CN110872285A - Heterocyclic compounds as receptor interacting protein 1(RIP1) kinase inhibitors - Google Patents

Heterocyclic compounds as receptor interacting protein 1(RIP1) kinase inhibitors Download PDF

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CN110872285A
CN110872285A CN201811014080.0A CN201811014080A CN110872285A CN 110872285 A CN110872285 A CN 110872285A CN 201811014080 A CN201811014080 A CN 201811014080A CN 110872285 A CN110872285 A CN 110872285A
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王能辉
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Ningbo Wenda Pharma Technology Ltd
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Abstract

The present invention provides heterocyclic compounds that are inhibitors of receptor interacting protein 1(RIP1) kinase. Specifically, the invention provides a compound shown as a formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. The compound of formula I has high-efficiency and high-selectivity inhibition effect on protein kinase (such as RIP 1).

Description

Heterocyclic compounds as receptor interacting protein 1(RIP1) kinase inhibitors
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a compound serving as a receptor interaction protein 1(RIP1) kinase inhibitor and a pharmaceutically acceptable salt thereof.
Background
Receptor interacting protein 1(RIP1) kinases are a class of serine/threonine protein kinases that can regulate the activity of the nuclear factor kB, are the cross-over point determining cell survival and death, and are key regulatory factors in the programmed necrosis (necroptosis) signaling pathway. Programmed cell death plays an important role in the aspects of ontogeny, steady-state maintenance of organisms, pathological processes and the like. Cell death mainly includes modes of apoptosis, necrosis, autophagy and the like. Among them, cell necrosis (necrosis) has long been known as a passive and unregulated process. However, recent studies have shown that cell necrosis is also closely regulated. Unlike apoptosis (apoptosis), cellular necrosis activates the immune response of the body, and local cellular necrosis of the body causes a global pathophysiological response. It is therefore involved in a number of pathological processes such as immune activation of viral infections (viralnfection), ischemic necrotic lesions (ischemic injures), and the development and progression of neurodegenerative diseases (neurogenetic diseases).
Programmed cell necrosis is a mode of cell death initiated by activation of kinases. Activation of death receptors (e.g., TNFR1) can ultimately induce programmed cell necrosis, and signaling to initiate cell necrosis is largely dependent on regulation by the kinases RIP1 and RIP 3. After necrosis occurs, RIP1 binds to RIP3 and activates the kinase activity of RIP3, and then RIP3 undergoes autophosphorylation, so that it can specifically bind to substrate MLKL, which in turn is phosphorylated by RIP 3. At this time, RIP1/RIP3/MLKL forms an active cell necrosis complex, and transmits a death signal to the downstream, so that programmed cell necrosis finally occurs. Apoptotic cells release their contents to the surroundings, which act as DAMPs (damage-associated molecular patterns) and stimulate inflammatory responses in the surrounding cells and activate the immune response of the body ((2008) nat. Rev. Immunol 8, 279-289).
Programmed cell necrosis plays important pathophysiological roles such as myocardial infarction, pancreatitis, ischemia reperfusion injury, sepsis, stroke, coronary heart disease, inflammatory bowel disease, retinitis, alcoholic fatty liver, non-alcoholic fatty liver, multiple sclerosis, dermatitis, psoriasis, chronic kidney disease, acute kidney disease, autoimmune hepatitis, hepatitis b, hepatitis c, acute insufficiency, neurodegenerative disease, gradually frozen human disease, parkinson, senile dementia, osteoporosis, arthritis, bacterial infection, cancer, atherosclerosis, heart failure, chronic obstructive pulmonary disease, diabetes, blood glucose regulation, protection during organ transplantation, aging resistance, obesity, and many other RIP1 kinase related diseases ((2014) NEJM 370, 455-465). In view of the importance of RIP1 kinase targeted therapy to avoid unwanted side effects on other cells of the body, there is an urgent need to find a potent, highly selective RIP1 kinase inhibitor for ameliorating diseases associated with programmed cell necrosis.
After the first RIP1 kinase inhibitor Necrostatin 1(Nec-1) was discovered ((2005) nat. chem. biol.1, 112-119), there are many RIP1 kinase inhibitors of different structures (WO2016/027253, WO2017/109724, WO2017/004500, WO2017/136727, WO2018/017435, WO 2018/073193).
However, the activity and safety of the currently available RIP1 kinase inhibitors are still unsatisfactory, and therefore, the development of a potent, safe and/or highly selective RIP1 kinase small molecule inhibitor is urgently needed in the art.
