WO2025165773A1

WO2025165773A1 - Inhibitors of receptor interacting protein kinase i for the treatment of disease

Info

Publication number: WO2025165773A1
Application number: PCT/US2025/013428
Authority: WO
Inventors: Naphtali REYNA; Fernando Alvarez; Philip Jones; William J. Ray; Matthew Hamilton; Richard T. Lewis
Original assignee: University of Texas System; University of Texas at Austin
Current assignee: University of Texas System; University of Texas at Austin
Priority date: 2024-02-01
Filing date: 2025-01-28
Publication date: 2025-08-07
Anticipated expiration: 2026-08-01

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 THE

TREATMENT OF DISEASE

[001] This application claims the benefit of priority of United States provisional application no. 63/548,783, filed February 01, 2024, the contents of which are incorporated by reference as if written herein in their entirety.

[002] 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.

[003] 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.

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

SUMMARY

[005] Provided is a compound of Formula I, or a pharmaceutically acceptable salt thereof. [006] Also provided is a pharmaceutical formulation comprising a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

[007] 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.

[008] 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.

[009] 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.

[010] 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.

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

DETAILED DESCRIPTION

[012] 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.

[013] 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.

[014] 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.

[015] 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.

[016] 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.).

[017] 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 herein may 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.

[018] 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.

[019] 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.

[020] 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.

[021] 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.

[022] 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.

[023] 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, causing regression 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.

[024] 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.

[025] 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.

[026] 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.

[027] 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.

[028] Provided is a compound of Formula I, or a pharmaceutically acceptable salt thereof. [029] In some embodiments, the compound of Formula I has the structure or a pharmaceutically acceptable salt thereof.

[030] 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).

[031] 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 quaternized 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; and benzyl 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.

[032] 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 imethylaniline, A-methylpiperidine, A-melhy 1 morpholine, dicyclohexylamine, procaine, dibenzylamine, A,iV-dibenzylphenethylamine, 1 -ephenamine, and A, A'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

|033 ] 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.

[034] 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.

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

[036] 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.

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

[038] 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.

[039] 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.

[040] 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.

[041] 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.

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

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

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

[045] 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.

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

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

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

|049] In some embodiments, the retinal disease is chosen from macular degeneration and retinitis.

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

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

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

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

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

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

[056] 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] In some embodiments, the cancer is a myelodysplastic syndrome (MDS).

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

[059] 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.

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

[061] Also provided is a method of treatment of a RIPK1 -mediated disease comprising the administration of:

(b) another therapeutic agent.

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

[063] 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.

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

[065] In the Examples below and throughout the disclosure, the following abbreviations may be used: RT = Room Temperature; SM = Starting Material; A1BN = azobisisobutyronitrile; DCE = dichloroethane; DCM = dichloromethane; DIEA or DIPEA = N,N-Diisopropylethylamine; DMF = dimethylformamide; EhN or TEA = triethylamine;

EtOAc = ethyl acetate; H2O = water; Mel = methyl iodide; MeOH = methanol; n-BuLi = n- butyllithium; NBS = n-bromosuccinimide; Pd(dppf)Ch = [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) dichloride; PE = petroleum ether; T4P = butylphosphonic anhydride; 'H-NMR = Proton Nuclear magnetic Resonance; LCMS = Liquid chromatography-mass spectrometry; TLC = thin layer chromatography; and HPLC = High Performance Liquid Chromatography. Other abbreviations may be used and will be familiar in context to those of skill in the art. SCHEMES

Scheme I

[066] Referring to Scheme I, Step 1 , to a solution of a compound of Formula 1 in a polar aprotic solvent, such as pyridine, is added a compound of Formula la and a coupling reagent, such as POCh. The mixture is stirred, optionally at reduced temperature. In some embodiments, the mixture is stirred from 1-2 h. The product, a compound of Formula 2, is isolated and purified using methods known in the art.

[067] Referring to Scheme I, Step 2, to a solution of the compound of Formula 2 in a polar aprotic solvent, such as DMF, is added a base, such as potassium carbonate, and a methylating agent, such as methyl iodide. The mixture is stirred, optionally at ambient temperature. In some embodiments, the mixture is stirred for 2-4 h. The product, a compound of Formula 3, is isolated and purified using methods known in the art.

