CN117105868A - Amide aldehyde dehydrogenase agonist, synthesis method and application thereof - Google Patents

Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to an amide aldehyde dehydrogenase agonist, a synthesis method and application thereof. The amide compounds provided by the invention have higher agonistic activity on ALDH2, so that the compounds have the potential of preparing therapeutic drugs for diseases related to the activity of the ALDH 2; (2) Compared with the positive control, the activity and the water solubility of the amide compound are obviously improved, and the amide compound has better drug property. Therefore, the compound has good development prospect.

Description

Amide aldehyde dehydrogenase agonist, synthesis method and application thereof

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to an amide aldehyde dehydrogenase agonist, a synthesis method and application thereof.

Background

Aldehyde dehydrogenase 2 (ALDH 2) is responsible for detoxification of exogenous alcohols, acetaldehyde produced by in vivo metabolism, acrolein in environmental pollution, and the like; is also responsible for detoxification of the final products of lipid peroxidation under endogenous oxidative stress, such as 4-hydroxynonenal (4-HNE) and Malondialdehyde (MDA), and is an important link of the oxidative stress defense system in vivo (Physiol Rev.2014, 94 (1): 1-34;Cardiovasc Res.2010, 88 (1): 51-7). There are significant species-diverse single nucleotide mutations in ALDH2, with about 35-45% of the east asian population carrying the low activity variant ALDH2 x 2, up to 65% in local areas of south china, while this ratio is very low in other species (Ann Hum genet.2009, 73:335-45).

Initially, researchers' knowledge of ALDH2 was primarily limited to its metabolism of alcohol intake in humans, and low activity variants ALDH2 x 2 are well known to limit the ability of humans to tolerate alcohol, thereby predisposing to acute alcoholism. Acute alcoholism is a clinically common disease, and patients with severe alcoholism can endanger the lives of the patients if the patients are not treated in time. Emergency measures such as promotion of alcohol excretion in the digestive tract, blood purification therapy, symptomatic support therapy, etc. are generally taken for severely poisoned patients. The most commonly used alcoholism treatment drugs in clinic at present comprise opioid receptor antagonists such as naloxone, naltrexone and the like, can only support treatment for symptoms, improve poisoning symptoms and have limited curative effect. After the human body drinks a lot of alcohol to consume the alcohol, most of the alcohol is metabolized in the liver except a small amount of non-metabolized alcohol which is volatilized through the respiratory tract or discharged from urine. Ethanol is oxidized to acetaldehyde under the action of Alcohol Dehydrogenase (ADH) in hepatocyte fluid, and acetaldehyde is oxidized to acetic acid by acetaldehyde dehydrogenase 2 (ALDH 2) in mitochondria, and acetic acid is unstable and decomposed to water and carbon dioxide. Ethanol itself is not very toxic, while acetaldehyde can combine with proteins, DNA and the like in vivo to form compounds that cause lipid peroxidation, mitochondrial damage and glutathione deficiency, causing alcoholism. ADH subtype ADH1C1 is the most critical for alcohol metabolism in vivo and metabolizes 41.5% of the ethanol in the liver. The ADH inhibitor methylpyrazole (4-MP) has been approved by the FDA for the treatment of ethylene glycol and methanol poisoning and is currently undergoing phase II clinical trials for acute alcoholism, which act therapeutically by slowing the production of acetaldehyde. The dual-function regulator of the ALDH2 and the ADH inhibitor can inhibit the metabolism of ethanol into acetaldehyde, promote the metabolism of acetaldehyde into acetic acid, thereby reducing the accumulation of acetaldehyde in the body, preventing and treating the injury of acetaldehyde to the human body, and is hopeful to radically treat acute alcoholism.

However, recent studies have shown that ALDH2 has a more extensive and important impact on human health (Annu Rev Pharmacol Toxicol.2015, 55107-27;Physiol Rev.2014, 94 (1): 1-34). First, long-term drinking by variant carriers carries a higher risk of multiple malignancies, most well evidenced by cancers of the upper digestive respiratory tract (UADT, including head, neck and esophagus) (oncotargett.2017, 8 (60): 102401-102412;Sci Rep.2017,7 (1): 9701). More importantly, even if the extrinsic factor of alcohol consumption is excluded, the low activity variant ALDH2 x 2 carrier has a higher health risk for oxidative stress related diseases, as ALDH2 is an important element of the oxidative stress defense system in vivo. Including cardiovascular and cerebrovascular diseases, diabetes, neurodegenerative diseases, fanconi anemia, pain, osteoporosis, radiodermatitis, malignant tumor metastasis, etc. In particular, close relation to cardiovascular and cerebrovascular diseases has been confirmed in recent years by a large number of studies, including acute (myocardial ischemia) and chronic (heart failure) cardiovascular diseases, ischemic brain injury, ischemic cerebral stroke (cerebral infarction) and the like (science.2008, 321 (5895): 1493-5; cell Res.2013, 23 (7): 915-30).

To date, only few small molecule agonists of ALDH2 have been reported to represent the drug Alda-1. The discovery of this class of compounds demonstrates the significance and feasibility of the development of ALDH2 small molecule agonists (science.2008, 321 (5895): 1493-5). However, the actual clinical application of the compounds is hindered due to the problems of poor water solubility, low activity, short half-life and other pharmacokinetic properties of the compounds. Since increasing the expression or activity of ALDH2 has been demonstrated to clearly have a protective effect against related diseases, development of small molecule agonists of ALDH2 has significant potential clinical application value. In addition, the ALDH2 small molecule agonist can also be used as an important molecular probe for further deeply exploring the target function and the relation between the target function and human health diseases.

Disclosure of Invention

The invention aims to provide a method for manufacturing a semiconductor device

A compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein,

x is C or N;

y is C or N; the dotted line represents a single bond and a double bond;

R ₁ 、R ₂ each independently selected from hydrogen, C _1-6 Alkyl, amino, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Cycloalkyl, or absent; or C as described therein _1-6 Alkyl, amino, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Cycloalkyl groups are optionally further selected from the group consisting of hydrogen atoms, C _1-6 Alkyl, halogen, hydroxy, amino, nitro, cyano, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Alkoxy, C _1-6 One or more substituents in cycloalkyl; or C as described _1-6 Alkyl, amino, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Cycloalkyl groups optionally being selected from hydrogen atoms, C _1-6 Alkyl, halogen, hydroxy, amino, nitro, cyano, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Further one or more substituents in the cycloalkyl group are optionally further substituted by one or more substituents selected from the group consisting of hydrogen atoms, C _1-6 Alkyl, halogen, hydroxy, amino, nitro, cyano, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Alkoxy, C _1-6 One or more substitutions in cycloalkyl;

R ₃ selected from hydrogen, C _1-6 Alkyl, amino, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Cycloalkyl, aryl, or absent; or C as described therein _1-6 Alkyl, amino, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Cycloalkyl, aryl is optionally further selected from hydrogen atoms, C _1-6 Alkyl, halogen, hydroxy, amino, nitro, cyano, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Alkoxy, C _1-6 One or more substituents in cycloalkyl;