Disclosure of Invention
The invention aims to provide a potent, safe and/or highly selective small-molecule inhibitor of RIP1 kinase.
In a first aspect of the present invention, there is provided a heterocyclic compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein the compound is represented by formula I:
Figure BDA0001785734480000021
wherein R is1Represents 1 to 3 substituents selected from the group consisting of: H. halogen, -OH, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C10 heteroaryl, C1-C4 carboxy, -CN, NO2；
R2Is a substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C10 heteroaryl, or substituted or unsubstituted 5-8 membered heterocycle;
wherein said substitution means one or moreEach hydrogen atom is independently substituted with a substituent selected from the group consisting of: H. halogen, -CN, NO2OH, -NRaRb, C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl, benzyl, C6-C10 aryl, C3-C10 heteroaryl,
wherein Ra and Rb are each independently H, C1-C3 alkyl, C3-C6 cycloalkyl.
In another preferred embodiment, R1Selected from the group consisting of: H. halogen, C1-C6 alkyl.
In another preferred embodiment, R1Selected from the group consisting of: H. f, Cl methyl, ethyl, n-propyl, isopropyl.
In another preferred embodiment, R1Is H.
In another preferred embodiment, R2Is substituted or unsubstituted phenyl or 5-6 membered heteroaryl.
In another preferred embodiment, the 5-8 membered heterocyclic ring contains 1-3 heteroatoms selected from N, O, or S.
In another preferred embodiment, the 5-8 membered heterocyclic ring is saturated, unsaturated, or partially unsaturated.
In another preferred embodiment, the compound is represented by formula II
Figure BDA0001785734480000031
Wherein the content of the first and second substances,
m, Q, V, Y and Z are each independently selected from the group consisting of: C. n, S, or O;
R3、R4、R5、R6and R7Each independently selected from the group consisting of: H. halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C3-C10 aryl, C3-C10 heteroaryl, -CN, NO2；
Figure BDA0001785734480000032
Represents a single bond or a double bond.
In another preferred embodiment, any one or more (e.g., 1-3) of M, Q, V, Y and Z are each independently N, S or O, and the remainder are C.
In another preferred embodiment, M, Q, V, Y and Z are each independently C or N.
In another preferred embodiment, V and Z are N, and M, Q and Y are C.
In another preferred embodiment, R3、R4、R5、R6And R7Any one or more (e.g., 1 to 3) of which are each independently selected from the group consisting of: halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C3-C10 aryl, C3-C10 heteroaryl, -CN, NO2(ii) a And the balance of H.
In another preferred embodiment, R6Selected from the group consisting of: halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C3-C10 aryl, C3-C10 heteroaryl, -CN, NO2(ii) a And R3、R4、R5And R7Is H.
In another preferred embodiment, R6is-CN.
In another preferred embodiment, the compound is:
Figure BDA0001785734480000041
in a second aspect of the present invention, there is provided a pharmaceutical composition comprising:
(i) a safe and effective amount of a heterocyclic compound as described in the first aspect, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof; and
(ii) a pharmaceutically acceptable carrier.
In a third aspect of the invention there is provided the use of a heterocyclic compound as described in the first aspect, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament (i) for the manufacture of a protein kinase inhibitor, (ii) for the manufacture of a medicament for the treatment of a protein kinase related disease, (iii) for the manufacture of a medicament for the treatment of a TNF related disease, and/or (iv) for the manufacture of a medicament for the treatment of a programmed cell necrosis related disease.
In another preferred embodiment, the protein kinase is a serine/threonine protein kinase.
In another preferred embodiment, the protein kinase is receptor interacting protein 1(RIP1) kinase.
In another preferred embodiment, the protein kinase related diseases include: myocardial infarction, pancreatitis, ischemia reperfusion injury, sepsis, stroke, coronary heart disease, inflammatory bowel disease, retinitis, alcoholic fatty liver, non-alcoholic fatty liver, multiple sclerosis, dermatitis, psoriasis, chronic kidney disease, acute kidney disease, autoimmune hepatitis, hepatitis b, hepatitis c, acute liver insufficiency, neurodegenerative disease, progressive freezing human disease, parkinson, senile dementia, osteoporosis, arthritis, bacterial infection, cancer, atherosclerosis, heart failure, chronic obstructive pulmonary disease, diabetes, blood glucose regulation, protection during organ transplantation, anti-aging, and/or obesity.