[068] Referring to Scheme I, Step 3, to a solution of the compound of Formula 3 in an organic solvent, such as ethyl acetate, is added a deprotecting reagent, such as hydrochloric acid. The mixture is stirred, optionally at ambient temperature. In some embodiments, the mixture is stirred for 12-24 h. The product, a compound of Formula 4, is isolated and purified using methods known in the art.

[069] Referring to Scheme I, Step 4, to a solution of the compound of Formula 4 in an organic solvent, such as chloroform, is added a base, such as triethylamine, and trityl chloride. The mixture is stirred, optionally at ambient temperature. In some embodiments, the mixture is stirred for 2-4 h. The product, a compound of Formula 5, is isolated and purified using methods known in the art.

[070] Referring to Scheme I, Step 5, to a solution of the compound of Formula 5 in a polar aprotic solvent, such as DMF, is added a base, such as cesium carbonate. The mixture is stirred, optionally at elevated temperature. In some embodiments, the mixture is stirred for 12-24 h. The product, a compound of Formula 6, is isolated and purified using methods known in the art.

[071] Referring to Scheme I, Step 6, to a solution of the compound of Formula 6 in an organic solvent, such as ethyl acetate, is added a deprotecting reagent, such as hydrochloric acid. The mixture is stirred, optionally at ambient temperature. In some embodiments, the mixture is stirred for 2-4 h. The product, a compound of Formula Int-1, is isolated and purified using methods known in the art.

[072] Referring to Scheme I, Step 7, to a solution of the compound of Formula Int-1 and Formula 12 in an organic solvent, such as DCM, is added a base, such as DIEA, and a coupling reagent, such as T4P. The mixture is stirred, optionally at reduced temperature. In some embodiments, the mixture is stirred for 1-2 h. The product, a compound of Example 1, is isolated and purified using methods known in the art. EXAMPLE 1

(S)-N-(8-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-4-(2- fluorophenyl)-5-(hydroxymethyl)pyrimidine-2-carboxamide

Step 1

Tert-butyl (S)-(3-(tert-butoxy)-l-((5-chloro-3-fluoropyridin-2-yl)amino)-l-oxopropan-2- yl)carbamate (2)

[073] To a solution of compound 1 (200 g, 1.36 mol, 1.00 eq) and compound la (392 g, 1.50 mol, 1.10 eq) in pyridine (1.20 L) was added POCI3 (230 g, 1.50 mol, 140 mL, 1.10 eq) slowly at 0 °C. The mixture was stirred at 0 °C for 2 hrs. The reaction mixture was added to H2O (1.00 L) at 20 °C, and then extracted with Ethyl acetate (400 mL x 3). The combined organic layers were washed with NaHCCh (500 mL) and brine (500 mL x 2), dried over Na^SCh, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with Petroleum ether/Ethyl acetate = 10/1 for 16 hrs, to give the title compound, 2 (306 g, 2.31 mol, 56.3% yield, 97.7% purity) as a light yellow solid. MS (ES+) C17H25CIFN3O4, requires: 389, found 390 [M+H]⁺.

Step 2

Tert-butyl (S)-(3-(tert-butoxy)-l-((5-chloro-3-fluoropyridin-2-yl)(methyl)amino)-l- oxopropan-2-yl)carbamate (3)

2 3

[074] To a solution of compound 2 (383 g, 982 mmol, 1.00 eq) and K2CO3 (543 g, 3.93 mol, 4.00 eq) in DMF (2.70 L) was added Mel (558 g, 3.93 mol, 245 mL, 4.00 eq). The mixture was stirred at 20 °C for 4 hrs. The reaction mixture quenched with H2O (1.50 L) and extracted with ethyl acetate (600 mL x 3). The combined organic layers were washed with brine (1.00 L x 3), dried over Na^SOr, filtered and concentrated under reduced pressure to give the title compound, 3 (480 g, 1.10 mol, 37.3% yield, 92.7% purity) as a brown gum. MS (ES+) C18H27CIFN3O4, requires 403, found 426 [M+Na]⁺.

Step 3 (S)-2-Amino-N-(5-chloro-3-tluoropyridin-2-yl)-3-hydroxy-N-methyIpropanamide (4)

3 4

[075] To a solution of compound 3 (100 g, 229 mmol, 1.00 eq) in Ethyl acetate (500 mL) was added HCI/ Ethyl acetate (4.00 M, 927 mL). The mixture was stirred at 20 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to give the title compound, 4 (77.0 g, crude, HCI) as a yellow solid. MS (ES+) C9H11CIFN3O2, requires 247, found 248 [M+H]⁺.

