Heterocyclic compound, and preparation method therefor and pharmaceutical use thereof

Abstract

The present invention relates to a heterocyclic compound, and a preparation method therefor and a pharmaceutical use thereof. Specifically, the present invention relates to a compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition or health care product containing same, a use thereof in the prevention or treatment of muscle atrophy and wasting-related diseases, including myogenic muscle atrophy, disuse muscle atrophy, sarcopenia, and neurogenic muscle atrophy, and a use thereof in the prevention and / or treatment of obesity, fatty liver, cardiovascular and cerebrovascular diseases, metabolic diseases, and anti-aging. 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 limb or vocal and swallowing muscle atrophy and weakness. Electromyography examination suggests extensive spinal cord anterior horn cell disease. Juvenile unilateral distal upper limb atrophy, also known as Hirayama disease, has an unknown cause 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 hands (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 disorder of protein, fat, carbohydrate and other substances in human body, and are risk factors leading to diabetes and cardio-cerebral vascular 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 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 various systems of human body, especially the cardio-cerebral vascular system. The course of the disease often lasts for many years, causing a decrease 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 reasons. The common feature of these diseases is that blood clots due to too high blood lipids, and then block blood vessels.

[0010] Cardiovascular diseases are a serious threat to human health and are the most important diseases threatening 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. The proportion in the cause of death is on the rise, and is the "number one killer" threatening human health and life. Almost one out of every three people in the world 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 body weight, and that in a female is 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 fatty degeneration 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 fatty degeneration 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 purpose of the present application is to provide a compound shown in general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture form thereof, or a pharmaceutically acceptable salt thereof,

[0016] wherein:

[0017] X1, X2, X3, X4, X5 are each independently selected from CH or N;

[0018] L1 is selected from

[0019] L2 is 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, hydroxyl, thiol, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0020] L3 is selected from bond, -C(O)-, -S(O)-, -S(O)2-, R 3 selected from hydrogen and C 1-6 alkyl;

[0021] R 1 selected from hydrogen, halogen, C 1-6 alkyl, said C 1-6 alkyl 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;

[0022] each R 2 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;

[0023] n is an integer from 0 to 4.

[0024] In a preferred embodiment, the compound according to the application of the 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 the general formula (II) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0025] wherein

[0026] R 4a and R 4b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl;

[0027] t is an integer from 1 to 10, preferably an integer from 1 to 6, more preferably an integer from 1 to 4.

[0028] X1to X5, R 1 , R 2 , L1, L3, n are as defined in general formula (I).

[0029] In another preferred embodiment, the compound according to the application of the 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 the general formula (III) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0030] wherein

[0031] Y1, Y2, Y3, Y4, Y5are each independently selected from CH or N;

[0032] each R 5 is each independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, thio, carboxy, ester, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0033] m is 0, 1 or 2;

[0034] X1to X5, R 1 , R 2 , L1, L3, n are as defined in general formula (I).

[0035] In another preferred 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 (IVA) or (IVB) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0036] wherein Y1to Y5, R 5 , m, X1to X5, R 1 , R 2 , L1, L3, n are as defined in general formula (III).

[0037] In another preferred 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 (V) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0038] wherein:

[0039] ring A is a saturated or partially saturated C 3-6 cycloalkyl, saturated or partially contained 4- to 6-membered heterocyclyl;

[0040] each R 6 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;

[0041] v is 0, 1 or 2;

[0042] X1to X5, R 1 , R 2 , L1, L3, n are as defined in general formula (I).

[0043] In another preferred embodiment, the compound according to the application of 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 ring A is selected from pyrrolidinyl, piperidinyl, piperazinyl, dihydropyridinyl, tetrahydropyridinyl.

[0044] In another preferred embodiment, the compound according to the application of the 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 the general formula (VI) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0045] wherein:

[0046] s1and s2are each independently 0 or 1 ;

[0047] X1to X5, R 1 , R 2 , L1, L3, R 6 , v, n are as defined in general formula (V).

[0048] In another preferred embodiment, the compound according to the application of the general formula (I), (II), (III), (IVA), (IVB), (V), (VI) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L1is selected from

[0049] In another preferred embodiment, the compound according to the application of the general formula (I), (II), (III), (IVA), (IVB), (V), (VI) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

[0050] L3is selected from -C(O)-, -S(O)-, -S(O)2-,

[0051] R 3 is selected from hydrogen and C 1-6 alkyl;

[0052] R 1 is selected from C 1-6 alkyl.

[0053] In another preferred embodiment, the compound according to the application of the general formula (I), (II), (III), (IVA), (IVB), (V), (VI) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

[0054] L3is selected from a bond;

[0055] R 3 selected from hydrogen and C 1-6 alkyl;

[0056] R 1 selected from halogen, C 1-6 alkyl.

[0057] In another preferred embodiment, the compound according to the application of the general formula (III), (IVA), (IVB) 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, Y4, Y5 are all CH, or one of Y1, Y2, Y3, Y4, Y5 is N and the others are CH; or two of Y1, Y2, Y3, Y4, Y5 are N and the others are CH; preferably Y1, Y2, Y3, Y4, Y5 are all CH, or Y4 is N and Y1, Y2, Y3, Y5 are CH, or Y3 is N and Y1, Y2, Y4, Y5 are CH.

[0058] In another preferred embodiment, the compound according to the application of the general formula (III), (IVA), (IVB) 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, Y4, Y5 are all CH, or one of Y1, Y2, Y3, Y4, Y5 is N and the others are CH; or two of Y1, Y2, Y3, Y4, Y5 are N and the others are CH; preferably Y1, Y2, Y3, Y4, Y5 are all CH, or Y4 is N and Y1, Y2, Y3, Y5 are CH, or Y3 is N and Y1, Y2, Y4, Y5 are CH.

[0059] In another preferred embodiment, the compound according to the application of the general formula (IVA) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y3 or Y4 is N and the others are CH.

[0060] In another preferred embodiment, the compound according to the application of the general formula (IVB) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y3 or Y5 is N and the others are CH.

[0061] In another preferred embodiment, the compound according to the application of the general formula (I), (II), (III), (IVA), (IVB), (V), (VI) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0062] wherein each R 2 each independently is selected from hydrogen, halogen, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0063] n is an integer from 0 to 4, preferably an integer from 0 to 3.

[0064] In another preferred embodiment, the compound according to the present application is a compound according to Formula (III), (IVA), (IVB), (V), (VI) as depicted below, or a tautomer, an entgegen- or an entran- isomer, or a mixture of these, or a pharmaceutically acceptable salt thereof, wherein each R 5 each independently is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0065] m is 0, 1 or 2, preferably 0 or 1.

[0066] In another preferred embodiment, the compound according to the present application is a compound according to Formula (V), (VI) as depicted below, or a tautomer, an entgegen- or an entran- isomer, or a mixture of these, or a pharmaceutically acceptable salt thereof, wherein each R 6 each independently is selected from hydrogen, oxo, C 1-6 alkyl;

[0067] v is 0, 1 or 2.

[0068] Typical compounds of the present application include, but are not limited to, the following compounds:

[0069] or a tautomer, an entgegen- or an entran- isomer, or a mixture of these, or a pharmaceutically acceptable salt thereof.

[0070] Typical compounds of the present application include, but are not limited to, the following compounds:

[0071] or a tautomer, an entgegen- or an entran- isomer, or a mixture of these, or a pharmaceutically acceptable salt thereof.

[0072] The present application also relates to a pharmaceutical composition comprising a compound according to the present application, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0073] The present application also relates to a health care composition comprising a compound according to the present application, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0074] The present application also relates to the use of a 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 pharmaceutical composition comprising the same, for the preparation of a medicament for preventing or treating muscle atrophy related diseases, obesity, fatty liver, cardiovascular and cerebrovascular diseases, metabolic diseases, and for the preparation of a medicament for anti-aging.

[0075] The present application also relates to the use of a 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, for the preparation of a health care product for muscle atrophy related diseases, obesity, fatty liver, cardiovascular and cerebrovascular diseases, metabolic diseases, and for the preparation of a health care product for anti-aging.

[0076] In some embodiments, the muscle atrophy related diseases according to the present application include myogenic muscle atrophy such as progressive muscular dystrophy, polymyositis, atrophic myotonia, secretory myopathy, disuse muscle atrophy, senile muscle atrophy, neurogenic muscle atrophy.

[0077] 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).

[0078] 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).

[0079] In some embodiments, the cardiovascular and cerebrovascular diseases according to the present application include arteriosclerosis, coronary heart disease, peripheral endarterial vascular disease, deep vein thrombosis, pulmonary embolism, transient ischemic attack (TIA), cerebral infarction, cerebral hemorrhage, hypertensive encephalopathy, cerebral arteritis, cerebrovascular dementia, venous sinus, cerebral vein thrombosis.

[0080] In some embodiments, the metabolic diseases according to the present application include diabetes, hypertension, hyperlipidemia, hyperglycemia.

[0081] The 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, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and 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 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 disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. 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.

[0082] Formulations for oral use 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 such as polyethylene glycol or an oil such as peanut oil, liquid paraffin or olive oil.

[0083] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, and gum arabic; dispersants or wetting agents, which may be naturally occurring phospholipids such as lecithin, or condensation products of olefinic oxygen and fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide and long-chain fatty alcohols, such as heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides, such as polyoxyethylene dehydrated sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose, saccharin, or aspartame.

[0084] Oil suspensions can be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, or mineral oils such as liquid paraffin. Oil suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavoring agents mentioned above can be added to provide a palatable formulation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole (BHA) or α-tocopherol.

[0085] The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate, and condensation products of said metaesters and ethylene oxide, such as poly(ethylene oxide) sorbitan monooleate. The emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs formulated with sweeteners such as glycerin, propylene glycol, sorbitol, or sucrose may be used. Such formulations may also contain moderating agents, preservatives, coloring agents, and antioxidants.

[0086] The pharmaceutical compositions of the present invention can be in the form of sterile injectable aqueous solutions. Acceptable solvents and media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated with a mixture of water and glycerol to form a microemulsion. The injection solution or microemulsion can be injected into the patient's bloodstream by local large-volume injection. Alternatively, it is preferable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device can be used.

[0087] The pharmaceutical compositions of this application can be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension can be formulated according to known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic 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.

[0088] The compounds of the present 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.

[0089] It is well known to the skilled person that the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the particular compound used, the age of the patient, the body weight of the patient, the health status of the patient, the sex of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination with other drugs, etc. In addition, the optimal treatment regime, e.g. the mode of treatment, the daily amount of the compound of general formula or the kind of the pharmaceutically acceptable salt, can be verified according to the conventional treatment regime.

[0090] The present application can contain a compound and its pharmaceutically acceptable salts, hydrates or solvates as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient, prepared into a composition, and prepared into a clinically acceptable dosage form. The derivatives of the present application can be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions, etc. The compounds 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. The combination therapy is achieved by administering each therapeutic component simultaneously, separately or sequentially.

[0091] Explanation of terms

[0092] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom between 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 membered, more preferably 7 to 10 membered. Spirocycloalkyl groups are classified as mono-, bi-, or polyspirocycloalkyl groups, preferably mono- and bi-spirocycloalkyl groups, according to the number of rings sharing a spiro atom. 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:

[0098] 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 membered, more preferably 7 to 10 membered. Fused cycloalkyl groups are classified as bi-, tri-, tetra-, or polycyclic, preferably bi- or tri-cyclic, more preferably 5 membered / 5 membered or 5 membered / 6 membered bi-cycloalkyl groups, according to the number of rings comprising the system. Non-limiting examples of fused cycloalkyl groups include:

[0099] 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:

[0100] 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.

[0101] 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.

[0102] 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 remainder of the 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:

[0103] 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 remainder of the 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:

[0104] 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 remainder of the 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:

[0105] 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:

[0106] etc.

[0107] 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.

[0108] 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:

[0109] 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.

[0110] 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:

[0111] 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.

[0112] 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.

[0113] 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 or both configurations. and

[0114] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is defined as above.

[0115] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is defined as above.

[0116] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is defined as above.

[0117] The term "hydroxyl" refers to the -OH group.

[0118] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0119] The term "amino" refers to -NH2.

[0120] The term "cyano" refers to -CN.

[0121] The term "nitro" refers to -NO2.

[0122] The term "oxo" refers to =O.

[0123] The term "thio" refers to =S.