In a fourth aspect of the present invention, there is provided a process for the preparation of a heterocyclic compound according to the first aspect, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, which comprises the steps of:
(1) reacting the compound of formula 6 with the compound of formula 5 to obtain a compound of formula 7;
Figure BDA0001785734480000051
(2) deprotecting the compound of formula 7 to provide a compound of formula 8; and
Figure BDA0001785734480000052
(3) reacting said compound of formula 8 with R2-X, thereby obtaining a compound of formula I;
Figure BDA0001785734480000053
wherein R is1、R2As defined above;
R10is a protecting group.
And X is Cl or Br.
In another preferred embodiment, R10is-BOC (tert-butyloxycarbonyl).
In another preferred embodiment, X is Cl.
In another preferred embodiment, the process for preparing the compound of formula 5 comprises the steps of:
(1.1) reacting the compound of formula 1 with the compound of formula 2 to obtain the compound of formula 3
Figure BDA0001785734480000061
(1.2) reacting the compound of formula 3 with methanesulfonyl chloride to obtain a compound of formula 4
Figure BDA0001785734480000062
(1.3) reacting the compound of formula 4 in an inert solvent in the presence of trifluoroacetic acid (TFA) to obtain the compound of formula 5
Figure BDA0001785734480000063
In a fifth aspect of the invention, there is provided an in vitro method of non-therapeutic inhibition of a protein kinase, wherein the method comprises the step of contacting the heterocyclic compound of the first aspect, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, with the protein kinase to thereby inhibit the activity of the protein kinase.
In another preferred embodiment, the protein kinase is receptor interacting protein 1 kinase.
In a sixth aspect of the invention, there is provided a method of inhibiting a therapeutic or non-therapeutic protein kinase in vivo, wherein the method comprises the steps of:
administering to a subject (subject) an effective amount of a heterocyclic compound according to the first aspect, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutical composition according to the second aspect, thereby inhibiting the activity of the protein kinase.
In another preferred embodiment, the subject is an animal; preferably a mammal; more preferably, it is a human.
In a seventh aspect of the present invention, there is provided a method of treating a protein kinase related disease, a TNF related disease, and/or a programmed cell necrosis related disease, the method comprising the steps of:
administering to a subject an effective amount of a heterocyclic compound as described in the first aspect, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutical composition as described in the second aspect.
In another preferred embodiment, the target is an animal; preferably a mammal; more preferably, it is a human.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 shows that the compound (NHWD-1062) according to one embodiment of the present invention is effective in treating TNF-induced systemic inflammatory response syndrome.
Detailed Description
The present inventors have made extensive and intensive studies and have developed for the first time a heterocyclic compound having a novel structure, a remarkable inhibitory activity and high safety. The compounds have excellent and high-selectivity inhibition effect on receptor interaction protein 1(RIP1) kinase, and can be used as RIP1 kinase inhibitors. The present invention has been completed based on this finding.
Term(s) for
As used herein, the term "alkyl" refers to a saturated straight or branched chain alkyl group, such as methyl, ethyl, isopropyl. Further, C1-C6 alkyl refers to alkyl groups containing 1-6 carbon atoms.
The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbyl moiety comprising at least one double bond, for example-CH ═ CH-CH 3.
The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbyl moiety comprising at least one triple bond, for example-C ≡ C-CH 3.
As used herein, the term "cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbyl moiety, such as cyclohexyl.
As used herein, the term "heterocycloalkyl" refers to a saturated cyclic moiety, such as 4-tetrahydropyranyl, that contains at least one ring heteroatom (e.g., N, O, or S).
As used herein, the term "aryl" refers to a hydrocarbyl moiety comprising one or more aromatic rings. Examples of aryl moieties include, but are not limited to, phenyl (Ph), naphthyl, pyrenyl, anthracenyl, and phenanthrenyl.
As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or fused ring aromatic group having a specified number of ring-forming carbon atoms (e.g., C)4-10I.e., having 4-10 ring-forming carbon atoms) and includes at least one identical or different heteroatom selected from N, O or S. Each ring atom may be optionally substituted. The heteroaryl group can be a 5-to 15-membered aromatic ring group having 1-5 heteroatoms each independently selected from N, O or S. Examples of heteroaryl groups are, for example (but not limited to): pyridine, pyrimidine, pyrrole, indazole, indole, furan, benzofuran, thiophene, or the like.
As used herein, substituted refers to substitution with one or more substituents.
