Heterocyclic compounds, preparation method therefor and medical uses thereof

Abstract

The present invention relates to heterocyclic compounds, a preparation method therefor and the medical uses thereof. Specifically, the present invention relates to compounds represented by general formula (I), a preparation method therefor, a pharmaceutical composition or health care product containing same, the use thereof for preventing or treating muscle atrophy-related diseases, including myogenic muscle atrophy, disuse muscle atrophy, age-related muscle atrophy and neurogenic muscle atrophy, the use thereof in preventing and / or treating obesity, fatty liver, cardiovascular and cerebrovascular diseases and metabolic diseases, and the anti-aging use thereof. The definition of each group in the general formula (I) is the same as that in the description.

Description

Heterocyclic compounds, methods of making and medical uses thereof TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and specifically relates to a heterocyclic compound, a preparation method thereof, a pharmaceutical composition containing the same, and the use of the compound in preventing or treating muscle atrophy related diseases including myogenic muscle atrophy, disuse muscle atrophy, senile muscle atrophy, neurogenic muscle atrophy, and in preventing and / or treating obesity, fatty liver, cardiovascular and cerebrovascular diseases, metabolic diseases, and anti-aging. The present application also relates to a health product containing the compound. BACKGROUND

[0002] Muscle atrophy and wasting [1,2] refers to the shrinkage of striated muscle volume compared with normal due to various reasons, muscle fiber becomes thin or even disappears, and the main clinical manifestations are muscle weakness, low muscle tone or spasticity, muscle atrophy or hypertrophy, reduced or disappeared tendon reflex, and no sensory disturbance and muscle fasciculation. Muscle atrophy related diseases include myogenic muscle atrophy, disuse muscle atrophy, senile muscle atrophy, and neurogenic muscle atrophy.

[0003] Myogenic muscle atrophy mainly refers to muscle atrophy caused by muscle itself lesions, including progressive muscular dystrophy, polymyositis, atrophic rigidity, and secretory myopathy. Progressive muscular dystrophy (MD) is a group of genetic diseases originating from muscle tissue, and often has a family history; the clinical features are slow onset and progressive muscle atrophy and weakness; mainly involving proximal limb muscles, and rarely involving distal muscles; tendon reflexes are lost, and muscle is pseudohypertrophic [3] . The serum creatine phosphokinase (CK) level of MD patients is significantly increased. The electromyogram of MD patients shows myogenic damage: spontaneous potential and fibrillation potential appear in the insertion potential, positive sharp wave increases, or muscle rigidity-like potential appears; the average time limit of motor unit potential is shortened when the muscle contracts slightly, the polyphasic potential increases, and the wave amplitude decreases; when the muscle contracts severely, it shows interference discharge, but the wave amplitude is low. Muscle tissue biopsy of MD can observe that: muscle fiber striations disappear, and the size is uneven, from polygonal to circular, atrophic small fibers are mixed in normal volume or hypertrophic muscle fibers in mosaic distribution; muscle membrane nuclei increase, are dense and dark, and are arranged in chains, and the nuclei move inside the cells; collagen between muscle fibers increases; there are fat cell infiltrations; and there are few inflammatory cell infiltrations [4] . According to the muscle involvement site of patients, MD can be divided into many types [5]: Duchenne type muscular dystrophy (DMD), Becker type muscular dystrophy (BMD), Emery-Dreifuss type muscular dystrophy (EDMD), limb-girdle muscular dystrophy (LGMD), facioscapulohumeral muscular dystrophy (FSHD), distal muscular dystrophy (DM), oculopharyngeal muscular dystrophy (OPMD), etc. In addition, congenital muscular dystrophy (CMD) is a type of severe muscular dystrophy that occurs after birth; myotonic muscular dystrophy (MMD) is a myotonic disease accompanied by progressive muscle weakness and muscle exhaustion, and distal limb and facial muscle weakness are the main clinical manifestations, which is a kind of muscle disease with multiple system damage, accompanied by gonadal atrophy, alopecia, heart and mental disorders. Although various types of muscular dystrophy candidate genes have been cloned, the pathogenesis is still unclear. According to the functional characteristics of the proteins encoded by the pathogenic genes, it is speculated that the pathogenesis of MD may have the following aspects [6] : destruction of muscle membrane integrity, loss of extracellular matrix and cytoskeleton contact, cytoskeleton organization defects, muscle fiber movement contraction disorders, structural protein glycosylation disorders, protein degradation abnormalities, weakened muscle fiber regeneration capacity, abnormal muscle cell apoptosis, and interruption of specific information transmission pathways in cells. In the face of such a complex and highly genetically heterogeneous group of myopathies, it is more difficult to find effective treatment targets.

[0004] Sarcopenia, also known as muscle atrophy, is a progressive decrease in skeletal muscle mass, muscle strength and motor function that occurs with the aging process. Skeletal muscle mass and strength peak in young adults. With age, there is a gradual decline around the age of 40, and a significant decrease in skeletal muscle mass and strength after the age of 50, and almost below 50% of the young age after the age of 80 [7,8] . The causes of sarcopenia are related to changes in hormone levels, imbalance between protein synthesis and degradation, neuro-muscular function decline and motor unit reorganization, mitochondrial chromosomal damage, free radical oxidative damage and impaired repair mechanisms of skeletal muscle, apoptosis, calcium homeostasis imbalance, changes in heat and protein intake, etc. Recent studies have shown that sarcopenia is closely related to the reduction in the number and functional changes of skeletal muscle stem cells. The defect in skeletal muscle regeneration in old age is related to the dysfunction of skeletal muscle stem cells [9] . During the aging process of skeletal muscle, skeletal muscle stem cells enter the pre-senescence state from the resting state, and under the pressure of regeneration and proliferation, their aging process is accelerated

[0010] . Two-thirds of skeletal muscle stem cells in old mice are defective, with low repair and regeneration capacity. This defect is related to the increased activity of p38α and p38β MAPK pathways. Inhibition of p38α and p38β, the functional stem cells still have rapid expansion, restoring the ability to regenerate and repair damaged skeletal muscle

[0011] It has also been found that with the aging of skeletal muscle stem cells, the activity of the JAK / STAT signaling pathway gradually increases, eventually leading to functional decline of stem cells. The JAK-STAT signal in old mice is significantly higher than that in young mice. Reducing the activity of Jak2 or Stat3 can significantly stimulate muscle stem cell proliferation in vitro and in vivo, and improve muscle regeneration

[0012] Therefore, regulating the function of skeletal muscle stem cells brings hope for intervention and treatment of senile muscle atrophy.

[0005] Disuse atrophy is mainly caused by long-term bed rest of patients due to fractures or upper motor neuron system diseases or other chronic diseases, long-term or little exercise of muscles, leading to muscle degradation and atrophy.

[0006] Neurogenic atrophy is a group of muscle atrophy caused by motor neuron and peripheral nerve diseases that innervate muscles. It mainly refers to the muscle atrophy caused by lower motor neuron diseases such as spinal cord anterior horn cells and their nerve axons. The main clinical manifestations are muscle weakness and muscle atrophy symptoms, and serum creatine phosphokinase (CK) and lactate dehydrogenase (LDH) are normal. Needle electromyography examination shows that abnormal spontaneous units may or may not be present, and the motor unit potential time limit is widened, the amplitude is increased, the phase is increased, and the recruitment is decreased

[0013] Neurogenic atrophy mainly includes amyotrophic lateral sclerosis (ALS), Hirayama disease (muscle atrophy in the affected forearm and palm), spinal muscle atrophy (muscle atrophy in both lower limbs), peroneal muscle atrophy (atrophy in both lower legs), and myasthenia gravis (MG). Amyotrophic lateral sclerosis is a motor neuron disease that may be related to genetic mutations. Clinically, it is characterized by asymmetric onset of muscle atrophy and weakness in limbs or phonation and swallowing muscles. Electromyography examination suggests extensive spinal cord anterior horn cell disease. Juvenile unilateral distal upper limb atrophy, also known as Hirayama disease, is of unknown etiology and may be related to cervical spinal cord disease. Clinically, it is mainly manifested as unilateral or bilateral distal upper limb atrophy, with obvious atrophy of small muscles in the hand (interosseous muscles, thenar muscles). Peroneal muscle atrophy and spinal muscle atrophy are also motor neuron diseases related to genetic factors, and both are manifested as muscle atrophy in the lower limbs, with replacement of diseased muscle fibers by adipose tissue. Myasthenia gravis is an autoimmune disease that mainly affects the acetylcholine receptors on the postsynaptic membrane of the neuromuscular junction.

[0007] Muscle atrophy patients lose the ability to take care of themselves due to muscle atrophy and muscle weakness

[0014] , limb movement is progressively aggravated, some patients have bulbar palsy symptoms, some patients have respiratory failure and heart dysfunction, which seriously threaten the lives of patients and also cause serious economic losses to society. There is still a strong unmet clinical need for effective drug treatment of this type of disease.

[0008] Metabolic diseases are pathological states of metabolic disorders of protein, fat, carbohydrate and other substances in the human body, and are risk factors leading to diabetes and cardiovascular and cerebrovascular diseases. They include obesity, hyperglycemia, hypertension, dyslipidemia, hypercoagulability, fatty liver, hyperinsulinemia, etc. Metabolic diseases can lead to hypertension, coronary heart disease, stroke, and even certain cancers, including sex hormone-related breast cancer, endometrial cancer, prostate cancer, and digestive system cancers such as pancreatic cancer, hepatobiliary cancer, and colon cancer. Metabolic diseases are widespread and are an important health threat to the human body, especially the cardiovascular and cerebrovascular systems. The course of the disease often lasts for many years, causing a decline in quality of life. There are many treatment options for metabolic diseases, but the medication time is long, and it is difficult to fundamentally correct the abnormal state.

[0009] Cardiovascular diseases (CVD) are a group of circulatory system diseases including cardiovascular diseases, pulmonary circulation diseases, and cerebrovascular diseases. Cardiovascular diseases include arteriosclerosis, coronary heart disease, peripheral end artery vascular disease, deep vein thrombosis, pulmonary embolism, etc. Cerebrovascular diseases include transient ischemic attack (TIA), cerebral infarction, cerebral hemorrhage, hypertensive encephalopathy, cerebral arteritis, cerebrovascular dementia, venous sinus and cerebral vein thrombosis, and cerebrovascular diseases caused by various causes. The common feature of these diseases is that blood clots due to high blood lipids, and then block blood vessels.

[0010] Cardiovascular diseases are a serious threat to human health and are the most important diseases that threaten human health and life in today's society. In recent years, the incidence of coronary heart disease and stroke has increased significantly, and both morbidity and mortality have shown a trend of younger age, with the number of deaths continuing to increase, and the proportion in the cause of death showing an upward trend, which is the "number one killer" that threatens human health and life. Almost one out of every three people who die worldwide dies of cardiovascular disease, causing great pain to families and huge losses to society. Cardiovascular diseases have different treatment options, but the disease and sequelae are relatively serious, and existing treatments are difficult to completely correct.

[0011] Obesity refers to excessive accumulation and / or abnormal distribution of fat in the body, and is a chronic metabolic disease caused by the interaction of various factors including genetics and environmental factors. It is reported that in 2008, there were 200 million adult men and 300 million adult women worldwide suffering from obesity

[0015] . It is estimated that the number of obese people worldwide will reach 1 billion by 2030

[0016] . The weight of adipose tissue in a normal adult male is about 15% to 18% of the body weight, and in a female, about 20% to 25%. With age, the proportion of body fat increases accordingly. Those with a body mass index [BMI = weight (Kg) / height 2 (m 2 )] greater than 28 are obese

[0017] Obesity can significantly increase the incidence and mortality of hypertension, diabetes and cardiovascular and cerebrovascular diseases

[0017] , which has become one of the important problems endangering global human health and the focus of social attention. The prevention and treatment of obesity has become a challenge for modern medicine. In 2008, the medical expenses for obesity in the United States alone reached 147 billion US dollars

[0018] . According to the statistics of BOS, the global weight loss drug market size was 1.56 billion US dollars in 2012, and the retail market size of weight loss drugs in China was 3.05 billion yuan, of which the market size of weight loss drugs (prescription drugs) was 1.68 billion yuan

[0019] . According to the current market forecast, the global market may reach 70 billion in the future, of which China will be nearly 10 billion yuan.

[0012] Fatty liver disease (FLD) is a pathological syndrome caused by various reasons, mainly diffuse steatosis of liver cells. When the fat content in the liver exceeds 5% of the liver wet weight, or more than 30% of the liver cells have steatosis and diffuse distribution in the whole liver, it is called fatty liver disease, simply called fatty liver. At present, fatty liver has become the first / second common liver disease in developed / developing countries, and has become the first liver disease in China. With the prevalence of obesity and metabolic diseases worldwide, fatty liver is growing rapidly and showing a low age trend. Although alcohol abuse and hepatitis C (HCV) infection are closely related to liver steatosis, the prevalence of fatty liver worldwide is closely related to the rapid growth of obesity prevalence. Fatty liver cannot be ignored for its harm to the human body. It can shorten the life of patients under 50 years old by 4 years and patients over 50 years old by 10 years.

[0013] Aging refers to the gradual decrease of the function of each organ of the body, manifested as structural and functional decline, and decreased adaptability and resistance

[0020] . With age, the bone tissue of the skeletal system gradually decreases in calcium, becomes brittle, and is prone to fracture. Wound healing is also slower than when young. In old age, the dermal papilla of the skin becomes low, the epidermis becomes thin, the reticular fibers of the dermis decrease, the elastic fibers gradually lose elasticity, the skin becomes loose, the water content of the dermis decreases, the subcutaneous fat decreases, the sweat glands and sebaceous glands atrophy, and age spots appear due to local melanocyte proliferation. The ratio of muscle weight to body weight decreases in old age, and the whole muscle atrophies, etc.

[0021] The function of each system declines, resulting in the loss of self-care ability, which brings inconvenience to the elderly and a heavy burden to the family. In 2014, there were more than 200 million people over 60 years old in China, accounting for 14.9% of the total population, and the proportion is increasing year by year, and the demand for anti-aging is huge. SUMMARY

[0014] The present inventors have designed and synthesized a series of heterocyclic compounds through intensive research, which not only exhibit excellent technical effects in preventing and treating muscle atrophy related diseases, but also produce excellent effects in resisting obesity, fatty liver, cardiovascular and cerebrovascular diseases, metabolic diseases, and anti-aging.

