Inhibitors of receptor interacting protein kinase i for the treatment of disease

Abstract

Disclosed herein are compounds which inhibit RIPK1, pharmaceutical compositions, and methods of treatment of RIPK1-mediated diseases, such as neurodegenerative disorders, inflammatory disorders, and cancer.

Description

INHIBITORS OF RECEPTOR INTERACTING PROTEIN KINASE I FOR THETREATMENT OF DISEASE

[0001] This application claims the benefit of priority of United States provisional application no. 63 / 548,787, filed February 01, 2024, the contents of which are incorporated by reference as if written herein in their entirety.

[0002] Receptor Interacting Protein Kinase 1 (RIPK1) has been reported to play a key role in the regulation of apoptotic or necroptotic cell death pathways, as well as coordinating the response to pro-inflammatory signaling in a number of cell types. RIPK1 can also, in different contexts, regulate apoptosis and inflammation. Given its role in inflammation, RIPK1 has been implicated in many diseases featuring chronic and acute inflammatory signaling, including viral infections, sepsis, retinal degeneration, traumatic brain injury, ischemic stroke, intracerebral hemorrhage, amyotrophic lateral sclerosis, acute kidney injury, myocardial reperfusion injury, Alzheimer's disease, ulcerative colitis, osteoarthritis, and others. In animal models of these diseases RIPK1 inhibitors such as necrostatin-1 have been shown to be effective, leading to the development of such molecules for clinical trials in a number of indications.

[0003] Despite this attention, there exists a need for compounds and methods targeting RIPK1 with improved potency. These compounds could be useful in the treatment of neurodegenerative disorders, particularly those disorders with an inflammatory component of cellular stress, along with neuropathies, retinal diseases, injuries to the CNS, autoimmune disorders, and inflammatory diseases, and cancer.

[0004] The present disclosure fulfills these and other needs, as evident in reference to the following disclosure.SUMMARY

[0005] Provided is a compound of Formula I,or a pharmaceutically acceptable salt thereof.

[0006] Also provided is a pharmaceutical formulation comprising a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

[0007] Also provided is a method of inhibition of RIPK1 , comprising contacting RIPK1 with a composition comprising a compound as recited herein, or a pharmaceutically acceptable salt thereof, or a formulation as recited herein.

[0008] Also provided is a method of treatment of a RIPK1 -mediated disease, comprising the administration of a therapeutically effective amount of a composition comprising a compound as recited herein, or a pharmaceutically acceptable salt thereof, or a formulation as recited herein, to a patient in need thereof.

[0009] Also provided is a method of treatment of injury to the CNS comprising the administration of a therapeutically effective amount of a composition comprising a compound as recited herein, or a pharmaceutically acceptable salt thereof, or a formulation as recited herein, to a patient in need thereof.

[0010] Also provided is a method of treatment of a RIPK1 -mediated disease comprising the administration of:(a) a therapeutically effective amount of a composition comprising a compound as recited herein; and(b) another therapeutic agent.

[0011] These and other aspects of the invention will be apparent upon reference to the following detailed description.DETAILED DESCRIPTION

[0012] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0013] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as“including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0014] Reference throughout this specification to “one embodiment” or “an embodiment” or “some embodiments” or “a certain embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” or “in some embodiments” or “in a certain embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0015] Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise.

[0016] When ranges of values are disclosed, and the notation “from m ... to n2” or “between m . . . and 112" is used, where m and U2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 M (micromolar),” which is intended to include 1 pM, 3 pM, and everything in between to any number of significant figures (e.g., 1.255 pM, 2.1 pM, 2.9999 pM, etc.).

[0017] Asymmetric centers exist in the compounds and pharmaceutically acceptable salts thereof, disclosed herein. These centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1 -isomers, and mixtures thereof. Individual stereoisomers of compounds, and pharmaceutically acceptable salts thereof, can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds, and pharmaceutically acceptable salts thereof, of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds, and pharmaceutically acceptable salts thereof, disclosed hereinmay exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.

[0018] Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0019] As used herein, "administering to a patient" refers to the process of introducing a composition or dosage form into the patient via an art-recognized means of introduction.

[0020] The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

[0021] The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co- administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0022] The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a clinical endpoint. The precise therapeutically effective amount for a subject may depend upon, e.g., the subject’s size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics selected for administration, and other variables known to those of skill in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.

[0023] As used herein, the term “treat,” “treating”, or “treatment” means the administration of therapy to an individual who already manifests at least one symptom of a disease or condition or who has previously manifested at least one symptom of a disease or condition. For example, “treating” can include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causingregression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. For example, the term “treating” in reference to a disorder means a reduction in severity of one or more symptoms associated with that particular disorder. Therefore, treating a disorder does not necessarily mean a reduction in severity of all symptoms associated with a disorder and does not necessarily mean a complete reduction in the severity of one or more symptoms associated with a disorder.