R ₄ selected from hydrogen, amino, halogen, C _1-6 Alkoxy, C _1-6 Cycloalkoxy, -NH (CH) ₂ ) _n R _aa The method comprises the steps of carrying out a first treatment on the surface of the Or wherein said amino, C _1-6 Alkoxy, C _1-6 The cycloalkoxy group is optionally further selected from hydrogen atoms, C _1-6 Alkyl, halogen, hydroxy, amino, nitro, cyano, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Alkoxy, C _1-6 One or more substituents in cycloalkyl; wherein said-NH (CH) ₂ ) _n R _aa N is 1, 2, 3, 4 or 5, R _aa Selected from C _1-6 Cycloalkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C _1-6 Alkenyl, C _1-6 Alkynyl, heterocyclyl, aryl, and heteroaryl;

R ₅ 、R ₆ each independently selected from H, halogen, C _1-6 Alkyl, C _1-6 Alkoxy or C _1-6 A carbonyl group; or R is ₅ 、R ₆ Are mutually connected to form five-membered cycloalkyl or five-membered heterocycloalkyl; wherein R is ₅ 、R ₆ Not simultaneously selected from H.

Preferably, the compound, stereoisomer thereof, or pharmaceutically acceptable salt, hydrate or solvate thereof:

wherein,

x is N;

y is N; the dotted line represents a single bond and a double bond;

R ₁ 、R ₂ each independently selected from hydrogen, C _1-6 Alkyl, C _1-6 Cycloalkyl, or absent; or C as described therein _1-6 Alkyl, C _1-6 Cycloalkyl radicals optionally further being selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 One or more substituents in cycloalkyl; r is R ₃ Selected from hydrogen, C _1-6 Alkyl, C _1-6 Cycloalkyl, aryl; or C as described therein _1-6 Alkyl, C _1-6 Cycloalkyl, aryl is optionally further selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 One or more substituents in cycloalkyl;

R ₄ selected from amino, halogen, C _1-6 Alkoxy, C _1-6 Cycloalkoxy, -NH (CH) ₂ ) _n R _aa The method comprises the steps of carrying out a first treatment on the surface of the Or C as described therein _1-6 Alkoxy groups further being selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 One or more substituents in cycloalkyl; wherein the method comprises the steps ofsaid-NH (CH) ₂ ) _n R _aa N is 1, 2, 3, 4 or 5, R _aa Selected from C _1-6 Cycloalkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C _1-6 Alkenyl, C _1-6 Alkynyl, heterocyclyl, aryl, and heteroaryl;

R ₅ 、R ₆ each independently selected from halogen, C _1-6 Alkyl, C _1-6 An alkoxy group; or R is ₅ 、R ₆ Are connected with each other to form five-membered cycloalkyl or five-membered heterocycloalkyl.

Preferably, the compound, stereoisomer thereof, or pharmaceutically acceptable salt, hydrate or solvate thereof:

wherein,

x is N;

y is N; the dotted line represents a single bond, a double bond;

R ₁ selected from hydrogen, C _1-6 Alkyl, C _1-6 Cycloalkyl, or absent; or C as described therein _1-6 The alkyl group being further selected from C _1-6 Alkoxy, C _1-6 One or more substituents in cycloalkyl;

R ₂ selected from hydrogen or absence;

R ₃ Selected from hydrogen, C _1-6 Alkyl, C _1-6 Cycloalkyl, aryl; or C as described therein _1-6 The alkyl groups and aryl groups are optionally further selected from hydrogen atoms, C _1-6 One or more substituents in cycloalkyl;

R ₄ selected from halogen, C _1-6 Alkoxy, C _1-6 Cycloalkoxy, -NH (CH) ₂ ) _n R _aa The method comprises the steps of carrying out a first treatment on the surface of the Or C as described therein _1-6 Alkoxy is further selected from C _1-6 One or more substituents in cycloalkyl; wherein said-NH (CH) ₂ ) _n R _aa ，n1, 2, 3, 4, R _aa Selected from C _1-6 Cycloalkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups;

R ₅ selected from C _1-6 Alkyl, C _1-6 An alkoxy group;

R ₆ selected from halogen, C _1-6 Alkyl, C _1-6 An alkoxy group;

or R is ₅ 、R ₆ Are connected with each other to form five-membered heterocyclic alkyl.

Preferably, the compound, stereoisomer thereof, or pharmaceutically acceptable salt, hydrate or solvate thereof:

wherein,

x is N;

y is N; the dotted line represents a single bond, a double bond;

R ₁ selected from hydrogen, C _1-6 Alkyl, C _1-6 Cycloalkyl, or absent; or C as described therein _1-6 The alkyl group being further selected from C _1-6 One or more substituents in cycloalkyl;

R ₂ selected from hydrogen or absence;

R ₃ selected from hydrogen, C _1-6 Alkyl, C _1-6 Cycloalkyl, aryl; or C as described therein _1-6 The alkyl group being further selected from C _1-6 One or more substituents in cycloalkyl;

R ₄ Selected from halogen, C _1-6 Alkoxy, C _1-6 Cycloalkoxy, -NH (CH) ₂ ) _n R _aa The method comprises the steps of carrying out a first treatment on the surface of the Or C as described therein _1-6 Alkoxy is further selected from C _1-6 One or more substituents in cycloalkyl; wherein said-NH (CH) ₂ ) _n R _aa N is 1, 2, 3, 4, R _aa Selected from C _1-6 Cycloalkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy compoundsA base;

R ₅ selected from C _1-6 An alkoxy group;

R ₆ selected from halogen;

or R is ₅ 、R ₆ Are connected with each other to form five-membered heterocyclic alkyl.

Preferably, the compound, stereoisomer thereof, or pharmaceutically acceptable salt, hydrate or solvate thereof:

wherein,

x is N;

y is N; the dotted line represents a single bond, a double bond;

R ₁ selected from hydrogen, C _1-6 Alkyl, C _1-6 Cycloalkyl, or absent; or C as described therein _1-6 The alkyl group being further selected from C _1-6 One or more substituents in cycloalkyl;

R ₂ selected from hydrogen or absence;

R ₃ selected from hydrogen, C _1-6 Alkyl, C _1-6 Cycloalkyl, benzene ring; or C as described therein _1-6 The alkyl group being further selected from C _1-6 One or more substituents in cycloalkyl;

R ₄ selected from halogen, C _1-6 Alkoxy, C _1-6 Cycloalkoxy, -NH (CH) ₂ ) _n R _aa The method comprises the steps of carrying out a first treatment on the surface of the Or C as described therein _1-6 Alkoxy is further selected from C _1-6 One or more substituents in cycloalkyl; wherein said-NH (CH) ₂ ) _n R _aa N is 1, 2, 3, 4, R _aa Selected from C _1-6 Cycloalkyl;

R ₅ selected from C _1-6 An alkoxy group;

R ₆ selected from halogen;

or R is ₅ 、R ₆ Are mutually connected to form five-membered oxacycloalkyl.

