia. Specific examples of clinical conditions based on hematologic tumors include leukemias such as chronic myelocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia and acute lymphocytic leukemia; plasma cell malignancies such as multiple myeloma, MGUS and Waldenstrom's macroglobulinemia; lymphomas such as non-Hodgkin's lymphoma, Hodgkin's lymphoma; and the like. Hematopoietic cancers also include lymphoid malignancies, which may affect the lymph nodes, spleens, bone marrow, peripheral blood, and/or extranodal sites. Lymphoid cancers include B-cell malignancies, which include, but are not limited to, B- cell non-Hodgkin's lymphomas (B-NHLs). B-NHLs may be indolent (or low-grade), intermediate grade (or aggressive) or high-grade (very aggressive). Indolent B cell lymphomas include follicular lymphoma (FL); small lymphocytic lymphoma (SLL); marginal zone lymphoma (MZL) including nodal MZL, extranodal MZL, splenic MZL and splenic MZL with villous lymphocytes; lymphoplasmacytic lymphoma (LPL); and mucosa-associated-lymphoid tissue (MALT or extranodal marginal zone) lymphoma. Intermediate-grade B-NHLs include mantle cell lymphoma (MCL) with or without leukemic involvement, diffuse large cell lymphoma (DLBCL), follicular large cell (or grade 3 or grade 3B) lymphoma, and primary mediastinal lymphoma (PML). High-grade B-NHLs include Burkitt's lymphoma (BL), Burkitt- like lymphoma, small non-cleaved cell lymphoma (SNCCL) and lymphoblastic lymphoma. Other B-NHLs include immunoblastic lymphoma (or immunocytoma), primary effusion lymphoma, HIV associated (or AIDS related) lymphomas, and post-transplant lymphoproliferative disorder (PTLD) or lymphoma. B-cell malignancies also include, but are not limited to, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), Waldenstrom's macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocyte (LGL) leukemia, acute lymphoid (or lymphocytic or lymphoblastic) leukemia, and Castleman's disease. NHL may also include T-cell non-Hodgkin's lymphoma s(T-NHLs), which include, but are not limited to T-cell non-Hodgkin's lymphoma not otherwise specified (NOS), peripheral T- cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoid disorder (AILD), nasal natural killer (NK) cell / T- cell lymphoma, gamma/delta lymphoma, cutaneous T cell lymphoma, mycosis fungoides, and Sezary syndrome. Hematopoietic cancers also include Hodgkin's lymphoma (or disease) including classical Hodgkin's lymphoma, nodular sclerosing Hodgkin's lymphoma, mixed cellularity Hodgkin's lymphoma, lymphocyte predominant (LP) Hodgkin's lymphoma, nodular LP Hodgkin's lymphoma, and lymphocyte depleted Hodgkin's lymphoma. Hematopoietic cancers also include plasma cell diseases or cancers such as multiple myeloma (MM) including smoldering MM, monoclonal gammopathy of undetermined (or unknown or unclear) significance (MGUS), plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenstrom's Macroglobulinemia, plasma cell leukemia, and primary amyloidosis (AL). Hematopoietic cancers may also include other cancers of additional hematopoietic cells, including polymorphonuclear leukocytes (or neutrophils), basophils, eosinophils, dendritic cells, platelets, erythrocytes and natural killer cells. Tissues which include hematopoietic cells referred herein to as "hematopoietic cell tissues" include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues, such as spleen, lymph nodes, lymphoid tissues associated with mucosa (such as the gut-associated lymphoid tissues), tonsils, Peyer's patches and appendix, and lymphoid tissues associated with other mucosa, for example, the bronchial linings. PHARMACEUTICAL COMPOSITIONS Compounds described herein may be administered orally or parenterally. As formulated into a dosage form suitable for administration, the compounds described herein can be used as a pharmaceutical composition for the prevention, treatment, or remedy of the above diseases. In clinical use of the compounds described herein, usually, the compound is formulated into various preparations together with pharmaceutically acceptable additives according to the dosage form and may then be administered. By "pharmaceutically acceptable" it is meant the additive, carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. As such, various additives ordinarily used in the field of pharmaceutical preparations are usable. Specific examples thereof include gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, corn starch, microcrystalline wax, white petrolatum, magnesium metasilicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hardened castor oil, polyvinylpyrrolidone, magnesium stearate, light silicic acid anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, hydroxypropyl cyclodextrin, and the like. Preparations to be formed with those additives include, for example, solid preparations such as tablets, capsules, granules, powders and suppositories; and liquid preparations such as syrups, elixirs and injections. These may be formulated according to conventional methods known in the field of pharmaceutical preparations. The liquid preparations may also be in such a form that may be dissolved or suspended in water or in any other suitable medium in their use. Especially for injections, if desired, the preparations may be dissolved or suspended in physiological saline or glucose liquid, and a buffer or a preservative may be optionally added thereto. The pharmaceutical compositions may contain the compound of the invention in an amount of from 1 to 99.9 % by weight, preferably from 1 to 60 % by weight of the composition. The compositions may further contain any other therapeutically-effective compounds. In case where the compounds of the invention are used for prevention or treatment for the above-mentioned diseases, the dose and the dosing frequency may be varied, depending on the sex, the age, the body weight and the disease condition of the patient and on the type and the range of the intended remedial effect. In general, when orally administered, the dose may be from 0.001 to 50 mg/kg of body weight/day, and it may be administered at a time or in several times. In specific embodiments, the dose is from about 0.01 to about 25 mg/kg/day, in particular embodiments, from about 0.05 to about 10 mg/kg/day. For oral administration, the compositions are preferably provided in the form of tablets or capsules containing from 0.01 mg to 1,000 mg. In specific embodiments, the dose is 0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 750, 850 or 1,000 milligrams of a