Step 4

(S)-N-(5-Chloro-3-fluoropyridin-2-yI)-3-hydroxy-N-methyl-2-(tritylamino)propanamide

(5) [076] To a solution of compound 4 (77.0 g, 271 mmol, 1.00 eq, HC1) and EtsN (137 g, 1.36 mol, 189 mL, 5.00 eq) in CHCh (770 mL) was added trityl chloride (90.7 g, 325 mmol, 1.20 eq) at 0 °C. The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was concentrated to remove CHCh, diluted with H2O (500 mL), and extracted with Ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na^SCh, filtered, concentrated under reduced pressure, and the crude was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate = 1/0 to 3/1, Rf = 0.33) to give the title compound, 5 (72.0 g, 146 mmol, 99.4% purity) as a light yellow gum. MS (ES+) C28H25CIFN3O2, requires 489, found 490 [M+H]⁺.

Step 5

(5)-8-Chloro-5-methyI-3-(tritylamino)-2,3-dihydropyrido[3,2-b][l,4]oxazepin-4(5H)-one

(6)

[077] To a solution of compound 5 (52.0 g, 105 mmol, 1.00 eq) in DMF (520 mL) was added CS2CO3 (120 g, 369 mmol, 3.50 eq). The mixture was stirred at 80 °C for 16 hrs. The reaction mixture was diluted with H2O (200 mL) and extracted with Ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and the crude was purified by column chromatography (SiCh, Petroleum ether/Ethyl acetate = 20/1 to 10/1, Rf = 0.42) to give the title compound 6 (41.0 g, 82.9 mmol, 78.5% yield, 95.0% purity) as a white solid. MS (ES+) C28H24CIN3O2, requires 469, found 470 [M+H]⁺.

Step 6 (S)-3-Amino-8-chloro-5-methyl-2,3-dihydropyrido[3,2-b][l,4]oxazepin-4(5H)-one (Int-1)

[078] To a solution of compound 6 (41.0 g, 82.9 mmol, 1.00 eq) in Ethyl acetate (400 mL) was added HCl/Ethyl acetate (4.00 M, 162 mL). The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure, and the crude was triturated with Ethyl acetate (200 mL) at 20 °C for 1 hr to give the title compound, Int-1 (21.6 g, 81.2 mmol, 97.9% yield, 99.3% purity, HC1) as a white solid. MS (ES+) C9H10CIN3O2, requires 227, found 228 [M+H]⁺.

Step 7

2-Chloro-4-(2-fluorophenyl)-5-methylpyrimidine (8)

[079] To a solution of compound 7 (110 g, 674 mmol, 1.00 eq) in THF (1.00 L) and H2O (330 mL) were added compound 7_A (94.4 g, 674 mmol, 1.00 eq), NazCCh (143 g, 1.35 mol, 2.00 eq) and Pd(dppf)C12 (24.7 g, 33.7 mmol, 0.05 eq) under N2. After stirring at 70 °C for 2 hrs, the mixture was concentrated in vacuum. TLC (Petroleum ether/Ethyl acetate = 5/1). The residue was purified by column chromatography (SiCL, Petroleum ether/Ethyl acetate = 50/1 to 20/1) to give the title compound 8 (365 g, 1.26 mol, 93.6% yield, 77.1% purity) as a white solid. MS (ES+) C11H8CIFN2, requires 222, found 223 [M+H]⁺.

Step 8

Methyl 4-(2-fluorophenyl)-5-methylpyrimidine-2-carboxylate (9)

8 9

[080] To a solution of compound 8 (90.0 g, 31 1 mmol, 1.00 eq) in MeOH (200 mL) was added Pd(dppf)Ch (11.4 g, 15.6 mmol, 0.05 eq) and EtsN (94.6 g, 934 mmol, 130 mL, 3.00 eq) under N2 atmosphere. The suspension was degassed and purged with CO for 3 times.

