Compound of thyroid hormone β receptor agonist and use thereof

Abstract

Disclosed in the present invention is a thyroid hormone β receptor agonist, which is a compound having a structure represented by formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Description

A compound of a thyroid hormone beta receptor agonist and application thereof TECHNICAL FIELD

[0001] The present application relates to the field of chemical pharmacy, in particular to a compound of a thyroid hormone beta receptor agonist and application thereof. BACKGROUND

[0002] Thyroid hormones affect almost all organs, especially the liver, and a large number of studies have shown that thyroid hormones may be crucial for the treatment of NAFLD or NASH. Thyroid hormones mainly include T4 and T3, which are maintained in balance in the body through the hypothalamic-pituitary-thyroid (H-P-T) axis. T4 can be converted to active T3, and T3 and reverse T3 (rT3) can be further converted to maintain balance. Thyroid hormone receptors (THR) are important members of the nuclear receptor superfamily, mainly responsible for mediating the role of T3 in the body. Thyroid hormone alpha 1, beta 1 and beta 2 are different subtypes of thyroid hormone receptors, which play their own unique physiological roles in the human body. Thyroid hormone alpha 1 receptor (THR alpha 1) is mainly expressed in the brain, heart and skeletal muscle, and after binding to T3, it can regulate the metabolism and function of these tissues; in the heart, THR alpha 1 may be involved in the regulation of myocardial contraction and relaxation, affecting the efficiency of heart pumping; in the brain and skeletal muscle, THR alpha 1 may be involved in nerve conduction and muscle contraction, affecting the function of the neuromuscular system. Thyroid hormone beta 1 receptor (THR beta 1) is mainly expressed in the brain, liver and kidney, and after binding to T3, it regulates the metabolism and function of these tissues. In the liver, THR beta 1 may be involved in the metabolism of cholesterol, protein and sugar, affecting blood lipid and blood sugar levels; in the brain, THR beta 1 may be involved in the synthesis and release of neurotransmitters, affecting cognitive and emotional functions. Thyroid hormone beta 2 receptor (THR beta 2) is mainly expressed in the hypothalamus, retina and pituitary, and after binding to T3, it regulates the metabolism and function of these tissues. In general, thyroid hormone alpha 1, beta 1 and beta 2 receptors play different physiological roles in the human body, together maintaining the normal metabolism and function of the body. If we can separate the role of thyroid hormone receptor beta 1 in regulating lipid and sugar metabolism from the potential side effects of other subtypes, we may obtain a new type of powerful drug.

[0003] Thyroid hormone beta receptor (THR beta) agonists are drugs that can mimic the action of thyroid hormone T3, and they can selectively activate THR beta. Compared with natural T3, THR beta agonists may have higher selectivity and specificity, and can more accurately regulate the physiological role of thyroid hormone. In the development of NASH, liver fat accumulation and inflammatory response are two core pathological processes. Therefore, T3 may have an important regulatory effect on these processes through the THR-beta mediated signaling pathway.

[0004] The final goal of this project is to develop new compounds with higher selectivity to THR-β, and to avoid activating the THR-α receptor which mediates the thyroid hormone activity outside the liver (including the heart and bone), without affecting the bone or heart parameters, and without affecting other hormones of the thyroid hormone pathway. The compounds have higher metabolic stability, stronger liver distribution, and more significant pharmacological effects and less side effects in clinical application, which has obvious advantages to meet the clinical drug requirements. SUMMARY

[0005] The present application provides a thyroid hormone β receptor agonist, which is a compound shown in the structure of formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof:

[0006] wherein,

[0007] X1 is selected from CH2, O, S, or a single bond;

[0008] R is selected from H, F, Cl, Br, I, OH, NH2, CN, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl or C 3-8 epoxyalkyl;

[0009] a is 0, 1, 2, 3 or 4, when a is 2, R is the same or different, when a is 3 or 4, R is the same, partially the same or completely different;

[0010] L1 is selected from

[0011] wherein, A1, A2 rings are each independently selected from:

[0012] L4 is selected from: -C(=O)-, -C 1-6 alkylene-, -C(=O)-C 1-6 alkylene-, wherein the alkylene can be partially or completely substituted by one or more groups independently selected from halogen, cyano, nitro, hydroxyl, amino, -C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 3-6 epoxyalkyl; X2, X3, X4 are each independently selected from CH2, O, S, NH or H; and when a is 3, X3 is not NH;

[0013] R3, R 41 , R 51 , R 52 each independently selected from the group consisting of: H, cyano, amino, hydroxyl, -C(=0)NH2, -C(=0)CH3, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 epoxyalkyl, said alkyl, alkoxy, cycloalkyl, epoxyalkyl being optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy;

[0014] R6is selected from the group consisting of: H, -COOH, -C(=0)NH2, -C(=0)CH3or

[0015] L2is independently selected from:

[0016] represents a double or single bond;

[0017] n is 0, 1, 2, 3, 4, 5, preferably when n is 2, R a1 are the same or different, when n is 3 or 4, R a1 are the same, partially the same or completely different;

[0018] k is 0, 1, 2, preferably when k is 2, R c3 or R c4 are the same or different;

[0019] t is 0, 1, 2, 3, 4, preferably when t is 2, R b5 , R b6 , R c5 or R c6 are the same or different, when t is 3 or 4, R b5 , R b6 , R c5 or R c6 are the same, partially the same or completely different;

[0020] i is 0, 1, 2, 3, 4; preferably when i is 2, R b3 or R b4 are the same or different, when i is 3 or 4, R b3 or R b4 are the same, partially the same or completely different;

[0021] A3, A4, A5, A6may each independently be selected from the group consisting of: C, N;

[0022] X5, X6, X7, X8may each independently be selected from: C, N or a single or double bond; and when X8is a single bond, R a2 is not carbonyl;

[0023] G1and G2are each independently selected from: -CH2-, -CH(R d1 )-, -CR e R d2 -, -C(=O)-, -NH-, -N(R f )-, -S(=O)(=O)-;

[0024] G3is selected from: -CH2-, -CH(R d1 )-, -CR e R d2 -, -C(=O)-, -NH-, -N(R f )-, -S(=O)(=O)-, -C(R t R v )-;

[0025] G4is selected from: a single bond, -CH2-, -CH(R d1 )-, -CR e R d2 -, -C(=O)-, -NH-, -N(R f )-, -S(=O)(=O)-, -C(R i R j )-, -C(=CH2)-;

[0026] R a1 , R a2 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R d1 , R d2 , R e are each independently selected from: H, halogen, -C(=O)-C 1-6 alkyl, hydroxyl, cyano, amino, -S(=O)(=O)-C 1-6 alkyl, -C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(CH2)m -aryl or -(CH2) m - heteroaryl, m is 0, 1, 2, 3, 4 or 5; wherein any two adjacent R b3 may be C 3-8 carbocyclic, C 3-8 carbocyclic, C 4-9 spirocyclic, phenyl, C 5-6 heteroaromatic, the heteroaromatic can be: spirocyclic can be: the carbocyclic, phenyl, C 5-6 heteroaromatic or spirocyclic can be substituted with any one or more R n ;

[0027] wherein when R e , R d2 are each C 1-6 alkyl, they can be joined to form a C 3-6 carbocyclic ring, which can be substituted with any one or more halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;

[0028] R f is selected from the group consisting of: H, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, -(CH2) m -aryl, -(CH2) m -heteroaryl or -S(=O)(=O)-C 1-6 alkyl, wherein m is 1, 2, 3, 4, 5, 6, the alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, heteroaryl can be substituted with any one or more R n ;

[0029] wherein, R n are each independently selected from the group consisting of: H, halogen, hydroxyl, cyano, amino, -S(=O)(=O)-C 1-6 alkyl, -C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(CH2) i -aryl or -(CH2) i -heteroaryl, i is 0, 1, 2, 3, 4 or 5;

[0030] when G3and G4are -N(R f )-, -C(Rt R v )-、-C(R i R j When )-, R f R t R v R i R j Each is independently selected from H, halogen, hydroxyl, cyano, amino, carboxyl, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 3-6 Epoxyalkyl, wherein the alkyl, alkoxy, cycloalkyl and epoxyalkyl can be any one or more halogens, C 1-6 Alkyl-substituted; wherein the R on G3 f R t Or R v It can interact with the R on the adjacent G4 atom i Or R j Formation C 3-8 Carbon ring, C 4-9 Spirocyclic rings and benzene rings; spirocyclic rings can be: The carbon ring or spiro ring can be any one or more R n Replaced;

[0031] R 61 R 71 R 72 R 73 Each is independently selected from: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 3-6 Epoxyalkyl, aryl, or aromatic heteroalkyl; the alkyl or alkoxy group may be one or more independently selected from halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or C 3-6 The cycloalkyl group is replaced by an epoxy alkyl group; the cycloalkyl, epoxy alkyl, aryl, or aromatic heteroyl group may be one or more independently selected from halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0032] This invention provides a thyroid hormone β-receptor agonist, which is a compound with the structure shown in formula (II), its optical isomer, or a pharmaceutically acceptable salt thereof:

[0033] in,

[0034] X1 can be independently selected from CH2, O, S, or a single bond;

[0035] R1, R2are each independently selected from the group consisting of: H, F, Cl, Br, I, OH, NH2, CN, NO2, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl or C 3-8 epoxyalkyl;

[0036] L1is selected from

[0037] wherein A1, A2rings are each independently selected from the group consisting of:

[0038] L4is selected from: -C(=O)-, -C 1-6 alkylene-, -C(=O)-C 1-6 alkylene-, wherein alkylene can be partially or totally substituted by one or more groups independently selected from halogen, cyano, nitro, hydroxyl, amino, -C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 3-6 epoxyalkyl;

[0039] X2, X3, X4are each independently selected from: CH2, O, S, NH or H;

[0040] R3, R 41 , R 51 , R 52 are each independently selected from: H, cyano, amino, hydroxyl, -C(=O)NH2, -C(=O)CH3, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 epoxyalkyl, said alkyl, alkoxy, cycloalkyl, epoxyalkyl can be substituted by one or more groups independently selected from halogen, cyano, nitro, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy;

[0041] R6is selected from: H, -COOH, -C(=O)NH2, -C(=O)CH3or

[0042] L2is independently selected from:

[0043] denotes a double or single bond;

[0044] n is 0, 1, 2, 3, 4, 5, preferably when n is 2, R a1 identical or different, when n is 3 or 4, R a1 identical, partially identical or completely different;

[0045] k is 0, 1, 2, preferably when k is 2, R c3 or R c4 identical or different;

[0046] t is 0, 1, 2, 3, 4, preferably when t is 2, R b5 , R b6 , R c5 or R c6 identical or different, when t is 3 or 4, R b5 , R b6 , R c5 or R c6 identical, partially identical or completely different;

[0047] i is 0, 1, 2, 3, 4; preferably when i is 2, R b3 or R b4 identical or different, when i is 3 or 4, R b3 or R b4 identical, partially identical or completely different;

[0048] A3, A4, A5, A6may each independently be selected from: C, N;

[0049] X5, X6, X7, X8may each independently be selected from: C, N or a single or double bond; and when X8is a single bond, R a2 is not a carbonyl group;

[0050] G1and G2are each independently selected from: -CH2-, -CH(R d1 )-, -CR e R d2 -, -C(=O)-, -N(R f )-, -S(=O)(=O)-;

[0051] G3is selected from: -CH2-, -CH(R d1 )-, -CR e R d2 -, -C(=O)-, -NH-, -N(R f )-, -S(=O)(=O)-, -C(R t R v )-;

[0052] G4is selected from: a single bond, -CH2-, -CH(Rd1 )-, -CR e R d2 -, -C(=O)-, -NH-, -N(R f )-, -S(=O)(=O)-, -C(R i R j )-, -C(=CH2)-;

[0053] R a1 , R a2 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R d1 , R d2 , R e each independently selected from the group consisting of: H, halogen, -C(=O)-C 1-6 alkyl, hydroxy, cyano, amino, -S(=O)(=O)-C 1-6 alkyl, -C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(CH2) m -aryl or -(CH2) m -arylhetero, m is 0, 1, 2, 3, 4 or 5; wherein any two adjacent R b3 may be C 3-8 carbocyclic, C 3-8 carbocyclic, C 4-9 spirocyclic, phenyl ring, C 5-6 aromatic heterocyclic ring, the aromatic heterocyclic ring can be: spirocyclic can be: the carbocyclic ring, phenyl ring, C 5-6 aromatic heterocyclic ring or spirocyclic ring can be substituted with any one or more R n ;

[0054] wherein when R e , R d2 are each C 1-6 alkyl, they can be linked to form a C 3-6 carbocyclic ring, the carbocyclic ring can be substituted with any one or more halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6 alkoxy or C1-6 Substituted with haloalkoxy groups;

[0055] R f Selected from: H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 3-6 Epoxyalkyl, -(CH2) m -Aryl, -(CH2) m -Aromaticyl or -S(=O)(=O)-C 1-6 Alkyl group, wherein m is 1, 2, 3, 4, 5, or 6, and the alkyl, alkoxy, cycloalkyl, epoxyalkyl, aryl, or aromatic heteroyl group may be any one or more R groups. n Replaced;

[0056] Among them, R n Each group is independently selected from: H, halogen, hydroxyl, cyano, amino, -S(=O)(=O)-C 1-6 Alkyl, -C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -(CH2) m -aryl or -(CH2) m -Aromatic hexyl group, where m is 0, 1, 2, 3, 4 or 5;

[0057] When G3 and G4 are respectively -N(R) f )-、-C(R t R v )-、-C(R i R j When )-, R f R t R v R i R j Each is independently selected from H, halogen, hydroxyl, cyano, amino, carboxyl, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 3-6 Epoxyalkyl, wherein the alkyl, alkoxy, cycloalkyl and epoxyalkyl can be any one or more halogens, C 1-6 Alkyl-substituted; wherein the R on G3 f R t or R v It can interact with the R on the adjacent G4 atom i or R j Formation C 3-8 Carbon ring, C 4-9 Spirocyclic rings and benzene rings; spirocyclic rings can be: The carbocyclic or spiro ring can be optionally substituted by one or more R n substituted;

[0058] R 61 , R 71 , R 72 , R 73 each independently selected from: C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 epoxyalkyl, aryl or heteroaryl; said alkyl or alkoxy can be substituted by one or more independently selected from halogen, cyano, nitro, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 3-6 epoxyalkyl; said cycloalkyl, epoxyalkyl, aryl or heteroaryl can be substituted by one or more independently selected from halogen, cyano, nitro, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy.

[0059] The present application provides a thyroid hormone beta receptor agonist which is a compound of the formula (III):

[0060] wherein,

[0061] X1may be independently selected from CH2, O, S, or a single bond;

[0062] R is selected from: H, F, Cl, Br, I, OH, NH2, CN, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl or C 3-8 epoxyalkyl;

[0063] a is 0, 1, 2, 3 or 4, when a is 2, R is the same or different, when a is 3 or 4, R is the same, partially the same or completely different;

[0064] L1is selected from

[0065] wherein, A1, A2rings are each independently selected from:

[0066] L4is selected from: -C(=O)-, -C 1-6alkylene-, -C(=O)-C 1-6 alkylene-, wherein alkylene can be partially or totally substituted by one or more groups independently selected from halogen, cyano, nitro, hydroxy, amino, -C(=O)NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 3-6 epoxyalkyl;

[0067] X2, X3, X4are each independently selected from CH2, O, S, NH or H; and when a is 3, X3is not NH;

[0068] R3, R 41 , R 51 , R 52 are each independently selected from H, cyano, amino, hydroxy, -C(=O)NH2, -C(=O)CH3, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 epoxyalkyl, said alkyl, alkoxy, cycloalkyl, epoxyalkyl can be substituted by one or more groups independently selected from halogen, cyano, nitro, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy;

[0069] R6is selected from H, -COOH, -C(=O)NH2, -C(=O)CH3or

[0070] G3is selected from -CH2-, -CH(R d1 )-, -CR e R d2 -, -C(=O)-, -NH-, -N(R f )-, -S(=O)(=O)-, -C(R t R v )-;

[0071] G4is selected from a single bond, -CH2-, -CH(R d1 )-, -CR e R d2 -, -C(=O)-, -NH-, -N(R f )-, -S(=O)(=O)-, -C(R i R j )-, -C(=CH2)-;

[0072] R a1 , R d1 , R d2 , R eeach independently selected from the group consisting of: H, halogen, -C(=O)-C 1-6 alkyl, hydroxy, cyano, amino, -S(=O)(=O)-C 1-6 alkyl, -C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(CH2) m -aryl or -(CH2) m -arylhetero, m is 0, 1, 2, 3, 4 or 5;

[0073] wherein when R e , R d2 are each C 1-6 alkyl, they can be linked to form a C 3-6 carbocyclic ring, which can be substituted with any one or more of halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;

[0074] R f is selected from the group consisting of: H, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, -(CH2) i -aryl, -(CH2) i -arylhetero or -S(=O)(=O)-C 1-6 alkyl, wherein i is 1, 2, 3, 4, 5, 6, said alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, arylhetero can be substituted with any one or more of R n ;

[0075] wherein, R n is each independently selected from the group consisting of: H, halogen, hydroxy, cyano, amino, -S(=O)(=O)-C 1-6 alkyl, -C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(CH2) i -aryl or -(CH2) i -arylhetero, i is 0, 1, 2, 3, 4 or 5;

[0076] when G3and G4are each -N(R f )-, -C(R t R v )-, -C(R iR j )-time, R f , R t , R v , R i , R j each independently is selected from H, halogen, hydroxyl, cyano, amino, carboxyl or C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 epoxyalkyl, which alkyl, alkoxy, cycloalkyl and epoxyalkyl can be substituted with any one or more halogen, C 1-6 alkyl; wherein R f , R t or R v on G3 can form with R i or R j on the adjacent G4 atom a C 3-8 carbocyclic ring, C 4-9 spirocyclic ring, which spirocyclic ring can be: which carbocyclic or spirocyclic ring can be substituted with any one or more R n .

[0077] The present application also provides a thyroid hormone beta receptor agonist which is a compound of the formula (IV):

[0078] wherein,

[0079] X1may be independently selected from CH2, O, S, or a single bond;

[0080] R is selected from: H, F, Cl, Br, I, OH, NH2, CN, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl or C 3-8 epoxyalkyl;

[0081] a is 0, 1, 2, 3 or 4, when a is 2, R is the same or different, when a is 3 or 4, R is the same, partially the same or completely different;

[0082] R 41 is selected from: H, cyano, amino, hydroxyl, -C(=O)NH2, -C(=O)CH3, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8Epoxyalkyl, wherein the alkyl, alkoxy, cycloalkyl, or epoxyalkyl group may be selected independently from one or more halogens, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Alkyl substitution;

[0083] G3 is selected from: -CH2-, -CH(R) d1 )-、-CR e R d2 -、-C(=O)-、-NH-、-N(R f -, -S(=O)(=O)-, -C(R) t R v )-;

[0084] G4 is selected from: single bond, -CH2-, -CH(R) d1 )-、-CR e R d2 -、-C(=O)-、-NH-、-N(R f -, -S(=O)(=O)-, -C(R) i R j -, -C(=CH2)-;

[0085] R d1 R d2 R e Each is independently selected from: H, halogens, -C(=O)-C 1-6 Alkyl, hydroxyl, cyano, amino, -S(=O)(=O)-C 1-6 Alkyl, -C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -(CH2) i -aryl or -(CH2) i -Aromatic heterol, where i is 0, 1, 2, 3, 4 or 5;

[0086] Where R e R d2 C 1-6 When alkyl groups are present, they can be linked together to form C10 groups. 3-6 A carbon ring, wherein the carbon ring may be any one or more halogens, -C 1-6 Alkyl, -C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituted with haloalkoxy groups;

[0087] R f Selected from: H, C 1-6 Alkyl, C 1-6 Alkoxy, C3-6 cycloalkyl, C 3-6 Epoxyalkyl, -(CH2) m -Aryl, -(CH2) m -Aromaticyl or -S(=O)(=O)-C 1-6 Alkyl group, wherein m is 1, 2, 3, 4, 5, or 6, and the alkyl, alkoxy, cycloalkyl, epoxyalkyl, aryl, or aromatic heteroyl group may be any one or more R groups. n Replaced;

[0088] Among them, R n Each group is independently selected from: H, halogen, hydroxyl, cyano, amino, -S(=O)(=O)-C 1-6 Alkyl, -C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -(CH2) m -aryl or -(CH2) m -Aromatic hexyl group, where m is 0, 1, 2, 3, 4 or 5;

[0089] When G3 and G4 are respectively -N(R) f )-、-C(R t R v )-、-C(R i R j When )-, R f R t R v R i R j Each is independently selected from H, halogen, hydroxyl, cyano, amino, carboxyl, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 3-6 Epoxyalkyl, wherein the alkyl, alkoxy, cycloalkyl and epoxyalkyl can be any one or more halogens, C 1-6 Alkyl-substituted; wherein the R on G3 f R t or R v It can interact with the R on the adjacent G4 atom i or R j Formation C 3-8 Carbon ring, C 4-9 Spirocyclic rings and benzene rings; spirocyclic rings can be: The carbon ring or spiro ring can be any one or more R n What it replaced.

[0090] In this invention, as one embodiment, in the compound with the structure shown in formula (I) or (II), L2 is: when A3 is C, L1 is when A3 is C, L1 is 41 is not hydrogen.

[0091] In the present application, as one of the embodiments, the above L2 is: when A3 is C, L1 is when A3 is C, L1 is a1 is OH, isopropyl.

[0092] In the present application, as one of the embodiments, the compound of the structure represented by the formula (I) or (II) is: L1 is wherein R6 is not when A3 is C, L1 is

[0093] In the present application, as one of the embodiments, the compound of the structure represented by the formula (I) or (II) is: wherein n is 2, R a1 L1 is wherein X3 is N, L4 is -C(=O)-, A3 is not C.

[0094] In the present application, as one of the embodiments, the compound of the structure represented by the formula (I) or (II) is: b2 L2 is L1 is R 41 R is -CN, R is not hydrogen. 73 is not hydrogen.

[0095] In the present application, as one of the embodiments, the compound of the structure represented by the formula (I) or (II) is: L1 is wherein R 73 Rb2 is not hydrogen or isopropyl, and R is not hydrogen when R is aryl, isopropyl. 73 is not hydrogen.

[0096] In the present application, as one of the embodiments, the compound of the structure represented by the formula (I) or (II) is: L1 is R is not hydrogen, halogen. b2 is not hydrogen, halogen.

[0097] In the present application, as one of the embodiments, the compound of the structure represented by the formula (I) or (II) is: L1 is R41 It should not be NH2, -CH3, or H. Should not be

[0098] In this invention, as one embodiment, in the compound with the structure shown in formula (Ⅰ), L2 is selected from... R 72 For H, R c1 It is an alkyl group, and L1 is... When R is a halogen, R 41 R is difluoromethyl or cyclopropyl or trifluoromethoxy.

[0099] In this invention, as one embodiment, in the compound with the structure shown in formula (Ⅰ), L2 is selected from... L1 is When R is cyclopropyl or trifluoromethoxy, or when R is a halogen, R 41 It is difluoromethyl.

[0100] In this invention, as one embodiment, in the compound with the structure shown in formula (Ⅰ), L2 is selected from... L1 is hour,

[0101] When R is cyclopropyl or trifluoromethoxy, or when R is a halogen, R 41 It is difluoromethyl;

[0102] The Selected from

[0103] In this invention, as one embodiment, in the compound with the structure shown in formula (Ⅰ), L2 is selected from... L1 is When R 41 For H or C 1-3 When R is alkyl, it is cyclopropyl or trifluoromethoxy; or when R is halogen, it is... 41 It is difluoromethyl.

[0104] In this invention, as one embodiment, in the compound with the structure shown in formula (Ⅰ), L2 is selected from... When R c1 When the carbonyl group is in the ortho position, L1 is... The R 41 For H, -CF2, or -CN or R6 is not hour,

[0105] When R is cyclopropyl or trifluoromethoxy, or when R is a halogen, R 41is difluoromethyl; said is selected from

[0106] In the present application, as one of the embodiments, in the compound of the structure represented by formula (I), L2 is selected from L1 is when X1 is O, R 41 is -CN, R is cyclopropyl or trifluoromethoxy, or R is halogen, R 41 is difluoromethyl.

[0107] In the present application, as one of the embodiments, in the compound of the structure represented by formula (I) or (II), L2 is selected from L1 is when X8 is not O, preferably N.

[0108] In the present application, as one of the embodiments, in the compound of the structure represented by formula (I) or (II), L2 is selected from L1 is when R 41 is H or C 1-3 alkyl, L1 is when X8 is not O, preferably N.

[0109] In the present application, as one of the embodiments, in the compound of the structure represented by formula (I) or (II), L2 is selected from L1 is (wherein R 41 is H or -CN) or (wherein R6 is not ), X8 is not O, preferably N.

[0110] In the present application, as one of the embodiments, in the compound of the structure represented by formula (I) or (II), L2 is selected from when X1 is O, R 41 is -CN, L1 is when X8 is not O, preferably N.

[0111] In the present application, as one of the embodiments, in the compound of the structure represented by formula (I) or (II), L2 is when X8 is not O, preferably N. is selected from

[0112] In the present application, as one of the embodiments, in the compound of the structure represented by formula (I) or (II), when L1 is L2 is and R f , R t or R v forms a C i carbon ring, C j spiro ring, benzene ring with R 3-8 or R 4-9 on the adjacent G4 atom.

[0113] In the present application, as one of the embodiments, the compound of the structure represented by formula (I) or (II) is such that L2 is when G1 is N, and L1 is ,

[0114] the is selected from

[0115] In the present application, as one of the embodiments, the compound of the structure represented by formula (I) or (II) is such that L2 is when G1 is N, and L1 is in combination, the does not include or the

[0116] In the present application, as one of the embodiments, in the compound of formula (I), (II) or (III), the R3, R 41 , R 51 , R 52 are each independently selected from H, -CN, -CF3, -CONH2, -CHF2, COOH.

[0117] In the present application, as one of the embodiments, in the compound of formula (I) or (II), L1 is:

[0118] The present application provides a thyroid hormone β receptor agonist as described above, in the compound of formula (I) or (II), L2 is selected from:

[0119] In the present application, the compound of the structure represented by formula (I) is such that R is preferably Cl, Br, cyclopropane, -OCF3.

[0120] In the compounds of formula (II), R1or R2is each independently selected from the group consisting of: Cl, Br, cyclopropane, -OCF3.

[0121] In the present application, as one of the embodiments, the C 1-6 Alkyl, as illustrative, includes, but is not limited to, methyl, ethyl, propyl, cyclopropyl, isobutyl, n-butyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl, isohexyl, 3-methylpentyl, 2-ethylbutyl, 2,2-dimethylbutyl, or 2,3-dimethylbutyl, and the like.

[0122] In the present application, as one of the embodiments, the C 1-6 Alkoxy, as illustrative, includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, isobutoxy, n-butoxy, sec-butoxy, t-butoxy, cyclobutoxy, pentoxy, isopentoxy, cyclopentoxy, hexoxy, isohexoxy, 3-methylpentoxy, 2-ethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, or cyclohexoxy, and the like.

[0123] In the present application, as one of the embodiments, the C 1-6 Haloalkyl, includes, but is not limited to, halomethyl, haloethyl, halopropyl, haloisopropyl, halocyclopropyl, haloisobutyl, halon-butyl, halosec-butyl, halot-butyl, halocyclobutyl, halopentyl, haloisopentyl, halocyclopentyl, halohexyl, haloisohexyl, halo-3-methylpentyl, halo-2-ethylbutyl, halo-2,2-dimethylbutyl, halo-2,3-dimethylbutyl, or halocyclohexyl, and the like.

[0124] In the present application, as one of the embodiments, the saturated or unsaturated C 3-8 Carbocyclic, C 3-8 Carbocyclic, C 3-8 Carbocyclic, C 3-8 Carbocyclic, C

[0125] In the present application, as one of the embodiments, the aryl group refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings that share pairs of adjacent carbon atoms) ring having a conjugated pi-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring can be fused to an arylhetero group, a heterocyclyl group, or a cycloalkyl ring, wherein the ring that is attached to the parent structure is the aryl ring. "Aryl ring" refers to the ring system in aryl; haloaryl refers to aryl substituted with any one or more halogens.

[0126] In the present application, as one embodiment, the aromatic hetero group 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. The heteroaryl group is preferably 5 to 12 membered, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, pyrazolyl, pyrimidyl or thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is the heteroaryl ring. "Heteroaromatic ring" refers to the ring system in a heteroaryl group; haloaromatic hetero group refers to an aromatic hetero group substituted with any one or more halogens.

[0127] In the present application, as one embodiment, the halogen or halo includes, but is not limited to, F, Cl, Br or I substitution.

[0128] In the present application, as one embodiment, the C 2～6 Alkene group, as an illustrative example, can be a linear chain alkenyl group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms and having at least one double bond at any position, including, for example, ethenylene, alkenylene, propenylene, butenylene, isoprenylene, butadienylene, pentenylene, pentadienylene, hexenylene, hexadienylene, etc.

[0129] In the present application, as one embodiment, the C 2～6 Alkene group, as an illustrative example, can be a linear chain alkenyl group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms and having at least one double bond at any position, including, for example, ethenylene, alkenylene, propenylene, butenylene, isoprenylene, butadienylene, pentenylene, pentadienylene, hexenylene, hexadienylene, etc.

[0130] Terminology:

[0131] The "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight chain or branched chain group comprising 1-6 carbon atoms, including, but not limited to, methyl, ethyl, propyl, pentyl, hexyl, t-butyl, s-butyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethyl 2-methylpropyl, 1,1,2-trimethylpropyl, etc. aliphatic alkyl groups.

[0132] The "cycloalkyl" refers to a saturated cyclic carbon chain structure molecule, which preferably comprises 3-6 carbon atoms, including, but not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc.

[0133] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ringed hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen or S(O) m m The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ringed hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen or S(O)

[0134] The term "alkoxy" and "cycloalkoxy" refers to -O-alkyl and -O-(cycloalkyl) groups, respectively, wherein alkyl and cycloalkyl are as defined above. Examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, and the like.

[0135] 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 completely conjugated pi-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is the aryl ring. The term "aromatic ring" refers to the ring system in aryl groups.

