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Definitions

• the present disclosure relates to heterocyclic compounds, preparation methods thereof, and their use as TAAR1 agonists in the treatment of related diseases.
• Trace amine receptors are a family of G protein-coupled receptors activated by endogenous biogenic amines. Six TAARs and three pseudogenes have been identified in humans. Among all TAARs, TAAR1 is the most studied and is widely expressed in the mammalian brain, particularly in limbic and monoaminergic regions. TAAR1 can regulate presynaptic dopaminergic neurotransmission function; it can also induce the activation of G protein-coupled inward rectifier potassium channels and reduce the firing frequency of neurons. TAAR1 may become a potential therapeutic target for the treatment of psychiatric disorders such as schizophrenia, depression, Parkinson's disease psychosis, psychobehavioral symptoms of dementia, anxiety, migraine, and ADHD.
• psychiatric disorders such as schizophrenia, depression, Parkinson's disease psychosis, psychobehavioral symptoms of dementia, anxiety, migraine, and ADHD.
• TAAR1 TAAR1 selective agonists.
• amphetamine was approved by the FDA for the treatment of attention deficit disorder with hyperactivity, but this The compound has strong excitability to the central nervous system. Short-term effects can cause accelerated heartbeat, increased blood pressure, feeling happy, and reduce fatigue. Long-term use can cause insomnia, irritability, delusions and hallucinations, violence and aggressive behavior and other adverse reactions. It has been listed as For controlled drugs.
• RG-7906, RO-5263397, and SEP-363856 are all TAAR1 selective agonists.
• RG-7906 is in clinical phase II
• RO-5263397 is in clinical phase I suspension
• SEP-363856 which is progressing the fastest, is in clinical phase II. It is in phase III clinical research stage. Therefore, there is a need to develop new TAAR1 agonists with improved safety and efficacy to meet the needs of patients.
• a 1 is selected from CR 2 or N atom
• a 2 is selected from CR 2 or O atom
• R 1 is selected from H, halogen, C 1-6 alkyl, or C 1-6 alkoxy;
• Each R 2 is independently selected from H, or C 1-6 alkyl.
• a 1 is selected from CR 2 or N atom
• a 2 is selected from CR 2 or O atom
• R 1 is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, methoxy , Ethoxy, n-propoxy, isopropoxy;
• Each R is independently selected from H, methyl, or ethyl.
• a 1 is selected from CR 2 or N atom
• a 2 is selected from CR 2 or O atom
• R 1 is selected from H, F, methyl, or methoxy
• Each R2 is independently selected from H, or methyl.
• a 1 is selected from CR 2 or N atom
• a 2 is selected from CR 2 or O atom
• R 1 is selected from H, F, methyl, or methoxy
• R 2 is independently selected from H, or methyl.
• a 1 is selected from CH, or N atoms
• a 2 is selected from CH 2 or O atom
• R 1 is selected from H, halogen, C 1-6 alkyl, or C 1-6 alkoxy;
• R 2 is selected from H, C 1-6 alkyl, or a group represented by the following formula:
• Z 1 is selected from bond, or C 1-3 alkyl
• a 1 is selected from CH, or N atoms
• a 2 is selected from CH 2 or O atom
• R 1 is selected from H, F, methyl, or methoxy
• R 2 is selected from H, methyl, or a group represented by the following formula:
• Z 1 is selected from bond, methyl, ethyl, n-propyl, isopropyl;
• a 1 is selected from CH, or N atoms
• a 2 is selected from CH 2 or O atom
• R 1 is selected from H, F, methyl, or methoxy
• R 2 is selected from H, methyl, isopropyl, OH,
• the compound represented by formula (IA-3) or (IA-4), its pharmaceutically acceptable salt, or stereoisomer is formula (IA-1) or (IA-2 ), a pharmaceutically acceptable salt thereof, or a prodrug of a stereoisomer.
• a 1 is selected from O atoms or S atoms
• (2)A 1 is selected from NH
• Each R 2 is independently selected from H, or C 1-6 alkyl
• (3)A 1 is selected from CH 2 ;
• Each R 2 is independently selected from H, or C 1-6 alkyl.
• a 1 is selected from O atom or S atom;
• R 2 is independently selected from H, or methyl.
• a 1 is selected from NH
• R 2 is independently selected from H, or methyl.
• a 1 is selected from CH 2 ;
• R 2 is independently selected from H, or methyl.
• a 1 is selected from O atoms or S atoms
• Each R 2 is independently selected from H, or methyl
• (2)A 1 is selected from NH
• Each R 2 is independently selected from H, or methyl
• (3)A 1 is selected from CH 2 ;
• Each R2 is independently selected from H, or methyl.