[0124] The term "carboxyl" refers to -C(O)OH.

[0125] The term "thiol" refers to -SH.

[0126] The term "ester" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are defined as above. ​

[0127] The term "alkylcarbonyl" means a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.

[0128] The term "alkylsulfonyl" means a -S(O)2R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.

[0129] The term "amino" means a -NR2group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.

[0130] "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.

[0131] "Substituted" means that one or more hydrogen atoms, preferably up to five, more preferably one to three, of a group are independently 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 one skilled in the art without undue effort, as to whether a substitution is possible or not. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturated (e.g., olefinic) bond.

[0132] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically / pharmaceutically acceptable salt or prodrug 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 an organism, and to facilitate absorption of the active ingredient, thereby facilitating biological utility.

[0133] "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

[0134] 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.

[0135] The compounds of this invention are prepared using convenient starting materials and common preparation steps. Typical or preferred reaction conditions are provided, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants. However, unless otherwise specified, other reaction conditions may also be adopted. Optimal conditions may vary depending on the specific reactants or solvents used, but in general, the optimal reaction steps and conditions can be determined.

[0136] In addition, some protecting groups may be used in this invention to protect certain functional groups from unnecessary reactions. Suitable protecting groups for various functional groups and their protection or deprotection conditions are well known to those skilled in the art. For example, TW Greene and GMWuts' "Protecting Groups in Organic Preparations" (3rd edition, Wiley, New York, 1999 and cited references in the book) describes in detail a large number of protecting or deprotecting groups.

[0137] The separation and purification of compounds and intermediates are carried out using appropriate methods and procedures depending on specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography, or a combination of the above methods. Specific methods can be found in the examples described in this invention. Of course, other similar separation and purification methods can also be used. Conventional methods (including physical constants and spectroscopic data) can be used for characterization.

[0138] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts were expressed in 10⁻¹⁰. -6 The unit (ppm) is given. NMR measurements were performed using a Brukerdps 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0139] MS measurements were performed using an LC (Agilent 1260 Infinity) / MS (G6125B) mass spectrometer (manufacturer: Agilent).

[0140] Preparative liquid chromatography was performed using an lc6000 high-performance liquid chromatograph (manufacturer: Innovation Tongheng). The chromatographic column was a Daisogel C18 10μm 100A (30mm × 250mm), and the mobile phase was acetonitrile / water.

[0141] Thin-layer chromatography (TLC) uses Qingdao Ocean Chemical GF254 silica gel plates. The silica gel plates used for reaction monitoring in TLC have a diameter of 0.20 mm to 0.25 mm, while those used for separation and purification have a diameter of 0.5 mm.

[0142] Silica gel column chromatography used Qingdao Marine Silica Gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

[0143] Known starting materials of the present application can be synthesized or purchased from commercial suppliers 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.

[0144] Unless otherwise specified in the examples, the reactions were carried out under a nitrogen atmosphere.

[0145] Argon or nitrogen atmosphere refers to the reaction bottle connected to an argon or nitrogen balloon with a volume of about 1 L.

[0146] Reaction solvent, organic solvent or inert solvent are each described as the solvent used under the described reaction conditions does not participate in the reaction, including, such as 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.

[0147] The chemical reactions described in the present application are generally carried out under normal pressure. The reaction time and conditions are, for example, completed at one atmosphere, between -78°C and 200°C, for about 1 to 24 hours. 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.

[0148] 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.

[0149] Examples

[0150] Example 1: Preparation of N-(3-fluorophenyl)-4-oxopentanamide (1)

[0151] To a solution of 3-fluoroaniline la (300 mg, 2.69 mmol) and 4-oxovaleric acid lb (376 mg, 3.23 mmol) and N,N-dimethylformamide (8 mL) was added DIEA (697 mg, 5.39 mmol) and HATU (1334 mg, 3.51 mmol), and the reaction was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction, and dichloromethane (40 mL x 3) was extracted. The organic phases were combined, 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 = 65:35) to obtain compound 1 (106 mg, white solid, 18.92%).

[0152] MS (ESI) m / z: 210.0 [M+H] + .

[0153] 1 H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.48 (d, J = 10.9 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.79 (t, J = 8.2 Hz, 1H), 2.90 (t, J = 6.3 Hz, 2H), 2.62 (t, J = 6.3 Hz, 2H), 2.23 (s, 3H).

[0154] Example 2: Preparation of N-(4-fluorophenyl)-4-oxovaleramide (2)

[0155] To a solution of 4-oxovaleric acid lb (1.0 g, 8.62 mmol), 4-fluoroaniline 2a (1.44 g, 12.93 mmol) and HBTU (4.90 g, 12.93 mmol) in DMF (10 mL) was added DIEA (5.0 g, 38.79 mmol), and the reaction was stirred at 35°C for 24 hours. Water (30 mL) was added to the reaction, and ethyl acetate (40 mL x 3) was extracted. 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 using eluent dichloromethane and ethyl acetate (V / V = 5:1) to obtain compound 2 (421 mg, white solid, 23.39%).

[0156] MS (ESI) m / z: 209.9 [M+H] + .

[0157] 1H NMR (400 MHz, CDC13) δ 7.65 (s, 1H), 7.46-7.43 (m, 2H), 6.99 (t, J = 8.7 Hz, 2H), 2.90 (t, J = 6.2 Hz, 2H), 2.61 (t, J = 6.2 Hz, 2H), 2.23 (s, 3H).

[0158] Example 3: Preparation of 4-oxo-N-(o-tolyl)pentanamide (3)

[0159] o-Toluidine 3a (500 mg, 4.67 mmol), 4-oxopentanoic acid 1b (650 mg, 6.60 mmol) and DMAP (1140 mg, 9.33 mmol) were dissolved in dichloromethane (12 mL), to which EDCI (1163 mg, 6.07 mmol) and HOBT (820 mg, 6.07 mmol) were added, and the reaction was stirred at room temperature for 16 hours. Water (30 mL) was added to the reaction, which was extracted with dichloromethane (30 mL x 3), and the combined organic phases were washed with 1N hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluents dichloromethane and ethyl acetate (V / V = 15:85) to obtain compound 3 (130 mg, white solid, 12.22%).

[0160] MS (ESI) m / z: 206.0 [M+H] + .

[0161] 1 H NMR (400 MHz, CDC13) δ 7.81 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.22-7.15 (m, 2H), 7.06 (d, J = 7.4 Hz, 1H), 2.92 (t, J = 6.0 Hz, 2H), 2.66 (t, J = 6.1 Hz, 2H), 2.28 (s, 3H), 2.22 (s, 3H).

[0162] Example 4: Preparation of 4-oxo-N-(m-tolyl)pentanamide (4)

[0163] m-methylaniline 4a (300 mg, 2.79 mmol) and 4-oxovaleric acid 1b (390 mg, 3.35 mmol) were dissolved in N,N-dimethylformamide (5 mL), to which DIEA (723 mg, 5.59 mmol) and HATU (1383 mg, 3.64 mmol) were added, and the reaction was stirred at room temperature for 16 hours. Water (30 mL) was added to the reaction, and ethyl acetate (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 petroleum ether and ethyl acetate (V / V = 60:40) to obtain compound 4 (109 mg, colorless oil, 19.03%).

[0164] MS (ESI) m / z: 206.0 [M+H] + .

[0165] 1 H NMR (400 MHz, DMSO) δ 9.85 (s, 1H), 7.41 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H), 2.73 (t, J = 6.6 Hz, 2H), 2.51 (t, J = 6.6 Hz, 2H), 2.26 (s, 3H), 2.12 (s, 3H).

[0166] Example 5: Preparation of 4-oxo-N-(2-(trifluoromethyl)phenyl)pentanamide (5)

[0167] 2-(trifluoromethyl)aniline 5a (1 g, 6.17 mmol), TCFH (2.6 g, 9.25 mmol) and NMI (608 mg, 7.40 mmol) were dissolved in acetonitrile (20 mL), and the reaction was stirred at room temperature for half an hour, to which 4-oxovaleric acid 1b (859 mg, 7.40 mmol) was added, and the reaction was stirred at room temperature for 4 hours. The reaction was concentrated, water (30 mL) was added, and ethyl acetate (30 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 methanol (V / V = 97:3) to obtain compound 5 (107 mg, white solid, 6.47%).

[0168] MS (ESI) m / z: 260.0 [M+H] + .

[0169] 1H NMR (400 MHz, CDC13) δ 8.10 (d, J = 7.6 Hz, 1H), 7.67 (t, J = 7.4 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 2.88 (t, J = 6.3 Hz, 2H), 2.66 (t, J = 6.3 Hz, 2H), 2.22 (s, 3H).

[0170] Example 6: Preparation of 4-oxo-N-(3-(trifluoromethyl)phenyl)pentanamide (6)

[0171] 3-(trifluoromethyl)aniline 6a (300 mg, 1.85 mmol) and 4-oxopentanoic acid lb (257 mg, 2.22 mmol) were dissolved in N,N-dimethylformamide (8 mL), to which DIEA (478 mg, 3.70 mmol) and HATU (914 mg, 2.40 mmol) were added, and the reaction solution was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction solution, which was extracted with dichloromethane (40 mL x 3), 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 with eluent petroleum ether and ethyl acetate (V / V = 67:33) to obtain compound 6 (113 mg, white solid, 20.79%).

[0172] MS (ESI) m / z: 259.9 [M+H] + .

[0173] 1 H NMR (400 MHz, CDC13) δ 7.82 (s, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 2.91 (t, J = 6.1 Hz, 2H), 2.64 (t, J = 6.1 Hz, 2H), 2.24 (s, 3H).

[0174] Example 7: Preparation of N-(2,3-dimethylphenyl)-4-oxopentanamide (7)

[0175] A mixture of 2,3-dimethylaniline 7a (500 mg, 4.31 mmol), 4-oxopentanoic acid 1b (626 mg, 5.17 mmol), HOBt (873 mg, 6.46 mmol), EDCI (1239 mg, 6.46 mmol) and DIPEA (1169 mg, 9.05 mmol) was dissolved in dichloromethane (10 mL). The reaction was stirred at 25 °C for 18 h after purging with nitrogen for 3 times. Water (30 mL) was added to the reaction mixture, and dichloromethane (20 mL x 2) was used to extract the mixture. The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane and ethyl acetate (5:1, V / V) as eluent to give compound 7 (94.7 mg, white solid, 10.0%).

[0176] MS (ESI) m / z: 220.0 [M+H] + .

[0177] 1 H NMR (400 MHz, DMSO) δ 9.34 (s, 1H), 7.08 (d, J = 7.3 Hz, 1H), 7.05-6.95 (m, 2H), 2.73 (t, J = 6.7 Hz, 2H), 2.54 (d, J = 6.7 Hz, 2H), 2.23 (s, 3H), 2.12 (s, 3H), 2.05 (s, 3H).

[0178] Example 8: Preparation of N-(3,4-dimethylphenyl)-4-oxopentanamide (8)

[0179] A mixture of 3,4-dimethylaniline 8a (1 g, 8.25 mmol), 4-oxopentanoic acid 1b (960 mg, 8.27 mmol), HOBt (1.35 g, 10 mmol), EDCI (1.91 g, 10 mmol) and DIPEA (2.15 g, 16.6 mmol) was dissolved in dichloromethane (30 mL). The reaction was stirred at 20 °C for 16 h. Water (30 mL) was added to the reaction mixture, and dichloromethane (30 mL x 3) was used to extract the mixture. The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether and ethyl acetate (4:1, V / V) as eluent to give compound 8 (275 mg, white solid, 15.2%).

[0180] MS (ESI) m / z: 220.0 [M+H] + .

[0181] 1H NMR (400 MHz, DMSO) δ 9.76 (s, 1H), 7.34 (s, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 2.71 (t, J = 6.6 Hz, 2H), 2.49-2.65 (m, 2H), 2.16 (s, 3H), 2.15 (s, 3H), 2.12 (s, 3H).

[0182] Example 9: Preparation of N-(2,3-difluorophenyl)-4-oxovaleramide (9)

[0183] 2,3-difluoroaniline 9a (1 g, 7.74 mmol), 4-oxovaleric acid 1b (898.8 mg, 7.74 mmol), HOBT (1.35 g, 10 mmol), EDCI (1.91 g, 10 mmol), DIPEA (2.15 g, 16.6 mmol) were dissolved in dichloromethane (30 mL), and the reaction solution was stirred at 20 °C for 16 hours. Water (30 mL) was added to the reaction solution, dichloromethane (30 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 petroleum ether and ethyl acetate (V / V = 3:1) to obtain compound 9 (127 mg, white solid, 7.2%).