As used herein, the term "substituted" (with or without "optionally" modifying) means that one or more hydrogen atoms on a particular group is replaced with a particular substituent. Particular substituents are those described correspondingly in the foregoing, or as appearing in the examples. Unless otherwise specified, an optionally substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituents may be the same or different at each position. A cyclic substituent, such as heterocycloalkyl, may be attached to another ring, such as cycloalkyl, to form a spiro bicyclic ring system, e.g., the two rings have a common carbon atom. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with the tissues of a subject (e.g., a human) without undue side effects. In some embodiments, pharmaceutically acceptable salts of a certain compound of the invention include salts of compounds of the invention having acidic groups (e.g., potassium, sodium, magnesium, calcium salts) or salts of compounds of the invention having basic groups (e.g., sulfate, hydrochloride, phosphate, nitrate, carbonate).
Active ingredient
As used herein, the terms "compound of the present invention" or "active ingredient of the present invention" are used interchangeably and refer to a heterocyclic compound of formula I in the first aspect of the present invention, or a pharmaceutically acceptable salt, or solvate, hydrate, racemate, stereoisomer, or prodrug thereof.
As used herein, the term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention with pharmaceutically acceptable inorganic and organic acids, wherein preferred inorganic acids include (but are not limited to): hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid; preferred organic acids include (but are not limited to): formic acid, acetic acid, propionic acid, succinic acid, naphthalenedisulfonic acid (1,5), sulfinic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, and amino acids.
As used herein, the term "pharmaceutically acceptable solvate" refers to a solvate of a compound of the present invention with a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable solvent includes (but is not limited to): water, ethanol, methanol, isopropanol, tetrahydrofuran and dichloromethane. Certain compounds of the present invention may exist in unsolvated as well as solvated forms, including hydrated forms. The solvated forms are generally equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polymorphic or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
In the present invention, in addition to the salt form, a compound in a prodrug form is also provided. Prodrugs of the compounds described herein are those compounds that are susceptible to chemical changes under physiological conditions to provide the compounds provided herein. In addition, prodrugs can be converted to the compounds provided herein in an ex vivo environment by chemical or biochemical methods. For example, a prodrug can be slowly converted to a compound provided herein when placed in a transdermal patch reservoir with a suitable enzyme or chemical agent. Preferably, the prodrug is a compound of formula I in the form of an ester.
Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., isolated enantiomers) are all intended to be included within the scope of the present invention. Where the compounds provided herein have a defined stereochemistry (denoted as R or S, or as indicated by a dashed or wedged bond), those compounds are understood by those skilled in the art to be substantially free of other isomers (e.g., at least 80%, 90%, 95%, 98%, 99% and up to 100% free of other isomers).
The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the isotopic atoms that constitute such compounds. The unnatural proportion of an isotope can be defined as ranging from the naturally-found amount of the atom in question to 100% of the amount of the atom. For example, the compounds may incorporate radioactive isotopes, such as tritium (A), (B), (C), (3H) Iodine-125 (125I) Or carbon-14 (14C) Or a non-radioactive isotopeE.g. deuterium (2H) Or carbon-13 (13C) In that respect Such isotopic variants can provide additional uses beyond those described herein. For example, isotopic variants of the compounds of the present invention can have additional uses, including but not limited to, as diagnostic and/or imaging agents, or as cytotoxic/radiotoxic therapeutic agents. In addition, isotopic variations of the compounds of the present invention can have altered pharmacokinetic and pharmacodynamic profiles that contribute to increased safety, tolerability, or efficacy during therapy. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
Preparation method
For the compounds of formula I according to the invention, they can be prepared by various methods which are well known to the person skilled in the art of organic synthetic chemistry. The compounds of the invention may be synthesized using the methods described hereinafter, together with synthetic methods known in the art of organic chemistry or variations thereon as understood by those skilled in the art.
The process for the preparation of the compounds of formula I according to the present invention the compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. It will be understood that where typical or preferred process conditions are given (i.e., reaction temperature, time, moles of reactants, solvent, pressure, etc.), other process conditions may also be used unless otherwise indicated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions may be determined by one skilled in the art by routine optimization procedures.
The methods described herein for the compounds of formula I according to the present invention may be monitored according to any suitable method known in the art. For example, nuclear magnetic resonance, mass spectrometry, HPLC, thin layer chromatography to monitor the product formation. The preparation of compounds may involve the protection and deprotection of multiple chemical groups. The need for protection and deprotection, and the choice of an appropriate protecting group, can be readily determined by those skilled in the art, and the chemistry of protecting Groups is described in Greene and Wuts, Protective Groups in Organic Synthesis, Third Edition, Wiley & Sons,1999.
Specifically, the synthetic route of the compound of formula I of the present invention is as follows:
Figure BDA0001785734480000101
Figure BDA0001785734480000111
in the formula, R1、R2、R10And X is as defined above.
In general, the compounds of the present invention can be prepared using the reaction schemes and procedures described above, but are not limited to reagents and solvents in the reaction conditions.