[0015] Therefore, the present application relates to a compound represented by general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0016] wherein:

[0017] X1is selected from CR 1 or N;

[0018] X2is selected from CR 2 or N;

[0019] X3is selected from CR 3 or N;

[0020] X4is selected from CR 4 or N;

[0021] L1is selected from a bond, -C(O)O-, -C(O)NR 7 -, -S(O)NR 7 -, -S(O)2NR 7 -, -NR 7 C(O)-, -NR 7 C(O)O-, -NR 7 S(O)-, -NR 7 S(O)2-, -OC(O)-, -O-, -NH-;

[0022] L2is selected from C 1-10 alkylene, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, the C 1-10 alkylene, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl is optionally substituted by one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0023] L3is selected from a bond, -C(O)-, -S(O)-, -S(O)2-, -C(O)NR 8 -, -S(O)NR8 -、-S(O)2NR 8 -、-NR 8 C(O)-、-NR 8 C(O)O-、 R 9 Selected from hydrogen and C 1-6 alkyl;

[0024] R 1 R 2 R 3 R 4 Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0025] R 5 Selected from hydrogen, halogens, C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl;

[0026] Each R 6 Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0027] Each R 7 Each is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0028] Each R 8 Each is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0029] i is 0, 1, or 2;

[0030] j is 0, 1, or 2;

[0031] n is an integer from 0 to 4.

[0032] In one embodiment, the compound according to the application of the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, is a compound of the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt,

[0033] wherein

[0034] X1to X4, R 5 , R 6 , L1, L2, L3, n are as defined in the general formula (I).

[0035] In another embodiment, the compound according to the application of the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, is a compound of the general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt,

[0036] wherein

[0037] X1to X4, R 5 , R 6 , L1, L2, L3, n are as defined in the general formula (I).

[0038] In another embodiment, the compound according to the application of the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, is a compound of the general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt,

[0039] wherein

[0040] X1to X3, R 5 , R 6 , L1, L2, L3, n are as defined in the general formula (I).

[0041] In another embodiment, the compound according to the application of the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, is a compound of the general formula (V) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt,

[0042] wherein,

[0043] X1~X3, R 5 , R 6 , L1, L2, L3, n are as defined in general formula (I).

[0044] In another embodiment, the compound according to the present application of general formula (IV) or general formula (V), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein X1is CR 1 or N, X2is CR 2 or N, X3is CR 3 ; R 1 , R 2 , R 3 are as defined in general formula (I).

[0045] In another embodiment, the compound according to the present application of general formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of general formula (VIA) or general formula (VIB), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0046] wherein:

[0047] X 1 is CH or N;

[0048] X 2 is CH or N;

[0049] Y1, Y2, Y3, Y4are each independently selected from CH or N;

[0050] each R 10 is each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0051] m is 0, 1 or 2;

[0052] i is 0, 1 or 2;

[0053] j is 0, 1 or 2;

[0054] R 5 , R 6L1, L3, n are as defined in general formula (I).

[0055] In another embodiment, the compound according to the application of general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of general formula (VII) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0056] wherein:

[0057] X 1 is CH or N;

[0058] X 2 is CH or N;

[0059] s1 is 0 or 1 ;

[0060] s2 is 0, 1 or 2;

[0061] each R 11 is each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0062] v is 0, 1 or 2;

[0063] i is 0, 1 or 2;

[0064] j is 0, 1 or 2;

[0065] R 5 , R 6 , L1, L3, n are as defined in general formula (I).

[0066] In another embodiment, the compound according to the application of general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of general formula (VIII) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0067] wherein:

[0068] X 1 is CH or N;

[0069] X 2 is CH or N;

[0070] R a and R b are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl;

[0071] t is an integer from 1 to 10, preferably an integer from 1 to 6, more preferably an integer from 1 to 4;

[0072] i is 0, 1 or 2;

[0073] j is 0, 1 or 2;

[0074] R 5 , R 6 , L1, L3, n are defined as in general formula (I).

[0075] In another embodiment, the compounds according to the application according to general formula (I), (II), (III), (IV), (V), (VIA), (VIB), (VII), (VIII) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein L1is selected from a bond, -C(O)O-, -C(O)NR 7 -, -S(O)NR 7 -, -S(O)2NR 7 -, -NR 7 C(O)-, -NR 7 C(O)O-, -O-, -NH-; R 7 is selected from hydrogen or C 1-6 alkyl.

[0076] In another embodiment, the compounds according to the application according to general formula (I), (II), (III), (IV), (V), (VIA), (VIB), (VII), (VIII) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein,

[0077] L3is selected from -C(O)-, -S(O)-, -S(O)2-, -C(O)NR 8 -, -NR 8 C(O)-,

[0078] R 8 is selected from hydrogen and C 1-6 alkyl;

[0079] R 9 is selected from hydrogen and C 1-6 alkyl;

[0080] R 5 selected from C 1-6 alkyl.

[0081] In another embodiment, the compound according to the application of the general formula (I), (II), (III), (IV), (V), (VIA), (VIB), (VII), (VIII) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

[0082] L3is selected from a bond;

[0083] R 5 selected from C 1-6 alkyl.

[0084] In another embodiment, the compound according to the application of the general formula (I), (II), (III), (IV), (V), (VIA), (VIB), (VII), (VIII) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

[0085] L1is selected from -C(O)O-, -C(O)NR 7 -, -S(O)NR 7 -, -S(O)2NR 7 -, -NR C(O)O-, -O-, -NH-;

[0086] L3is selected from -C(O)-, -S(O)-, -S(O)2-;

[0087] R 5 selected from C 1-6 alkyl;

[0088] R 7 selected from hydrogen or C 1-6 alkyl.

[0089] In another embodiment, the compound according to the application of the general formula (I), (II), (III), (IV), (V), (VIA), (VIB), (VII), (VIII) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

[0090] L1is selected from -C(O)O-, -C(O)NR 7 -, -S(O)NR 7 -, -S(O)2NR 7 -, -NR 7C(O)-, -NR 7 C(O)O-, -O-, -NH-; R 7 selected from hydrogen or C 1-6 alkyl;

[0091] L3is selected from -C(O)NR 8 -, -NR 8 C(O)-,

[0092] R 5 selected from hydrogen and C 1-6 alkyl;

[0093] R 8 selected from hydrogen and C 1-6 alkyl;

[0094] R 9 selected from C 1-6 alkyl.

[0095] In another embodiment, the compound according to the application of the general formula (I), (II), (III), (IV), (V), (VIA), (VIB), (VII), (VIII) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

[0096] L1is selected from -C(O)NR 7 -, -S(O)NR 7 -;

[0097] L3is selected from a bond;

[0098] R 5 selected from C 1-6 alkyl;

[0099] R 7 selected from hydrogen or C 1-6 alkyl.

[0100] In another embodiment, the compound according to the application of the general formula (I), (II), (III), (IV), (V), (VIA), (VIB), (VII), (VIII) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L1is a bond;

[0101] L2is a 4- to 6-membered saturated or partially saturated heterocyclyl; optionally substituted with one or more groups selected from oxo, C 1-6 alkyl;

[0102] L3is a bond;

[0103] R 5is hydrogen.

[0104] In another embodiment, the compounds according to the application of the general formula (I), (II), (III) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4are CH, or one of X1, X2, X3, X4is N and the others are CH; or two of X1, X2, X3, X4are N and the others are CH; preferably X1, X2, X3, X4, X5are CH, or one of X1, X2, X3, X4is N and the others are CH.

[0105] In another embodiment, the compounds according to the application of the general formula (IV), (V) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3are CH, or one of X1, X2, X3is N and the others are CH.

[0106] In another embodiment, the compounds according to the application of the general formula (VIA), (VIB), (VII), (VIII) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein X1, X2are CH, or one of X1, X2is N and the others are CH.

[0107] In another embodiment, the compounds according to the application of the general formula (VIA), (VIB) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y1, Y2, Y3, Y4are CH, or one of Y1, Y2, Y3, Y4is N and the others are CH.

[0108] In another embodiment, the compounds according to the application of the general formula (I), (II), (III), (IV), (V), (VIA), (VIB), (VII), (VIII) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R 6 is independently selected from hydrogen, halogen, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; preferably hydrogen; n is 0 or 1.

[0109] In another embodiment, the compound according to the application of the general formula (I), (VIA), (VIB), (VII), (VIII) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein i is 1, j is 1 or 2.

[0110] In another embodiment, the compound according to the application of the general formula (VIA), (VIB) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R 10 is each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; preferably hydrogen; m is 0 or 1.

[0111] In another embodiment, the compound according to the application of the general formula (VII) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R 11 is each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; preferably hydrogen; v is 0 or 1.

[0112] Typical compounds of the application include, but are not limited to, the following compounds:

[0113] or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

[0114] The present application also relates to a pharmaceutical composition comprising a compound according to the application or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0115] The present application also relates to a health care composition comprising a compound according to the application or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0116] The present application also relates to the use of the compound according to the present application or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a health care composition comprising the same, in the preparation of a health care product for preventing or treating muscle atrophy related diseases, obesity, fatty liver, cardiovascular and cerebrovascular diseases, metabolic diseases, and in the preparation of a health care product for anti-aging.

[0117] The present application also relates to the use of the compound according to the present application or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a health care composition comprising the same, in the preparation of a health care product for preventing or treating muscle atrophy related diseases, obesity, fatty liver, cardiovascular and cerebrovascular diseases, metabolic diseases, and in the preparation of a health care product for anti-aging.

[0118] In some embodiments, the muscle atrophy related diseases according to the present application include myogenic muscle atrophy such as progressive muscular dystrophy, polymyositis, myotonic dystrophy, secretory myopathy, disuse muscle atrophy, senile muscle atrophy, neurogenic muscle atrophy.

[0119] In some embodiments, the progressive muscular dystrophy according to the present application is congenital muscular dystrophy (CMD) or myotonic muscular dystrophy (MMD), such as Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy (LGMD), facioscapulohumeral muscular dystrophy (FSHD), distal muscular dystrophy (DM), oculopharyngeal muscular dystrophy (OPMD).

[0120] In some embodiments, the neurogenic muscle atrophy according to the present application includes amyotrophic lateral sclerosis (ALS), Hirayama disease, spinal muscular atrophy, peroneal muscular atrophy, myasthenia gravis (MG).

[0121] In some embodiments, the cardiovascular and cerebrovascular diseases according to the present application include arteriosclerosis, coronary heart disease, peripheral end artery vascular disease, deep vein thrombosis, pulmonary embolism, transient ischemic attack (TIA), cerebral infarction, cerebral hemorrhage, hypertensive encephalopathy, cerebral arteritis, cerebral vascular dementia, venous sinus, cerebral vein thrombosis.

[0122] In some embodiments, the metabolic diseases according to the present application include diabetes, hypertension, hyperlipidemia, hyperglycemia.

[0123] Pharmaceutical compositions containing the active ingredient can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, sachets, cachets, or as a syrup or elixir. The compositions can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. Such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be inert excipients, such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, cros Carmellose sodium, corn starch or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques in order to mask the unpleasant taste of the drug or delay the release of the drug in the gastrointestinal tract and thereby provide a sustained release of the drug. For example, a water soluble taste masking material such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or a time delay material such as ethylcellulose, cellulose acetate butyrate can be used.

[0124] Oral preparations can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier or an oil medium, for example, polyethylene glycol or oil such as peanut oil, liquid paraffin or olive oil.

[0125] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and gum tragacanth; dispersing or wetting agents, which can be a naturally occurring phosphatide, for example, lecithin, or an ester or partial ester of a fatty acid, for example, polyoxyethylene stearate, or a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene sorbitrmonolaurate, or a condensation product of an alkylene oxide with partial esters of fatty acids, for example, polyoxyethylene sorbitan monooleate; and preservatives, for example, methyl or propyl p-hydroxybenzoate and flavoring agents. The aqueous suspensions can also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.

[0126] Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl wax, which enhances the stability of the suspension by increasing the viscosity. Sweetening agents and flavouring agents can be added to provide a palatable vehicle for the active ingredient. These compositions can be preserved by the addition of an antioxidant such as butylated hydroxyanisole or α-tocopherol.

[0127] The pharmaceutical compositions of this application can also be in the form of oil-in- water emulsions. The oily phase can be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as liquid paraffin or mixtures of these. Suitable emulsifying agents can be naturally occurring phosphatides, such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, e.g. sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, e.g. polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening, flavouring and preservative agents.

[0128] The pharmaceutical compositions of this application can be in the form of a sterile injectable aqueous or oleaginous suspension. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0129] The pharmaceutical compositions of this application can be in the form of a sterile injectable aqueous or oleaginous suspension. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0130] The compounds of this application can be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and other glycerides.

[0131] It is well within the skill of the art to determine the appropriate dosage of a drug depending on a variety of factors, including but not limited to the activity of the particular compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the like. Also, the optimum therapeutic regimen can be determined in accordance with conventional therapeutic practice, taking into account the mode of administration, the day-to-day variation in the potency of the compound of general formula or the kind of pharmaceutically acceptable salt.

[0132] The present application can contain a compound and its pharmaceutically acceptable salt, hydrate or solvate as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and prepared into a clinically acceptable dosage form. The derivative of the present application can be used in combination with other active ingredients, provided that they do not produce other adverse effects, such as an allergic reaction, etc. The compound of the present application can be used as the only active ingredient, or in combination with other drugs for treating diseases associated with tyrosine kinase activity. Combination therapy is achieved by administering each therapeutic component simultaneously, separately or sequentially.

[0133] Explanation of terms

[0134] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0135] The term "alkyl" refers to saturated aliphatic hydrocarbon groups which are straight-chain or branched-chain groups containing 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 12 carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-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, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-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, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, the substituents preferably being one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.

[0136] 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, for example ethenyl, 1- propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. The alkenyl group can be substituted or unsubstituted, and when substituted, the substituent groups are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0137] The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, for example ethynyl, propynyl, butynyl, and the like. The alkynyl group can be substituted or unsubstituted, and when substituted, the substituent groups are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0138] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 carbon atoms, more preferably comprising 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 spirocyclic, fused, and bridged cycloalkyl groups.