• X 1 is selected from S atom or O atom
• X 2 is selected from CH
• X 2 is selected from S atom or O atom
• X 1 is selected from CH
• Y 1 is selected from O atoms
• Y 2 is selected from C (R 5a R 5b ), Y 3 is selected from C (R 6a R 6b ), when When it is a double bond, Y 2 is selected from CR 5a and Y 3 is selected from CR 6a ;
• R 3a and R 3b are selected from H, the other is selected from C 1-6 alkyl, or both R 3a and R 3b are selected from C 1-6 alkyl;
• Y 1 is selected from NR 4 or S atoms
• Y 2 is selected from C (R 5a R 5b ), Y 3 is selected from C (R 6a R 6b ), when When it is a double bond, Y 2 is selected from CR 5a and Y 3 is selected from CR 6a ;
• R 3a and R 3b are selected from H, the other is selected from C 1-6 alkyl, or both R 3a and R 3b are selected from H;
• R 4 is independently selected from H or C 1-6 alkyl
• Y 3 is selected from O atoms, NR 6 , or S atoms;
• Y 1 is selected from C(R 4a R 4b ) or Y 1 does not exist, Y 2 is selected from C(R 5a R 5b );
• R 3a and R 3b are independently selected from H or C 1-6 alkyl
• R 6 is independently selected from H or C 1-6 alkyl.
• Y 1 is selected from O atoms
• Y 2 is selected from C (R 5a R 5b ), Y 3 is selected from C (R 6a R 6b ), when When it is a double bond, Y 2 is selected from CR 5a and Y 3 is selected from CR 6a ;
• R 3a and R 3b are selected from H, the other is selected from C 1-6 alkyl, or both R 3a and R 3b are selected from C 1-6 alkyl;
• R 5a , R 5b , R 6a are independently selected from H, C 1-6 alkyl, C 1-3 alkoxy C 1-3 alkyl, or C 6-10 aryl
• R 5a and R 5b are independently selected from H, C 1-6 alkyl, C 1-3 alkoxy C 1-3 alkyl, or C 6-10 aryl, and R 6a and R 6b are simultaneously selected from C 1-6 alkyl;
• R 5a and R 5b are simultaneously selected from C 1-6 alkyl, and R 6a and R 6b are independently selected from H, C 1-6 alkyl, C 1-3 alkoxy C 1-3 alkyl, or C 6-10 aryl;
• Y 1 is selected from NR 4 or S atoms
• Y 2 is selected from C (R 5a R 5b ), Y 3 is selected from C (R 6a R 6b ), when When it is a double bond, Y 2 is selected from CR 5a and Y 3 is selected from CR 6a ;
• R 3a and R 3b are selected from H, and the other is selected from C 1-6 alkyl;
• R 4 is independently selected from H or C 1-6 alkyl
• Y 3 is selected from O atoms, NR 6 , or S atoms;
• Y 1 is selected from C(R 4a R 4b ) or Y 1 does not exist, Y 2 is selected from C(R 5a R 5b );
• R 3a and R 3b are independently selected from H or C 1-6 alkyl
• R 6 is independently selected from H or C 1-6 alkyl.
• X 1 is selected from S atom or O atom
• X 2 is selected from CH; others Variables are as defined in this disclosure.
• X 2 is selected from S atom or O atom, and X 1 is selected from CH; others Variables are as defined in this disclosure.
• R 3a and R 3b are selected from H, the other is selected from methyl, or both R 3a and R 3b are selected from methyl;
• R 4 is independently selected from H, or methyl
• R 6 is independently selected from H or methyl
• X 1 is selected from S atom or O atom, X 2 is selected from CH;
• Y 1 is selected from O atoms
• Y 2 is selected from C (R 5a R 5b ), Y 3 is selected from C (R 6a R 6b ), when When it is a double bond, Y 2 is selected from CR 5a and Y 3 is selected from CR 6a ;
• R 3a and R 3b are selected from H, the other is selected from methyl, or both R 3a and R 3b are selected from methyl;
• formula (II) its pharmaceutically acceptable salt, or stereoisomer
• X 1 is selected from S atom or O atom, X 2 is selected from CH;
• Y 1 is selected from O atoms
• Y 2 is selected from C (R 5a R 5b )
• Y 3 is selected from C (R 6a R 6b )
• Y 2 is selected from CR 5a and Y 3 is selected from CR 6a ;
• R 3a and R 3b are selected from H, the other is selected from methyl, or both R 3a and R 3b are selected from methyl;
• R 5a , R 5b , and R 6a are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl
• R 5a and R 5b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, and R 6a and R 6b are simultaneously selected from methyl;
• R 5a and R 5b are simultaneously selected from methyl, and R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl.