Pharmaceutical composition
The present invention also provides a pharmaceutical composition having excellent, high-selectivity protein kinase inhibitory effects, comprising: (i) a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, as active ingredient, and (ii) one or more pharmaceutically acceptable carriers.
The compound itself or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof can be administered orally in the form of tablets, capsules, granules, powders or syrups, or non-orally in the form of injections, in a mixture with pharmaceutically acceptable excipients, diluents, and the like. The pharmaceutical composition preferably contains 0.01-99% by weight of the compound of formula I of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof as an active ingredient, more preferably 0.1-90% by weight of the active ingredient.
The above preparation can be prepared by conventional pharmaceutical method. Examples of pharmaceutically acceptable adjuvants which may be used include excipients (e.g. saccharide derivatives such as lactose, sucrose, glucose, mannitol and sorbitol, starch derivatives such as corn starch, potato starch, dextrin and carboxymethyl starch, cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, acacia, dextran, silicate derivatives such as magnesium aluminium metasilicate, phosphate derivatives such as calcium phosphate, carbonate derivatives such as calcium carbonate, sulphate derivatives such as calcium sulphate and the like), binders (e.g. gelatin, polyvinylpyrrolidone and polyethylene glycol), disintegrants (e.g. cellulose derivatives such as sodium carboxymethyl cellulose, polyvinylpyrrolidone), lubricants (e.g. talc, calcium stearate, magnesium stearate, spermaceti, boric acid, sodium benzoate, leucine), Stabilizers (methyl paraben, propyl paraben, etc.), flavoring agents (e.g., commonly used sweeteners, acidulants, flavors, etc.), diluents, and solvents for injection (e.g., water, ethanol, glycerin, etc.).
The amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutical composition thereof to be administered varies depending on the age, sex, race, condition, etc. of the patient.
Pharmaceutical compositions and methods of administration
Because the compound of the formula I has excellent inhibitory activity on protein kinase (receptor interacting protein 1, RIP1), the compound of the invention and various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and a pharmaceutical composition containing the compound as a main active ingredient can be used for treating, preventing and relieving diseases related to the activity or expression amount of the protein kinase (receptor interacting protein 1, RIP 1).
In the present invention, the compounds of the present invention are useful for the treatment of (but not limited to) the following diseases: myocardial infarction, pancreatitis, ischemia reperfusion injury, sepsis, stroke, coronary heart disease, inflammatory bowel disease, retinitis, alcoholic fatty liver, non-alcoholic fatty liver, multiple sclerosis, dermatitis, psoriasis, chronic kidney disease, acute kidney disease, autoimmune hepatitis, hepatitis b, hepatitis c, acute liver insufficiency, neurodegenerative disease, progressive freezing human disease, parkinson, senile dementia, osteoporosis, arthritis, bacterial infection, cancer, atherosclerosis, heart failure, chronic obstructive pulmonary disease, diabetes, blood glucose regulation, protection during organ transplantation, aging resistance, obesity, and other diseases associated with too high RIP1 kinase activity.
The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 5-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
Figure BDA0001785734480000121
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 5 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The main advantages of the invention include:
(a) the compounds of the present invention have excellent in vitro and in vivo inhibitory activity against RIP 1.
(b) The compound of the invention has good safety and selectivity.
(c) The compound of the invention has simple preparation method and high yield.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally followed by conventional conditions, such as Sambrook et al, molecular cloning: the conditions described in the laboratory Manual (New York: Cold Spring harbor laboratory Press, 1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
EXAMPLE 1 preparation of Compound I
Figure BDA0001785734480000141
Step A
Figure BDA0001785734480000151
Compound 2 (N-tert-butoxycarbonylhydroxylamine) (542mg, 4.10mmol) was added to DMF (10ml), cooled to 0 ℃ in an ice bath, and then sodium hydrogen (180mg,4.5mmol, 60%) was added, after completion of the addition, reaction was maintained at 0 ℃ for half an hour, a solution of compound 1((R) - (+) -3-chloro-1-phenyl-1-propanol) (350mg, 2mmol) in DMF (5ml) was slowly added dropwise, the resulting reaction solution was reacted first at 0 ℃ for half an hour and then at room temperature for 3 days, TLC showed the completion of the reaction, a saturated ammonium chloride solution was added, the resulting aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the solution was spin-dried and passed through a silica gel column (mobile phase PE: EA ═ 10:1-1:1) to obtain compound 3 as a colorless oil.