[0139] The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 members sharing one carbon atom between the rings (referred to as a spiro atom), which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 members, more preferably 7 to 10 members. Spirocycloalkyl groups are classified as mono-, bi-, or polycycloalkyl groups according to the number of spiro atoms shared between the rings, preferably mono- and bi-spirocycloalkyl groups. More preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono-spirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0140] The term "fused cycloalkyl" refers to a fully carbon polycyclic group of 5 to 20 members, each ring in the system sharing an adjacent pair of carbon atoms with other rings in the system, in which one or more rings can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 members, more preferably 7 to 10 members. Fused cycloalkyl groups are classified as bi-, tri-, tetra-, or polycyclic according to the number of rings comprising the group, preferably bi- or tri-cyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bi-cyclic groups. Non-limiting examples of fused cycloalkyl groups include:

[0141] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group of 5 to 20 members, any two rings of which share two non-adjacent carbon atoms, which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably, 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings comprising the bridged cycloalkyl group, it can be referred to as bicyclic, tricyclic, tetracyclic or polycyclic, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0142] The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring that is attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, norbornyl, and the like. The cycloalkyl group can 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, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0143] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring system of 3 to 20 ring atoms, of which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) but excluding -O-O-, -O-S- or -S-S- ring moieties, the remaining ring atoms being carbon. Preferably, 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably, 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably, 4 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, preferably 1,2,5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclyl groups include spirocyclic, fused and bridged heterocyclyl groups.

[0144] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, sharing one atom (referred to as the spiro atom) between single rings, of which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) mheteroatoms, the remaining ring atoms being carbon. It can contain one or more double bonds, but no ring has a completely conjugated pi-electron system. It is preferably 6- to 14-membered, more preferably 7- to 10-membered. Spiroheterocyclyl groups are classified as mono-, bi-, or polyspiroheterocyclyl groups depending on the number of spiro atoms shared between rings, preferably mono- and bispiroheterocyclyl groups. More preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monosprioheterocyclyl groups. Non-limiting examples of spiroheterocyclyl groups include:

[0145] The term "fused heterocyclyl" refers to a polycyclic heterocyclic radical of 5- to 20-membered, in which each ring in the system shares an adjacent pair of atoms with the other ring(s) in the system, one or more rings can contain one or more double bonds, but no ring has a completely conjugated pi-electon system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) m heteroatoms, the remaining ring atoms being carbon. It is preferably 6- to 14-membered, more preferably 8- to 10-membered. It can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl groups depending on the number of rings comprising the ring system, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl groups. Non-limiting examples of fused heterocyclyl groups include:

[0146] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic radical of 5- to 14-membered, in which any two rings share two non-adjacent atoms, it can contain one or more double bonds, but no ring has a completely conjugated pi-electon system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) m heteroatoms, the remaining ring atoms being carbon. It is preferably 6- to 14-membered, more preferably 8- to 10-membered. It can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl groups depending on the number of rings comprising the ring system, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

[0147] The heterocyclyl ring can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0148] etc.

[0149] Heterocyclyl can 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, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.

[0150] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings which share adjacent pairs of carbon atoms) ring systems having a conjugated pi-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, i.e., a fused ring aryl, wherein the ring which is attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0151] Aryl can 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, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0152] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5- to 10-membered, containing 1 to 3 heteroatoms; more preferably 5- or 6-membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, and the like, preferably imidazolyl, thiazolyl, pyrazolyl, or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, i.e., a fused ring heteroaryl, wherein the ring which is attached to the parent structure is the heteroaryl ring, non-limiting examples of which include:

[0153] Heteroaryl can 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, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0154] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups can 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, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0155] In the chemical structure of the compounds of the present disclosure, the bond represents unspecified configuration, i.e. if chiral isomers exist in the chemical structure, the bond may be or both configurations.

[0156] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is defined as above.

[0157] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is defined as above.

[0158] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is defined as above.

[0159] The term "hydroxyl" refers to the -OH group.

[0160] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0161] The term "amino" refers to -NH2.

[0162] The term "cyano" refers to -CN.

[0163] The term "nitro" refers to -NO2.

[0164] The term "oxo" refers to =O.

[0165] The term "thio" refers to =S.

[0166] The term "carboxyl" refers to -C(O)OH.

[0167] The term "thiol" refers to -SH.

[0168] The term "ester" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are defined as above.

[0169] ​The term "alkylcarbonyl" means a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.

[0170] The term "alkylsulfonyl" means a -S(O)2R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.

[0171] The term "amino" means a -NR2group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.

[0172] "Optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and thus the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl can or can not be present, and the description includes instances where the heterocyclyl group is substituted with alkyl and instances where the heterocyclyl group is not substituted with alkyl.

[0173] "Substituted" means that one or more hydrogen atoms, preferably up to five, more preferably one to three, of a group are independently of each other replaced with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which can be determined (experimentally or theoretically) by a person skilled in the art without undue effort, as to whether a substitution is possible or not. For example, an amino group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturated (e.g. olefinic) bond.

[0174] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, and to facilitate absorption of the active ingredient.

[0175] "Pharmaceutically acceptable salt" refers to those salts of the compounds of the present application which are safe and effective for use in mammals, and which possess the desired biological activity. DETAILED DESCRIPTION

[0176] The compounds of the present application and their preparation are further understood by the examples, which illustrate some of the methods of making or using the compounds. It is to be understood, however, that these examples do not limit the scope of the application. Variations of the present application now known or further developed are considered to fall within the scope of the present application described and claimed herein.

[0177] The compounds of the present application are prepared using convenient starting materials and general synthetic procedures. The present application provides exemplary or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratios of reactants. However, unless otherwise specified, other reaction conditions can be employed. Optimum conditions can vary with the particular reactants or solvents used, but will be determined by one of ordinary skill in the art by no more than routine optimization.

[0178] In addition, some protecting groups can be used in the present application to protect certain functional groups from unwanted reactions. Protecting groups suitable for a variety of functional groups and their protecting or deprotecting conditions are well known to those skilled in the art. For example, a large number of protecting groups are described in detail in the protection or deprotection of T. W. Greene and G. M. Wuts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley, New York, 1999 and references therein.

[0179] The separation and purification of compounds and intermediates are carried out by appropriate methods and procedures according to the specific requirements, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer chromatography, preparative high performance liquid chromatography or a combination of the above. The specific use thereof can be found in the examples described in the present application. Of course, other similar separation and purification means can also be used. They can be characterized using conventional methods, including physical constants and spectral data.

[0180] The structure of the compounds is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift is given in units of 10 -6 (ppm). The NMR is measured by a Bruker dps 300 nuclear magnetic instrument, and the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0181] The MS is measured by LC (Agilent 1260 Infinity) / MS (G6125B) mass spectrometer (manufacturer: Agilent).

[0182] The preparative liquid chromatography uses an lc6000 high performance liquid chromatograph (manufacturer: Innovative Technology). The chromatographic column is Daisogel C18 10 μm 100A (30 mm x 250 mm), and the mobile phase is acetonitrile / water.

[0183] The thin layer chromatography (TLC) uses Qingdao Haoyang Chemical GF254 silica gel plate. The silica gel plate used for reaction monitoring in thin layer chromatography has a specification of 0.20 mm to 0.25 mm, and the silica gel plate used for separation and purification in thin layer chromatography has a specification of 0.5 mm.

[0184] Silica gel column chromatography uses Qingdao Marine Silica Gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

[0185] Known starting materials of the present application can be synthesized or purchased from commercial sources such as Beijing Coupling, Sigma, Biotrend, Eishiming, Shanghai Shuya, Shanghai Inokai, Anjieji Chemical, Shanghai Bide, Nanjing Yushi, etc. according to methods known in the art.

[0186] Unless otherwise specified in the examples, the reactions can be carried out under a nitrogen atmosphere.

[0187] Argon or nitrogen atmosphere refers to connecting a reaction bottle to an argon or nitrogen balloon with a volume of about 1 L.

[0188] Reaction solvent, organic solvent or inert solvent each refers to the solvent used under the reaction conditions described does not participate in the reaction, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, diethyl ether, methanol, nitrogen-methyl pyrrolidone (NMP), pyridine, etc. Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0189] The chemical reactions described in the present application are generally carried out under normal pressure. The reaction time and conditions are, for example, completed in about 1 to 24 hours at one atmosphere between -78°C and 200°C. If the reaction is overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.

[0190] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as familiar to those skilled in the art. In addition, any method and material similar or equivalent to that described can be applied to the method of the present application.

[0191] Examples

[0192] Example 1: Preparation of 6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl 4-oxopentanoate (1)

[0193] Example 2: Preparation of 6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl 4-oxopentanoate (2)

[0194] Example 3: Preparation of 2,3-dihydro-1H-inden-5-yl (2-oxopropyl)carbamate (3)

[0195] Example 4: Preparation of 2,3-dihydro-1H-inden-5-yl acetyl glycinate (4)

[0196] Example 5: Preparation of 2,3-dihydro-lH-inden-5-yl 4-amino-4-oxobutanoate (5)

[0197] 4-amino-4-oxobutanoic acid 5a (300 mg, 2.56 mmol), 2,3-dihydro-lH-inden-5-ol a (344 mg, 2.56 mmol) and DMAP (32 mg, 0.26 mmol) were dissolved in dichloromethane (5 mL), the reaction solution was reduced to 0°C under nitrogen atmosphere, EDCI (737 mg, 3.84 mmol) was added thereto, and the reaction solution was stirred at room temperature for 4 hours. Water (30 mL) was added to the reaction solution, dichloromethane (40 mL x 3) was extracted, the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent dichloromethane and ethyl acetate (V / V = 5:1) to obtain compound 5 (129.72 mg, white solid, 21.73%).

[0198] MS (ESI) m / z: 234 [M+H] + .

[0199] 1 H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 8.1 Hz, 1H), 6.93 (s, 1H), 6.82 (dd, J = 8.0, 1.6 Hz, 1H), 5.54 (d, J = 91.2 Hz, 2H), 2.90 (dt, J = 16.1, 7.3 Hz, 6H), 2.63 (t, J = 6.7 Hz, 2H), 2.09 (p, J = 7.4 Hz, 2H).

[0200] Example 6: Preparation of 2,3-dihydro-lH-inden-5-yl 4-(dimethylamino)-4-oxobutanoate (6)

[0201] Example 7: Preparation of 2,3-dihydro-lH-inden-5-yl N-acetyl-N-methylglycinate (7)

[0202] N-Acetyl-N-methylglycine 7a (350 mg, 2.67 mmol), compound a (358 mg, 2.67 mmol) and DMAP (33 mg, 0.27 mmol) were dissolved in dichloromethane (5 mL), the reaction was reduced to 0°C under nitrogen atmosphere, DCC (551 mg, 2.67 mmol) was added thereto, the reaction was stirred at 20°C for 2 hours, then water (30 mL) was added to the reaction, dichloromethane was extracted (40 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent dichloromethane and ethyl acetate (V / V = 5:1) to obtain compound 7 (350 mg, white solid, 53.0%).

[0203] MS (ESI) m / z: 248 [M+H] + .

[0204] 1 H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 8.1 Hz, 1H), 6.95 (s, 1H), 6.84 (dd, J = 8.1, 1.6 Hz, 1H), 4.31 (d, J = 34.4 Hz, 2H), 3.11 (d, J = 37.9 Hz, 3H), 2.95-2.83 (m, 4H), 2.16 (d, J = 11.9 Hz, 3H), 2.13-2.04 (m, 2H).

[0205] Example 8: Preparation of 1-(2-((2,3-dihydro-1H-inden-5-yl)oxy)pyridin-4-yl)ethan-1-one (8)

[0206] Step 1: Preparation of 2-((2,3-dihydro-1H-inden-5-yl)oxy)-4-iodopyridine (8a)

[0207] Compound a (1 g, 7.46 mmol) was dissolved in DMF (10 mL), the reaction was reduced to 0°C under nitrogen atmosphere, NaH (328 mg, 8.21 mmol) was added thereto, the reaction was stirred at 0°C for 30 minutes, then 2-chloro-4-iodopyridine (2.68 g, 11.19 mmol) was added, the reaction was stirred at room temperature for 4 hours. Ice water (10 mL) was added to the reaction, ethyl acetate was extracted (30 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V = 10:1) to obtain compound 8a (1 g, white solid, 40%).

[0208] MS (ESI) m / z: 337.8 [M+H] + .

[0209] Step 2: Preparation of 2-((2,3-dihydro-1H-inden-5-yl)oxy)-4-(1- ethoxyvinyl)pyridine (8c)

[0210] Compound 8a (800 mg, 2.37 mmol) and compound 8b (1.29 g, 3.56 mmol) were dissolved in DMF (10 mL), under nitrogen atmosphere, triethylamine (719 mg, 7.12 mmol) and Pd(PPh3)4(274 mg, 0.24 mmol) were added, the reaction was stirred at 110 °C for 2 hours. The reaction was cooled, water (10 mL) was added to the reaction, extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give the crude compound 8c (900 mg).

[0211] MS (ESI) m / z: 281.8 [M+H] + .

[0212] Step 3: Preparation of 1-(2-((2,3-dihydro-1H-inden-5-yl)oxy)pyridin-4- yl)ethan-1-one (8)

[0213] Compound 8c (900 mg) was added with 1N hydrochloric acid (10 mL), stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction, extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V = 5:1) to give compound 8 (120 mg, white solid, 20%).

[0214] MS (ESI) m / z: 281.8 [M+H] + .

[0215] 1 HNMR (400MHz, CDCI3) δ 8.33 (d, J = 5.2 Hz, 1H), 7.39 (dd, J = 5.2, 1.0 Hz, 1H), 7.32 (s, 1H), 7.25-7.22 (m, 1H), 6.98 (s, 1H), 6.88 (dd, J = 8.0, 1.5 Hz, 1H), 2.91 (q, J = 7.1 Hz, 4H), 2.60 (s, 3H), 2.11 (m, 2H).

[0216] Example 9: Preparation of N-(2,3-dihydro-1H-inden-5-yl)-N-methyl-4- oxopentanamide (9)

[0217] Step 1: Preparation of N-(2,3-dihydro-lH-inden-5-yl)-4-oxopentanamide (9a)

[0218] 4-oxopentanoic acid (1.6 g, 13.8 mmol), EDCI (3.97 g, 20.70 mmol), HOBt (2.8 g, 20.70 mmol) were dissolved in dichloromethane (20 mL), replaced with nitrogen for three times, and stirred at room temperature for 5 min. 2,3-dihydro-lH-inden-5-amine b (2 g, 15.18 mmol) and NMM (5.58 g, 55.20 mmol) were added, and the reaction solution was stirred at 25 °C for 2 h. Water (40 mL) was added to the reaction solution, dichloromethane (40 mL x 3) was extracted, the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V = 3: 1) to obtain compound 9a (2.3 g, colorless oil, 50.72%).