• X 1 is selected from S atom or O atom, X 2 is selected from CH;
• Y 1 is selected from NR 4 or S atoms
• Y 2 is selected from C (R 5a R 5b ), Y 3 is selected from C (R 6a R 6b ), when When it is a double bond, Y 2 is selected from CR 5a and Y 3 is selected from CR 6a ;
• R 3a and R 3b are selected from H, the other is selected from methyl, or both R 3a and R 3b are selected from H;
• R 4 is independently selected from H or methyl
• X 1 is selected from S atom or O atom, X 2 is selected from CH;
• Y 1 is selected from NR 4 or S atoms
• Y 2 is selected from C (R 5a R 5b ), Y 3 is selected from C (R 6a R 6b ), when When it is a double bond, Y 2 is selected from CR 5a and Y 3 is selected from CR 6a ;
• R 3a and R 3b are selected from H, and the other is selected from methyl;
• R 4 is independently selected from H or methyl
• X 1 is selected from S atom or O atom, X 2 is selected from CH;
• Y 3 is selected from O atoms, NR 6 , or S atoms;
• Y 1 is selected from C(R 4a R 4b ) or Y 1 does not exist, Y 2 is selected from C(R 5a R 5b );
• R 3a and R 3b are independently selected from H or methyl
• R 6 is independently selected from H or methyl.
• X 1 is selected from S atom or O atom, X 2 is selected from CH;
• Y 3 is selected from O atoms, NR 6 , or S atoms;
• Y 1 is selected from C(R 4a R 4b ) or Y 1 does not exist, Y 2 is selected from C(R 5a R 5b );
• R 3a and R 3b are independently selected from H or methyl
• R 6 is independently selected from H or methyl.
• X 1 is selected from S atoms, X 2 is selected from CH;
• Y 1 is selected from NR 4 or S atoms
• Y 2 and Y 3 are both selected from CH 2 ,
• R 3a and R 3b are selected from H, and the other is selected from methyl;
• R 4 is selected from H or C 1-6 alkyl, preferably H or methyl.
• X 1 is selected from S atom or O atom
• X 2 is selected from CH
• X 2 is selected from S atom or O atom
• X 1 is selected from CH
• Y 1 is selected from O atoms
• Y 2 is selected from C (R 5a R 5b ), Y 3 is selected from C (R 6a R 6b ), when When it is a double bond, Y 2 is selected from CR 5a and Y 3 is selected from CR 6a ;
• R 3a and R 3b are selected from H, the other is selected from C 1-6 alkyl, or both R 3a and R 3b are selected from C 1-6 alkyl;
• Y 1 is selected from NR 4 or S atoms
• Y 2 is selected from C (R 5a R 5b ), Y 3 is selected from C (R 6a R 6b ), when When it is a double bond, Y 2 is selected from CR 5a and Y 3 is selected from CR 6a ;
• R 3a and R 3b are selected from H, the other is selected from C 1-6 alkyl, or both R 3a and R 3b are selected from H;
• R 4 is independently selected from H or C 1-6 alkyl
• Y 3 is selected from O atoms, NR 6 , or S atoms;
• Y 1 is selected from C(R 4a R 4b ) or Y 1 does not exist, Y 2 is selected from C(R 5a R 5b );
• R 3a and R 3b are independently selected from H or C 1-6 alkyl
• R 6 is independently selected from H or C 1-6 alkyl.
• Y 1 is selected from O atoms
• Y 2 is selected from C (R 5a R 5b )
• Y 3 is selected from C (R 6a R 6b )
• Y 2 is selected from CR 5a and Y 3 is selected from CR 6a ;
• R 3a and R 3b are selected from H, the other is selected from C 1-6 alkyl, or both R 3a and R 3b are selected from C 1-6 alkyl;
• R 5a , R 5b , R 6a are independently selected from H, C 1-6 alkyl, C 1-3 alkoxy C 1-3 alkyl, or C 6-10 aryl
• R 5a and R 5b are independently selected from H, C 1-6 alkyl, C 1-3 alkoxy C 1-3 alkyl, or C 6-10 aryl, and R 6a and R 6b are simultaneously selected from C 1-6 alkyl;
• R 5a and R 5b are simultaneously selected from C 1-6 alkyl, and R 6a and R 6b are independently selected from H, C 1-6 alkyl, C 1-3 alkoxy C 1-3 alkyl, or C 6-10 aryl;
• Y 1 is selected from NR 4 or S atoms
• Y 2 is selected from C (R 5a R 5b ), Y 3 is selected from C (R 6a R 6b ), when When it is a double bond, Y 2 is selected from CR 5a and Y 3 is selected from CR 6a ;
• R 3a and R 3b are selected from H, and the other is selected from C 1-6 alkyl;
• R 4 is independently selected from H or C 1-6 alkyl
• Y 3 is selected from O atoms, NR 6 , or S atoms;
• Y 1 is selected from C(R 4a R 4b ) or Y 1 does not exist, Y 2 is selected from C(R 5a R 5b );
• R 3a and R 3b are independently selected from H or C 1-6 alkyl
• R 6 is independently selected from H or C 1-6 alkyl.