The mixture was stirred under CO (45 Psi.) at 70 °C for 16 hrs. The mixture of four batches were combined, concentrated under reduced pressure, diluted with H2O (1.00 L), and extracted with Ethyl acetate (1.00 L x 2). The combined organic layer was washed with brine, dried over Na2SO4 filtered, and concentrated. TLC (Petroleum ether/Ethyl acetate = 2/1). The crude was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate - 20/1 to 2/1) to give the title compound 9 (163 g, 650 mmol, 52.1% yield, 98.2% purity) as a yellow solid. MS (ES+) C13H11FN2O2, requires 246, found 247 [M+H]⁺. ' H NMR: (400 MHz, CDCI3), d 8.87 (s, 1H), 7.58-7.52 (m, 2H), 7.39-7.34 (m, 1H), 7.27-7.22 (m, 1H), 4.12 (s, 3H), 2.40 (s, 3H). ¹⁹F NMR: (400 MHz, CDCI3), 8 -114.15.

Step 9

Methyl 5-(bromomethyI)-4-(2-fluorophenyl)pyrimidine-2-carboxylate (10)

[081] To a solution of compound 9 (100 g, 398 mmol, 1.00 eq) in DCE (1.00 L) were added AIBN (32.7 g, 199 mmol, 0.50 eq) and NBS (142 g, 798 mmol, 2.00 eq). After stirring at 80 °C for 16 hrs. The mixture was concentrated, diluted with H2O (800 mL) and extracted with Ethyl acetate (800 mL x 2). The combined organic layer was washed with brine, dried over NazSC filtered, and concentrated under reduced pressure to give the title compound 10 (45.0 g, 121 mmol, 30.5% yield, 87.9% purity) as a brown solid. TLC (Petroleum ether/Ethyl acetate = 1/1). MS (ES+) C13H10BrFN2O2, requires 324/6, found 325/7 [M+H]⁺.

Step 10

4-(2-Fluorophenyl)-5-(hydroxymethyl)pyrimidine-2-carboxylic acid (11)

[082] To a solution of compound 10 (40.0 g, 108 mmol, 1 .00 eq) in H2O (200 mL) and dioxane (200 mL) was added K2CO3 (74.7 g, 540 mmol, 5.00 eq). The mixture was stirred at 80 °C for 1 hr. The mixture was concentrated under reduced pressure, dissolved in H2O (200 mL), and then acidified (addition of HC1 (2.00 M) to adjust the pH to 2). The resulting mixture was extracted with Ethyl acetate (200 ml x 3), the organic layers combined, dried with Na2SC>4, filtered, and concentrated under reduce pressure to give the title compound, 11 (20.0 g, 63.1 mmol, 58.3% yield, 78.3% purity) as a brown solid. The residue was used without further purification. MS (ES+) C12H9FN2O3, requires 248, found 249 [M+H]⁺.

Step 11 (S)-N-(8-Chloro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yl)-4-(2- fluorophenyl)-5-(hydroxymethyl)pyrimidine-2-carboxamide (Example 1) xamp e

|083 ] To a solution of compound 11 (20.0 g, 63.1 mmol, 1.00 eq) and compound Int-1 (14.4 g, 63.1 mmol, 1.00 eq) in dichloromethane (200 mL) was added T4P (54.5 g, 75.7 mmol, 50.0% purity, 1.20 eq) and DIEA (32.6 g, 252 mmol, 43.9 mL, 4.00 eq) at -10 °C. The mixture was stirred at -10 °C for 1 hr. The reaction mixture was quenched by ice water 100 mL at 0 °C, extracted with dichloromethane (100 mL x 3), the organic layers combined, washed with aq. NaHCCL (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (10.1 g, 20.9 mmol, 33.3% yield, 95.1% purity) as an off-white solid. TLC (Petroleum ether/Ethyl acetate = 1/2) MS (ES+) C21H17CIFN5O4, requires 457, found 458 [M+H]⁺. *H NMR: (400 MHz, DMSO-7₆), <5 9.12-9.10 (m, 2H), 8.43 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.65-7.55 (m, 2H), 7.43-7.38 (m, 2H), 5.60 (t, J = 5.6 Hz, 1H), 5.02-4.96 (m, 1H), 4.77-4.72 (m, 1H), 4.65-4.60 (m, 1H), 4.48 (d, 7 = 5.6 Hz, 2H), 3.35 (s, 3H). ¹⁹F NMR: (400 MHz, DMSO-d₆). <5 -115.87.