[0136] The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5- to 12-membered, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, and the like, preferably imidazolyl, pyrazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is the heteroaryl ring. The term "heteroaromatic ring" refers to the ring system in heteroaryl groups.

[0137] The term "spirocyclic" refers to a polycyclic group of 5- to 20-membered rings sharing a single carbon atom (termed a spiro atom) between the rings, which can contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably 5- to 14-membered. Spirocycloalkyl groups are classified as mono-, bi-, or polyspirocycloalkyl groups, preferably mono- and bi-spirocycloalkyl groups, depending on the number of spiro atoms shared between the rings. More preferably 3-membered / 3-membered, 3-membered / 4-membered, 3-membered / 5-membered, or 3-membered / 6-membered mono-spirocycloalkyl groups. The term "spirocarbocyclic ring" refers to the ring system in spirocycloalkyl groups.

[0138] The term "halo" refers to a group that can be substituted with any one or more of F, Cl, Br, I atoms.

[0139] In some embodiments, the thyroid hormone beta receptor agonist of the present application is selected from the following compounds:

[0140] In some embodiments, the thyroid hormone beta receptor agonist of the present application is selected from the following:

[0141] The present application provides the use of the above-mentioned compounds, optical isomers thereof or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of diseases including but not limited to obesity, diabetes, atherosclerosis, hypothyroidism, lipid metabolism disorder, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, nonalcoholic fatty liver disease, liver fibrosis, neurodegenerative disease, hypertension or heart disease.

[0142] The present application provides a pharmaceutical composition comprising any of the above-mentioned compounds, optical isomers thereof or pharmaceutically acceptable salts thereof.

[0143] The compounds of the present application can selectively activate THR-β with less effect on THR-α receptor. This selective activation mechanism enables the drug to avoid extrahepatic effects when exerting therapeutic effects, thereby improving therapeutic effects and reducing adverse reactions. By optimizing the structure of the compound, we expect to reduce side effects while ensuring drug activity, thereby providing a safer and more effective treatment for NASH patients. The clinical application may have more significant efficacy and less side effects, which has obvious advantages in meeting clinical drug use. DETAILED DESCRIPTION

[0144] The following examples are used to further illustrate the present application, but in no way limit the effective scope of the present application.

[0145] Example 1

[0146] Step 1: To compound 1-1 (1000 mg, 6.1 mmol) in THF (10 mL) at 0 °C, compound 1-2 (1220 mg, 6.7 mmol) and TEA (670 mg, 6.7 mmol) were added slowly, and the reaction was stirred at room temperature for 3 hours. The mixture was quenched with ice water (15 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, hexane / ethyl acetate, 10%) to give compound 1-3 (1.8 g) as a yellow oil. Yield: 85.25%.

[0147] LCMS: Rt = 1.500 min, MS: 309.90 [M+H] +

[0148] Step 2: To a solution of compound 1-3 (1.5 g, 0.0048 mol) in DMSO (15 mL), isopropylamine (compound 1-4, 0.31 g, 0.0052 mol) was added at room temperature, the reaction was warmed to 40 °C and stirred for 6 h. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Si02, hexane / ethyl acetate, 25%) to afford compound 1-5 (0.7 g) as yellow oil. Yield: 44.77%.

[0149] LCMS: Rt = 1.044 min, MS: 352.95 [M+H] +

[0150] Step 3: NaBH4(48.37 mg, 1.2797 mmol) was added portion wise to a solution of compound 1-5 (450 mg, 1.2797 mmol) in EtOH (10 mL) at 0 °C, stirred at room temperature for 16 h. The reaction was quenched with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Si02, hexane / ethyl acetate, 15%) to afford compound 1-6 (200 mg) as yellow oil. Yield: 60.02%.

[0151] LCMS: Rt = 0.367 min, MS: 209.05 [M+H] +

[0152] Step 4: To a solution of compound 1-6 (200 mg, 0.96 mmol) in THF (10 mL), CDI (171.1 mg, 1.056 mmol) was added at room temperature, the reaction was warmed to 80 °C and stirred for 4 h. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Si02, hexane / ethyl acetate, 50%) to afford compound 1-7 (200 mg) as yellow oil. Yield: 80.01%.

[0153] LCMS: Rt = 1.108 min, MS: 235.1 [M+H] +

[0154] Step 5: To a solution of compound 1-7 in DCM (10 mL) was added BBr3 (577.42 mg, 2.3049 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water (15 mL) and extracted with DCM (15 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (SiO2, Hexanes / EtOAc, 50%) to afford compound 1-8 (170 mg) as a yellow solid. Yield: 90.41%.

[0155] LCMS: Rt = 0.876 min, MS: 221.05 [M+H] +

[0156] Step 6: To a solution of compound 1-8 (180 mg, 0.8172 mmol) in DMF (2 mL) was added 1,3-dichloro-2-fluoro-5-nitrobenzene (206 mg, 0.9806 mmol) and DIPEA (211 mg, 1.6344 mmol) at room temperature. The reaction was heated to 60 °C for 2 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (SiO2, Hexanes / Ethyl acetate, 25%) to afford compound 1-10 (200 mg) as a yellow solid. Yield: 53.70%.

[0157] LCMS: Rt = 1.466 min, MS: 410.00 [M+H] +

[0158] Step 7: To a mixture of compound 1-10 (200 mg, 0.4875 mmol) in EtOH / H2O (9 mL) was added iron powder (136 mg, 2.4375 mmol) and NH4CI (104.3 mg, 1.95 mmol) at room temperature. The reaction was heated to 80 °C for 2 h. The reaction was quenched with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was concentrated in vacuo to afford the crude product of compound 1-11 (160 mg), which was used directly in the next step without further purification. Yield: 69.05%.

[0159] LCMS: Rt = 1.275 min, MS: 380.05 [M+H] +

[0160] Step 8: A solution of compound 1-11 (60 mg, 0.1578 mmol) and NaNCte (14.15 mg, 0.2051 mmol) in cone. HC1 was added to a mixture of N-(2-cyanoacetyl)glycine ethyl ester (compound 1-12, 29.57 mg, 0.1893 mmol) in pyridine and water at 0 °C. The reaction was stirred at 0 °C for 2.5 h. The reaction was quenched with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was concentrated in vacuo to give the crude product of compound 1-13 (50 mg), which was used directly in the next step without further purification. Yield: 46.32 %.

[0161] LCMS: Rt = 1.345 min, MS: 547.1 [M+H] +

[0162] Step 9: NaOAc (17.92 mg, 0.183 mmol) was added to a solution of compound 1-13 (50 mg, 0.0913 mmol) in DMAc (1 mL) in portions under nitrogen protection. The reaction was heated at 120 °C for 2 h. After completion of the reaction, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by semi-preparative HPLC (eluent: acetonitrile-water with formic acid, 5% to 30%) to give compound 1 (6 mg) as a yellow solid. Yield: 12.60 %.

[0163] HPLC: Purity: 95.809% (214 nm) and 94.571% (254 nm).

[0164] LCMS: Rt = 1.310 min, MS: 501.1 [M+H] +

[0165] 1 H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 9.06 (s, 1H), 7.77 (s, 2H), 6.77 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 6.66 (dd, J = 8.4, 2.8 Hz, 1H), 4.64 (q, J = 6.4 Hz, 1H), 4.24 (dt, J = 13.6, 6.8 Hz, 1H), 1.19 (dd, J = 13.6, 6.4 Hz, 6H), 1.12 (d, J = 6.8 Hz, 3H).

[0166] Example 2

[0167] Step 1: Compound A2 (1.26 g, 5.2 mmol) was added to a solution of DMAc (15 mL) under nitrogen at 100 °C, followed by the addition of t-BuOK (0.7 g, 6.2 mmol) and stirring for 1 h. Compound A1 (1 g, 5.2 mmol) was added and stirred at 130 °C for 6 h. After cooling to room temperature, it was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with brine, dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography on silica gel (eluted with DCM / hexane, 10% to 20%) to obtain white solid compound A3 (0.8 g) with a yield of 38.46%.

[0168] LCMS: m / z = 396.85 [M+H+2] + .

[0169] Step 2: AcONa (210 mg, 2.6 mmol) was added to a solution of compound A3 (0.5 g, 1.3 mmol) in ethyl acetate (15 mL) under nitrogen, and the mixture was stirred at 110 °C for 12 h, concentrated in vacuo, adjusted to pH 8 with a NaHCO3 solution, and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, and concentrated to obtain white solid compound A4 (480 mg) with a yield of 99.0%.

[0170] LCMS: m / z = 378.95 [M+H+2] +

[0171] Step 3: Pd(dppf)Cl2DCM (49.18 mg, 0.06 mmol) was added to a solution of compound A4 (477 mg, 1.26 mmol) and potassium carbonate (523 mg, 3.78 mmol) in DMF (5 mL) under nitrogen at 25 °C. The reaction mixture was stirred at 25 °C for 16 h, diluted with water (20 mL), and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine, dried over sodium sulfate, concentrated, and purified by column chromatography on silica gel (eluted with ethyl acetate / hexane, 0% to 15%) to obtain white solid compound A5 (350 mg) with a yield of 55.12%.

[0172] LCMS: m / z = 498.90 [M+H+2] +

[0173] Step 4: Compound A5 (4 g, 8 mmol, 1.0 eq), KOH (580 mg, 10.4 mmol, 1.3 eq), tBuXPhos (340 mg, 0.8 mmol, 0.1 eq) and Pd2(dba)3 (730 mg, 0.8 mmol, 0.1 eq) were added to a 1.4-dioxane / H2O = 1:1 (80 mL) mixed solution and stirred at 100 °C for 16 h. The mixture was quenched with H2O (100 mL) and the combined organic phase was washed with EtOAc (100 mL x 3) and saturated brine for 3 times, dried over anhydrous Na2SO4 and concentrated in vacuo. The mixture was purified by flash chromatography (hexane / ethyl acetate = 82:18) to give compound 2-1 (1.6 g) as a white solid, yield: 41.25%.

[0174] LCMS: Rt = 1.472 min, m / z = 435.0 [M+H] + .

[0175] Step 5: Potassium carbonate (476.24 mg, 3.4458 mmol) was added to a solution of compound 2-1 (500 mg, 1.1486 mmol) and compound 2-2 (208.45 mg, 1.2634 mmol) in DMF and heated to reflux for 2 h. The reaction mixture was evaporated in vacuo to give compound 2-3, which was used directly in the next step without purification.

[0176] LCMS: Rt = 1.543 min, m / z = 519.0 [M+H] + .

[0177] Step 6: Compound 2-3 (500 mg, 0.9627 mmol) and I2 (12.22 mg, 0.0481 mmol) were dissolved in methanol and refluxed for 72 h. The reaction mixture was evaporated in vacuo and the crude product was purified by flash chromatography (dichloromethane / methanol = 95% / 5%) to give compound 2-4 (560 mg) as a colorless oil, yield 94.94%.

[0178] 1H NMR (400 MHz, DMSO) δ 7.37 (s, 1H), 7.23 (s, 2H), 7.04 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 5.15-5.11 (m, 1H), 4.91 - 4.79 (m, 2H), 4.72 (t, J = 5.2 Hz, 1H), 3.72 (s, 3H), 3.69 (s, 3H), 3.61 - 3.54 (m, 2H), 3.10 - 3.02 (m, 1H), 2.11 - 1.98 (m, 2H), 1.16 (d, J = 6.8 Hz, 6H).

[0179] Step 7: To a solution of compound 2-4 (500 mg, 0.9068 mmol) and TEA (110.11 mg, 1.0881 mmol) in DCM, TsCl (190.17 mg, 0.9974 mmol) was added, stirred at room temperature for 16 hours. The reaction mixture was evaporated in vacuum, purified by flash chromatography (EA / PE: 1 / 1) to give compound 2-5 (480 mg) as colorless oil in 67.51% yield.

[0180] 1 H NMR (400 MHz, DMSO) δ 7.73 (d, J = 8.0 Hz, 2H), 7.38 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.12 (s, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 5.13 - 5.10 (m, 1H), 4.85 (s, 2H), 4.25 - 4.19 (m, 1H), 4.14 - 4.09 (m, 1H), 3.70 (s, 3H), 3.67 (s, 3H), 3.09 - 3.04 (m, 1H), 2.30 (s, 1H), 2.19 (d, J = 5.6 Hz, 1H), 1.16 (d, J = 6.8 Hz, 6H).

[0181] Step 8: To a solution of compound 2-5 (200 mg, 0.2834 mmol) in THF (100 mL), LiHMDS (0.4 mL, 0.4251 mmol) was added at -60 °C under nitrogen atmosphere, and stirred for 2 hours. The reaction mixture was diluted with water 20 mL, and extracted with EA (20 mL x 3). The organic was washed with saturated brine (30 mL x 2), dried over sodium sulfate, and then filtered. The filtrate was evaporated in vacuum to give the crude product, which was purified by flash chromatography (0-15% EA in PE) to give compound 2-6 (140 mg) as yellow oil in 92.63% yield.

[0182] LCMS: Rt = 1.666 min, MS Found: 533.1 [M+H] +

[0183] Step 9: To a solution of compound 2-6 (100 mg, 0.1875 mmol) in THF (100 mL) was added 2N LiOH (2 mL) and stirred at room temperature for 16 h. The reaction mixture was diluted with 20 mL water and extracted with MTBE (20 mL x 2). The aqueous solution was adjusted to pH 4 with 1 N hydrochloric acid solution and extracted with EtOAc (20 mL x 2). It was washed with saturated brine (30 mL x 2), dried over sodium sulfate, and filtered. The filtrate was evaporated in vacuum to get compound 2-7 (100 mg) as colorless oil, yield: 97.55%.

[0184] LCMS: Rt = 1.534 min, m / z = 519.1 [M+H] +

[0185] Step 10: To a solution of compound 2-7 (100 mg, 0.1925 mmol) in ACN was slowly added cerium ammonium nitrate (CAN), 211.06 mg, 0.385 mmol) at 0 °C and stirred at 20 °C for 3 h. The organic solvent was evaporated by rotary evaporation and compound 2 (35 mg) was obtained as white solid by preparative liquid chromatography (Gemini 5um C18 column, 150*21.2 mm eluted with 30% to 90% MeCN / H2O containing 0.1% formic acid) with a yield of 45.30%.

[0186] HPLC: Purity: 99.51% (214 nm)

[0187] LCMS: Rt = 1.30 min, m / z = 399.0 [M+H] +

[0188] 1 H NMR (400 MHz, DMSO) δ 13.15 (s, 1H), 12.16 (s, 1H), 7.37 (s, 1H), 7.14 (s, 2H), 3.07-3.00 (m, 1H), 1.57 (s, 2H), 1.33 (s, 2H), 1.18 (d, J = 6.8 Hz, 6H).

[0189] Example 3 and Example 4

[0190] Step 1: In a round bottom flask, 3-1 (4 g, 22.5 mmol, 1.0 eq), bismuth nitrate (10.66 g, 27 mmol, 1.2 eq) were dissolved in tetrahydrofuran (22 mL) and the reaction mixture was heated to 70 °C and stirred for 16 h under nitrogen atmosphere. At the end of the reaction, the reaction mixture was quenched with 20 mL of water and extracted with ethyl acetate 3 times, 20 mL each time, washed the organic layer with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to get the crude product. The crude product obtained from the above procedure 3-2 (4 g, 50% purity) was used as such for the next reaction without further purification.

[0191] LCMS: Rt = 1.211 min, MS: 222.0 [M-H] -

[0192] Step 2: 3-2 (4 g, 17.9 mmol, 1.0 eq) was dissolved in ethanol (40 mL) at 25 °C and to this solution, palladium on carbon catalyst (0.4 g) was added slowly. The above reaction mixture was stirred for 16 h under hydrogen atmosphere at 25 °C till the completion of the reaction. Then the mixture was filtered through celite and the filtrate was concentrated under vacuum to get the crude product 3-3 (2.2 g) which was used as such for the next reaction without further purification.

[0193] LCMS: Rt = 0.359 min, MS: 194.0 [M+H] +

[0194] Step 3: 3-3 (2.2 g, 11.4 mmol, 1.0 eq) was dissolved in tetrahydrofuran (50 mL) and to this solution, di-tert-butyl dicarbonate (2.99 g, 13.6 mmol, 1.2 eq) was added slowly. The reaction mixture was heated to 70 °C and stirred for 3 h under nitrogen atmosphere. At the end of the reaction, the reaction mixture was quenched with 20 mL of water and extracted with ethyl acetate 3 times, 20 mL each time, washed the organic layer with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to get the crude product. The product was purified by flash preparative liquid chromatography (petroleum ether / ethyl acetate = 85:15) to get the target compound 3-4 (1.64 g) as a brown solid in 43.86% yield.

[0195] LCMS: Rt = 1.292 min, MS: 292.0 [M-H] -

[0196] Step 4: In a round bottom flask, 3-4 (800 mg, 2.73 mmol, 1.0 eq), 3-5 (521 mg, 2.73 mmol, 1.0 eq), potassium carbonate (1130 mg, 8.18 mmol, 3.0 eq) were dissolved in N’N-dimethylformamide (10 mL) and the reaction was heated to 100 °C and stirred for 16 h under nitrogen atmosphere. At the end of the reaction, the reaction was quenched with 20 mL of water and extracted with ethyl acetate 3 times, 20 mL each time, washed the organic layer with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to get the crude product. The crude product obtained above was purified by flash preparative liquid chromatography (petroleum ether / ethyl acetate = 90:10) to get mixture 3-6 and 3-6a (600 mg, 3 / 1) as white solid in 44.22% yield.

[0197] LCMS: Rt = 1.640 min, MS: 448.1 [M+H] +

[0198] Step 5: In a round bottom flask, 3-6 and 3-6a (600 mg, 1.34 mmol, 1.0 eq), sodium acetate (330 mg, 4.02 mmol, 3.0 eq) were dissolved in acetic acid (5 mL) and the reaction was heated to 110 °C and stirred for 12 h until the completion of the reaction. At the end of the reaction, the reaction was quenched with 20 mL of water and extracted with ethyl acetate 3 times, 20 mL each time, washed the organic layer with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to get the crude product. The crude product obtained above 3-7 and 3-7a (400 mg, 90% purity) was used as such in the next step without further purification.

[0199] LCMS: Rt = 1.158 min, MS: 372.0 [M+H] +

[0200] Step 6: In a round bottom flask, 3-7 and 3-7a (400 mg, 1.08 mmol, 1.0 eq) were dissolved in sodium hydroxide in methanol (1 M, 4 mL) and the reaction was heated to 95 °C and stirred for 12 h until the completion of the reaction. At the end of the reaction, the reaction was quenched with 20 mL of water and extracted with ethyl acetate 3 times, 20 mL each time, washed the organic layer with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to get the crude product. The crude product obtained above 3-8 and 3-8a (390 mg, 90% purity) was used as such in the next step without further purification.

[0201] LCMS: Rt = 1.169 min, MS: 330.1 [M+H] +

[0202] Step 7: To a solution of 3-8 and 3-8a (390 mg, 1.18 mmol, 1.0 eq) in concentrated hydrochloric acid (2 mL) was added slowly a solution of sodium nitrite (90 mg, 1.3 mmol, 1.1 eq) in 1 mL of water at 0 °C. After the mixture was stirred at 0 °C for 1 h, the resulting mixture was added dropwise to a solution of 3-9 (203 mg, 1.3 mmol, 1.1 eq) in 2.5 mL of pyridine at 0 °C. Then, the reaction was stirred at 0 °C for 1 h until the reaction was completed. Upon completion of the reaction, the reaction was quenched with 20 mL of water and extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The crude product 3-10 and 3-10a (400 mg, 60% purity) obtained above was used in the next step without further purification.

[0203] LCMS: Rt = 1.274 min, MS: 497.1 [M+H] +

[0204] Step 8: In a round bottom flask, 3-10 and 3-10a (200 mg, 0.4 mmol, 1.0 eq), potassium acetate (158 mg, 1.6 mmol, 4.0 eq) were dissolved in N’N-dimethylacetamide (5 mL) and the reaction was heated to 120 °C and stirred for 2 h under nitrogen atmosphere. Upon completion of the reaction, the reaction was quenched with 15 mL of water and extracted with ethyl acetate (3 x 15 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. Purification by HPLC (acetonitrile-water (0.1% trifluoroacetic acid)) gave 3 (96.3 mg) and 4 (29.54 mg) as white solids.

[0205] Compound 3: HPLC: Purity: 99.06% (214 nm) and 99.19% (254 nm).

[0206] LCMS: Rt = 1.139 min, MS: 451.0 [M+H] +

[0207] 1 H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 12.28 (s, 1H), 7.70 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.59 (dd, J = 8.8, 2.4 Hz, 1H), 7.33 (s, 1H), 3.04 - 3.01 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H).

[0208] Compound 4: HPLC: Purity: 95.83% (214 nm) and 94.18% (254 nm).

[0209] LCMS: Rt = 1.111 min, MS: 451.0 [M+H] +

[0210] 1 H NMR (400 MHz, DMSO) δ 13.18 (s, 1H), 12.20 (s, 1H), 7.72 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 8.8, 2.4 Hz, 1H), 6.85 (s, 1H), 3.03 - 3.00 (m, 1H), 1.26 (d, J = 6.8 Hz, 6H).

[0211] Example 5

[0212] Step 1: Compound 5-1 (4 g, 19.3 mmol, 1.0 eq) was added to 98% concentrated sulfuric acid (2 mL) at 0 °C, then the mixture was warmed to 95 °C and stirred for 2 hours. The reaction was quenched with ice water, the residue was filtered and concentrated to give 2.5 g of white solid compound 5-2 (yield 65.28%), without further purification.

[0213] LCMS: Rt = 0.799 min, MS: 189.7 [M+H] +

[0214] Step 2: Compound 5-2 (1.5 g, 7.9 mmol, 1.0 eq) and palladium on carbon catalyst (0.17 g, 1.5 mmol, 0.2 eq) were dissolved in 30 mL of methanol in a hydrogenation kettle, and 2-3 MPa of hydrogen was added, the reaction system was warmed to 60 °C and stirred for 16 hours. The residue was filtered and concentrated, and the crude product was purified by flash column chromatography (n-hexane: ethyl acetate = 1: 1) to give 0.57 g of white solid compound 5-3 (yield 35.44%).

[0215] LCMS: Rt = 1.335 min, MS: 192.0 [M+H] +

[0216] Step 3: To a solution of compound 5-3 (560 mg, 2.93 mmol, 1.0 eq) in dichloromethane (10 mL) was added boron tribromide (1467.3 mg, 5.86 mmol, 2.0 eq) at 0 °C, and the mixture was stirred at low temperature for 1 h. The reaction was quenched with ice water, and the residue was filtered and concentrated to give 450 mg of compound 5-4 (78.05% yield) as a white solid without further purification.

[0217] LCMS: Rt = 0.536 min, MS: 175.6 [M-H] -

[0218] Step 4: To a solution of compound 5-4 (400 mg, 2.2573 mmol) and N,N- diisopropylethylamine (583.47 mg, 4.5146 mmol) in N,N-dimethylformamide was added 3,5-dichloro-4-fluoronitrobenzene (compound 5-5, 474.01 mg, 2.2573 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction solvent was evaporated, and the residue was purified by flash column chromatography (0% to 5% methanol in dichloromethane) to give 620 mg of compound 5-6 (59.84% yield) as a yellow solid.

[0219] 1 H NMR (400 MHz, DMSO) δ 10.06 (s, 1H), 8.53 (s, 2H), 6.84 (d, J = 2.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.65 (dd, J = 8.8, 2.8 Hz, 1H), 3.04 - 3.01 (m, 1H), 2.57 (dd, J = 16.0, 6.4 Hz, 1H), 2.25 - 2.20 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H).

[0220] Step 5: Compound 5-6 (600 mg, 1.6341 mmol), iron powder (456.32 mg, 8.1705 mmol) and ammonium chloride (437.04 mg, 8.1705 mmol) were dissolved in a mixed solution of ethanol and water at room temperature, and the mixture was heated to reflux and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with 20 mL of water, and extracted with 20 mL of ethyl acetate three times. The organic phases were combined, washed with 30 mL of saturated brine twice, and dried over anhydrous sodium sulfate. After the drying agent was removed by filtration, the system was evaporated to give 550 mg of compound 5-7 (94.82% yield) as a white solid directly.

[0221] 1H NMR (400 MHz, DMSO) δ 9.98 (s, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 2.8 Hz, 3H), 6.49 (dd, J = 8.4, 2.8 Hz, 1H), 5.63 (s, 2H), 3.01 (m, 1H), 2.54 - 2.50 (m, 1H), 2.20 - 2.16 (m, 1H), 1.13 (d, J = 6.8 Hz, 3H).

[0222] Step 6: To a mixture of compound 5-7 (400 mg, 2.2573 mmol) and sodium nitrite (133.01 mg, 1.9276 mmol) in 4 N aqueous hydrochloric acid at 0 °C, a solution of N-cyanoacety urethane (compound 5-8, 277.83 mg, 1.7793 mmol, ) in pyridine / water was added. The reaction mixture was stirred at low temperature for 2.5 h. The reaction mixture was filtered and the filter cake (containing compound 5-9) was used directly in the next step.

[0223] LCMS: Rt = 1.265 min, MS Found: 504.0 [M+H] +

[0224] Step 7: Compound 5-9 (250 mg, 0.4957 mmol) and potassium acetate (243.24 mg, 2.4785 mmol) were dissolved in N,N-dimethylformamide at room temperature, and the reaction mixture was heated to 120 °C and stirred for 2 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (3x). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated after removing the drying agent, and the crude product was purified by preparative liquid chromatography to give 150 mg of compound 5 as an off-white solid (yield 64.06%).

[0225] HPLC: Purity: 97.52% (214 nm) and 97.53% (254 nm).

[0226] LCMS: Rt = 1.229 min, MS Found: 458.0 [M+H] +

[0227] 1H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 10.04 (s, 1H), 7.79 (s, 2H), 6.84 (d, J = 2.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.59 (dd, J = 8.8, 2.8 Hz, 1H), 3.08 - 3.03 (m, 1H), 2.60 - 2.56 (m, 1H), 2.25 - 2.19 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H).

[0228] Example 6

[0229] Step 1: Compound 6-1 (17.56 g, 121.8 mmol, 1.0 eq) was added dropwise to a solution of compound 6-2 (15 g, 121.8 mmol, 1.0 eq) and NaOH (490 mg, 12.8 mmol, 2.0 eq) in anhydrous toluene (150 mL) under nitrogen protection at 0 °C. After addition, it was stirred at 110 °C for 16 h. It was quenched with H2O (20 mL), extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuum. The crude product was purified by flash column chromatography (Hexanes / EtOAc = 66:34) to give compound 6-3 (21 g) as a white solid, yield: 70.11%.

[0230] LCMS: Rt = 0.963 min, MS: 222.1 [M-H] +

[0231] Step 2: A solution of compound 6-3 (10 g, 45.2 mmol) in 70% H2SO4 (25 mL) was stirred at 60 °C for 5 h. It was quenched with H2O (120 mL), the precipitate was collected, and the filter cake was washed with water to give compound 6-4 (8 g) as a white solid, yield: 78.32%.

[0232] LCMS: Rt = 1.039 min, MS: 204.0 [M-H] +

[0233] Step 3: A mixture solution of compound 6-4 (4 g, 19.7 mmol, 1.0 eq), PMBC1 (4.63 g, 29.5 mmol, 1.5 eq) and Cs2C03(19.26 g, 59.1 mmol, 3.0 eq) in DMAc (20 mL) was stirred at 120 °C for 10 h. It was quenched with H20 (50 mL), extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2S04and concentrated in vacuo. The crude product was purified by flash column chromatography (Hexanes / EtOAc = 60:40) to give compound 6-5 (3 g) as a white solid. Yield: 42.13%.

[0234] LCMS: Rt = 1.346 min, MS: 324.1 [M+H] +

[0235] Step 4: Compound 6-6 (6.82 g, 31 mmol) was cooled to 0 °C in THF (80 mL), n-BuLi (12.9 mL, 2.4 M) was added slowly. After the addition, it was stirred for 0.5 h, then compound 6-5 (2 g, 6.2 mmol) was added, finally the reaction was raised to 65 °C and stirred for 16 h. It was quenched with H20 (100 mL), extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2S04and concentrated in vacuo. The crude product was purified by flash column chromatography to give compound 6-7 (1.7 g) as a yellow oil. Yield: 78.43%.

[0236] 1 H NMR (400 MHz, DMSO) d 7.09 - 7.05 (m, 3H), 6.88 - 6.81 (m, 3H), 6.68 (dd, J = 9.2, 2.8 Hz, 1H), 5.16 - 4.93 (m, 2H), 3.71 (s, 3H), 3.70 (s, 3H), 2.63 - 2.54 (m, 1H), 2.10 - 2.06 (m, 1H), 1.60 - 1.56 (m, 1H), 1.14 - 1.05 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H), 0.65 (t, J = 4.4 Hz, 1H).

[0237] Step 5: To a solution of compound 6-7 (2 g, 0.0059 mol) in TFA (20 mL), CF3CO3H (2 mL) was added under nitrogen protection, the reaction was raised to 50 °C and stirred for 2 h. The residue was filtered and extracted with ethyl acetate (20 mL x 3), washed with brine (50 mL), dried over Na2S04. The residue was purified by flash column chromatography (hexanes: ethyl acetate = 4: 1) to give compound 6-8 (0.6 g) as a yellow solid. Yield: 42.37%.

[0238] LCMS: Rt = 1.064 min, MS: 218.1 [M+H] +

[0239] Step 6: BBr3(1038 mg, 4.1424 mmol) was added dropwise into a solution of compound 6-8 (300 mg, 1.381 mmol) in DCM (10 mL) at 0 °C, and stirred at room temperature for 2 h. The residue was filtered and extracted with DCM (20 mL x 3), washed with brine (50 mL) and dried over Na2S04. The residue was purified by flash column chromatography (Hexane: Ethyl acetate = 1: 1) to afford compound 6-9 (300 mg) as a yellow solid in 90.87% yield.

[0240] LCMS: Rt = 0.824 min, MS: 204.1 [M+H] +

[0241] Step 7: Compound 6-10 (371.96 mg, 1.7713 mmol) and DIPEA (381.5 mg, 2.9522 mmol) were added to a solution of compound 6-9 (300 mg, 1.4761 mmol) in DMF (5 mL) at room temperature, and the reaction was stirred at 60 °C for 2 h. The residue was extracted with ethyl acetate (10 mL x 3), washed with brine (20 mL) and dried over Na2S04. The residue was purified by flash column chromatography (Hexane: Ethyl acetate = 4: 1) to afford compound 6-11 (260 mg) as a yellow solid in 40.32% yield.