[0024] The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0025] Those skilled in the art will appreciate that the invention(s) described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention(s) includes all such variations and modifications. The invention(s) also includes all the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of steps or features unless specifically stated otherwise.

[0026] The present invention(s) is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention(s), as described herein.

[0027] It is appreciated that certain features of the invention(s), which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention(s), which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0028] Provided is a compound of Formula I,or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the compound of Formula I has the structureor a pharmaceutically acceptable salt thereof.

[0030] The compounds disclosed herein can exist as pharmaceutically acceptable salts. The present disclosure includes compounds listed herein in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non- pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

[0031] The term “pharmaceutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds disclosed herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate , succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds disclosed herein can be quatemized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; andbenzyl and phenethyl bromides. Examples of acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

[0032] Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of pharmaceutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine , pyridine, / V, A-dunethylaniline, A-methylpiperidine, A-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, 7V,iV-dibenzylphenethylamine, 1 -ephenamine, and A'W-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0033] While it may be possible for the compounds, and pharmaceutically acceptable salts thereof, of the subject disclosure to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation.

[0034] Also provided is a pharmaceutical formulation comprising a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound, or pharmaceutically acceptable salts thereof, of the subject disclosure or a pharmaceutically acceptable salt thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0035] Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of the active ingredient.

[0036] Compounds, or pharmaceutically acceptable salts thereof, may be administered at a dose of from 0.1 to 500 mg / kg per day. The dose range for adult humans is generally from 5 mg to 2 g / day. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0037] The compounds, or pharmaceutically acceptable salts thereof, can be administered in various modes. In some embodiments, the pharmaceutical formulation is formulated for oral administration.

[0038] In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds herein, or pharmaceutically acceptable salt thereof, is hypertension, then it may be appropriate to administer an antihypertensive agent in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein, or pharmaceutically acceptable salts thereof, may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit of experienced by a patient may be increased by administering one of the compounds described herein, or pharmaceutically acceptable salts thereof, with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.

[0039] In any case, the multiple therapeutic agents (at least one of which is a compound disclosed herein, or a pharmaceutically acceptable salt thereof) may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.

[0040] Also provided is a method of inhibition of RIPK1 , comprising contacting RIPK1 with a composition comprising a compound as recited herein, or a pharmaceutically acceptable salt thereof, or a formulation as recited herein.

[0041] Also provided is a method of treatment of a RIPK1 -mediated disease, comprising the administration of a therapeutically effective amount of a composition comprising a compound as recited herein, or a pharmaceutically acceptable salt thereof, or a formulation as recited herein, to a patient in need thereof.

[0042] In some embodiments, the disease is chosen from a neurological disease, a neuropathy, an autoimmune disorder, an inflammatory disease, or cancer.

[0043] In some embodiments, the disease is a neurological disease.

[0044] In some embodiments, the neurological disease is accompanied by an inflammatory component of cellular stress.

[0045] In some embodiments, the neurological disease is chosen from Multiple Sclerosis, Neimann-Pick disease, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Lewy body dementia, frontotemporal dementia, glutamine expansion disease, Huntington’s disease, Kennedy’s disease, and spinocerebellar ataxia.

[0046] In some embodiments, the disease is a neuropathy.

[0047] In some embodiments, the neuropathy is chosen from diabetic neuropathy and chemotherapy-induced neuropathy.

[0048] In some embodiments, the disease is a retinal disease.

[0049] In some embodiments, the retinal disease is chosen from macular degeneration and retinitis.

[0050] In some embodiments, the disease is an autoimmune disorder.

[0051] In some embodiments, the autoimmune disorder is chosen from ulcerative colitis, rheumatoid arthritis, psoriasis, lupus, and inflammatory bowel disease.

[0052] In some embodiments, the disease is an inflammatory disease.

[0053] In some embodiments, the inflammatory disease is found in one or more organs chosen from the lung, heart, kidney, and liver.

[0054] In some embodiments, the disease is cancer.

[0055] In some embodiments, the cancer can be treated by promoting an appropriate immune response to the tumor.

[0056] In some embodiments, the appropriate immune response to the tumor comprises, or results in, one or more of the following:• an increase in the number or activity, or degree of tumor infiltration, of cytotoxic T- lymphocytes and / or natural killer cells;• an increase in the number or activity of M 1 macrophages in the tumor microenvironment and / or a decrease in the in the number or activity of M2 macrophages in the tumor microenvironment;• a decrease in the number or activity of regulatory T cells; and• a decrease in the number or activity of myeloid-derived suppressor cells.[057 J In some embodiments, the cancer is a myelodysplastic syndrome (MDS).

[0058] In some embodiments, the cancer is acute myeloid leukemia (AML).