[0219] MS (ESI) m / z: 232.1 [M+H] + .

[0220] Step 2: Preparation of N-(2,3-dihydro-lH-inden-5-yl)-N-methyl-4-oxopentanamide (9)

[0221] Compound 9a (400 mg, 1.72 mmol), CH3I (1.96 g, 13.83 mmol), Cs2CO3 (1.69 g, 5.18 mmol) were dissolved in DMF (4 mL), replaced with nitrogen for three times, and the reaction solution was stirred at 25 °C for 16 h. Water (10 mL) was added to the reaction solution, ethyl acetate (20 mL x 3) was extracted, the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V = 1: 1) to obtain compound 9 (200 mg, yellow oil, 44.78%).

[0222] MS (ESI) m / z: 246.1 [M+H] + .

[0223] 1H NMR (400 MHz, DMSO) δ 7.28 (d, J = 7.7 Hz, 1H), 7.17 (s, 1H), 7.06 (d, J = 7.5 Hz, 1H), 3.09 (s, 3H), 2.87 (dd, J = 11.4, 6.9 Hz, 4H), 2.59 (t, J = 6.3 Hz, 2H), 2.17 (d, J = 5.5 Hz, 2H), 2.05 (s, 3H), 2.05 - 1.99 (m, 2H).

[0224] Example 10: Preparation of 4-oxo-N-(5,6,7,8-tetrahydronaphthalen-2-yl)pentanamide (10)

[0225] 5,6,7,8-Tetrahydronaphthalen-2-amine c (500 mg, 3.94 mmol), 4-oxopentanoic acid (512 mg, 4.42 mmol) and HATU (1679 mg, 4.42 mmol) were dissolved in dichloromethane (10 mL), to which DIEA (1316 mg, 10.19 mmol) was added, and the reaction was replaced with nitrogen three times. The reaction was stirred at 20 °C for 2 hours. Water (30 mL) was added to the reaction, and dichloromethane (40 mL x 3) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent dichloromethane and ethyl acetate (V / V = 1:1) to obtain compound 10 (120 mg, white solid, 14.3%).

[0226] MS (ESI) m / z: 246 [M+H] + .

[0227] 1 H NMR (400 MHz, DMSO) δ 9.75 (s, 1H), 7.29 (s, 1H), 7.25 - 7.18 (m, 1H), 6.93 (d, J = 8.3 Hz, 1H), 2.71 (t, J = 6.6 Hz, 2H), 2.68 - 2.59 (m, 4H), 2.49 - 2.46 (m, 2H), 2.12 (s, 3H), 1.70 (d, J = 2.7 Hz, 4H).

[0228] Example 11: Preparation of N-(3-oxobutyl)-5,6,7,8-tetrahydronaphthalene-2- carboxamide (11)

[0229] Step 1: Preparation of 5,6,7,8-tetrahydronaphthalene-2-carbonyl chloride (11a)

[0230] Step 1: Preparation of 5,6,7,8-tetrahydronaphthalene-2-carboxylic acid d

[0231] Step 2: Preparation of N-(3-oxobutyl)-5,6,7,8-tetrahydronaphthalene-2- carboxamide (11)

[0232] Compound 11a (120 mg, 0.97 mmol), TEA (376 mg, 2.91 mmol) were dissolved in dichloromethane (15 mL), 4-aminobutan-2-one hydrochloride (227 mg, 1.13 mmol) was added to the reaction solution at 0 °C, and the reaction solution was stirred at room temperature for 1 h. Water (30 mL) was added to the reaction solution, and dichloromethane (40 mL x 3) was extracted. The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent dichloromethane and ethyl acetate (V / V = 4:1) to obtain compound 11 (136 mg, white solid, 40.23%).

[0233] MS (ESI) m / z: 246 [M+H] + .

[0234] 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (t, J = 5.4 Hz, 1H), 7.498-7.46 (m, 2H), 7.07 (d, J = 8.6 Hz, 1H), 3.37 (td, J = 6.9, 5.6 Hz, 2H), 2.70-2.64 (m, 6H), 2.07 (s, 3H), 1.70 (dt, J = 6.5, 3.4 Hz, 4H).

[0235] Example 12: Preparation of 1-(2-((5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyridin-4- yl)ethan-1-one (12)

[0236] Compound c (250 mg, 1.70 mmol), 1-(2-chloropyridin-4-yl)ethan-1-one (264 mg, 1.70 mmol) and cesium carbonate (1.66 g, 5.09 mmol) were dissolved in toluene (10 mL), to which palladium acetate (38 mg, 0.17 mmol) and BINAP (211 mg, 0.34 mmol) were added, and the reaction was stirred at 100 °C for 5 hours after replacing the nitrogen gas three times. Water (30 mL) was added to the reaction solution, and dichloromethane (40 mL x 3) was extracted. The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane and ethyl acetate (V / V = 1:1) as an eluent to obtain compound 12 (192.21 mg, orange solid, 41.2%).

[0237] MS (ESI) m / z: 267.0 [M+H] + .

[0238] 1 H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 5.2 Hz, 1H), 7.23 (s, 1H), 7.10 (dd, J = 5.3, 1.3 Hz, 1H), 7.06 (d, J = 0.9 Hz, 2H), 7.02 (s, 1H), 6.77 (s, 1H), 2.76 (d, J = 4.2 Hz, 4H), 2.54 (s, 3H), 1.81 (dt, J = 6.4, 3.3 Hz, 4H).

[0239] Example 13: Preparation of N-(5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (13)

[0240] Compound c (1.65 g, 3.39 mmol) and pyridine (0.37 mL, 4.59 mmol) were dissolved in ethyl acetate (10 mL), and the reaction was stirred at 25 °C for 16 hours after replacing the nitrogen gas three times. To the reaction solution, water (30 mL) was added, and dichloromethane (40 mL x 3) was extracted. The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane and ethyl acetate (V / V = 5:1) as an eluent to obtain compound 13 (126.13 mg, white solid).

[0241] MS (ESI) m / z: 190.1 [M+H] + .

[0242] 1H NMR (400 MHz, DMSO) δ 9.73 (s, 1H), 7.32 - 7.25 (m, 1H), 7.23 (dd, J = 8.2, 2.1 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 2.64 (d, J = 7.0 Hz, 4H), 2.00 (s, 3H), 1.74 - 1.66 (m, 4H).

[0243] Example 14: Preparation of N-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-amine (14)

[0244] Compound c (300 mg, 2.04 mmol) and 2-bromopyridine (1.61 g, 10.19 mmol) were added into a round-bottom flask, and the reaction was stirred at 110 °C for 2 h. Water (30 mL) was added into the reaction, and dichloromethane (40 mL x 3) was used to extract the reaction. The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent dichloromethane and ethyl acetate (V / V = 3:1) to obtain compound 14 (133 mg, white solid, 27.63%).

[0245] MS (ESI) m / z: 225 [M+H] + .

[0246] 1 H NMR (400 MHz, CDCl3) δ 8.17 (dd, J = 4.9, 0.9 Hz, 1H), 7.51 - 7.43 (m, 1H), 7.02 (d, J = 12.0 Hz, 3H), 6.84 (d, J = 8.4 Hz, 1H), 6.69 (dd, J = 6.7, 5.3 Hz, 1H), 6.58 (s, 1H), 2.75 (d, J = 5.7 Hz, 4H), 1.80 (dt, J = 6.5, 3.3 Hz, 4H).

[0247] Example 15: Preparation of 1-(6-((5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyridin-3-yl)ethan-1-one (15)

[0248] Compound c (250 mg, 1.70 mmol) and 1-(6-bromopyridin-3-yl)ethan-1-one (340 mg, 1.70 mmol) were added to a 50 mL single-necked flask, replaced with nitrogen three times, and reacted at 100 °C for 2 hours. Water (10 mL) was added to the reaction solution, dichloromethane was extracted (10 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate (5 ml) was added to the residue to recrystallize, to obtain compound 15 (147.5 mg, yellow solid, 40.6%).

[0249] MS (ESI) m / z: 267.2 [M+H] + .

[0250] 1 H NMR (400 MHz, CDCl3) δ = 8.75 (d, J = 2.1, 1H), 8.04 (dd, J = 8.9, 2.3, 1H), 7.17 (s, 1H), 7.12-7.02 (m, 3H), 6.79 (d, J = 8.9, 1H), 2.77 (d, J = 2.9, 4H), 2.53 (s, 3H), 1.81 (dt, J = 6.6, 3.4, 4H).

[0251] Example 16: Preparation of 1-(6-((5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyridin-2-yl)ethan-1-one (16)

[0252] Compound c (309 mg, 2.09 mmol), cesium carbonate (1710 mg, 5.25 mmol), Pd2(dba)3 (267.04 mg, 0.175 mmol) and Xantphos (203 mg, 0.35 mmol) were dissolved in 1,4-dioxane (8 mL), replaced with nitrogen three times, and the reaction solution was stirred at 90 °C for 4 hours. Water (30 mL) was added to the reaction solution, dichloromethane was extracted (40 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V = 5:1) to obtain compound 16 (150 mg, yellow solid, 32.19%).

[0253] MS (ESI) m / z: 267.2 [M+H] + .

[0254] 1H NMR (400 MHz, CDC13) δ 7.59 (t, J = 7.9 Hz, 1H), 7.44 (d, J = 7.3 Hz, 1H), 7.17 (s, 1H), 7.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.50 (br s, 1H) 2.76 (d, J = 6.9 Hz, 4H), 2.68 (s, 3H), 1.83 - 1.79 (m, 4H).

[0255] Example 17: Preparation of 4-oxo-N-(5,6,7,8-tetrahydronaphthalen-l-yl)pentanamide (17)

[0256] Step 1: Preparation of 4-oxo-N-(5,6,7,8-tetrahydronaphthalen-l-yl)pentanamide (17)

[0257] MS (ESI) m / z: 246.0 [M+H] + .

[0258] 1 H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.02 (t, J = 7.7 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 2.75 - 2.68 (m, 4H), 2.58 - 2.53 (m, 4H), 2.12 (s, 3H), 1.75 - 1.63 (m, 4H).

[0259] Example 18: Preparation of 3-acetyl-l-methyl-5-((5,6,7,8-tetrahydronaphthalen-2- yl)amino)pyridin-4(lH)-one (18)

[0260] Step 1: Preparation of 3-bromo-l-methyl-5-((5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyridin- 4(lH)-one (18a)

[0261] To a solution of 3,5-di bromo-1-methylpyridin-4(1H)-one (0.4 g, 1.50 mmol) in 1,4-dioxane (15 mL) was added compound c (222 mg, 1.65 mmol), palladium acetate (35 mg, 0.15 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.17 g, 0.30 mmol) and cesium carbonate (1.47 g, 4.51 mmol) successively, the reaction was stirred at 100 °C for 12 h under nitrogen atmosphere. Water (40 mL) was added to the reaction mixture, and extracted with ethyl acetate (30 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using eluent of petroleum ether and ethyl acetate (V / V = 5:1) to give compound 18a (350 mg, 70%).

[0262] MS (ESI) m / z: 333.0, 335.0 [M+H] + .

[0263] Step 2: Preparation of 3-(1-ethoxyvinyl)-1-methyl-5-((5,6,7,8-tetrahydronaphthalen-2- yl)amino)pyridin-4(1H)-one (18b)

[0264] Compound 18a (350 mg, 1.05 mmol) and compound 8b (570 mg, 1.575 mmol) were dissolved in DMF (10 mL), and tetraphenylphosphonium palladium (122 mg, 0.105 mmol) was added under nitrogen atmosphere. The reaction was stirred at 110 °C for 10 h. After cooling, saturated sodium chloride solution (30 mL) was added to the reaction mixture, and extracted with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 18b (400 mg).

[0265] Step 3: Preparation of 3-acetyl-1-methyl-5-((5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyridin- 4(1H)-one (18)

[0266] To a solution of compound 18b (400 mg) in tetrahydrofuran (15 mL) was added 1N hydrochloric acid (5 ml), and stirred at room temperature for 5 h. Water (20 mL) was added to the reaction mixture, and extracted with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using eluent of petroleum ether and ethyl acetate (V / V = 10:1), concentrated, and recrystallized with petroleum ether and ethyl acetate to give compound 18 (63.2 mg, yellow solid, 20.3%).

[0267] MS (ESI) m / z: 297.0 [M+H] + .

[0268] 1 H NMR (400 MHz, CDC13) δ 8.19 (s, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.92 (dd, J = 8.1, 2.3 Hz, 1H), 6.88 - 6.84 (m, 1H), 3.78 (s, 3H), 2.82 (s, 3H), 2.75 (d, J = 5.5 Hz, 4H), 1.81 (dt, J = 6.6, 3.4 Hz, 4H).

[0269] Example 19: Preparation of 2-methyl-N-(5,6,7,8-tetrahydronaphthalen-2-yl)isonicotinamide (19)

[0270] 2-methylisonicotinic acid (200 mg, 1.46 mmol), DIEA (565.80 mg, 4.38 mmol), HATU (832.73 mg, 2.19 mmol) were dissolved in DCM (5 mL), replaced with nitrogen for three times, stirred at room temperature for 10 minutes. Compound c (236.24 mg, 1.61 mmol) was added to the reaction solution, the reaction solution was stirred at 25°C for 2 hours, water (20 mL) was added to the reaction solution, DCM was extracted (20 mL x 3), the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent DCM and MeOH (V / V = 10:1) to obtain compound 19 (241 mg, colorless solid, 61.82%).

[0271] MS (ESI) m / z: 267.0 [M+H] + .

[0272] 1 H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 8.58 (d, J = 5.1 Hz, 1H), 7.67 (s, 1H), 7.60 (d, J = 5.0 Hz, 1H), 7.44 (s, 1H), 7.41 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 2.71 - 2.61 (m, 4H), 2.53 (s, 3H), 1.69 (t, J = 2.8 Hz, 4H).