[0242] LCMS: Rt = 1.437 min, MS: 393.0 [M+H] +

[0243] Step 8: To a mixture of compound 6-11 (400 mg, 1.0172 mmol) in EtOH / H20 (12 mL) was added iron powder (284.05 mg, 5.086 mmol) and NH4CI (217.64 mg, 4.0688 mmol) slowly at room temperature, and the reaction was stirred at 80 °C for 2 h. The residue was filtered and concentrated. Purification by flash column chromatography (DCM: MeOH = 10: 1) afforded compound 6-12 (390 mg) as a yellow solid in 95.00% yield.

[0244] LCMS: Rt = 1.236 min, MS: 363.0 [M+H] +

[0245] Step 9: At 0°C, a 12N HCl aqueous solution containing compound 6-12 (350 mg, 0.9636 mmol) and NaNO2 (86.43 mg, 1.2526 mmol) was added to a pyridine / water mixed solution of compound 6-13 (180.55 mg, 1.1563 mmol). The reaction was stirred at 0°C for 2.5 h. The residue was extracted with ethyl acetate (10 mL × 3), washed with brine (10 mL), dried over Na2SO4, and concentrated. Purification was performed by rapid column chromatography (DCM:MeOH = 10:1) to give an orange solid compound 6-14 (300 mg), yield: 46.96%.

[0246] LCMS: Rt=1.315min, MS: 530.1[M+H] +

[0247] Step 10: At room temperature, AcOK (111.04 mg, 1.1314 mmol) was added to a DMAc (15 mL) solution of compound 6-14 (300 mg, 0.5657 mmol), and the reaction was stirred at 120 °C for 2 hours. The system was purified by preparative liquid chromatography to give a yellow solid compound 6 (80 mg), yield: 27.74%.

[0248] LCMS: Rt=1.275min, MS: 484.1[M+H] +

[0249] Step 11: Purify 80 mg of compound 6 with SFC to obtain yellow solid compound 6-P1 (18.89 mg) and yellow solid compound 6-P2 (20.69 mg).

[0250] LCMS: Rt=1.275min, MS: 524.0[M+H] +

[0251] Compound 6-P1: HPLC: Purity: 99.598% (214 nm) and 98.572% (254 nm)

[0252] LCMS:Rt=1.275min,MS Calcd.:484.29,MS Found:484.05[M+H] +

[0253] 1H NMR (400 MHz, DMSO) δ 13.28 (s, 1H), 9.94 (s, 1H), 7.80 (s, 2H), 7.03 (d, J = 2.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.57 (dd, J = 8.8, 2.8 Hz, 1H), 2.44 - 2.40 (m, 1H), 1.78 (dd, J = 9.6, 5.2 Hz, 1H), 1.52 (dd, J = 9.6, 4.4 Hz, 1H), 1.02 - 0.98 (m, 1H), 0.83 (t, J = 7.2 Hz, 3H), 0.67 (t, J = 4.8 Hz, 1H).

[0254] Compound 6-P2: HPLC: Purity: 99.447% (214 nm) and 98.639% (254 nm)

[0255] LCMS: Rt = 1.277 min, MS Calcd.: 484.29, MS Found: 484.05 [M+H] +

[0256] 1 H NMR (400 MHz, DMSO) δ 13.28 (s, 1H), 9.94 (s, 1H), 7.80 (s, 2H), 7.03 (d, J = 2.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.57 (dd, J = 8.8, 2.8 Hz, 1H), 2.44 - 2.40 (m, 1H), 1.78 (dd, J = 9.6, 5.2 Hz, 1H), 1.52 (dd, J = 9.6, 4.4 Hz, 1H), 1.02 - 0.98 (m, 1H), 0.83 (t, J = 7.2 Hz, 3H), 0.67 (t, J = 4.8 Hz, 1H).

[0257] Example 7

[0258] Step 1: Compound 7-1 (20 g, 0.16 mol, 1.0 eq) and compound 7-2 (27.5 g, 0.21 mol, 1.3 eq) were dissolved in toluene (200 mL) under nitrogen protection, the reaction was raised to 110 °C and stirred for 4 hours. The mixture was filtered and concentrated, the crude product was purified by flash column chromatography (hexane: ethyl acetate = 1:1) to obtain pink solid compound 7-3 (16 g), yield: 35.71%.

[0259] LCMS: Rt = 1.011 min, MS: 280.1 [M+H] +

[0260] Step 2: A solution of compound 7-3 (10 g, 0.038 mol, 1.0 eq) in 70% H₂SO₄ (10 mL) was stirred at 95 °C for 6 h. The reaction was quenched with ice water, filtered, and concentrated. A green solid mixture 7-4 (7 g) was obtained, which required no further purification; yield: 43.04%.

[0261] LCMS: Rt=0.895min, MS: 230.1[M+H] +

[0262] Step 3: PMBCl (7.14 g, 45.6 mmol, 1.5 eq), K₂CO₃ (10.5 g, 76 mmol, 2.5 eq), and compound 7-4 (7 g, 30.4 mmol, 1.0 eq) were mixed in DMF (80 mL) and stirred at 60 °C for 4 h. The mixture was filtered, extracted with ethyl acetate (100 mL × 3), washed with brine (500 mL), and dried over Na₂SO₄. The crude product was purified by rapid column chromatography (hexane:ethyl acetate = 3:1) to give a white solid compound 7-5 (2.7 g), yield: 15.13%.

[0263] LCMS: Rt=1.597min, MS: 470.1[M+H] +

[0264] 1 H NMR (400MHz, DMSO) δ7.53(d,J=9.2Hz,1H),7.37(d,J=8.8Hz,3H),7.21–7.16(m,4H),6.96–6.90( m,2H),6.89–6.85(m,2H),5.48(s,2H),5.08(s,2H),3.74(d,J=1.8Hz,3H),3.70(d,J=1.8Hz,3H).

[0265] Step 4: Compounds 7-5 (1.2 g, 2.6 mmol) and 7-6 (1.5 g, 5.2 mmol, 2.0 eq) were dissolved in THF (50 mL), and the reaction mixture was cooled to -78 °C. LiHMDS (1.0 M, THF, 1.7 g, 10.4 mmol, 4.0 eq) was added, and the mixture was stirred for 16 hours. The reaction was quenched with saturated NaHCO3 aqueous solution, extracted with ethyl acetate (30 mL × 3), washed with brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was purified by rapid column chromatography (hexane:ethyl acetate = 3:1) to give a pale yellow solid, compound 7-7 (600 mg), yield: 42.31%.

[0266] LCMS: Rt=2.013min, MS: 484.1[M+H]+

[0267] 1 H NMR (400 MHz, DMSO) δ 7.35 (d, J = 8.4 Hz, 2H), 7.18 - 7.09 (m, 3H), 6.96 - 6.92 (m, 4H), 6.87 (d, J = 8.8 Hz, 2H), 4.97 (s, 2H), 3.77 - 3.67 (m, 8H), 2.75 - 2.73 (m, 1H), 2.13 - 2.09 (m, 1H), 1.22 - 1.17 (m, 1H).

[0268] Step 5: To a solution of compound 7-7 (600 mg, 1.24 mmol, 1.0 eq) in TFA (8 mL), CF3SO3H / H2O (1 : 10, 0.8 mL) was added, the reaction was stirred at 50 °C for 2 h. The residue was quenched with saturated NaHC03 aqueous solution, extracted with ethyl acetate (10 mL x 3), washed with brine (10 mL), dried over anhydrous sodium sulfate. The crude product was purified by flash column chromatography (DCM:MeOH = 10: 1) to give compound 7-8 (210 mg) as a yellow solid, yield: 62.5%.

[0269] LCMS: Rt = 0.891 min, MS: 244.2 [M+H] +

[0270] 1 H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 9.34 (s, 1H), 7.03 (s, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.68 (dd, J = 8.8, 2.4 Hz, 1H), 2.40 - 2.36 (m, 1H), 2.00 - 1.98 (m, 1H), 1.08 (t, J = 6.0 Hz, 1H).

[0271] Step 6: Compound 7-8 (180 mg, 0.74 mmol, 1.0 eq), compound 7-9 (154.8 mg, 0.74 mmol, 1.0 eq) and DIEA (190.5 mg, 1.47 mmol, 2.0 eq) were dissolved in DMF (5 mL), the reaction was stirred at 60 °C for 1 h. The residue was extracted with ethyl acetate (10 mL x 3), washed with brine (20 mL), dried over anhydrous sodium sulfate. The crude product was purified by flash column chromatography (DCM:MeOH = 10: 1) to give compound 7-10 (280 mg) as a yellow solid, yield: 83.12%.

[0272] LCMS: Rt = 1.306 min, MS: 433.0 [M+H] +

[0273] Step 7: Compound 7-10 (250 mg, 0.58 mmol, 1.0 eq), iron powder (160.8 mg, 2.88 mmol, 5.0 eq) and NH4CI (308 mg, 5.76 mmol, 10.0 eq) were dissolved in EtOH / H2O (5 / 1, 5 mL) under nitrogen, stirred at 80 °C for 2 h. The system was filtered, and the crude product was purified by flash column chromatography (DCM:MeOH = 10:1) to give compound 7-11 (200 mg) as a yellow solid in 81.64% yield.

[0274] LCMS: Rt = 1.124 min, MS: 403.0 [M+H] +

[0275] Step 8: A solution of compound 7-11 (180 mg, 0.46 mmol, 1.0 eq) in HC1 (2 mL) was added to a solution of NaNCte (39.94 mg, 0.58 mg, 1.3 eq) in H2O (1.6 mL) at 0 °C, stirred at 0 °C for 1 h. The above system was added to a mixture of compound 7-12 (83.4 mg, 0.53 mmol, 1.2 eq) in pyridine (2 mL) and H2O (4 mL) at 0 °C, and stirred at 0 °C for another 1 h. The system was extracted with ethyl acetate (10 mL x 3), washed with brine (10 mL), dried over Na2S04 and concentrated. The crude product was purified by flash column chromatography (DCM:MeOH = 10:1) to give compound 7-13 (140 mg) as a red solid in 41.28% yield.

[0276] LCMS: Rt = 1.216 min, MS: 570.1 [M+H] +

[0277] Step 9: Compound 7-13 (120 mg, 0.21 mmol, 1.0 eq) and KOAc (61.8 mg, 0.63 mmol, 3.0 eq) were dissolved in DMAc (3 mL), and the reaction was heated to 110 °C in an oil bath, stirred for 4 h. The residue was purified by preparative liquid chromatography to give compound 7 (90 mg) as a light yellow solid in 79.95% yield.

[0278] LCMS: Rt = 1.269 min, MS: 524.0 [M+H] +

[0279] Step 10: 90 mg of 7 was purified by SFC to give compound 7-P1 (25 mg) as a light yellow solid in 24.74% yield and compound 7-P2 (27 mg) as a light yellow solid in 26.73% yield.

[0280] LCMS: Rt = 1.309 min, MS: 524.0 [M+H]+

[0281] Compound 7-P1 : HPLC: Purity: 99.765% (214 nm) and 99.745% (254 nm)

[0282] LCMS: Rt = 1.309 min, MS Calcd.: 523.01, MS Found: 524.0 [M+H] +

[0283] 1 H NMR (400 MHz, DMSO) δ 13.26 (s, 1H), 10.45 (s, 1H), 7.83 (s, 2H), 7.06 (d, J = 2.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.81 (dd, J = 8.8, 2.8 Hz, 1H), 2.45 (s, 1H), 2.05 - 2.03 (m, 1H), 1.24 (t, J = 5.6 Hz, 1H).

[0284] Compound 7-P2: HPLC: Purity: 99.281% (214 nm) and 99.091% (254 nm)

[0285] LCMS: Rt = 1.304 min, MS Calcd.: 523.01, MS Found: 524.0 [M+H]+

[0286] 1 H NMR (400 MHz, DMSO) δ 13.28 (s, 1H), 10.46 (s, 1H), 7.83 (s, 2H), 7.06 (d, J = 2.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.82 (dd, J = 8.8, 2.8 Hz, 1H), 2.45 (s, 1H), 2.05 - 2.03 (m, 1H), 1.24 (t, J = 5.6 Hz, 1H).

[0287] Example 8

[0288] Step 1 : Compound 8-1 (10 g, 0.073 mol) was dissolved in DCM (100 mL) and TEA (14.7 g, 0.1458 mol) and MsCI (16.7 g, 0.1458 mol) were added dropwise at 0 °C under nitrogen protection. The mixture was stirred at room temperature for 2 hours. The mixture was quenched with ice water (100 mL) and extracted with DCM (100 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Si02, hexane / ethyl acetate, 5%) to give compound 8-2 (6 g) as a white solid in 36.35% yield.

[0289] LCMS: Rt = 0.970 min, MS: 214.0 [M-H] +

[0290] Step 2: To a solution of compound 8-2 (6 g, 0.0279 mol) in DCM (60 mL) was added Boc20 (9.13 g, 0.0418 mol), TEA (5.64 g, 0.0558 mol) and DMAP (0.34 g, 0.0027 mol) dropwise at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was quenched with water (100 mL) and extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Si02, hexane / ethyl acetate, 45%) to give compound 8-3 (7.3 g) as a white oil in 74.55% yield.

[0291] 1 H NMR (400 MHz, DMSO) d 7.19 (dd, J = 8.4, 2.8 Hz, 1H), 6.87 (s, 1H), 6.83 - 6.71 (m, 1H), 3.76 (s, 3H), 3.52 (s, 3H), 2.18 (s, 3H), 1.40 (s, 9H).

[0292] Step 3: To a solution of compound 8-3 (3 g, 0.0095 mol) in CCI4(30 mL) was added NBS (3.38 g, 0.019 mol) and AIBN (1.87 g, 0.0114 mol) slowly. The mixture was stirred at 80 °C for 1.5 hours. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (DCM mL x 3). The organic layer was rotary evaporated to give the crude product of compound 8-4 (6.9 g), which was used directly for the next step without further purification. Yield: 86.32%.

[0293] LCMS: Rt = 1.365 min, MS: No MS

[0294] Step 4: To a solution of compound 8-4 (2.6 g, 0.0066 mol) in DMF (26 mL), NaH (0.19 g, 0.0079 mol) was added portionwise at room temperature under nitrogen atmosphere. The mixture was stirred at 75 °C for 0.5 h. The reaction was quenched with water (30 ml) and extracted with ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Si02, hexane / ethyl acetate, 45%) to give compound 8-5 (1.1 g) as yellow oil. Yield: 50%.

[0295] 1 H NMR (400 MHz, CDC13) δ 7.20 (d, J = 8.8 Hz, 1H), 6.82 (dd, J = 8.8, 2.8 Hz, 1H), 6.73 (d, J = 2.8 Hz, 1H), 3.80 (s, 3H), 3.57 - 3.49 (m, 2H), 3.26 - 3.18 (m, 2H), 1.56 (s, 9H).

[0296] Step 5: To a solution of compound 8-5 (1.1 g, 0.0035 mol) in DCM (50 mL), BBr3(4.38 g, 0.0175 mol) was added dropwise at 0 °C and stirred at room temperature for 1 h. It was quenched with water (30 mL) and extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Si02, hexane / ethyl acetate, 25%) to give compound 8-6 (0.6 g) as yellow solid. Yield: 77.14%.

[0297] LCMS: Rt = 0.597 min, MS: 198.0 ([M-H] + ).

[0298] Step 6: To a solution of compound 8-6 (550 mg, 2.7607 mmol) in DMF (15 mL), 3,5-dichloro-4-fluoronitrobenzene (compound 8-7, 608.71 mg, 2.8987 mmol) and DIEA (713.59 mg, 5.5214 mmol) were added respectively at room temperature and stirred at 60 °C for 3 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound 8-8 (690 mg) as yellow solid. Yield: 48.64%.

[0299] LCMS: Rt = 1.314 min, MS: 386.95 [M-H] + .

[0300] Step 7: To a mixture of compound 8-8 (690 mg, 1.7728 mmol) in ethanol-water (2:1), iron powder (495.05 mg, 8.8639 mmol) and NH4CI (379.31 mg, 7.0912 mmol) were added. The mixture was stirred at 80 °C for 1 h. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was concentrated under vacuum to give the crude product of compound 8-9 (550 mg), which was used directly in the next step without further purification. Yield: 73.41 %.

[0301] LCMS: Rt = 1.314 min, MS: 356.90 [M-H] + .

[0302] Step 8: NaNCte (15 mg, 0.2171 mmol) was added dropwise to a mixture of compound 8-9 (60 mg, 0.167 mmol) and concentrated hydrochloric acid in water (1 mL) at 0 °C. After addition, it was stirred at 0 °C for 0.5 h. The resulting mixture was added dropwise to a mixture of compound 8-10 (31.29 mg, 0.2004 mmol) in pyridine (1 mL) and H2O (2 mL) at 0 °C. Then it was stirred at 0 °C for 2.5 h. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was concentrated under vacuum to give the crude product of compound 8-11 (100 mg), which was used directly in the next step without further purification. Yield: 91.02 %.

[0303] LCMS: Rt = 1.243 min, MS: 524.00 [M-H] + .

[0304] Step 9: To a solution of compound 8-11 (100 mg, 0.19 mmol) in DMAc (2 mL) was added potassium acetate (37.29 mg, 0.39 mmol) at room temperature. The reaction was heated to 120 °C and stirred for 2 h. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by semi-preparative HPLC (acetonitrile / water, 5% to 30% with formic acid) to give compound 8 (16.9 mg) as a yellow solid. Yield: 18.32 %.

[0305] HPLC: Purity: 99.202 % (214 nm) and 98.512 % (254 nm).

[0306] LCMS: Rt = 1.206 min, MS: 477.9 [M-H] +

[0307] 1 H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 9.93 (s, 1H), 7.80 (s, 2H), 6.80 - 6.70 (m, 3H), 3.74 - 2.94 (m, 4H).

[0308] Example 9 and Example 10

[0309] Step 1: To a solution of compound 9-1 (11 g, 50.5 mmol) in CH3CN (110 mL) was added K2CO3 (20.94 g, 151.5 mmol) and BnBr (9.5 g, 55.5 mmol) at room temperature. The reaction was warmed to 80 °C and stirred for 2 h, then cooled to 0 °C and suction filtered. The filtrate was concentrated under vacuum, and the residue was slurried in EtOAc / Hexanes = 1 / 2 (100 mL). The solid was collected by suction filtration to give 15 g of compound 9-2 as a white solid. Yield: 96.48%.

[0310] 1 H NMR (400 MHz, DMSO) δ 8.46 (d, J = 2.8 Hz, 1H), 8.28 (dd, J = 9.2, 2.8 Hz, 1H), 7.50 (d, J = 7.2 Hz, 2H), 7.46 - 7.41 (m, 3H), 7.37 (t, J = 7.2 Hz, 1H), 5.39 (s, 2H).

[0311] Step 2: Compound 9-3 (4.6 g, 53.5 mmol), Pd(OAc)2 (1.09 g, 4.87 mmol), PCy3 (4.1 g, 14.6 mmol), K3PO4 (31 g, 146.1 mmol) and water (15 mL) were added to a solution of compound 9-2 (15 g, 48.7 mmol) in toluene (120 mL) under nitrogen protection, then the reaction was warmed to 120 °C and stirred for 16 h. After the reaction was cooled, water (200 mL) was added, and the organic layer was extracted with ethyl acetate (100 mL x 3), and the combined organic layer was washed with brine (150 mL). After drying and filtration, the solvent was rotary evaporated, and the crude product was purified by flash column chromatography to give 9.5 g of compound 9-4 as a yellow solid. Yield: 72.47%.

[0312] 1H NMR (400 MHz, DMSO) δ 8.08 (dd, J = 9.2, 2.8 Hz, 1H), 7.68 (d, J = 2.8 Hz, 1H), 7.51 (d, J = 7.2 Hz, 2H), 7.43 (t, J = 7.2 Hz, 2H), 7.37 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 9.2 Hz, 1H), 5.33 (s, 2H), 2.24 - 2.15 (m, 1H), 1.06 - 0.96 (m, 2H), 0.77 - 0.74 (m, 2H).

[0313] Step 3: To a solution of compound 9-4 (2.5 g, 9.3 mmol) in MeOH (30 mL) was added Pd / C (0.25 g) and ammonia (0.2 mL) under hydrogen atmosphere (50 Psi) and stirred at 40 °C for 4 h. The reaction was concentrated and the residue was slurried in 25 mL of ethyl acetate. The solid was collected by suction filtration to give 1.2 g of brown solid compound 9-5. Yield: 86.64 %.

[0314] 1 H NMR (400 MHz, DMSO) δ 8.20 (s, 1H), 6.46 (d, J = 8.4 Hz, 1H), 6.19 (dd, J = 8.4, 2.8 Hz, 1H), 5.98 (d, J = 2.8 Hz, 1H), 4.28 (s, 2H), 2.02 - 1.98 (m, 1H), 0.86 - 0.67 (m, 2H), 0.54 - 0.33 (m, 2H).

[0315] Step 4: Compound 9-6 (1.28 g, 6.7 mmol) and K2CO3 (1.85 g, 13.4 mmol) were added to a solution of compound 9-5 (1 g, 6.7 mmol) in DMSO (25 mL) at room temperature and the reaction was heated to 90 °C for 4 h. After completion, water (100 mL) was added to the system and extracted with ethyl acetate (50 mL x 3) and the combined organic layer was washed with brine (20 mL). After drying and filtration, the solvent was evaporated and the crude product was purified by flash column chromatography to give 0.95 g of yellow oily mixture (10-7 / 9-7A = 4 / 1). Yield: 46.64 %.

[0316] 1H NMR (400 MHz, DMSO) δ 7.73 (s, 0.25H), 7.36 (s, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 0.25H), 6.40 (dd, J = 8.4, 2.8 Hz, 1.25H), 6.22 (d, J = 2.8 Hz, 0.25H), 6.18 (d, J = 2.8 Hz, 1H), 4.96 - 4.93 (m, 2.5H), 3.28 - 3.24 (m, 0.25H), 3.16 - 3.08 (m, 1H), 1.70 - 1.66 (m, 1.25H), 1.31 (d, J = 6.8 Hz, 1.5H), 1.24 (d, J = 6.8 Hz, 6H), 0.74 - 0.68 (m, 2.5H), 0.51 - 0.47 (m, 2.5H).

[0317] Step 5: To a solution of compound 10-7 and 9-7A (1 g, 3.3 mmol) in acetic acid (20 mL) was added sodium acetate (0.81 g, 9.9 mmol) at room temperature, the reaction was stirred at 95 °C for 16 h. Water (100 mL) was added to the reaction, extracted with ethyl acetate (30 mL x 3), the organic layers were combined and washed with saturated brine (30 mL) and sodium bicarbonate aqueous solution (30 mL). After drying and filtration, the solvent was removed by rotary evaporation, the crude product was purified by flash column chromatography to give 1.0 g of yellow oil mixture (10-8 / 9-8A = 4 / 1). Yield: 92.78 %.

[0318] LCMS: Rt = 0.998 min, MS: 328.1 [M+H] +

[0319] Step 6: 10-8 and 9-8A (1 g, 3.3 mmol) were dissolved in NaOH / MeOH (20 mL, 1 M) solution, stirred at 95 °C for 16 h. Water (20 mL) and ethyl acetate (20 mL) were added, the pH was adjusted to 2 with hydrochloric acid, the water layer was separated and collected and adjusted to pH ~ 9 with NaHC03. Extracted with ethyl acetate (10 mL x 3), the organic layers were combined and washed with saturated brine (20 mL). After drying and filtration, 500 mg of yellow oil mixture (10-9 / 9-9A = 4 / 1) was obtained. Yield: 57.36 %.

[0320] 1H NMR (400 MHz, DMSO) δ 12.00 (s, 1H), 11.92 (s, 0.25H), 7.12 (s, 1H), 6.73 - 6.70 (m, 1.5H), 6.38 - 6.34 (m, 1.25H), 6.16 (d, J = 2.4 Hz, 0.25H), 6.12 (d, J = 2.4 Hz, 1H), 4.86 (s, 2.5H), 3.04 - 2.97 (m, 1.25H), 1.83 - 1.67 (m, 1.25H), 1.25 (d, J = 6.8 Hz, 1.5H), 1.15 (d, J = 6.8 Hz, 6H), 0.87 - 0.73 (m, 2.5H), 0.55 - 0.41 (m, 2.5H).

[0321] Step 7: To a solution of compound 10-9 and 9-9A (200 mg, 0.70 mmol) and concentrated hydrochloric acid (180 μί, 2.166 mmol) in AcOH (1.5 mL) was added dropwise a solution of sodium nitrite (51.26 mg, 0.743 mmol) in water (1.5 mL) at 0 °C. The reaction was stirred at 0 °C for 0.5 h, then N-cyanoacetureide (109.4 mg, 0.701 mmol) and AcONa (177.6 mg, 2.166 mmol) were added and stirred at 0 °C for 1.5 h. The reaction was filtered, the solid was washed with water and dried under vacuum to give a yellow solid mixture of 10-11 and 9-11A (200 mg). Yield: 62.43 %.

[0322] LCMS (10-11): Rt = 1.270 min, MS: 453.15 [M+H] +

[0323] Step 8: A solution of 9-11A and 10-11 (280 mg, 0.618 mmol) in N,N- dimethylacetamide (3 mL) was warmed to 115 °C under nitrogen protection, then potassium acetate (66.8 mg, 0.681 mmol) was added and stirred at 115 °C for 2 h. The reaction was purified by preparative liquid chromatography (Gemini 5 μιη C18 column, 150*21.2 mm, eluent 30%-90% acetonitrile-water mixture containing 0.1% formic acid) to give two yellow solid compounds 9 (105 mg) and 10 (30 mg) respectively.

[0324] Compound 9: HPLC: Purity: 97.47% (214 nm) and 97.66% (254 nm).

[0325] LCMS: Rt = 1.211 min, MS Calcd.: 406.14, MS Found: 407.05 [M+H] +

[0326] 1 H NMR (400 MHz, DMSO) δ 13.04 (s, 1H), 12.15 (s, 1H), 7.30 (s, 1H), 7.27 (dd, J = 9.2, 5.2 Hz, 2H), 7.08 (s, 1H), 3.07 - 3.00 (m, 1H), 2.02 - 1.92 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H), 0.95 - 0.88 (m, 2H), 0.63 - 0.56 (m, 2H).

[0327] Compound 10: HPLC: Purity: 99.00% (214 nm) and 99.56% (254 nm).

[0328] LCMS: Rt = 1.189 min, MS Calcd.: 406.14, MS Found: 407.05 [M+H] +

[0329] 1 H NMR (400 MHz, DMSO) δ 13.04 (s, 1H), 12.07 (s, 1H), 7.32 - 7.30 (m, 2H), 7.12 (d, J = 2.4 Hz, 1H), 6.81 (s, 1H), 3.14 - 3.07 (m, 1H), 1.95 - 1.86 (m, 1H), 1.28 (d, J = 6.8 Hz, 3H), 0.95 - 0.87 (m, 2H), 0.63 - 0.56 (m, 2H).

[0330] Example 11

[0331] Step 1: In a round bottom flask, compound A5 (4 g, 8 mmol, 1.0 eq), potassium hydroxide (580 mg, 10.4 mmol, 1.3 eq), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (340 mg, 0.8 mmol, 0.1 eq), tris(dibenzylideneacetone)dipalladium (730 mg, 0.8 mmol, 0.1 eq) were dissolved in 1,4-dioxane / water = 1:1 (80 mL), the reaction was heated to 100 °C and stirred for 16 hours under nitrogen protection. At the end of the reaction, the reaction was quenched with 100 mL of water, extracted with ethyl acetate 3 times, 100 mL each time, the organic layer was washed with brine and dried over anhydrous sodium sulfate, concentrated under vacuum to obtain the crude product. Purification by flash preparative liquid chromatography (petroleum ether / ethyl acetate = 82:18) to obtain the target compound 2-1 (1.6 g), white solid, yield: 41.25%.

[0332] LCMS: Rt = 1.472 min, MS: 435.0 [M+H] + .

[0333] Step 2: Sodium methoxide (124 mg, 2.29 mmol, 2.0 eq) was dissolved in methanol (10 mL) at 25 °C, to this solution was added compound 2-1 (500 mg, 1.15 mmol, 1.0 eq). After the above mixture solution was stirred at 25 °C for 5 minutes, compound 11-3 was added dropwise and continued to stir for 5 minutes. Subsequently, the above reaction system was heated to 70 °C and stirred for 18 hours until the reaction was completed. At the end of the reaction, the reaction was quenched with 10 mL of water, extracted with ethyl acetate 3 times, 10 mL each time, the organic layer was washed with brine and dried over anhydrous sodium sulfate, concentrated under vacuum to obtain the crude product. Purification by flash preparative liquid chromatography (petroleum ether / ethyl acetate = 85:15) to obtain the target compound 11-4 (600 mg), white solid, yield: 64.67%.

[0334] LCMS: Rt = 1.551 min, MS: 565.1 [M+H] + .

[0335] Step 3: In a round bottom flask, compound 11-4 (500 mg, 0.884 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (5 mL), to this solution was added trifluoromethanesulfonic acid (0.5 mL), the reaction system was heated to 50 °C and stirred for 7 hours until the reaction was completed. At the end of the reaction, the reaction was quenched with 10 mL of water, extracted with ethyl acetate 3 times, 10 mL each time, the organic layer was washed with brine and dried over anhydrous sodium sulfate, concentrated under vacuum to obtain the crude product. The 11-5 crude product obtained by the above operation (300 mg, 75% purity) was directly used in the next step reaction.

[0336] LCMS: Rt = 1.319 min, MS: 445.0 [M+H] +

[0337] Step 4: Compound 11-5 (20 mg, 0.045 mmol, 1.0 eq) was dissolved in ammonia in methanol solution (7 M, 0.5 mL) at room temperature, the reaction system was stirred at room temperature for 16 hours until the reaction was completed. At the end of the reaction, the reaction system was quenched with 10 mL of water, extracted with ethyl acetate 3 times, 10 mL each time, the organic layer was washed with brine, and anhydrous sodium sulfate was added to dry, concentrated in vacuum to obtain the crude product. Purification by HPLC (acetonitrile-water (0.1% formic acid)) to obtain the target compound 11 (1.82 mg), white solid.