[0059] Also provided is a method of treatment of injury to the CNS comprising the administration of a therapeutically effective amount of a composition comprising a compound as recited herein, or a pharmaceutically acceptable salt thereof, or a formulation as recited herein, to a patient in need thereof.

[0060] In some embodiments, said injury is chosen from traumatic brain injury and stroke.

[0061] Also provided is a method of treatment of a RIPK1 -mediated disease comprising the administration of:(c) a therapeutically effective amount of a composition comprising a compound as recited herein; and(d) another therapeutic agent.

[0062] In some embodiments, the other therapeutic agent is a checkpoint inhibitor.

[0063] In some embodiments, the checkpoint inhibitor is chosen from an anti-PDl inhibitor, an anti-PDLl inhibitor, an anti-CTLA4 inhibitor, an anti-OX50 inhibitor, an anti- TIM3 inhibitor, and an anti-LAG3 inhibitor.

[0064] Further embodiments include the embodiments disclosed in the following Schemes and Examples, which are not to be construed as limiting in any way.

[0065] In the Examples below and throughout the disclosure, the following abbreviations may be used: RT = Room Temperature; SM = Starting Material; DCM = dichloromethane; DMAP = 4-dimethylaminopyridine; DMF = dimethylformamide; DMP = Dess-Martin periodinane; El N or TEA = triethyl amine; H2O = water; MeOH = methanol; Pd(dppf)Ch = [l,r-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; PE = petroleum ether;TBSC1 - rert-butyldimethylsilyl chloride; TFA = trifluoroacetic acid; THF - tetrahydrofuran;1H-NMR = Proton Nuclear magnetic Resonance; LCMS = Liquid chromatography-mass spectrometry; TLC = thin layer chromatography; and HPLC = High Performance LiquidChromatography. Other abbreviations may be used and will be familiar in context to those of skill in the art.SCHEMESScheme IFormula I

[0066] Referring to Scheme I, Step 1 , to a solution of a compound of Formula 1 in methanol is added SOCh. The mixture is stirred, optionally at elevated temperature. In some embodiments, the mixture is stirred from 2-4 h. The product, a compound of Formula 2, is isolated and purified using methods known in the art.

[0067] Referring to Scheme I, Step 2, to a solution of the compound of Formula 2 in methanol is added a non-nucleophilic base, such as triethylamine, and a catalyst, such as Pd(dppf)C12. The mixture is purged and degassed, then stirred under a CO atmosphere, optionally at elevated temperature. In some embodiments, the mixture is stirred for 12-24 h. The product, a compound of Formula 3, is isolated and purified using methods known in the art.

[0068] Referring to Scheme I, Step 3, to a solution of a compound of Formula 3 in a polar aprotic solvent, such as THF, is added a reducing agent, such as LiBFU. The mixture is stirred, optionally at reduced temperature. In some embodiments, the mixture is stirred from 12-24 h. The product, a compound of Formula 4, is isolated and purified using methods known in the art.

[0069] Referring to Scheme I, Step 4, to a solution of a compound of Formula 4 in a polar aprotic solvent, such as DMF, is added TBSC1, a non-nucleophilic base, such as imidazole, and a catalyst, such as DMAP. The mixture is stirred, optionally at reduced temperature. In some embodiments, the mixture is stirred from 12-24 h. The product, a compound of Formula 5, is isolated and purified using methods known in the art.

[0070] Referring to Scheme I, Step 5, to a solution of a compound of Formula 5 in an organic solvent, such as DCM, is added an oxidizing agent, such as DMP. The mixture is stirred, optionally at ambient temperature. In some embodiments, the mixture is stirred from 12-24 h. The product, a compound of Formula 6, is isolated and purified using methods known in the art.

[0071] Referring to Scheme I, Step 6, to a solution of a compound of Formula 6 in a polar aprotic solvent, such as THF, is added a compound of Formula 6a. The mixture is stirred, optionally at elevated temperature. In some embodiments, the mixture is stirred from 12-24 h. The product, a compound of Formula 7, is isolated and purified using methods known in the art.

[0072] Referring to Scheme I, Step 7, to a solution of hydrazine in a polar aprotic solvent, such as THF, is added a compound of Formula 7. The mixture is stirred, optionally at reduced temperature. In some embodiments, the mixture is stirred from 12-24 h. The product, a compound of Formula 8, is isolated and purified using methods known in the art.

[0073] Referring to Scheme I, Step 8, to a solution of a compound of Formula 8 in an organic solvent, such as DCM, is added a non-nucleophilic base, such as triethylamine, and a compound of Formula 8a. The mixture is stirred, optionally at ambient temperature. In someembodiments, the mixture is stirred from 12-24 h. The product, a compound of Formula 9, is isolated and purified using methods known in the art.