[0184] MS (ESI) m / z: 227.9 [M+H] + .

[0185] 1 H NMR (400 MHz, DMSO) δ 9.94 (s, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.19-7.10 (m, 2H), 2.74 (t, J = 6.5 Hz, 2H), 2.60 (t, J = 6.5 Hz, 2H), 2.12 (s, 3H).

[0186] Example 10: Preparation of N-(2,6-difluorophenyl)-4-oxovaleramide (10)

[0187] Compound 10 (200 mg, white solid, 22.5%) was obtained by purifying the residue by flash column chromatography (C18, ACN / H2O, 33%) from the reaction of 2,5-difluoroaniline 10a (500 mg, 3.8727 mmol) dissolved in dichloromethane (10 mL), replaced with nitrogen three times, adding 4-oxovaleryl chloride 10b (1042 mg, 7.7454 mmol) and triethylamine (392 mg, 3.8727 mmol) to it, and stirring the reaction at 25 °C for 2 hours. The solvent was removed by concentration under reduced pressure. The residue was purified by flash column chromatography (C18, ACN / H2O, 33%) to obtain compound 10 (200 mg, white solid, 22.5%).

[0188] MS (ESI) m / z: 228.0 [M+H] + .

[0189] 1 H NMR (400 MHz, DMSO) δ 9.70 (s, 0.5H), 7.53-7.10 (m, 2.5H), 6.15 (s, 0.5H), 2.75-2.53 (m, 2H), 2.48-2.38 (m, 1H), 2.34-2.14 (m, 1H), 2.11 (s, 2H), 1.31 (s, 1H).

[0190] Example 11: Preparation of N-(3,4-difluorophenyl)-4-oxovaleramide (11)

[0191] Compound 11 (100 mg, white solid, 14.5%) was obtained by purifying the residue with silica gel column chromatography with eluent dichloromethane and ethyl acetate (V / V = 5:1) from the reaction of 4-oxovaleric acid 1b (350 mg, 3.02 mmol) dissolved in dichloromethane (10 mL), replaced with nitrogen three times, adding oxalyl chloride (342 mg, 2.71 mmol) to it, adding 10 mg of N,N-dimethylformamide dropwise, and stirring the reaction at 20 °C for 10 hours. To the reaction, 3,4-difluoroaniline 11a (500 mg, 3.8 mmol) and N,N-diisopropylethylamine (500 mg, 3.8 mmol) were added, stirred for 5 hours, 50 mL of water was added, 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 dichloromethane and ethyl acetate (V / V = 5:1) to obtain compound 11 (100 mg, white solid, 14.5%).

[0192] MS (ESI) m / z: 228.1 [M+H] + .

[0193] 1H NMR (400 MHz, DMSO) δ 10.19 (s, 1H), 7.76 (ddd, J = 13.3, 7.5, 2.5 Hz, 1H), 7.36 (q, J = 10.6 Hz, 1H), 7.25-7.22 (m, 1H), 2.74 (t, J = 6.5 Hz, 2H), 2.53 (s, 2H), 2.12 (s, 3H).

[0194] Example 12: Preparation of 4-oxo-N-phenylpentanamide (12)

[0195] A mixture of 4-oxopentanoic acid 1b (700 mg, 6.03 mmol), aniline 12a (618 mg, 6.63 mmol), HATU (3.44 g, 9.05 mmol) and DIEA (2.33 g, 18.09 mmol) was dissolved in dichloromethane (7 mL), replaced with nitrogen for three times, and stirred at 25 °C for 2 hours. Water (10 mL) was added to the reaction mixture, which was extracted with dichloromethane (10 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 dichloromethane and ethyl acetate (V / V = 10:1) to obtain compound 12 (210.62 mg, white solid, 18.3%).

[0196] MS (ESI) m / z: 192 [M+H] + .

[0197] 1 H NMR (400 MHz, MeOD) δ = 7.53 (d, J = 7.9, 2H), 7.46 (t, J = 7.4, 2H), 7.39 (t, J = 7.3, 1H), 7.31 (t, J = 8.6, 4H), 7.09 (t, J = 7.4, 1H), 2.87 (t, J = 6.5, 2H), 2.82–2.71 (m, 1H), 2.64 (t, J = 6.6, 2H), 2.53 (ddd, J = 17.2, 9.5, 3.8, 1H), 2.42–2.24 (m, 2H), 2.22 (s, 3H), 1.39 (s, 3H).

[0198] Example 13: Preparation of N-(4-fluorophenyl)-2,2-dimethyl-3- (methylsulfonyl)propanamide (13)

[0199] Step 1: Preparation of 2,2-dimethyl-3-(methylthio)propanoic acid (13b)

[0200] To a solution of 3-chloro-2,2-dimethylpropanoic acid 13a (1.5 g, 11 mmol) in DMF (10 mL) was added sodium thiomethoxide (1.54 g, 22 mmol). 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 13b (1.5 g, 4.0 g, clear oil, 64.5%).

[0201] MS (ESI) m / z: 149.0 [M+H] + .

[0202] 1 H NMR (400 MHz, CDC13) δ 2.76 (s, 2H), 2.16 (s, 3H), 1.30 (s, 6H).

[0203] Step 2: Preparation of N-(4-fluorophenyl)-2,2-dimethyl-3-(methylthio)propanamide (13c)

[0204] Compound 13b (500 mg, 3.37 mmol), N,N-diisopropylethylamine (2.18 g, 16.89 mmol) and HATU (1.93 g, 5.06 mmol) were dissolved in DMF (10 mL), replaced with nitrogen three times, stirred for 30 min, and then 4-fluoroaniline 2a (378 mg, 3.37 mmol) was added thereto. The reaction was stirred at room temperature for 2 h. Water (30 mL) was added to the reaction, and dichloromethane (40 mL x 3) was extracted. 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 13c (580 mg, light yellow solid, 71.2%).

[0205] MS (ESI) m / z: 242.0 [M+H] + .

[0206] Step 3: Preparation of N-(4-fluorophenyl)-2,2-dimethyl-3-(methylsulfonyl)propanamide (13)

[0207] Compound 13c (520 mg, 2.14 mmol), m-chloroperbenzoic acid (900 mg, 10.74 mmol) were dissolved in dichloromethane (20 mL), replaced with nitrogen for 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 eluent of dichloromethane and ethyl acetate (V / V = 10:1), and freeze-dried to obtain compound 13 (287.94 mg, 48.9%, white solid).

[0208] MS (ESI) m / z: 274.0 [M+H] + .

[0209] 1 H NMR (400 MHz, CDCl3) δ 7.57 (brs, 1H), 7.48-7.42 (m, 2H), 7.07-6.98 (m, 2H), 3.46 (s, 2H), 2.93 (s, 3H), 1.56 (s, 6H).

[0210] Example 14: Preparation of 2,2-dimethyl-3-(methylsulfonyl)-N-(o-tolyl)propanamide (14)

[0211] Step 1: Preparation of 2,2-dimethyl-3-(methylthio)-N-(o-tolyl)propanamide (14a)

[0212] 2-methylaniline 3a (500 mg, 4.62 mmol), N,N-diisopropylethylamine (2.98 g, 23.14 mmol) and HATU (2.64 g, 6.94 mmol) were dissolved in DMF (10 mL), replaced with nitrogen for three times, stirred for 30 minutes, and 2,2-dimethyl-3-(methylthio)propanoic acid 13b (700 mg) was added thereto. The reaction was stirred at room temperature for 6 hours. Water (30 mL) was added to the reaction, 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 of dichloromethane and ethyl acetate (V / V = 5:1) to obtain compound 14a (400 mg, white solid).

[0213] MS (ESI) m / z: 238.0 [M+H] + .

[0214] Step 2: Preparation of 2,2-dimethyl-3-(methylsulfonyl)-N-(o-tolyl)propanamide (14)

[0215] Compound 14a (400 mg, 1.68 mmol), m-chloroperbenzoic acid (1.45 g, 8.40 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 eluted with dichloromethane and ethyl acetate (V / V = 5:1), and freeze-dried to obtain compound 14 (330.17 mg, 72.5%, white solid).

[0216] MS (ESI) m / z: 270.0 [M+H] + .

[0217] 1 H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz, 1H), 7.42 (brs, 1H), 7.25-7.19 (m, 2H), 7.11 (t, J = 7.4 Hz, 1H), 3.49 (s, 2H), 2.94 (s, 3H), 2.29 (s, 3H), 1.60 (s, 6H).

[0218] Example 15: Preparation of N-(2,6-dimethylphenyl)-2,2-dimethyl-3- (methylsulfonyl)propanamide (15)

[0219] Step 1: Preparation of 2,2-dimethyl-3-(methylthio)propanoyl chloride (15a)

[0220] Compound 13b (600 mg, 4.02 mmol) was dissolved in dichloromethane (10 mL), the reaction was reduced to 0°C, and oxalyl chloride (1.02 g, 8.02 mmol) was added thereto, and the reaction was stirred at 25°C for 4 hours. The reaction was concentrated under reduced pressure to obtain a crude product (600 mg, yellow oil).

[0221] Step 2: Preparation of N-(2,6-dimethylphenyl)-2,2-dimethyl-3- (methylthio)propanamide (15c)

[0222] The crude product 15a (487 mg, 4.02 mmol) was dissolved in dichloromethane (20 mL), N,N-diisopropylethylamine (2.59 g, 20.1 mmol) was added, and after stirring for 5 minutes under a nitrogen atmosphere at 0°C, 2,5-dimethylaniline 15b (600 mg) was added, and the reaction was stirred at room temperature for 6 hours. The reaction was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether and ethyl acetate (V / V = 1:1) to obtain compound 15c (500 mg, white solid).

[0223] MS (ESI) m / z: 252.1 [M+H] + .

[0224] Step 3: Preparation of N-(2,6-dimethylphenyl)-2,2-dimethyl-3- (methylsulfonyl)propanamide (15)

[0225] Compound 15c (500 mg, 1.98 mmol), m-chloroperbenzoic acid (1.72 g, 9.92 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) as eluent, and freeze-dried to obtain compound 15 (455.15 mg, 80.8%, white solid).

[0226] MS (ESI) m / z: 284.1 [M+H] + .

[0227] 1 H NMR (400 MHz, CDCl3) δ 7.14-7.05 (m, 4H), 3.51 (s, 2H), 2.96 (s, 3H), 2.25 (s, 6H), 1.63 (s, 6H).

[0228] Example 16: Preparation of N-(4-fluoro-2,6-dimethylphenyl)-1-methyl-2-oxo-1,2- dihydropyridine-4-carboxamide (16)

[0229] Step 1: Preparation of 1-methyl-2-oxo-1,2-dihydropyridine-4-carbonyl chloride (16b)

[0230] 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid 16a (3.0 g, 19.60 mmol), DMF (0.03 g, 0.39 mmol) were dissolved in DCM (30 mL), replaced with nitrogen three times, and stirred at 0 °C for 10 minutes. Oxalyl chloride (2.99 g, 23.52 mmol) was added to the reaction solution, and the reaction solution was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 16b (3.2 g, yellow solid, 76.02%), which was directly used in the next step.

[0231] Step 2: Preparation of N-(4-fluoro-2,6-dimethylphenyl)-1-methyl-2-oxo-1,2- dihydropyridine-4-carboxamide (16)

[0232] Compound 16 (130 mg, colorless solid, 25.02%) was obtained by dissolving 4-fluoro-2,6-dimethylaniline 16c (243.33 mg, 1.74 mmol), DIEA (1129.82 mg, 8.74 mmol) in DCM (3 mL), replacing nitrogen for three times, stirring at 0 °C for 10 minutes. Compound 16b (300 mg, 1.74 mmol) was added dropwise into the reaction solution, then stirring at room temperature for 2 h. After stirring for 2 hours, water (20 mL) was added into 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 ethyl acetate (V / V = 10:1) to give compound 16 (130 mg, colorless solid, 25.02%).

[0233] MS (ESI) m / z: 275.0 [M+H] + .

[0234] 1 HNMR (400MHz, DMSO) δ 9.86 (brs, 1H), 7.85 (d, J = 7.0 Hz, 1H), 6.99 (d, J = 9.4 Hz, 2H), 6.96 (d, J = 1.7 Hz, 1H), 6.59 (dd, J = 7.0, 1.9 Hz, 1H), 3.48 (s, 3H), 2.16 (s, 6H).