[0338] HPLC: Purity: 97.82% (214 nm).

[0339] LCMS: Rt = 0.999 min, MS: 415.0 [M+H] + .

[0340] 1 H NMR (400 MHz, DMSO) δ 12.18 (s, 1H), 7.73 - 7.66 (m, 4H), 7.38 (s, 1H), 7.22 (s, 2H), 5.15 (s, 1H), 3.07 - 2.98 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H).

[0341] Example 12

[0342] Step 1: To compound 12-1 (5 g, 26.4 mmol) stirred in N,N-dimethylformamide (50 mL) at room temperature under nitrogen protection, potassium carbonate (10.95 g, 79.1 mmol) and 4-methoxychlorobenzene (6.2 g, 39.5 mmol) were added. The reaction mixture was stirred at 60 °C for 16 hours, after the reaction was completed, quenched with water (10 mL) and extracted with ethyl acetate. The combined organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (mobile phase polarity ethyl acetate / petroleum ether, 0% to 50%) to obtain white solid product 12-2 (4.8 g), yield: 58.33%.

[0343] LCMS: Rt = 1.294 min, MS Found: 310.05 [M+H] +

[0344] Step 2: Compound 12-3 (9.18 g, 41.7 mmol) was cooled to 0 °C in tetrahydrofuran (80 mL), n-butyllithium (17.4 mL, 2.4 M) was added. The reaction was stirred at 0 °C for 0.5 h, compound 2 (4.3 g, 13.9 mmol) was added. The reaction was stirred at 60 °C for 4 h. After the reaction was completed, it was quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography to give the product (3.1 g) as yellow oil, yield: 68.97%.

[0345] 1 H NMR (400 MHz, DMSO) δ 7.10 - 7.06 (m, 3H), 6.86 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 9.2 Hz, 1H), 6.68 (dd, J = 9.2, 2.8 Hz, 1H), 5.28 - 4.86 (m, 2H), 3.71 (s, 3H), 3.70 (s, 3H), 2.15 - 2.11 (m, 1H), 1.59 - 1.48 (m, 4H), 0.66 (t, J = 4.4 Hz, 1H).

[0346] Step 3: Compound 12-4 (2.5 g, 7.7 mmol) was added to trifluoroacetic acid (20 mL) solution, trifluoromethanesulfonic acid (2 mL) was added. The reaction was heated to 50 °C and stirred for 4 h, water (100 mL) was added, extracted with ethyl acetate (25 mL x 3), the pH of the organic layer was adjusted to 9 with sodium bicarbonate solution, dried and concentrated, the crude product was purified by silica gel column chromatography to give yellow solid 12-5 (1.3 g). Yield: 82.74%.

[0347] 1 H NMR (400 MHz, DMSO) δ 9.81 (s, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.71 (dd, J = 8.8, 2.4 Hz, 1H), 3.72 (s, 3H), 1.81 - 1.77 (m, 1H), 1.48 (d, J = 7.6 Hz, 4H), 0.59 (t, J = 4.4 Hz, 1H).

[0348] Step 4: Compound 12-5 (1.3 g, 6.4 mmol) was cooled to 0 °C in dichloromethane (10 mL), boron tribromide (8.02 g, 32 mmol) was slowly added. The reaction was stirred at 0 °C for 1 h, 10 mL ice water was added. The filtered product 12-6 was yellow solid 1 g, yield: 81.25%.

[0349] LCMS: Rt = 0.757 min, MS Found: 190.00 [M+H] +

[0350] Step 5: To a solution of compound 12-6 (700 mg, 3.7 mmol) in N,N- dimethylformamide (10 mL) was added compound 12-7 (777 mg, 3.7 mmol) and N,N- diisopropylethylamine (956.27 mg, 7.4 mmol). The reaction was stirred at 60 °C for 3 h, the mixture was extracted with ethyl acetate and water. The combined organic phase was washed with water and saturated brine, dried over sodium sulfate, concentrated in vacuum, purified by silica gel column chromatography (methanol / dichloromethane, 0%~10% elution) to give 1 g yellow solid 12-8, yield 70.57%.

[0351] LCMS: MS: 378.90 [M+H] +

[0352] Step 6: To a solution of compound 12-8 (380 mg, 1 mmol) in ethanol / water = 1:1 (10 mL) was added zinc powder (327.73 mg, 5.01 mmol) and ammonium chloride (268.01 mg, 5.01 mmol) and stirred at 25 °C under nitrogen. The reaction mixture was stirred at 25 °C for 3 h, extracted with ethyl acetate. The combined organic phase was washed with water and saturated brine, dried over sodium sulfate, concentrated to give the product (290 mg) as yellow solid 12-9, yield: 82.04%.

[0353] LCMS: Rt = 1.630 min, MS: 348.95 [M+H] +

[0354] Step 7: To a solution of compound 12-9 (200 mg, 0.573 mmol) was stirred 12 M hydrochloric acid (143 μL, 1.718 mmol) in acetic acid (2.5 mL), dropwise sodium nitrite (41.89 mg, 0.6299 mmol) in water (2.5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h, added compound 12-10 (98.36 mg, 0.63 mmol) and sodium acetate (140 mg, 1.718 mmol), stirred at 0 °C for 1.5 h, filtered, washed with water, dried in vacuum to give compound 12-11 (260 mg, 87.04%) as yellow solid.

[0355] LCMS: Rt = 1.274 min, MS Found: 515.80 [M+H] +

[0356] Step 8: Compound 12-11 (350 mg, 0.678 mmol) was dissolved in N,N- dimethylacetamide (5 mL) and potassium acetate (73.18 mg, 0.746 mmol) was added under nitrogen at 115 °C. The reaction mixture was stirred at 115 °C for 2 h and purified by Prep-HPLC (Gemini 5um C18 column, 150*21.2 mm, eluted with 30%~90% acetonitrile / water (containing 0.1% FA)) to give 12 (125 mg, yield 35.0%) as a yellow solid.

[0357] HPLC: Purity: 96.03% (214 nm) and 95.38% (254 nm).

[0358] LCMS: Rt = 1.241 min, MS Calcd.: 469.03, MS Found: 469.95 [M+H] +

[0359] 1 H NMR (400 MHz, DMSO) d 13.27 (s, 1H), 9.94 (s, 1H), 7.80 (s, 2H), 7.11 (d, J = 2.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.50 (dd, J = 8.8, 2.8 Hz, 1H), 1.86 - 1.75 (m, 1H), 1.51 - 1.48 (m, 1H), 1.43 (s, 3H), 0.68 (t, J = 4.8 Hz, 1H).

[0360] Step 9: Compound 12-P1 and 12-P2: The racemate of compound 12 was further separated by SFC (column: 20 mm id*250 mm, 5 pm; mobile phase: carbon dioxide / methanol (0.1% NH3) = 60 / 40) to give compound 12-P1 (28.02 mg, 99% ee) as the first elute. Further elution gave compound 12-P2 (22.05 mg, 99% ee).

[0361] 12-P1: HPLC: Purity: 99.76% (214 nm) and 99.69% (254 nm).

[0362] LCMS: Rt = 1.243 min, MS Calcd.: 469.03, MS Found: 470.00 [M+H] + .

[0363] 1H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 9.94 (s, 1H), 7.81 (s, 2H), 7.11 (d, J = 2.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.49 (dd, J = 8.8, 2.8 Hz, 1H), 1.85 - 1.81 (m, 1H), 1.50 - 1.44 (m, 1H), 1.44 (s, 3H), 0.68 (t, J = 4.8 Hz, 1H).

[0364] 12-P2: HPLC: Purity: 97.64% (214 nm) and 96.21% (254 nm).

[0365] LCMS: Rt = 1.243 min, MS Calcd.: 469.03, MS Found: 470.00 [M+H] + .

[0366] 1 H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 9.94 (s, 1H), 7.81 (s, 2H), 7.11 (d, J = 2.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.49 (dd, J = 8.8, 2.8 Hz, 1H), 1.85 - 1.81 (m, 1H), 1.50 - 1.44 (m, 1H), 1.44 (s, 3H), 0.68 (t, J = 4.8 Hz, 1H).

[0367] Example 13

[0368] Step 1 : To a solution of compound 13-6A (500 mg, 3.9023 mmol) in N,N- dimethylformamide (8 mL) was added 4-methoxybenzyl chloride (916.70 mg, 5.8534 mmol) and potassium carbonate (809 mg, 5.8534 mmol) under nitrogen protection at room temperature. The mixture was stirred at 80 °C for 3 hours. The mixture was extracted with ice water (20 mL) and ethyl acetate (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by preparative HPLC (acetonitrile in water (formic acid) 5%~30%) to give the product compound 13-6 (200 mg) as a white solid. Yield: 19.61%.

[0369] 1H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 7.15 (t, J = 5.6 Hz, 2H), 6.97 - 6.83 (m, 2H), 4.44 (s, 2H), 3.72 (s, 3H), 1.27 (s, 6H).

[0370] Step 2: Compound A5 (1 g, 2 mmol) was dissolved in diethyl ether (20 mL) and cooled to -78 °C, n-butyllithium (1 mL, 2.4 M) was added slowly. The reaction was stirred for 0.5 h. Morpholine-4-carboxaldehyde (compound 13-2, 460 mg, 4 mmol, was added. The reaction was stirred for 0.5 h. Water (20 mL) was added to the reaction and extracted with ethyl acetate (10 mL x 3) and the combined organic layers were washed with brine (20 ml). After drying and filtration, it was concentrated in vacuum. The crude product was purified by column chromatography to get 290 mg of yellow solid 13-3. Yield: 32.3%.

[0371] 1 H NMR (400 MHz, DMSO) δ 9.99 (s, 1H), 8.14 (s, 2H), 7.47 (s, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 4.84 (s, 2H), 3.71 (s, 3H), 3.13 - 3.04 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H).

[0372] Step 3: A solution of compound 13-3 (250 mg, 0.56 mmol, 1.0 eq) was dissolved in methanol (5 mL), sodium borohydride (42 mg, 1.12 mmol, 2.0 eq) was added slowly at 0 °C under nitrogen. The mixture was slowly heated to room temperature and stirred for 1 h. The mixture was extracted with water (10 mL) and ethyl acetate (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuum. The obtained crude product 13-4 (190 mg, about 90% purity) was used directly for the next step.

[0373] LCMS: Rt = 1.449 min, MS: 449.1 [M+H] +

[0374] Step 4: To a solution of compound 13-4 (180 mg, 0.4 mmol, 1.0 eq) in dichloromethane (10 mL) was added carbon tetrabromide (159 mg, 0.48 mmol, 1.2 eq) and triphenylphosphine (158 mg, 0.6 mmol, 1.5 eq) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 1 h. It was extracted with water (10 mL) and dichloromethane (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The mixture was purified by column chromatography to give compound 13-5 (180 mg) as a white solid. Yield: 78.96 %.

[0375] LCMS: Rt = 1.702 min, MS: 513.0 [M+H] +

[0376] Step 5: To a solution of sodium hydride (6 mg, 0.2537 mmol) in N,N- dimethylformamide (1 mL) was added compound 13-6 (58.16 mg, 0.2342 mmol) at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 10 min. Then compound 13-5 (100 mg, 0.1952 mmol) was added. The resulting solution was slowly warmed to room temperature and stirred for 50 min. It was extracted with water (10 mL) and ethyl acetate (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography to give compound 13-7 (80 mg) as a white solid. Yield: 54.25 %.

[0377] LCMS: Rt = 1.666 min, MS: 679.15 [M-H] +

[0378] Step 6: To a solution of compound 13-7 (80 mg, 0.1177 mmol) in acetonitrile (2 mL) was added dropwise a solution of cerium ammonium nitrate (193.58 mg, 0.3531 mmol) in water (1 mL) at 0 °C under nitrogen and the solution was stirred at room temperature for 16 h. After completion of the reaction, the resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by HPLC (acetonitrile in water (formic acid) 5-30 %) to give product 13 (12.63 mg, 24.21 % yield) as a yellow solid.

[0379] HPLC: Purity: 99.248 % (214 nm).

[0380] LCMS: Rt = 1.191 min, MS: 437.00 [M-H] +

[0381] 1 H NMR (400 MHz, DMSO) δ 12.17 (s, 1H), 10.98 (s, 1H), 7.57 (s, 2H), 7.38 (s, 1H), 4.46 (s, 2H), 3.04 - 3.00 (m, 1H), 1.27 (s, 6H), 1.19 (d, J = 6.8 Hz, 6H).

[0382] Example 14

[0383] Step 1: To a solution of compound 13-3 (100 mg, 0.2236 mmol) in ethanol / water (4 mL), compound 14-2 (62.66 mg, 0.626 mmol) was added and stirred at 90 °C, piperidine (55.21 mg, 0.648 mmol) was added. The reaction mixture was stirred at 90 °C for 16 h, the residue was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with water and saturated brine, dried over sodium sulfate, concentrated in vacuum and purified with Prep-TLC (MeOH / DCM, 1 / 10) to give the product compound 14-3 (40 mg) as a white solid, yield: 33.45 %.

[0384] LCMS: Rt = 1.405 min, MS: 529.05 [M+H] +

[0385] Step 2: To a solution of compound 14-3 (40 mg, 0.0756 mmol) in ethyl acetate (2 mL), 10% palladium on carbon (1.61 mg) was added. The mixture was evacuated, backfilled with hydrogen three times and then charged with hydrogen. The resulting mixture was stirred at room temperature for 16 h. The mixture was filtered and concentrated in vacuum to give the product compound 14-4 (34 mg) as a white solid with 83.73 % yield.

[0386] LCMS: Rt = 1.408 min, MS: 531.10 [M+H] +

[0387] Step 3: Compound 14-4 (34 mg, 0.064 mmol) was dissolved in acetonitrile (2 mL) and stirred under nitrogen at 0 °C, a solution of cerium ammonium nitrate (105.26 mg, 0.192 mmol) in water (0.8 mL) was added dropwise. The reaction mixture was stirred at 25 °C for 2 h and purified by Prep-HPLC (Gemini 5um C18 column, 150*21.2 mm, 30%~90% acetonitrile / water with 0.1% formic acid) to give the product 14 (10 mg) as a white solid with 37.66 % yield.

[0388] HPLC: Purity: 98.83% (214 nm).

[0389] LCMS: Rt = 1.079 min, MS: 411.00 [M+H] +

[0390] 1 H NMR (400 MHz, DMSO) δ 12.20 (s, 1H), 10.65 (s, 1H), 8.02 (s, 1H), 7.43 (s, 2H), 7.37 (s, 1H), 4.41 (t, J = 5.6 Hz, 1H), 3.08 - 2.98 (m, 2H), 2.94 - 2.89 (m, 1H), 1.19 (d, J = 6.8 Hz, 6H). Example 15

[0391] Step 1 : Compound 13-3 (100 mg, 0.224 mmol, 1.0 eq), compound 15-2 (52.38 mg, 0.4472 mmol, 2.0 eq) and ammonium acetate (34.47 mg, 0.4472 mmol, 2.0 eq) were mixed in acetic acid (2 mL) and heated to 110 °C and stirred for 72 h. After completion of the reaction, it was quenched with water (1 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane / methanol) to afford compound 15-3 (120 mg) as a yellow solid in 88.37% yield.

[0392] LCMS: Rt = 1.409 min, MS: 546.0 [M+H] +

[0393] Step 2: To a solution of compound 15-3 (50 mg, 0.0915 mmol, 1.0 eq) in ethyl acetate (2 mL) was added Pd / C (15 mg) and hydrogen was replaced, stirred at room temperature for 12 h. After completion of the reaction, the mixture was filtered, water (5 mL) was added and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford compound 15-4 (50 mg) as a colorless oil in 89.73% yield.

[0394] LCMS: Rt = 1.338 min, MS: 548.0 [M+H] +

[0395] Step 3: Compound 15-4 (45 mg, 0.0821 mmol, 1.0 eq) was dissolved in acetonitrile (2 mL) solution and stirred at 0 °C, a solution of cerium nitrate ammine (135.03 mg, 0.2463 mmol, 3.0 eq) in water (1 mL) was added dropwise slowly. The reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the mixture was quenched with water (1 mL) and purified by preparative HPLC (acetonitrile-water (0.1% trifluoroacetic acid)) to afford 15 (14 mg) as a yellow solid, yield: 37.88%.

[0396] HPLC: Purity: 99.95% (214 nm)

[0397] 1 H NMR (400 MHz, DMSO) d 12.18 (d, J = 10.0 Hz, 2H), 7.53 (s, 2H), 7.38 (s, 1H), 5.02 (dd, J = 8.8, 5.2 Hz, 1H), 3.45 - 3.43 (m, 1H), 3.20 - 3.16 (m, 1H), 3.07 - 3.00 (m, 1H), 1.19 (d, J = 6.8 Hz, 6H).

[0398] Example 16

[0399] Step 1: Compound 16-1 (4.5 g, 0.0174 mol, 1.0 eq), trimethylsilyl cyanide (2.59 g, 0.0261 mol, 1.5 eq) and tetrabutylammonium fluoride (1 M, 0.0261 L) were mixed in acetonitrile (45 mL) and stirred at room temperature for 6 h. After completion of the reaction, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to afford compound 16-2 (3.3 g) as a yellow solid, yield: 83.33%.

[0400] LCMS: Rt = 0.984 min, MS: 206.1 [M+H] +

[0401] Step 2: Compound 16-2 (3.3 g, 0.0161 mol, 1.0 eq) and sodium hydride (1.61 g, 0.0402 mol, 2.5 eq) were mixed in N,N-dimethylformamide (35 mL) at 0 °C and stirred for 30 min under nitrogen. Then compound 16-3 (3.63 g, 0.0193 mol, 1.2 eq) was added and the reaction mixture was stirred at room temperature for 3 h. After the reaction was completed, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give compound 16-4 (2.4 g) as a yellow solid in 57.76% yield.

[0402] LCMS: Rt = 1.027 min, MS: 232.1 [M+H] +

[0403] Step 3: Compound 16-4 (2.48 g, 0.0107 mol, 1.0 eq) and cobalt dichloride hexahydrate (2.78 g, 0.0214 mol, 2.0 eq) were mixed in ethanol (50 mL) at 0 °C, and sodium borohydride (1.21 g, 0.0321 mol, 3.0 eq) was added slowly. The reaction mixture was stirred at 80 °C for 6 h. After the reaction was completed, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel chromatography (dichloromethane / methanol) to give compound 16-5 (1.3 g) as a yellow oil in 54.21% yield.

[0404] LCMS: Rt = 0.863 min, MS: 204.1 [M+H] +

[0405] Step 4: To a solution of compound 16-5 (500 mg, 2.4602 mmol, 1.0 eq) in dichloromethane (8 mL) was added boron tribromide (1849.01 mg, 7.3805 mmol, 3.0 eq) at 0 °C under nitrogen, and the reaction mixture was stirred at 0 °C for 2 h. After the reaction was completed, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel chromatography (dichloromethane / methanol) to give compound 16-6 (370 mg) as a yellow oil in 71.53% yield.

[0406] LCMS: Rt = 0.669 min, MS: 190.1 [M+H] +

[0407] Step 5: Compound 16-6 (370 mg, 1.9555 mmol, 1.0 eq), compound 16-7 (410.64 mg, 1.9555 mmol, 1.0 eq) and N,N-diisopropylethylamine (505.46 mg, 3.911 mmol, 2.0 eq) were mixed in N,N-dimethylformamide (4 mL) and heated to 60 °C and stirred for 4 h. After completion of the reaction, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane / methanol) to afford compound 16-88 (700 mg) as a yellow solid in 84.96% yield.

[0408] LCMS: Rt = 1.223 min, MS: 378.9 [M+H] +

[0409] Step 6: Compound 16-8 (700 mg, 1.846 mmol, 1.0 eq), iron powder (618.59 mg, 11.076 mmol, 6.0 eq) and ammonium chloride (987.43 mg, 18.46 mmol, 10.0 eq) were dissolved in ethanol / water = 3:1 (4 mL), heated to 80 °C in an oil bath and refluxed for 6 h. After completion of the reaction, the mixture was filtered, the filtrate was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford compound 16-9 (200 mg) as a colorless oil in 64.95% yield.

[0410] LCMS: Rt = 1.065 min, MS: 349.0 [M+H] +

[0411] Step 7: To a solution of compound 16-9 (65 mg, 0.1861 mmol, 1.0 eq) in dilute hydrochloric acid (0.5 mL) was added slowly dropwise a solution of sodium nitrite (16.69 mg, 0.2419 mmol, 1.3 eq) in water (1 mL) at 0 °C and the mixture was stirred at 0 °C for 1 hour. Then, compound 16-10 (34.87 mg, 0.2233 mmol, 1.2 eq) was dissolved in pyridine (1 mL) and water (2 mL) and the above mixture was added dropwise thereto. The mixture was stirred at 0 °C for 2 hours. The mixture was quenched with water (2 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford compound 16-11 (90 mg) as a red solid in 84.31% yield.

[0412] LCMS: Rt = 1.150 min, MS: 516.1 [M+H] +

[0413] Step 8: To a solution of compound 16-11 (90 mg, 0.1743 mmol, 1.0 eq) in N,N- dimethylacetamide (3 mL) was added potassium acetate (34.21 mg, 0.3486 mmol, 2.0 eq), heated to 110 °C and stirred for 3 h. The mixture was quenched with water (1 mL) and purified by preparative HPLC (acetonitrile-water (0.1% trifluoroacetic acid)) to give 16 (20 mg) as a yellow solid in 23.18% yield.

[0414] HPLC: Purity: 99.77% (214 nm) and 99.44% (254 nm).

[0415] 1 H NMR (400 MHz, DMSO) δ 13.29 (s, 1H), 7.95 (s, 1H), 7.87 - 7.80 (m, 3H), 6.72 (d, J = 2.4 Hz, 1H), 6.59 - 6.54 (m, 1H), 3.22 (s, 2H), 1.05 - 0.99 (m, 4H).

[0416] Example 17

[0417] Step 1: To a solution of compound 17-1 (9 g, 58.8 mmol) and pyridine (5.12 g, 64.6 mmol) in dichloromethane (80 mL) was added a solution of compound 17-2 (5.83 g, 61.7 mmol) in dichloromethane (20 mL) dropwise at 0 °C under nitrogen, stirred for 3 h at 25 °C, diluted with water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over sodium sulfate, concentrated and then purified by silica gel column chromatography (ethyl acetate / petroleum ether, 30%~50% elution) to give 17-3 (10 g, yield: 79.76%) as a white solid.

[0418] 1 H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 7.25 (s, 1H), 6.97 (d, J = 2.8 Hz, 1H), 6.78 (dd, J = 8.8, 2.8 Hz, 1H), 5.27 (t, J = 5.6 Hz, 1H), 4.45 (d, J = 5.6 Hz, 2H), 3.73 (s, 3H), 3.61 (s, 3H).

[0419] Step 2: To a solution of compound 17-3 (10.8 g, 51.1 mmol) in dichloromethane (120 mL) was added pyridinium chlorochromate (12.12 g, 56.2 mmol) and aluminum oxide (30 g) and the reaction mixture was stirred at 25 °C for 3 h. The resulting mixture was purified by column chromatography on silica gel (eluting with ethyl acetate / petroleum ether, 0% to 30%) to give 17-4 (9 g, yield: 83.37%) as a white solid.

[0420] LCMS: Rt = 0.995 min, MS: 210.00 [M+H] +

[0421] Step 3: Compound 17-5 (0.64 g, 10.8 mmol) was added to a solution of compound 17-4 (1.5 g, 7.2 mmol) in formic acid (25 mL) sequentially. The resulting mixture was heated at 150 °C for 12 h. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over sodium sulfate, concentrated and purified by column chromatography on silica gel (eluting with ethyl acetate / petroleum ether, 0% to 30%) to give 17-6 (0.5 g, yield: 30.56%) as a white solid.

[0422] LCMS: Rt = 1.069 min, MS: 221.00 [M+H] +

[0423] Step 4: Compound 17-6 (500 mg, 2.27 mmol) was added to and slowly dropped into boron tribromide (2843.10 mg, 11.35 mmol) in dichloromethane (10 mL) stirred at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The resulting mixture was quenched with water and filtered to give 17-7 (400 mg, yield: 84.59%) as a yellow solid.

[0424] LCMS: Rt = 0.834 min, MS: 207.00 [M+H] +

[0425] Step 5: Compound 17-7 (360 mg, 1.74 mmol) and compound 17-8 (439.85 mg, 2.09 mmol) were added to a solution of N,N-dimethylformamide (6 mL) stirred under nitrogen protection at 60 °C, and N,N-diisopropylethylamine (676.77 mg, 5.24 mmol) was added. The reaction mixture was stirred at 60 °C for 3 h and extracted with ethyl acetate and water. The organic phase was washed with water and saturated brine, dried over sodium sulfate, concentrated in vacuum and purified by column chromatography on silica gel (eluting with methanol / dichloromethane, 0% to 10%) to give 17-9 (600 mg, yield 85.88%) as a yellow solid.

[0426] LCMS: Rt = 1.099 min, MS: 366.00 [M+H] +

[0427] Step 6: To a solution of compound 17-9 (350 mg, 0.883 mmol) in ethanol / tetrahydrofuran / water = 1:1:2 (10 mL) was added zinc powder (288.88 mg, 4.41 mmol) and ammonium chloride (236.24 mg, 4.41 mmol) and stirred at 25 °C under nitrogen. The reaction mixture was stirred at 25 °C for 3 h, extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over sodium sulfate and concentrated to get yellow solid 17-10 (230 mg, yield: 70.38%).

[0428] LCMS: Rt = 1.099 min, MS: 366.00 [M+H] +

[0429] Step 7: To a stirred solution of compound 17-10 (230 mg, 0.628 mmol) in acetic acid (2.5 mL) at 0 °C was added 12 M hydrochloric acid (157 μL, 1.884 mmol) and a solution of sodium nitrite (45.93 mg, 0.666 mmol) in water (2.5 mL) was added drop wise. The reaction mixture was stirred at 0 °C for 0.5 h, added compound 17-11 (107.86 mg, 0.69 mmol) and sodium acetate 654 mg, 1.884 mmol), stirred at 0 °C for 1.5 h, filtered, washed with water and dried under vacuum to get compound 17-12 (200 mg, 59.11%) as a yellow solid.

[0430] LCMS: Rt = 1.099 min, MS: 366.00 [M+H] +

[0431] Step 8: Compound 17-12 (250 mg, 0.469 mmol) was dissolved in N,N- dimethylacetamide (5 mL) and potassium acetate (50.6 mg, 0.515 mmol) was added at 115 °C under nitrogen stirring. The reaction mixture was stirred at 115 °C for 2 h and purified using prep-HPLC (Gemini 5um C18 column, 150*21.2 mm eluted with 30% to 90% acetonitrile / water containing 0.1% FA) to get compound 17 (70 mg, 30.34%) as a yellow solid.

[0432] HPLC: Purity: 98.87% (214 nm) and 98.58% (254 nm).

[0433] LCMS: Rt = 1.293 min, MS Calcd.: 486.06, MS Found: 487.05 [M+H] +

[0434] 1 H NMR (400 MHz, DMSO) δ 13.29 (s, 1H), 9.10 (s, 1H), 7.79 (s, 2H), 6.73 (dd, J = 8.8, 6.4 Hz, 3H), 4.62 - 4.42 (m, 1H), 4.24 (s, 2H), 1.09 (d, J = 6.8 Hz, 6H).

[0435] Example 18

[0436] Step 1: Compound 18-1 (600 mg, 2.87 mmol, 1.0 eq) and compound 18-2 (461 mg, 4.3 mmol, 1.5 eq) were dissolved in formic acid (10 mL) and reacted by microwave at 140 °C for 1 hour. The mixture was concentrated and purified by silica gel column (petroleum ether: ethyl acetate = 1:1) to give compound 18-3 (600 mg), white solid, yield: 74.07%.

[0437] LCMS: Rt = 1.057 min, MS: 269.1 [M+H] +

[0438] 1 H NMR (400 MHz, DMSO) δ 9.14 (s, 1H), 7.36 - 7.26 (m, 5H), 6.72 - 6.67 (m, 3H), 4.53 (s, 2H), 4.27 (s, 2H), 3.65 (s, 3H).

[0439] Step 2: Compound 18-3 (600 mg, 2.24 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and boron tribromide (1120 mg, 4.47 mmol, 2.0 eq) was added at 0 °C and stirred at 0 °C for 1 hour. The reaction was quenched with water, extracted with dichloromethane / isopropanol (20 mL x 3), the combined organic layers were washed with brine (20 mL) and dried over anhydrous sodium sulfate, concentrated and purified by silica gel column (dichloromethane:methanol = 10:1) to give compound 18-4 (500 mg), yellow solid, yield: 79.14%.

[0440] LCMS: Rt = 0.881 min, MS: 255.1 [M+H] +

[0441] Step 3: Compound 18-4 (500 mg, 1.97 mmol, 1.0 eq) and N, N- diisopropylethylamine (508 mg, 3.93 mmol, 2.0 eq) were dissolved in N, N- dimethylformamide (8 mL), compound 18-5 (412.9 mg, 1.97 mmol, 1.0 eq) was added at 0 °C, and the temperature was raised to 60 °C and stirred for 1 h. Extraction was performed with ethyl acetate (10 mL x 3), the combined organic layers were washed with brine (20 mL), and dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column (dichloromethane: methanol = 10: 1) to give compound 18-6 (600 mg), yellow solid, yield: 61.82%.

[0442] LCMS: Rt = 1.350 min, MS: 444.0 [M+H] +

[0443] Step 4: Compound 18-6 (600 mg, 1.35 mmol, 1.0 eq), iron powder (377.1 mg, 6.75 mmol, 5.0 eq) and ammonium chloride (722.4 mg, 13.50 mmol, 10.0 eq) were dissolved in ethanol / water (5 / 1, 12 mL) and stirred at 80 °C for 2 h. The residue was filtered and concentrated and purified on a silica gel column (dichloromethane: methanol = 10: 1) to give compound 18-7 (400 mg), yellow solid, yield: 64.35%

[0444] LCMS: Rt = 1.184 min, MS: 414.0 [M+H] +

[0445] Step 5: Compound 18-7 (200 mg, 0.48 mmol, 1.0 eq) was dissolved in concentrated hydrochloric acid (2 mL), an aqueous solution (2 mL) of sodium nitrite (43.3 mg, 0.63 mg, 1.3 eq) was added at 0 °C, and stirred for 1 h. Compound 18-8 (90.5 mg, 0.58 mmol, 1.2 eq) was dissolved in pyridine (2 mL) and water (4 mL) and added to the reaction at 0 °C and continued to stir for 1 h at 0 °C. Extraction was performed with ethyl acetate (10 mL x 3), the combined organic layers were washed with brine (20 mL), and dried over anhydrous sodium sulfate, concentrated and no further purification was performed to obtain crude compound 18-9 (200 mg) as a yellow solid, yield: 64.23%.