[0273] Example 20: Preparation of 6-methyl-N-(5,6,7,8-tetrahydronaphthalen-2-yl)nicotinamide (20)

[0274] The preparation method is the same as that of Example 19, except that 6-methylnicotinic acid is used instead of 2-methylisonicotinic acid, to obtain compound 20 (colorless solid).

[0275] MS (ESI) m / z: 267.0 [M+H] + .

[0276] 1 HNMR (400MHz, DMSO) δ 10.18 (s, 1H), 8.98 (d, J = 1.5 Hz, 1H), 8.18 (dd, J = 8.1, 2.1 Hz, 1H), 7.49-7.38 (m, 3H), 7.02 (d, J = 8.2 Hz, 1H), 2.74-2.64 (m, 4H), 2.55 (s, 3H), 1.73 (s, 4H).

[0277] Example 21: Preparation of 1-methyl-2-oxo-N-(5,6,7,8-tetrahydronaphthalen-2-yl)- 1,2-dihydropyridine-4-carboxamide (21)

[0278] A solution of 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (200 mg, 1.30 mmol), DIEA (506.4 mg, 3.91 mmol), HATU (744.87 mg, 1.95 mmol) in DMF (3 mL) was stirred at room temperature for 5 min after being replaced with nitrogen for three times. Compound c (192 mg, 1.306 mmol) was added to the reaction solution, which was stirred at 25 °C for 2 h. Water (40 mL) was added to the reaction solution, which was extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent of petroleum ether and ethyl acetate (V / V = 3:1) to obtain compound 21 (120 mg, colorless solid, 30.92%).

[0279] MS (ESI) m / z: 283.0 [M+H] + .

[0280] 1HNMR (400 MHz, CDC13) δ 8.83 (s, 1H), 7.52 (s, 1H), 7.46 (dd, J = 8.2, 1.8 Hz, 1H), 7.41 (d, J = 7.0 Hz, 1H), 7.19 (d, J = 1.5 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.75 (dd, J = 7.0, 1.8 Hz, 1H), 3.59 (s, 3H), 2.81 - 2.70 (m, 4H), 1.79 (dt, J = 6.5, 3.5 Hz, 4H).

[0281] Example 22: Preparation of 4-acetyl-N-(5,6,7,8-tetrahydronaphthalen-2- yl)benzamide (22)

[0282] Compound c (215 mg, 1.46 mmol) was added to the reaction solution, and the mixture was stirred at 25 °C for 1 h. Water (30 mL) was added to the reaction solution, and dichloromethane (40 mL x 3) was extracted. The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent dichloromethane and ethyl acetate (V / V = 2: 1) to obtain compound 22 (125 mg, white solid, 33.22%).

[0283] MS (ESI) m / z: 294 [M+H] + .

[0284] 1 HNMR (400 MHz, CDC13) δ 8.83 (s, 1H), 7.52 (s, 1H), 7.46 (dd, J = 8.2, 1.8 Hz, 1H), 7.41 (d, J = 7.0 Hz, 1H), 7.19 (d, J = 1.5 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.75 (dd, J = 7.0, 1.8 Hz, 1H), 3.59 (s, 3H), 2.81 - 2.70 (m, 4H), 1.79 (dt, J = 6.5, 3.5 Hz, 4H).

[0285] Example 23: Preparation of 3-acetyl-N-(5,6,7,8-tetrahydronaphthalen-2- yl)benzamide (23)

[0286] Compound 23 (154 mg, colorless solid, 21.13%) was obtained by the same method as the preparation of Example 11, except that 3-acetylbenzoic acid (250 mg, 1.52 mmol), compound c (224 mg, 1.52 mmol), EDCI (438 mg, 2.28 mmol), HOBt (309 mg, 2.28 mmol), DIEA (590 mg, 4.57 mmol) were dissolved in DMF (5 mL), replaced with nitrogen for three times, and the reaction solution was stirred at 25 °C for 4 hours. Water (20 mL) was added to the reaction solution, extracted with DCM (20 mL x 3), the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent of dichloromethane and ethyl acetate (V / V = 10:1) to obtain compound 23 (154 mg, colorless solid, 21.13%).

[0287] MS (ESI) m / z: 294.1 [M+H] + .

[0288] 1 HNMR (400MHz, DMSO) δ 10.28 (s, 1H), 8.49 (t, J = 1.6 Hz, 1H), 8.26-8.10 (m, 2H), 7.68 (t, J = 7.7 Hz, 1H), 7.54-7.39 (m, 2H), 7.03 (d, J = 8.2 Hz, 1H), 2.77-2.68 (m, 4H), 2.67 (s, 3H), 1.79-1.69 (m, 4H).

[0289] Example 24: Preparation of N-(2-oxopropyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (24)

[0290] Compound 24 (185.92 mg, white solid, 39.2%) was obtained by the same method as the preparation of Example 11, except that 3-aminopropan-2-one hydrochloride was used instead of 4-aminobutan-2-one hydrochloride.

[0291] MS (ESI) m / z: 232.0 [M+H] + .

[0292] 1 HNMR (400MHz, CDCl3) δ 7.51 (d, J = 8.6 Hz, 2H), 7.11 (d, J = 7.8 Hz, 1H), 6.86 (brs, 1H), 4.35 (d, J = 4.2 Hz, 2H), 2.79 (d, J = 3.2 Hz, 4H), 2.26 (s, 3H), 1.80 (t, J = 2.9 Hz, 4H).

[0293] Example 25: Preparation of 1-acetyl-N-(5,6,7,8-tetrahydronaphthalen-2-yl)piperidine- 4-carboxamide (25)

[0294] 1-acetylpiperidine-4-carboxylic acid (250 mg, 1.46 mmol), DIEA (566.19 mg, 4.38 mmol), HATU (666.30 mg, 1.75 mmol) were dissolved in DCM (5 ml), replaced with nitrogen for three times, stirred at room temperature for 10 min. Compound c (257.98 mg, 1.75 mmol) was added to the reaction solution, which was stirred at 25 °C for 6 hours. Water (40 mL) was added to the reaction solution, which was extracted with DCM (40 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent dichloromethane and methanol (V / V = 10:1) to obtain compound 25 (319 mg, colorless solid, 71.27%).

[0295] MS (ESI) m / z: 301.1 [M+H] + .

[0296] 1 HNMR (400MHz, CDCI3) δ 9.69 (s, 1H), 7.28 (s, 1H), 7.21 (dd, J = 8.2, 1.8 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 4.35 (d, J = 13.1 Hz, 1H), 3.82 (d, J = 13.6 Hz, 1H), 3.07-2.95 (m, 1H), 2.66-2.58 (m, 4H), 2.58-2.48 (m, 2H), 1.96 (s, 3H), 1.79-1.69 (m, 2H), 1.68-1.62 (m, 4H), 1.52 (qd, J = 12.6, 4.3 Hz, 1H), 1.38 (qd, J = 12.6, 4.3 Hz, 1H).

[0297] Example 26: Preparation of 1-acetyl-N-(5,6,7,8-tetrahydronaphthalen-2-yl)azetidine-3- carboxamide (26)

[0298] The same as the preparation method of Example 25, except that 1-acetylazetidine-3-carboxylic acid was used instead of 1-acetylpiperidine-4-carboxylic acid to obtain compound 26.

[0299] MS (ESI) m / z: 273.1 [M+H] + .

[0300] 1HNMR (400 MHz, MeOD) δ = 7.32 - 7.23 (m, 2H), 7.00 (d, J = 8.2, 1H), 4.39 (d, J = 7.2, 2H), 4.16 (dd, J = 14.8, 7.5, 2H), 3.55 (dt, J = 14.6, 7.2, 1H), 2.74 (d, J = 6.7, 4H), 1.90 (s, 3H), 1.84 - 1.77 (m, 4H).

[0301] Example 27: Preparation of l-acetyl-N-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrrolidine-3- carboxamide (27)

[0302] The same preparation method as Example 25, except using l-acetylpyrrolidine-3-carboxylic acid instead of l-acetylpiperidine-4-carboxylic acid, to give compound 27.

[0303] MS (ESI) m / z: 287.1 [M+H] + .

[0304] Example 27A and 27B: Preparation of (R)-l-acetyl-N-(5,6,7,8-tetrahydronaphthalen-2- yl)pyrrolidine-3-carboxamide (27A) and (S)-l-acetyl-N-(5,6,7,8-tetrahydronaphthalen-2- yl)pyrrolidine-3-carboxamide (27B)

[0305] Compound 27 (390 mg) was separated by SFC (CHIRALPAK AD-H, 250 mm x 20 mm, 5 μm, 35% EtOH (NH4OH 0.2%), flow rate: 40 g / min) to give compound 27A (92 mg), 27B (120 mg).

[0306] 27A:

[0307] MS (ESI) m / z: 287.1 [M+H] + .

[0308] 1 HNMR (400 MHz, CD3OD) δ = 7.20 (dd, J = 9.5, 7.3, 2H), 6.95 (d, J = 8.2, 1H), 3.79 - 3.35 (m, 4H), 3.12 (s, 1H), 2.70 (d, J = 6.3, 4H), 2.24 (dd, J = 6.7, 3.3, 2H), 2.05 (d, J = 4.1, 3H), 1.79 - 1.71 (m, 4H).

[0309] 27B:

[0310] MS (ESI) m / z: 287.1 [M+H] + .

[0311] 1 HNMR (400MHz, CD3OD) δ = 7.21 (dd, J = 12.7, 4.1, 2H), 6.98 - 6.92 (m, 1H), 3.77 - 3.35 (m, 4H), 3.24 - 3.06 (m, 1H), 2.70 (d, J = 6.2, 4H), 2.29 - 2.07 (m, 2H), 2.05 (d, J = 4.0, 3H), 1.81 - 1.71 (m, 4H).

[0312] Example 28A: Preparation of (R)-1-acetyl-N-(5,6,7,8-tetrahydronaphthalen-2- yl)pyrrolidine-2-carboxamide (28A)

[0313] To the solution of acetyl-D-proline (0.3 g, 1.89 mmol) in dichloromethane (15 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.54 g, 2.84 mmol), 1-hydroxybenzotriazole (0.39 g, 2.84 mmol), N,N-diisopropylethylamine (1.22 g, 9.49 mmol). After stirring at 25 °C for 10 min, compound c (0.28 g, 1.89 mmol) was added. The reaction was stirred at 25 °C for 6 h. The reaction was washed with saturated citric acid solution (50 mL x 2), saturated sodium carbonate solution (50 mL x 2) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution of petroleum ether and ethyl acetate (V / V = 2:1) to give compound 28A (290.77 mg, white solid, 53.4%).

[0314] MS (ESI) m / z: 287.0 [M+H] + .

[0315] 1H NMR (400 MHz, CDC13) δ 9.53 (br s, 1H), 7.29 - 7.27 (m, 1H), 7.24 (dd, J = 9.1, 0.8 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 4.78 (d, J = 7.7 Hz, 1H), 3.60 - 3.50 (m, 1H), 3.44 (td, J = 10.0, 7.1 Hz, 1H), 2.77 - 2.67 (m, 4H), 2.62 (dd, J = 12.2, 6.3 Hz, 1H), 2.24 - 2.15 (m, 1H), 2.14 (s, 3H), 2.03 (dt, J = 6.8, 5.5 Hz, 1H), 1.85 - 1.79 (m, 1H), 1.78 - 1.73 (m, 4H).

[0316] Example 28B: Preparation of (S)-1-acetyl-N-(5,6,7,8-tetrahydronaphthalen-2- yl)pyrrolidine-2-carboxamide (28B)

[0317] Compound 28B was obtained in the same manner as in the preparation of Example 28A, except that acetyl-L-proline was used instead of acetyl-D-proline.

[0318] MS (ESI) m / z: 287.0 [M+H] + .

[0319] 1 H NMR (400 MHz, CDC13) δ 9.55 (br s, 1H), 7.29 - 7.27 (m, 1H), 7.24 (dd, J = 8.2, 2.1 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 4.78 (d, J = 7.7 Hz, 1H), 3.60 - 3.50 (m, 1H), 3.43 (td, J = 10.0, 7.1 Hz, 1H), 2.76 - 2.68 (m, 4H), 2.61 (dd, J = 12.5, 6.5 Hz, 1H), 2.24 - 2.15 (m, 1H), 2.15 (s, 3H), 2.07 - 1.99 (m, 1H), 1.88 - 1.79 (m, 1H), 1.78 - 1.73 (m, 4H).

[0320] Example 29: Preparation of N-(2,3-dihydro-1H-inden-5-yl)-5,5,5-trifluoro-4- methylpentanamide (29)

[0321] Step 1: Preparation of 4,4,4-trifluoro-3-methylbutan-1-ol (29b)

[0322] Ethyl 4,4,4-trifluoro-3-methylbutanoate 29a (4.0 g, 21.7 mL, 10.86 mmol) was added dropwise to a cold solution (0 °C) of LiAlH4(1 M, 16.3 mL, 16.3 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature for 20 h. After quenching with water, it was extracted with diethyl ether (20 ml x 3). The combined organic layer was washed with brine, dried over Na2S04, filtered, and the filtrate was concentrated under vacuum (5 °C) to give compound 29b (3 g, yellow oil, 97.24 %).

[0323] 1 H NMR (400 MHz, CDCl3) δ 3.73 - 3.61 (m, 2H), 2.53 - 2.32 (m, 1H), 1.96 (ddd, J = 11.5, 10.3, 6.3 Hz, 2H), 1.59 - 1.42 (m, 1H), 1.14 (d, J = 7.0 Hz, 3H).

[0324] Step 2: Preparation of 4,4,4-trifluoro-3-methylbutyl methanesulfonate (29c)

[0325] Ethyl 4,4,4-trifluoro-3-methylbutanoate 29a (4.0 g, 21.7 mL, 10.86 mmol) was added dropwise to a cold solution (0 °C) of LiAlH4(1 M, 16.3 mL, 16.3 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature for 20 h. After quenching with water, it was extracted with diethyl ether (20 ml x 3). The combined organic layer was washed with brine, dried over Na2S04, filtered, and the filtrate was concentrated under vacuum (5 °C) to give compound 29b (3 g, yellow oil, 97.24 %).