• X 1 is selected from S atom or O atom, and X 2 is selected from CH; other variables As defined in this disclosure.
• X 2 is selected from S atom or O atom, and X 1 is selected from CH; other variables As defined in this disclosure.
• R 3a and R 3b are selected from H, the other is selected from methyl, or both R 3a and R 3b are selected from methyl;
• R 4 is independently selected from H, or methyl
• R 6 is independently selected from H or methyl
• X 1 is selected from S atom or O atom, X 2 is selected from CH;
• Y 1 is selected from O atoms
• Y 2 is selected from C (R 5a R 5b ), Y 3 is selected from C (R 6a R 6b ), when When it is a double bond, Y 2 is selected from CR 5a and Y 3 is selected from CR 6a ;
• R 3a and R 3b are selected from H, the other is selected from methyl, or both R 3a and R 3b are selected from methyl;
• X 1 is selected from S atom or O atom, X 2 is selected from CH;
• Y 1 is selected from O atoms
• Y 2 is selected from C (R 5a R 5b )
• Y 3 is selected from C (R 6a R 6b )
• Y 2 is selected from CR 5a and Y 3 is selected from CR 6a ;
• R 3a and R 3b are selected from H, the other is selected from methyl, or both R 3a and R 3b are selected from methyl;
• R 5a , R 5b , and R 6a are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl
• R 5a and R 5b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl, and R 6a and R 6b are simultaneously selected from methyl;
• R 5a and R 5b are simultaneously selected from methyl, and R 6a and R 6b are independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, and phenyl.
• X 1 is selected from S atom or O atom, and X 2 is selected from since CH;
• Y 1 is selected from NR 4 or S atoms
• Y 2 is selected from C (R 5a R 5b ), Y 3 is selected from C (R 6a R 6b ), when When it is a double bond, Y 2 is selected from CR 5a and Y 3 is selected from CR 6a ;
• R 3a and R 3b are selected from H, the other is selected from methyl, or both R 3a and R 3b are selected from H;
• R 4 is independently selected from H or methyl
• X 1 is selected from S atom or O atom, and X 2 is selected from since CH;
• Y 1 is selected from NR 4 or S atoms
• Y 2 is selected from C (R 5a R 5b ), Y 3 is selected from C (R 6a R 6b ), when When it is a double bond, Y 2 is selected from CR 5a and Y 3 is selected from CR 6a ;
• R 3a and R 3b are selected from H, and the other is selected from methyl;
• R 4 is independently selected from H or methyl
• X 1 is selected from S atom or O atom, and X 2 is selected from since CH;
• Y 3 is selected from O atoms, NR 6 , or S atoms;
• Y 1 is selected from C(R 4a R 4b ) or Y 1 does not exist, Y 2 is selected from C(R 5a R 5b );
• R 3a and R 3b are independently selected from H or methyl
• R 6 is independently selected from H or methyl.
• X 2 is selected from S atom or O atom, and X 1 is selected from since CH;
• Y 1 is selected from O atoms
• Y 2 is selected from C (R 5a R 5b ), Y 3 is selected from C (R 6a R 6b ), when When it is a double bond, Y 2 is selected from CR 5a and Y 3 is selected from CR 6a ;
• R 3a and R 3b are selected from H, the other is selected from methyl, or both R 3a and R 3b are selected from methyl;
• X 2 is selected from S atom or O atom, and X 1 is selected from since CH;
• Y 1 is selected from NR 4 or S atoms
• Y 2 is selected from C (R 5a R 5b )
• Y 3 is selected from C (R 6a R 6b )
• Y 2 is selected from CR 5a and Y 3 is selected from CR 6a ;
• R 3a and R 3b are selected from H, the other is selected from methyl, or both R 3a and R 3b are selected from H;
• R 4 is independently selected from H or methyl
• X 2 is selected from S atom or O atom, and X 1 is selected from since CH;
• Y 3 is selected from O atoms, NR 6 , or S atoms;
• Y 1 is selected from C(R 4a R 4b ) or Y 1 does not exist, Y 2 is selected from C(R 5a R 5b );
• R 3a and R 3b are independently selected from H or methyl
• R 6 is independently selected from H or methyl.