The invention also provides a preferable scheme, wherein the compound shown in the formula I, a stereoisomer or a pharmaceutically acceptable salt, hydrate or solvate thereof has the following structure:

the invention also relates to a technical scheme, a pharmaceutical composition comprising a therapeutically effective dose of the compound of the formula I, a stereoisomer or a pharmaceutically acceptable salt, hydrate or solvate thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

The invention also relates to a technical scheme, and the compound of the formula I, a stereoisomer or a pharmaceutically acceptable salt, hydrate or solvate thereof, or the application of the pharmaceutical composition in preparing medicines for treating diseases or symptoms related to the activity of aldehyde dehydrogenase 2.

In some preferred embodiments, the disease or condition associated with aldehyde dehydrogenase 2 activity includes acute alcoholism, malignancy, cardiovascular and cerebrovascular disease, diabetes, neurodegenerative disease, fanconi anemia, pain, osteoporosis, radiodermatitis, and metastasis of malignancy;

In some preferred embodiments, the cardiovascular and cerebrovascular diseases include myocardial ischemia, heart failure, ischemic brain injury, and ischemic stroke.

The present application also relates to a technical scheme, wherein the compound of formula I, and stereoisomers thereof, or pharmaceutically acceptable salts, hydrates or solvates thereof, or the pharmaceutical composition is to be administered by a route selected from intramuscular, intravenous, subcutaneous, topical and oral.

The term "alkyl" in the present application refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 8 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms, most preferably an alkyl group containing from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, with methyl, ethyl, isopropyl, t-butyl, haloalkyl, deuteroalkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl being preferred.

The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, and most preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms in which one or more ring atoms are selected from nitrogen, oxygen or S (O) _m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; most preferably containing 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with oxetanyl, pyrrolidinonyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl being preferred. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups; the heterocyclic groups of the spiro ring, the condensed ring and the bridged ring are optionally connected with other groups through single bonds, or are further connected with other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups through any two or more atoms on the ring in a parallel ring mode.

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl. The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, and thiazolyl; more preferably triazolyl, pyrrolyl, thienyl, thiazolyl, pyridyl and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.

The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.

"haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.

"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

"alkynyl" refers to (CH≡C-), wherein the alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.

"halogen" means fluorine, chlorine, bromine or iodine.

"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "optionally alkyl-substituted heterocyclic group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

Throughout the specification, groups and substituents thereof may be selected by those skilled in the art to provide stable moieties, as well as intermediate compounds useful as pharmaceutically acceptable compounds and/or in the manufacture of pharmaceutically acceptable compounds.

The compounds of formula I may exist in free form (without ionization) or may form salts which are also within the scope of the present invention. Unless otherwise indicated, references to compounds of the present invention should be understood to include references to the free forms and salts thereof. Furthermore, the term "salt" may include zwitterionic (inner salts), for example when the compounds of formula I contain a basic moiety (such as an amine or pyridine or imidazole ring) and an acidic moiety (such as a carboxylic acid). Pharmaceutically acceptable (i.e., non-toxic physiologically acceptable) salts are preferred, such as, for example, acceptable metal and amine salts wherein the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts may be used, for example, in isolation or purification steps that may be employed during preparation, and are therefore encompassed within the scope of the invention.

Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid (e.g., trifluoroacetic acid)), adipates, alginates, ascorbates, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorites, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride (formed with hydrochloric acid), hydrobromide (formed with hydrogen bromide), hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate (formed with maleic acid), methanesulfonate (formed with methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectate, persulfate, 3-phenylpropionate, phosphate, bitrates, pivalate, propionate, salicylate, succinate, sulfate (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrate, thiocyanate, tosylate, undecanoate, and the like.

Exemplary basic salts include ammonium salts; alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc and aluminum salts; salts with organic bases (e.g., organic amines) such as trialkylamines (e.g., triethylamine), procaine, dibenzylamine, N-benzyl- β -phenethylamine, 1-dibenzylmethylamine, N' -dibenzylethylenediamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, or similar pharmaceutically acceptable amines; and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (e.g., chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (e.g., sulfates of dimethyl, diethyl, dibutyl and diamyl), long chain halides (e.g., chlorides, bromides and iodides of decyl, lauryl, myristyl and stearyl), aralkyl halides (e.g., bromides of benzyl and phenethyl). Preferred salts include monohydrochloride, bisulfate, mesylate, phosphate or nitrate.

The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by making the acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups (e.g., amines); and basic or organic salts of acidic groups (e.g., carboxylic acids). Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from the following mineral acids: such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; salts prepared from organic acids: such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid (pamoic), maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like.

Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both; in general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

All stereoisomers of the compounds of the invention are contemplated, either as mixtures or in pure or substantially pure form. Stereoisomers may include compounds that are optical isomers by having one or more chiral atoms, as well as compounds that are optical isomers by virtue of limited rotation about one or more bonds (atropisomers). The definition of a compound according to the invention covers all possible stereoisomers and mixtures thereof. It very specifically encompasses both the racemic form and the isolated optical isomer having the specified activity. The racemic forms can be resolved by physical methods such as, for example, fractional crystallization, separation or crystallization of diastereoisomeric derivatives or separation by chiral column chromatography. The individual optical isomers may be obtained from the racemates by conventional methods (such as, for example, salt formation with an optically active acid followed by crystallization).

The present invention is intended to include all isotopes of atoms present in the compounds of the invention. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include ¹³ C and C ¹⁴ C. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein using an appropriate isotopically-labeled reagent in place of an otherwise-used unlabeled reagent.

Prodrugs and solvates of the compounds of the invention are also contemplated. The term "prodrug" means a compound that undergoes chemical conversion by metabolic or chemical processes after being administered to a subject to produce a compound of formula I and/or a salt and/or solvate thereof. Any compound that will be converted in vivo to provide a bioactive agent (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxyl group can form a physiologically hydrolyzable ester that acts as a prodrug by hydrolyzing in vivo to produce the compound of formula I itself. Such prodrugs are preferably administered orally, as in many cases hydrolysis occurs mainly under the influence of digestive enzymes. Parenteral administration may be used in cases where the ester itself is active or in those cases where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of the compounds of formula I include C _1-6 Alkyl benzyl, 4-methoxybenzyl, indanyl, phthaloyl, methoxymethyl, C _1-6 alkanoyloxy-C _1-6 Alkyl (e.g., acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), C _1-6 alkoxycarbonyloxy-C _1-6 Alkyl (e.g. methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl), glycinyloxymethyl, phenylglycinyloxymethyl, (5-methyl-2-oxo-1, 3-dioxol-4-yl) -methyl and other well known physiology, such as used in the penicillin and cephalosporin fieldsAnd a hydrolyzable ester. Such esters may be prepared by conventional techniques known in the art.

The compounds of formula I and salts thereof may exist in their tautomeric forms, wherein the hydrogen atoms are transposed to the other parts of the molecule and thus the chemical bonds between the atoms of the molecule are rearranged. It is to be understood that all tautomeric forms, as long as they can exist, are included within the present invention. In addition, the compounds of the present invention may have both trans and cis isomers.

It is also understood that solvates (e.g., hydrates) of the compounds of formula I are also within the scope of the present invention. Methods of solvation are well known in the art.