[0235] Example 17: Preparation of 3-acetyl-N-(2,6-dimethylphenyl)benzamide (17)

[0236] Step 1: Preparation of 3-acetylbenzoyl chloride (17b)

[0237] Compound 17b (550 mg, yellow oil) was obtained by dissolving 3-acetylbenzoyl chloride 17a (500 mg, 3.04 mmol) in dichloromethane (10 mL) and adding two drops of N,N-dimethylformamide dropwise, cooling the reaction mixture to 0 °C in an ice bath, slowly adding oxalyl chloride (549 mg, 4.56 mmol) dropwise, slowly warming to room temperature, and stirring the reaction at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give crude compound 17b (550 mg, yellow oil). It was used directly in the next step without purification.

[0238] MS (ESI) m / z: 275.0 [M+H] + .

[0239] Step 2: Preparation of 3-acetyl-N-(2,6-dimethylphenyl)benzamide (17)

[0240] Compound 15b (442 mg, 3.65 mmol) was dissolved in dichloromethane (10 mL), and N, N-diisopropyl ethylamine (590 mg, 4.56 mmol) and compound 17b (550 mg, 2.78 mmol) were added dropwise in turn. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash chromatography with eluent (PE:EA = 3:1) to obtain compound 17 (120 mg, white solid, 14%).

[0241] MS (ESI) m / z: 268.1 [M+H] + .

[0242] 1 H NMR (400 MHz, DMSO) δ 9.97 (s, 1H), 8.55 (t, J = 1.5 Hz, 1H), 8.24 (d, J = 7.8 Hz, 1H), 8.17 (dd, J = 7.8, 1.3 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.14 (s, 3H), 2.67 (s, 3H), 2.19 (s, 6H).

[0243] Example 18: Preparation of N-(2,6-dimethylphenyl)-4-(dimethylphosphoryl)benzamide (18)

[0244] Step 1: Preparation of N-(2,6-dimethylphenyl)-4-iodobenzamide (18b) 4-Iodobenzoyl chloride 18a (1.2 g, 4.51 mmol), compound 15b (546.47 mg, 4.51 mmol) and TEA (1.36 g, 13.53 mmol) were dissolved in DCM (10 mL), replaced with nitrogen three times, and the reaction solution was stirred at 25 °C for 3 hours. Water (40 mL) was added to the reaction solution, and DCM was extracted (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 petroleum ether and ethyl acetate (V / V = 3:1) to obtain compound 18b (1.35 g, colorless oil, 85.27%).

[0245] MS (ESI) m / z: 352.1 [M+H].

[0246] Step 2: Preparation of N-(2,6-dimethylphenyl)-4-(dimethylphosphoryl)benzamide (18) Compound 18b (600 mg, 1.71 mmol), dimethylphosphoryl oxide (400.05 mg, 5.13 mmol), PD2(DBA)3 (156.45 mg, 0.17 mmol), Xantphos (98.86 mg, 0.17 mmol) and TEA (518.65 mg, 5.12 mmol) were dissolved in DMF (10 mL) and stirred at 110 °C for 4 h. Water (30 mL) was added to the reaction solution, which was 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, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Gemini 5u C18 150 x 21.2 mm, CH3CN aqueous solution (0.1% FA), flow rate: 20 ml / min; wavelength: 214 nm; sample injection DMSO (+ optional formic acid and water), gradient from 10% to 95% CH3CN) to give compound 18 (139.4 mg, colorless solid, 25.72%).

[0247] MS (ESI) m / z: 302.1 [M+H] + . 1 HNMR (400MHz, CDC13) δ = 8.06 (d, J = 7.3, 2H), 7.93-7.84 (m, 2H), 7.48 (s, 1H), 7.16 (dt, J = 9.1, 4.7, 3H), 2.30 (s, 6H), 1.81 (s, 3H), 1.78 (s, 3H).

[0248] Example 19: Preparation of N-(4-fluoro-2,6-dimethylphenyl)-1- (methylsulfonyl)piperidine-4-carboxamide (19)

[0249] Step 1: Preparation of 1-(methylsulfonyl)piperidine-4-carboxylic chloride (19b)

[0250] Compound 19a (800 mg, 3.86 mmol), DMF (5.6 mg, 0.07 mmol) were dissolved in DCM (4 mL), replaced with nitrogen three times, and stirred at 0 °C for 10 min. Oxalyl chloride (587.9 mg, 4.63 mmol) was added to the reaction solution, which was then allowed to return to room temperature and stirred for 1 h. The reaction solution was concentrated under reduced pressure to give compound 19b (860 mg, yellow solid, 98.71%), which was directly used in the next step.

[0251] Step 2: Preparation of N-(4-fluoro-2,6-dimethylphenyl)-1-(methylsulfonyl)piperidine-4- carboxamide (19)

[0252] Compound 16c (129.5 mg, 0.93 mmol), DIEA (224.19 mg, 2.21 mmol) were dissolved in DCM (5 mL) solution, replaced with nitrogen three times, stirred at 0 °C for 10 min. Compound 19b (200 mg, 0.88 mmol) was added dropwise into the reaction solution, stirred at room temperature for 2 h. 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 petroleum ether and ethyl acetate (V / V = 1:1) to obtain compound 19 (104.12 mg, colorless solid, 33.99%).

[0253] MS (ESI) m / z: 329.1 [M+H] + .

[0254] 1 H NMR (400 MHz, DMSO) δ 9.16 (s, 1H), 6.89 (d, J = 9.4 Hz, 2H), 3.58 (dt, J = 12.3, 3.3 Hz, 2H), 2.85 (s, 3H), 2.75 (td, J = 11.7, 1.9 Hz, 2H), 2.51 - 2.47 (m, 1H), 2.08 (s, 6H), 1.91 (dd, J = 13.3, 2.5 Hz, 2H), 1.66 (qd, J = 12.5, 3.9 Hz, 2H).

[0255] Example 20: Preparation of N-(2-fluorophenyl)-4-oxopentanamide (20)

[0256] Compound 20 was prepared in the same manner as in the preparation of Example 1, except that 2-fluoroaniline 20a was used instead of 3-fluoroaniline 1a.

[0257] MS (ESI) m / z: 209.9 [M+H] + .

[0258] 1 H NMR (400 MHz, CDCl3) δ 8.26 (t, J = 8.1 Hz, 1H), 7.67 (s, 1H), 7.12 - 7.00 (m, 3H), 2.90 (t, J = 6.3 Hz, 2H), 2.68 (t, J = 6.3 Hz, 2H), 2.23 (s, 3H).

[0259] Example 21: Preparation of 4-oxo-N-(p-tolyl)pentanamide (21)

[0260] A mixture of 4-oxopentanoic acid 1b (600 mg, 5.16 mmol) and HOBT (837 mg, 6.20 mmol) was dissolved in a mixed solution of dichloromethane (15 mL) and triethylamine (2 mL), and the reaction was replaced with nitrogen three times. The reaction was reduced to 0°C, and EDCI (1188 mg, 6.20 mmol) was added thereto. After the reaction was stirred at room temperature for 1 hour, 4-methylaniline 21a (664 mg, 6.50 mmol) was slowly added to the reaction system, and the reaction was stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, and 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 dichloromethane and ethyl acetate (V / V = 7:1) to obtain compound 21 (470 mg, white solid, 43.43%).

[0261] MS (ESI) m / z: 206.0 [M+H] + .

[0262] 1 H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.35 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 8.2 Hz, 2H), 2.87 (t, J = 6.3 Hz, 2H), 2.59 (t, J = 6.3 Hz, 2H), 2.29 (s, 3H), 2.20 (s, 3H).

[0263] Example 22: Preparation of 4-oxo-N-(4-(trifluoromethyl)phenyl)pentanamide (22)

[0264] A mixture of 4-oxopentanoic acid 1b (1 g, 6.2 mmol), 4-trifluoromethylaniline 22a (720 mg, 6.2 mmol), HOBt (1.01 g, 7.4 mmol), DIPEA (1.6 g, 7.4 mmol), and EDCI (1.4 g, 7.4 mmol) was dissolved in dichloromethane (10 mL), and the reaction was replaced with nitrogen three times. The reaction was stirred at 20°C for 16 hours. Water (30 mL) was added to the reaction solution, and ethyl acetate (100 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 = 5:1) to obtain compound 22 (288 mg, white solid, 17.9%).

[0265] MS (ESI) m / z: 259.9 [M+H].

[0266] 1 H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 2.76 (t, J = 6.5 Hz, 2H), 2.57 (t, J = 6.5 Hz, 2H), 2.13 (s, 3H).

[0267] Example 23: Preparation of N-(2,6-dimethylphenyl)-4-oxopentanamide (23)

[0268] To a solution of 4-oxopentanoic acid 1b (500 mg, 4.31 mmol) in thionyl chloride (3 mL) was added dimethylformamide (32 mg, 0.43 mmol) at 0 °C. The resulting solution was stirred at room temperature for 16 h. The solvent was then removed in vacuo. The crude product in dichloromethane (3 mL) was added dropwise to 2,5-dimethylaniline 23a (417 mg, 3.44 mmol) and triethylamine (871 mg, 8.62 mmol) at 0 °C and the solution was stirred for 2 h. The solvent was then removed in vacuo. The residue was purified by column chromatography on silica gel using n-hexane / ethyl acetate (0-50%) as eluent to give compound 23 (yellow solid, 100 mg, 10.62%).

[0269] MS (ESI) m / z: 220.1 [M+H] + .

[0270] 1 H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 7.05 - 6.93 (m, 3H), 2.72 (t, J = 6.8 Hz, 2H), 2.53 (t, J = 6.8 Hz, 2H), 2.13 - 2.06 (m, 9H).

[0271] Example 24: Preparation of N-phenylacetamide (24)

[0272] Compound 3a (943 mg, 8.82 mmol), acetic anhydride (300 mg, 2.94 mmol) were dissolved in dichloromethane (10 mL), replaced with nitrogen for three times, the reaction solution was stirred at 25 °C for 2 hours, water (10 mL) was added to the reaction solution, dichloromethane was extracted (10 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 dichloromethane and ethyl acetate (V / V = 10:1) to obtain compound 24 (105.09 mg, white solid, 35.7%).

[0273] MS (ESI) m / z: 150 [M+H] + .

[0274] 1 H NMR (400 MHz, CDCl3) δ = 7.68 (d, J = 7.8, 1H), 7.20-7.11 (m, 3H), 7.07 (d, J = 7.2, 1H), 2.22 (s, 3H), 2.16 (s, 3H).

[0275] Example 25: Preparation of N-(4-fluoro-2-methylphenyl)-4-oxopentanamide (25)

[0276] 4-Fluoro-2-methylaniline 25a (593 mg, 4.74 mmol), 4-oxopentanoic acid 1b (500 mg, 4.31 mmol), HATU (2456 mg, 6.46 mmol) and DIEA (1670 mg, 12.92 mmol) were dissolved in dichloromethane (15 mL) solution, the reaction solution was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction solution, dichloromethane was extracted (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 dichloromethane and ethyl acetate (V / V = 5:1) to obtain compound 25 (339 mg, pink solid, 35.27%).

[0277] MS (ESI) m / z: 224 [M+H] + .

[0278] 1H NMR (400 MHz, d6-DMSO) δ 9.31 (s, 1H), 7.31 (dd, J = 8.7, 5.8 Hz, 1H), 7.06 (dd, J = 9.7, 2.8 Hz, 1H), 6.96 (td, J = 8.6, 2.9 Hz, 1H), 2.74 (t, J = 6.7 Hz, 2H), 2.54 (d, J = 6.7 Hz, 2H), 2.15 (d, J = 23.3 Hz, 6H).

[0279] Example 26: Preparation of N-(4-fluorophenyl)-l-methyl-2-oxo-l,2- dihydropyridine-4-carboxamide (26)

[0280] Compound 26 was prepared in the same manner as described in the preparation of Example 16, except that compound 2a was used instead of compound 16c.

[0281] MS (ESI) m / z: 247.0 [M+H] + .

[0282] 1 H NMR (400 MHz, CDC13) δ 9.44 (s, 1H), 7.85 - 7.79 (m, 2H), 7.44 (d, J = 7.0 Hz, 1H), 7.31 (s, 1H), 7.05 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 6.9 Hz, 1H), 3.60 (s, 3H).