[0326] 1 H NMR (400 MHz, CDCl3) δ 3.73 - 3.61 (m, 2H), 2.53 - 2.32 (m, 1H), 1.96 (ddd, J = 11.5, 10.3, 6.3 Hz, 2H), 1.59 - 1.42 (m, 1H), 1.14 (d, J = 7.0 Hz, 3H).

[0327] Step 3: Preparation of 5,5,5-trifluoro-4-methylpentanenitrile (29d)

[0328] In a solution of 5,5,5-trifluoro-4-methylpentanenitrile 29d (480 mg, 2.85 mmol) in MeOH (10 mL) and H2O (10 mL) was added NaOH (457 mg, 11.4 mmol). The mixture was stirred at 50 °C for 16 h. Diluted with water (20 mL), extracted with DCM (20 mL x 3). The aqueous phase was adjusted to pH = 3 with 1 N HC1, extracted with DCM (20 mL x 3), the combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum at 5 °C to give compound 29e (290 mg, yellow oil, 53.67%).

[0329] 1 H NMR (400 MHz, CDC13) δ 2.45 (pt, J = 21.9, 7.1 Hz, 3H), 2.13 - 1.99 (m, 1H), 1.83 - 1.63 (m, 1H), 1.18 (d, J = 7.0 Hz, 3H).

[0330] Step 4: Preparation of 5,5,5-trifluoro-4-methylpentanoic acid (29e)

[0331] In a solution of 5,5,5-trifluoro-4-methylpentanenitrile 29d (480 mg, 2.85 mmol) in MeOH (10 mL) and H2O (10 mL) was added NaOH (457 mg, 11.4 mmol). The mixture was stirred at 50 °C for 16 h. Diluted with water (20 mL), extracted with DCM (20 mL x 3). The aqueous phase was adjusted to pH = 3 with 1 N HC1, extracted with DCM (20 mL x 3), the combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum at 5 °C to give compound 29e (290 mg, yellow oil, 53.67%).

[0332] MS (ESI) m / z: 169.1 [M-H] + .

[0333] 1 H NMR (400 MHz, CDC13) δ 2.45 (pt, J = 21.9, 7.1 Hz, 3H), 2.13 - 1.99 (m, 1H), 1.83 - 1.63 (m, 1H), 1.18 (d, J = 7.0 Hz, 3H).

[0334] Step 5: Preparation of N-(2,3-dihydro-lH-inden-5-yl)-5,5,5-trifluoro-4- methylpentanamide (29)

[0335] A mixture of 5,5,5-trifluoro-4-methylpentanoic acid 29e (290 mg, 1.7 mmol), 2,3-dihydro-1H-indol-5-amine b (227 mg, 1.7 mmol), HATU (777 mg, 2 mmol) and DIPEA (661 mg, 5 mmol) in DMF (10 mL) was stirred for 2 h. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using petroleum ether and ethyl acetate (V / V = 94:6) as eluent to give compound 29 (221 mg, white solid, 43.92%).

[0336] MS (ESI) m / z: 286.0 [M+H] + .

[0337] 1 HNMR (400MHz, CDCI3) δ 7.45 (s, 1H), 7.19-7.03 (m, 3H), 2.87 (dt, J = 11.0, 7.4 Hz, 4H), 2.51-2.25 (m, 3H), 2.13-2.02 (m, 3H), 1.86-1.76 (m, 1H), 1.15 (d, J = 7.0 Hz, 3H).

[0338] Example 30: Preparation of N-(2,3-dihydro-1H-inden-5-yl)-5,5,5-trifluoro-4- (trifluoromethyl)pentanamide (30)

[0339] Step 1: Preparation of N-(2,3-dihydro-1H-inden-5-yl)acrylamide (30a)

[0340] Compound b (2 g, 15.0 mmol) and DIEA (2.9 g, 22.5 mmol) were dissolved in dichloromethane (30 mL), the reaction was reduced to 0 °C, acryloyl chloride (1.5 g, 16.5 mmol) was added thereto, the reaction was stirred at room temperature for 2 h, concentrated under reduced pressure, the residue was purified by column chromatography on silica gel using petroleum ether and ethyl acetate (V / V = 85:15) as eluent to give compound 30a (1.8 g, brown solid, 64.00%).

[0341] MS (ESI) m / z: 188.1 [M+H] + .

[0342] Step 2: Preparation of N-(2,3-dihydro-1H-inden-5-yl)-5,5,5-trifluoro-4-hydroxy-4- (trifluoromethyl)pentanamide (30b)

[0343] Compound 30a (893 mg, 4.77 mmol), triphenylphosphine (3003 mg, 11.45 mol) and (Ir(dFCF3ppy)2dtbbpy)PF6(107 mg, 0.095 mmol) were added into 1,1,1,3,3,3-hexafluoropropan-2-one trihydrate (700 mg, 3.18 mmol) dissolved in acetonitrile (32 mL). The reaction was purged with argon for three times and stirred at room temperature under irradiation of 30 W blue LED for 16 h. The reaction was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent of petroleum ether and ethyl acetate (V / V = 80:20) to give compound 30b (500 mg, yellow solid, 44.00%).

[0344] MS (ESI) m / z: 356.0 [M+H] + .

[0345] Step 3: Preparation of 5-((2,3-dihydro-1H-inden-5-yl)amino)-1,1,1-trifluoro-5-oxo-2- (trifluoromethyl)pentan-2-yl 4-methylbenzoate (30c)

[0346] Compound 30b (500 mg, 1.40 mmol) was dissolved in dichloromethane (10 mL), and DMAP (34 mg, 0.28 mmol), Et3N (212 mg, 2.10 mol) and 4-methylbenzoyl chloride (260 mg, 1.68 mmol) were added into the solution. The reaction was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with eluent of petroleum ether and ethyl acetate (V / V = 85:15) to give compound 30c (460 mg, yellow solid, 69.14%).

[0347] MS (ESI) m / z: 474.0 [M+H] + .

[0348] Step 4: Preparation of N-(2,3-dihydro-1H-inden-5-yl)-5,5,5-trifluoro-4- (trifluoromethyl)pentanamide (30)

[0349] A dry three-necked flask was purged with argon three times, to which was added SmI2(39 mL, 3.9 mmol, 0.1 M in THF) followed by HMPA (0.002 L, 0.03 mol). The solution immediately turned purple. The solution was then heated to reflux, at which time compound 30c (4.5 g, 0.02 mol) was dissolved in minimal THF and added quickly. The reaction was monitored by TLC (reaction was complete within 10 min). The reaction was quenched by the addition of ammonium chloride (100 mL) and extracted with dichloromethane (60 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Daisogel C18 10 μm 100A (30 mm x 250 mm) with a mixture of water (with 0.1% FA) and acetonitrile of decreasing polarity (40-70%) as eluent) to give compound 30 (115 mg, white solid, 34.83%).

[0350] MS (ESI) m / z: 340.0 [M+H] + .

[0351] 1 H NMR (400 MHz, CDC13) δ 7.43 (s, 1H), 7.19 - 7.04 (m, 3H), 3.33 - 3.18 (m, 1H), 2.93 - 2.83 (m, 4H), 2.59 (t, J = 7.2 Hz, 2H), 2.27 (q, J = 7.0 Hz, 2H), 2.12 - 2.02 (m, 2H).

[0352] Example 31 and 32: Preparation of N-(2,3-dihydro-lH-inden-5-yl)-3- (methylsulfinyl)propanamide (31) and N-(2,3-dihydro-lH-inden-5-yl)-3- (methylsulfonyl)propanamide (32)

[0353] Step 1: Preparation of N-(2,3-dihydro-lH-inden-5-yl)-3-(methylthio)propanamide (31a)

[0354] To a solution of compound b (1 g, 7.46 mmol) in dichloromethane (30 mL) was added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.15 g, 11.19 mmol), 1-hydroxybenzotriazole (1.52 g, 11.19 mmol), N,N-diisopropylethylamine (4.81 g, 37.3 mmol), stirred at 25 °C for 10 min, then 3-(methylthio)propanoic acid (0.91 g, 7.46 mmol) was added. The reaction was stirred at 25 °C for 2 h. The reaction was washed with saturated citric acid solution (50 mL x 2), saturated sodium carbonate solution (50 mL x 2) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution of petroleum ether and ethyl acetate (V / V = 1:1) to give compound 31a (1 g, white solid, 56.8%).

[0355] MS (ESI) m / z: 236.0 [M+H] + .

[0356] Step 2: Preparation of N-(2,3-dihydro-lH-inden-5-yl)-3-(methylsulfinyl)propanamide (31)

[0357] Compound 31a (400 mg, 1.69 mmol) was dissolved in a mixture of 1,4-dioxane and methanol (1 / 1, 16.9 mL / 16.9 mL), and a selective fluorinating reagent (900 mg, 2.54 mmol) was added. The reaction was stirred at room temperature for 16 h. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution of dichloromethane and methanol (V / V = 10:1) to give compound 31 (290.17 mg, white solid, 67.9%).

[0358] MS (ESI) m / z: 252.2 [M+H] + .

[0359] 1 H NMR (400 MHz, CDC13) δ 8.27 (br s, 1H), 7.46 (s, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 3.27 (dt, J = 13.3, 6.7 Hz, 1H), 3.07 - 2.99 (m, 1H), 2.96 (t, J = 6.4 Hz, 2H), 2.87 (dt, J = 10.8, 7.5 Hz, 4H), 2.67 (s, 3H), 2.11 - 2.01 (m, 2H).

[0360] Step 3: Preparation of N-(2,3-dihydro-lH-inden-5-yl)-3-(methylsulfonyl)propanamide (32)

[0361] Compound 31a (400 mg, 1.69 mmol), m-chloroperbenzoic acid (1.47 g, 8.47 mmol) were dissolved in dichloromethane (20 mL), nitrogen was replaced for three times, the reaction was stirred at room temperature for 16 hours. Filtration, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent dichloromethane and methanol (V / V = 10:1), freeze-drying to obtain compound 32 (169.79 mg, 37.4%, white solid).

[0362] MS (ESI) m / z: 268.1 [M+H] + .

[0363] 1 H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.32 (brs, 1H), 7.19-7.11 (m, 2H), 3.48 (t, J = 7.0 Hz, 2H), 2.98 (s, 3H), 2.89 (ddd, J = 14.8, 12.7, 7.2 Hz, 6H), 2.07 (p, J = 7.5 Hz, 2H).

[0364] Examples 33 and 34: Preparation of N-(1,1,1-trifluoro-4-(methylsulfinyl)butan-2-yl)-2,3-dihydro-1H-inden-5-amine (33) and N-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)-2,3-dihydro-1H-inden-5-amine (34)

[0365] Step 1: Preparation of 3-((2,3-dihydro-1H-inden-5-yl)amino)-4,4,4-trifluorobutanoic acid (33b)

[0366] Compound b (2000 mg, 15.03 mmol), ethyl 4,4,4-trifluoro-3-oxobutanoate 33a (2765 mg, 15.03 mmol) and p-toluenesulfonic acid (258 mg, 1.5 mmol) were dissolved in ethanol (50 mL), the reaction was stirred at 80°C for 16 hours, then cooled to 0°C, sodium borohydride (1134 mg, 30.06 mmol) was slowly added to the reaction at 0°C, the reaction was restored to room temperature, and stirred at room temperature for 2 hours. Diluted with water (100 mL), remove ethanol under reduced pressure, extracted with dichloromethane (100 mL x 3), combined organic phase, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V = 60:40) to obtain compound 33b (1800 mg, yellow oil, 43.95%).

[0367] MS (ESI) m / z: 74.0 [M+H]+ .

[0368] Step 2: Preparation of 3-((2,3-dihydro-1H-inden-5-yl)amino)-4,4,4- trifluorobutan-1-ol (33c)

[0369] Compound 33b (1800 mg, 6.59 mmol) was dissolved in tetrahydrofuran (30 mL), the reaction was lowered to 0 °C, lithium aluminum hydride tetrahydrofuran solution (10 mL, 1 N) was added thereto, replaced with nitrogen three times, the reaction was raised to room temperature, and the reaction was stirred at room temperature for 5 hours. Sodium sulfate (3500 mg) was added to the reaction to quench, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V = 40:60) to obtain compound 33c (1.2 g, colorless oil, 70.33%).

[0370] MS (ESI) m / z: 259.9 [M+H] + .

[0371] Step 3: Preparation of 3-((2,3-dihydro-1H-inden-5-yl)amino)-4,4,4- trifluorobutyl methanesulfonate (33d)

[0372] Compound 33c (700 mg, 2.7 mmol) and DIEA (350 mg, 2.7 mmol) were dissolved in dichloromethane (10 mL), Ms2O (469 mg, 2.7 mmol) in dichloromethane (10 mL) was added dropwise at 0 °C, the reaction was stirred at room temperature for 3 hours, then diluted with water (50 mL), extracted with dichloromethane (20 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V = 65:35) to obtain compound 33d (570 mg, colorless oil, 62.7%).

[0373] MS (ESI) m / z: 338.0 [M+H] + .

[0374] Step 4: Preparation of N-(1,1,1-trifluoro-4-(methylthio)butan-2-yl)-2,3- dihydro-1H-inden-5-amine (33e)

[0375] Compound 33d (570 mg, 1.69 mmol) was dissolved in DMF (8 mL), sodium thiomethoxide (1050 mg, 15 mmol) was added, after the reaction was stirred at 70 °C for 5 hours, diluted with water (50 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V = 60:40) to give compound 33e (400 mg, white oil, 81.9%).

[0376] MS (ESI) m / z: 290.1 [M+H] + .

[0377] Step 5: Preparation of N-(1,1,1-trifluoro-4-(methylsulfinyl)butan-2-yl)-2,3-dihydro-1H-inden-5-amine (33)

[0378] Compound 33e (400 mg, 1.38 mmol) was dissolved in dichloromethane (10 mL), the reaction was reduced to 0 °C, mCPBA (237 mg, 1.38 mmol) was added, after the reaction was stirred at room temperature for 1 hour, diluted with saturated aqueous sodium thiosulfate solution (30 mL), extracted with dichloromethane (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V = 80:20) to give compound 33 (280 mg, yellow solid, 66.66%).

[0379] MS (ESI) m / z: 305.9 [M+H] + .