As used herein, the term "treatment" encompasses treatment of a disease state in a mammal, particularly a human, and includes: (a) Preventing or delaying the onset of a disease state in a mammal, particularly when such mammal is susceptible to, but has not been diagnosed as having, the disease state; (b) inhibiting the disease state, i.e., arresting its development; and/or (c) effecting a complete or partial reduction in symptoms or disease states and/or alleviating, ameliorating, reducing or curing the disease or disorder and/or symptoms thereof.

The compositions of the invention may contain other therapeutic agents as described above and may be formulated according to techniques such as those well known in the art of pharmaceutical formulation, for example by using conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type suitable for the desired mode of administration (e.g., excipients, binders, preservatives, stabilizers, flavouring agents, etc.).

Thus, the invention further includes a combination comprising one or more compounds of formula I and a pharmaceutically acceptable carrier.

By "pharmaceutically acceptable carrier" is meant a medium that is generally accepted in the art for delivery of bioactive agents to animals, particularly mammals. Pharmaceutically acceptable carriers are formulated according to many factors within the knowledge of one of ordinary skill in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated; a subject to be administered a composition comprising a pharmaceutical agent; the intended route of administration of the composition; and targeted therapeutic indications. Pharmaceutically acceptable carriers include both aqueous and nonaqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include many different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons well known to those of ordinary skill in the art (e.g., stabilizing the active agent, binder, etc.). A description of suitable pharmaceutically acceptable carriers and the factors involved in their selection are found in a variety of readily available sources, such as, for example, remington's Pharmaceutical Sciences, 17 th edition (1985), which is incorporated herein by reference in its entirety.

The compounds of formula I may be administered by any means suitable for the condition to be treated, which may depend on the need for site-specific treatment or the amount of drug to be delivered. For example, the compounds may be delivered orally, such as in the form of tablets, capsules, granules, powders, or liquid formulations including syrups; topical delivery, such as in the form of a solution, suspension, gel, or ointment; sublingual delivery; oral delivery; parenteral delivery, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as a sterile injectable aqueous or nonaqueous solution or suspension); nasal delivery, such as by inhalation spray; topical delivery, such as in the form of a cream or ointment; rectal delivery, such as in the form of suppositories; or liposome delivery. Dosage unit formulations containing non-toxic pharmaceutically acceptable vehicles or diluents can be administered. The compounds may be administered in a form suitable for immediate release or extended release. Immediate release or prolonged release may be achieved with a suitable pharmaceutical composition or, particularly in the case of prolonged release, with a device such as a subcutaneous implant or osmotic pump.

A therapeutically effective amount of a compound of the invention can be determined by one of ordinary skill in the art and includes exemplary dosages of about 0.05-1000mg/kg, 1-50mg/kg, 5-250mg/kg, 250-1000mg/kg body weight of the active compound per day for a mammal, which can be administered as a single dose or as separate divided doses (e.g., 1 to 4 times per day). It will be appreciated that the particular dosage level and dosage frequency of any particular subject may vary and will depend upon a variety of factors including the activity of the particular compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex, and diet of the subject, the mode and time of administration, the rate of excretion, drug combination, and the severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species, such as humans, and domestic animals, such as dogs, cats, horses, and the like.

The term "aldehyde dehydrogenase" or "ALDH" refers to a DNA that is capable of being expressed in NAD ⁺ Dependence or NADP ⁺ In a dependent reaction, an enzyme that oxidizes an aldehyde (such as an exogenous aldehyde, a biogenic aldehyde, or an aldehyde produced from an ingested, inhaled, or absorbed compound) to its corresponding acid. For example, ALDH oxidizes aldehydes produced by the decomposition of the following compounds: such as ingestion, absorption, inhalation, or oxidative stress, or normal metabolic processes, such as conversion of retinol to retinoic acid. An example of a biogenic aldehyde is acetaldehyde produced by the action of alcohol dehydrogenase activity on ethanol intake. Aldehyde dehydrogenases also exhibit esterase activity and/or reductase activity.

The term "ALDH" includes ALDH found in cytosol, mitochondria, microsomes, or other cellular compartments. The term "ALDH" includes ALDHs that are found primarily in one or a few tissues, such as cornea, saliva, liver, etc., or stem cells and embryos. The term "ALDH" includes any known ALDH isozymes including ALDH1, ALDH2, ALDH3, ALDH4, ALDH5, and the like.

The term "aldehyde dehydrogenase 2" or "ALDH2" refers to the enzyme that is found in NAD ⁺ In a dependent reaction, an enzyme that oxidizes an aldehyde (such as an exogenous aldehyde, a biogenic aldehyde, or an aldehyde produced from an ingested, inhaled, or absorbed compound) to its corresponding acid. For example, ALDH2 is capable of oxidizing aldehydes generated by decomposition of toxic compounds generated during, for example, ingestion, absorption, inhalation, or normal metabolic processes. Mitochondrial ALDH2 is found naturally in mitochondria.

The term "ALDH2" includes ALDH2 of various species. The amino acid sequences of ALDH2 of various species are publicly available. For example, the amino acid sequence of human ALDH2 is found in GenBank accession numbers AAH02967 and np_000681; the amino acid sequence of the mouse ALDH2 is shown in GenBank accession number NP-033786; the amino acid sequence of rat ALDH2 is shown in GenBank accession No. NP-115792.

The compounds of the present invention may be synthesized by a variety of methods available to those skilled in the art of organic chemistry. General synthetic schemes for preparing the compounds of the invention are described below. These schemes are illustrative and are not intended to limit the possible techniques that one of skill in the art may use to prepare the compounds disclosed herein. Different methods of preparing the compounds of the present invention will be apparent to those skilled in the art. Alternatively, the various steps in the synthesis may be performed in alternating order to obtain the desired compound or compounds. Examples of compounds of the invention prepared by the methods described in the general schemes are given in the preparations and examples section listed below.

The Chinese naming of the compound in the invention conflicts with the structural formula, and the structural formula is taken as the reference; except for obvious structural errors.

The invention has the beneficial effects that:

1. the amide compounds of the invention show high agonistic activity to ALDH2, so that the compounds have the effect of preparing therapeutic drugs for diseases related to the activity of ALDH 2.

2. Compared with the positive control, the activity and the water solubility of the amide compound are obviously improved, and the amide compound has better drug property. Therefore, the compound of the invention is expected to have good development prospect.

Detailed Description

The invention is illustrated but not limited by the following examples. Simple alternatives and modifications of the invention will be apparent to those skilled in the art and are within the scope of the invention as defined by the appended claims.