[0283] Example 27: Preparation of N-(2,6-dimethylphenyl)-l-methyl-2-oxo-l,2- dihydropyridine-4-carboxamide (27)

[0284] Compound 27 was prepared in the same manner as described in the preparation of Example 16, except that compound 15b was used instead of compound 16c.

[0285] MS (ESI) m / z: 247.0 [M+H] + .

[0286] 1 H NMR (400 MHz, CDC13) δ 9.44 (s, 1H), 7.85 - 7.79 (m, 2H), 7.44 (d, J = 7.0 Hz, 1H), 7.31 (s, 1H), 7.05 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 6.9 Hz, 1H), 3.60 (s, 3H).

[0287] Example 28: Preparation of l-methyl-2-oxo-N-(o-tolyl)-l,2-dihydropyridine-4- carboxamide (28)

[0288] Compound 28 was prepared in the same manner as for the preparation of Example 16, except substituting compound 3a for compound 16c.

[0289] MS (ESI) m / z: 243.1 [M+H] + .

[0290] 1 HNMR (400 MHz, CDC13) δ 7.89 (d, J = 7.8 Hz, 1H), 7.72 (br s, 1H), 7.44 (d, J = 6.9 Hz, 1H), 7.29 - 7.25 (m, 1H), 7.23 (d, J = 7.0 Hz, 1H), 7.17 - 7.11 (m, 1H), 7.02 (s, 1H), 6.70 (d, J = 6.9 Hz, 1H), 3.61 (s, 3H), 2.31 (s, 3H).

[0291] Example 29: Preparation of N-(2-fluoro-6-methylphenyl)-l-methyl-2-oxo-l,2- dihydropyridine-4-carboxamide (29)

[0292] Compound 29 was prepared in the same manner as for the preparation of Example 16, except substituting 2-methyl-5-fluoroaniline 29a for compound 16c.

[0293] MS (ESI) m / z: 261.0 [M+H] + .

[0294] 1 HNMR (400 MHz, DMSO) δ 10.03 (br s, 1H), 7.85 (d, J = 7.0 Hz, 1H), 7.27 (dt, J = 7.9, 6.8 Hz, 1H), 7.16 - 7.09 (m, 2H), 6.97 (d, J = 1.5 Hz, 1H), 6.59 (dd, J = 7.0, 1.9 Hz, 1H), 3.48 (s, 3H), 2.21 (s, 3H).

[0295] Example 30: Preparation of 6-methyl-N-(o-tolyl)nicotinamide (30)

[0296] Compound 30 (166 mg, colorless solid, 33.65%) was obtained by the following procedures: Compound 30 (300 mg, 2.18 mmol), compound 3a (256.13 mg, 2.39 mmol), EDCI (626.86 mg, 3.27 mmol) and HOBt (441.84 mg, 3.27 mmol) were dissolved in DCM (5 mL), replaced with nitrogen for three times, and the reaction solution was stirred at 25 °C for 2 h. Water (20 mL) was added to the reaction solution, and DCM (20 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 of petroleum ether and ethyl acetate (V / V = 3:1) to obtain compound 30 (166 mg, colorless solid, 33.65%).

[0297] MS (ESI) m / z: 227.1 [M+H] + .

[0298] 1 HNMR (400MHz, DMSO) δ = 9.99 (s, 1H), 9.02 (d, J = 1.3, 1H), 8.21 (dd, J = 8.0, 2.0, 1H), 7.42 (d, J = 8.1, 1H), 7.35 (d, J = 7.4, 1H), 7.28 (d, J = 7.4, 1H), 7.21-7.16 (m, 2H), 2.56 (s, 3H), 2.24 (s, 3H).

[0299] Example 31: Preparation of N-(2,6-dimethylphenyl)-6-methylnicotinamide (31)

[0300] Step 1: Preparation of 6-methylnicotinic acid (31a)

[0301] Compound 31a (600 mg, 4.37 mmol) and DMF (6.4 mg, 0.08 mmol) were dissolved in DCM (3 mL), replaced with nitrogen for three times, and stirred at 0 °C for 10 min. Oxalyl chloride (665.6 mg, 5.24 mmol) was added to the reaction solution, and then the reaction solution was restored to room temperature and stirred for 1 h. The reaction solution was concentrated under reduced pressure to obtain compound 31a (650 mg, yellow solid, 95.6%), which was directly used in the next step.

[0302] Step 2: Preparation of N-(2,6-dimethylphenyl)-6-methylnicotinamide (31)

[0303] Compound 15b (256.85 mg, 2.12 mmol), DIEA (821.96 mg, 6.36 mmol) were dissolved in DCM (5 mL), replaced with nitrogen for three times, stirred at 0 °C for 10 min. Compound 31a (330 mg, 2.12 mmol) was added dropwise into the reaction solution, stirred at room temperature for 2 h. Water (20 mL) was added into 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 petroleum ether and ethyl acetate (V / V = 10: 1) to obtain compound 31 (200 mg, colorless solid, 24.88%).

[0304] MS (ESI) m / z: 241.0 [M+H] + .

[0305] 1 HNMR (400MHz, MeOD) δ = 9.00 (d, J = 2.0, 1H), 8.26 (dd, J = 8.1, 2.3, 1H), 7.45 (d, J = 8.1, 1H), 7.12 (d, J = 2.9, 3H), 2.61 (s, 3H), 2.24 (s, 6H).

[0306] Example 32: Preparation of N-(4-fluorophenyl)-6-methylnicotinamide (32)

[0307] Compound 32 was prepared in the same manner as in the preparation of Example 31, except that compound 2a was used instead of compound 15b.

[0308] MS (ESI) m / z: 231.0 [M+H] + .

[0309] 1 HNMR (400MHz, MeOD) δ = 9.00 (d, J = 2.0, 1H), 8.26 (dd, J = 8.1, 2.3, 1H), 7.45 (d, J = 8.1, 1H), 7.12 (d, J = 2.9, 3H), 2.61 (s, 3H), 2.24 (s, 6H).

[0310] Example 33: Preparation of 4-acetyl-N-(2,6-dimethylphenyl)benzamide (33)

[0311] Step 1: Preparation of 4-acetylbenzoyl chloride (33b)

[0312] Compound 33b (0.9 g, yellow solid, 81.11%) was obtained by reducing pressure concentration of the reaction solution, which was directly used for the next step.

[0313] Step 2: Preparation of 4-acetyl-N-(2,6-dimethylphenyl)benzamide (33)

[0314] Compound 15b (199.09 mg, 1.64 mmol), DIEA (636.99 mg, 4.92 mmol) were dissolved in DCM (5 mL), replaced with nitrogen for three times, stirred at 0 ℃ for 10 minutes. Compound 33b (300 mg, 1.64 mmol) was added dropwise into the reaction solution, stirred at room temperature for 2 hours. Water (40 mL) was added into the reaction solution, extracted with DCM (40 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 of petroleum ether and ethyl acetate (V / V = 10:1) to obtain compound 33 (115 mg, colorless solid, 24.88%).

[0315] MS (ESI) m / z: 268.2 [M+H] + .

[0316] 1 HNMR (400MHz, CDCI3) δ 8.03 (dd, J = 26.0, 8.2 Hz, 4H), 7.47 (s, 1H), 7.20-7.10 (m, 3H), 2.67 (s, 3H), 2.29 (s, 6H).

[0317] Example 34: Preparation of 4-acetyl-N-(o-tolyl)benzamide (34)

[0318] Compound 34 was prepared in the same manner as in the preparation of Example 33, except that compound 3a was used instead of compound 15b.

[0319] MS (ESI) m / z: 254.2 [M+H] + .

[0320] 1H NMR (400 MHz, DMSO) δ 10.07 (s, 1H), 8.12-8.07 (m, 4H), 7.35 (d, J = 7.4 Hz, 1H), 7.31-7.27 (m, 1H), 7.23 (td, J = 7.6, 1.9 Hz, 1H), 7.21-7.16 (m, 1H), 2.65 (s, 3H), 2.24 (s, 3H).

[0321] Example 35: Preparation of 4-acetyl-N-(4-fluorophenyl)benzamide (35)

[0322] Compound 35 was prepared in the same manner as in the preparation of Example 33, except that compound 2a was used instead of compound 15b.

[0323] MS (ESI) m / z: 254.2 [M+H] + .

[0324] 1 H NMR (400 MHz, DMSO) δ 10.47 (s, 1H), 8.11-8.05 (m, 4H), 7.82-7.78 (m, 2H), 7.24-7.18 (m, 2H), 2.65 (s, 3H).

[0325] Example 36: Preparation of 1-acetyl-N-(4-fluorophenyl)piperidine-4-carboxamide (36)

[0326] Step 1: Preparation of 1-acetyl piperidine-4-carboxamide (36b)

[0327] 1-acetyl piperidine-4-carboxylic acid 36a (1.0 g, 5.84 mmol), DMF (8.5 mg, 0.12 mmol) were dissolved in DCM (10 mL), replaced with nitrogen for three times, stirred at 0 °C for 10 minutes. Oxalyl chloride (889.7 mg, 7.01 mmol) was added to the reaction solution, the reaction solution was restored to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 36b (1 g, yellow solid, 90.24 %), which was directly used in the next step.

[0328] Step 2: Preparation of 1-acetyl-N-(4-fluorophenyl)piperidine-4-carboxamide (36)

[0329] Compound 2a (175.79 mg, 1.58 mmol), DIEA (613.37 mg, 4.74 mmol) were dissolved in DCM (5 mL), replaced with nitrogen for three times, stirred at 0 °C for 10 min. Compound 36b (300 mg, 1.58 mmol) was added dropwise into the reaction solution, stirred at room temperature for 2 h. Water (40 mL) was added into the reaction solution, extracted with DCM (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 = 5:1) to obtain compound 36 (178 mg, colorless solid, 40.44%).

[0330] MS (ESI) m / z: 265.0 [M+H] + .

[0331] 1 H NMR (400 MHz, DMSO) δ 9.96 (s, 1H), 7.61 (dd, J = 8.8, 5.1 Hz, 2H), 7.13 (t, J = 8.8 Hz, 2H), 4.40 (d, J = 13.0 Hz, 1H), 3.87 (d, J = 13.5 Hz, 1H), 3.06 (t, J = 11.9 Hz, 1H), 2.64 - 2.53 (m, 2H), 2.01 (s, 3H), 1.80 (t, J = 11.0 Hz, 2H), 1.58 (qd, J = 12.5, 3.9 Hz, 1H), 1.43 (qd, J = 12.5, 4.1 Hz, 1H).

[0332] Example 37: Preparation of 1-acetyl-N-(o-tolyl)piperidine-4-carboxamide (37)

[0333] Compound 37 was prepared in the same manner as in the preparation of Example 36, except that compound 3a was used instead of compound 2a.

[0334] MS (ESI) m / z: 261.0 [M+H] + .

[0335] 1H NMR (400 MHz, CDC13) δ = 7.75 (d, J = 7.8, 1H), 7.20 (dd, J = 12.9, 4.9, 2H), 7.13 - 7.04 (m, 2H), 4.64 (d, J = 10.3, 1H), 3.90 (s, 1H), 3.15 (t, J = 12.0, 1H), 2.73 (t, J = 11.7, 1H), 2.59 - 2.47 (m, 1H), 2.25 (s, 3H), 2.11 (s, 3H), 1.98 (s, 2H), 1.86 - 1.69 (m, 2H).

[0336] Example 38: Preparation of l-acetyl-N-(2,6-dimethylphenyl)piperidine-4- carboxamide (38)

[0337] Compound 38 was prepared in the same manner as the preparation method of Example 36, except that compound 15b was used instead of compound 2a.

[0338] MS (ESI) m / z: 275.1 [M+H] + .

[0339] 1 H NMR (400 MHz, DMSO) δ 9.18 (s, 1H), 7.05 (s, 3H), 4.39 (d, J = 12.9 Hz, 1H), 3.87 (d, J = 13.5 Hz, 1H), 3.10 (t, J = 11.9 Hz, 1H), 2.63 (t, J = 11.9 Hz, 2H), 2.11 (s, 6H), 2.01 (s, 3H), 1.85 (t, J = 12.5 Hz, 2H), 1.71 - 1.55 (m, 1H), 1.54 - 1.42 (m, 1H).