EXAMPLE 2

(S)-N-(8-chIoro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][l,4]oxazepin-3-yI)-5- (hydroxymethyl)-4-phenylpyrimidine-2-carboxamide

[084] The synthesis of Example 2 is described in WO2021173917, the contents of which are hereby incorporated by reference.

[085] 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.

[086]

Pharmacokinetics

[087] Male rats (SD strain, purchased from Shanghai JH Laboratory Animal Co. LTD) weighing 200-300 g were used for this study. Animals were fasted overnight and fed 4 h postdose. Water was made available ad libitum for all animals. The test article was dosed via dorsal foot vein and via oral gavage, respectively. Blood samples were collected via tail vein from all animals at predose and at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h postdose into tubes containing the anticoagulant K2 EDTA. Plasma was separated from the blood by centrifugation at 4 °C and stored at -70 °C until analysis. The test article concentrations in plasma were quantified using the LC-MS/MS method.

Sample Collection for PK/PD Analysis

|088 ] Tumor and plasma were harvested at the desired time point after the last dose. Blood was obtained via the retro-orbital sinus into a Vacutainer K2 EDTA tube to a volume of 250 pL. The Vacutainer vials were centrifuged for 10 min as 2000g without braking. The supernatant (plasma) was carefully aspirated into a microcentrifuge tube and placed onto dry ice prior to storage at -80 °C. Tumor samples from the right flank were obtained and cut into several (at least 5 or 6) approximately 100 mg pieces of comparable size with a scalpel. These pieces are immediately placed into a labeled cryovial and snap frozen in liquid nitrogen prior to storage at -80 °C. KYN and Trp were purchased from Sigma- Aldrich. L- Kynurenine-d6 (KYN-d6) and L -tryptophan-d5 (Trp-d5) were purchased from Cambridge Isotope Laboratories. DMSO was purchased from Sigma-Aldrich. Acetonitrile, methanol, isopropanol, water, and formic acid (all LC-MS grade) were obtained from Fisher Chemicals (Fair Lawn, NJ, USA). Blank human plasma samples from healthy donors were purchased from Bioreclamation IVT (Baltimore, MD, USA).

Stock Solutions, Standards, and Quality Controls

[089] The analyte reference standard (KYN and Trp) stock solutions were prepared at 1.00 mg/mL in water. Working solutions were obtained by diluting stock solutions to 100 pL/mL. KYN-d6 and Trp-d5 internal standard solutions were also prepared in water. Calibration standards and QC samples of KYN and TRP were prepared in acetonitrile in the range from 1 to 200 ng/mL. Calibration standards and QC samples of IACS compounds were prepared in the range from 1 to 1000 ng/mL by spiking work solutions to blank rat plasma.

Liquid Chromatography

[090] Quantitative analysis was performed using a Shimadzu Nexera X2 LC system consisting of a binary pump, a column oven, a DAD detector, and an autosampler with a 10 pL injection loop autosampler. The autosampler temperature was set at 4 °C.

Chromatographic separation was carried out on a Supelco Ascentis Express RP-Amide column (30 x 2.1 mm, 2.7 pm) for KYN and TRP and on a Supelco Ascentis Express Cl 8 column (20 x 2.1 mm, 2.7 pm) for IACS compounds. The column temperature was maintained at 40 °C. For the analysis of KYN and TRP, mobile phase A was 0.1 acetic acid in water and mobile phase B was 0.1% acetic acid in acetonitrile. The mobile phase was delivered in a gradient mode: 80% B (0-1 min), 80-10% B (1-3 min), 10% B (3-5 min), 10- 80% B (5-5.3 min), and 80% B (5.3-10 min). The column temperature was 40 °C, and the flow rate was 0.5 mL/min. For the analysis of IACS compounds, mobile phase A was 0.1 acetic acid in water and mobile phase B was 0.1% acetic acid in acetonitrile. The mobile phase was delivered in a gradient: 5% B (0-0.3 min), 5-95% (0.3-1.3 min), 95% (1.31-1.60 min), and 5% (1.61-2.00 min). Wash solvent 1 was 50% methanol in water and wash solvent 2 was 0.2% formic acid in a mixture of acetonitrile, methanol, isopropanol, and water (50:50:50:50, v/v/v/v).