Example 1: preparation of Compound 13

The synthetic route is as follows:

1) Preparation of 2, 6-dichloro-N- (3-fluoro-4-methoxybenzyl) -3-nitrobenzamide

3, 4-dichloro-5-nitrobenzoic acid (284 mg,4.3 mmol) and HATU (2421 mg,6.4 mmol) were weighed into a round bottom flask, 5ml of anhydrous DMF and 2.2ml of anhydrous DIPEA were added in sequence under the protection of argon, and finally 0.7ml of 3-fluoro-4-methoxybenzylamine was added and the mixture was stirred at room temperature for 2.5h. After the reaction was completely completed by TLC, the reaction solution was poured into dilute hydrochloric acid, extracted with ethyl acetate multiple times, and saturated sodium chloride solution was added to prevent the system from emulsifying, the upper organic phase solution was collected, washed with saturated sodium bicarbonate solution, the upper organic phase solution was collected, dried over anhydrous sodium sulfate and filtered, and the collected organic phase was subjected to spin-drying evaporation, and the obtained preliminary product was purified by forward silica gel chromatography (petroleum ether/ethyl acetate). A yellow solid was obtained (760 mg, yield approximately 48%).

2) Preparation of 6-chloro-N- (3-fluoro-4-methoxybenzyl) -2- (isopropylamino) -3-nitrobenzamide:

2, 6-dichloro-N- (3-fluoro-4-methoxybenzyl) -3-nitrobenzamide (400 mg,1.1 mmol) and anhydrous potassium carbonate (583 mg,4.2 mmol) were weighed in a round bottom flask, 4ml of anhydrous DMSO and 0.18ml of propyl-2-amine were added, the mixture was placed in an oil bath, heated to 80 ℃ for reaction for 4h under reflux, TLC was monitored, after the reaction was completed, the reaction system solution was poured into water, and then extracted with dichloromethane for a plurality of times, the lower organic phase solution was collected, dried and filtered by anhydrous sodium sulfate, and the collected organic phase was subjected to spin-drying evaporation, and the obtained preliminary product was purified by a forward silica gel chromatographic column (petroleum ether/ethyl acetate). After work up, a yellow solid was obtained (121 mg, yield about 29%).

3) Preparation of 3-amino-6-chloro-N- (3-fluoro-4-methoxybenzyl) -2- (isopropylamino) benzamide:

6-chloro-N- (3-fluoro-4-methoxybenzyl) -2- (isopropylamino) -3-nitrobenzamide (121 mg,0.3 mmol) was weighed out in a round bottom flask and dissolved in 6ml of absolute ethanol, absolute ammonium chloride (65.4 mg,1.2 mmol) was dissolved in 2ml of water, and when placed in an oil bath to heat under reflux to 80℃iron powder (144 mg,2.5 mmol) was added, TLC monitored for reaction, and after completion of the 1h reaction, the reaction system was filtered with celite and rinsed with methanol. The reaction system liquid was evaporated by spin-drying, the dark brown object obtained by spin-drying was added to water, followed by multiple extraction with ethyl acetate, the lower organic solution was collected, dried with anhydrous sodium sulfate and filtered, the organic phase was evaporated by spin-drying, and the obtained preliminary product was purified by separation with a forward silica gel chromatography plate (petroleum ether/ethyl acetate). A semi-solid pale yellow object (74 mg, yield about 66%) was obtained.

4) Preparation of Compound 13:

3-amino-6-chloro-N- (3-fluoro-4-methoxybenzyl) -2- (isopropylamino) benzamide (138 mg,0.4 mmol) and 1, 2-diformylhydrazine (166 mg,1.9 mmol) were weighed into a long reaction tube, 5ml of anhydrous pyridine, 0.7ml of anhydrous triethylamine and 1.4ml of trimethylchlorosilane were sequentially added under the protection of argon, stirring at a low temperature for five minutes, and placed into an oil bath pot for reflux reaction at 110 ℃ for 7h, TLC monitoring reaction was carried out, after the reaction was completed, the reaction system solution was evaporated by spin-drying, the dark brown solid obtained by spin-drying was dissolved in 8ml of ethyl acetate, and then poured into water, the lower organic solution was collected by multiple extraction with ethyl acetate, dried and filtered using anhydrous sodium sulfate, the organic phase was evaporated by spin-drying, and the obtained product was preliminarily purified by separation with a forward silica gel chromatography plate (dichloromethane/methanol). Compound 13 (79 mg, yield about 56%) was obtained as a pale yellow solid.

Example 2: preparation of Compounds 1, 3, 4, 5, 6, 11 and 27

Example 1 was repeated with the difference that: different starting materials were used to produce compounds 1, 3, 4, 5, 6, 11 and 27 in table 1. The method comprises the following steps: compounds 1, 3, 4, 5, 6, 11 and 27 were prepared using cyclopropylmethylamine, methylamine hydrochloride, ethylamine, cyclobutylmethylamine, 2-methylpropan-1-amine, cyclopropylamine and cyclopropylethylamine instead of the starting propyl-2-amine in example 1, respectively.

Example 3: preparation of Compound 21

The synthetic route is as follows:

1) Preparation of 6-chloro-2- ((cyclopropylmethyl) amino) -N- (3-fluoro-4-methoxybenzyl) -3-nitrobenzamide:

the detailed synthesis was similar to that of example 1, 6-chloro-N- (3-fluoro-4-methoxybenzyl) -2- (isopropylamino) -3-nitrobenzamide, except that cyclopropylmethylamine was used instead of propyl-2-amine, and the reaction was refluxed at 80℃for 1.5 hours to obtain a yellow solid (47 mg, yield about 22%).

2) Preparation of 2- ((cyclopropylmethyl) amino) -N- (3-fluoro-4-methoxybenzyl) -6-methoxy-3-nitrobenzamide:

6-chloro-2- ((cyclopropylmethyl) amino) -N- (3-fluoro-4-methoxybenzyl) -3-nitrobenzamide (540 mg,1.3 mmol) and anhydrous potassium carbonate (831 mg,5.3 mmol) are weighed into a round bottom flask, 5ml of anhydrous DMSO and 0.1ml of methanol are added under the protection of argon, the mixture is placed into an oil bath to be heated to 110 ℃ for reaction for 10 hours under reflux, TLC monitors the reaction, after the reaction is completed, the reaction system liquid is poured into water, ethyl acetate is used for multiple extraction, the lower organic phase solution is collected, the collected organic phase is dried and filtered by anhydrous sodium sulfate, the dried organic phase is evaporated in a rotary manner, and the obtained primary product is separated and purified (petroleum ether/ethyl acetate) by a forward silica gel chromatographic column. After work up, a yellow solid was obtained (80 mg, yield about 15%).

3) Preparation of 3-amino-2- ((cyclopropylmethyl) amino) -N- (3-fluoro-4-methoxybenzyl) -6-methoxybenzamide:

the detailed synthesis was similar to that of example 1, 3-amino-6-chloro-N- (3-fluoro-4-methoxybenzyl) -2- (isopropylamino) benzamide, except that the starting material in the reduction was 2- ((cyclopropylmethyl) amino) -N- (3-fluoro-4-methoxybenzyl) -6-methoxy-3-nitrobenzamide, which was refluxed at 80 ℃ under argon protection to give a dark brown oily body (20 mg, yield about 54%).

4) Preparation of compound 21:

the detailed synthesis of compound 21 was similar to that of compound 13, except that the starting material in the cyclization reaction was 3-amino-2- ((cyclopropylmethyl) amino) -N- (3-fluoro-4-methoxybenzyl) -6-methoxybenzamide, which upon completion of the treatment afforded compound 21 as a white solid (20 mg, yield approximately 21.6%).