[0380] 1 HNMR (400MHz, DMSO) δ 6.93 (d, J = 8.1 Hz, 1H), 6.62 (s, 1H), 6.51 (dd, J = 8.1, 1.9 Hz, 1H), 5.83-5.77 (m, 1H), 4.34-4.30 (m, 1H), 2.90-2.80 (m, 1H), 2.78-2.66 (m, 5H), 2.53 (d, J = 5.1 Hz, 3H), 2.13-2.06 (m, 1H), 2.00-1.87 (m, 3H).

[0381] Step 6: Preparation of N-(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)-2,3-dihydro-1H-inden-5-amine (34)

[0382] Compound 33 (150 mg, 0.49 mmol) was dissolved in dichloromethane (5 mL), the reaction was reduced to 0°C, mCPBA (84 mg, 0.49 mmol) was added thereto, after the reaction was stirred at room temperature for 1 hour, saturated aqueous sodium thiosulfate solution (15 mL) was added for dilution, extracted with dichloromethane (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V = 60:40) to obtain compound 34 (103 mg, yellow solid, 65.6%).

[0383] MS (ESI) m / z: 322.2 [M+H] + .

[0384] 1 HNMR (400MHz, DMSO) δ 6.94 (d, J = 8.1 Hz, 1H), 6.61 (s, 1H), 6.50 (dd, J = 8.1, 1.9 Hz, 1H), 5.83 (d, J = 8.1 Hz, 1H), 4.37-4.34 (m, 1H), 3.24-3.14 (m, 2H), 3.01 (s, 3H), 2.78-2.66 (m, 4H), 2.20-2.10 (m, 1H), 2.04-1.92 (m, 3H).

[0385] Example 35: Preparation of N-(2,3-dihydro-1H-inden-5-yl)-4,4,4-trifluoro-3- methylbutane-1-sulfonamide (35)

[0386] Step 1: Preparation of S-(4,4,4-trifluoro-3-methylbutyl)thioacetate (35b)

[0387] 4,4,4-trifluoro-3-methylbutyl methanesulfonate 35a (1.9 g, 8.6 mmol) was dissolved in acetone (100 mL), potassium thioacetate (1.96 g, 17.2 mmol) was added thereto, and the reaction was stirred at 60°C under reflux for 6 hours, and then cooled to room temperature. Water (50 mL) was added to the reaction, extracted with diethyl ether (50 mL x 3), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 5-10°C to obtain compound 35b (1.34 g, brown oil, yield 77.91%).

[0388] 1HNMR (400 MHz, CDC13) δ 3.03 - 2.96 (m, 1H), 2.92 - 2.84 (m, 1H), 2.34 (s, 3H), 2.31 - 2.20 (m, 1H), 1.97 - 1.89 (m, 1H), 1.66 - 1.57 (m, 1H), 1.15 (d, J = 7.0 Hz, 3H).

[0389] Step 2: Preparation of N-(2,3-dihydro-lH-inden-5-yl)-4,4,4-trifluoro-3- methylbutane- 1 -sulfonamide (35)

[0390] Compound 35b (100 mg, 0.499 mmol) was dissolved in dichloromethane (6 mL), water (27 mg, 1.498 mmol) and trifluoromethanesulfonic acid (150 mg, 0.999 mmol) were added, the reaction system was cooled to 0 °C, and chlorine was bubbled into the reaction system. After 1.5 hours, argon was bubbled to remove excess chlorine to obtain a reaction solution.

[0391] Compound b (66.5 mg, 0.499 mmol) was dissolved in dichloromethane (5 mL), triethylamine (404 mg, 3.995 mmol) was added, and the reaction solution of the first step was added dropwise. The mixture was stirred at room temperature for 0.5 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with sodium chloride brine (20 x 2 mL), dried over Na2S04and concentrated under vacuum to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate: dichloromethane = 0-10%) and preparative high performance liquid chromatography (the chromatographic column was Gemini C18 4.6 x 150 mm, 5 μm, 0.05% TFA water / acetonitrile as the mobile phase) to obtain compound 35 (15.6 mg, white solid, yield 10.03%).

[0392] MS (ESI) m / z: 306.1 [M+H] + .

[0393] 1 HNMR (400 MHz, MeOD) δ 7.11 (d, J = 8.0 Hz, 1H), 6.97 (s, 1H), 6.85 (d, J = 8.0 Hz, 1H), 3.17 - 2.97 (m, 2H), 2.90 - 2.78 (m, 4H), 2.51 - 2.41 (m, 1H), 2.12 - 2.01 (m, 3H), 1.78 - 1.68 (m, 1H), 1.18 (d, J = 6.9 Hz, 3H).

[0394] Example 36: Preparation of N-(2,3-dihydro-lH-inden-5-yl)-3-oxobutane-l- sulfonamide (36)

[0395] Step 1: Preparation of N-(2,3-dihydro-lH-inden-5-yl)methanesulfonamide (36a)

[0396] Compound b (2 g, 15 mmol) was dissolved in dichloromethane (80 mL), pyridine (2.37 g, 30 mmol) and Ms20 (2.87 g, 16.5 mmol) were added, the reaction was stirred at room temperature for 16 hours. 1M HC1 (100 mL) was added to the reaction, dichloromethane was extracted (100 mL x 3), the organic phase was combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V = 5:3) to obtain compound 36a (2.8 g, light yellow solid, 88.67%).

[0397] MS (ESI) m / z: 212.1 [M+H] + .

[0398] Step 2: Preparation of N-(2,3-dihydro-lH-inden-5-yl)-3-hydroxybutane-1-sulfonamide (36b)

[0399] Compound 36a (500 mg, 2.367 mmol) was dissolved in tetrahydrofuran (10 mL), replaced with nitrogen three times, and the reaction was reduced to -78°C. 2M LDA tetrahydrofuran solution (2.4 mL, 4.733 mmol) was added, and the reaction was stirred at -78°C for 30 minutes. 2-methyl epoxide (178.43 mg, 3.076 mmol) was added, and the reaction was stirred at room temperature for 16 hours. Saturated ammonium chloride solution (50 mL) was added to quench the reaction, dichloromethane was extracted (50 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent petroleum ether and ethyl acetate (V / V = 5:3) to obtain compound 36b (350 mg, light yellow oil, 54.91%).

[0400] MS (ESI) m / z: 270.1 [M+H] + .

[0401] 1H NMR (400 MHz, CDCI3) δ 7.17 (d, J = 8.0 Hz, 1 H), 7.12 (s, 1 H), 6.97 (dd, J = 8.0, 2.1 Hz, 1 H), 6.53 (s, 1 H), 3.99 - 3.90 (m, 1 H), 3.32 - 3.14 (m, 2 H), 2.88 (dd, J = 16.6, 7.7 Hz, 4 H), 2.14 - 1.85 (m, 4 H), 1.67 (s, 1 H), 1.23 (d, J = 6.2 Hz, 3 H).

[0402] Step 3: Preparation of N-(2,3-dihydro-1 H-inden-5-yl)-3-oxobutane-1 -sulfonamide (36)

[0403] Compound 36b (350 mg, 1.299 mmol) was dissolved in dichloromethane (40 mL), to which PCC (588.21 mg, 2.729 mmol) was added, and the reaction was stirred at room temperature for 4 hours. Water (50 mL) was added to quench the reaction, and dichloromethane (50 mL x 3) was used to extract the reaction, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent petroleum ether and ethyl acetate (V / V = 5:3) to obtain compound 36 (204 mg, white solid, 60.65%).

[0404] MS (ESI) m / z: 268.1 [M+H] + .

[0405] 1 H NMR (400 MHz, CDCI3) δ 7.20 - 7.10 (m, 2 H), 6.99 (dd, J = 7.9, 1.9 Hz, 1 H), 6.57 (s, 1 H), 3.36 (t, J = 7.3 Hz, 2 H), 2.99 (t, J = 7.3 Hz, 2 H), 2.88 (dd, J = 16.7, 7.7 Hz, 4 H), 2.20 (s, 3 H), 2.08 (p, J = 7.5 Hz, 2 H).

[0406] Example 37: Preparation of 2,2-dimethyl-3-(methylsulfonyl)-N-(5,6,7,8- tetrahydronaphthalen-2-yl)propanamide (37)

[0407] Step 1: Preparation of 2,2-dimethyl-3-(methylthio)propanoic acid (37b)

[0408] To a solution of 3-chloro-2,2-dimethylpropionic acid 37a (2 g, 14.7 mmol) in DMF (20 mL) was added sodium thiomethoxide (2.06 g, 29.4 mmol) and the reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated sodium bicarbonate solution to pH = 8 and washed with diethyl ether (3 x 75 mL). The aqueous layer was acidified with concentrated hydrochloric acid to pH = 1 and extracted with diethyl ether (3 x 75 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude compound 37b (2 g, clear oil, 91.86 %).

[0409] MS (ESI) m / z: 149.0 [M+H] + .

[0410] 1 H NMR (400 MHz, CDC13) δ 2.76 (s, 2H), 2.16 (s, 3H), 1.30 (s, 6H).

[0411] Step 2: Preparation of 2,2-dimethyl-3-(methylthio)-N-(5,6,7,8-tetrahydronaphthalen-2- yl)propanamide (37c)

[0412] Compound 37b (300 mg, 2.03 mmol), N,N-diisopropylethylamine (1.31 g, 10.13 mmol) and HATU (1.16 g, 3.04 mmol) were dissolved in DMF (10 mL), replaced with nitrogen three times, stirred for 30 min, and compound c (298.61 mg, 2.03 mmol) was added thereto, and the reaction was stirred at room temperature for 2 h. Water (30 mL) was added to the reaction, extracted with dichloromethane (40 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent dichloromethane and ethyl acetate (V / V = 5:1) to give compound 37c (350 mg, light yellow solid, 62.20 %).

[0413] MS (ESI) m / z: 278.4 [M+H] + .

[0414] Step 3: Preparation of 2,2-dimethyl-3-(methylsulfonyl)-N-(5,6,7,8-tetrahydronaphthalen-2- yl)propanamide (37)

[0415] Compound 37c (350 mg, 1.26 mmol), m-chloroperbenzoic acid (1.09 g, 6.32 mmol) were dissolved in dichloromethane (20 mL), replaced with nitrogen three times, and the reaction was stirred at room temperature for 16 hours. Filtration, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with dichloromethane and ethyl acetate (V / V = 10:1) elution, freeze-drying to obtain compound 37 (180.75 mg, 43.98%, white solid).

[0416] MS (ESI) m / z: 310.1 [M+H] + .

[0417] 1 HNMR (400MHz, DMSO) δ 9.12 (brs, 1H), 7.28 (d, J = 6.8 Hz, 2H), 6.96 (d, J = 8.9 Hz, 1H), 3.59 (s, 2H), 2.95 (s, 3H), 2.66 (d, J = 6.7 Hz, 4H), 1.71 (t, J = 2.8 Hz, 4H), 1.39 (s, 6H).

[0418] Example 38: Preparation of 3-(dimethylphosphoryl)-N-(5,6,7,8-tetrahydronaphthalen-2- yl)propanamide (38)

[0419] Step 1: Preparation of N-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (38a)

[0420] Compound c (500 mg, 3.40 mmol) and DIPEA (878 mg, 6.79 mmol) were dissolved in dichloromethane (10 mL), and the reaction mixture was cooled to 0°C in an ice bath, to which acryloyl chloride (338 mg, 3.74 mmol) was slowly added dropwise, slowly warmed to room temperature, and the reaction was stirred at room temperature for 1 hour. Water (30 mL) was added to the reaction, dichloromethane was extracted (20 mL x 3), the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 38a (650 mg, brown oil, 85%). Used directly in the next step without purification.

[0421] MS (ESI) m / z: 202.2 [M+H] + .

[0422] Step 2: Preparation of 3-(dimethylphosphoryl)-N-(5,6,7,8-tetrahydronaphthalen-2-yl)propanamide (38)

[0423] Dimethylphosphoryl oxide (504 mg, 6.46 mmol) and tributylphosphine (980 mg, 4.84 mmol) were dissolved in acetonitrile (10 mL), to which compound 38a (650 mg, 3.23 mmol) was added, and the reaction was stirred at room temperature for 36 hours. The reaction was concentrated under reduced pressure, and the residue was purified by C-18 reverse phase column chromatography with eluent (30-65% MeCN in water) to obtain compound 38 (103.7 mg, white solid, 11%).

[0424] MS (ESI) m / z: 280.1 [M+H] + .

[0425] 1 H NMR (400 MHz, CDC13) δ 9.16 (s, 1H), 7.30-7.28 (m, 2H), 6.98 (d, J = 8.1 Hz, 1H), 2.83-2.75 (m, 2H), 2.72 (d, J = 7.7 Hz, 4H), 2.16 (dd, J = 17.4, 7.3 Hz, 2H), 1.76 (m, 4H), 1.56 (d, J = 12.6 Hz, 6H).

[0426] Example 39: Preparation of 2-(6,7-dihydro-5H-pentacyclo[b]pyridin-3-yl)-3- methylcyclopent-2-en-1-one (39)

[0427] 3-bromo-6,7-dihydro-5H-pentacyclo[b]pyridine 39a (600 mg, 3.03 mmol), hexane-2,5-dione (3.45 g, 30.29 mmol), (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyl di-tert-butylphosphine (335.66 mg, 0.61 mmol), palladium (n-cinnamyl) chloride dimer (155.11 mg, 0.30 mmol) and cesium carbonate (1.48 g, 4.54 mmol) were dissolved in 1,4 dioxane (12 mL), replaced with nitrogen three times, and the reaction was stirred at 80°C for 3 hours. Water (10 mL) was added to the reaction, which was extracted with dichloromethane (10 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification was performed by Prep-HPLC (Gemini 5u C18 150 x 21.2 mm, acetonitrile aqueous solution (0.1% FA), flow rate: 20 ml / min; wavelength: 214 nm; sample injection DMSO (+ optional formic acid and water), gradient elution from 5% to 95% acetonitrile) to obtain compound 39 (73.27 mg, white solid, 11.26%).

[0428] MS (ESI) m / z: 214 [M+H] + .

[0429] 1 H NMR (400 MHz, CD3OD) δ = 8.12 (s, 1H), 7.56 (s, 1H), 2.98 (t, J = 7.6, 4H), 2.79-2.67 (m, 2H), 2.58-2.47 (m, 2H), 2.23-2.10 (m, 5H).