[0446] LCMS: Rt = 1.157 min, MS: 579.0 [M] +

[0447] Step 6: Compound 18-9 (150 mg, 0.26 mmol, 1.0 eq) was dissolved in anhydrous methanol (5 mL), sodium cyanoborohydride (48.7 mg, 0.78 mmol, 3.0 eq) was added at 0 °C, and stirred at room temperature for 16 h. The reaction was quenched with water, extracted with dichloromethane (10 mL x 3), the combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column (dichloromethane: methanol = 10:1) to give compound 18-10 (80 mg) as a yellow solid in 51.66% yield.

[0448] LCMS: Rt = 1.420 min, MS: 581.0 [M+H] +

[0449] 1 H NMR (400 MHz, DMSO) δ 12.13 (s, 1H), 10.89 (s, 1H), 9.26 (s, 1H), 8.00 (s, 2H), 7.35-7.26 (m, 5H), 6.76 (d, J = 8.8 Hz, 1H), 6.67-6.56 (m, 2H), 4.50 (s, 2H), 4.28-4.16 (m, 4H), 1.27 (t, J = 7.2 Hz, 3H).

[0450] Step 7: Compound 18-10 (80 mg, 0.14 mmol, 1.0 eq) and potassium acetate (40.5 mg, 0.41 mmol, 3.0 eq) were dissolved in N,N-dimethylacetamide (2 mL), heated to 110 °C and stirred for 2 h. The reaction was purified by Genal Prep HPLC to give compound 18 (10 mg) as a yellow solid in 13.15% yield.

[0451] HPLC: Purity: 98.004% (214 nm) and 97.216% (254 nm)

[0452] LCMS: Rt = 1.391 min, MS: 535.0 [M+H] +

[0453] 1 H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 9.27 (s, 1H), 7.77 (s, 2H), 7.30 - 7.20 (m, 5H), 6.78 (d, J = 8.8 Hz, 1H), 6.69 - 6.65 (m, 2H), 4.50 (s, 2H), 4.28 (s, 2H).

[0454] Example 19

[0455] Step 1: 4-methoxyaniline (compound 19-1, 10 g, 0.0812 mol,) and aluminum trichloride (11.9 g, 0.089 mol) were dissolved in dry toluene (150 mL), then boron trichloride (1.00 M in dichloromethane, 90 mL) was added slowly. Then, acetonitrile (13.8 g, 0.336 mL) was added dropwise to the mixture at 0 °C. The mixture was heated at 110 °C for 2 h. The mixture was cooled to room temperature. Then, aqueous hydrochloric acid (1 M, 150 mL) was added to the mixture. The mixture was heated at 80 °C for 0.5 h. The mixture was extracted with ice water (200 mL) and ethyl acetate (200 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography to give compound 19-2 (3.6 g) as a red solid. Yield: 24.14%.

[0456] LCMS: Rt = 0.931 min, MS: 466 [M+H] +

[0457] Step 2: To a solution of compound 19-2 (2 g, 0.0121 mol) in dichloromethane (30 mL) was added 2-isocyanopropane (compound 19-3, 1.54 g, 0.0181 mol) and triethylamine (2.45 g, 0.0242 mol) at room temperature. The mixture was heated at 50 °C for 16 h. The mixture was extracted with ice water (30 mL) and dichloromethane (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography to give compound 19-4 (2.2 g) as a yellow solid. Yield: 65.29%.

[0458] LCMS: Rt = 1.118 min, MS: 251.1 [M+H] +

[0459] Step 3: To a solution of compound 19-4 (200 mg, 0.7991 mmol) in dichloroethane (2 mL) was added p-toluenesulfonic acid (412.82 mg, 2.3973 mmol) at room temperature. The mixture was heated at 90 °C for 2 h. It was extracted with sodium bicarbonate (15 mL) and ethyl acetate (15 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography to give compound 19-5 (140 mg) as a yellow oil. Yield: 60.34%

[0460] LCMS: Rt = 0.654 min, MS: 233.1 [M+H] +

[0461] Step 4: To a solution of compound 19-5 (1.4 g, 0.0060 mol) in dichloromethane (28 mL) was added boron tribromide (7.52 g, 0.03 mol) dropwise at 0 °C. The mixture was stirred at room temperature for 2 h. Extracted with ethyl acetate (15 mL x 3) and water (15 mL). The organic layer was concentrated under vacuum to get crude compound 19-6 (1.1 g). Yield: 66.67 %.

[0462] LCMS: Rt = 0.431 min, MS: 218.6 [M+H] +

[0463] Step 5: To a solution of compound 19-6 (1.1 g, 0.0050 mol) in N,N- dimethylformamide (10 mL) was added N,N-diisopropylethylamine (1.29 g, 0.01 mol) and compound 19-7 (1.05 g, 0.005 mmol) at room temperature. The mixture was heated at 60 °C for 2 h. Extracted with ethyl acetate (15 mL x 3) and water (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography to get compound 19-8 (800 mg) as a yellow solid. Yield: 32.00 %.

[0464] LCMS: Rt = 1.232 min, MS: 408.0 [M+H] +

[0465] Step 6: To a solution of compound 19-8 (80 mg, 0.1960 mmol) in ethanol / water (1.5 mL) was added iron powder (0.67 g, 0.012 mol) and ammonium chloride (42 mg, 0.784 mmol) at room temperature. The mixture was heated at 80 °C for 2 h. Extracted with ethyl acetate (15 mL x 3) and water (15 mL). The organic layer was concentrated under vacuum to get crude compound 19-9 (75 mg). Yield: 80.92 %.

[0466] LCMS: Rt = 1.328 min, MS: 378.1 [M+H] +

[0467] Step 7: To a solution of compound 19-9 (150 mg, 0.3966 mmol) in 12 M hydrochloric acid (1.5 mL) was added dropwise a solution of sodium nitrite (35.58 mg, 0.5155 mmol) in water (1 mL) at 0 °C. After addition, the solution was stirred at 0 °C for 0.5 h. The resulting mixture was added dropwise to a stirred solution of compound 19-10 (68.12 mg, 0.4362 mmol) in pyridine (1 mL) and water (2 mL) at 0 °C. The mixture was then stirred at 0 °C for 2.5 h. Extraction was performed with ethyl acetate (15 mL x 3) and water (15 mL). The organic layer was concentrated under vacuum to give crude compound 19-11 (60 mg). Yield: 19.42%.

[0468] LCMS: Rt = 1.430 min, MS: 547.0 [M+H] +

[0469] Step 8: To a solution of compound 19-11 (60 mg, 0.1100 mmol) in N,N- dimethylformamide, (1 mL) was added sodium acetate (21.59 mg, 0.22 mmol) at room temperature. The mixture was heated at 120 °C for 2 h. After completion of the reaction, the resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by HPLC (acetonitrile in water (formic acid) 5-30%) to give the product 19 (9.9 mg, yield: 16.36%) as a white solid.

[0470] HPLC: Purity: 91.533% (214 nm) and 93.483% (254 nm).

[0471] LCMS: Rt = 1.110 min, MS: 499.0 [M+H] +

[0472] 1 H NMR (400 MHz, DMSO) δ 13.24 (s, 1H), 9.84 (s, 1H), 7.80 (s, 2H), 7.18 (s, 1H), 6.83 (t, J = 6.8 Hz, 1H), 6.73 (dd, J = 8.7, 2.8 Hz, 1H), 4.82 (s, 1H), 4.50 (s, 1H), 4.40 - 4.25 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H).

[0473] Example 20

[0474] Step 1 : Compound 20-1 (5 g, 33.7 mmol, 1.0 eq) and Raney nickel (1.98 g, 33.7 mmol, 1.0 eq) were dissolved in methanol (60 mL) and ammonia water (6 mL) and stirred at 60 °C under a hydrogen atmosphere (3 MPa) for 16 hours. After filtration and concentration, purification was performed on a silica gel column (dichloromethane:methanol = 10:1) to obtain compound 20-2 (3 g) as a yellow oil at a yield of 52.52%.

[0475] LCMS: Rt = 0.859 min, MS: 153.0 [M+H] +

[0476] 1 H NMR (400 MHz, DMSO) δ 6.69 (s, 1H), 6.55 (s 2H), 3.62 (s, 3H), 3.59 (s, 2H).

[0477] Step 2: To a solution of compound 20-2 (2 g, 13.1 mmol, 1.0 eq) in dichloromethane (20 mL) were added triethylamine (2.65 g, 26.2 mmol, 2.0 eq) and compound 20-3 (1.87 g, 13.1 mmol, 1.0 eq) at 0 °C and stirred at room temperature for 3 hours. Extraction was performed with dichloromethane (20 mL x 3), the combined organic layers were washed with brine (30 mL), dried by adding anhydrous sodium sulfate, and concentrated, followed by purification on a silica gel column (petroleum ether:dichloromethane = 3:1) to obtain compound 20-4 (2 g) as a white solid at a yield of 29.77%.

[0478] LCMS: Rt = 1.204 min, MS: 259.0 [M+H] +

[0479] Step 3: Compound 20-4 (1 g, 3.9 mmol, 1.0 eq), N,N'-carbonyldiimidazole (1.90 g, 11.6 mmol, 3.0 eq), and N,N-diisopropylethylamine (1.51 g, 11.6 mmol, 3.0 eq) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 60 °C for 16 hours. The reaction was quenched with ice water, extracted with ethyl acetate (20 mL x 3), the combined organic layers were washed with brine (50 mL), dried by adding anhydrous sodium sulfate, and concentrated, followed by purification on a silica gel column (dichloromethane:methanol = 10:1) to obtain compound 20-5 (900 mg) as a light yellow solid at a yield of 71.79%.

[0480] LCMS: Rt = 1.392 min, MS: 285.0 [M+H] +

[0481] 1 H NMR (400 MHz, DMSO) δ 10.16 (s, 1H), 6.96 (s, 1H), 6.83 (s, 2H), 4.81 (s, 2H), 4.20-4.05 (m, 1H), 3.71 (s, 3H), 1.32 (d, J = 6.0 Hz, 6H).

[0482] Step 4: Compound 20-5 (500 mg, 1.76 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), boron tribromide (1321.6 mg, 5.28 mmol, 3.0 eq) was added at 0 °C and stirred at 0 °C for 1 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (10 mL x 3), the combined organic layers were washed with brine (20 mL) and dried over anhydrous sodium sulfate, concentrated and compound 20-6 (480 mg) was obtained as a yellow solid without further purification, yield: 90.88 %.

[0483] LCMS: Rt = 1.117 min, MS: 271.0 [M+H] +

[0484] Step 5: Compound 20-6 (480 mg, 1.78 mmol, 1.0 eq), compound 20-7 (372.90 mg, 1.78 mmol, 1.0 eq) and N,N-diisopropylethylamine (459 mg, 3.55 mmol, 2.0 eq) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 60 °C for 1 h. Extracted with ethyl acetate (20 mL x 3), the organic layer was washed with brine (60 mL) and dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column (dichloromethane:methanol = 10:1) to give compound 20-8 (450 mg) as a yellow solid, yield: 41.84 %.

[0485] LCMS: Rt = 1.274 min, MS: 460.0 [M+H] +

[0486] Step 6: Compound 20-8 (450 mg, 0.98 mmol, 1.0 eq), iron powder (273 mg, 4.89 mmol, 5.0 eq) and ammonium chloride (522.9 mg, 9.78 mmol, 10.0 eq) were dissolved in ethanol / water (5 / 1, 12 mL) and stirred at 80 °C for 2 h. Filtered and concentrated, purified on a silica gel column (dichloromethane:methanol = 10:1) to give compound 20-9 (400 mg) as a yellow solid, yield: 76.07 %.

[0487] LCMS: Rt = 1.109 min, MS: 430.0 [M+H]+

[0488] Step 7: Compound 20-9 (200 mg, 0.46 mmol, 1.0 eq) was dissolved in concentrated hydrochloric acid (2 mL), sodium nitrite (41.7 mg, 0.60 mg, 1.3 eq) in water (6 mL) was added at 0 °C and stirred at 0 °C for 1 h. Compound 20-10 (87.1 mg, 0.56 mmol, 1.2 eq) was dissolved in pyridine (2.5 mL) and water (5 mL), added to the reaction at 0 °C and continued to stir at 0 °C for 1 h. Extracted with ethyl acetate (10 mL x 3), the organic layer was washed with brine (30 mL) and dried over anhydrous sodium sulfate, concentrated and purified with silica gel column (dichloromethane:methanol = 10:1) to give compound 20-11 (100 mg) as a red solid, yield: 22.70 %.

[0489] LCMS: Rt = 1.327 min, MS: 597.1 [M+H] +

[0490] Step 8: Compound 20-11 (85 mg, 0.14 mmol, 1.0 eq) and potassium acetate (41.9 mg, 0.43 mmol, 3.0 eq) were dissolved in N,N-dimethylacetamide (2 mL), heated to 110 °C and stirred for 2 h. The reaction was purified by Genal Prep HPLC to give compound 20 (22 mg) as a light yellow solid, yield: 36.31 %.

[0491] HPLC: Purity: 99.797 % (214 nm) and 99.827 % (254 nm)

[0492] LCMS: Rt = 1.162 min, MS Calcd.: 550.02, MS Found: 551.0 [M+H] +

[0493] 1 H NMR (400 MHz, DMSO) d 10.28 (s, 1H), 7.80 (s, 2H), 7.01 (d, J = 2.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.75 (dd, J = 8.8, 2.8 Hz, 1H), 4.83 (s, 2H), 4.17 - 4.03 (m, 1H), 1.31 (d, J = 6.8 Hz, 6H).

[0494] Example 21

[0495] Step 1: To a solution of 2-bromo-1-fluoro-4-nitrobenzene (compound 21-1, 3 g, 0.0136 mol), cyclopropyl boronic acid (compound 21-2, 1.75 g, 0.0204 mol) and potassium carbonate (3.76 g, 0.0272 mol) in 1,4-dioxane was added 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (0.5 g, 0.0006 mol). The flask was evacuated and purged with nitrogen three times. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with water 20 mL and extracted with ethyl acetate (20 mL x 3). The organics were washed with brine (30 mL x 2), dried over sodium sulfate and filtered. The filtrate was evaporated under vacuum to get the crude product which was purified on silica gel column (pet. ether 0-10% ethyl acetate) to get compound 21-3 (1.9 g) as colorless oil. Yield: 77.21%.

[0496] 1 H NMR (400 MHz, DMSO) δ 8.12 - 8.07 (m, 1H), 7.83 (dd, J = 6.4, 2.8 Hz, 1H), 7.45 (t, J = 9.2 Hz, 1H), 2.19 - 2.08 (m, 1H), 1.12 - 1.04 (m, 2H), 0.91 - 0.85 (m, 2H).

[0497] Step 2: To a solution of 2-cyclopropyl-1-fluoro-4-nitrobenzene (compound 21-3, 500 mg, 2.7599 mmol), 3-isopropyl-4-methoxyphenol (458.74 mg, 2.7599 mmol) and potassium carbonate (762.89 mg, 5.5198 mmol) in N,N-dimethylformamide (10 mL) was stirred at 80 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organics were washed with brine (30 mL x 2), dried over sodium sulfate and filtered. The filtrate was evaporated under vacuum to get the crude product which was purified on silica gel column (100% n-hexane) to get compound 21-4 (515 mg) as colorless oil with 39.90% yield.

[0498] LCMS: Rt = 1.902 min, MS Found: 327.7 [M+H] +

[0499] Step 3: To a solution of 2-cyclopropyl-l-(3-isopropyl-4-methoxyphenoxy)-4- nitrobenzene (compound 21-4, 200 mg, 0.6109 mmol) in dichloromethane was added boron tribromide (459.13 mg, 1.8327 mmol) and stirred at 0 °C for 2 h. Then the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (30 mL x 2) and dried over sodium sulfate, filtered. The filtrate was evaporated under vacuum to get the crude product which was purified by flash chromatography (100% dichloromethane) to get compound 21-5 (148 mg) as a brown solid in 77.31% yield.

[0500] 1 H NMR (400 MHz, DMSO) δ 9.46 (s, 1H), 7.99 (dd, J = 9.2, 2.8 Hz, 1H), 7.75 (d, J = 2.8 Hz, 1H), 6.92 (d, J = 2.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 6.80 (dd, J = 8.8, 2.8 Hz, 1H), 6.71 (d, J = 9.2 Hz, 1H), 3.25 - 3.18 (m, 1H), 2.30 - 2.25 (m, 1H), 1.15 (d, J = 6.8 Hz, 6H), 1.06 - 1.02 (m, 2H), 0.87 - 0.82 (m, 2H).

[0501] Step 4: To 4-(2-cyclopropyl-4-nitrophenoxy)-2-isopropylphenol (compound 21-5, 150 mg, 0.4787 mmol) in ether and water was added iron powder (133.68 mg, 2.3935 mmol) and ammonium chloride (128.03 mg, 2.3935 mmol) and refluxed for 16 h. The reaction mixture was filtered and the filtrate was evaporated under vacuum to get compound 21-6 (150 mg) as a white solid in 99.52% yield.

[0502] 1 H NMR (400 MHz, DMSO) δ 9.46 (s, 1H), 7.99 (dd, J = 9.2, 2.8 Hz, 1H), 7.75 (d, J = 2.8 Hz, 1H), 6.92 (d, J = 2.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 6.80 (dd, J = 8.8, 2.8 Hz, 1H), 6.71 (d, J = 9.2 Hz, 1H), 3.25 - 3.18 (m, 1H), 2.30 - 2.25 (m, 1H), 1.15 (d, J = 6.8 Hz, 6H), 1.06 - 1.02 (m, 2H), 0.87 - 0.82 (m, 2H).

[0503] Step 5: A mixture of 4-(4-amino-2-cyclopropylphenoxy)-2-isopropylphenol (compound 21-6, 50 mg, 0.1765 mmol) and sodium nitrite (17.05 mg, 0.2471 mmol) in 6N aqueous hydrochloric acid was added to a solution of ethyl N-(2-cyanoacetyl)carbamate (compound 21-7, 35.83 mg, 0.2294 mmol) in pyridine and water and stirred at 0 °C for 2.5 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (30 mL x 2) and then dried over sodium sulfate and filtered. The filtrate was evaporated under vacuum to give 21-8 crude product which was used in the next reaction without further purification.

[0504] LCMS: Rt = 1.444 min, MS Found: 451.2 [M+H] +

[0505] Step 6: Sodium acetate (45.51 mg, 0.555 mmol) was added to a solution of compound 21-8 (50 mg, 0.111 mmol) in N,N-dimethylformamide and stirred at 120 °C for 1 h. The organic phase was combined and concentrated under vacuum and purified by preparative high performance liquid chromatography to give compound 21 (10.08 mg) as a yellow solid. Yield: 21.98 %.

[0506] HPLC: Purity: 97.97 % (214 nm) and 97.79 % (254 nm)

[0507] LCMS: Rt = 1.388 min, MS Calcd.: 404.15, MS Found: 402.9 [M+H] +

[0508] 1 H NMR (400 MHz, DMSO) d 12.99 (s, 1H), 9.27 (s, 1H), 7.17 (dd, J = 8.8, 2.4 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 2.8 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.68 (dd, J = 8.8, 2.8 Hz, 1H), 3.23 - 3.16 (m, 1H), 2.21 - 2.16 (m, 1H), 1.14 (d, J = 6.8 Hz, 6H), 1.01 - 0.95 (m, 2H), 0.66 (q, J = 6.0 Hz, 2H).

[0509] Example 22

[0510] Step 1 : A mixture of compound 2-1 (250 mg, 0.5743 mmol), acrylonitrile (2.5 mL) and triethylamine (87.01 mg, 0.8614 mmol) was refluxed for 48 h. Then, the mixture was filtered through celite. The filtrate was concentrated under vacuum to get crude 22-2 (70 mg) which was used directly in the next step. Yield: 22.46%.

[0511] LCMS: Rt = 1.533 min, MS: 488.05 [M+H] +

[0512] Step 2: Compound 22-2 (70 mg, 0.1433 mmol) was dissolved in 12 M hydrochloric acid (4 mL), the mixture was heated at 100 °C for 3 h. Then, the mixture was filtered through celite. The filtrate was concentrated under vacuum to get crude 22-3 (65 mg) which was used directly in the next step. Yield: 93.72%.

[0513] LCMS: Rt = 1.454 min, MS: 507.05 [M+H] +

[0514] Step 3: To a solution of compound 22-3 (80 mg, 0.1577 mmol) in acetonitrile (1.5 mL) was added dropwise a solution of cerium ammonium nitrate (259.36 mg, 0.4731 mmol) in water (0.75 mL) at 0 °C under N2protection. After addition, the solution was stirred at room temperature for 16 h. After reaction, the resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by HPLC (acetonitrile in water (trifluoroacetic acid) 5%~30%) to give product 22 (10 mg, 16.23% yield) as a white solid.

[0515] HPLC: Purity: 99.514% (214 nm).

[0516] LCMS: Rt = 1.110 min, MS: 387.00 [M-H] +

[0517] 1H NMR (400 MHz, DMSO) δ 12.38 (s, 1H), 12.15 (s, 1H), 7.35 (s, 1H), 7.22 (s, 2H), 4.23 (t, J = 6.0 Hz, 2H), 3.05 - 3.01 (m, 1H), 2.69 (t, J = 6.0 Hz, 2H), 1.18 (d, J = 6.8 Hz, 6H).

[0518] Example 23

[0519] Step 1: A solution containing compound A5 (3 g, 0.0060 mol, 1.0 eq), triethylamine (1.21 g, 0.012 mol, 2.0 eq), 1,3-bis(diphenylphosphino)propane (7.42 g, 0.0180 mol, 3.0 eq) and palladium acetate (0.13 g, 0.0006 mol, 0.1 eq) in acetonitrile / methanol = 5:1 (82 mL) was placed in a heating to 90 °C and stirred for 18 hours. After the reaction was completed, the mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give compound 23-2 (2.5 g) as a white solid, yield: 78.33%.

[0520] LCMS: Rt = 2.144 min, MS: 477.0 [M+H] +

[0521] Step 2: Compound 23-2 (1 g, 0.0021 mol, 1.0 eq) and hydrazine hydrate (1.05 g, 0.021 mol, 10.0 eq) were dissolved in ethanol (10 mL) and heated to 80 °C reflux for 6 hours. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel chromatography (dichloromethane / methanol) to give compound 23-3 (0.6 g) as a colorless oil, yield: 52.38%.

[0522] LCMS: Rt = 1.127 min, MS: 477.0 [M+H] +

[0523] Step 3: To a solution of compound 23-3 (500 mg, 1.0475 mmol, 1.0 eq) and triethylamine (317.99 mg, 3.1425 mmol, 3.0 eq) in dichloromethane (5 mL) stirred at 0 °C under air was added compound 23-4 (128.33 mg, 1.0475 mmol, 1.0 eq) and stirred at room temperature for 2 h. Then p-toluenesulfonyl chloride (199.71 mg, 1.0475 mmol, 1.0 eq) was added and the reaction mixture was stirred at room temperature for 16 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by silica gel chromatography (dichloromethane / methanol) to give compound 23-5 (300 mg) as a yellow solid in 47.26% yield.

[0524] LCMS: Rt = 1.575 min, MS: 545.0 [M+H] +

[0525] Step 4: A solution containing compound 23-5 (200 mg, 0.3667 mmol, 1.0 eq) in 7 M ammonia in methanol (5 mL) was heated to 80 °C and refluxed for 12 h. Concentrated in vacuum to give compound 23-6 (100 mg) as a yellow oil in 46.28% yield.

[0526] LCMS: Rt = 1.357 min, MS: 529.1 [M+H] +

[0527] Step 5: To a solution of compound 23-6 (100 mg, 0.1886 mmol, 1.0 eq) in acetonitrile (1 mL) was added dropwise a solution of cerium nitrate ammine (310.18 mg, 0.5658 mmol, 3.0 eq) in water (0.5 mL) at 0 °C and the reaction mixture was stirred at room temperature for 3 h. The mixture was quenched with water (1 mL) and purified by preparative HPLC (acetonitrile-water (0.1% trifluoroacetic acid)) to give compound 23 (18.5 mg) as a yellow solid in 22.69% yield.

[0528] HPLC: Purity: 99.91% (214 nm) and 99.91% (254 nm).

[0529] 1H NMR (400 MHz, DMSO) δ 12.27 (s, 1H), 8.74 (s, 1H), 8.34 (s, 1H), 8.27 (d, J = 1.2 Hz, 2H), 7.46 (s, 1H), 3.09 - 3.02 (m, 1H), 1.20 (d, J = 6.8 Hz, 6H).

[0530] Example 24

[0531] Step 1: To a solution of compound 24-1 (500 mg, 1.1512 mmol) in N,N- dimethylformamide was added methyl 2-bromoacetate (compound 24-2, 193.72 mg, 1.2663 mmol) and N,N-diisopropyl ethylamine (446.34 mg, 3.4536 mmol) and stirred at 60 °C for 16 hours. The reaction mixture was diluted with water 20 mL and extracted with ethyl acetate (20 mL x 3). The organic was washed with brine (30 mL x 2), dried over sodium sulfate and then filtered. The filtrate was evaporated in vacuum to get the crude product which was purified by flash (ethyl acetate in petroleum ether 0-25%) to get compound 24-3 (400 mg) as a yellow solid with 71.5% yield.

[0532] 1 H NMR (400 MHz, DMSO) δ 7.31 (s, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 6.76 (s, 2H), 6.55 (t, J = 6.4 Hz, 1H), 4.86 (s, 2H), 4.02 (d, J = 6.4 Hz, 2H), 3.71 (s, 3H), 3.67 (s, 3H), 3.06 - 3.02 (m, 1H), 1.15 (d, J = 6.8 Hz, 6H).

[0533] Step 2: To a solution of (3,5-dichloro-4-(5-isopropyl-l-(4-methoxybenzyl)-6-oxo-l,6- dihydropyridin-3-yl)oxy-phenyl) glycine methyl ester (compound 24-3, 400 mg, 0.8231 mmol) and N,N-diisopropyl ethylamine (531.89 mg, 4.1155 mmol) in dichloromethane was added tert-butyl (chlorosulfonyl)carbamate (compound 24-4, 356.67 mg, 1.6462 mmol) at 0 °C, then stirred at 25 °C for 16 h. Then trifluoroacetic acid was added to the above mixture, stirred for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic was washed with brine (30 mL x 2), dried over sodium sulfate and filtered. The filtrate was evaporated in vacuum to give the crude product which was purified by flash chromatography (0-50% ethyl acetate in hexane) to give compound 24-5 (180 mg) as a yellow solid in 38.71% yield.

[0534] 1 H NMR (400 MHz, DMSO) δ 7.64 (s, 2H), 7.51 (s, 2H), 7.41 (s, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 4.85 (s, 2H), 4.54 (s, 2H), 3.71 (s, 3H), 3.65 (s, 3H), 3.11 - 3.01 (m, 1H), 1.17 (d, J = 6.8 Hz, 6H).

[0535] Step 3: To a solution of compound 24-5 (150 mg, 0.2562 mmol) in tetrahydrofuran was added sodium hydride (20.5 mg, 0.5124 mmol) at 0 °C and stirred for 1 h under nitrogen atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic was washed with brine (30 mL x 2), dried over sodium sulfate and then filtered. The filtrate was evaporated in vacuum to give the crude product which was purified by flash chromatography (0-25% ethyl acetate in hexane) to give compound 24-6 (148 mg) as a white solid in 99.18% yield.

[0536] 1 H NMR (400 MHz, DMSO) δ 7.38 (s, 1H), 7.22 (s, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 4.87 (s, 2H), 4.10 (s, 2H), 3.71 (s, 3H), 3.07 - 3.03 (m, 1H), 1.17 (d, J = 6.8 Hz, 6H).

[0537] Step 4: 5-(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6- dihydropyridin-3-yl)oxy)phenyl)-1,2,5-thiadiazolidine-3-ium 1,1-dioxide (24-6, 25 mg, 0.0452 mmol) was stirred in trifluoroacetic acid and trifluoromethanesulfonic acid at 50 °C for 20 min. The organic phase was combined and concentrated in vacuo, purified by preparative high performance liquid chromatography (Gemini 5um C18 column, 150*21.2mm, 30%~90% acetonitrile / water with 0.1% FA) to give compound 24 (4 mg) as a white solid in 19.47% yield.

[0538] HPLC: Purity: 96.72% (214 nm) & 94.50% (254 nm)

[0539] LCMS: Rt = 1.237 min, MS Calcd.: 432.01, MS Found: 433.0 [M-H] +

[0540] 1 H NMR (400 MHz, CDC13) δ 7.31 (s, 2H), 7.18 (s, 1H), 4.47 (s, 2H), 3.26 - 3.19 (m, 1H), 1.30 (d, J = 6.8 Hz, 6H).

[0541] Examples 25, 26, 27

[0542] Step 1: In a round-bottom flask, compound A5 (1 g, 2 mmol, 1.0 eq), compound 25-2 (570 mg, 4 mmol, 2.0 eq), compound 25-5 (57 mg, 0.4 mmol, 0.2 eq), cuprous iodide (38 mg, 0.2 mmol, 0.1 eq), potassium carbonate (555 mg, 4 mmol, 2.0 eq) were dissolved in 1,4-dioxane (6 mL), the reaction system was heated to 120 °C, stirred for 16 hours under nitrogen protection. When the reaction was completed, the reaction system was quenched with 20 mL of water, extracted with ethyl acetate for 3 times, 20 mL each time, the organic layer was washed with brine and anhydrous sodium sulfate was added to dry, concentrated in vacuo to obtain the crude product. Purified by flash preparative liquid chromatography (petroleum ether / ethyl acetate = 45:55) to obtain the target compound 25-3 (450 mg), yellow solid, yield: 36.07%.