compound described herein. This dosage regimen may be adjusted to provide the optimal therapeutic response. COMBINATION THERAPY The compounds of the present invention are further useful in methods for the prevention or treatment of the aforementioned diseases, disorders and conditions in combination with other therapeutic agents. The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds described herein or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered in an amount commonly used therefore, contemporaneously or sequentially with a compound described herein or a pharmaceutically acceptable salt thereof. When a compound described herein is used contemporaneously with one or more other drugs, the pharmaceutical composition may in specific embodiments contain such other drugs and the compound described herein or its pharmaceutically acceptable salt in unit dosage form. However, the combination therapy may also include therapies in which the compound described herein or its pharmaceutically acceptable salt and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound described herein or a pharmaceutically acceptable salt thereof. EXAMPLES The compounds of the present invention can be prepared according to the following schemes and examples, or modifications thereof, using available starting materials, reagents and conventional synthetic procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in detail. The general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes and descriptions. General Scheme 1 One general strategy for the synthesis of compounds of type G1.8 is via a four-step procedure shown in General Scheme 1, wherein R 1 and R 2 are as defined in Formula I. In the first step, aldehydes G1.1 can be combined with phosphorous ylide G1.2 in solvents such as THF to form unsaturated aldehyde intermediates of type G1.3. In the second step, intermediates of type G1.3 can be treated with hydrazine in solvents such as THF or t-BuOH to provide dihydropyrazole intermediates such as G1.4. In the third step, intermediates of type G1.4 can be combined with nitrophenyl carbonochloridate (G1.5) in the presence of a base to generate nitrophenyl carbamate intermediates G1.6. Bases such as potassium carbonate or triethylamine, and solvents such as THF or DCM, can be used. In the fourth step, intermediates of type G1.6 can be combined with substituted azetidines G1.7 in the presence of base to form urea products G1.8. Bases such as DIPEA, triethylamine, and cesium carbonate, and solvents such as DMF, DMSO, and DCM, can be used. Products of type G1.8 can be purified by silica gel chromatography or preparative reverse-phase HPLC. General Scheme 2 One general strategy for the synthesis of compounds of type G2.3 is via a one-step procedure shown in General Scheme 2, wherein R 2 is as defined in Formula I, Ar is an electron- deficient heteroaryl group, and R 4 , taken together with the nitrogen to which it is attached, is a urea or carbamate group. Hydroxyazetidines G2.1 can be treated with sodium hydride, then combined with electron-deficient heteroaryl chlorides G2.2 in solvents such as THF to form heteroaryl ethers of type G2.3. Products of type G2.3 can be purified by silica gel chromatography or preparative reverse-phase HPLC. Abbreviations used herein have the following meaning: General Experimental Information: Unless otherwise noted, all reactions were magnetically stirred and performed under an inert atmosphere such as nitrogen or argon. Unless otherwise noted, “concentrated” means evaporating the solvent from a solution or mixture using a rotary evaporator or vacuum pump. Unless otherwise noted, flash chromatography was carried out on an ISCO®, Analogix®, or Biotage® automated chromatography system using a commercially available cartridge as the column. Columns were usually filled with silica gel as the stationary phase. Reverse phase preparative HPLC conditions can be found at the end of the experimental section. Aqueous solutions were concentrated on a Genevac® evaporator or were lyophilized. Unless otherwise noted, proton nuclear magnetic resonance ( 1 H NMR) spectra and proton-decoupled carbon nuclear magnetic resonance ( 13 C{ 1 H} NMR) spectra were recorded on 400 500 or 600 MHz Bruker or Varian NMR spectrometers at ambient temperature All chemical shifts (δ) were reported in parts per million (ppm). Proton resonances were referenced to residual protium in the NMR solvent, which can include, but is not limited to, CDCl3, DMSO- d 6 , and MeOD-d 4 . Carbon resonances are referenced to the carbon resonances of the NMR solvent. Data are represented as follows: chemical shift, multiplicity (br = broad, br s = broad singlet, s = singlet, d = doublet, dd = doublet of doublets, ddd = doublet of doublet of doublets, t = triplet, q = quartet, m = multiplet), coupling constants (J) in Hertz (Hz), integration. Preparation of Intermediate A.2, bicyclo[2.2.1]heptane-1-carbaldehyde. Scheme A A stirring mixture of bicyclo[2.2.1]heptan-1-ylmethanol (830 mg, 6.25 mmol) in DCM (10 mL) was cooled to 0 °C and then treated with PCC (2.29 g, 10.6 mmol) and Celite® (700 mg). The resulting mixture was warmed to 20 °C and stirred for 16 h. After completion of the reaction, silica gel (1 g) was added, and the resulting mixture was filtered, rinsing with DCM (3 x 50 mL). The filtrate was directly concentrated at a temperature of 0 °C to provide bicyclo[2.2.1]heptane-1-carbaldehyde. 1 H NMR (400 MHz, CDCl3) ^ 9.87 (s, 1 H), 2.47-2.40 (m, 1 H), 1.94-1.87 (m, 2 H), 1.77-1.70 (m, 2 H), 1.67-1.53 (m, 2 H), 1.39 (d, J = 7.3 Hz, 4 H). Preparation of Intermediate B.3, (E)-3-(3,5-difluorophenyl)acrylaldehyde. Scheme B A stirring mixture of 3,5-difluorobenzaldehyde (3.0 g, 21.1 mmol) in THF (50 mL) was treated with 2-(triphenylphosphoranylidene)acetaldehyde (7.1 g, 23.2 mmol), and the resulting mixture was stirred at 80 °C for 15 h. The reaction mixture was then directly concentrated, and the crude residue was purified by silica gel chromatography (gradient elution: 0-50% EtOAc/hexanes) to provide (E)-3-(3,5-difluorophenyl)acrylaldehyde. MS (ESI) m/z calculated for C 9 H 7 F 2 O [M+H] + 169, found 169. Preparation of Intermediate C.2, (E)-3-(3,5-difluorophenyl)acrylaldehyde. Scheme C Intermediate C.2 was also synthesized according to the method shown in Scheme B, starting from C.1. MS (ESI) m/z calculated for C9H9NO [M+H] + 166, found 166. Preparation of Intermediate D.2, (E)-3-(5-fluoro-6-methylpyridin-3-yl)acrylaldehyde. Scheme D A stirring mixture of nicotinaldehyde (8.0 g, 74.7 mmol) in THF (50 mL) was treated with 2-(triphenylphosphoranylidene)acetaldehyde (25.0 g, 82.0 mmol), and the resulting mixture was stirred at 25 °C for 15 h. The reaction mixture was then directly concentrated, and the crude residue was purified by silica gel chromatography (elution: 9% EtOAc/petroleum ether) to provide (E)-3-(pyridin-3-yl)acrylaldehyde. 