[0430] Biological test

[0431] Test Example 1: Effect of the compound of the present application on asymmetric division of skeletal muscle stem cells

[0432] Male C57BL / 6 mice (purchased from Janvier Labs) at 8 weeks of age were sacrificed by cervical dislocation, and extensor digitorum longus muscles were dissected and rinsed twice with phosphate buffered saline (PBS) (8 g NaCl, 0.2 g KCl, 0.24 g KH2PO4, 2.94 g Na2HPO4.12H2O, dissolved in 1 L of deionized water, and adjusted to pH 7.4). Freshly prepared 1 mg / ml digestion solution (collagenase I (Gibico) dissolved in DMEM medium (Gibico)) was added, and the muscles were digested in an incubator (37℃, 5% CO2) for 60 minutes. Single muscle fibers were picked under a stereomicroscope.

[0433] The picked single muscle fibers were cultured in DMEM medium (Gibico) containing 10% fetal bovine serum (Ausbian), 1% penicillin (Biotopped), and 1% streptomycin (Amresco). At the same time, the picked single muscle fibers were treated with 50 μm and 100 μm of the compound of the present application for 42 hours, respectively. DMSO treatment was used as a control group. The compound of the present application was prepared by dissolving the compound in DMSO to a concentration of 400 mM, filtering bacteria with a 0.22 μm filter, and aliquoting, and storing at 4℃. After 42 hours of compound treatment, Pax7 immunofluorescence staining was performed. The proportion of asymmetric division of skeletal muscle stem cells was counted, and the difference between the proportion of asymmetric division of the compound treatment group and the proportion of asymmetric division of the DMSO control group was used as an indicator for evaluating the efficacy of the compound.

[0434] Table 1 below shows the results of the efficacy evaluation of the compound of the present application in promoting asymmetric division of skeletal muscle stem cells.

[0435] Table 1, Efficacy evaluation of the compound of the present application in promoting asymmetric division of skeletal muscle stem cells

[0436] Conclusion: As shown in Table 1 above, the compounds of the present application can promote asymmetric division of skeletal muscle stem cells.

[0437] Test Example 2: Effect of the compound of the present application on lipid droplet formation in adipocytes

[0438] This test was performed to examine the effect of the compound of the present application on lipogenesis and lipid droplet formation using primary adipocytes isolated from subcutaneous adipose tissue.

[0439] C57BL / 6 mice (purchased from Vantian) aged 2-3 weeks were sacrificed by cervical dislocation and the subcutaneous adipose tissue at the inguinal region was isolated. The tissue was rinsed twice with phosphate buffered saline (PBS) (8 g NaCl, 0.2 g KCl, 0.24 g KH2PO4, 2.94 g Na2HPO4.12H2O, dissolved in 1 L of deionized water, pH adjusted to 7.4), cut into small pieces and added with freshly prepared digestion solution (DMEM / F-12 (1:1) (Gibico) medium containing 1 mg / mL collagenase I (Gibico)) and incubated in an incubator (37°C) for 60 minutes with gentle mixing 1-2 times. The digested tissue was diluted with PBS buffer and filtered through a 40 μm cell strainer (Falcon) and centrifuged at 1500 rpm for 10 minutes. The cell pellet was resuspended in proliferation medium (DMEM / F-12 (1:1), 10% calf serum (Ausbian), 1% penicillin and 1% streptomycin) and incubated in an incubator (37°C, 5% CO2). The medium was changed after 12 hours. The cells were subcultured when they reached 90% confluence.

[0440] The cells were seeded in 24-well plates and the medium was changed every other day. When the cells reached 60-70% confluence, the medium was changed to differentiation medium I (DMEM / F-12 (1:1), 5% fetal bovine serum (Ausbian), 1% penicillin (biotopped) and 1% streptomycin (amresco)). Two days later, the cells were induced to differentiate by changing the medium to differentiation medium II (DMEM / F-12 (1:1), 5% fetal bovine serum, 1% penicillin and 1% streptomycin, 1 μM dexamethasone (Sigma), 0.25 mM 3-isobutyl-l-methylxanthine (Sigma), 0.5 μg / mL insulin (biosharp), 60 μM indomethacin (Sigma)). Two days later, the medium was changed to differentiation medium III (DMEM / F-12 (1:1), 5% fetal bovine serum, 1% penicillin and 1% streptomycin, 0.5 μg / mL insulin). At the same time when the differentiation was initiated (i.e., when the medium was changed to differentiation medium II), the cells were treated with different concentrations of the compound of the present application and DMSO buffer as a control.

[0441] Bodipy (Life technology, D3922) was used to stain lipid droplets after 1 day of treatment, and the culture was terminated. Bodipy is a green fluorescent labeled liposoluble dye. After the cell culture was completed, Bodipy was added to the culture medium at a ratio of 1:1000. After 20 minutes, the lipid droplets stained by Bodipy were observed under a fluorescence microscope. The PE high content imaging system (Operetta CLS, PerkinElmer) was used to image and quantify the area of the lipid droplets. The ratio of the area of the lipid droplets in the compound treatment group to the area of the lipid droplets in the control group was used as the evaluation effect of the compound.

[0442] Table 2 below shows the effect of the compounds of the present application on the formation of lipid droplets in adipocytes.

[0443] Table 2, pharmacodynamic evaluation of the compounds of the present application on the formation of lipid droplets in adipocytes

[0444] Conclusion: As shown in Table 2 above, after treatment with the compounds of the present application, the area of the lipid droplets was significantly reduced compared with the control group, indicating that the compounds of the present application significantly inhibited the formation of lipid droplets during the differentiation of primary adipocytes.

[0445] References

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Claims

1. A compound of the general formula (I) ###0001### or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. wherein: X1is selected from CR 1 or N; X2is selected from CR 2 or N; X3is selected from CR 3 or N; X4is selected from CR 4 or N; L1is selected from the group consisting of a bond, -C(O)O-, -C(O)NR 7 -, -S(O)NR 7 -, -S(O)2NR 7 -, -NR 7 C(O)-, -NR 7 C(O)O-, -NR 7 S(O)-, -NR 7 S(O)2-, -OC(O)-, -O-, -NH-; L2is selected from C 1-10 alkylene, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, said C 1-10 alkylene, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, thio, carboxy, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; L3is selected from a bond, -C(O)-, -S(O)-, -S(O)2-, -C(O)NR 8 -, -S(O)NR 8 -, -S(O)2NR 8 -, -NR 8 C(O)-, -NR 8 C(O)O-, R 9 selected from hydrogen and C 1-6 alkyl; R 1 , R 2 , R 3 , R 4 each independently is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 5 selected from hydrogen, halogen, C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxyl, thiol, carboxyl, ester, oxo, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; Each R 6 Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl. Each R 7 Each is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; Each R 8 Each is independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; i is 0, 1 or 2; j is 0, 1 or 2; n is an integer from 0 to 4.

2. The compound of claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, X1to X4, R 5 , R 6 , L1, L2, L3, n are as defined in claim 1.

3. The compound of formula (I) according to claim 1, which is a compound of formula (III) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, X1to X4, R 5 , R 6 , L1, L2, L3, n are as defined in claim 1.

4. The compound of claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (IV), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, X1to X3, R 5 , R 6 , L1, L2, L3, n are as defined in claim 1.

5. The compound of claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (V), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, X1to X3, R 5 , R 6 , L1, L2, L3, n are as defined in claim 1.

6. The compound of formula (I) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 4 or 5, wherein, X1is CR 1 or N, X2is CR 2 or N, X3is CR 3 ; R 1 , R 2 , R 3 as defined in claim 1.

7. The compound of formula (I) according to claim 1, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (VIA) or (VIB), ###00019### (VIA) (VIB) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. wherein: X 1 is CH or N; X 2 is CH or N; Y1, Y2, Y3, Y4are each independently selected from CH or N; preferably, Y1, Y2, Y3, Y4are all CH, or one of Y1, Y2, Y3, Y4is N and the rest are CH; Each R 10 Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl. m is 0, 1 or 2; i is 0, 1 or 2; j is 0, 1 or 2; R 5 , R 6 , L1, L3, n are as defined in claim 1.

8. The compound of claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (VII), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein: X 1 is CH or N; X 2 is CH or N; s1is 0 or 1; s2is 0, 1 or 2; Each R 11 Each is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl. v is 0, 1 or 2; i is 0, 1 or 2; j is 0, 1 or 2; R 5 , R 6 , L1, L3, n are as defined in claim 1.

9. The compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, which is a compound of formula (VIII) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: X 1 is CH or N; X 2 is CH or N; R a and R b are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl; t is an integer from 1 to 10, preferably an integer from 1 to 6, more preferably an integer from 1 to 4; i is 0, 1 or 2; j is 0, 1 or 2; R 5 , R 6 , L1, L3, n are as defined in claim 1.

10. The compound of Formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9, wherein, L1is selected from a bond, -C(O)O-, -C(O)NR 7 -, -S(O)NR 7 -, -S(O)2NR 7 -, -NR 7 C(O)-, -NR 7 C(O)O-, -O-, -NH-; R 7 is selected from hydrogen or C 1-6 alkyl.

11. The compound according to any one of claims 1 to 10, wherein L3is selected from -C(O)-, -S(O)-, -S(O)2-, -C(O)NR 8 -, -NR 8 C(O)-, R 8 selected from hydrogen and C 1-6 alkyl; R 9 selected from hydrogen and C 1-6 alkyl; R 5 selected from C 1-6 alkyl.

12. The compound according to any one of claims 1 to 10, wherein L3is selected from a bond; R 5 selected from C 1-6 alkyl.

13. The compound according to any one of claims 1 to 9, wherein L1is selected from -C(O)O-, -C(O)NR 7 -, -S(O)NR 7 -, -NR 7 C(O)O-, -O-, -NH-; L3is selected from -C(O)-, -S(O)-, -S(O)2-; R 5 selected from C 1-6 alkyl; R 7 selected from hydrogen or C 1-6 alkyl.

14. The compound according to any one of claims 1 to 9, wherein L1is selected from -C(O)O-, -C(O)NR 7 -, -S(O)NR 7 -, -S(O)2NR 7 -, -NR 7 C(O)-, -NR 7 C(O)O-, -O-, -NH-; R 7 is selected from hydrogen or C 1-6 alkyl; L3is selected from -C(O)NR 8 - and -NR 8 C(O)-, R 5 selected from hydrogen and C 1-6 alkyl; R 8 selected from hydrogen and C 1-6 alkyl; R 9 selected from C 1-6 alkyl.

15. The compound according to any one of claims 1 to 9, wherein L1is selected from -C(O)NR 7 - and -S(O)NR 7 -; L3is selected from a bond; R 5 selected from C 1-6 alkyl; R 7 selected from hydrogen or C 1-6 alkyl.

16. The compound of claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, L1is a bond; L2is 4- to 6-membered saturated or partially saturated heterocyclyl; optionally substituted with one or more groups selected from oxo, C 1-6 one or more groups selected from oxo, C L3is a bond; R 5 is hydrogen or C 1-6 alkyl.

17. A compound of Formula (I) as defined in any one of claims 1 to 3, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, X1, X2, X3, X4are all CH, or one of X1, X2, X3, X4is N and the rest are CH; or two of X1, X2, X3, X4are N and the rest are CH; preferably, X1, X2, X3, X4, X5are all CH, or one of X1, X2, X3, X4is N and the rest are CH.

18. The compound of claim 4 or 5, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, X1, X2, X3are all CH, or one of X1, X2, X3is N and the rest are CH.

19. The compound of Formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 7 to 9, wherein, X1, X2are all CH, or one of X1, X2is N and the rest is CH.

20. The compound of claim 7, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, Y1, Y2, Y3, Y4are all CH, or one of Y1, Y2, Y3, Y4is N and the rest are CH.

21. The compound of Formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20, wherein, each R is independently selected from hydrogen, halogen, nitro, C 6 each independently selected from hydrogen, halogen, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; preferably hydrogen; n is 0 or 1.

22. The compound of any one of claims 1, 7 to 9, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, i is 1, j is 1 or 2.

23. The compound of claim 7, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from hydrogen, halogen, C 10 each R is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1- 6haloalkoxy; preferably hydrogen; m is 0 or 1.

24. The compound of claim 8, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R 11 are each independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1- 6haloalkoxy; preferably hydrogen; v is 0 or 1.

25. A compound of Formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 24, wherein the compound is selected from:

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25, or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

27. A health care composition comprising a compound of Formula (I) according to any one of claims 1 to 25, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

28. Use of a compound of Formula (I) according to any one of claims 1 to 25, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, for the manufacture of a medicament for preventing or treating muscle atrophy related diseases, obesity, fatty liver, cardiovascular and cerebrovascular diseases, metabolic diseases, and for the manufacture of a medicament for anti-aging.

29. Use of a compound of Formula (I) according to any one of claims 1 to 25, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a health care composition according to claim 27, for the manufacture of a health care product for muscle atrophy related diseases, obesity, fatty liver, cardiovascular and cerebrovascular diseases, metabolic diseases, and for the manufacture of a health care product for anti-aging.

30. The use according to claim 28 or 29, wherein the muscle atrophy related diseases include myogenic muscle atrophy such as progressive muscular dystrophy, polymyositis, myotonic dystrophy, disuse muscle atrophy, senile muscle atrophy, neurogenic muscle atrophy.

31. The use according to claim 30, wherein the progressive muscular dystrophy is congenital muscular dystrophy (CMD) or myotonic muscular dystrophy (MMD), such as Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy (LGMD), facioscapulohumeral muscular dystrophy (FSHD), distal muscular dystrophy (DM), oculopharyngeal muscular dystrophy (OPMD).

32. The use according to claim 30, wherein the neurogenic muscle atrophy includes amyotrophic lateral sclerosis (ALS), Hirayama disease, spinal muscular atrophy, Charcot-Marie-Tooth disease, myasthenia gravis (MG).

33. The use according to claim 28 or 29, wherein the cardiovascular and cerebrovascular diseases include arteriosclerosis, coronary heart disease, peripheral arterial vascular disease, deep vein thrombosis, pulmonary embolism, transient ischemic attack (TIA), cerebral infarction, cerebral hemorrhage, hypertensive encephalopathy, cerebral arteritis, cerebral vascular dementia, venous sinus, cerebral vein thrombosis.

34. The use according to claim 28 or 29, wherein the metabolic diseases are diabetes, hypertension, hyperlipidemia, hyperglycemia.

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