Example 4: preparation of Compound 2

The synthetic route is as follows:

1) Preparation of 2, 6-bis ((cyclopropylmethyl) amino) -N- (3-fluoro-4-methoxybenzyl) -3-nitrobenzamide:

the detailed synthesis was similar to that of example 1, except that the starting material in the nucleophilic substitution reaction was excessive cyclopropylmethylamine, which was refluxed at 100 ℃ under argon protection for 11.5h, and after the treatment, a pink solid (350 mg, yield about 63%) was obtained.

2) Preparation of 3-amino-2, 6-bis ((cyclopropylmethyl) amino) -N- (3-fluoro-4-methoxybenzyl) benzamide:

the detailed synthesis was similar to that of example 1, except that 2, 6-bis ((cyclopropylmethyl) amino) -N- (3-fluoro-4-methoxybenzyl) -3-nitrobenzamide was used as the starting material in the reduction reaction, and the reaction was refluxed at 80 ℃ under argon protection to give a dark blue oily substance (150 mg, yield about 34%) after the completion of the treatment.

3) Preparation of compound 2:

the detailed synthesis was similar to that of compound 13, except that the starting material in the cyclization reaction was 3-amino-2, 6-bis ((cyclopropylmethyl) amino) -N- (3-fluoro-4-methoxybenzyl) benzamide, which upon completion of the treatment afforded compound 2 as an off-white solid (20 mg, yield about 40%).

Example 5: preparation of Compound 10

The synthetic route is as follows:

3-amino-6-chloro-N- (3-fluoro-4-methoxybenzyl) -2- (methylamino) benzamide (40 mg,0.1 mmol) of example 2, benzene 1,2, 3-triol (2 mg,0.01 mmol) was weighed into a round bottom flask, 5ml of absolute methanol was added, 0.1ml of ethylamine was added, and the mixture was allowed to stand in air at 60℃for reflux reaction for 48 hours, after completion of the TLC monitoring reaction, the reaction system liquid was evaporated by spin-drying, and the obtained preliminary product was purified by forward silica gel column chromatography (dichloromethane/methanol). After completion of the work-up, compound 10 (20 mg, yield about 41%) was obtained as an off-white solid.

Example 6: preparation of Compounds 7, 8, 9, 12, 14, 16, 19, 22, 26, 31

Example 5 was repeated with the difference that: different starting materials were used to produce compounds 7, 8, 9, 12, 14, 16, 19, 22, 26, 31 in table 1. The method comprises the following steps: compounds 7, 8, 9, 14, 16, 19 and 26 were prepared using cyclopropylmethylamine, 2-methylpropan-1-amine, 3-methylbutan-1-amine, cyclopropylethylamine, benzylamine, 4-methylpent-1-amine and 3, 3-dimethylbut-1-amine instead of the starting ethylamine in example 5. Compounds 12 and 22 were prepared using cyclopropylmethylamine, cyclopropylethylamine instead of the starting ethylamine in example 5, and cyclopropylmethylamine instead of the starting methylamine hydrochloride in example 5. Compound 31 was prepared using 3, 4-methylenedioxybenzylamine instead of the starting 3-fluoro-4-methoxybenzylamine of example 5 and cyclopropylethylamine instead of the starting ethylamine of example 5.

Example 7: preparation of Compound 17

The synthesis method comprises the following steps:

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1) Preparation of N- (3-fluoro-4-methoxybenzyl) -6-methoxy-2- (methylamino) -3-nitrobenzamide:

the reaction system was poured into water after completion of the reaction by tlc monitoring, and then extracted with ethyl acetate for several times, the lower organic phase solution was collected, dried over anhydrous sodium sulfate and filtered, and the collected organic phase was evaporated by spin drying under argon protection, and the obtained preliminary product was purified by forward silica gel column chromatography (petroleum ether/ethyl acetate). After work up, a yellow solid was obtained (300 mg, yield about 41%).

2) Preparation of 3-amino-N- (3-fluoro-4-methoxybenzyl) -6-methoxy-2- (methylamino) benzamide:

the detailed synthesis was similar to that of example 1, except that N- (3-fluoro-4-methoxybenzyl) -6-methoxy-2- (methylamino) -3-nitrobenzamide was used as the starting material in the reduction reaction, and the reaction was refluxed at 80℃under argon atmosphere to give a dark brown oily substance (60 mg, yield: about 54%) after the completion of the treatment.

3) Preparation of compound 17:

the detailed synthesis of compound 17 was similar to that of compound 10, except that 3-amino-N- (3-fluoro-4-methoxybenzyl) -6-methoxy-2- (methylamino) benzamide and cyclopropylmethylamine were used as starting materials in the cyclization reaction, and reflux reaction was carried out at 60 ℃ for 72 hours to give compound 17 (20 mg, yield about 29%) as a white solid after the completion of the treatment.

Example 8: preparation of Compounds 20, 23, 24, 25, 28, 29 and 32

Example 7 was repeated with the difference that: different starting materials were used to produce compounds 20, 23, 24, 25, 28, 29 and 32 in table 1. The method comprises the following steps: compounds 20, 24 and 25 were prepared using cyclopropylmethanol, ethanol and cyclopropanol instead of the starting methanol in example 7. Cyclopropylmethylamine substituted for the starting methylamine hydrochloride in example 7, compound 23 was prepared. Compound 28 was prepared using cyclopropylethylamine instead of the starting cyclopropylethylamine in example 7. Compound 29 was prepared using cyclopropylmethanol instead of the starting material methanol in example 7 and cyclopropylethylamine instead of the starting material cyclopropylmethylamine in example 7. Compound 32 was prepared using 3, 4-methylenedioxybenzylamine instead of the starting 3-fluoro-4-methoxybenzylamine of example 7.

Example 9: preparation of Compound 30

The synthetic route is as follows:

the reaction system was poured into water after completion of the TLC monitoring reaction, extracted with ethyl acetate several times, the lower organic phase solution was collected, dried and filtered using anhydrous sodium sulfate, and the collected organic phase was evaporated by spin drying, and the resulting preliminary product was separated and purified by a forward silica gel column chromatography. After completion of the work-up, compound 30 (50 mg, yield: about 16%) was obtained as a yellow solid

Example 10: preparation of Compound 15

The synthetic route is as follows:

compound 14 (90 mg,0.2 mmol) from example 6 dissolved in 3ml methanol was added to a 50ml round bottom flask equipped with a magnetic stirrer. To the stirred solution was added 6ml of 35% hydrochloric acid solution. Stirred at room temperature for 24h. The solvent was removed under reduced pressure to give compound 15 (95 mg, yield: about 97%) as a white solid.

Example 11: preparation of Compound 18

Example 10 was repeated with the difference that: different starting materials were used to produce compound 18 of table 1. The method comprises the following steps: compound 17 was used instead of starting compound 14 in example 10 to produce compound 18.

The chemical structure and nuclear magnetism hydrogen spectrum and mass spectrum data of the target product of the formula I synthesized by the invention are shown in table 1.