[0074] Referring to Scheme I, Step 9, to a solution of a compound of Formula 9 in an organic solvent, such as DCM, is added a strong acid, such as trifluoroacetic acid. The mixture is stirred, optionally at ambient temperature. In some embodiments, the mixture is stirred from 4-6 h. The intermediate product is concentrated under vacuum and redissolved in a polar aprotic solvent, such as THF, and treated with a base, such as sodium bicarbonate. The mixture is stirred, optionally at ambient temperature. In some embodiments, the mixture is stirred from 1-2 h. The product, a compound of Formula I, is isolated and purified using methods known in the art. Individual enantiomers can be separated by using methods known in the art, such as chiral chromatography.S)-5-((3-(5-(2,5-difluoro-4-(hydroxymethyl)phenyl)-4,5-dihydro-lH-pyrazole-l- carbonyI)bicyclo[l.l.l]pentan-l-yl)methoxy)pyrazine-2-carbonitriIeStep 1 methyl 4-bromo-2, 5-difluoro-benzoate

[0075] To a solution of 4-bromo-2,5-difluoro-benzoic acid (15 g, 63.29 mmol, 1 eq) in MeOH (150 mL) was added SOCh (15.06 g, 126.58 mmol, 9.18 mL, 2 eq). The mixture was stirred at 70 °C for 3 hours. The mixture was concentrated under reduced pressure, then poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phase wascombined and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of0-20% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to afford methyl 4-bromo-2,5- difluoro-benzoate (15.5 g, 61.75 mmol, 97.56% yield) as a white solid.

[0076] ’H NMR (400 MHz, CHLOROFORM-d) 5 = 7.72 (ddd, J= 1.8, 6.2, 8.2 Hz, 1H),7.42 (ddd, 7 = 1.5, 5.4, 9.3 Hz, 1H), 3.96 (d, J = 1.3 Hz, 3H).Step 2 dimethyl 2,5-difluorobenzene- 1 ,4-dicarboxyIate

[0077] To a solution of methyl 4-bromo-2,5-difluoro-benzoate (15.5 g, 61.75 mmol, 1 eq) in MeOH (164 mb) were added Pd(dppf)Ch (2.26 g, 3.09 mmol, 0.05 eq) and TEA (12.50 g, 123.49 mmol, 17.19 mL, 2 eq) under nitrogen atmosphere. The mixture was purged and degassed by CO for 3 times, then the mixture was stirred at 80 °C for 16 hours under CO (50 psi). The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to afford dimethyl 2,5- difluorobenzene-l,4-dicarboxylate (10 g, 43.45 mmol, 70.36% yield) as a light yellow solid.

[0078] ’H NMR (400 MHz, CHLOROFORM-d) 5 = 7.71 (t, J = 7.8 Hz, 2H), 3.97 (s, 6H).Step 3[2,5-difluoro-4-(hydroxymethyl)phenyl]methanol3 4

[0079] To a solution of dimethyl 2,5-difluorobenzene-l,4-dicarboxylate (10 g, 43.45 mmol, 1 eq) in THF (100 mL) was added LiBH4 (4.370 g, 200.61 mmol, 4.62 eq) at 0 °C portion wise under nitrogen atmosphere. The mixture was stirred at 0 °C for 2 hours. And then stirred at 25 °C for 16 hours. The mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL x 3), washed with water (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure which was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient @ lOOmL / min) to afford [2,5-difluoro-4-(hydroxymethyl)phenyl]methanol (6.2 g, 35.60 mmol, 81.94% yield) as a white solid.

[0080] ’H NMR (400 MHz, CHLOROFORM-d) 5 = 7.09 (t, J = 7.9 Hz, 2H), 4.68 (s, 4H).Step 4[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,5-difluoro-phenyI]methanol

[0081] To a solution of [2,5-difhioro-4-(hydroxymethyl) phenyl]methanol (6.2 g, 35.60 mmol, 1 eq) and imidazole (1.94 g, 28.48 mmol, 0.8 eq) in DMF (62 mL) were added TBSC1 (3.22 g, 21.36 mmol, 2.62 mL, 0.6 eq) and DMAP (434.96 mg, 3.56 mmol, 0.1 eq) at 0 °C. After stirring at 25 °C for 16 hours, the mixture was poured into ethyl acetate (100 mL), washed with water (100 mL), brine (100 mL x 3), dried over NazSCL, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-25% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford [4- [[tert-butyl (dimethyl) silyl]oxymethyl]-2, 5-difluoro-phenyl]methanol (3.9 g, 13.52 mmol, 37.98% yield) as a white solid.