1 H NMR (400 MHz, CDCl 3 ) ^ 9.54 (d, J = 8.1 Hz, 1 H), 7.12 (d, J = 15.7 Hz, 1 H), 6.14 (dd, J = 7.8, 15.9 Hz, 1 H), 2.41-2.35 (m, 1H), 1.65 (br s, 2 H), 1.60-1.55 (m, 2 H), 1.52-1.46 (m, 2 H), 1.42 (s, 4 H). Compounds in Table 1 were prepared according to Scheme D and General Scheme 1, starting from the appropriate commercially available aldehyde intermediate. A slightly modified procedure was used wherein THF was replaced by DCM. Compounds in Table 1 were purified by silica gel chromatography. Table 1. Intermediate Compounds Prepared According to General Scheme 1 and Scheme D Preparation of Intermediate E.1, (E)-3-(bicyclo[2.2.1]heptan-1-yl)acrylaldehyde. Scheme E A stirring mixture of bicyclo[2.2.1]heptane-1-carbaldehyde (1.0 g, 7.25 mmol) in THF (10 mL) was treated with 2-(triphenylphosphoranylidene)acetaldehyde (1.99 g, 6.52 mmol), and the resulting mixture was stirred at 40 °C for 72 h. The reaction mixture was then directly concentrated, and the crude residue was purified by silica gel chromatography (gradient elution: 0-2% EtOAc/petroleum ether) to provide (E)-3-(bicyclo[2.2.1]heptan-1-yl)acrylaldehyde. 1 H NMR (400 MHz, CDCl 3 ) δ 9.54 (d, J = 8.1 Hz, 1 H), 7.12 (d, J = 15.7 Hz, 1 H), 6.14 (dd, J = 15.9, 7.8 Hz, 1 H), 2.41-2.35 (m, 1 H), 1.65 (br s, 2 H), 1.60-1.55 (m, 2 H), 1.52-1.46 (m, 2 H), 1.42 (s, 4 H). Preparation of Intermediate F.1, 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole. Scheme F A 100 mL round bottom flask was charged with hydrazine hydrate (2.88 ml, 59.5 mmol) and THF (6 mL). A solution of (E)-3-(3,5-difluorophenyl)acrylaldehyde (1.0 g, 5.95 mmol) in THF (17.8 mL) was then added dropwise over the course of 3 min. The reaction mixture was stirred at 25 °C for 30 min. The reaction mixture was then directly concentrated in vacuo at a water bath temperature of 40 °C. The crude residue was dried under vacuum for 10 min to provide 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole, which was used directly in the subsequent reaction. MS (ESI) m/z calculated for C 9 H 9 F 2 N 2 [M+H] + 183, found 183. Compounds in Table 2 were prepared according to Scheme F and General Scheme 1, starting from the appropriate commercially available acrylaldehyde intermediate or C.2, D.2, D.3, or D.4. Some compounds in Table 2 were isolated with slightly modified procedures from Scheme F. For Intermediates F.2 through F.4, the reaction was directly concentrated and the crude residue purified by silica gel chromatography. For Intermediates F.5 and F.6, the reactions were extracted with DCM, and the crude residue was used directly in the subsequent reaction. Table 2. Intermediate Compounds Prepared According to General Scheme 1 and Scheme F Preparation of Intermediate G.1, 5-(bicyclo[2.2.1]heptan-1-yl)-4,5-dihydro-1H-pyrazole. Scheme G A stirring solution of (E)-3-(bicyclo[2.2.1]heptan-1-yl)acrylaldehyde (10 mg, 0.067 mmol) in t-BuOH (2 mL) was treated with hydrazine hydrochloride (9.1 mg, 0.133 mmol). The resulting mixture was then heated to 90 °C and stirred for 16 h. After cooling, the reaction mixture was then directly concentrated to provide 5-(bicyclo[2.2.1]heptan-1-yl)-4,5-dihydro-1H- pyrazole, which was used directly in the subsequent reaction. MS (ESI) m/z calculated for C 10 H 17 N 2 [M+H] + 165, found 165. Preparation of Intermediates H.2 and H.3, tert-butyl (R)-5-(4-chlorophenyl)-4,5-dihydro-1H- pyrazole-1-carboxylate and tert-butyl (S)-5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole-1- carboxylate. Scheme H Step 1 – Synthesis of Intermediate H.1, tert-butyl 5-(4-chlorophenyl)-4,5-dihydro-1H- pyrazole-1-carboxylate. A stirring solution of 5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole (7.50 g, 41.5 mmol) in MeOH (200 mL) was treated with di-tert-butyl dicarbonate (23.9 mL, 104 mmol). The resulting mixture was stirred at 25 °C for 15 h. The reaction mixture was then directly concentrated and the crude residue was purified by silica gel chromatography (gradient elution: 0-15% EtOAc/petroleum ether) to provide tert-butyl 5-(4-chlorophenyl)-4,5-dihydro-1H- pyrazole-1-carboxylate. MS (ESI) m/z calculated for C 10 H 10 ClN 2 O 2 [M+H-(C 4 H 8 )] + 225, found 225. Step 2 - SFC Separation of tert-butyl 5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole-1- carboxylate. Tert-butyl 5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole-1-carboxylate was purified by CHIRAL-Prep SFC [Column: Phenomenex Synergi C18, 150x30mm: Gradient elution: 27-47% (0.1% TFA in MeCN)/CO 2 over 9 min; Flow rate: 25 mL/min; Column temp: 40 °C; 220 nm; First Eluting Peak (H.2); Second Eluting Peak (H.3)]. This provided tert-butyl (R)-5-(4- chlorophenyl)-4,5-dihydro-1H-pyrazole-1-carboxylate (H.2) and tert-butyl (S)-5-(4- chlorophenyl)-4,5-dihydro-1H-pyrazole-1-carboxylate (H.3). Compounds in Table 3 were prepared according to Scheme H, starting from intermediate F.4. SFC conditions are provided following the table. Table 3. Intermediate Compounds Prepared According to Scheme H Intermediates H.4/H.5 Tert-butyl 5-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carboxylate was purified by CHIRAL-Prep SFC [Column: Chiralpak AD-3, 150x4.6mm; Gradient elution: 5-40% (0.05% diethylamine in EtOH)/CO 2 over 5 min, followed by 40-5% (0.05% diethylamine in EtOH)/CO 2 for 0.5 min, then 5% (0.05% diethylamine in EtOH)/CO2 for 1.5 min; Flow rate: 2.5 mL/min; Column temp: 35 °C; First Eluting Peak (H.4); Second Eluting Peak (H.5)]. Preparation of Intermediate I.2, tert-butyl 5-(5-cyanopyridin-3-yl)-4,5-dihydro-1H-pyrazole- 1-carboxylate. Scheme I Step 1 – Synthesis of Intermediate I.1, tert-butyl 5-(5-bromopyridin-3-yl)-4,5-dihydro-1H- pyrazole-1-carboxylate. A stirring solution of 4-bromo-2-(4,5-dihydro-1H-pyrazol-5-yl)pyridine (2.5 g, 11.1 mmol) in MeOH (80 mL) was treated with di-tert-butyl dicarbonate (12.7 ml, 55.3 mmol). The resulting mixture was stirred at 25 °C for 15 h. The reaction mixture was then directly concentrated and the crude residue was purified by preparative TLC (silica gel, eluent: 50% EtOAc/petroleum ether) to provide tert-butyl 5-(5-bromopyridin-3-yl)-4,5-dihydro-1H-pyrazole- 1-carboxylate. MS (ESI) m/z calculated for C 13 H 17 BrN 3 O 2 [M+H] + 326, found 326, 328. Step 2 - Preparation of Intermediate I.2, tert-butyl 5-(5-cyanopyridin-3-yl)-4,5-dihydro-1H- pyrazole-1-carboxylate. A solution of tert-butyl 5-(4-bromopyridin-2-yl)-4,5-dihydro-1H-pyrazole-1-carboxylat e (2.0 g, 6.13 mmol) in DMF (40 mL) was treated with dicyanozinc (3.32 g, 28.3 mmol), zinc (80 mg, 1.23 mmol), dppf (680 mg, 1.23 mmol) and Pd 2 (dba) 3 (561 mg, 0.613 mmol) under an atmosphere of nitrogen. The resulting mixture was stirred at 110 °C for 12 h. The reaction mixture was then directly purified by preparative TLC (silica gel, eluent: 50% EtOAc/petroleum ether) to provide tert-butyl 5-(4-cyanopyridin-2-yl)-4,5-dihydro-1H-pyrazole-1-carboxylat e. MS (ESI) m/z calculated for C 14 H 17 N 4 O 2 [M+H] + 273, found 273. Preparation of Intermediate J.1, (S)-5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole, TFA salt. Scheme J A solution of tert-butyl (S)-5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole-1-carboxylate (1.40 g, 4.99 mmol) in DCM (15 mL) and TFA (15 mL) was stirred at 20 °C for 1 h. The reaction mixture was then directly concentrated to provide (S)-5-(4-chlorophenyl)-4,5-dihydro- 1H-pyrazole, which was used in the subsequent reaction without further purification. MS (ESI) m/z calculated for C9H10ClN2 [M+H] + 181, found 181. Compounds in Table 4 were prepared according to Scheme J, starting from intermediates H.4, H.5, or I.2. In the case of J.2 and J.3, the reaction was run in a 4 M solution of HCl in dioxane, instead of a mixture of DCM and TFA. Table 4. Intermediate Compounds Prepared According to Scheme J Preparation of Intermediate K.2, 4-nitrophenyl (S)-5-(4-chlorophenyl)-4,5-dihydro-1H- pyrazole-1-carboxylate. Scheme K A solution of (S)-5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazole (901 mg, 4.99 mmol) in DCM (20 mL) was treated with 4-nitrophenyl carbonochloridate (1.51 g, 7.48 mmol) and triethylamine (2.07 mL, 15.0 mmol). The resulting mixture was stirred at 20 °C for 16 h. The reaction was quenched with water (20 mL), then the layers were separated, and the aq. layer was extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated. The crude residue was then purified by silica gel chromatography (gradient elution: 0-10% EtOAc/petroleum ether) to provide 4-nitrophenyl (S)-5-(4- chlorophenyl)-4,5-dihydro-1H-pyrazole-1-carboxylate. MS (ESI) m/z calculated for C16H13ClN3O4 [M+H] + 346, found 346. Compounds in Table 5 were prepared according to Scheme K and General Scheme 1, starting from intermediates F.3, J.2, J.3, G.1, F.5, J.4, or F.7. For K.7 through K.9, a slightly modified procedure was used wherein Et3N was replaced by DIPEA, and the reaction mixture was directly concentrated prior to silica gel chromatography. K.6 and K.8 were separated from their enantiomers by SFC following purification with silica gel chromatography. SFC conditions are provided following the table. Table 5. Intermediate Compounds Prepared According to General Scheme 1 and Scheme K Intermediate K.6 4-nitrophenyl 5-(bicyclo[2.2.1]heptan-1-yl)-4,5-dihydro-1H-pyrazole-1-carb oxylate was purified by CHIRAL-Prep SFC [Column: Daicel Chiralcel OJ-H, 250x30mm; 30% i-PrOH/CO 2 ; Flow rate: 60 mL/min; First Eluting Peak (enantiomer of K.6); Second Eluting Peak (K.6)]. Intermediate K.8 4-nitrophenyl 5-(5-cyanopyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carboxylat e was purified by CHIRAL-Prep SFC [Column: Daicel Chiralpak AD, 250x30mm; 60% EtOH/CO 2 ; Flow rate: 80 mL/min; First Eluting Peak (enantiomer of K.8); Second Eluting Peak (K.8)]. Preparation of Intermediate L.1, 4-nitrophenyl 5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole-1-carboxylate. Scheme L A 500 mL round bottom flask containing 5-(3,5-difluorophenyl)-4,5-dihydro-1H- pyrazole (1.08 g, 5.93 mmol) was charged with potassium carbonate (1.23 g, 8.89 mmol) and THF (148 mL).4-nitrophenyl carbonochloridate (3.58 g, 17.79 mmol) was then added, and the resulting mixture was stirred at 25 °C for 2 h. Sat. aq. NaHCO3 (75 mL) and DCM (200 mL) were then added and the layers were separated. The aq. phase was extracted with DCM (2 x 100 mL), and the combined organic layer was dried over MgSO4 and concentrated. The crude residue was then purified by silica gel chromatography (gradient elution: 0-100% EtOAc/hexanes) to provide 4-nitrophenyl 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carboxylate. MS (ESI) m/z calculated for C 16 H 12 F 2 N 3 O 4 [M+H] + 348, found 348. SFC Separation of 4-nitrophenyl 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carboxylate. Scheme M 4-nitrophenyl 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carboxylate was purified by CHIRAL-Prep SFC [Column: AD-H, 21x250mm: 25% [MeOH w/ 0.1% NaOH]/CO 2 ; Flow rate: 70 mL/min; 220 nm; First Eluting Peak (M.1); Second Eluting Peak (M.2)]. This provided 4-nitrophenyl (R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carboxylate (M.1) and 4-nitrophenyl (S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carboxylate (M.2). Compounds in Table 6 were separated similarly to Scheme M, starting from intermediates K.7 or K.9. SFC conditions are provided following the table. Table 6. Intermediate Compounds Prepared According to Scheme M Intermediate M.3 4-nitrophenyl 5-(5-fluoropyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carboxyla te was purified by CHIRAL-Prep SFC [Column: Daicel Chiralpak IC, 250x50mm; 55% EtOH/CO2; Flow rate: 200 mL/min; First Eluting Peak (M.3); Second Eluting Peak (Enantiomer of M.3)]. Intermediate M.4 4-nitrophenyl 5-(5-fluoro-6-methylpyridin-3-yl)-4,5-dihydro-1H-pyrazole-1- carboxylate was purified by CHIRAL-Prep SFC [Column: Daicel Chiralpak OJ, 250x30mm: 20% [0.1% NH4OH in EtOH]/CO2; Flow rate: 60 mL/min; First Eluting Peak (Enantiomer of M.4); Second Eluting Peak (M.4)]. Preparation of Intermediates N.3 and N.4, tert-butyl (2S,3R and 2R,3S)-2-methyl-3- phenoxyazetidine-1-carboxylate and tert-butyl (2S,3S and 2R,3R)-2-methyl-3- phenoxyazetidine-1-carboxylate. Scheme N Step 1 – Synthesis of Intermediate N.2, tert-butyl 2-methyl-3- ((methylsulfonyl)oxy)azetidine-1-carboxylate. Triethylamine (0.502 mL, 3.61 mmol) and MsCl (0.156 mL, 2.00 mmol) were added to a stirred solution of tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate (300 mg, 1.60 mmol) in DCM (6.4 mL) that had been cooled to 0 °C. The reaction mixture was stirred at 0 °C for 10 min, then warmed to 25 °C and stirred for 18 h. Water (8 mL) and DCM (2 mL) were then added, and the layers sere separated. The aq. layer was extracted with DCM (2 