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Example 12: ALDH2 agonist activity assay

The basic principle of the target compound ALDH2 agonistic activity test is that the enzyme is positioned in NAD ⁺ With the aid of (a) oxidation of acetaldehyde to acetic acid, with simultaneous reduction of NAD ⁺ NADH, therefore, the rate of NADH formation is proportional to the activity of ALDH2, and a dye is used to couple with NADH to form a yellow product, and the absorbance value of the yellow product at 450nm is monitored to obtain the concentration change of NADH. From this, the agonistic activity of the enzyme under the action of the target compound can be calculated. The maximum activation times of the compounds to the enzyme are measured as evaluation indexes, and the ALDH2 agonist Alda-1 is used as a control drug.

Numbering of compounds	Maximum activation multiple
		12	++++
14	++++
		17	++++
21	++++
		22	++++
23	++++
		28	++++
31	++++
		32	++++

^* ++++: the activity is more than 200% of that of the positive medicine Alda-1; +++: the activity is 150-200% of that of the positive medicine Alda-1; ++: the activity is 100-150% of that of the positive medicine Alda-1; +: the activity was comparable to that of the positive drug Alda-1 (science.2008, 321 (589) 5):1493-5)

The results show that the amide compounds of the invention show good ALDH2 agonistic activity, so that the compounds have potential application in preparing medicines for treating diseases related to the ALDH2 activity. Compounds 1 to 11, 13, 15 to 16, 18 to 20, 24 to 27, and 29 to 30 also have good ALDH2 agonistic activity.

Example 13: determination of solubility

HPLC methods were used to test the solubility of some of the target compounds. By accurately weighing a proper amount of sample, gradually adding physiological saline, shaking in an oscillator until the sample is fully dissolved, and detecting by HPLC, a standard curve is obtained. A sample saturated solution was then prepared in a similar manner and tested using the HPLC method. The results show that the solubility of compounds 15 and 18 in physiological saline is improved by more than 100 times compared with that of Alda-1, and the solubility of other compounds in physiological saline is improved by more than 10 times compared with that of Alda-1.

Example 14: protective Activity test in the nerve cell glycoxygen deprivation model (OGD)

The protection of a portion of the target compounds against neuroblastoma cells SH-SY5Y treated with glucose oxygen deprivation (OGD) was examined using the MTT method. These models can to some extent each simulate global level cerebral ischemia reperfusion injury. Neuroblastoma cells SH-SY5Y with good growth state are grown at a ratio of 5×10 ⁴ The plating density of each/mL was plated on 96-well cell culture plates and given OGD treatment and drug stimulation, respectively. mu.L of MTT solution (5 mg/mL, i.e., 0.5% MTT) was added to each well, incubation was continued in an incubator at 37℃for 4 hours, and the viability of the cells was determined after treatment. Wherein the survival rate of the cells of the normal group which is not treated by OGD is unified as 100%, and the survival rate of the cells of the other groups is the ratio of the cells of the other groups to the normal group. The results show that the cell viability of the 100 mu M compound groups treated with compounds 14, 15, 17 and 18 is significantly better than that of the positive drug Alda-1 treated group.

Example 15: protection activity test on rat myocardial and cerebral ischemia reperfusion injury model

Healthy SD rats are subjected to grouping after adaptive feeding, each group of rats is anesthetized by diethyl ether, hearts are separated, a 5/0 atraumatic suture line is used for penetrating through the superficial layer of cardiac muscle at the lower edge of auricles, and the rats are subjected to ischemia for 35min by a push tube method and then are subjected to filling for 60min. The test sample or control was administered 5min prior to ischemia. After the experiment, abdominal aorta was collected, centrifuged at 3000 rpm for 10min, and CK (creatine kinase) activity and LDH (lactate dehydrogenase) activity were measured. The heart was taken and cut into 4 pieces from the apex of the heart along the area below the ligation site. TTC staining, tracing the myocardium after staining, photographing, and calculating the ratio of the dead area of the peduncles to the area of the ischemic area. The results show that the myocardial infarction area of the rats after single administration of the compounds 15 and 18 at 20mg/kg is obviously reduced compared with the model control group, and the effect of the positive medicament Alda-1 with the same molar concentration dosage is obviously better.

Healthy SD rats were grouped after adaptive feeding, after each group of rats was anesthetized with chloral hydrate, and after 15min of dosing, the rats were subjected to MCAO surgery and reperfusion for 24h after 2h of ischemia. All groups of rats are anesthetized by chloral, then brain tissues are taken after end breakage, the rats are put into 1% TTC dye solution for incubation, 4% paraformaldehyde is used for fixation, and the rats are photographed to count cerebral infarction volume. The results show that the cerebral infarction area of the rats after single administration of the compounds 15 and 18 at 20mg/kg is obviously reduced compared with the model control group, and the effect of the positive medicament Alda-1 with the same molar concentration dosage is obviously better.

The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and improvements could be made by those skilled in the art without departing from the inventive concept, which falls within the scope of the present invention.

Claims (10)

1. A compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein,

x is C, O or N;

y is C, O or N; the dotted line represents a single bond, a double bond, or a single bond by double bond;

R ₁ 、R ₂ each independently selected from hydrogen, C _1-6 Alkyl, amino, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Cycloalkyl, or absent; or C as described therein _1-6 Alkyl, amino, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Cycloalkyl radicals optionally further being selected from hydrogen atoms, C _1-6 Alkyl, halogen, hydroxy, amino, nitro, cyano, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Alkoxy, C _1-6 One or more substituents in cycloalkyl; or C as described _1-6 Alkyl, amino, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Cycloalkyl groups optionally being selected from hydrogen atoms, C _1-6 Alkyl, halogen, hydroxy, amino, nitro, cyano, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Further one or more substituents in the cycloalkyl group are optionally further substituted by one or more substituents selected from the group consisting of hydrogen atoms, C _1-6 Alkyl, halogen, hydroxy, amino, nitro, cyano, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Alkoxy, C _1-6 One or more substitutions in cycloalkyl;

R ₃ selected from hydrogen, C _1-6 Alkyl, amino, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Cycloalkyl, aryl, or absent; or C as described therein _1-6 Alkyl, amino, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Cycloalkyl, aryl is optionally further selected from hydrogen atoms, C _1-6 Alkyl, halogen, hydroxy, amino, nitro, cyano, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Alkoxy, C _1-6 One or more substituents in cycloalkyl;

R ₄ selected from hydrogen, amino, halogen, C _1-6 Alkoxy, C _1-6 Cycloalkoxy, -NH (CH) ₂ ) _n R _aa The method comprises the steps of carrying out a first treatment on the surface of the Or wherein said amino, C _1-6 Alkoxy, C _1-6 The cycloalkoxy group is optionally further selected from hydrogen atoms, C _1-6 Alkyl, halogen,Hydroxy, amino, nitro, cyano, C _1-6 Alkenyl, C _1-6 Alkynyl, C _1-6 Alkoxy, C _1-6 One or more substituents in cycloalkyl; wherein said-NH (CH) ₂ ) _n R _aa N is 1, 2, 3, 4 or 5, R _aa Selected from C _1-6 Cycloalkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C _1-6 Alkenyl, C _1-6 Alkynyl, heterocyclyl, aryl, and heteroaryl;

R ₅ 、R ₆ each independently selected from H, halogen, C _1-6 Alkyl, C _1-6 Alkoxy or C _1-6 A carbonyl group; or R is ₅ 、R ₆ Are mutually connected to form five-membered cycloalkyl or five-membered heterocycloalkyl; wherein R is ₅ 、R ₆ Not simultaneously selected from H.