[0340] Example 39: Preparation of N-(4-fluorophenyl)-4-(methylsulfonyl)benzamide (39)

[0341] Step 1: Preparation of 4-(methylsulfonyl)benzoyl chloride (39b)

[0342] 4-(Methylsulfonyl)benzoyl chloride (39a) (600 mg, 2.99 mmol), DMF (4.4 mg, 0.06 mmol) were dissolved in DCM (10 mL), replaced with nitrogen three times, and stirred at 0 °C for 10 min. Oxalyl chloride (455.4 mg, 3.58 mmol) was added to the reaction solution, and the reaction solution was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain compound 39b (640 mg, yellow solid, 98.19%), which was directly used in the next step.

[0343] Step 2: Preparation of N-(4-fluorophenyl)-4-(methylsulfonyl)benzamide (39)

[0344] Compound 2a (152.8 mg, 1.37 mmol), DIEA (354.1 mg, 2.74 mmol) were dissolved in DCM (5 mL), replaced with nitrogen for three times, stirred at 0 °C for 10 minutes. Compound 39b (300 mg, 1.37 mmol) was added dropwise into the reaction solution, stirred at room temperature for 2 hours. Water (20 mL) was added into 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, 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 = 10:1) to obtain compound 39 (209.72 mg, colorless solid, 52.23%).

[0345] MS (ESI) m / z: 293.9 [M+H] + .

[0346] 1 HNMR (400MHz, DMSO) δ = 10.52 (s, 1H), 8.13 (d, J = 8.4, 2H), 8.05 (d, J = 8.4, 2H), 7.80-7.73 (m, 2H), 7.19 (t, J = 8.9, 2H), 3.26 (s, 3H).

[0347] Example 40: Preparation of N-(2,6-dimethylphenyl)-4-(methylsulfonyl)benzamide (40)

[0348] Compound 40 was prepared in the same manner as in the preparation of Example 39, except that compound 15b was used instead of compound 2a.

[0349] MS (ESI) m / z: 304.1 [M+H] + .

[0350] 1 HNMR (400MHz, CDCl3) δ = 8.04 (dd, J = 21.8, 8.5, 4H), 7.65 (s, 1H), 7.21-7.06 (m, 3H), 3.08 (s, 3H), 2.27 (s, 6H).

[0351] Example 41: Preparation of N-(4-fluorophenyl)-1-(methylsulfonyl)piperidine-4-carboxamide (41)

[0352] Compound 41 was prepared in the same manner as in the preparation of Example 19, except that compound 2a was used in place of compound 16c.

[0353] MS (ESI) m / z: 301.0 [M+H] + .

[0354] 1 NMR (400 MHz, DMSO) δ 9.95 (s, 1H), 7.58 (dd, J = 9.0, 5.1, 2H), 7.09 (t, J = 8.9, 2H), 3.57 (d, J = 11.9, 2H), 2.85 (s, 3H), 2.76 - 2.67 (m, 2H), 2.42 - 2.37 (m, 1H), 1.92 - 1.80 (m, 2H), 1.67 - 1.57 (m, 2H).

[0355] Example 42: Preparation of N-(2,6-dimethylphenyl)-1-(methylsulfonyl)piperidine-4- carboxamide (42)

[0356] Compound 42 was prepared in the same manner as in the preparation of Example 19, except that compound 15b was used in place of compound 16c.

[0357] MS (ESI) m / z: 311.2 [M+H] + .

[0358] 1 H NMR (400 MHz, DMSO) δ 9.19 (s, 1H), 7.02 (s, 3H), 3.58 (dt, J = 11.9, 3.3 Hz, 2H), 2.85 (s, 3H), 2.75 (td, J = 11.9, 2.4 Hz, 2H), 2.52 - 2.47 (m, 1H), 2.08 (s, 6H), 1.91 (dd, J = 13.2, 2.5 Hz, 2H), 1.67 (qd, J = 12.4, 4.1 Hz, 2H).

[0359] Example 43: Preparation of N-(2,6-dimethylphenyl)-3-(methylsulfonyl)benzamide (43)

[0360] Step 1: Preparation of 3-(methylsulfonyl)benzoyl chloride (43b)

[0361] Compound 43b (304 mg, 1.39 mmol) was added into the solution of compound 15b (140 mg, 1.16 mmol) and N,N-diisopropyl ethylamine (350 mg, 3.47 mmol) in dichloromethane (5 mL) under nitrogen atmosphere. The reaction was stirred at 20 °C for 2 h. Water (30 mL) was added into the reaction solution. The mixture was extracted with dichloromethane (40 mL x 3). The organic phase was combined and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using eluent of petroleum ether and ethyl acetate (V / V = 3:1) to give compound 43 (109 mg, yellow solid, 31.1%).

[0362] MS (ESI) m / z: 219 [M+H] + .

[0363] Step 2: Preparation of N-(2,6-dimethylphenyl)-3-(methylsulfonyl)benzamide (43)

[0364] Compound 43b (304 mg, 1.39 mmol) was added into the solution of compound 15b (140 mg, 1.16 mmol) and N,N-diisopropyl ethylamine (350 mg, 3.47 mmol) in dichloromethane (5 mL) under nitrogen atmosphere. The reaction was stirred at 20 °C for 2 h. Water (30 mL) was added into the reaction solution. The mixture was extracted with dichloromethane (40 mL x 3). The organic phase was combined and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using eluent of petroleum ether and ethyl acetate (V / V = 3:1) to give compound 43 (109 mg, yellow solid, 31.1%).

[0365] MS (ESI) m / z: 219 [M+H] + .

[0366] 1 H NMR (400 MHz, DMSO) δ 10.07 (s, 1H), 8.50 (s, 1H), 8.33 (d, J = 7.8 Hz, 1H), 8.14 (s, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.15 (s, 3H), 3.30 (s, 3H), 2.20 (s, 6H).

[0367] Example 44: Preparation of 3-acetyl-4-fluoro-N-(4-fluorophenyl)benzamide (44)

[0368] Compound 44a (120 mg, 0.66 mmol), compound 2a (88 mg, 0.79 mmol), DMAP (8 mg, 0.06 mmol) were dissolved in DCM (5 mL) and replaced with nitrogen for three times. The reaction was cooled to 0 °C, and triethylamine (200 mg, 1.98 mmol) and EDCI (253 mg, 1.32 mmol) were added into the reaction. The reaction was stirred at 25 °C for 16 hours. Water (20 mL) was added into the reaction, and DCM (20 mL x 3) was used to extract the reaction. 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 of petroleum ether and ethyl acetate (V / V = 3:1) to give compound 44 (92.65 mg, colorless solid, 48.49%).

[0369] MS (ESI) m / z: 276.1 [M+H] + .

[0370] 1 HNMR (400MHz, DMSO) δ 10.49 (s, 1H), 8.42 (dd, J = 7.1, 2.4 Hz, 1H), 8.23 (ddd, J = 8.6, 4.7, 2.5 Hz, 1H), 7.80-7.75 (m, 2H), 7.54 (dd, J = 10.9, 8.7 Hz, 1H), 7.25-7.18 (m, 2H), 2.65 (d, J = 4.2 Hz, 3H).

[0371] Example 45: Preparation of 3-acetyl-4-fluoro-N-(4-nitrophenyl)benzamide (45)

[0372] Step 1: Preparation of 3-acetyl-4-fluorobenzoyl chloride (45a)

[0373] Compound 44a (500 mg, 2.75 mmol), DMF (20.05 mg, 0.27 mmol) were dissolved in DCM (5 mL) and replaced with nitrogen for three times, and stirred at 0 °C for 10 minutes. Oxalyl chloride (699 mg, 5.50 mmol) was added into the reaction, and the reaction was stirred at 25 °C for 1 hour. The reaction was concentrated under reduced pressure to give compound 45a (500 mg, yellow solid, 81.72%), which was used directly in the next step.

[0374] Step 2: Preparation of 3-acetyl-4-fluoro-N-(4-nitrophenyl)benzamide (45)

[0375] Compound 45a (184 mg, 1.14 mmol), Et3N (288 mg, 2.85 mmol) were dissolved in DCM (5 mL) and stirred at 0 °C for 10 min. Compound 45b (157 mg, 1.14 mmol) was added, and the reaction was stirred at room temperature for 3 h. Water (20 mL) was added to the reaction, and the mixture was extracted with DCM (20 mL x 3). The organic phase was combined, washed with saturated NaCl solution, dried over anhydrous Na2S04, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether and ethyl acetate (5:1, V / V) as eluent to give compound 45 (74 mg, colorless solid, 24.50%).

[0376] MS (ESI) m / z: 303.1 [M+H] + .

[0377] 1 HNMR (400MHz, DMSO) δ 10.97 (s, 1H), 8.45 (dd, J = 7.0, 2.3 Hz, 1H), 8.30-8.25 (m, 3H), 8.06 (d, J = 9.2 Hz, 2H), 7.58 (dd, J = 10.8, 8.8 Hz, 1H), 2.66 (d, J = 4.2 Hz, 3H).

[0378] Example 46: Preparation of 3-acetyl-4-fluoro-N-(4-(trifluoromethyl)phenyl)benzamide (46)

[0379] Compound 45a (184 mg, 1.14 mmol), Et3N (288 mg, 2.85 mmol) were dissolved in DCM (5 mL) and stirred at 0 °C for 10 min. Compound 45b (157 mg, 1.14 mmol) was added, and the reaction was stirred at room temperature for 3 h. Water (20 mL) was added to the reaction, and the mixture was extracted with DCM (20 mL x 3). The organic phase was combined, washed with saturated NaCl solution, dried over anhydrous Na2S04, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether and ethyl acetate (5:1, V / V) as eluent to give compound 45 (74 mg, colorless solid, 24.50%).

[0380] MS (ESI) m / z: 326.0 [M+H] + .

[0381] 1H NMR (400 MHz, DMSO) δ 10.76 (s, 1H), 8.44 (dd, J = 7.0, 2.3 Hz, 1H), 8.26 (ddd, J = 8.3, 4.5, 2.4 Hz, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H), 7.56 (dd, J = 10.7, 8.8 Hz, 1H), 2.66 (d, J = 4.1 Hz, 3H).

[0382] Example 47: Preparation of 4-acetyl-N-(4-(trifluoromethyl)phenyl)benzamide (47)

[0383] Compound 47 was prepared in the same manner as in the preparation of Example 33, except that compound 46a was used instead of compound 15b.

[0384] MS (ESI) m / z: 308.0 [M+H] + .

[0385] 1 H NMR (400 MHz, DMSO) δ 10.76 (s, 1H), 8.44 (dd, J = 7.0, 2.3 Hz, 1H), 8.26 (ddd, J = 8.3, 4.5, 2.4 Hz, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H), 7.56 (dd, J = 10.7, 8.8 Hz, 1H), 2.66 (d, J = 4.1 Hz, 3H).

[0386] Example 48: Preparation of N-(4-fluorophenyl)-3-oxobutane-1-sulfonamide (48)

[0387] Step 1: Preparation of methyl 3-(N-(4-fluorophenyl)sulfonyl)propanoate (48b)

[0388] Methyl 3-(chlorosulfonyl)propanoate 48a (2.52 g, 13.498 mmol, 1.5 eq), triethylamine (4.55 g, 44.995 mmol, 5.0 eq) and 4-dimethylaminopyridine (0.22 g, 1.800 mmol, 0.2 eq) were added to dichloromethane (30 mL) and stirred at room temperature for 2 hours. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was dried over anhydrous sodium sulfate. Filtration was followed by concentration of the filtrate under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to give compound 48b (1.4 g, yield 59.54%, purity 82.2%) as a light yellow solid.

[0389] ESI / MS (m / z): 259.90 [M+H] + .

[0390] Step 2: Preparation of 3-(N-(4-fluorophenyl)sulfamoyl)-N-methoxy-N-methyl- propionamide (48c)

[0391] To a solution of compound 48b (1.37 g, 5.244 mmol, 1.0 eq) and methoxy(methyl)amine hydrochloride (0.77 g, 7.866 mmol, 1.5 eq) in tetrahydrofuran (20 mL) was added isopropylmagnesium chloride (10.49 mL, 20.976 mmol, 4.0 eq, 2.0 M in tetrahydrofuran) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 4 h. The reaction was diluted with water (150 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with saturated brine (30 mL). The organic phase was concentrated and the residue was separated by column chromatography on silica gel (petroleum ether: ethyl acetate = 1: 1) to give compound 48c (600 mg, yield 39.41%, purity 85.1%) as a yellow solid.