• X 1 is selected from S atom or O atom, and X 2 is selected from since CH;
• Y 3 is selected from O atoms, NR 6 , or S atoms;
• Y 1 is selected from C(R 4a R 4b ) or Y 1 does not exist, Y 2 is selected from C(R 5a R 5b );
• R 3a and R 3b are independently selected from H or methyl
• R 6 is independently selected from H or methyl.
• X 1 is selected from S atom, and X 2 is selected from CH;
• Y 1 is selected from NR 4 or S atoms
• Y 2 and Y 3 are both selected from CH 2 ,
• R 3a and R 3b are selected from H, and the other is selected from methyl;
• R 4 is selected from H or C 1-6 alkyl, preferably H or methyl.
• X 3 is selected from S atoms or O atoms
• Y 2 is selected from C(R 5a R 5b ), Y 3 is selected from O atom, NR 6 , or S atom;
• R 3a and R 3b are independently selected from H or C 1-6 alkyl
• R 5a is independently selected from H, C 1-6 alkyl, C 1-3 alkoxy C 1-3 alkyl, or C 6-10 aryl
• R 6 is independently selected from H or C 1-6 alkyl.
• R 3a and R 3b are independently selected from H or methyl
• R 5a is independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl
• R 6 is independently selected from H or methyl.
• X 3 is selected from S atoms or O atoms
• Y 2 is selected from C(R 5a R 5b ), Y 3 is selected from O atom, NR 6 , or S atom;
• R 3a and R 3b are independently selected from H or C 1-6 alkyl
• R 5a is independently selected from H, C 1-6 alkyl, C 1-3 alkoxy C 1-3 alkyl, or C 6-10 aryl
• R 5b is independently selected from C 1-6 alkyl, C 1-3 alkane
• Oxygen C 1-3 alkyl, or C 6-10 aryl, or R 5a and R 5b together form an oxo group (-C O);
• R 6 is independently selected from H or C 1-6 alkyl.
• R 3a and R 3b are independently selected from H or methyl
• R 5a is independently selected from H, methyl, ethyl, n-propyl, isopropyl, methoxymethyl, phenyl
• R 6 is independently selected from H or methyl.
• the present disclosure also provides a pharmaceutical composition, including any of the above compounds or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
• the pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, granules, injections, etc.
• the pharmaceutical composition can be administered orally or parenterally (eg, intravenously, subcutaneously, topically, etc.). The dosage can be adjusted appropriately according to the patient's age, gender and disease type.
• the general daily dosage is about 1-200 mg.
• the present disclosure also provides the use of the above compounds, their pharmaceutically acceptable salts, stereoisomers, or pharmaceutical compositions in the preparation of TAAR, especially TAAR1 agonist drugs.
• the present disclosure also provides the use of the above compounds, their pharmaceutically acceptable salts, stereoisomers, or pharmaceutical compositions in the preparation of drugs for treating TAAR, especially TAAR1-mediated related diseases.
• the present disclosure also provides the use of the above-mentioned compounds, their pharmaceutically acceptable salts, stereoisomers, or pharmaceutical compositions to prevent and/or treat TAAR, especially TAAR1-mediated related diseases.
• the present disclosure provides methods of treating, preventing and/or controlling various central nervous system (CNS) related diseases or symptoms using the compounds provided by the present disclosure, pharmaceutically acceptable salts, stereoisomers, or compositions thereof.
• the present disclosure also provides compounds provided by the present disclosure, pharmaceutically acceptable salts, stereoisomers, or compositions thereof for the preparation of medicaments for treating, preventing, and/or controlling various central nervous system (CNS)-related diseases or symptoms. applications in.
• the central nervous system (CNS) diseases or symptoms include, but are not limited to: schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, psychotic disorder, schizophrenia personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, mental disorder due to physical illness, drug (e.g., cocaine, alcohol, amphetamine)-induced psychosis, psychoaffective disorder , aggressive psychosis, Parkinson's psychosis, irritant psychosis, Tourette's syndrome, organic or NOS psychosis, epilepsy, seizures, agitation, post-traumatic stress disorder, behavioral disorders, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Dyskinesias, Huntington's disease, dementia, affective disorders, anxiety disorders, affective psychoses (e.g., depression, e.g., major depressive disorder and dysthymia); bipolar disorder Disorders such as bipolar depression; mania; seasonal affective psychosis; and attention deficit disorder
• neuropathic pain neuropathic pain susceptibility states and inflammatory pain
• fibromyalgia migraine, cognitive impairment, movement disorder, restless leg syndrome (RLS), multiple sclerosis
• psychiatric Substance abuse e.g., nicotine, cocaine
• stress-related disorders e.g., acute stress disorder, post-traumatic stress disorder, adjustment disorders
• sexual dysfunction eating disorders, body temperature homeostasis and dysfunction
• sleep disorders sleep apnea, narcolepsy
• excessive daytime sleepiness jet lag, drowsiness side effects of medications
• insomnia sleep and circadian rhythm disorders
• energy expenditure and anabolic disorders vomiting, Lesche-Nyhane disease, Wilson disease, autism, Huntington's disease Chorea and premenstrual dysphoria.