Step B
Figure BDA0001785734480000152
Adding the compound 3(4.4g,16.45mmol) into dichloromethane (200ml) solution, then adding triethylamine (4.5mmol,33mmol), cooling the reaction solution to 0 ℃ by using an ice bath, then dropwise adding methylsulfonyl chloride (1.4ml,19mmol), continuing to react at 0 ℃ for 2 hours after the addition is finished, TLC shows that the reaction is finished, adding 400ml of water, separating an organic phase, extracting an aqueous phase by using dichloromethane, combining the organic phases, washing by saturated sodium chloride, drying by using anhydrous sodium sulfate, and spin-drying the obtained residue to pass through a silica gel column (the mobile phase of the silica gel column uses PE: EA ═ 10:1-1:1) to obtain the compound 4.
Step C
Figure BDA0001785734480000153
Compound 4(3.4g,10mmol) was dissolved in dichloromethane (100ml) and TFA (10ml) was added and stirred at room temperature for 2 hours, TLC showed the reaction was complete, the reaction solution was added to saturated sodium bicarbonate, the organic phase was separated, extracted with dichloromethane, after combining the organic phases, washed with saturated sodium bicarbonate solution and saturated sodium chloride, and after drying the organic phase over anhydrous sodium sulfate, it was spin dried to give compound 5, which was used in the next step without further purification.
Step D
Figure BDA0001785734480000161
Compound 6 (1-tert-butoxycarbonylpiperidine-4-carboxylic acid) (2.7g,12mmol) was added to a DMF (40ml) solution, followed by HATU (4.6g,12mmol) and stirred at room temperature for 1 hour, then compound 5(1.5g,10 mmol) was added to the reaction solution and stirred at room temperature overnight, TLC showed the reaction to be complete, 100ml of water was added, extraction was performed three times with ethyl acetate, the organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the resulting residue was spin-dried over a silica gel column (mobile phase PE: EA ═ 3:1) to give compound 7 as a pale yellow solid. MS (ESI) M/z 361.2(M + H +).1HNMR (400MHz, CDCl3)7.1-7.3(M, 5H), 5.3(M, 1H), 4.2(M, 1H), 4.1(M, 2H), 3.8(M,1H), 2.7-2.8(M,4H), 2.2-2.3(M, 1H), 1.8(M, 1H), 1.6(M, 3H), 1.37(s, 9H).
Step E
Figure BDA0001785734480000162
Compound 7(720mg,2mmol) was added to anhydrous dichloromethane (15ml), followed by addition of TFA (3ml) in ice bath for two hours at room temperature, TLC showed the reaction to be complete, the reaction solution was added to 50ml saturated sodium bicarbonate solution, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and spin dried to give compound 8, which was used in the next step without further purification.
Step F
Figure BDA0001785734480000171
Compound 8(800mg, crude) was added to a DMF (8ml) solution, then DBU (912mg, 6mmol) was added, then compound 9 (6-chloro-4-pyrimidinecarbonitrile) (552mg,4mmol) was added, reaction was carried out at 80 ℃ for 6 hours, TLC showed a large amount of the starting compound 8 remaining, then compound 9 (6-chloro-4-pyrimidinecarbonitrile) (276mg,2mmol) was added, the reaction temperature was raised to 100 ℃ for 12 hours, the reaction solution was poured into water, extraction was carried out with dichloromethane, the organic phases were combined, washed with water, saturated sodium chloride, after drying with anhydrous sodium sulfate, the resulting residue was spin-dried on a silica gel column (mobile phase PE: EA ═ 3:1) to give a crude product, which was further subjected to high performance liquid phase preparation to give compound I (also referred to as "compound NHWD-1062").
MS(ESI)m/z:364.4(M+H+).1HNMR(400MHz，CDCl3)8.6(s，1H)，7.2-7.4(m，5H)，6.8(s，1H)，5.4(m，1H)，4.3(m，2H)，3.9(m,1H)，3.1-3.2(m，3H)，2.8(m,1H)，2.4(m,1H)，2.1(m，1H)，1.7-1.9(m，3H)，1.3(m，1H).
Example 2 in vitro Activity assay
(1) ADP-Glo activity test.
Compound I (prepared in example 1) was tested for RIP1 inhibitory activity using the Cisbio kinEASE STK kit and the Promega ADP-Glo kinase kit in combination. Test compound I was dissolved in DMSO to give a 10mM stock. Compound I was further diluted with DMSO to 100-fold the concentration to be tested. Test compound I was diluted 1:40 with kinase buffer (HEPES250mM, NaN30.1%, BSA 0.05%, Orthofanadate 0.5mM, pH 7.0). mu.L of diluted Compound I was added to 384 well plates.