[0082] 1H NMR (400 MHz, CDCh) 5 = 7.20 (dd, J = 6.0, 10.0 Hz, 1H), 7.11 (dd, J = 6.0,9.7 Hz, 1H), 4.78 (s, 2H), 4.75 (s, 2H), 0.97 (s, 9 H), 0.14 (s, 6H).Step 54-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,5-difluoro-benzaldehyde

[0083] To a solution of [4-[[tert-butyl(dimethyl)silyl] oxymethyl] -2,5-difluoro-phenyl] methanol (5.2 g, 18.03 mmol, 1 eq) in DCM (50 mL) was added DMP (9.18 g, 21.64 mmol, 6.70 mL, 1.2 eq) . The mixture was stirred at 25 °C for 16 hours. The mixture was filtered, and filtrate was concentrated under reduced pressure which was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to afford 4-[[tert- butyl(dimethyl)silyl]oxymethyl]-2,5-difluoro-benzaldehyde (4.2 g, 14.67 mmol, 81.34% yield)as colorless oil.

[0084] 'H NMR (400 MHz, CHLOROFORM-d) 5 = 10.32 (d, J = 3.0 Hz, 1H), 7.49 (dd, 7 = 5.3, 9.2 Hz, 1H), 7.39 (dd, 7 = 5.4, 10.5 Hz, 1H), 4.84 (t, 7 = 1.0 Hz, 2H), 0.99 (s, 9H), 0.17 (s, 6H).Step 6 (E)-3-[4-[l-[tert-butyl(diinethyl)silyl]oxyethyl]-2,5-difluoro-phenyl]prop-2-enal

[0085] To a solution of 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,5-difluoro- benzaldehyde (4 g, 13.97 mmol, 1 eq) in THF (40 mL) was added 2-(triphenyl-L5- phosphanylidene) acetaldehyde, 6a (4.25 g, 13.97 mmol, 1 eq). The mixture was stirred at 80 °C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to afford (E)-3-[4- [[tert-butyl(dimethyl)silyl]oxymethyl]-2,5-difluoro-phenyl]prop-2-enal (2.5 g, 8.00 mmol, 57.28% yield) as a white solid.

[0086] ' l l NMR (400 MHz, CHLOROFORM-d) 5 = 9.58 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 16.1 Hz, 1H), 7.17 (dd, 7 = 5.9, 10.5 Hz, 1H), 7.06 (dd, 7= 5.8, 9.9 Hz, 1H), 6.58 (dd, 7 = 7.6, 16.1 Hz, 1H), 4.66 (s, 2H), 0.82 (s, 9H), 0.00 (s, 6H).Step 75-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-difluorophenyl)-4,5-dihydro-lH-pyrazole

[0087] To a solution of NH2NH2.H2O (1.92 g, 37.59 mmol, 1.86 mL, 98% purity, 5.59 eq) in THF (4 mL) was added a solution of (E)-3-|4-| | tertbutyl (dime thyl) silyl] oxymethyl] -2,5-difluoro-phenyl] prop-2-enal (2.1 g, 6.72 mmol,1 eq) in THF (10 mL) under 0 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue(combined with another batch) was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-25% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to afford 5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-difluorophenyl)-4,5-dihydro-lH- pyrazole (2.0 g, 6.13 mmol) as light yellow oil.

[0088] 1H NMR (400 MHz, CHLOROFORM-d) 5 = 6.99 - 7.07 (m, 2H), 6.71 (s, 1H),4.85 (t, 7 = 10.3 Hz, 1H), 4.63 (s, 2H), 2.95 - 3. 17 (m, 1H), 2.47 - 2.52 (m, 1H), 0.83 (s, 9H), 0.00 (s, 6H).Step 8 5-((3-(5-(4-(((tert-butyldimethylsilyl)oxy)methyI)-2,5-difluorophenyI)-4,5-dihydro-lH- pyrazole-l-carbonyl)bicyclo[l.l.l]pentan-l-yl)methoxy)pyrazine-2-carbonitrile

[0089] To a solution of 5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-difluorophenyl)- 4,5-dihydro-lH-pyrazole (2 g, 6.13 mmol, 1 eq) in DCM (20 mL) were added 3-[(5- cyanopyrazin-2-yl)oxymethyl]bicyclo[l.l. l]pentane-l -carbonyl chloride, 8a (previously described, WO2021062199A1) (1.94 g, 7.35 mmol, 1.2 eq) and TEA (1.86 g, 18.38 mmol, 2.56 mL, 3 eq) . The mixture was stirred at 25 °C for 16 hours. The mixture was poured into water (20 mL), extracted with CHCh (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure which was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-25% Ethyl acetate / Petroleum ether gradient @ 80 mL / min). 5-((3-(5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5- difluorophenyl)-4, 5 -dihydro- 1 H-pyrazole- 1 -carbonyl)bicyclo[ 1.1.1 ]pentan- 1 - yl)methoxy)pyrazine-2-carbonitrile (2.9 g, 5.24 mmol, 85.49% yield) was obtained as light yellow oil.