[0543] LCMS: Rt = 1.439 min, MS: 559.1 [M+H] +

[0544] Step 2: In a round bottom flask, compound 25-3 (450 mg, 0.8 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (6 mL), to this solution triflic acid (0.6 mL) was added drop wise, the reaction was heated to 50 °C and stirred for 2 h till the completion of the reaction. At the end of the reaction, the reaction was quenched with 10 mL of water, extracted with ethyl acetate 3 times, 10 mL each, washed the organic layer with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to get the crude product. The crude product 25-4 (240 mg, 80% purity) obtained above was used directly for the next reaction.

[0545] LCMS: Rt = 1.189 min, MS: 439.0 [M+H] +

[0546] Step 3: In a round bottom flask, compound 25-4 (180 mg, 0.41 mmol, 1.0 eq), lithium hydroxide (29.5 mg, 1.23 mmol, 3.0 eq) was dissolved in methanol / water = 2 / 1 (6 mL), the reaction was heated to 40 °C and stirred for 2 h under nitrogen atmosphere. At the end of the reaction, the reaction was quenched with 20 mL of water, extracted with ethyl acetate 3 times, 20 mL each, washed the organic layer with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to get the crude product. Purification by HPLC (ACN-H20 (0.1% TFA)) gave compound 25 (183.04 mg) as a white solid in 94.53% yield.

[0547] HPLC: Purity: 95.57% (214 nm), 93.65% (254 nm).

[0548] LCMS: Rt = 1.004 min, MS: 425.0 [M+H] +

[0549] 1 H NMR (400 MHz, DMSO) δ 12.22 (s, 1H), 11.22 (s, 1H), 8.10 (s, 2H), 7.96 (s, 1H), 7.42 (s, 1H), 3.06 - 3.03 (m, 1H), 1.19 (d, J = 6.8 Hz, 6H).

[0550] Step 4: In a round bottom flask, compound 25 (150 mg, 0.35 mmol, 1.0 eq), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (108 mg, 0.56 mmol, 1.6 eq), 1- hydroxybenzotriazole (76 mg, 0.56 mmol, 1.6 eq), N'N-diisopropylethylamine (228 mg, 1.76 mmol, 5.0 eq) were dissolved in N'N-dimethylacetamide (5 mL) and the reaction was stirred at 0 °C under nitrogen atmosphere for 1.5 h. After completion of the pre-reaction, ammonium chloride (38 mg, 0.7 mmol, 2.0 eq) was added to the reaction mixture at 0 °C, then the reaction mixture was allowed to warm up to room temperature and stirred for 14.5 h until completion of the reaction. At the end of the reaction, the reaction mixture was quenched with 10 mL of water, extracted with ethyl acetate 3 times, 10 mL each time, washed the organic layer with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to get the crude product. Purification by HPLC (acetonitrile-water (0.1% trifluoroacetic acid)) gave compound 26 (43.56 mg) as a white solid in 27.64% yield.

[0551] HPLC: Purity: 93.99% (214 nm), 93.63% (254 nm).

[0552] LCMS: Rt = 0.965 min, MS: 424.0 [M+H] +

[0553] 1 H NMR (400 MHz, DMSO) d 12.22 (s, 1H), 10.97 (s, 1H), 7.98 (s, 2H), 7.79 (d, J = 2.0 Hz, 1H), 7.42 (s, 1H), 7.40 (s, 2H), 1.19 (d, J = 6.8 Hz, 6H).

[0554] Step 5: In a round bottom flask, compound 26 (30 mg, 0.07 mmol, 1.0 eq), Burgess reagent (50.5 mg, 0.21 mmol, 3.0 eq) were dissolved in 1,2-dichloroethane (5 mL) and the reaction was heated to 50 °C and stirred under nitrogen atmosphere for 1 h. At the end of the reaction, the reaction mixture was quenched with 10 mL of water, extracted with ethyl acetate 3 times, 10 mL each time, washed the organic layer with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to get the crude product. Purification by HPLC (acetonitrile-water (0.1% trifluoroacetic acid)) gave 27 (1.76 mg) as a yellow solid in 5.23% yield.

[0555] HPLC: Purity: 84.64% (214 nm), 85.74% (254 nm).

[0556] LCMS: Rt = 1.088 min, MS: 406.0 [M+H] +

[0557] Example 28

[0558] Step 1: To a solution of compound 15-1 (50 mg, 0.0915 mmol, 1.0 eq) in acetonitrile / water = 2:1 (1.5 mL) was added cerium ammonium nitrate (150.49 mg, 0.2745 mmol, 3.0 eq) at 0 °C, the reaction mixture was stirred at room temperature for 4 h. The mixture was quenched with water (1 mL) and purified by preparative HPLC (acetonitrile-water (0.1% trifluoroacetic acid)) to give 28 (4 mg) as a yellow solid, yield: 9.73%.

[0559] HPLC: Purity: 89.40% (214 nm) and 93.48% (254 nm)

[0560] 1 H NMR (400 MHz, DMSO) d 12.80 (s, 1H), 12.23 (s, 1H), 7.80 - 7.79 (m, 3H), 7.43 (s, 1H), 3.08 - 3.01 (m, 1H), 1.19 (d, J = 6.8 Hz, 6H).

[0561] Example 29

[0562] Step 1: To a solution of 12-8 (500 mg, 1.3186 mmol, 1.0 eq) in N,N- dimethylformamide (5 mL) stirred under nitrogen at 0 °C was added sodium hydride (105.48 mg, 2.6372 mmol, 2.0 eq) and stirred for 0.5 h. Then, iodomethane (280.74 mg, 1.9779 mmol, 1.5 eq) was added and the reaction mixture was stirred at room temperature for 2.5 h. The mixture was quenched with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give compound 29-1 (300 mg) as a yellow solid, yield: 52.07%.

[0563] LCMS: Rt = 1.332 min, MS: 393.0 [M+H] +

[0564] Step 2: Compound 29-1 (300 mg, 0.7629 mmol, 1.0 eq), iron powder (255.65 mg, 4.5774 mmol, 6.0 eq) and ammonium chloride (408.08 mg, 7.6290 mmol, 10.0 eq) were dissolved in ethanol / water = 3:1 (4 mL), heated to 80 °C in an oil bath and refluxed for 6 h. After completion of the reaction, the mixture was filtered, the filtrate was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give compound 29-2 (200 mg) as a colorless oil in 64.95% yield.

[0565] LCMS: Rt = 1.147 min, MS: 363.0 [M+H] +

[0566] Step 3: To a solution of compound 29-2 (200 mg, 0.5506 mmol, 1.0 eq) in hydrochloric acid (1 mL) was added dropwise a solution of sodium nitrite (49.39 mg, 0.7157 mmol, 1.3 eq) in water (2 mL) at 0 °C and the mixture was stirred at 0 °C for 1 h. Then, compound 29-3 (103.16 mg, 0.6607 mmol, 1.2 eq) was dissolved in pyridine (2 mL) and water (4 mL) and the above mixture was added dropwise thereto. The mixture was stirred at 0 °C for 2 h. The mixture was quenched with water (2 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give compound 29-4 (200 mg) as a red solid in 61.64% yield.

[0567] LCMS: Rt = 1.223 min, MS: 530.0 [M+H] +

[0568] Step 4: To a solution of compound 29-4 (200 mg, 0.3771 mmol, 1.0 eq) in N,N- dimethylacetamide (3 mL) was added potassium acetate (111.03 mg, 1.1313 mmol, 3.0 eq), heated to 115 °C and stirred for 3 h. The mixture was quenched with water (1 mL) and purified by preparative HPLC (acetonitrile-water (0.1% trifluoroacetic acid)) to give compound 29 (135.7 mg) as a yellow solid in 70.59% yield.

[0569] HPLC: Purity: 98.65% (214 nm) and 97.92% (254 nm).

[0570] 1H NMR (400 MHz, DMSO) δ 13.29 (s, 1H), 7.82 (s, 2H), 7.22 (d, J = 2.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.55 (dd, J = 8.8, 2.8 Hz, 1H), 3.19 (s, 3H), 2.06 - 2.03 (m, 1H), 1.53 - 1.49 (m, 1H), 1.47 (s, 3H), 0.69 (t, J = 4.4 Hz, 1H).

[0571] Example 30

[0572] Step 1: To a solution of compound 30-3 (3 g, 5 mmol) in tetrahydrofuran (30 mL) was added 1 N hydrochloric acid solution (6 ml). The reaction mixture was stirred at 25 °C for 1 h, extracted with ethyl acetate. The combined organic phase was washed with water and saturated brine, dried over sodium sulfate, concentrated, purified by silica gel column chromatography (eluted with ethyl acetate / hexane, 0%~80%) to give white solid 30-4 (2 g, yield: 92.00%).

[0573] LCMS: Rt = 1.478 min, MS: 434.00 [M+H] +

[0574] Step 2: To a solution of compound 30-3 (3 g, 5 mmol) in tetrahydrofuran (30 mL) was added 1 N hydrochloric acid solution (6 ml). The reaction mixture was stirred at 25 °C for 1 h, extracted with ethyl acetate. The combined organic phase was washed with water and saturated brine, dried over sodium sulfate, concentrated, purified by silica gel column chromatography (eluted with ethyl acetate / hexane, 0%~80%) to give white solid 30-4 (2 g, yield: 92.00%).

[0575] LCMS: Rt = 1.478 min, MS: 434.00 [M+H] +

[0576] Step 3: To a stirred solution of compound 30-4 (500 mg, 1.15 mmol), compound 30-5 (269.15 mg, 1.61 mmol) and N,N-diisopropylethylamine (297.56 mg, 2.3 mmol) in 1,3-dimethyl-2-imidazolidinone (4 mL) was stirred at 100 °C under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 2 h, purified on Biotage Isolera One (C18 column, eluted with 10-90% acetonitrile / water containing 0.1% ammonia water) to afford 30-6 (200 mg, yield: 33.05%) as a white solid.

[0577] LCMS: Rt = 1.364 min, MS: 520.20 [M+H] +

[0578] Step 4: To a stirred solution of compound 30-6 (25 mg, 0.048 mmol) in trifluoroacetic acid (0.4 mL) was added trifluoromethanesulfonic acid (0.2 mL) at 50 °C. The reaction mixture was stirred at 50 °C for 1 h, purified on prep-HPLC (Gemini 5um C18 column, 150*21.2 mm, 30%~90% acetonitrile / water containing 0.1% FA) to afford the product 30 (1.5 mg, yield: 7.71%) as a yellow solid.

[0579] HPLC: Purity: 98.11% (214 nm) and 98.59% (254 nm).

[0580] LCMS: Rt = 1.246 min, MS Calcd.: 399.08, MS Found: 399.95 [M+H] +

[0581] 1 H NMR (400 MHz, DMSO) d 12.13 (s, 1H), 7.31 (s, 1H), 6.54 (s, 2H), 3.05-2.97 (m, 1H), 1.43 (s, 6H), 1.17 (d, J = 6.8 Hz, 6H).

[0582] Example 31

[0583] Step 1: To a solution of compound 31-1 (10 g, 0.0799 mol) in dichloromethane (100 mL) was added N-bromosuccinimide (17.06 g, 0.0958 mol) at 0 °C. The mixture was stirred at room temperature for 0.5 h. Extracted with dichloromethane (100 mL x 3) and water (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography to give compound 31-2 (4.8 g) as a red solid. Yield: 28.04%.

[0584] 1 H NMR (400 MHz, DMSO) δ 11.76 (s, 1H), 7.18 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 3.71 (s, 3H).

[0585] Step 2: To a solution of compound 31-2 (2000 mg, 9.803 mmol) in ethylene glycol dimethyl ether (30 mL) was added compound 31-3 (2000 mg, 11.763 mmol) and cesium carbonate (6388.0 mg, 19.606 mmol) under nitrogen protection. The mixture was heated at 80 °C for 6 h. Extracted with water (30 mL) and ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography to give compound 31-4 (1.8 g) as a yellow oil. Yield: 44.77%.

[0586] LCMS: Rt = 1.017 min, MS: 247.90 [M+H] +

[0587] Step 3: Compound 31-4 (1.9 g, 0.0077 mol) was dissolved in dioxane (30 mL), then pinacol diborane (2.35 g, 0.0092 mol), potassium acetate (1.51 g, 0.0154 mol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.56 g, 0.0007 mol) were added, the mixture was heated at 90 °C for 1 h. Extracted with water (15 mL) and ethyl acetate (15 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography to give compound 31-5 (0.6 g) as a yellow oil. Yield: 23.38%.

[0588] LCMS: Rt = 1.542 min, MS: 294.1 [M+H] +

[0589] Step 4: To a solution of compound 31-5 (500 mg, 1.7055 mmol) in N,N- dimethylformamide (5 mL) was added dropwise a solution of hydrogen peroxide (51.05 mg, 1.5008 mmol) at 0 °C, the mixture was stirred at room temperature for 12 hours. Extraction with water (15 mL) and ethyl acetate (15 mL x 3), the organic layer was concentrated under vacuum to give the crude compound 31-6 (290 mg). Yield: 69.61 %.

[0590] LCMS: Rt = 0.913 min, MS: 184.1 [M+H] +

[0591] Step 5: To a solution of compound 31-6 (220 mg, 1.2008 mmol) in N,N- dimethylformamide (3 mL) was added compound 31-7 (252 mg, 1.2008 mmol) and N,N- diisopropylethylamine (310.38 mg, 2.4016 mmol), the mixture was stirred at room temperature for 2 hours. Extraction with water (15 mL) and ethyl acetate (15 mL x 3), the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography to give compound 31-8 (150 mg) as a yellow solid. Yield: 30.12 %.

[0592] LCMS: Rt = 1.607 min, MS: 372.9 [M-H] +

[0593] Step 6: To a solution of compound 31-8 (200 mg, 0.5359 mmol) in ethanol / water (3 mL) was added iron powder (149.65 mg, 2.6795 mmol) and ammonium chloride (114.66 mg, 2.1436 mmol), the mixture was heated at 80 °C for 2 hours. Extraction with water (15 mL) and ethyl acetate (15 mL x 3), the organic layer was concentrated under vacuum to give the crude compound 31-9 (150 mg). Yield: 73.41 %.

[0594] LCMS: Rt = 1.412 min, MS: 343.0 [M+H] +

[0595] Step 7: Compound 31-9 (60 mg, 0.1748 mmol) and sodium nitrite (15.68 mg, 0.2272 mmol) were added to 12 N aqueous hydrochloric acid solution, which was added to a solution of ethyl N-(2-cyanoacetyl)carbamate (compound 31-10, 30 mg, 0.1922 mmol) in pyridine and water at 0 °C and stirred at 0 °C for 2.5 h. Extraction was performed with water (15 mL) and ethyl acetate (15 mL x 3), and the organic layer was concentrated under vacuum to obtain crude compound 31-11 (70 mg). Yield: 70.65%.

[0596] LCMS: Rt = 1.458 min, MS: 510.05 [M-H] +

[0597] Step 8: To a solution of compound 31-11 (50 mg, 0.0980 mmol) in N,N- dimethylacetamide (1 mL) was added potassium acetate (19.24 mg, 0.196 mmol) and the mixture was heated at 120 °C for 2 h. After the reaction was completed, extraction was performed with water (10 mL) and ethyl acetate (5 mL x 3), and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by HPLC (acetonitrile in water (formic acid) 5-30%) to obtain the product 31 as a yellow solid (18 mg, 39.18% yield).

[0598] HPLC: Purity: 99.846% (214 nm) and 99.808% (254 nm).

[0599] LCMS: Rt = 1.292 min, MS: 464.0 [M+H] +

[0600] 1 H NMR (400 MHz, DMSO) δ 13.73 - 12.91 (m, 1H), 7.80 (s, 2H), 7.17 (d, J = 2.8 Hz, 1H), 7.07 (d, J = 2.8 Hz, 1H), 5.46 - 4.93 (m, 1H), 3.79 (s, 3H), 1.26 (d, J = 6.4 Hz, 6H).

[0601] Example 32

[0602] Step 1: To a solution of compound 32-1a (3 g, 0.0186 mol, 1.0 eq.) in DMF (30 mL) was added NaH (1.86 g, 0.0465 mol, 2.5 eq.) at 0 °C under nitrogen protection. The reaction was stirred at 0 °C for 1 h, then PMBCl (8.74 g, 0.0558 mol, 3.0 eq.) was added, the system was raised to 60 °C and stirred for 5 h. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with saturated brine. It was dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and purified by silica gel column chromatography (PE / EtOAc) to give compound 32-1 (4 g) as a white solid. Yield: 48.39%.

[0603] LCMS: Rt = 1.439 min, MS: 402.1 [M+H] +

[0604] Step 2: A solution of compound 32-1 (500 mg, 1.2455 mmol, 1.0 eq.) and compound 32-2 (787.58 mg, 2.491 mmol, 2.0 eq.) in THF (10 mL) was stirred at -78 °C under nitrogen protection, and LiHMDS (5 mL, 1 N in hexane) was added dropwise. The reaction mixture was stirred at -78 °C for 12 h, quenched with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc) to give compound 32-3 (410 mg) as a white solid with a yield of 66.80%.

[0605] LCMS: Rt = 1.561 min, MS: 444.2 [M+H] +

[0606] Step 3: Compound 32-3 (410 mg, 0.9244 mmol, 1.0 eq.) was dissolved in a mixture of TFA / TfOH = 10:1 (5 mL) in a round-bottom flask, and the reaction was heated to 50 °C in an oil bath with stirring for 4 h. The mixture was concentrated in vacuum and purified by silica gel column chromatography (DCM / MeOH) to give compound 32-4 (180 mg) as a colorless oily liquid with a yield of 86.23%.

[0607] LCMS: Rt = 0.712 min, MS: 204.2 [M+H] +

[0608] Step 4: In a round-bottom flask, compound 32-4 (180 mg, 0.8857 mmol, 1.0 eq.), compound 32-5 (185.99 mg, 0.8857 mmol, 1.0 eq.) and DIPEA (343.40 mg, 2.6571 mmol, 3.0 eq.) were dissolved in DMF (3 mL), the reaction was heated to 60 °C and stirred for 6 h. The system was quenched with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by silica gel column chromatography (DCM / MeOH) to obtain compound 32-6 (200 mg) as a yellow solid in a yield of 51.69%.

[0609] LCMS: Rt = 1.448 min, MS: 393.0 [M+H] +

[0610] Step 5: Compound 32-6 (200 mg, 0.5086 mmol, 1.0 eq.), iron powder (170.43 mg, 3.0516 mmol, 6.0 eq.) and NH4CI (272.05 mg, 5.086 mmol, 10.0 eq.) were placed in a mixed solution of EtOH / H2O = 3:1 (4 mL), the reaction was heated to 80 °C and stirred for 6 h. The reaction was purified by silica gel column chromatography (DCM / MeOH) to obtain compound 32-7 (300 mg) as a yellow oil in a yield of 68.21%.

[0611] LCMS: Rt = 1.092 min, MS: 363.0 [M+H] +

[0612] Step 6: To a solution of compound 32-7 (180 mg, 0.4955 mmol, 1.0 eq.) in HCl (1 mL) was added dropwise a solution of NaNO2(44.45 mg, 0.6441 mmol, 1.3 eq.) in water (2 mL) at 0 °C, and the reaction was stirred at 0 °C for 1 h. Then compound 32-8 (92.84 mg, 0.5946 mmol, 1.2 eq.) was dissolved in a mixed solution of pyridine (2 mL) and H2O (4 mL), and the previous reaction solution was added dropwise to the current mixture. The reaction system was continued to stir at 0 °C for 2 h, quenched with water (2 mL) and extracted with ethyl acetate (5 mL x 3) and washed with brine. It was dried over anhydrous sodium sulfate and concentrated in vacuum to obtain compound 32-9 (230 mg) as a red solid in a yield of 78.77%.

[0613] LCMS: Rt = 1.314 min, MS: 532.0 [M+H] +

[0614] Step 7: A solution of compound 32-9 (200 mg, 0.3771 mmol, 1.0 eq.) and KOAc (111.03 mg, 1.1313 mmol, 3.0 eq.) in N,N-dimethylacetamide (3 mL) was heated to 115 °C and stirred for 4 h. The reaction was quenched with water (1 mL) and purified with preparative liquid chromatography (eluent: acetonitrile-water with 0.1% trifluoroacetic acid) to afford compound 32 (113 mg) as a yellow solid in 59.08% yield.

[0615] 1 H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 10.05 (s, 1H), 7.80 (s, 2H), 6.88 6.82 (m, 2H), 6.68 (dd, J = 8.8, 2.8 Hz, 1H), 2.42 (d, J = 7.6 Hz, 1H), 1.82 (dd, J = 7.6, 1.2 Hz, 1H), 1.27 (s, 3H), 0.76 (s, 3H).

[0616] Step 8: Two yellow solids, 32-P1 (37.29 mg) and 32-P2 (39.76 mg) were obtained by SFC separation of 32 (110 mg). Compound 32-P1: HPLC: Purity: 99.14% (214 nm) and 98.64% (254 nm).

[0617] 1 H NMR (400 MHz, DMSO) δ 10.03 (s, 1H), 7.80 (s, 2H), 7.07 (s, 1H), 6.83 (d, J = 8.8 Hz, 2H), 6.67 (dd, J = 8.8, 2.8 Hz, 1H), 2.41 (d, J = 7.6 Hz, 1H), 1.80 (d, J = 7.6 Hz, 1H), 1.26 (s, 3H), 0.76 (s, 3H).

[0618] Compound 32-P2: HPLC: Purity: 99.21% (214 nm) and 98.55% (254 nm).

[0619] 1 H NMR (400 MHz, DMSO) δ 10.03 (s, 1H), 7.80 (s, 2H), 7.07 (s, 1H), 6.83 (d, J = 8.8 Hz, 2H), 6.67 (dd, J = 8.8, 2.8 Hz, 1H), 2.41 (d, J = 7.6 Hz, 1H), 1.80 (d, J = 7.6 Hz, 1H), 1.26 (s, 3H), 0.76 (s, 3H).

[0620] Example 33

[0621] Step 1 : To a solution of compound 31-9 (45 mg, 0.1311 mmol) in DMF (5 mL), 1- dodecanethiol (185.74 mg, 0.9177 mmol) and sodium methoxide (49.58 mg, 0.9177 mmol) were added at room temperature. The reaction was stirred at 120 °C for 6 h. The mixture was quenched with ice water (15 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Si02, hexane / ethyl acetate 25%) to afford compound 33-2 (20 mg) as a yellow solid. Yield: 41.72 %.

[0622] LCMS: Rt = 1.307 min, MS: 328.95 [M+H] +

[0623] Step 2: To a solution of compound 33-2 (24 mg, 0.0729 mmol) and NaNCte (6.04 mg, 0.0874 mmol) in concentrated aqueous HC1 at 0 °C, compound 33-3 (12.52 mg, 0.0801 mmol) in pyridine / water mixture was added. The reaction was stirred at 0 °C for 2.5 h. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was concentrated in vacuo to afford compound 33-4 (20 mg) as a crude product, which was used directly in the next step without further purification. Yield: 44.17 %.

[0624] LCMS: Rt = 1.392 min, MS: 496.1 [M+H] +

[0625] Step 3: To a solution of compound 33-4 (50 mg, 0.1007 mmol) in DMAc (1.5 mL), potassium acetate (19.77 mg, 0.2014 mmol) was added at room temperature. The reaction was heated to 115 °C for 2 h. Upon completion, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by semi-preparative HPLC (ACN / H20 (FA) 5% to 30%) to afford compound 33 (0.6 mg) as an orange solid. Yield: 1.29 %.

[0626] HPLC: Purity: 98.579 % (214 nm) and 95.112 % (254 nm).

[0627] LCMS: Rt = 1.208 min, MS: 450.0 [M+H] +

[0628] Example 34

[0629] Step 1: To a solution of compound 34-1 (1 g, 5.6 mmol, 1.0 eq) in DCM (6 mL) was added BBr3(3.65 g, 14.5 mmol, 2.6 eq) dropwise at 0 °C under nitrogen atmosphere. After the addition was completed, the reaction was stirred at 0 °C for 30 min, then was allowed to warm to room temperature slowly and stirred for 1.5 h. The reaction was quenched with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography (DCM / MeOH = 95:5) to give compound 34-2 (0.8 g) as a red solid with a yield of 78.57%.

[0630] 1 H NMR (400 MHz, DMSO) d 10.75 (s, 1H), 9.54 (s, 1H), 7.01 (dd, J = 8.4, 2.4 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H).

[0631] Step 2: Compound 34-2 (790 mg, 4.84 mmol, 1.0 eq), compound 34-3 (1017 mg, 4.84 mmol, 1.0 eq) and DIPEA (1252 mg, 9.68 mmol, 2.0 eq) were dissolved in DMF (6 mL) and the reaction was stirred at 60 °C for 5 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography (Hexanes / EtOAc = 45:55) to give compound 34-4 (760 mg) as a red solid with a yield of 40.00%.

[0632] LCMS: Rt = 1.290 min, MS: 350.9 [M-H] -

[0633] Step 3: To a solution of compound 34-4 (700 mg, 1.98 mmol, 1.0 eq) in EtOH (16 mL) was added TMSCHN2(2.0 mL, 2 M, 2.0 eq) and TEA (401 mg, 3.96 mmol, 2.0 eq) dropwise under nitrogen atmosphere. The reaction was stirred at 25 °C for 16 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography (Hexanes / EtOAc = 45:55) to give compound INTA (500 mg) as a white solid in 59.55% yield.

[0634] LCMS: Rt = 1.284 min, MS: 380.9 [M+H] +

[0635] Step 4: Compound INTA (400 mg, 1.05 mmol, 1.0 eq), compound 34-5 (196 mg, 1.15 mmol, 1.1 eq) and Cs2CO3(684 mg, 2.1 mmol, 2.0 eq) were dissolved in DMAc (20 mL) and the reaction was stirred at 120 °C for 2 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography (Hexanes / EtOAc = 98:2) to give compound 34-6 (140 mg) as a white solid in 28.37% yield.

[0636] LCMS: Rt = 1.718 min, MS: 423.0 [M+H] +

[0637] Step 5: Compound 34-6 (120 mg, 0.28 mmol, 1.0 eq), iron powder (79 mg, 1.4 mmol, 5.0 eq) and NH4CI (152 mg, 2.8 mmol, 10.0 eq) were dissolved in EtOH / H2O = 5:1 (6 mL) and the reaction was stirred at 80 °C for 2 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Compound 34-7 (120 mg, about 90% purity) was obtained as a crude product and used directly in the next step without further purification.

[0638] LCMS: Rt = 1.572 min, MS: 393.0 [M+H] +

[0639] Step 6: A solution of NaNCte (23 mg, 0.34 mmol, 1.1 eq) in water (2 mL) was added dropwise to a solution of compound 34-7 (120 mg, 0.31 mmol, 1.0 eq) in 12 M HC1 (1 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 h after the addition was completed. The resulting mixture was added dropwise to a solution of compound 34-8 (52 mg, 0.34 mmol, 1.1 eq) in pyridine (4 mL), and the reaction was stirred at 0 °C for 1 h. The reaction was quenched with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. Compound 34-9 (150 mg, about 50% purity) was obtained and used directly in the next step without further purification.

[0640] LCMS: Rt = 1.598 min, MS: 560.1 [M+H] +

[0641] Step 7: KOAc (105 mg, 1.08 mmol, 4.0 eq) was added to a solution of compound 34-9 (150 mg, 0.27 mmol, 1.0 eq) in DMAc (10 mL), and the mixture was stirred at 120 °C for 3 h. The reaction was quenched with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by preparative liquid chromatography (eluent: acetonitrile-water mixture containing 0.1% TFA) to give compound 34 (10.63 mg) as a white solid in 6.87% yield.

[0642] HPLC: Purity: 98.47% (214 nm) and 98.70% (254 nm).

[0643] LCMS: Rt = 1.582 min, MS: 514.1 [M+H] +

[0644] 1 H NMR (400 MHz, DMSO) δ 13.31 (s, 1H), 7.85 (s, 2H), 7.70 (d, J = 9.2 Hz, 1H), 7.59 (s, 1H), 7.27 (dd, J = 9.2, 2.4 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 5.51 - 5.45 (m, 1H), 3.82 (s, 3H), 1.35 (d, J = 6.0 Hz, 6H).

[0645] Example 35

[0646] Step 1 : Compound 12-6 (450 mg, 2.37 mmol) and compound 21-3 (517 mg, 2.85 mmol) were dissolved in DMF (5 mL), the system was raised to 100 °C, K2CO3 (986 mg, 7.13 mmol) was added, and the reaction was stirred at 100 °C for 3 h. The system was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (eluted with ethyl acetate / hexane, 0%~50%) to obtain compound 35-1 (630 mg) as a yellow solid, yield: 74.85%.

[0647] LCMS: Rt = 1.424 min, MS: 351.15 [M+H] +

[0648] Step 2: Compound 35-1 (400 mg, 1.14 mmol) was dissolved in EtOH / THF / H2O = 1:1:2 (8 mL) under nitrogen protection, and the system was raised to 40 °C. NH4CI (305.35 mg, 5.7 mmol) and zinc powder (373.4 mg, 5.7 mmol) were added, and the reaction was stirred at 40 °C for 3 h. Diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to obtain compound 35-2 (300 mg) as a yellow solid, yield: 81.19%.

[0649] LCMS: Rt = 0.942 min, MS: 321.10 [M+H] +

[0650] Step 3: To a solution of compound 35-2 (400 mg, 1.24 mmol) and 12M HCl (320 μL, 3.85 mmol) in AcOH (5 mL) at 0 °C, a solution of NaNO2 (91.32 mg, 1.32 mmol) in H2O (5 mL) was added dropwise, and the reaction was stirred at 0 °C for 0.5 h. Compound 35-3 (214.43 mg, 1.37 mmol) and AcONa (307.13 mg, 3.74 mmol) were added, and the mixture was stirred at 0 °C for 1.5 h. Filtration, water washing, and vacuum drying yielded compound 35-4 (200 mg) as a yellow solid, yield: 32.53%.