x 8 mL), and the combined organic layers were dried over MgSO4 and concentrated to provide tert-butyl 2- methyl-3-((methylsulfonyl)oxy)azetidine-1-carboxylate, which was used directly in the subsequent reaction. MS (ESI) calculated for C6H12NO5S [M+H-(C4H8)] + 210, found 210. Step 2 – Preparation of Intermediates N.3 and N.4, tert-butyl (2S,3R and 2R,3S)-2-methyl-3- phenoxyazetidine-1-carboxylate and tert-butyl (2S,3S and 2R,3R)-2-methyl-3- phenoxyazetidine-1-carboxylate. A 40 mL scintillation vial was charged with tert-butyl 2-methyl-3- ((methylsulfonyl)oxy)azetidine-1-carboxylate (430 mg, 1.62 mmol), phenol (198 mg, 2.11 mmol), and cesium carbonate (792 mg, 2.43 mmol). DMF (8.1 mL) was then added, and the resulting mixture was stirred at 120 °C for 18 h. After cooling, the reaction mixture was poured into Et2O (50 mL) and water (50 mL). The layers were then separated, and the aq. layer was extracted with Et 2 O (2 x 50 mL). The combined organic layers were washed with water (2 x 20 mL) and brine (15 mL), dried over MgSO4, and concentrated. The crude residue was then purified by silica gel chromatography (gradient elution: 0-100% EtOAc/hexanes) to provide tert- butyl (2S,3R and 2R,3S)-2-methyl-3-phenoxyazetidine-1-carboxylate as the first eluting peak, and tert-butyl (2S,3S and 2R,3R)-2-methyl-3-phenoxyazetidine-1-carboxylate as the second eluting peak. MS (ESI) m/z calculated for C11H14NO3 [M+H-(C4H8)] + 208, found 208. SFC Separation of tert-butyl (2S,3R and 2R,3S)-2-methyl-3-phenoxyazetidine-1-carboxylate. Scheme O Tert-butyl (2S,3R and 2R,3S)-2-methyl-3-phenoxyazetidine-1-carboxylate was purified by CHIRAL-Prep SFC [Column: Lux-2, 21x250mm: 5% [MeOH w/ 0.1% NaOH]/CO 2 ; Flow rate: 70 mL/min; 220 nm; First Eluting Peak (O.1); Second Eluting Peak (O.2)]. This provided tert-butyl (2S,3R or 2R,3S)-2-methyl-3-phenoxyazetidine-1-carboxylate (O.1) and tert-butyl (2R,3S or 2S,3R)-2-methyl-3-phenoxyazetidine-1-carboxylate (O.2). Preparation of Intermediate P.3, tert-butyl (2R,3R)-3-(4-fluorophenoxy)-2-methylazetidine- 1-carboxylate. Scheme P A solution of tert-butyl (2R,3R)-3-hydroxy-2-methylazetidine-1-carboxylate (50 mg, 0.267 mmol) in DCE (5 mL) was treated with (4-fluorophenyl)boronic acid (299 mg, 2.14 mmol), DMAP (6.5 mg, 0.053 mmol), pyridine (63 mg, 0.801 mmol) and 4Å molecular sieves (1 g). The resulting mixture was stirred 20 °C for 10 min, then Cu(OAc)2 (48.5 mg, 0.267 mmol) was added. The reaction mixture was then stirred at 90 °C under an atmosphere of oxygen for 24 h. The reaction mixture was then directly filtered, rinsing with DCM (2 x 20 mL). Water (30 mL) was added to the filtrate and the resulting mixture was extracted with DCM (3 x 30 mL), washed with brine (20 mL), dried over Na 2 SO 4 , and concentrated. The crude residue was purified by silica gel chromatography (gradient elution: 0-18% EtOAc/petroleum ether) to provide tert-butyl (2R,3R)-3-(4-fluorophenoxy)-2-methylazetidine-1-carboxylate. MS (ESI) m/z calculated for C11H10FNO3 [M+H-(C4H8)] + 226, found 226. Compounds in Table 7 were prepared according to Scheme P, starting from commercially available azetidinols and (4-fluorophenyl)boronic acid. Table 7. Intermediate Compounds Prepared According to Scheme P Scheme Q Intermediate Q.3 was also synthesized according to the method shown in Scheme P, starting from Q.1 and phenylboronic acid. 1 H NMR (400 MHz, CDCl 3 ) ^ 7.29 (s, 1 H), 7.25 (s, 1 H), 7.02-6.94 (m, 1 H), 6.75-6.68 (m, 2 H), 4.16 (d, J = 9.6 Hz, 2 H), 3.97 (d, J = 9.6 Hz, 2 H), 2.06 (q, J = 7.6 Hz, 2 H), 1.45 (s, 9 H), 0.96-0.88 (m, 3 H). Preparation of Intermediate R.3, tert-butyl 3-((6-cyanopyrimidin-4-yl)oxy)azetidine-1- carboxylate Scheme R Sodium hydride was added to stirred solution of tert-butyl 3-hydroxyazetidine-1- carboxylate (tert-butyl 3-hydroxyazetidine-1-carboxylate) (500 mg, 2.89 mmol) in THF (29 mL) that had been cooled to 0 °C. The resulting cloudy suspension was stirred for 15 min at 0 °C, then a solution of 6-chloropyrimidine-4-carbonitrile (403 mg, 2.89 mmol) in THF (1 mL) was added. The reaction was stirred at 0 °C for 10 min, then warmed to 25 °C and stirred for 2 h. Water (5 mL) and DCM (15 mL) were then added, and the resulting biphasic mixture was stirred at 25 °C for 5 min. The layers were then separated, and the aq. layer was extracted with DCM (15 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude residue was purified by silica gel chromatography (gradient elution: 0-100% EtOAc/hexanes) to provide tert-butyl 3-((6-cyanopyrimidin-4-yl)oxy)azetidine-1-carboxylate. MS (ESI) m/z calculated for C13H17N4O3 [M+H] + 277, found 277. Compounds in Table 8 were prepared using a similar procedure to Scheme R, starting from the appropriate commercially available azetidinol and either 4-chloropicolinonitrile or bromocyclobutane. A slight modification was employed, replacing THF with DMF as the solvent. For R.4, R.5, and R.7, the reaction was run at 40 °C following the addition of 4- chloropicolinonitrile. Compounds in Table 8 were purified by silica gel chromatography or preparative TLC (silica gel). Table 8. Intermediate Compounds Prepared According to Scheme R Preparation of Intermediate S.2, tert-butyl 3-(cyclopentyloxy)azetidine-1-carboxylate. Scheme S Sodium hydride (277 mg, 6.93 mmol) was added to stirred solution of tert-butyl 3- hydroxyazetidine-1-carboxylate (150 mg, 0.866 mmol) in THF (18 mL) that had been cooled to 0 °C. The resulting cloudy suspension was stirred for 30 min at 0 °C, and then bromocyclopentane (0.70 mL, 6.93 mmol) was added. The reaction mixture was then stirred at 0 °C for an additional 10 min, then heated at 75 °C for 3 days. After cooling, the reaction was then poured into water (30 mL) and DCM (40 mL), and the resulting biphasic mixture was stirred at 25 °C for 5 min. The layers were then separated, and the aq. layer was extracted with DCM (2 x 30 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude residue was then purified by silica gel chromatography (gradient elution: 0-100% [25% EtOH in EtOAc]/hexanes) to provide tert-butyl 3-(cyclopentyloxy)azetidine-1-carboxylate. MS (ESI) m/z calculated for C 9 H 16 NO 3 [M+H-(C 4 H 8 )] + 186, found 186. Preparation of Intermediate T.3, tert-butyl 3-((6-cyanopyridin-3-yl)oxy)azetidine-1- carboxylate. Scheme T A stirring mixture of 5-hydroxypicolinonitrile (100 mg, 0.833 mmol) and K2CO3 (230 mg, 1.67 mmol) in DMF (0.5 mL) was cooled to 0 °C. Tert-butyl 3-iodoazetidine-1-carboxylate (0.290 mL, 1.67 mmol) was then added, and the reaction mixture was heated to 80 °C and