2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein,

x is N;

y is N; the dotted line represents a single bond and a double bond;

R ₁ 、R ₂ each independently selected from hydrogen, C _1-6 Alkyl, C _1-6 Cycloalkyl, or absent; or C as described therein _1-6 Alkyl, C _1-6 Cycloalkyl radicals optionally further being selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 One or more substituents in cycloalkyl; r is R ₃ Selected from hydrogen, C _1-6 Alkyl, C _1-6 Cycloalkyl, aryl; or C as described therein _1-6 Alkyl, C _1-6 Cycloalkyl, aryl is optionally further selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 One of cycloalkyl groupsOr a plurality of substituents;

R ₄ selected from amino, halogen, C _1-6 Alkoxy, C _1-6 Cycloalkoxy, -NH (CH) ₂ ) _n R _aa The method comprises the steps of carrying out a first treatment on the surface of the Or C as described therein _1-6 Alkoxy groups further being selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 One or more substituents in cycloalkyl; wherein said-NH (CH) ₂ ) _n R _aa N is 1, 2, 3, 4 or 5, R _aa Selected from C _1-6 Cycloalkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, halogen, cyano, nitro, hydroxy, amino, C _1-6 Alkenyl, C _1-6 Alkynyl, heterocyclyl, aryl, and heteroaryl;

R ₅ 、R ₆ each independently selected from halogen, C _1-6 Alkyl, C _1-6 An alkoxy group; or R is ₅ 、R ₆ Are connected with each other to form five-membered cycloalkyl or five-membered heterocycloalkyl.

3. The compound of claim 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein,

x is N;

y is N; the dotted line represents a single bond, a double bond;

R ₁ selected from hydrogen, C _1-6 Alkyl, C _1-6 Cycloalkyl, or absent; or C as described therein _1-6 The alkyl group being further selected from C _1-6 Alkoxy, C _1-6 One or more substituents in cycloalkyl;

R ₂ Selected from hydrogen or absence;

R ₃ selected from hydrogen, C _1-6 Alkyl, C _1-6 Cycloalkyl, aryl; or C as described therein _1-6 The alkyl groups and aryl groups are optionally further selected from hydrogen atoms、C _1-6 One or more substituents in cycloalkyl;

R ₄ selected from halogen, C _1-6 Alkoxy, C _1-6 Cycloalkoxy, -NH (CH) ₂ ) _n R _aa The method comprises the steps of carrying out a first treatment on the surface of the Or C as described therein _1-6 Alkoxy is further selected from C _1-6 One or more substituents in cycloalkyl; wherein said-NH (CH) ₂ ) _n R _aa N is 1, 2, 3, 4, R _aa Selected from C _1-6 Cycloalkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups;

R ₅ selected from C _1-6 Alkyl, C _1-6 An alkoxy group;

R ₆ selected from halogen, C _1-6 Alkyl, C _1-6 An alkoxy group;

or R is ₅ 、R ₆ Are connected with each other to form five-membered heterocyclic alkyl.

4. A compound according to claim 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein,

x is N;

y is N; the dotted line represents a single bond, a double bond;

R ₁ selected from hydrogen, C _1-6 Alkyl, C _1-6 Cycloalkyl, or absent; or C as described therein _1-6 The alkyl group being further selected from C _1-6 One or more substituents in cycloalkyl;

R ₂ selected from hydrogen or absence;

R ₃ selected from hydrogen, C _1-6 Alkyl, C _1-6 Cycloalkyl, aryl; or C as described therein _1-6 The alkyl group being further selected from C _1-6 One or more substituents in cycloalkyl;

R ₄ Selected from halogen, C _1-6 Alkoxy, C _1-6 Cycloalkoxy, -NH (CH) ₂ ) _n R _aa The method comprises the steps of carrying out a first treatment on the surface of the Or C as described therein _1-6 Alkoxy is further selected from C _1-6 One or more substituents in cycloalkyl; wherein said-NH (CH) ₂ ) _n R _aa N is 1, 2, 3, 4, R _aa Selected from C _1-6 Cycloalkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy groups;

R ₅ selected from C _1-6 An alkoxy group;

R ₆ selected from halogen;

or R is ₅ 、R ₆ Are connected with each other to form five-membered heterocyclic alkyl.

5. The compound of claim 4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein,

x is N;

y is N; the dotted line represents a single bond, a double bond;

R ₁ selected from hydrogen, C _1-6 Alkyl, C _1-6 Cycloalkyl, or absent; or C as described therein _1-6 The alkyl group being further selected from C _1-6 One or more substituents in cycloalkyl;

R ₂ selected from hydrogen or absence;

R ₃ selected from hydrogen, C _1-6 Alkyl, C _1-6 Cycloalkyl, benzene ring; or C as described therein _1-6 The alkyl group being further selected from C _1-6 One or more substituents in cycloalkyl;

R ₄ selected from halogen, C _1-6 Alkoxy, C _1-6 Cycloalkoxy, -NH (CH) ₂ ) _n R _aa The method comprises the steps of carrying out a first treatment on the surface of the Or C as described therein _1-6 Alkoxy group is furtherThe step quilt is selected from C _1-6 One or more substituents in cycloalkyl; wherein said-NH (CH) ₂ ) _n R _aa N is 1, 2, 3, 4, R _aa Selected from C _1-6 Cycloalkyl;

R ₅ selected from C _1-6 An alkoxy group;

R ₆ selected from halogen;

or R is ₅ 、R ₆ Are mutually connected to form five-membered oxacycloalkyl.

6. The compound according to any one of claims 1 to 5, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the formula I is selected from the group consisting of:

7. a pharmaceutical composition comprising a therapeutically effective dose of a compound of formula I as defined in any one of claims 1 to 6, and stereoisomers, or pharmaceutically acceptable salts, hydrates or solvates thereof, and 9 one or more pharmaceutically acceptable carriers, diluents or excipients.

8. Use of a compound of formula I according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the treatment of a disease or condition associated with aldehyde dehydrogenase 2 activity.

9. The use according to claim 8, wherein the diseases or symptoms associated with aldehyde dehydrogenase 2 activity include acute alcoholism, malignancy, cardiovascular and cerebrovascular diseases, diabetes, neurodegenerative diseases, fanconi anemia, pain, osteoporosis, radiodermatitis, and metastasis of malignancy; the cardiovascular and cerebrovascular diseases comprise myocardial ischemia, heart failure, ischemic brain injury and ischemic cerebral apoplexy.

10. The use according to claim 9, wherein the compound of formula I, and stereoisomers thereof, or pharmaceutically acceptable salts, hydrates or solvates thereof, or the pharmaceutical composition is to be administered by a route selected from intramuscular, intravenous, subcutaneous, topical and oral.