[0651] LCMS: Rt = 1.285 min, MS: 488.15 [M+H] +

[0652] Step 4: To a solution of compound 35-4 (300 mg, 0.6154 mmol) in DMAc (6 mL) was added AcOK (66.43 mg, 0.6769 mmol) under nitrogen protection. The reaction was stirred at 115 °C for 2 h. Concentrated in vacuum to get the crude product, which was purified by prep-LC (Gemini 5 pm C18 column 150*21.2 mm, ACN / H20, 20 mL / min) to give compound 35 (120 mg) as a yellow solid in 42.73% yield.

[0653] LCMS: Rt = 1.226 min, MS: 442.10 [M+H] +

[0654] Step 5: Compound 35 racemate was further separated by SFC (column: 20 mm I.D.*250 mm, 5 pm; mobile phase: C02 / MeOH (0.1% NH3) = 60 / 40) to give the first elute compound 35-P1 (61.72 mg, 99% ee) and the second elute compound 35-P2 (54.54 mg, 99% ee).

[0655] Compound 35-P1 : HPLC: Purity: 99.86% (214 nm) and 99.83% (254 nm).

[0656] LCMS: Rt = 1.228 min, MS Calcd.: 441.14, MS Found: 442.10 [M+H] +

[0657] 1 H NMR (400 MHz, DMSO) d 13.01 (s, 1H), 9.99 (s, 1H), 7.21 - 7.16 (m, 2H), 7.05 (d, J = 2.4 Hz, 1H), 6.89 - 6.82 (m, 2H), 6.78 (d, J = 2.4 Hz, 1H), 2.19 - 2.07 (m, 1H), 1.85 - 1.81 (m, 1H), 1.54 - 1.52 (m, 1H), 1.45 (s, 3H), 0.97 - 0.95 (m, 2H), 0.68 (t, J = 4.4 Hz, 3H).

[0658] Compound 35-P2: HPLC: Purity: 99.89% (214 nm) and 99.70% (254 nm).

[0659] LCMS: Rt = 1.237 min, MS Calcd.: 441.14, MS Found: 442.10 [M+H]+

[0660] 1 H NMR (400 MHz, DMSO) δ 13.00 (s, 1H), 9.99 (s, 1H), 7.23 - 7.18 (m, 2H), 7.05 (d, J = 2.4 Hz, 1H), 6.70 - 6.83 (m, 2H), 6.78 (dd, J = 8.8, 2.4 Hz, 1H), 2.19 - 2.11 (m, 1H), 1.85 - 1.83 (m, 1H), 1.53 - 1.50 (m, 1H), 1.45 (s, 3H), 0.96 (dd, J = 8.4, 2.0 Hz, 2H), 0.67 (d, J = 4.0 Hz, 3H). Example 36

[0661] Step 1 : To a solution of compound 36-1 (300 mg, 0.735 mmol) in EtOAc (10 mL), Pd / C (156.4 mg, 1.47 mmol) was added. The mixture was evacuated and filled with hydrogen gas, repeated for three times, and the hydrogenation was stirred at room temperature for 16 h. The system was filtered with celite, and the filtrate was concentrated in vacuo to give the crude product of compound 36-2 (50 mg), which was used directly in the next step without further purification.

[0662] LCMS: Rt = 1.170 min, MS: 380.00 [M+H] +

[0663] Step 2: To a solution of compound 36-2 (50 mg, 0.1315 mmol) and NaNCte (11.80 mg, 0.1709 mmol) in cone. HC1 at 0 °C, compound 36-3 (24.64 mg, 0.1578 mmol) in pyridine / water mixture was added, and the reaction was stirred at 0 °C for 2.5 h. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was concentrated in vacuo to give the crude product of compound 36-4 (50 mg), which was used directly in the next step without further purification. Yield: 34.75 %.

[0664] LCMS: Rt = 1.331 min, MS: 545.00 [M-H] +

[0665] Step 3: To a solution of compound 36-4 (60 mg, 0.1096 mmol) in DMA (1 mL) was added AcOK (21.51 mg, 0.2192 mmol) in portions under nitrogen protection. The reaction was stirred at 120 °C for 1 h. After completion of the reaction, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 3) and washed with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by semi-preparative liquid chromatography (ACN / H20 (TFA) 5%~30%) to give compound 36 (5.5 mg) as a yellow solid in 9.95% yield.

[0666] HPLC: Purity: 99.034% (214 nm) and 99.254% (254 nm).

[0667] LCMS: Rt = 1.171 min, MS: 501.0 [M+H] +

[0668] 1 H NMR (400 MHz, DMSO) δ 13.31 (s, 1H), 11.33 (s, 1H), 7.85 (s, 2H), 7.47 (dd, J = 8.8, 3.2 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 5.27 - 4.88 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H).

[0669] Example 37

[0670] Step 1: Compound 37-1 (400 mg, 0.0059 mol) was added to a solution of TFA (5 mL) and CF3SO3H (0.5 mL) under nitrogen protection. The reaction was stirred at 50 °C for 3 h. The mixture was filtered and extracted with EtOAc (20 mL x 3) and washed with brine (50 mL) and dried over sodium sulfate. The residue was purified by flash chromatography (hexane:EtOAc = 4:1) to give compound 37-2 (250 mg) as a yellow solid in 87.36% yield.

[0671] LCMS: Rt = 1.110 min, MS: 218.1 [M+H] +

[0672] Step 2: To a solution of compound 37-2 (300 mg, 1.381 mmol) in DCM (5 mL) was added BBr3(1038 mg, 4.1424 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 1 h. The mixture solution was filtered and extracted with DCM (20 mL x 3), washed with brine (50 mL) and dried over sodium sulfate. The residue was purified by flash chromatography (Hexane:EtOAc = 1:1) to give compound 37-3 (220 mg) as a yellow solid in 70.55% yield.

[0673] LCMS: Rt = 0.869 min, MS: 204.0 [M+H] +

[0674] Step 3: To a solution of compound 37-3 (100 mg, 0.492 mmol) in DMF (2 mL) was added compound 37-4 (124 mg, 0.5904 mmol) and DIPEA (127 mg, 0.984 mmol). The mixture was heated at 60 °C for 2 h. The mixture solution was extracted with EtOAc (10 mL x 3), washed with brine (20 mL) and dried over sodium sulfate. The residue was purified by flash chromatography (Hexane:EtOAc = 4:1) to give compound 37-5 (120 mg) as a yellow solid in 55.83% yield.

[0675] 1 H NMR (400 MHz, DMSO) d 9.93 (s, 1H), 8.54 (s, 2H), 6.94 (d, J = 2.8 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.74 - 6.61 (m, 1H), 2.42 - 2.35 (m, 1H), 2.25 - 2.09 (m, 1H), 1.51 - 1.37 (m, 1H), 1.12 - 0.99 (m, 1H), 0.88 (t, J = 7.2 Hz, 3H), 0.65 (s, 1H).

[0676] Step 4: To a solution of compound 37-5 (200 mg, 0.5086 mmol) in EtOH / H2O (3 mL) was added iron (142 mg, 2.543 mmol) and ammonium chloride (109 mg, 2.0344 mmol) slowly. The mixture was heated at 80 °C for 2 h. The mixture solution was filtered and concentrated, then purified by flash chromatography (DCM:MeOH = 10:1) to give compound 37-6 (130 mg) as a yellow solid in 66.85% yield.

[0677] LCMS: Rt = 1.278 min, MS: 363.0 [M+H] +

[0678] Step 5: A mixture of compound 37-6 (100 mg, 0.2753 mmol) and sodium nitrite (25 mg, 0.3578 mmol) in 12 N hydrochloric acid solution was slowly added to a stirred solution of compound 37-7 (51.58 mg, 0.3303 mmol) in pyridine / water (20 mL) at 0 °C for 2.5 h, the mixture was extracted with EtOAc (10 mL x 3), washed with brine (10 mL), dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (DCM:MeOH = 10:1) to give compound 37-8 (80 mg) as an orange solid in 49.33% yield.

[0679] LCMS: Rt = 1.344 min, MS: 530.1 [M+H]+

[0680] Step 6: To a solution of compound 37-8 (70 mg, 0.132 mmol) in DMAc (1.2 mL) was added KOAc (26 mg, 0.264 mmol). The mixture was heated at 115 °C for 2 h. The residue was purified by Prep-HPLC to give compound 37 (30 mg) as a yellow solid in 27.74% yield.

[0681] Step 7: Compound 37 (30 mg) was purified by SFC method to give 37-P1 (10.58 mg) as a yellow solid, 37-P2 (7.20 mg) as a yellow solid.

[0682] 37-P1: HPLC: Purity: 99.754% (214 nm) and 98.734% (254 nm).

[0683] LCMS: Rt = 1.247 min, MS Found: 494.9 [M+H].

[0684] 1 H NMR (400 MHz, DMSO) δ 13.28 (s, 1H), 9.91 (s, 1H), 7.80 (s, 2H), 6.89 (d, J = 2.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.63 (dd, J = 8.8, 2.8 Hz, 1H), 2.44 (d, J = 3.6 Hz, 1H), 2.17 - 2.13 (m, 1H), 1.43 (dd, J = 8.8, 4.0 Hz, 1H), 1.06 - 1.02 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H), 0.64 (t, J = 4.8 Hz, 1H).

[0685] Example 38

[0686] Step 1 : To a mixture of compound 38-1 (6.0 g, 0.0454 mol, 1.0 eq) and TEA (12.4 g, 0.1225 mol, 2.7 eq) in DCM (60 mL) was added chloro(methoxy)methane (compound 38-2, 4.72 g, 0.0499 mol, 1.1 eq) at 0 °C for 2 h, quenched with water (100 mL), extracted with DCM (100 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2S04and concentrated. Compound 38-3 (8.0 g) was obtained as a white solid in 88.11% yield.

[0687] LCMS: Rt = 0.728 min, MS: 191.1 [M-H]+

[0688] Step 2: Compound 38-3 (8.4 g, 0.0442 mol, 1 eq) was stirred with AcOH (5 mL) at 110 °C for 6 h, the mixture was purified by silica gel column chromatography (2% MeOH / DCM) to give compound 38-4 (1.78 g) as a yellow liquid in 22.85% yield. LCMS: Rt = 0.715 min, MS: 156.9 [M-H] +

[0689] Step 3: To a mixture of compound 12-9 (280 mg, 0.8018 mmol, 1 eq) and LiHMDS (2 mL, 1 M) in toluene (4 mL) was added compound 38-4 (152.13 mg, 0.9621 mmol, 1.2 eq) at 25 °C for 12 h. It was purified by high performance liquid chromatography ((ACN-H20 (0.1% NH 3· H2O)) to give compound 38 (159.9 mg) as a white solid in 42.37% yield.

[0690] HPLC: Purity: 99.962% (214 nm) and 99.182% (254 nm).

[0691] LCMS: Rt = 1.247 min, MS Found: 494.9 [M+H]

[0692] 1H NMR (400 MHz, DMSO) δ 10.55 (s, 1H), 9.90 (s, 1H), 8.13 (s, 2H), 7.04 (d, J = 2.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.46 (dd, J = 8.8, 2.8 Hz, 1H), 1.83 - 1.79 (m, 1H), 1.49 (dd, J = 9.6, 4.4 Hz, 1H), 1.43 (s, 3H), 0.66 (t, J = 4.8 Hz, 1H).

[0693] Step 4: Compound 38 (130 mg) was resolved by SFC to give 38-P1 (48.92 mg) as a white solid and 38-P2 (44.28 mg) as a white solid.

[0694] 38-P1: HPLC: Purity: 99.638% (214 nm) and 99.669% (254 nm)

[0695] 1 H NMR (400 MHz, DMSO) δ 10.55 (s, 1H), 9.90 (s, 1H), 8.13 (s, 2H), 7.04 (d, J = 2.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.46 (dd, J = 8.8, 2.8 Hz, 1H), 1.83 - 1.79 (m, 1H), 1.49 (dd, J = 9.6, 4.4 Hz, 1H), 1.43 (s, 3H), 0.66 (t, J = 4.8 Hz, 1H).

[0696] 38-P2: HPLC: Purity: 99.477% (214 nm) and 99.682% (254 nm).

[0697] 1 H NMR (400 MHz, DMSO) δ 10.55 (s, 1H), 9.90 (s, 1H), 8.13 (s, 2H), 7.04 (d, J = 2.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.46 (dd, J = 8.8, 2.8 Hz, 1H), 1.83 - 1.79 (m, 1H), 1.49 (dd, J = 9.6, 4.4 Hz, 1H), 1.43 (s, 3H), 0.66 (t, J = 4.8 Hz, 1H).

[0698] Example 39

[0699] Step 1 : To a solution of compound INT1-1 (10 g, 0.0521 mol) in ACN (100 mL) was added compound INT1-2 (21.2 g, 0.1042 mol). The mixture was heated and stirred at 80 °C for 2 hours. Then, to the mixture was added sodium iodide (7.82 g, 0.0521 mol) and PMBCl (9.79 g, 0.0625 mol). The mixture was heated at 80 °C for 14 hours. After cooling to room temperature, it was filtered with celite, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (silica, PE / EA 25%) to give compound INT1-3 (10 g) as a yellow solid. Yield: 55.28%.

[0700] LCMS: Rt = 1.123 min, MS: 311.90 [M-H] + .

[0701] Step 2: To a solution of compound INT1-3 (10 g, 0.0320 m 0mol) in DMF (70 mL) was added NaH (1.15 g, 0.048 mol) dropwise at 0 °C. The mixture was stirred at 0 °C for 0.5 hours. Then, the resulting mixture was added dropwise to BOMCl (6 g, 0.038 mol). The mixture was stirred at room temperature for 11.5 hours. Then, it was quenched with water (200 mL) and extracted with EA (200 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography (silica, PE / EA 20%) to give compound INT1-4 (4.5 g) as a white oil. Yield: 44.77%.

[0702] 1 H NMR (400 MHz, DMSO) d 7.41 - 7.10 (m, 7H), 6.91 (t, J = 12.0 Hz, 2H), 5.34 (s, 2H), 4.99 (s, 2H), 4.61 (s, 2H), 3.74 (s, 3H).

[0703] Step 3: Compound INT1-4 (3.6 g, 0.0083 mol) and compound INT1-5 (2.56 g, 0.0166 mol) were dissolved in 1,4-dioxane / H20 = 3:1 (56 mL), potassium carbonate (3.44 g, 0.0249 mol) and Pd(dppf)Cl2(0.61 g, 0.0008 mol) were added under nitrogen. The mixture was heated at 80 °C for 6 hours. Then, quenched with water (200 mL), EA (200 mL x 3) extraction. The organic layer was dried over anhydrous sodium sulfate, vacuum filtered and concentrated. The crude product was purified by column chromatography (silica, PE / EA 15%) to give compound INT1-6 (1.4 g) as a white oil. Yield: 39.76%.

[0704] LCMS: Rt = 1.487 min, MS: 380.0 [M+H] +

[0705] Step 4: Compound INT1-6 (1.5 g, 0.004 mol), NaIO4(1.71 g, 0.008 mol) and K2OsO4.2H2O (0.15 g, 0.0004 mol) were added to a mixture solution of t-BuOH (30 mL), water (30 mL) and MeCN (30 mL). The mixture was stirred at room temperature for 3 hours. Quenched with water (200 mL), EA (200 mL x 3) extraction. The organic layer was dried over anhydrous sodium sulfate, vacuum filtered and concentrated. The crude product was purified by column chromatography (silica, PE / EA 15%) to give compound INT1-7 (1.2 g) as a white oil. Yield: 67.50%.

[0706] 1 H NMR (400 MHz, DMSO) d 9.73 (s, 1H), 7.53 - 7.16 (m, 7H), 6.93 (d, J = 8.8 Hz, 2H), 5.32 (s, 2H), 5.14 (s, 2H), 4.60 (d, J = 5.6 Hz, 2H), 3.74 (s, 3H).

[0707] Step 5: DAST (compound INT1-8, 1.26 g, 0.0078 mol) was slowly added to a solution of compound INT1-7 (1.5 g, 0.0039 mol) in DCM (30 mL) at 0 °C under nitrogen protection. The mixture was stirred at room temperature for 5 hours. Quenched with water (30 mL), DCM (15 mL x 3) extraction. The organic layer was dried over anhydrous sodium sulfate, vacuum filtered and concentrated. The crude product was purified by column chromatography (silica, PE / EA 25%) to give compound INT1-9 (0.9 g) as a white oil. Yield: 51.28%.

[0708] 1 H NMR (400 MHz, DMSO) δ 7.41 - 7.13 (m, 7H), 7.04 - 6.69 (m, 3H), 5.31 (s, 2H), 5.05 (s, 2H), 4.61 (s, 2H), 3.74 (s, 3H).

[0709] Step 6: To a mixture of water (12 mL) and ACN (24 mL) was added cerium ammonium nitrate (900 mg, 6.6936 mmol) and INT 1-9 (900 mg, 2.2312 mmol) at 0 °C. After addition, the solution was allowed to warm to room temperature and the solution was stirred for 16 h. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (silica, PE / EA 25%) to give compound INT 1 (480 mg) as a white oil. Yield: 68.36%.

[0710] LCMS: Rt = 1.136 min, MS: 281.95 [M-H] +

[0711] Step 7: Compound 12-9 (2.8 g, 0.008 mol, 1 eq) was added to MeCN (20 mL), followed by the addition of tert-butyl nitrite (1.87 g, 0.016 mol, 2 eq) and CuBr2(1.38 g, 0.0096 mol, 1.2 eq) and heated at room temperature for 3 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2S04and concentrated. The concentrated solution was purified by silica gel column chromatography (3% MeOH / DCM) to give compound 39-2 (2.0 g) as a yellow solid in 57.50% yield.

[0712] LCMS: Rt = 1.571 min, MS: 411.9 [M-H] +

[0713] Step 8: Compound 39-2 (108.45 mg, 1.6945 mmol, 1 eq) was added to 7 mL of DMF, NaH (344.99 mg, 2.7112 mmol, 1.6 eq) was added and the reaction was stirred at 0 °C for 0.5 h, then PMBCl (344.99 mg, 2.7112 mmol, 1.3 eq) was added and the reaction was stirred at 25 °C for 1.5 h, quenched with water (15 mL), extracted with ethyl acetate (20 mL x 3). The organic phase was collected, washed with brine, dried over anhydrous Na2S04, and then concentrated. The concentrated solution was purified by silica gel column chromatography (60% EtOAc / PE) to give compound 39-3 (500 mg) as a yellow solid with a yield of 52.57%.

[0714] LCMS: Rt = 1.792 min, MS: 531.8 [M-H] +

[0715] Step 9: Compound 39-3 was mixed with 1,4-dioxane, then B2Pin2 (714.33 mg, 2.813 mmol, 2 eq), potassium acetate (207.05 mg, 2.1097 mmol, 1.5 eq) and Pd(dppf)Cl2 (102.96 mg, 0.1406 mmol, 0.1 eq) were added and the reaction was stirred at 70 °C under nitrogen for 4 h, the concentrated solution was purified by silica gel column chromatography (3% MeOH / DCM) to give compound 39-4 (2.813 mg) as a yellow solid with a yield of 58.19%.

[0716] Step 10: Compound 39-4 (700 mg, 1.206 mmol, 1 eq) was dissolved in acetone:H20 = 2:1 (9 mL), NaIO4 (283.96 mg, 1.3269 mmol, 1.1 eq) and NH4OAc (669.47 mg, 8.6853 mmol, 7.2 eq) were added and the reaction was stirred at 25 °C for 16 h, the mixture was filtered to give compound 39-5 (260 mg, yellow solid) with a yield of 38.94%.

[0717] LCMS: Rt = 1.424 min, MS: 498.0 [M+H] +

[0718] Step 11: Compound 39-5 (210 mg, 0.4215 mmol, 1 eq), compound INT1 (131.32 mg, 0.4636 mmol, 1.1 eq), pyridine (83.35 mg, 1.0537 mmol, 2.5 eq) and Cu(OAc)2(114.84 mg, 0.6322 mmol, 1.5 eq) were added into DCE (40 mL) and reacted at 40 °C for 16 h. The residue was purified by silica gel column chromatography (3% MeOH / DCM) to give compound 39-6 (160 mg) as a yellow solid in 46.45% yield.

[0719] LCMS: Rt = 1.690 min, MS: 734.9 [M+H] +

[0720] Step 12: Compound 39-6 was placed in a mixture of TFA / TfOH = 10:1 (1.2 mL) and stirred at 25 °C for 5 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2S04and concentrated. Purification by silica gel column chromatography (4% MeOH / DCM) gave compound 39-7 (80 mg) as a yellow solid in 71.74% yield.

[0721] LCMS: Rt = 1.472 min, MS: 614.9 [M+H] +

[0722] Step 13: Compound 39-7 (80 mg, 0.130 mmol, 1 eq) was added into a solution of TFA / TfOH = 10:1 (1 ml) and reacted at 40 °C for 5 h. Purification by high performance liquid chromatography (ACN-H20 (0.1% FA)) gave compound 39 (13.1 mg) as a white solid in 20.15% yield.

[0723] HPLC: Purity: 99.842% (214 nm) and 99.861% (254 nm)

[0724] LCMS: Rt = 1.247 min, MS Found: 494.9 [M+H]

[0725] 1H NMR (400 MHz, DMSO) δ 12.87 (s, 1H), 9.95 (s, 1H), 7.83 (s, 2H), 7.12 (d, J = 2.8 Hz, 1H), 6.93 - 6.80 (m, 2H), 6.49 (dd, J = 8.8, 2.8 Hz, 1H), 1.85 - 1.81 (m, 1H), 1.53 - 1.49 (m, 1H), 1.44 (s, 3H), 0.68 (t, J = 4.4 Hz, 1H).

[0726] Step 14: Compound 39 (10 mg) was resolved by SFC to give compound 39-P1 (3.02 mg) as a white solid and compound 39-P2 (3.13 mg) as a white solid.

[0727] Compound 39-P1: HPLC: Rt = 3.040 min, Purity: 99.859% (214 nm) and 99.861% (254 nm)

[0728] LCMS: MS Found: 494.9 [M+H]

[0729] Compound 39-P2: HPLC: Rt = 3.046 min, Purity: 99.203% (214 nm) and 99.607% (254 nm)

[0730] LCMS: MS Found: 494.9 [M+H]

[0731] Example 40

[0732] Step 1: Compound 40-1 (24.0 g, 0.1083 mol, 1 eq) was dissolved in 4N HC1 in H20 (240 mL) and reacted at 110 °C for 7 h. The mixture was filtered, and the filter cake was collected to give compound 40-2 (21.7 g) as a yellow solid. Yield: 93.72%.

[0733] LCMS: Rt = 0.881 min, MS: 204.1 [M-H] +

[0734] Step 2: To a solution of compound 40-2 (22.5 g, 0.1107 mol, 1 eq) in THF (400 mL), MeMgBr (92.2 mL, 3 M, 0.2767 mol, 2.5 eq) was added and stirred at 25 °C for 3 h, quenched with water (300 mL), extracted with EtOAc (400 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by silica gel column chromatography (3% MeOH / DCM) to give compound 40-3 (23.5 mg) as a yellow solid in 91.96% yield.

[0735] LCMS: Rt = 0.847 min, MS: 220.2 [M-H] +

[0736] Step 3: To a solution of compound 40-3 (22 g, 0.1003 mol, 1 eq) in DCE (40 mL), TFA (171.54 g, 1.5045 mol, 15 eq) and Et3SiH (116.62 g, 1.003 mol, 10 eq) were added and reacted at 70 °C for 16 h. The mixture was quenched with water (20 mL), extracted with EtOAc (400 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated. The residue was purified in 25% DCM / PE, filtered, and dried under vacuum to give compound 40-4 (19 g) as a yellow solid in 91.33% yield.

[0737] LCMS: Rt = 1.075 min, MS: 204.2 [M+H] +

[0738] Step 4: To a solution of compound 40-4 (18.0 g, 0.0886 mol, 1 eq) in DMF (180 mL), PMBC1 (16.65 g, 0.1063 mol, 1.2 eq) and K2C03(24.49 g, 0.1772 mol, 2 eq) were added and reacted at 60 °C for 5 h. The mixture was quenched with water (200 mL), extracted with EtOAc (400 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by silica gel column chromatography (60% EtOAc / PE) to give compound 40-5 (17 g) as a yellow solid in 56.32% yield.

[0739] LCMS: Rt = 1.433 min, MS: 324.1 [M+H] +

[0740] Step 5: Compound 40-6 (65.36 g, 0.2970 mol, 6 eq) was dissolved in DMSO (100 mL) and stirred at 25 °C for 1 h, then NaH (11.88 g, 0.2970 mol, 6 eq) was added. The mixture was stirred at 100 °C for 15 h. The mixture was quenched with water (200 mL) and extracted with EtOAc (400 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by column chromatography on silica gel (9% EtOAc / PE) to give compound 40-7 (3.2 g) as a yellow solid in 18.18% yield.

[0741] LCMS: Rt = 1.460 min, MS: 338.1 [M+H] +

[0742] Step 6: Compound 40-7 (3.1 g, 0.0092 mol, 1 eq) was dissolved in a mixed solution of CF3S03H:TFA = 1:10 (33 mL) and stirred at 50 °C for 3 h, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3% MeOH / DCM) to give compound 40-8 (1.7 g) as a yellow solid in 80.43% yield.

[0743] LCMS: Rt = 1.103 min, MS: 218.00 [M+H] +

[0744] Step 7: To a solution of compound 40-8 (1.58 g, 0.0073 mol, 1 eq) in DCM (20 mL) was added BBr3 (5.49 g, 0.0219 mmol, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 3 h. The mixture was quenched with saturated NaC03 solution (30 mL) and extracted with EtOAc (30 mL x 3). The organic layer was dried over Na2S04, filtered and concentrated. The product compound 40-9 (1.4 g) was a yellow solid in 89.04% yield.

[0745] LCMS: Rt = 0.861 min, MS: 204.2 [M+H]+

[0746] Step 8: Compound 40-9 (1.2 g, 0.0059 mol, 1 eq), compound 40-10 (1.36 g, 0.0064 mol, 1.1 eq) and DIPEA (1.91 g, 0.0147 mol, 2.5 eq) were added to 30 mL of DMF solution, and reacted at 60 °C for 3 h, then quenched with water (30 mL) and extracted with ethyl acetate (40 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by silica gel column chromatography (50% EtOAc / PE) to give 1.6 g of compound 40-11 as a yellow solid, in a yield of 66.10%.

[0747] LCMS: Rt = 1.474 min, MS: 393.0 [M-H] +

[0748] Step 9: Compound 40-11 (1.1 g, 0.0028 mol, 1 eq) and Fe (1.09 g, 0.0196 mol, 7 eq) and NH4CI (1.50 g, 0.028 mol, 10 eq) were added to a mixture of EtOH / H20 = 10 / 1 (12 mL) respectively, and reacted at 80 °C for 3 h. The residue was purified by silica gel column chromatography (40% EtOAc / PE) to give compound 40-12 (1.0 g) as a yellow solid, in a yield of 92.86%.

[0749] LCMS: Rt = 1.282 min, MS: 363.0 [M-H] +

[0750] Step 10: Compound 40-12 (770 mg, 2.1198 mmol, 1 eq), CuBr2(364.90 mg, 2.5437 mmol, 1.2 eq) and t-BuONO (437.19 mg, 4.2396 mmol, 2 eq) were added to MeCN (8 mL) solution at 0 °C respectively. The temperature was raised to 25 °C and stirred for 3 h. The mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by silica gel column chromatography (15% EtOAc / PE) to give compound 40-13 (550 mg) as a white solid, in a yield of 57.71%.

[0751] LCMS: Rt = 1.636 min, MS: 427.8 [M+H]+

[0752] Step 11: Compound 40-13 (500 mg, 1.1706 mmol, 1 eq) was added into DMF (5 mL) solution, NaH (74.92 mg, 1.8729 mmol, 1.6 eq) was added at 0 °C, stirred for 0.5 h, then PMBCl (238.32 mg, 1.5217 mmol, 1.3 eq) was added, the temperature was raised to 25 °C, and the reaction was carried out for 2.5 h. The mixture was quenched with water (10 mL), extracted with ethyl acetate (20 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated. Purification by silica gel column chromatography (40% EtOAc / PE) gave compound 40-14 (470 mg) as a white solid in 69.70% yield.

[0753] LCMS: Rt = 1.855 min, MS: 548.0 [M+H] +

[0754] Step 12: Compound 40-14 (530 mg, 0.9684 mmol eq) was added into dioxane (6 mL), B2Pin2 (491.83 mg, 1.9368 mmol, 2 eq), KOAc (142.56 mg, 1.4526 mmol, 1.5 eq) and Pd(dppf)Cl2 (70.86 mg, 0.9684 mmol, 0.1 eq) were added, and the reaction was carried out at 70 °C for 16 h. The mixture was quenched with water (10 mL), extracted with ethyl acetate (20 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2S04, and concentrated. The residue was purified by silica gel column chromatography (4% MeOH / DCM) to give 40-15 (370 mg) as a yellow solid in 64.08% yield.

[0755] LCMS: Rt = 1.976 min, MS: 594.0 [M+H] +

[0756] Step 13: Compound 40-15 (310 mg, 0.8413 mmol, 1 eq) was dissolved in a mixed solution of acetone:H20 = 2:1 (6 mL), NaIO4 (167.43 mg, 1.2619 mmol, 1.5 eq) and NH4OAc (289.47 mg, 6.0573 mmol, 7.2 eq) were added, and the reaction was carried out at 25 °C for 16 h. The mixture was filtered, and the filter cake was obtained as a yellow solid. The product was compound 40-16 (200 mg) as a yellow solid in 68.18% yield.

[0757] LCMS: Rt = 1.504 min, MS: 512.0 [M+H] +

[0758] Step 14: Compound 40-16 (200 mg, 0.3905 mmol, 1 eq), compound INT1 (121.66 mg, 0.42955 mmol, 1.1 eq), pyridine (77.22 mg, 0.9762 mmol, 2.5 eq) and Cu(OAc)2(106.39 mg, 0.5857 mmol, 1.5 eq) were added to DCE (2 mL) solution respectively and reacted at 40 °C for 3 h, the residue was purified by silica gel column chromatography (3% MeOH / DCM) to obtain compound 40-17 (160 mg) as a yellow solid in a yield of 51.93%.