• the present disclosure provides methods of treating, preventing, and/or controlling cardiovascular or metabolic diseases using the compounds provided by the present disclosure, pharmaceutically acceptable salts, stereoisomers, or compositions thereof.
• the present disclosure also provides the use of the compounds provided by the present disclosure, their pharmaceutically acceptable salts, stereoisomers, or compositions in the preparation of medicaments for treating, preventing, and/or controlling cardiovascular or metabolic diseases.
• the cardiovascular or metabolic diseases include but are not limited to: diabetes, diabetic complications, obesity, dyslipidemia, and hypertension.
• Figure 1 Pharmacodynamic evaluation of compounds 1-b and L27 in mouse hyperactivity model.
• Figure 2 Pharmacodynamic evaluation of compounds 1-b and 2-a in mouse hyperactivity model.
• pharmaceutically acceptable refers to compounds, compositions and/or dosage forms that are suitable for use in contact with human and animal tissues within the scope of reliable medical judgment, without Excessive toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
• the "pharmaceutically acceptable salt” mentioned in the present disclosure refers to the salt of the compound of the present disclosure, which is prepared from a compound with a specific substituent found in the present disclosure and a relatively non-toxic acid and base.
• acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
• pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts; salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid.
• Certain compounds of the present disclosure contain basic functional groups that can be converted into any acid addition salt.
• Certain compounds of the present disclosure may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of this disclosure.
• Compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.
• salts of the present disclosure can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases.
• salts are prepared by reacting these compounds in their free acid or base form with a stoichiometrically appropriate amount in water or an organic solvent or a mixture of both. Prepared by reacting with base or acid.
• pharmaceutically acceptable carrier refers to any representative carrier of any preparation or carrier medium that can deliver an effective amount of the active substance of the present disclosure, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient, including but not limited to : Binders, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, etc.
• the present disclosure is intended to include all isotopes of the atoms present in the compounds of the present disclosure.
• Isotopes include those atoms with the same atomic number but different mass numbers.
• isotopes of hydrogen include deuterium and tritium.
• Isotopes of carbon include 13C and 14C .
• Isotopically labeled compounds of the present disclosure may generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using appropriate isotopically labeled reagents in place of otherwise used non-labeled reagents.
• alkyl is used to represent a linear or branched saturated hydrocarbon group, which may be monosubstituted (e.g. -CH 2 F) or polysubstituted (e.g. -CF 3 ), which may be monovalent (e.g. Methyl), divalent (such as methylene) or polyvalent (such as methine).
• C 1 -C 12 represents 1 to 12 carbons
• C 1 -12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12
• alkyl groups include methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl , s-butyl, t-butyl), pentyl (such as n-pentyl, isopentyl, neopentyl, 1-ethylpropyl), hexyl (such as n-hexyl, isohexyl, 1 , 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl), n-heptyl (Me),
• halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
• haloalkyl is used to mean mono-/polyhalogenated linear or branched alkyl groups.
• Typical haloalkyl groups include C 1-6 haloalkyl groups, such as C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 haloalkyl groups.
• examples of C 1 -C 6 haloalkyl include, but are not limited to: fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoromethyl Ethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, and pentachloroethyl.
• alkoxy represents the above-mentioned alkyl groups (including cycloalkyl or haloalkyl) having the specified number of carbon atoms connected through an oxygen bridge.
• Typical alkoxy groups include C 1-6 alkoxy groups, such as: C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy groups, C 3 , C 4 , C 5 , C 6 alkoxy groups Cycloalkoxy group, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 haloalkoxy group.
• alkoxy examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, S- Pentyloxy, hexyloxy, 2-ethylbutoxy.
• cycloalkoxy examples include, but are not limited to: cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy.
• haloalkoxy examples include, but are not limited to: fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2-fluoroethoxy , 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy , pentachloroethoxy.
• cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which may be mono- or poly-substituted, and may be monovalent, divalent or polyvalent. Examples of these cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
• aryl refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing pairs of adjacent carbon atoms) groups having a conjugated ⁇ electron system, such as phenyl and naphthalene group, preferably phenyl.