Human RIP1, STK substrate S3 and ATP were diluted with kinase buffer to concentrations of 5 ng/. mu.L, 10. mu.M and 250. mu.M, respectively. Then to a 348 well plate to which compound I had been added, 1. mu.L of diluted human RIP1, 1. mu.L of STK substrate S3, and 1. mu.L of ATP were added in that order. The final concentrations of human RIP1, STK substrate S3, and ATP in the reaction well were 1 ng/. mu.L, 2. mu.M, and 50. mu.M, respectively.
Compound I, human RIP1, substrate and ATP were incubated together at room temperature for 3 hours.3 hours later, 5. mu.L of Promega ADP-Glo reagent was added. The reaction was stopped and the remaining ATP was removed. The mixture after the termination of the reaction was incubated at room temperature for 40 minutes.
Then, 10. mu.L of Promega ADP-Glo kinase assay reagent was added to convert ADP produced by the kinase reaction into ATP. The ATP further initiates the luminescence reaction of luciferase and luciferin. After 30 minutes of reaction, the luminescence signal was detected with a PerkinElmer EnVision Multilabel plate reader.
The inhibition rate of each well was calculated from the total active and background signal wells, while half the inhibitory activity (IC50) was fitted to each test compound using professional mapping analysis software Prism 5.0, and the results are shown in table l.
(2) U937 cell assay
Viability assay for rescue of TNF-alpha/Z-VAD-FMK-induced necrotic cells the in vitro activity of RIP1 kinase inhibitors was tested using human monocytic leukemia U937 cells.
U937 cell cultures were performed using RMPI 1640 medium containing 10% fetal bovine serum, 100units/mL penicillin and 100ug/mL streptomycin.
Test compound I (prepared in example 1) was dissolved in DMSO to give 10mM stock of test compound I, which was then diluted with DMSO to 100-fold of the final reaction concentration, TNF α was dissolved in phosphate buffer containing 0.1% bovine serum albumin to 100. mu.g/mL and frozen for use, and Z-VAD-FMK was dissolved in DMSO to give 50mM stock for use.
Test compound I was diluted in medium at a ratio of 1:25, TNF-alpha and Z-VAD-FMK were diluted in medium to 400ng/ml and 400 uM.
U937 cells in logarithmic growth phase were harvested, centrifuged, resuspended in fresh medium, and plated at a density of 15000 cells per well in 96 well cell culture plates at 50ul per well. Simultaneously, 25ul of diluted compound I solution and 25ul of TNF-alpha/Z-VAD-FMK were added. The final concentrations of TNF-alpha and Z-VAD-FMK were 100ng/mL and 100. mu.M, respectively.
The cells were placed at 37 c,5％CO2incubate in incubator for 24 hours. After 24hr, 100ul CellTiterGlo was added to each well, and the mixture was shaken and left for 10min at room temperature in the dark. The luminescence signal was read with a PerkinElmer EnVision microplate reader.
The effect of compound I in rescuing TNF α/QVD-induced necrotic cells was tested by calculating the inhibition rate of each well through full activity and background signal wells, while fitting half the inhibitory activity (IC50) to each test compound I using professional mapping analysis software Prism 5.0, the results of which are shown in table l.
Watch l
Figure BDA0001785734480000191
Example 3 in vivo Activity assay
Animal model of TNF-induced systemic inflammatory response syndrome:
the mouse source mTNF- α and Z-VAD-FMK are prepared by purchasing mouse source mTNF- α from Nanjing Kingsler biology company and Z-VAD-FMK from Selleck company, measuring 30ug mTNF each time and dissolving in 200ul endoxin-free PBS and each 0.25mg Z-VAD-FMK in 5ul DMSO, and diluting with 195ul endoxin-free PBS.
Preparation of mouse model of TNF-induced systemic inflammatory response syndrome: male C57Bl/6J mice were selected for 8-10 weeks. The hairs were shaved (upper abdomen), grouped (5 per group), and 3 measurements were averaged with a thermometer (ohm dragon infrared electronic thermometer MC-872).