[0090] H NMR (400 MHz, CHLOROFORM-d) 5 = 8.32 (d, 7 = 1.4 Hz, 1H), 8.18 (d, 7 = 1.3 Hz, 1H), 7.07 (dd, J = 5.8, 10.4 Hz, 1H), 6.84 (t, J = 1.6 Hz, 1H), 6.55 (dd, 7= 5.9, 9.8 Hz, 1H), 5.39 (dd, 7 = 5.1, 12.0 Hz, 1H), 4.63 - 4.58 (m, 2H), 4.36 (s, 2H), 3.26 (ddd, 7 = 1.4, 12.0, 18.7 Hz, 1H), 2.69 - 2.57 (m, 1H), 2.09 (s, 6H), 0.83 (s, 9H), 0.00 (s, 6H).Step 94-(l-(3-(((5-cyanopyrazin-2-yI)oxy)methyl)bicyclo[l.l.l]pentane-l-carbonyl)-4,5- dihydro-lH-pyrazol-5-yl)-2,5-difluorobenzyl 2,2,2-trifluoroacetate

[0091] To a solution of 5-((3-(5-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5- difluorophenyl)-4, 5 -dihydro- 1 H-pyrazole- 1 -carbonyl)bicyclo[ 1.1.1 ]pentan- 1 - yl)methoxy)pyrazine-2-carbonitrile (2.6 g, 4.70 mmol, 1 eq) in DCM (30 mL) was added TFA (16.06 g, 140.88 mmol, 10.43 mL, 30 eq). The mixture was stirred 25 °C for 5 hours. The mixture was concentrated under reduced pressure to obtain a residue which was used directly without further purification4-(l-(3-(((5-cyanopyrazin-2- yl)oxy)methyl)bicyclo[ 1. 1. 1 ]pentane- 1 -carbonyl)-4,5-dihydro- 1 H-pyrazol-5-yl)-2,5- difluorobenzyl 2,2,2-trifluoroacetate (2.5 g, 4.67 mmol, 99.43% yield) was obtained as yellow oil.

[0092] MS (ES+) C24H18O4N5F5 requires: 535, found 536[M+H]+Step 10 5-((3-(5-(2,5-difluoro-4-(hydroxymethyl)phenyl)-4,5-dihydro-lH-pyrazole-l- carbonyl)bicyclo[l.l.l]pentan-l-yl)methoxy)pyrazine-2-carbonitrile

[0093] To a solution of 4-(l-(3-(((5-cyanopyrazin-2- yl)oxy)methyl)bicyclo[ 1.1.1 ]pentane- 1 -carbonyl)-4,5-dihydro- 1 H-pyrazol-5-yl)-2,5- difluorobenzyl 2,2,2-trifluoroacetate (2.5 g, 4.67 mmol, 1 eq) in THF (20 mL) and H2O (20 mL) was added NaHCCL (784.52 mg, 9.34 mmol, 363.20 pL, 2 eq). After stirring at 25 °C for 1 hour, the mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent Petroleum ether / Ethyl acetate = 20 / 1 to 5 / 1) to afford a residue (2.2 g) of title compound that was used as is for SFC purification.Step 11 (R)-5-((3-(5-(2,5-difluoro-4-(hydroxymethyl)phenyl)-4,5-dihydro-lH-pyrazole-l- carbonyl)bicyclo[l.l.l]pentan-l-yl)methoxy)pyrazine-2-carbonitrile (P2, Peak 2)

[0094] The product from step 10 was purified by SFC separation (column: REGIS (S, S) WHELK-Oi (250 mm*25mm, lOum) ;mobile phase: [0.1%NH3H2O MEOH];B%: 60%-60%, 3.6;60min. The eluent was concentrated and freeze dried to afford Pl, Peak 1: (R)-5-((3-(5- (2,5-difluoro-4-(hydroxymethyI)phenyI)-4,5-dihydro-lH-pyrazoIe-l- carbonyl)bicyclo[l.l.l]pentan-l-yl)methoxy)pyrazine-2-carbonitrile (835.3 mg, 1.86 mmol, 38.98% yield, 98% purity) as a white solid.

[0095] MS (ES+) C22H19O3N5F2 requires: 439, found 440[M+H]+;:H NMR (400 MHz, CDCL) 5 = 8.44 (d, J = 1.2 Hz, 1H), 8.30 (d, J = 1.2 Hz, 1H), 7.17 (dd, J = 5.9, 10.1 Hz, 1H),6.97 (t, J = 1.5 Hz, 1H), 6.72 (dd, J = 5.9, 9.7 Hz, 1H), 5.51 (dd, J = 5.3, 12.0 Hz, 1H), 4.75 - 4.64 (m, 2H), 4.48 (s, 2H), 3.39 (ddd, J = 1.3, 12.1, 18.7 Hz, 1H), 2.79 - 2.71 (m, 1H), 2.21 (s, 6H).