• bond/single bond refers to the chemical bond between atoms used to connect or interact with each other, such as ionic bonds, covalent bonds, coordination bonds, etc.; in the molecular structure of organic compounds, “bond/single bond” "Single bond” is usually a covalent bond. When one or more variables between two atoms/groups is defined as a “bond/single bond”, it usually means that the two atoms/groups are directly connected by a “bond/single bond”.
• prodrug refers to a form of a compound that can be converted by metabolism in the body to be biologically active.
• the absolute configuration can be confirmed by conventional technical means in the art.
• single crystal X-ray diffraction uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal.
• the light source is CuK ⁇ radiation.
• the scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
• the instrument used for hydrogen nuclear magnetic spectrum detection of the disclosed compounds is Bruker/AVANCE NEO 400MHz.
• reaction solution was slowly poured into ice water, and extracted twice with petroleum ether (50 mL). The combined organic phases were washed once with brine (30 mL) and dried over anhydrous Na 2 SO 4 to obtain a petroleum ether solution of compound 13-2 (100 mL). Ethanolamine (1.60g, 26.2mmol, 5.00eq) was added to the petroleum ether solution of compound 13-2, and the reaction solution was heated to 50°C and stirred for 3 hours. LCMS detected that compound 13-2 reacted completely. The reaction solution was cooled to 20°C, Boc 2 O (5.71g, 26.2mmol, 6.01mL, 5.00eq) was added in batches, and the reaction solution was stirred at 20°C for 2 hours.
• reaction solution was slowly quenched by adding saturated potassium hydroxide solution to pH>7, and extracted with methyl tert-butyl ether.
• the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to obtain a crude product. .
• Compound 28 was purified by high performance liquid chromatography, and then separated and purified by SFC (column: DAICEL CHIRALPAK AY-H (250mm * 30mm, 10um); mobile phase: A: CO 2 , B: (0.1% NH 3 H 2 O MeOH); B%: 20%-20%, 4min) to obtain yellow oily compound 28-a (retention time: 0.812min, 65.8mg, 333 ⁇ mol, yield 61.5%) and yellow oily compound 28-b (retention time: 0.954min, 66.1mg, 334 ⁇ mol, yield 61.8%).
• the reaction was heated to 85°C and stirred for 3 hours. LCMS detected that the compound reacted completely. .
• the reaction solution was concentrated to dryness under reduced pressure.
• the crude product was dissolved in ethyl acetate (200 mL), washed with brine (50.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product.
• the reaction solution was directly suspended to dryness, and the pH of the crude product was adjusted to 9 with sodium carbonate solution, ethyl acetate (20.0mL x 3), dichloromethane (20.0mL x 2), and extracted five times.
• the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product.
• the crude product was prepared and isolated to obtain compound 34 (15.7 mg, 73.5 ⁇ mol, yield 2.41%) as a brown oil.
• reaction solution was cooled to 0°C, quenched dropwise with H 2 O (20.0 mL), extracted three times with ethyl acetate (40.0 mL x 3), the organic phase was washed with NaCl (100 mL), and dried over anhydrous sodium sulfate to obtain the crude product.
• 3-aminoethylthiophene (1.10g, 6.72mmol, 1eq, HCl) and 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde (1.27g, 6.72 mmol, 1.00eq) and trifluoroacetic acid (66.0mg, 579 ⁇ mol, 42.9 ⁇ L, 2eq) were dissolved in 1,2-dichloroethane (10mL) and replaced with nitrogen three times. Then the temperature of the mixture was raised to 45°C and stirred for 12 hours. .
• Dissolve compound 42-3 (1.00g, 2.60mmol, 1.00eq, 2HCl) and hydrazine hydrate (800mg, 16.0mmol, 777 ⁇ L, 6.16eq) in anhydrous water into ethanol (10 ml) and replaced with nitrogen three times, then raised the temperature of the system to 40°C and stirred in a nitrogen atmosphere for 0.5 hours. After LCMS monitoring of the complete reaction, the reaction solution was quenched with 2M ammonium chloride aqueous solution (50ml) at 0°C and diluted with water (50mL).
• reaction solution was extracted with dichloromethane (15mL ⁇ 2), and brine (50mL ⁇ 1 ), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product.
• the crude product was purified by high-performance liquid chromatography (hydrochloric acid system) to obtain the green gummy product compound 42-4 (crude product, hydrochloride).
• the aqueous phase was extracted with ethyl acetate (50ml ⁇ 3), the organic phases were combined and washed with brine (50ml ⁇ 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
• Dissolve compound 43-2 (11.7g, 41.4mmol, 1eq), thiourea (3.15g, 41.4mmol, 1eq), water (747mg, 41.4mmol, 747 ⁇ L, 1eq) in ethanol (50.0mL), and replace nitrogen three times, and then refluxed at 100°C for 5 hours.