stirred for 3 days. After cooling, water (5 mL) and Et 2 O (6 mL) were added. The layers were then separated, and the aq. layer was extracted with Et2O (2 x 10 mL). The combined organic layers were washed with water (2 x 5 mL) and brine (5 mL), dried over MgSO 4 and concentrated. The crude residue was then purified by silica gel chromatography (gradient elution: 0-20% MeOH in DCM) to provide tert-butyl 3-((6-cyanopyridin-3-yl)oxy)azetidine-1-carboxylate. MS (ESI) m/z calculated for C10H10N3O3 [M+H-(C4H8)] + 220, found 220. Preparation of Intermediate U.2, tert-butyl 3-(3-cyanophenoxy)azetidine-1-carboxylate. Scheme U A stirring mixture of 3-hydroxybenzonitrile (500 mg, 4.20 mmol) in DMF (10 mL) was cooled to 0 °C and treated with sodium hydride (201 mg, 5.04 mmol). The resulting mixture was stirred at 20 °C for 30 min, then tert-butyl 3-iodoazetidine-1-carboxylate (1.55 g, 5.46 mmol) was added. The reaction mixture was then stirred at 40 °C for 2 h. After cooling, water (20 mL) and EtOAc (20 mL) were added and the layers were separated. The aq. layer was extracted with EtOAc (2 x 10 mL), and the combined organic layers were washed with brine (2 x 30 mL), dried over Na2SO4 and concentrated. The crude residue was purified by preparative TLC (silica gel, eluent: 17% EtOAc/petroleum ether) to provide tert-butyl 3-(3-cyanophenoxy)azetidine-1- carboxylate. MS (ESI) m/z calculated for C11H11N2O3 [M+H-(C4H8)] + 219, found 219. Preparation of Intermediate V.5, tert-butyl 3-((2-cyanopyridin-4-yl)difluoromethyl)azetidine- 1-carboxylate. Scheme V Step 1 – Synthesis of Intermediate V.3, tert-butyl 3-(2-chloroisonicotinoyl)azetidine-1- carboxylate. A mixture of tert-butyl 3-(2-tosylhydrazineylidene) azetidine-1-carboxylate (1.0 g, 2.95 mmol), Cs2CO3 (1.44 g, 4.42 mmol) and 2-chloroisonicotinaldehyde (417 mg, 2.95 mmol) in dioxane (20 mL) was heated to 110 °C and stirred for 6 h. The reaction was then quenched with sat. aq. NH4Cl (30 mL), extracted with EtOAc (3 x 40 mL), dried over Na2SO4, and concentrated. The crude residue was then purified by silica gel chromatography (gradient elution: 0-30% EtOAc/petroleum ether) to provide tert-butyl 3-(2-chloroisonicotinoyl)azetidine- 1-carboxylate. MS (ESI) calculated for C10H10ClN2O3 [M+H-(C4H8)] + 241, found 241. Step 2 – Synthesis of Intermediate V.4, tert-butyl 3-((2-chloropyridin-4- yl)difluoromethyl)azetidine-1-carboxylate. Tert-butyl 3-(2-chloroisonicotinoyl)azetidine-1-carboxylate (150 mg, 0.505 mmol) was treated with DAST (7 mL), and the resulting mixture was stirred at 50 °C for 12 h. The reaction was then quenched with sat. aq. NaHCO 3 (40 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over Na 2 SO 4 and concentrated. The crude residue was then purified by preparative TLC (silica gel, eluent: 25% EtOAc/petroleum ether) to provide tert-butyl 3-((2-chloropyridin-4-yl)difluoromethyl)azetidine- 1-carboxylate. MS (ESI) calculated for C10H10ClF2N2O2 [M+H-(C4H8)] + 263, found 263. Step 3 – Preparation of Intermediate V.5, tert-butyl 3-((2-cyanopyridin-4- yl)difluoromethyl)azetidine-1-carboxylate. A solution of tert-butyl 3-((2-chloropyridin-4-yl)difluoromethyl)azetidine-1-carboxyl ate (50 mg, 0.094 mmol) in DMF (1 mL) was treated with dicyanozinc (33.2 mg, 0.282 mmol), zinc (2.5 mg, 0.038 mmol), dppf (21 mg, 0.038 mmol) and Pd2(dba)3 (17 mg, 0.019 mmol) under an atmosphere of nitrogen. The resulting mixture was stirred at 110 °C for 12 h. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated. The crude residue was then purified by preparative TLC (silica gel, eluent: 25% EtOAc/petroleum ether) to provide tert- butyl 3-((2-cyanopyridin-4-yl)difluoromethyl)azetidine-1-carboxyla te. MS (ESI) m/z calculated for C11H10F2N3O2 [M+H-(C4H8)] + 254, found 254. Preparation of Intermediate W.4, tert-butyl 3-(1-phenylethyl)azetidine-1-carboxylate. Scheme W Step 1 – Synthesis of Intermediate W.3, tert-butyl 3-(1-(2-tosylhydrazono)ethyl)azetidine-1- carboxylate. A solution of tert-butyl 3-acetylazetidine-1-carboxylate (200 mg, 1.00 mmol) in toluene (2 ml) was treated with 4-methylbenzenesulfonohydrazide (374 mg, 2.01 mmol) and 4Å molecular sieves. The resulting reaction mixture was stirred at 120 °C for 8 h. The reaction was then filtered and concentrated to provide tert-butyl 3-(1-(2-tosylhydrazono)ethyl)azetidine-1- carboxylate, which was used directly in the subsequent reaction. 1 H NMR (400 MHz, CDCl 3 ) δ 7.83 (d, J = 8.4 Hz, 2 H), 7.50 (s, 1 H), 7.30 (d, J = 8.0, 2 H), 4.02-3.95 (m, 2 H), 3.90-3.84 (m, 2 H), 3.32-2.23 (m, 1 H), 2.41 (s, 3 H), 1.79 (s, 3 H), 1.41 (s, 9 H). Step 2 – Preparation of Intermediate W.4, Preparation of Intermediate P.5, tert-butyl 3-(1- phenylethyl)azetidine-1-carboxylate. A mixture of tert-butyl 3-(1-(2-tosylhydrazono)ethyl)azetidine-1-carboxylate (30 mg, 0.082 mmol), K2CO3 (33.8 mg, 0.245 mmol) and phenylboronic acid (14.9 mg, 0.122 mmol) in dioxane (1.5 mL) was heated to 110 °C and stirred for 5 h. The reaction was then directly filtered and concentrated. The crude residue was purified by preparative TLC (silica gel, eluent: EtOAc) to provide tert-butyl 3-(1-phenylethyl)azetidine-1-carboxylate. 1 H NMR (400 MHz, CDCl 3 ) δ 7.29-7.23 (m, 2 H), 7.21-7.18 (m, 1 H), 7.15-7.11 (m, 2 H), 4.08-4.02 (m, 1 H), 3.74- 3.66 (m, 2 H), 3.47-3.43 (m, 1 H), 2.87-2.82 (m, 1 H), 2.70-2.65 (m, 1 H), 1.40 (s, 9 H), 1.18 (d, J = 6.8 Hz, 3 H). Preparation of Intermediate X.3, tert-butyl 3-((2-cyanopyridin-4-yl)methyl)azetidine-1- carboxylate. Scheme X A stirred mixture of 4-chloropyridine-2-carbonitrile (78 mg, 0.560 mmol), tert-butyl 3- (bromomethyl)azetidine-1-carboxylate (100 mg, 0.400 mmol), tetrabutylammonium iodide (73.8 mg, 0.200 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (35.1 mg, 0.160 mmol), and pyridine-2-carboximidamide hydrochloride (31.5 mg, 0.200 mmol) in DMA (3 mL) was stirred under nitrogen atmosphere at 20 °C. Manganese (7.5 µL, 0.999 mmol) was then added and the reaction mixture was stirred at 75 °C for 16 h. After cooling, the reaction was quenched with water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 and concentrated. The crude residue was purified by preparative TLC (silica gel, eluent: 33% EtOAc/petroleum ether) to provide tert- butyl 3-((2-cyanopyridin-4-yl)methyl)azetidine-1-carboxylate. MS (ESI) m/z calculated for C11H12N3O2 [M+H-(C4H8)] + 218, found 218. Preparation of Intermediate Y.1, tert-butyl 3-cyclobutoxyazetidine-1-carboxylate. Scheme Y