[0392] ESI / MS (m / z): 290.95 [M+H] + .

[0393] Step 3: Preparation of N-(4-fluorophenyl)-3-oxobutane-1-sulfonamide (48)

[0394] To a solution of compound 48c (550.00 mg, 1.895 mmol, 1.0 eq) in tetrahydrofuran (11 mL) was added methylmagnesium bromide (5.68 mL, 5.685 mmol, 3.0 eq, 1.0 M in tetrahydrofuran) dropwise at -78 °C under nitrogen atmosphere. After the addition was completed, the mixture was stirred at -78 °C for 10 min and then was allowed to warm to 0 °C and stirred for another 2 h. The reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) at 0 °C, diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phase was washed with saturated brine (30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was separated by reverse phase preparative chromatography (mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile) to give compound 48 (115.9 mg, yield 24.94%, purity 98.2%) as a grey solid.

[0395] ESI / MS (m / z): 243.95 [M+H] + .

[0396] 1H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.34 - 7.11 (m, 4H), 3.23 (t, J = 7.2 Hz, 2H), 2.88 (t, J = 7.2 Hz, 2H), 2.12 (s, 3H).

[0397] 19 F NMR (377 MHz, DMSO-d6) δ -118.89.

[0398] Example 49: Preparation of N-(4-nitrophenyl)-3-oxobutane-1-sulfonamide (49)

[0399] Step 1: Preparation of N-(4-nitrophenyl)but-3-yn-1-sulfonamide (49a)

[0400] To a solution of p-nitroaniline 45b (1.45 g, 10.486 mmol, 2.0 eq) and triethylamine (1.06 g, 10.486 mmol, 2.0 eq) in dichloromethane (30 mL) was added but-3-yn-1-sulfonyl chloride 49b (800 mg, 5.243 mmol, 1.0 eq) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction was concentrated under reduced pressure. The resulting residue was isolated by column chromatography on silica gel (petroleum ether: ethyl acetate = 3: 1) to give compound 49a (450 mg, 33.76% yield, 100% purity) as a white solid.

[0401] ESI / MS (m / z): 253.0 [M-H] - .

[0402] Step 2: Preparation of N-(4-nitrophenyl)-3-oxobutane-1-sulfonamide (49)

[0403] To a solution of compound 49a (450 mg, 1.770 mmol, 1.0 eq) in methanol (10 mL) and water (1 mL) was added silver hexafluoroantimonate (121.63 mg, 0.354 mmol, 0.2 eq) at room temperature. The resulting mixture was stirred at 75 °C overnight. After the reaction was completed, the reaction was cooled to room temperature. Diluted with water (30 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic phase was washed with saturated brine (60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was isolated by reverse phase preparative chromatography (mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile) to give compound 49 (194.5 mg, yield 40.36%, purity 99.4%) as a gray solid.

[0404] ESI / MS (m / z): 271.0 [M-H]- .

[0405] 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.24 (d, J = 2.2 Hz, 1H), 8.22 (d, J = 1.8 Hz, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.37 (d, J = 1.8 Hz, 1H), 3.48 (t, J = 7.1 Hz, 2H), 2.94 (t, J = 7.1 Hz, 2H), 2.14 (s, 3H).

[0406] Example 50: Preparation of 3-oxo-N-(4-(trifluoromethyl)phenyl)butane-1- sulfonamide (50)

[0407] Compound 50 was prepared in the same manner as the preparation of Example 48, except that 4-trifluoromethylaniline 46a was used instead of 4-fluoroaniline 2a.

[0408] ESI / MS (m / z): 293.85. [M-H] - .

[0409] 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 3.37 (t, J = 7.1 Hz, 2H), 2.89 (t, J = 7.1 Hz, 2H), 2.11 (s, 3H).

[0410] Example 51: Preparation of 1-acetyl-N-(4-nitrophenyl)pyrrolidine-3-carboxamide (51)

[0411] Step 1: Preparation of tert-butyl 3-((4-nitrophenyl)carbamoyl)pyrrolidine-1- carboxylate (51b)

[0412] To a solution of 1-(tert-butylcarbonyl)-pyrrolidine-3-carboxylic acid 51a (1 g, 4.646 mmol, 1.0 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.65 g, 6.969 mmol, 1.5 eq) in N,N-dimethylformamide (20 mL) was added N,N-diisopropylethylamine (1.80 g, 13.938 mmol, 3.0 eq) at room temperature. The reaction was stirred at room temperature for 10 min. To the above solution was added p-nitroaniline 45b (770.04 mg, 5.575 mmol, 1.2 eq) at room temperature. The reaction was continued at room temperature for 2 h. The reaction was quenched with water. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was isolated by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to give compound 51b (800 mg, 51.35% yield, 99% purity) as a white solid.

[0413] MS (ESI) M / Z: 336.0 [M+H] + .

[0414] Step 2: Preparation of N-(4-nitrophenyl)pyrrolidine-3-carboxamide (51b)

[0415] To a solution of compound 51b (500 mg, 1.476 mmol, 1.0 eq) in dichloromethane (20 mL) was added trifluoroacetic acid (4 mL) at room temperature. The reaction was stirred at room temperature for 1 h. The reaction was directly concentrated to give crude compound 51b (500 mg) as a light yellow oil. The crude was used directly in the next step without purification.

[0416] MS (ESI) M / Z: 236.0 [M+H] + .

[0417] Step 3: Preparation of 1-acetyl-N-(4-nitrophenyl)pyrrolidine-3-carboxamide (51)

[0418] To a solution of compound 51b (500 mg, 2.125 mmol, 1.0 eq) and triethylamine (2150.82 mg, 21.250 mmol, 10.0 eq) in dichloromethane (10 mL) was added acetyl chloride (181.36 μL, 2.550 mmol, 1.2 eq) slowly at room temperature. The reaction was stirred at room temperature for 1 h, quenched with water. The reaction mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phase was washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude was separated by reverse phase chromatography (mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile) to afford compound 51 as a white solid (176.5 mg, yield 29.95%, purity 98.6%).

[0419] MS (ESI) M / Z: 278.1 [M+H] + .

[0420] 1 H NMR (400 MHz, DMSO-d6) δ 10.75 - 10.60 (m, 1H), 8.26 - 8.19 (m, 2H), 7.89 - 7.83 (m, 2H), 3.76 - 3.54 (m, 2H), 3.52 - 3.30 (m, 2H), 3.30 - 3.14 (m, 1H), 2.28 - 1.98 (m, 2H), 2.00 - 1.90 (m, 3H).

[0421] Example 52: Preparation of 6-fluoro-N-(4-(trifluoromethyl)phenyl)nicotinamide (52)

[0422] Step 1: Preparation of 6-fluoronicotinoyl chloride (52b)

[0423] To a solution of 6-fluoronicotinic acid 52a (300 mg, 2.13 mmol), DMF (15.53 mg, 0.21 mmol) in DCM (5 mL) was purged with nitrogen for three times and stirred at 0 °C for 10 min. Oxalyl chloride (541 mg, 4.26 mmol) was added to the reaction mixture, which was stirred at 25 °C for 1 h, then concentrated under reduced pressure to give compound 52b (300 mg, yellow solid, 79.72%) which was used directly for the next step.

[0424] Step 2: Preparation of 6-fluoro-N-(4-(trifluoromethyl)phenyl)nicotinamide (52)

[0425] Compound 52b (364.53 mg, 2.26 mmol), Et3N (677.89 mg, 5.24 mmol) were dissolved in DCM (5 mL) and stirred at 0 °C for 10 min. Compound 46b (300 mg, 1.89 mmol) was added, and the reaction was stirred at room temperature for 3 h. Water (20 mL) was added to the reaction, and DCM (20 mL x 3) was used to extract the organic phase. The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2S04, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether and ethyl acetate (5:1, by volume) as the eluent to give compound 52 (120 mg, colorless solid, 20.12%).

[0426] MS (ESI) m / z: 285.1 [M+H] + .

[0427] 1 HNMR (400MHz, DMSO) δ 10.49 (s, 1H), 8.81 (d, J = 2.4 Hz, 1H), 8.49 (td, J = 8.3, 2.5 Hz, 1H), 7.79-7.74 (m, 2H), 7.37 (dd, J = 8.6, 2.6 Hz, 1H), 7.25-7.19 (m, 2H).

[0428] Example 53: Preparation of 6-fluoro-N-(4-nitrophenyl)nicotinamide (53)

[0429] Compound 52a (400 mg, 2.83 mmol), compound 45b (490 mg, 3.40 mmol), DMAP (35 mg, 0.28 mmol) were dissolved in DCM (5 mL), and the reaction was replaced with nitrogen three times. The reaction was cooled to 0 °C, and triethylamine (861 mg, 8.50 mmol) and EDCI (1.09 g, 5.67 mmol) were added to the reaction. The reaction was stirred at 25 °C for 16 h, water (20 mL) was added to the reaction, and DCM (20 mL x 3) was used to extract the organic phase. The combined organic phase was washed with saturated NaCl solution, dried over anhydrous Na2S04, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether and ethyl acetate (5:1, by volume) as the eluent to give compound 53 (130 mg, colorless solid, 15.80%).

[0430] MS (ESI) m / z: 262.1 [M+H] + .

[0431] 1HNMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.85 (d, J = 2.5 Hz, 1H), 8.53 (td, J = 8.2, 2.6 Hz, 1H), 8.30 (m, 2H), 8.04 (m, 2H), 7.41 (dd, J = 8.6, 2.6 Hz, 1H).

[0432] Example 54: Preparation of 4-acetyl-N-(4-nitrophenyl)benzamide (54)

[0433] Compound 33a (500 mg, 3.05 mmol), compound 45b (505 mg, 3.65 mmol), DMAP (37 mg, 0.30 mmol) were dissolved in DCM (8 mL) and replaced with nitrogen for three times. The reaction was cooled to 0 °C, and triethylamine (925 mg, 9.14 mmol) and EDCI (1.17 g, 6.09 mmol) were added to the reaction. The reaction was stirred at 25 °C for 16 hours. Water (20 mL) was added to the reaction, and DCM (20 mL x 3) was used for extraction. 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 of petroleum ether and ethyl acetate (V / V = 5:1) to obtain compound 54 (160.90 mg, colorless solid, 16.72%).

[0434] MS (ESI) m / z: 285.1 [M+H] + .

[0435] 1 HNMR (400 MHz, DMSO) δ 10.96 (s, 1H), 8.30-8.28 (m, 2H), 8.15-8.07 (m, 6H), 2.66 (s, 3H).

[0436] Example 55: Preparation of 4-fluoro-N-(3-oxobutyl)benzamide (55)

[0437] Step 1: Preparation of 4-fluoro-N-(2-(2-methyl-1,3-dioxolan-2-yl)ethyl)benzamide (55b)

[0438] A solution of 4-fluorobenzoic acid (0.50 g, 3.569 mmol, 1.0 eq), triethylamine (1.08 g, 10.707 mmol, 3.0 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.04 g, 5.354 mmol, 1.5 eq) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min. Then 2-(2-methyl-1,3-dioxolan-2-yl)ethan-1-amine (0.56 g, 4.283 mmol, 1.2 eq) was added and the resulting mixture was stirred at room temperature for 2 h. After completion of the reaction, it was diluted with water (100 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get compound 55b (1.5 g, crude) as a light yellow solid which was used directly for the next step.

[0439] ESI / MS (m / z): 254.10 [M+H] + .

[0440] Step 2: Preparation of 4-fluoro-N-(3-oxobutyl)benzamide (55)

[0441] To compound 55b (700.0 mg, 2.764 mmol, 1.0 eq) was added hydrochloric acid (8.0 mL, 2M in water) and tetrahydrofuran (4.0 mL) at room temperature and stirred for 2 h at room temperature. The reaction was concentrated under reduced pressure. The resulting residue was separated by reverse phase preparative chromatography (mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile) to get compound 55 (184.4 mg, yield 31.89%, purity 98.9%) as a grey solid.

[0442] ESI / MS (m / z): 210.10 [M+H] + .

[0443] 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (t, J = 5.3 Hz, 1H), 7.95 - 7.82 (m, 2H), 7.36 - 7.22 (m, 2H), 3.49 - 3.36 (m, 2H), 2.73 (t, J = 6.9 Hz, 2H), 2.12 (s, 3H).