[0096] P2, Peak 2: (S)-5-((3-(5-(2,5-difluoro-4-(hydroxymethyl)phenyl)-4,5-dihydro- lH-pyrazole-l-carbonyl)bicyclo[l.l.l]pentan-l-yl)methoxy)pyrazine-2-carbonitrile (833.5 mg, 1.86 mmol, 38.90% yield, 98% purity) as a white solid. P2, Peak 2. The compound was assigned as the (S) enantiomer due to the observed potency, and consideration of the known binding mode of similar molecules for which the RIPK1 protein-inhibitor co- crystal structures have been obtained.

[0097] MS (ES+) C22H19O3N5F2 requires: 439, found 440[M+H]+; H NMR (400 MHz, CDCL) 5 = 8.45 (d, J = 1.3 Hz, 1H), 8.31 (d, J = 1.3 Hz, 1H), 7.18 (dd, J = 5.8, 10.1 Hz, 1H),6.98 (t, J = 1.5 Hz, 1H), 6.73 (dd, J = 5.9, 9.7 Hz, 1H), 5.52 (dd, J = 5.3, 12.0 Hz, 1H), 4.71 (d, J = 2.8 Hz, 2H), 4.49 (s, 2H), 3.40 (ddd, J = 1.3, 12.1, 18.7 Hz, 1H), 2.82 - 2.71 (m, 1H), 2.22 (s, 6H).

[0098] The activity of the compound in Example 1 as a RIPK1 inhibitor is illustrated in the following assays. The compounds described herein can be tested for efficacy in the treatment or prevention of symptoms or indications of RIPK1 -mediated diseases using techniques well known to those in the art.Biological Activity AssaysHuman U937 Cellular Necroptosis Assay

[0099] The human monocytic cell line U937 (CRL- 1593.2) was purchased from ATCC. The cells were routinely maintained in RPMI-1640 Medium (Gibco, Catalog #11875-093) supplemented with 10% heat inactivated fetal bovine serum (Gibco, Catalog #16140-071), 100 units / mL penicillin and 100 pg / mL streptomycin (Gibco, Catalog #15140-122), in a humidified incubator (37°C, 5% CO2). For the assay, cells were resuspended in RPMI-1640 phenol red free Media (Gibco, Catalog # 11835-030) supplemented with 10% fetal bovine serum (Sigma, Catalog #F2442), lOOunits / mL penicillin and 100 pg / mL streptomycin. Cells were stimulated with 25 ng / mL human TNFalpha (Cell Sciences, Catalog #CSI15659B) and 25pM z-VAD-FMK (R&D Systems, Catalog #FMK001) followed by seeding 5000 cells per well in a volume of 40 pL to a white, CulturPlate-384 (Perkin Elmer, Catalog #6007680). Stock solutions of the test compounds were prepared in 100% DMSO (Sigma, Catalog #D2650) and serially diluted 1:3 using 100% DMSO. Compounds were additionally diluted 1:40 in assay medium, and 10 pL / well was transferred to the plate. Following the compound addition, the plate was incubated at 37°C and 5% CO2 for 22 h. After 22 h, viability was assessed with the addition of 20 pL of Cell Titer-Gio 2.0 (Promega, Catalog #G9243). The tissue culture plate was shaken on an orbital shaker at 300RPM for 15 minutes at rt in the dark. Luminescence was measured using a PerkinElmer Envision™ plate reader. IC50 values were calculated using a four-parameter logistic curve fit using Genedata Screener software. Results are shown below.Hepatocyte Stability Assay

[0100] Hepatocytes may be purchased from Bioreclamation IVT, Xenotech, or RILD. Stock solutions were prepared at 10 mM in DMSO for the test compound. Aliquots of the stock solutions were diluted to 200 pM with DMSO and then further diluted to 2 pM with KHB buffer. Hepatocytes were counted and then the cell suspensions were diluted to theappropriate density (viable cell density = 2 x 106 cells / mL). 50 pL of pre-warmed 2 pM test compound was added to the wells designated for different time points. For 0 min, 100 pL of ACN containing internal standard (IS) was added to the wells followed by 50 pL of hepatocytes solution, before sealing the wells. 50 pL of pre-warmed hepatocytes solution was added to the wells designated for 15 min, 30 min, 60 min and 120 min, and timing was started. The assay plate was placed in an incubator at 37 °C. At 15 min, 30 min, 60 min and 120 min, 100 pL of ACN (IS) was added to the wells, respectively. The corresponding wells were then sealed. After quenching, the plate was sonicated for 5 min and then centrifuged at 5594 x g for 15 min (Thermo Multifuge x 3R). 50 pL of the supernatant was transferred from each well into a 96-well sample plate containing 120 pL of ultra-pure water for LC / MS analysis. The peak area response ratio (PARR) to IS of the compounds at 15 min, 30 min, 60 min, and 120 min was compared to the PARR at 0 min to determine the percent of the test compound remaining at each time point. Half-lives were calculated using Excel software, fitting to a single-phase exponential decay equation. See J. Med. Chem. 2020, 63, 17, 9888- 9911.Table 1. hU937 Cellular necroptosis and stability comparison assaya = Example 207, WO20211062119 b = Example 342, WO20211062119 c = Example 343, WO20211062119Clim = intrinsic clearance m / r / d / mk / h = mouse / rat I dog / monkey / human tin = half life101011 Example 1 further shows improved hepatocyte stability with regard to Example 4, the closest related compound in potency. The observed improvements to potency combined with the slight improvements in hepatocyte stability should result in better predicted pharmacokinetics with a lower efficacious dose for Example 1.