A solution of 1-benzhydryl-3-cyclobutoxyazetidine (20 mg, 0.068 mmol) in EtOH (1 mL) was treated with Boc 2 O (0.032 mL, 0.136 mmol) and Pd/C (0.73 mg, 6.8 µmol). The resulting mixture was stirred at 20 °C for 1 h under hydrogen atmosphere. The reaction mixture was then filtered and concentrated to provide tert-butyl 3-cyclobutoxyazetidine-1-carboxylate, which was used directly in the subsequent reaction. MS (ESI) m/z calculated for C8H14NO3 [M+H-(C 4 H 8 )] + 172, found 172. Preparation of Intermediate Z.1, 6-(azetidin-3-yloxy)pyrimidine-4-carbonitrile hydrochloride. Scheme Z HCl (4 M in dioxane, 0.353 mL, 1.41 mmol) was added to a stirred solution of tert-butyl 3-((6-cyanopyrimidin-4-yl)oxy)azetidine-1-carboxylate (78 mg, 0.282 mmol) in DCM (2.8 mL). The resulting mixture was stirred at 25 °C for 18 h. The solid precipitate that formed during the reaction was then filtered, and the precipitate rinsed with 5 mL DCM. This provided 6-(azetidin- 3-yloxy)pyrimidine-4-carbonitrile hydrochloride. MS (ESI) m/z calculated for C 8 H 9 N 4 O [M+H] + 177, found 177. Compounds in Table 9 were prepared according to Scheme Z, starting from tert-butyl 3- benzoylazetidine-1-carboxylate or intermediate T.3. Table 9. Intermediate Compounds Prepared According to Scheme Z Preparation of Intermediate AA.1, (2S,3S and 2R,3R)-2-methyl-3-phenoxyazetidine. Scheme AA HCl (4 M in dioxane, 0.266 mL, 1.06 mmol) was added to a stirred solution of tert-butyl (2S,3R and 2R,3S)-2-methyl-3-phenoxyazetidine-1-carboxylate (56 mg, 0.213 mmol) in DCM (2.1 mL). The resulting mixture was stirred at 25 °C for 18 h. Sat. aq. NaHCO3 (10 mL) and DCM (5 mL) were then added, and the resulting biphasic mixture was stirred for 5 min. The layers were then separated, and the aq. layer was extracted with DCM (3 x 12 mL). The combined organic layers were dried over MgSO 4 and concentrated to provide (2S,3S and 2R,3R)-2-methyl-3-phenoxyazetidine, which was used directly in the subsequent reaction. MS (ESI) m/z calculated for C 10 H 14 NO [M+H] + 164, found 164. Compounds in Table 10 were prepared according to Scheme AA, starting from intermediates O.1, O.2 or S.2. Table 10. Intermediate Compounds Prepared According to Scheme AA Preparation of Intermediate AB.2, 3-((4-bromophenyl)sulfonyl)azetidine hydrochloride. Scheme AB HCl (4 M in dioxane, 0.199 mL, 0.797 mmol) was added to a stirred solution of tert- butyl 3-((4-bromophenyl)sulfonyl)azetidine-1-carboxylate (60 mg, 0.159 mmol) in dioxane (1 mL). The resulting mixture was stirred at 25 °C for 4 h, then directly concentrated to provide 3- ((4-bromophenyl)sulfonyl)azetidine hydrochloride, which was used in the subsequent reaction without further purification. MS (ESI) m/z calculated for C9H11BrNO2S [M+H] + 276, found 276, 278. Scheme AC
Intermediate AC.2 was also synthesized according to the method shown in Scheme AB, starting from AC.1. MS (ESI) m/z calculated for C9H11BrNS [M+H] + 244, found 244, 246. Preparation of Intermediate AD.1, (2R,3R)-3-(4-fluorophenoxy)-2-methylazetidine, TFA salt. Scheme AD A solution of tert-butyl (2R,3R)-3-(4-fluorophenoxy)-2-methylazetidine-1-carboxylate (35 mg, 0.124 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at 30 °C for 1 h. The reaction mixture was then directly concentrated to provide (2R,3R)-3-(4-fluorophenoxy)-2- methylazetidine, TFA salt, which was used directly in the subsequent reaction. MS (ESI) m/z calculated for C10H13FNO [M+H] + 182, found 182. Compounds in Table 11 were prepared according to Scheme AD, starting from intermediates P.4, P.5, P.6, R.4, R.5, R.6, R.7, V.5, W.4, U.2, Q.3, X.3, or Y.1. Table 11. Intermediate Compounds Prepared According to Scheme AD
Preparation of Example 1.1, (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3- methyl-3-phenoxyazetidin-1-yl)methanone, TFA salt. Scheme 1 A 2 mL Biotage® microwave vial was charged with a 0.37 M DMSO solution of 4- nitrophenyl (S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carboxy late (0.29 mL, 0.107 mmol), 3-methyl-3-phenoxyazetidine, HCl (21.4 mg, 0.107 mmol) and DIPEA (18.7 µl, 0.107 mmol), and the vial was evacuated and backfilled with nitrogen (3x). DMF (1.6 mL) was added, and the vial was heated under microwave irradiation at 150 °C for 30 min. After completion, the reaction was filtered and purified via reversed phase HPLC [Method A]. This provided (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-m ethyl-3-phenoxyazetidin-1- yl)methanone, TFA salt. MS (ESI) m/z calculated for C 20 H 20 F 2 N 3 O 2 [M+H] + 372, found 372. 1 H NMR (600 MHz, DMSO-d 6 ) ^ 7.31-7.27 (m, 2 H), 7.12-7.07 (m, 1 H), 7.02 (br s, 1 H), 6.96 (t, J = 7.3 Hz, 1 H), 6.92-6.87 (m, 2 H), 6.78 (d, J = 7.9 Hz, 2 H), 5.23 (dd, J – 12.1, 6.5 Hz, 1 H), 4.24-4.09 (m, 4 H), 3.38 (ddd, J = 18.7, 12.2, 1.5 Hz, 1 H), 2.64 (ddd, J = 18.7, 6.5, 1.6 Hz, 1 H), 1.62 (s, 3 H). RIPK1 EC 50 2.5 nM. The following examples in Table 12 were prepared according to Scheme 1 and General Scheme 1 above, using intermediates L.1, M.2, or M.1, and the appropriate azetidine or azetidine hydrochloride coupling partner, either commercially available or intermediates Z.1, AA.2, AA.3, AA.1, Z.2, AA.4, AC.2, or AB.2. For Example 1.18 through Example 1.55, a slightly modified procedure was used wherein DIPEA was replaced by cesium carbonate, and the reaction was run at 100 °C for 16 h using conventional heating. The compounds were generally purified by reversed phase HPLC and SFC. Where isomers were separated by SFC conditions are provided, following the table. Table 12. Examples Prepared According to General Scheme 1 and Scheme 1 Example 1.6 (R and S)-6-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-c arbonyl)azetidin-3- yl)oxy)pyrimidine-4-carbonitrile, TFA salt was purified by CHIRAL-Prep SFC [Column: AS-H, 21x250mm: 20% [MeOH w/ 0.1% NaOH]/CO 2 ; Flow rate: 70 mL/min; 220 nm; Second Eluting Peak (1.6); the first eluting peak was the enantiomer of 1.6]. Example 1.12/1.13 ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)((2R ,3R and 2S,3S)-2-methyl-3- phenoxyazetidin-1-yl)methanone, TFA salt was purified by CHIRAL-Prep SFC [Column: Lux- 2, 21x250mm; 20% [MeOH w/ 0.1% NaOH]/CO 2 ; Flow rate: 70 mL/min; 220 nm; First Eluting Peak (1.12); Second Eluting Peak (1.13)]. Preparation of Example 2.1, (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3- methoxyazetidin-1-yl)methanone. Scheme 2 A stirring solution of (S)-4-nitrophenyl 5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole- 1-carboxylate (60 mg, 0.173 mmol) in DCM (1 mL) was treated with 3-methoxyazetidine hydrochloride (57 mg, 0.464 mmol) and triethylamine (96 μL, 0.691 mmol). The resulting mixture was stirred at 30 °C for 2 h, then directly concentrated and purified via reverse-phase HPLC [Method A]. This provided (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3- methoxyazetidin-1-yl)methanone. MS (ESI) m/z calculated for C14H16F2N3O2 [M+H] + 296, found 296. 