[0444] 19 F NMR (377 MHz, DMSO-d6) δ -109.67.

[0445] Example 56: Preparation of 4-nitro-N-(3-oxobutyl)benzamide (56)

[0446] The preparation method of Example 55, except that 4-nitrobenzoic acid is used instead of 4-fluorobenzoic acid, to obtain compound 56.

[0447] ESI / MS (m / z): 235.05 [M-H] - .

[0448] 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (t, J = 5.5 Hz, 1H), 8.35 - 8.27 (m, 2H), 8.09 - 8.01 (m, 2H), 3.47 (td, J = 6.8, 5.3 Hz, 2H), 2.76 (t, J = 6.8 Hz, 2H), 2.13 (s, 3H).

[0449] Example 57: Preparation of N-(3-oxobutyl)-4-(trifluoromethyl)benzamide (57)

[0450] The preparation method of Example 55, except that 4-nitrobenzoic acid is used instead of 4-fluorobenzoic acid, to obtain compound 56.

[0451] MS (ESI) M / Z: 260.10 [M+H] + .

[0452] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 5.5 Hz, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H), 3.46 (td, J = 6.8, 5.4 Hz, 2H), 2.74 (t, J = 6.9 Hz, 2H), 2.13 (s, 3H).

[0453] 19 F NMR (377 MHz, DMSO-d6) δ -61.29.

[0454] Example 58: Preparation of 1-acetyl-N-(4-fluorophenyl)pyrrolidine-3-carboxamide (58)

[0455] The preparation method of Example 51, except that compound 2a is used instead of compound 45b, to obtain compound 58.

[0456] MS (ESI) M / Z: 251.1 [M+H] + .

[0457] 1H NMR (400 MHz, DMSO-d6) δ 10.12 (d, J = 10.5 Hz, 1H), 7.67 - 7.57 (m, 2H), 7.20 - 7.09 (m, 2H), 3.74 - 3.53 (m, 2H), 3.52 - 3.25 (m, 2H), 3.24 - 3.03 (m, 1H), 2.23 - 1.97 (m, 2H), 1.95 (d, J = 3.9 Hz, 3H).

[0458] 19 F NMR (377 MHz, DMSO-d6) δ -60.361.

[0459] Example 59: Preparation of l-acetyl-N-(4-(trifluoromethyl)phenyl)pyrrolidine-3- carboxamide (59)

[0460] Compound 59 was prepared in the same manner as in the preparation of Example 51, except that compound 46a was used instead of compound 45b.

[0461] MS (ESI) m / z: 301.1 [M+H] + .

[0462] 1 H NMR (400 MHz, DMSO-d6) δ 10.55 - 10.40 (m, 1H), 7.87 - 7.79 (m, 2H), 7.72 - 7.62 (m, 2H), 3.75 - 3.55 (m, 2H), 3.52 - 3.29 (m, 2H), 3.28 - 3.12 (m, 1H), 2.27 - 1.98 (m, 2H), 1.96 (d, J = 4.5 Hz, 3H).

[0463] 19 F NMR (377 MHz, DMSO-d6) δ -60.361.

[0464] Example 60: Preparation of 6-fluoro-N-(4-fluorophenyl)nicotinamide (60)

[0465] Compound 60 was prepared in the same manner as in the preparation of Example 53, except that compound 2a was used instead of compound 45b.

[0466] MS (ESI) m / z: 301.1 [M+H] + .

[0467] 1H NMR (400 MHz, DMSO) δ 10.77 (s, 1H), 8.84 (d, J = 2.5 Hz, 1H), 8.52 (td, J = 8.3, 2.6 Hz, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.76 (d, J = 8.6 Hz, 2H), 7.40 (dd, J = 8.6, 2.6 Hz, 1H).

[0468] Example 61: Preparation of 2,2-dimethyl-3-(methylsulfonyl)-N-(4- (trifluoromethyl)phenyl)propanamide (61)

[0469] Compound 46a (219.55 mg, 1.36 mmol) and potassium carbonate (630.24 mg, 4.56 mmol) were dissolved in acetonitrile (5 mL), replaced with nitrogen for three times, stirred at 0 °C for 10 min. Compound 61a (300 mg, 1.52 mmol) was added into the reaction solution, stirred at room temperature for 16 h. Water (20 mL) was added into the reaction solution, extracted with EA (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. Purification was performed by Prep-HPLC (Gemini-C18 150 x 21.2 mm, 5 um, flow rate: 20 ml / min; wavelength: 214 nm, mobile phase: ACN-H2O (0.1% TFA) = 40:60-95:5) to obtain compound 61 (107.25 mg, colorless solid, 21.84%).

[0470] MS (ESI) m / z: 324.1 [M+H] + .

[0471] 1 H NMR (400 MHz, DMSO) δ 9.60 (s, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 3.65 (s, 2H), 2.98 (s, 3H), 1.42 (s, 6H).

[0472] Biological tests

[0473] Test Example 1: Effect of the compound of the present application on asymmetric division of skeletal muscle stem cells

[0474] Male C57BL / 6 mice (purchased from Janvier) at 8 weeks of age were sacrificed by cervical dislocation, and the extensor digitorum longus muscle was 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 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 muscle was incubated in an incubator (37°C, 5% CO2) for 60 minutes. Single muscle fibers were picked under a stereomicroscope.

[0475] The picked single muscle fibers were cultured in DMEM medium (Gibico) containing 10% fetal bovine serum (Ausbian), 1% penicillin (Biotopped), and 1% streptomycin (Amresco). Meanwhile, 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 the solution through a 0.22 μm filter to remove bacteria, and aliquoting the solution, which was stored at 4°C. After the compound was treated for 42 hours, Pax7 immunofluorescence staining was performed. The proportion of asymmetric division of skeletal muscle stem cells was counted, and the proportion of asymmetric division of the compound-treated group was subtracted from the proportion of asymmetric division of the DMSO control group to obtain the pharmacodynamic evaluation index.

[0476] Table 1 below shows the pharmacodynamic evaluation results of the compound of the present application in promoting asymmetric division of skeletal muscle stem cells.

[0477] Table 1, pharmacodynamic evaluation of the compound of the present application in promoting asymmetric division of skeletal muscle stem cells

[0478] Conclusion: As shown in Table 1 above, the compound of the present application can promote asymmetric division of skeletal muscle stem cells.

[0479] Test Example 2: Effect of the compound of the present application on lipid droplet formation in adipocytes

[0480] In this test, primary adipocytes isolated and cultured from subcutaneous adipose tissue were used to detect the effect of the compound of the present application on lipid synthesis and lipid droplet formation.

[0481] 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 dissected. 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 deionized water, pH adjusted to 7.4) and minced. Freshly prepared digestion solution (DMEM / F-12 (1:1) (Gibico) medium containing 1 mg / mL collagenase I (Gibico)) was added and the tissue was digested 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% fetal bovine 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.

[0482] For compound treatment, 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 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 as the induction of differentiation (i.e. when the medium was changed to differentiation medium II), different concentrations of the compounds of the application were added and DMSO buffer was used as a control.

[0483] Respectively in the treatment of 1 day, end culture, using Bodipy (Life technology, D3922) staining lipid droplets. Bodipy is a green fluorescent labeled liposoluble dye, after cell culture, according to 1:1000 ratio added to the culture medium, 20 minutes after using fluorescence microscope observation has been Bodipy (Life technology, D3922) stained lipid droplets. Using PE high content imaging system (OperettaCLS, PerkinElmer) imaging and quantification of lipid droplets area. The ratio of lipid droplet area of compound treatment group and control group lipid droplet area as the evaluation effect of compound.

[0484] The following table 2 is the effect of the compound of the present application on adipocyte lipid droplet formation.

[0485] Table 2, the pharmacodynamic evaluation of the compound of the present application on adipocyte lipid droplet formation

[0486] Conclusion: as shown in the above table 2, after the treatment of the compound of the present application, compared with the control group, the area of lipid droplet is significantly reduced, which shows that the compound of the present application can significantly inhibit the formation of lipid droplet in the differentiation process of primary adipocyte.

[0487] References

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Claims

1. A compound of general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: X1, X2, X3, X4, X5are each independently selected from CH or N; L1is selected from 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-, R 3 selected from hydrogen and C 1-6 alkyl; R 1 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 2 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. n is an integer from 0 to 4.

2. The compound of formula (I) according to claim 1, which is a compound of formula (II) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, R 4a and R 4b are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; t is an integer from 1 to 10, preferably an integer from 1 to 6, more preferably an integer from 1 to 4; X1to X5, R 1 , R 2 , L1, 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: Y1, Y2, Y3, Y4, Y5are each independently selected from CH or N; Each R 5 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; X1to X5, R 1 , R 2 , L1, L3, n are as defined in claim 1.

4. The compound of formula (I) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to claim 3, which is a compound of formula (IVA) or (IVB) or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y1to Y5, R 5 , m, X1to X5, R 1 , R 2 , L1, L3, n are as defined in claim 3.

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: Ring A is a saturated or partially saturated C 3-6 cycloalkyl, saturated or partially saturated 4- to 6-membered heterocyclyl; 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. v is 0, 1 or 2. X1to X5, R 1 , R 2 , L1, L3, n are as defined in claim 1.

6. The compound according to claim 5, wherein ring A is selected from pyrrolidinyl, piperidinyl, piperazinyl, dihydropyridinyl, tetrahydropyridinyl, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 5, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (VI), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein: s1and s2are each independently 0 or 1; X1to X5, R 1 , R 2 , L1, L3, R 6 , v, n are as defined in claim 5.

8. 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 7, wherein, L1is selected from 9. The compound according to any one of claims 1 to 8, wherein L3is selected from -C(O)-, -S(O)-, -S(O)2-, R 3 selected from hydrogen and C 1-6 alkyl; R 1 selected from C 1-6 alkyl.

10. The compound according to any one of claims 1 to 8, wherein L3is selected from a bond; R 3 selected from hydrogen and C 1-6 alkyl; R 1 selected from halogen, C 1-6 alkyl.

11. 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 10, wherein, X1, X2, X3, X4, X5are each CH, or one of X1, X2, X3, X4, X5is N and the others are CH; or two of X1, X2, X3, X4, X5are N and the others are CH; preferably, X1, X2, X3, X4, X5are each CH.

12. The compound of claim 3, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, Y1, Y2, Y3, Y4, Y5are each CH, or one of Y1, Y2, Y3, Y4, Y5is N and the others are CH; or two of Y1, Y2, Y3, Y4, Y5are N and the others are CH; preferably, Y1, Y2, Y3, Y4, Y5are each CH, or Y4is N and Y1, Y2, Y3, Y5are CH, or Y3is N and Y1, Y2, Y4, Y5are CH.

13. The compound of claim 4, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein In general formula (IVA), Y3or Y4is N and the others are CH; In general formula (IVB), Y3or Y5is N and the others are CH.

14. 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 13, wherein, Each R 2 Each is independently selected from hydrogen, halogen, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups; n is an integer from 0 to 4, preferably an integer from 0 to 3.

15. The compound of claim 3 or 4, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, Each R 5 Each is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups; m is 0, 1 or 2, preferably 0 or 1.

16. The compound of any one of claims 5 to 7, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, Each R 6 Each is independently selected from hydrogen, oxo group, C 1-6 alkyl; v is 0, 1 or 2.

17. A compound of general formula (I) as defined in any one of claims 1 to 16, or a tautomer, meso, racemic, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

18. 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 16, wherein the compound is selected from:

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. A health care composition comprising a compound according to any one of claims 1 to 18, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. Use of a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19, 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.

22. Use of a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, or a health care composition according to claim 20, 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.

23. The use according to claim 21 or 22, wherein the muscle atrophy related diseases include myogenic muscle atrophy such as progressive muscular dystrophy, polymyositis, atrophic scleroderma, secretory myopathy, disuse muscle atrophy, senile muscle atrophy, neurogenic muscle atrophy.

24. The use according to claim 23, 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).

25. The use according to claim 23, wherein the neurogenic muscle atrophy includes amyotrophic lateral sclerosis (ALS), Hirayama disease, spinal muscular atrophy, peroneal muscular atrophy, myasthenia gravis (MG).

26. The use according to claim 21 or 22, wherein the cardiovascular and cerebrovascular diseases 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.

27. The use according to claim 21 or 22, wherein the metabolic diseases are diabetes, hypertension, hyperlipidemia, hyperglycemia.

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