Mass Spectrometry

[091] Eluents from column were monitored using an AB Sciex 5500 triple quadrupole mass spectrometer with an ESI source. A mass spectrometer was operated in the positive ion mode and its operation parameters were optimized to maximize its sensitivity by a direct infusion of analytes at 10 ng/mL in an acetonitrile/water (1:2, v/v): ion spray voltage of 5500 V, CAD 8, curtain gas 35, Gasl 35, Gas2 50, and source temperature 400 °C. The MS data were first acquired by a Sciex software Analyst version 1.6.2 and then processed using Sciex software Multi Quant version 3.0.2. KYN, TRP, and IACS compounds were detected in MRM mode and their corresponding mass spectrometry parameters reported. PK parameters were estimated using Phoenix WinNonlin 8.3 software.

Sample Preparation

[092] For the analysis of KYN and TRP in plasma samples, an aliquot of 25 pL of standards, QC samples, and clinical human plasma samples was manually transferred to a well of a 1 mL 96-DW plate. Two hundred microliters of acetonitrile that was chilled at 4°C were added to wells using a liquid-liquid handling robot, Biomek FXP Automation Workstation. After vortexing for 10 min, samples were centrifuged at 4000 rpm and 4 °C for 10 min. One hundred microliters of supernatant were diluted with 200 pL of acetonitrile/water (1: 1) containing 250 ng/mL KYN-d6 and 250 ng/mL TRP-5. After vortexing for 5 min, samples were centrifuged at 4000 rpm and 4 °C for 5 min. An aliquot of 2 pL was injected into the LC system for separation and analysis. For the analysis of IACS compounds in plasma samples: an aliquot of 25 pL of standards, QC samples, and clinical human plasma samples were manually transferred to a well of a 1 mL 96-DW plate. Two hundred microliters of acetonitrile containing IACS-5318 at 5 ng/mL as the internal standard that was chilled at 4 °C were added to wells using a liquid-liquid handling robot, Biomek FX^P Automation Workstation. After vortexing for 10 min, samples were centrifuged at 4000 rpm and 4 °C for 10 min. One hundred microliters of supernatant were diluted with 200 pL of water. After vortexing for 5 min, samples were centrifuged at 4000 rpm and 4 °C for 5 min. An aliquot of 2 pL was injected into the LC system for separation and analysis. For analysis of tumor tissue samples, tumor tissue samples were homogenized using OminiBEAD Ruptor24 coupled with Omini BR CRYO to make homogenates at 100 mg(tissue)/mL in MeOH/H2 O (8:2). The volume (pL) of this solvent added to the vial containing tumor tissue was [(1000 x weight (mg)/100) - weight (mg)] assuming that the density of the tissue was 1.0. After homogenization, homogenates were centrifuged at 15,000 rpm and 4 °C for 15 min. An aliquot of 100 pL of the supernatant was diluted with 100 pL of ACN/H2O (1 :1) containing 250 ng/mL Trp-d5 and 250 ng/mL KYN-d6 as IS, vortexed for 15 s, and centrifuged at 15,000 rpm and 4 °C for 5 min before injection for the analysis of KYN and TRP. For the analysis of IACS compounds, 50 pL of the supernatant was diluted with 150 pL of acetonitrile containing an internal standard at 5 ng/mL. The injection volume was 2 pL.

Human U937 Cellular Necroptosis Assay (hU937)

[093] 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 L 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 300 RPM for 15 minutes at rt in the dark. Luminescence was measured using a PerkinElmer Envision™ plate reader. TC50 values were calculated using a four-parameter logistic curve fit using Genedata Screener software. Results are shown below.

Table l.Necroptosis and IV PK Parameters in Rats

Cl = clearance;

V_ss = steady-state volume of distribution;

T 1/2 = half life;

AUCinf = area under the curve (from zero to infinity);

F = bioavailability

Table 2. Human PK Prediction (rat only)

Rat wt = 0.023 kg

Human Predicted Cl (ml/min/kg) = 0.152 x Rat Cl (ml/min/kg)

Human Predicted Vd_SS = ran Vd_ss

[094] Example 1 is closely matched to Example 2 via structure but displays improved steady-state volume of distribution, which in turn leads to a nearly 2-fold increase in the predicted half-life in humans. Improvements are also seen in clearance, which is predicted to also improve in humans (Tables 1 and 2). [095] 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.

[096] 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

CLAIMS What is claimed is:

1 . A compound of Formula I or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, having the structure a pharmaceutically 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.

11. 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 8, 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 of Ml 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.