1 H NMR (500 MHz, CDCl 3 ) ^ 6.71-6.80 (m, 3 H), 6.67 (tt, J = 9.0, 2.5 Hz, 1 H), 5.26 (dd, J = 12.0, 6.5 Hz, 1 H), 4.24-4.39 (m, 2 H), 4.15-4.21 (m, 1 H), 3.95-4.11 (m, 2 H), 3.31-3.37 (m, 1 H), 3.29 (s, 3 H), 2.67 (ddd, J = 18.5, 6.5, 1.5 Hz, 1 H). RIPK1 EC5011.0 nM. The following examples in Table 13 were prepared according to Scheme 2 and General Scheme 1 above, using intermediates M.2, K.3, K.2, K.5, K.4, K.6, M.3, M.4, K.8, K.7, or K.9, and the appropriate azetidine or azetidine salt coupling partner, either commercially available or intermediates AD.2, AD.1, AD.3, AD.4, AD.8, AD.5, AD.7, AD.6, AD.9, AD.10, AD.11, AD.12, AD.13, or AD.14. For Example 2.18 through Example 2.47, a slightly modified procedure was used wherein Et 3 N was replaced by DIPEA. The compounds were generally purified by reversed phase HPLC and SFC. Where isomers were separated by SFC conditions are provided, following the table. Table 13. Examples Prepared According to General Scheme 1 and Scheme 2 Example 2.4/2.5 (3-phenoxyazetidin-1-yl)(5-phenyl-4,5-dihydro-1H-pyrazol-1-y l)methanone was purified by CHIRAL-Prep SFC [Column: DAICEL CHIRALPAK AD, 250x30mm: 40% [0.1% NH4OH in i-PrOH]/CO 2 ; Flow rate: 70 mL/min; First Eluting Peak (2.4); Second Eluting Peak (2.5)]. Example 2.31 (R and S)-(5-(5-fluoro-6-methylpyridin-3-yl)-4,5-dihydro-1H-pyrazol -1-yl)(3-(4- fluorophenoxy)azetidin-1-yl)methanone, TFA salt was purified by CHIRAL-Prep SFC [Column: Daicel Chiralpak AD, 250x30mm: 55% [EtOH w/ 0.1% NH4OH]/CO2; Flow rate: 80 mL/min; Second Eluting Peak (2.31); the first eluting peak was the enantiomer of 2.31]. Example 2.40 (R and S)-(3-(4-fluorophenoxy)-3-methylazetidin-1-yl)(5-(5-fluoropy ridin-3-yl)-4,5- dihydro-1H-pyrazol-1-yl)methanone, TFA salt was purified by CHIRAL-Prep SFC [Column: Daicel Chiralpak AD, 250x30mm: 40% [i-PrOH w/ 0.1% NH 4 OH]/CO 2 ; Flow rate: 70 mL/min; Second Eluting Peak (2.40); the first eluting peak was the enantiomer of 2.40]. Example 2.42/2.43 ((S)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-( (R and S)-1- phenylethyl)azetidin-1-yl)methanone was purified by CHIRAL-Prep SFC [Column: DAICEL CHIRALPAK AD, 250x30mm: 35% [0.1% NH4OH in EtOH]/CO2; Flow rate: 70 mL/min; First Eluting Peak (2.42); Second Eluting Peak (2.43)] Preparation of Example 3.1, (S)-4-((1-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1- carbonyl)azetidin-3-yl)oxy)picolinonitrile, TFA salt. Scheme 3 A stirring solution of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3- hydroxyazetidin-1-yl)methanone (28.1 mg, 0.100 mmol) in THF (0.75 mL) was cooled to 0 °C and treated with NaH (60% in mineral oil, 6.0 mg, 0.150 mmol). The resulting mixture was stirred at 0 °C for 20 min, and then it was transferred to a 5 mL Biotage® microwave vial containing 4-chloropicolinonitrile (22.7 mg, 0.164 mmol) and a stir bar. The reaction mixture was then stirred at 25 °C for 2.5 h, then quenched with sat. aq. NH4Cl (2 mL) and DCM (2 mL). The layers were separated, and the aq. layer was extracted with DCM (2 x 3 mL). The combined organic layers were concentrated, and the crude residue was taken up in DMSO (2 mL), filtered and purified via reversed phase HPLC [Method A] This provided (S)-4-((1-(5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)azetidin- 3-yl)oxy)picolinonitrile, TFA salt. MS (ESI) m/z calculated for C19H16F2N5O2 [M+H] + 384, found 384. 1 H NMR (500 MHz, DMSO-d6) ^ 8.58-8.53 (m, 1 H), 7.64 (s, 1 H), 7.26-7.20 (m, 1 H), 7.15-7.05 (m, 1 H), 7.02 (s, 1 H), 6.94-6.86 (m, 2 H), 5.27-5.19 (m, 1 H), 5.17 (br s, 1 H), 4.53 (br s, 2 H), 3.98 (br s, 2 H), 3.46-3.36 (m, 1 H), 2.68-2.50 (m, 1 H). RIPK1 EC 50 6.6 nM. The following examples in Table 14 were prepared according to Scheme 3 and General Scheme 2 above, using Example 1.15 and the appropriate commercial heteroaryl halide coupling partner. Table 14. Examples Prepared According to General Scheme 2 and Scheme 3 Reverse Phase prep-HPLC Methods: Method A – TFA Modifier C18 reverse-phase Prep-HPLC (gradient elution, MeCN/H 2 O/0.1% TFA). Electrospray (ESI) Mass-triggered fraction collection was employed using positive ion polarity scanning to monitor for the target mass. Method B – Basic Modifier C18 reverse-phase Prep-HPLC (gradient elution, MeCN/H 2 O/basic modifier – either 0.1% NH4OH or 0.05% NH4HCO3). Electrospray (ESI) Mass-triggered fraction collection was employed using positive ion polarity scanning to monitor for the target mass. RIPK1-ADP-Glo Enzymatic Assay The enzymatic activity of RIPK1 is measured using an assay derived from ADP-Glo kit (Promega TM ), which provides a luminescent-based ADP detection system. Specifically, the ADP generated by RIPK1 kinase is proportionally detected as luminescent signals in a homogenous fashion. In this context, the assessment of the inhibitory effect of small molecules (EC 50 ) is measured by the effectiveness of the compounds to inhibit the ATP to ADP conversion by RIPK1. In this assay, the potency (EC50) of each compound was determined from a ten-point (1:3 serial dilution; top compound concentration of 100000 nM) titration curve using the following outlined procedure. To each well of a white ProxiPlus 384 well-plate, 30 nL of compound (1% DMSO in final assay volume of 3 µL) was dispensed, followed by the addition of 2 µL of 1x assay buffer (25 mM Hepes 7.3, 20 mM MgCl 2 , 50 mM NaCl, 1 mM DTT, 0.005% Tween20, and 0.02% BSA) containing 37.5 nM of GST-RIPK1 (recombinant GST-RIPK1 kinase domain (residues 1-327) enzyme produced from baculovirus-transfected Sf21 cells: MW = 62 kDa). Plates were placed in an ambient temperature humidified chamber for a 30 minutes pre- incubation with compound. Subsequently, each reaction was initiated by the addition of 1 µL 1x assay buffer containing 900 µM ATP and 3 µM dephosphorylated-MBP substrate. The final reaction in each well of 3 μL consists of 25 nM of GST-RIPK1, 300 µM ATP, and 3 µM dephosphorylated-MBP. Kinase reactions were allowed to proceed for 150 minutes prior to adding ADP-Glo reagents per Promega’s outlined kit protocol. Dose-response curves were generated by plotting percent effect (% product conversion; Y-axis) vs. Log 10 compound concentrations (X-axis). EC50 values were calculated using a non-linear regression, four- parameters sigmoidal dose-response model.