• LCMS monitors the end of the reaction, and the reaction solution is directed to the next step.
• Dissolve compound 10 (100 mg, 502 ⁇ mol, 1.00 eq) in DCM (10.0 mL), cool to -75°C, and add compound BBr 3 (377 mg, 1.51 mmol, 145 ⁇ L, 3.00 eq) dropwise. After the dropwise addition, the temperature is naturally raised to 20 °C and stir for 2 hours. LCMS detection shows compound 10 reaction completely. The reaction solution was cooled to -20°C, MeOH (10.0 mL) was slowly added dropwise to quench, and the reaction solution was stirred at low temperature for 10 minutes. The reaction solution was directly transferred to the next step without concentration and purification.
• Test Example 1 Evaluation of the internal and external functional activities of cell synapses in vitro
• Detection reagent HitHunter cAMP Assay Detection Kit
• Cell treatment cAMP Hunter cell line was cultured at 37°C, 5% CO 2 until the confluence was 70-80%. Harvest the cells and adjust the cell density to 1.5 Incubate the plate overnight at 37 °C, 5% CO2 . Discard the cell culture medium and add 15 ⁇ L of 2:1 HBSS/10mM Hepes:cAMP XS+Ab reagent to each well. Use experimental buffer to dilute the sample stock solution into a 4X sample according to the concentration gradient, add 5 ⁇ L of 4X sample to each well, and incubate at 37°C or room temperature for 30 or 60 minutes. Add 20 ⁇ L cAMP XS+ED/CL mixed lysis buffer to each well and incubate for 1 hour. Add 20 ⁇ L cAMP XS+EA reagent to each well and incubate at room temperature for 3 hours. The chemiluminescence signal is read with a PerkinElmer Envision TM detector.
• the compounds of the present disclosure show good TAAR1 agonistic activity.
• Rat SD rat, weight 200-250g
• Reagents acetonitrile, MERCK; methanol, MERCK; formic acid, Sigma; tolbutamide, Sigma.
• SD rats were administered intravenously (IV) and intragastrically (IG). Three SD rats in each group were administered compounds 1-b, 2-a and L27 respectively.
• the solvents were DMSO and Tween80.
• Whole blood was collected at 0, 5 min (intravenous), 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h respectively.
• Reagents acetonitrile, MERCK; methanol, MERCK; formic acid, Sigma; tolbutamide, Sigma.
• L15 hydrochloride was administered by gavage at a dose of 2 mg/kg (calculated as free base). There were 2 Beagle dogs in each group. The solvents were DMSO and Tween80, at 0, 5 min, 15 min, 30 min, 1 h, respectively.
• Whole blood was collected at 2h, 3h, 4h, 6h, 8h, 12h, and 24h. The whole blood was placed in a heparinized EP tube and centrifuged at 13500 rpm for 10 min to separate the plasma. After pretreatment, the plasma is analyzed by LC-MS/MS to determine the concentration of the analyte in the plasma. The results are shown in Table 4:
• mice C57 mice, weight 20-22g
• Reagents physiological saline
• Instruments electronic balance, METTLER TOLEDO; TopScan monitoring system.
• MK-801 can induce hyperactivity in mice and is often used in the preclinical evaluation of antipsychotic drugs.
• the modeling method in this experiment is: a single intraperitoneal injection of MK-801 into mice at a dose of 0.8 mg/kg.
• mice were randomly divided into model group, 1-b group, and L27 group, with 10 animals in each group. See Table 5 for details.
• L27 group is equimolar dose of 1-b.
• mice were randomly divided into each group.
• the sample to be tested was given to the test sample by intragastric administration in a single dose as shown in Table 5 and then placed in the activity room. 30 minutes later, each mouse was given 0.8 mg/kg MK- through intraperitoneal injection. 801 model was built, reset in the activity room, and the TopScan monitoring system was used to record and analyze the activity distance (mm) of the mice after modeling (i.e. within 30-60 minutes after drug administration).
• TopScan monitoring system uses the TopScan monitoring system to record and analyze the activity distance (mm) of the mice after modeling (30-60 minutes after drug administration). Record the total distance of activity of mice after modeling (30-60 min after administration).
• Graphpad 5.0 software was used for data analysis and processing, and ANOVA test was used to compare the total distance of activities within 30-60 minutes between each administration group and the model group. All tests were two-sided tests, and p ⁇ 0.05 indicated that the difference was statistically significant. significance.
• mice were randomly divided into model group, 1-b group, and 2-a group, with 5 animals in each group. See Table 6 for details. Model preparation, test methods, observation indicators, and statistical methods are the same as in Test Example 4.

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