[0102] All references, patents or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein in their entireties. Where any inconsistencies arise, material literally disclosed herein controls.

[0103] From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this disclosure, and without departing from the spirit and scope thereof, can make various changes and modifications of the disclosure to adapt it to various usages and conditions.

Claims

CLAIMSWhat is claimed is:or a pharmaceutically acceptable salt thereof.The compound of claim 1, having the structurepharmaceutically acceptable salt thereof.

3. A pharmaceutical formulation comprising a compound as recited in claim 1 or 2, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

4. The pharmaceutical formulation as recited in claim 3, formulated for oral administration.

5. The pharmaceutical formulation as recited in claim 3 or 4, additionally comprising another therapeutic agent.

6. A method of inhibition of RIPK1, comprising contacting RIPK1 with a composition comprising a compound as recited in claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a formulation as recited in any one of claims 3-5.

7. A method of treatment of a RIPK1 -mediated disease, comprising the administration of a therapeutically effective amount of a composition comprising a compound as recited in claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a formulation as recited in any one of claims 3-5, to a patient in need thereof.

8. The method as recited in claim 7, wherein the disease is chosen from a neurological disease, a neuropathy, an autoimmune disorder, an inflammatory disease, or cancer.

9. The method as recited in claim 8, wherein the disease is a neurological disease.

10. The method as recited in claim 9, wherein the neurological disease is accompanied by an inflammatory component of cellular stress.1 1. The method as recited in claim 9, wherein the neurological disease is chosen from Multiple Sclerosis, Neimann-Pick disease, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Lewy body dementia, frontotemporal dementia, glutamine expansion disease, Huntington’s disease, Kennedy’s disease, and spinocerebellar ataxia.

12. The method as recited in claim 8, wherein the disease is a neuropathy.

13. The method as recited in claim 12, wherein the neuropathy is chosen from diabetic neuropathy and chemotherapy- induced neuropathy.

14. The method as recited in claim 8, wherein the disease is a retinal disease.

15. The method as recited in claim 14, wherein the retinal disease is chosen from macular degeneration and retinitis.

16. The method as recited in claim 87, wherein the disease is an autoimmune disorder.

17. The method as recited in claim 16, wherein the autoimmune disorder is chosen from ulcerative colitis, rheumatoid arthritis, psoriasis, lupus, and inflammatory bowel disease.

18. The method as recited in claim 8, wherein the disease is an inflammatory disease.

19. The method as recited in claim 18, wherein the inflammatory disease is found in one or more organs chosen from the lung, heart, kidney, and liver.

20. The method as recited in claim 8, wherein the disease is cancer.

21. The method as recited in claim 20, wherein the cancer can be treated by promoting an appropriate immune response to the tumor.

22. The method as recited in claim 21 , wherein the appropriate immune response to the tumor comprises, or results in, one or more of the following:• an increase in the number or activity, or degree of tumor infiltration, of cytotoxic T- lymphocytes and / or natural killer cells;• an increase in the number or activity of M 1 macrophages in the tumor microenvironment and / or a decrease in the in the number or activity of M2 macrophages in the tumor microenvironment;• a decrease in the number or activity of regulatory T cells; and• a decrease in the number or activity of myeloid-derived suppressor cells.

23. The method as recited in claim 20, wherein the cancer is a myelodysplastic syndrome (MDS).

24. The method as recited in claim 20, wherein the cancer is acute myeloid leukemia (AML).

25. A method of treatment of injury to the CNS comprising the administration of a therapeutically effective amount of a composition comprising a compound as recited in claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a formulation as recited in any one of claims 3-5 to a patient in need thereof.

26. The method as recited in claim 25, wherein said injury is chosen from traumatic brain injury and stroke.

27. A method of treatment of a RIPK1 -mediated disease comprising the administration of:(a) a therapeutically effective amount of a composition comprising a compound as recited in claim 1 or 2; and(b) another therapeutic agent.

28. The method as recited in claim 27, wherein the disease is cancer.

29. The method as recited in claim 27, wherein the other therapeutic agent is a checkpoint inhibitor.

30. The method as recited in claim 29, wherein the checkpoint inhibitor is chosen from an anti-PDl inhibitor, an anti-PDLl inhibitor, an anti-CTLA4 inhibitor, an anti-OX50 inhibitor, an anti-TIM3 inhibitor, and an anti-LAG3 inhibitor.