The process for establishing the TNF-induced systemic inflammatory response syndrome model comprises the steps of dividing the experiment into four groups, (1) a blank control group, measuring the body temperature of each mouse 30min after 100 mu l (100 ul/mouse and gastric lavage) of corn oil is first performed for 20 min, measuring the body temperature of each mouse 30min after PBS (200 ul/mouse) is injected into the tail vein, (2) a TNF induction group, measuring the body temperature of each mouse 30min after 100 mu l (100 ul/mouse) of corn oil is first performed for 20 min, measuring the body temperature of each mouse 30min after mTNF- α (30 mu g/mouse and 200 ul/mouse) is performed for 30 mu g/gastric lavage, measuring the body temperature of each mouse 30min after MTNF- α (30 mu g/mouse and 200 ul/mouse) is performed for intraperitoneal injection, measuring the body temperature of each mouse 30min after TNF + NHWD-1062 (compound I prepared in example 1), mixing the corn oil 100 mu l (100 ul/mouse) with the NHWD-1062(10mg/kg) for 20 min, measuring the body temperature of each mouse 100 mu g/mouse after the injection is performed for 20 min, measuring the tail vein injection, measuring the body temperature of each mouse 10 mg/mouse after the mouse is performed for 20 min, measuring the tail vein injection, measuring the mouse 10 mg/10 min, measuring the body temperature of the mouse after the mice (10 mg/10 mg) of corn oil injection, measuring the mice after the gastric lavage) is performed for the mice and the mice after the mice (10 min, measuring the mice) of the mice) for the mice after the mice are performed for 20 min, and the mice (10 mg/10 min, and the.
It can be seen from figure 1 that compound I significantly ameliorates the TNF-induced systemic inflammatory response syndrome.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A heterocyclic compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein the compound is represented by formula I
Figure FDA0001785734470000011
Wherein R is1Represents 1 to 3 substituents selected from the group consisting of: H. halogen, -OH, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C10 heteroaryl, C1-C4 carboxy, -CN, NO2；
R2Is a substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C10 heteroaryl, or substituted or unsubstituted 5-8 membered heterocycle;
wherein said substitution means that one or more hydrogen atoms are each independently substituted by a substituent selected from the group consisting ofAnd (3) substitution: H. halogen, -CN, NO2OH, -NRaRb, C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl, benzyl, C6-C10 aryl, C3-C10 heteroaryl,
wherein Ra and Rb are each independently H, C1-C3 alkyl, C3-C6 cycloalkyl.
2. The heterocyclic compound of claim 1, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, wherein R is R1Selected from the group consisting of: H. halogen, C1-C6 alkyl.
3. The heterocyclic compound of claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein the compound is of formula II:
Figure FDA0001785734470000021
wherein the content of the first and second substances,
m, Q, V, Y and Z are each independently selected from the group consisting of: C. n, S, or O;
R3、R4、R5、R6and R7Each independently selected from the group consisting of: H. halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C3-C10 aryl, C3-C10 heteroaryl, -CN, NO2；
Figure FDA0001785734470000022
Represents a single bond or a double bond.
4. The heterocyclic compound of claim 3, or a pharmaceutically acceptable salt or solvate thereof, where V and Z are N, and M, Q and Y are C.
5. The heterocyclic compound of claim 1, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, where the compound of formula I is
Figure FDA0001785734470000023
6. A pharmaceutical composition, comprising:
(i) a safe and effective amount of the heterocyclic compound of claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof; and
(ii) a pharmaceutically acceptable carrier.
7. The use of a heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the preparation of (i) a protein kinase inhibitor, (ii) a medicament for the treatment of a protein kinase related disease, (iii) a medicament for the treatment of a TNF related disease, and/or (iv) a medicament for the treatment of a programmed cell necrosis related disease.
8. A process for the preparation of a heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which comprises the steps of:
(1) reacting the compound of formula 6 with the compound of formula 5 to obtain a compound of formula 7;
Figure FDA0001785734470000031
(2) deprotecting the compound of formula 7 to provide a compound of formula 8; and
Figure FDA0001785734470000032
(3) converting said formula 8 intoCompound and R2-X, thereby obtaining a compound of formula I;
Figure FDA0001785734470000033
wherein R is1、R2Is as defined in claim 1;
R10is a protecting group;
and X is Cl or Br.
9. The method of claim 8, wherein the compound of formula 5 is prepared by a process comprising the steps of:
(1.1) reacting the compound of formula 1 with the compound of formula 2 to obtain the compound of formula 3
Figure FDA0001785734470000034
(1.2) reacting the compound of formula 3 with methanesulfonyl chloride to obtain a compound of formula 4
Figure FDA0001785734470000035
(1.3) reacting the compound of formula 4 in an inert solvent in the presence of trifluoroacetic acid to obtain the compound of formula 5
Figure FDA0001785734470000036
10. A method for non-therapeutic inhibition of a protein kinase in vitro, comprising the steps of: contacting the heterocyclic compound of claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, with the protein kinase to inhibit the activity of the protein kinase.
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