[0759] LCMS: Rt = 1.762 min, MS: 749.1 [M+H] +

[0760] Step 15: Compound 40-17 (110 mg, 0.1467 mmol, 1 eq) was dissolved in TFA / TfOH = 5:1 (1.2 mL) mixed solution and stirred at 40 °C for 16 h, the residue was purified by high performance liquid chromatography (ACN-H20 (0.1% FA)) to obtain compound 40 (67.36 mg) as a white solid in a yield of 89.23%.

[0761] HPLC: Purity: 99.756% (214 nm) and 99.693% (254 nm)

[0762] LCMS: Rt = 3.887 min, MS Found: 508.9 [M+H] +

[0763] 1 H NMR (400 MHz, DMSO) d 12.85 (s, 1H), 9.91 (s, 1H), 7.83 (s, 2H), 6.8 - 6.65 (m, 3H), 6.63 (dd, J = 8.8, 2.8 Hz, 1H), 2.46 - 2.43 (m, 1H), 2.17 - 2.13 (m, 1H), 1.43 (dd, J = 8.8, 4.4 Hz, 1H), 1.07 - 1.03 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H), 0.64 (t, J = 4.8 Hz, 1H).

[0764] Step 16: 45 mg of compound 40 was purified by SFC resolution to obtain 40-P1 (12.34 mg) as a white solid and 40-P2 (14.52 mg) as a white solid.

[0765] 40-P1: HPLC: Purity: 98.315% (214 nm) and 97.425% (254 nm)

[0766] 1 H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 9.90 (s, 1H), 7.83 (s, 2H), 6.92 - 6.77 (m, 3H), 6.63 (dd, J = 8.8, 2.8 Hz, 1H), 2.44 (d, J = 3.6 Hz, 1H), 2.18 - 2.13 (m, 1H), 1.42 (dd, J = 8.8, 4.4 Hz, 1H), 1.09 - 1.01 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H), 0.64 (t, J = 4.8 Hz, 1H).

[0767] 40-P2: HPLC: Purity: 98.666% (214 nm) and 98.039% (254 nm)

[0768] 1 H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 9.90 (s, 1H), 7.83 (s, 2H), 6.92 - 6.77 (m, 3H), 6.63 (dd, J = 8.8, 2.8 Hz, 1H), 2.46 - 2.43 (m, 1H), 2.18 - 2.13 (m, 1H), 1.45 - 1.40 (m, 1H), 1.10 - 0.97 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H), 0.64 (t, J = 4.8 Hz, 1H)

[0769] Example 41

[0770] Step 1: To a solution of compound 40-12 (100 mg, 0.2753 mmol, 1 eq) and compound 38-4 (52.23 mg, 0.3303 mmol, 1.2 eq) in toluene (5 mL) was added LIHMDS (0.7 mL) at 25 °C and the reaction was continued for 16 h. Purification by Prep-HPLC (ACN-H2O (0.1% NH3.H2O)) gave compound 41 (87.5 mg) as a white solid in 66.22% yield.

[0771] HPLC: Purity: 99.962% (214 nm) and 99.182% (254 nm)

[0772] 1H NMR (400 MHz, DMSO) δ 10.61 (s, 1H), 9.87 (s, 1H), 8.12 (s, 2H), 6.84 (d, J = 2.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.59 (dd, J = 8.8, 2.8 Hz, 1H), 2.41 (dd, J = 8.8, 5.2 Hz, 1H), 2.15 (dd, J = 14.0, 7.2 Hz, 1H), 1.41 (dd, J = 8.8, 4.4 Hz, 1H), 1.05 (dd, J = 14.0, 7.2 Hz, 1H), 0.88 (t, J = 7.2 Hz, 3H), 0.63 (t, J = 4.8 Hz, 1H).

[0773] Step 2: Compound 41 was resolved by SFC to give 41-P1 (13.90 mg) as a white solid and 41-P2 (12.12 mg) as a white solid.

[0774] 41-P1: HPLC: Purity: 98.182% (214 nm) and 97.930% (254 nm)

[0775] 1 H NMR (400 MHz, DMSO) δ 10.61 (s, 1H), 9.87 (s, 1H), 8.12 (s, 2H), 6.84 (d, J = 2.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.59 (dd, J = 8.8, 2.8 Hz, 1H), 2.41 (dd, J = 8.8, 5.2 Hz, 1H), 2.15 (dd, J = 14.0, 7.2 Hz, 1H), 1.41 (dd, J = 8.8, 4.4 Hz, 1H), 1.05 (dd, J = 14.0, 7.2 Hz, 1H), 0.88 (t, J = 7.2 Hz, 3H), 0.63 (t, J = 4.8 Hz, 1H).

[0776] 41-P2: HPLC: Purity: 98.308% (214 nm) and 97.991% (254 nm)

[0777] 1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.87 (s, 1H), 8.06 (s, 2H), 6.85 (d, J = 2.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.59 (dd, J = 8.8, 2.8 Hz, 1H), 2.41 (d, J = 3.2 Hz, 1H), 2.20 - 2.13 (m, 1H), 1.42 (dd, J = 8.8, 4.4 Hz, 1H), 1.06 (dd, J = 14.4, 7.2 Hz, 1H), 0.88 (t, J = 7.2 Hz, 3H), 0.63 (t, J = 4.8 Hz, 1H).

[0778] Example 42

[0779] Step 1: To a solution of compound 42-1a (3 g, 0.0186 mol, 1.0 eq.) in DMF (30 mL) was added NaH (1.86 g, 0.0372 mol, 2.0 eq.) at 0 °C under nitrogen protection. The reaction was stirred at 0 °C for 0.5 h, then PMBCl (8.74 g, 0.0558 mol, 3.0 eq.) was added, and then the temperature was raised to 60 °C and stirred for 2.5 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with saturated brine. It was dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and purified by silica gel column chromatography (PE / EtOAc) to give compound 42-1 (3.0 g) as a white solid. Yield: 36.02 %.

[0780] LCMS: Rt = 1.403 min, MS: 402.9 [M+H]+

[0781] Step 2: A solution of compound 42-1 (500 mg, 1.2455 mmol, 1.0 eq.) and compound 42-2 (852.42 mg, 2.491 mmol, 2.0 eq.) in THF (10 mL) was stirred at -78 °C under nitrogen protection, and LiHMDS (833.64 mg, 4.982 mmol, 4.0 eq.) was added dropwise. The reaction mixture was stirred at -78 °C for 12 h, quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc) to give compound 42-3 (350 mg) as a white solid, yield: 53.86 %.

[0782] 1H NMR (400 MHz, DMSO) δ 7.34 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.99 (s, 1H), 6.92 (d, J = 8.0 Hz, 2H), 6.85 - 6.81 (m, 3H), 6.73 (d, J = 8.8 Hz, 1H), 5.22 - 4.85 (m, 4H), 3.74 (s, 3H), 3.70 (s, 3H), 2.63 (d, J = 7.6 Hz, 1H), 2.36 (d, J = 7.6 Hz, 1H), 1.92 - 1.88 (m, 1H), 1.82 - 1.55 (m, 4H), 1.55 - 1.41 (m, 1H), 1.28 - 1.13 (m, 1H), 0.89 - 0.84 (m, 1H).

[0783] Step 3: A solution of compound 3 (350 mg, 0.7453 mmol, 1.0 eq.) in TFA / CF3SO3H = 10 / 1 (5.5 mL) was heated to 50 °C in an oil bath, after stirring for 18 hours, the mixture was concentrated in vacuum. The residue was purified by silica gel chromatography (DCM / MeOH) to give compound 42-4 (200 mg) as a yellow solid, yield: 99.49%.

[0784] 1 H NMR (400 MHz, DMSO) δ 9.77 (s, 1H), 9.01 (s, 1H), 6.66 (d, J = 8.8 Hz, 2H), 6.52 (dd, J = 8.4, 2.4 Hz, 1H), 2.45 (d, J = 7.6 Hz, 1H), 2.01 (d, J = 7.6 Hz, 1H), 1.92 - 1.80 (m, 1H), 1.80 - 1.54 (m, 4H), 1.52 - 1.48 (m, 1H), 1.24 - 1.20 (m, 1H), 0.91 - 0.86 (m, 1H).

[0785] Step 4: A mixture of compound 42-4 (200 mg, 0.8723 mmol, 1.0 eq.), compound 42-5 (201.49 mg, 0.9595 mmol, 1.1 eq.) and DIPEA (338.21 mg, 2.6169 mmol, 3.0 eq.) was dissolved in DMF (10 mL) and stirred at 60 °C for 6 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH) to give compound 42-6 (150 mg) as a yellow solid, yield: 36.91%.

[0786] LCMS: Rt = 1.532 min, MS: 418.9 [M+H]+

[0787] Step 5: A mixture of compound 42-6 (150 mg, 0.3578 mmol, 1.0 eq.), Fe (119.90 mg, 2.1468 mmol, 6.0 eq.) and NH4CI (191.39 mg, 3.5780 mmol, 10.0 eq.) was dissolved in EtOH / H2O = 3:1 (3 mL) mixed solution, heated to 80 °C in an oil bath and refluxed for 6 hours. The mixture was filtered and purified by silica gel chromatography (dichloromethane / methanol) to obtain compound 42-7 (100 mg) as a yellow oil, yield: 64.62%.

[0788] 1 H NMR (400 MHz, DMSO) d 9.94 (s, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.72 - 6.63 (m, 3H), 6.55 (dd, J = 8.8, 2.8 Hz, 1H), 5.63 (s, 2H), 2.55 (d, J = 7.6 Hz, 1H), 2.08 - 1.97 (m, 1H), 1.89 - 1.72 (m, 2H), 1.69 - 1.55 (m, 3H), 1.53 - 1.42 (m, 1H), 1.21 - 1.17 (m, 1H), 0.93 - 0.83 (m, 1H).

[0789] Step 6: To a solution of compound 42-7 (200 mg, 0.5154 mmol, 1.0 eq.) in HC1 (1 mL) was added dropwise a solution of NaNCte (46.23 mg, 0.6700 mmol, 1.3 eq.) in H2O (2 mL) at 0 °C and stirred for 1 hour at 0 °C. Subsequently, compound 42-8 (96.51 mg, 0.6184 mmol, 1.2 eq.) was dissolved in pyridine (2 mL) and H2O (4 mL) and added dropwise to the above mixture. Stirring was continued at 0 °C for 2 hours. The reaction was terminated with H2O (2 mL) and extracted with EtOAc (5 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2S04and concentrated in vacuo to obtain compound 42-9 (200 mg) as a red solid, yield: 68.43%.

[0790] LCMS: Rt = 1.381 min, MS: 556.0 [M+H]+

[0791] Step 7: A solution of compound 42-9 (70 mg, 0.1261 mmol, 1.0 eq.) and KOAc (37.13 mg, 0.3782 mmol, 2.0 eq.) in DMAc (5 mL) was heated to 115 °C and stirred for 4 h. After the reaction was completed, the mixture was quenched with H2O (1 mL) and purified by preparative high-performance liquid chromatography (ACN-H2O (0.1% trifluoroacetic acid)) to give compound 42 (22 mg) as a yellow solid in 32.51% yield.

[0792] Step 8: 42-P1 and 42-P2: The racemate of compound 42 was further separated by SFC (column: 20 mm id*250 mm, 5 pm; mobile phase: carbon dioxide / methanol (0.1% NH3) = 60 / 40) to give compound 42-P1 (12.8 mg, 99% ee) as the first eluent. Further elution gave compound 42-P2 (5.7 mg, 99% ee), both as yellow solids.

[0793] 42-P1: HPLC: Purity: 99.25% (214 nm) and 98.80% (254 nm).

[0794] 1 H NMR (400 MHz, DMSO) d 13.27 (s, 1H), 10.01 (s, 1H), 7.80 (s, 2H), 6.84 (dd, J = 8.8, 6.0 Hz, 2H), 6.67 (dd, J = 8.8, 2.8 Hz, 1H), 2.60 (d, J = 7.6 Hz, 1H), 2.05 (d, J = 7.6 Hz, 1H), 1.80 - 1.76 (m, 2H), 1.71 - 1.55 (m, 3H), 1.55 - 1.42 (m, 1H), 1.28 - 1.16 (m, 1H), 0.91 - 0.89 (m, 1H).

[0795] 42-P2: HPLC: Purity: 99.06% (214 nm) and 98.41% (254 nm).

[0796] 1H NMR (400 MHz, DMSO) δ 13.28 (s, 1H), 10.01 (s, 1H), 7.80 (s, 2H), 6.83 (dd, J = 8.4, 5.8 Hz, 2H), 6.67 (dd, J = 8.8, 2.8 Hz, 1H), 2.60 (d, J = 7.6 Hz, 1H), 2.05 (d, J = 7.2 Hz, 1H), 1.89 - 1.72 (m, 2H), 1.72 - 1.56 (m, 3H), 1.56 - 1.41 (m, 1H), 1.28 - 1.16 (m, 1H), 0.93 - 0.89 (m, 1H).

[0797] Test Example 1: THRs Coactivator Recruitment HTRF Assay

[0798] 1.1. Experimental Methods:

[0799] 1.1 Preparation of Compound Dose Gradient Solutions

[0800] 1) Triiodothyronine (T3) was prepared as a 20 mM stock solution in DMSO and MGL-3196 was prepared as a 50 mM stock solution in DMSO and stored at -20 °C. Test compounds were prepared as 20 mM stock solutions and stored in a nitrogen cabinet.

[0801] 2) T3 was diluted from the stock concentration to a 0.1 mM source concentration in DMSO and MGL-3196 and test compounds were diluted from the stock concentration to a 5 mM source concentration in DMSO with a DMSO content of 100%.

[0802] 3) Compound dilution solutions were prepared in a 384-well LDV plate by adding 10 L DMSO in columns 1, 4 through 12, 10 L of 0.1 mM T3 in column 2, and 15 L of 0.1 mM T3, 5 mM T3, and 5 mM of the other test compound in column 3 from top to bottom.

[0803] 4) The compounds were diluted 3-fold using a Bravo liquid handler by transferring 5 L of compound from column 3 to column 4, mixing, and then transferring 5 L of compound from column 4 to column 5, mixing, and so on through column 12. Column 1, the DMSO blank, was not mixed.

[0804] 5) According to the experimental design table (Table 1), the above diluted compound solution was transferred 200 nL into 384 test plate (Corning-4512, 10 dose responses for each compound and in duplicate) by Echo pipetting system, at this time DMSO was 100%. Among them, the positive control well was added with 200 nL of the highest concentration of T3, and the negative control well was added with 200 nL of DMSO, and the DMSO content was diluted to 1% in a final system of 20 μL.

[0805] Table 1 Experimental design table

[0806] Note: The "compound number to be tested" in the experimental design table 1 is only used to illustrate the idea and method of experimental design, and this number does not represent the specific compound number in the preparation examples.

[0807] 1.2 Preparation of 4x THRs working solution

[0808] 1) Dilute the THRα and THRβ proteins to 4x working concentration with buffer, at this time the protein concentration is 4 nM.

[0809] 2) According to the experimental design table, add the protein solution to the corresponding wells of the test plate containing 200 nL of compound at a volume of 5 μL per well. At this time, the concentration of THRα and THRβ proteins is 4 nM, and the DMSO content is 4%.

[0810] 3) Centrifuge at 1000 rpm for 1 minute.

[0811] 1.3 Preparation of 4x SRCs working solution

[0812] 1) Dilute the SRCs to 4x working concentration with buffer, at this time the concentration is 400 nM.

[0813] 2) Add the prepared SRCs solution to the corresponding wells of the above test plate containing 200 nL of compound and 5 uL of THR protein at a volume of 5 μL per well, and the test compound is diluted by 50 times, and the DMSO content is 2%.

[0814] 3) Centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 30 minutes after sealing the film.

[0815] 1.4 Preparation of detection reagent

[0816] 1) Dilute MAb Anti GST-Eu cryptate and Streptavidin-XL665 into 2x working mixed solution with buffer.

[0817] 2) Add 10 μL of the 2x working mix to each well of the assay plate (Streptavidin-XL665 to SRCs at a concentration ratio of 1:16), final DMSO content 1%.

[0818] 3) Centrifuge at 1000 rpm for 1 minute.

[0819] 4) Read continuously for 30 minutes using a microplate reader.

[0820] 2. Results

[0821] In this experiment, 1uM T3 in the high control well was taken as 100% activation, and the low control well contained 1% DMSO as 0% activation. XLfit was used to determine whether each round of data met the experimental standard according to the four-parameter logistic dose-response equation, and the concentration of the compound required for 50% activation (EC 50 ) was calculated, wherein the positive compounds were Triiodothyronine (T3) and MGL-3196, which were used to illustrate the technical effect of the compounds of the present application.

[0822] The experimental results show that the compounds of the present application have strong THRβ agonistic activity and strong THRα / β selectivity. In particular, compounds 7-P2, compound 15, compound 37, compound 38, compound 39, compound 39-P1, compound 40 and compound 41 have more similar selectivity to THRβ than MGL-3196, and can be used as candidate compounds. The specific data are shown in Table 2.

[0823] Table 2. Compound EC 50 values and selectivity summary Note: " / " represents exceeding the detection limit; "NA" means not detected. Explanation: The numbered compounds in Table 2 are consistent with the compound numbers in the preparation examples of the present application.

[0824] Experimental Example 2: Study on the activation level of THRs reporter gene

[0825] 2. Experimental method:

[0826] 1.1 Experimental steps

[0827] 1) Cell culture conditions: complete growth medium: in order to prepare the complete growth medium, the following ingredients are added to the basal medium: fetal bovine serum to a final concentration of 10%; penicillin-streptomycin for cell culture to a final concentration of 1%.

[0828] 2) Passage: preheat the complete medium to 37℃. Use a 10cm culture dish for cell culture. Passage the cells at a ratio of 1:3 every three days. Before passage, observe the cell state under a microscope, such as the size of the spheroids, light transmittance, etc.

[0829] 3) Recovery: The following procedure is used to thaw cells in cryovials. Cells are not contaminated prior to shipping and care should be taken to avoid contamination during handling, and a mask, gloves, and lab coat should be worn during the thawing process. Pre-warm a centrifuge tube containing 10 mL of media in a 37°C water bath. When removing the cryovial from the freezer, use forceps and immediately place in a covered container to transfer to the cell culture room. Briefly place the frozen cell vial in a 37°C water bath under aseptic conditions until only small ice crystals remain and the cell pellet is almost completely thawed (about 1 minute). Note: Longer incubation times can result in cell death. Transfer the thawed cells to a sterile 15 mL centrifuge tube containing pre-warmed media. Centrifuge at 1000 rpm for 5 minutes and gently pour off the supernatant. Add 2 mL of media to resuspend the cells and mix the cells gently several times with a 1 mL pipette. Transfer the cells to a 10 cm dish and incubate at 37°C / 5% C02. Depending on the doubling time of the cell line, passage the cells every 2-3 days. Please refer to the “Passaging” procedure.

[0830] 4) Cryopreservation: The following procedure is used to freeze cells in 10 cm dishes. Care should be taken to avoid contamination during handling. Remove the 10 cm dish from the incubator and place in a safety cabinet. Remove the cell supernatant and wash with 5 mL IX PBS. Remove the PBS and trypsinize the cells with 2 mL of 0.05% trypsin. Resuspend the detached cells in 10 mL of fresh cell culture media. Count the cells by using a cell counter and centrifuge the collected cells at 1000 rpm for 5 minutes. After centrifugation, gently pour off the supernatant. Resuspend the cell pellet in the pre-prepared freezing reagent (FBS supplemented with 10% (v / v) DMSO). Dilute the resuspended cells to the appropriate concentration (6*10e6-1*10e7 cells / mL) depending on the cell number. Transfer 1 mL of the cell freezing solution to a 2 mL cryovial. (Cryogenic container Mr. Frosty TM Pre-cool the cryopreservation box to 4°C) Transfer the cryovials to -80°C and store overnight before transferring to the gas phase of a liquid nitrogen tank for long-term storage. Cryopreservation: Freezing medium: FBS supplemented with 10% (v / v) DMSO. Storage temperature: Gas phase of liquid nitrogen. Culture conditions: Air, 95%; Carbon dioxide (C02), 5%, 37°C.

[0831] 1.2 Cell plating (Day 1)

[0832] 1) Pre-warm PBS, 0.05% trypsin, cell culture media with 37°C water.

[0833] 2) Observe the cells under a microscope to assess the degree of confluence and confirm the absence of bacterial and fungal contaminants.

[0834] 3) Remove media, wash cells with 5 mL PBS and aspirate. Add 2 mL 0.05% trypsin in a 10 cm petri dish. Place dish in incubator for a few minutes, or until cells detach. Add 8 mL fresh cell culture media, rinse cells and transfer to a centrifuge tube.

[0835] 4) Centrifuge collected cells at 1000 rpm for 5 minutes.

[0836] 5) After centrifugation, discard supernatant. Resuspend cell pellet with 5 mL cell culture media.

[0837] 6) Take 20 μL of resuspended cells for cell counting. Add 20 μL trypan blue to 20 μL cell suspension, count cells using CellCounter Star, and record number of live cells and viability in cell tracking sheet.

[0838] 7) Adjust volume of suspension using cell culture media to achieve cell concentration.

[0839] [Corr. According to Rule 91 17.06.2025]8) Transfer 45 μL of cell suspension to each well of a 384-well plate (Corning 3765) according to Table 3 (including all control wells and test compound wells).

[0840] 9) Incubate overnight at 37 °C and 5% CO2.

[0841] Table 3 Experimental design table

[0842] Explanation: The "test compound number" in the experimental design table of Table 3 is only an exemplary illustration to illustrate the idea and method of experimental design, and does not represent the specific numbered compounds prepared in the embodiments of the present application.

[0843] 1.3 Preparation of concentration gradient compound solution (Day 2)

[0844] 1) T3 was dissolved in 100% DMSO to a 20 mM stock solution. Resmetirom was dissolved in 100% DMSO to a 50 mM stock solution and stored at -20 °C.

[0845] 2) Dilute compounds from stock concentration to source concentration with DMSO. Except for the source solution concentration of T3 is 0.02 mM, the other compounds are 20 mM, and the DMSO content is 100%.

[0846] 3) Serial 3-fold dilution of compounds in 384-well LDV plates. Add 10 μL DMSO to columns 4-12. Serially transfer 5 μL of compound from column 3 to column 4, column 4 to column 5, … column 11 to column 12 by BRAVO, with 100% DMSO content.

[0847] 4) Serially transfer 3 μL of compound into a new 384-well plate containing 57 μL assay buffer to make Inter plate by BRAVO. In this plate, the compound is 3-fold serial dilution, 10 dose responses, with 5% DMSO content.

[0848] [Corr. According to Rule 91, 17.06.2025]5) Finally, according to Table 3, serially transfer 5 μL volume of compound from Inter plate to 384-well plate cell assay plate (Corning 3765, pre-plated with 45 μL cells, 10 dose responses for each compound and in duplicate) by BRAVO. Except for the highest dose concentration of T3 is 0.1 μM, the rest of the compounds are 100 μM, with 0.5% DMSO content.

[0849] 6) Incubate overnight at 37°C and 5% CO2.

[0850] 1.4 Detection (Day 3)

[0851] 1) Let all assay compounds (reagents and samples) equilibrate to room temperature before assay. Take the assay plate out of the 37°C, 5% CO2 incubator and equilibrate to room temperature for 5-10 minutes.

[0852] 2) Add 50 μL Bright-Lite reagent to the assay plate.

[0853] 3) Wait for 2 minutes before measuring luminescence. Luminescence intensity will decay gradually.

[0854] 2. Results

[0855] This experiment utilizes the stable cell lines THRα and THRβ reporter gene, the positive control well contains cells and 0.1 uM T3 as 100% activation, and the negative control well contains cells and 0.5% DMSO as 0% activation. Using XLfit, according to the four-parameter logistic dose-response equation, determine whether each round of data meets the experimental standard, and calculate the concentration of compound required for 50% activation (EC 50 ), in which the positive compounds are T3 and Resmetirom, to illustrate the technical effect of the compounds of the present application.

[0856] The experimental results show that the compounds of the present application have strong THRβ agonistic activity and strong THRα / β selectivity. The specific data are shown in Table 4.

[0857] Table 4 Compounds EC 50 Values and selectivity summary Explanation: The numbered compounds in Table 4 correspond to the compound numbers in the preparation examples of the present application.

Claims

1. A thyroid hormone β-receptor agonist, which is a compound of formula (I), its optical isomer, or a pharmaceutically acceptable salt thereof: wherein, X1is selected from CH2, O, S, or a single bond; R is selected from: H, F, Cl, Br, I, OH, NH2, CN, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, or C 3-8 epoxyalkyl; a is 0, 1, 2, 3 or 4, when a is 2, R is the same or different, when a is 3 or 4, R is the same, partially the same or completely different; L1is selected from wherein A1, A2rings are each independently selected from: L4 is selected from: -C(=O)-, -C 1-6 Alkylene-, -C(=O)-C 1-6 Alkylene-, wherein the alkylene group may be partially or wholly selected from one or more independently selected from halogen, cyano, nitro, hydroxy, amino, -C(=O)NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or C 3-6 Substituted with epoxy alkyl groups; X2, X3, X4are each independently selected from: CH2, O, S, NH or H; and when a is 3, X3is not NH; R3, R 41 , R 51 , R 52 are each independently selected from the group consisting of H, cyano, amino, hydroxy, -C(=O)NH2, -C(=O)CH3, carboxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 epoxyalkyl, which alkyl, alkoxy, cycloalkyl, epoxyalkyl can be substituted by one or more substituents independently selected from halogen, cyano, nitro, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy; R6is selected from: H, -COOH, -C(=0)NH2, -C(=0)CH3or L2is independently selected from: represents a double bond or a single bond; n is 0, 1, 2, 3, 4, 5, preferably when n is 2, R a1 identical or different, when n is 3 or 4, R a1 identical, partially identical or completely different; k is 0, 1, 2, preferably when k is 2, R c3 or R c4 are the same or different; t is 0, 1, 2, 3, 4, preferably when t is 2, R b5 , R b6 , R c5 or R c6 are identical or different, when t is 3 or 4, R b5 , R b6 , R c5 or R c6 are identical, partially identical or completely different; i is 0, 1, 2, 3, 4; preferably when i is 2, R b3 or R b4 are identical or different, when i is 3 or 4, R b3 or R b4 are identical, partially identical or completely different; A3, A4, A5, A6may be each independently selected from: C, or N; X5, X6, X7, X8may each be independently selected from: C, N, a single bond or a double bond; and when X8is a single bond, R a2 is not carbonyl; G1and G2are each independently selected from the group consisting of: -CH2-, -CH(R d1 )-, -CR e R d2 -, -C(=O)-, -N(R f )-, -S(=O)(=O)-; G3is selected from -CH2-, -CH(R d1 )-, -CR e R d2 -, -C(=O)-, -NH-, -N(R f )-, -S(=O)(=O)-, -C(R t R v )-; G4is selected from a single bond, -CH2-, -CH(R d1 )-, -CR e R d2 -, -C(=O)-, -NH-, -N(R f )-, -S(=O)(=O)-, -C(R i R j )-, -C(=CH2)-; R a1 , R a2 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R d1 , R d2 , R e are each independently selected from the group consisting of: H, halogen, -C(=O)-C 1-6 alkyl, hydroxy, cyano, amino, -S(=O)(=O)-C 1-6 alkyl, -C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(CH2) m -aryl or -(CH2) m - heteroaryl, said m is 0, 1, 2, 3, 4 or 5; wherein when i is 2, 3, 4 or 5, any two adjacent R b3 may be taken together to form a C 3-8 carbocyclic ring, C 3-8 carbocyclic heterocyclic ring, C 4-9 spirocyclic ring, benzene ring, C 5-6 aromatic heterocyclic ring, which aromatic heterocyclic ring can be: The spirocycle can be: The carbocyclic, benzene, C 5-6 The aromatic heterocycle or spirocycle can be optionally substituted with any one or more R n substituents; wherein when R e , R d2 are each C 1-6 alkyl, they can be joined to form a C 3-6 carbocyclic ring, which can be substituted with any one or more halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; R f is selected from the group consisting of: H, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, -(CH2) m -aryl, -(CH2) m -arylhetero, or -S(=O)(=O)-C 1-6 alkyl, wherein m is 1, 2, 3, 4, 5, or 6, said alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, arylhetero can be optionally substituted by any one or more R n ; Among them, R n Each group is independently selected from: H, halogen, hydroxyl, cyano, amino, -S(=O)(=O)-C 1-6 Alkyl, -C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy group, -(CH2) m -aryl or -(CH2) m -Aromatic hexyl group, where m is 0, 1, 2, 3, 4 or 5; When G3 and G4 are respectively -N(R) f )-、-C(R t R v )-、-C(R i R j When )-, R f R t R v R i R j Each is independently selected from H, halogen, hydroxyl, cyano, amino, carboxyl, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 3-6 Epoxyalkyl, wherein the alkyl, alkoxy, cycloalkyl and epoxyalkyl can be any one or more halogens, C 1-6 Alkyl-substituted; wherein the R on G3 f R t Or R v It can interact with the R on the adjacent G4 atom i Or R j Formation C 3-8 Carbon ring, C 4-9 Spirocyclic rings and benzene rings; spirocyclic rings can be: The carbocyclic or spiro ring can be optionally substituted by any one or more R n substituted; R 61 , R 71 , R 72 , R 73 are each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 epoxyalkyl, aryl or araheteroyl; said alkyl or alkoxy can be substituted with one or more independently selected from halogen, cyano, nitro, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 3-6 epoxyalkyl; said cycloalkyl, epoxyalkyl, aryl or araheteroyl can be substituted with one or more independently selected from halogen, cyano, nitro, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy.

2. The thyroid hormone beta receptor agonist of claim 1, wherein, which is a compound of the structure of Formula (II), an optical isomer thereof, or a pharmaceutically acceptable salt thereof: wherein, X1may be independently selected from CH2, O, S, or a single bond; R1, R2are each independently selected from the group consisting of: H, F, Cl, Br, I, OH, NH2, CN, NO2, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl or C 3-8 epoxyalkyl; L1is selected from wherein A1, A2rings are each independently selected from: L4is selected from the group consisting of: -C(=O)-, -C(=O)O-, 1-6 alkylene-, -C(=O)-C 1-6 alkylene-, -C(=O)-C 1-6 alkylene-, -C(=O)-C 1-6 alkylene-, -C(=O)-C 3-6 alkylene-, -C(=O)-C 3-6 alkylene-, -C(=O)-C X2, X3, X4are each independently selected from: CH2, O, S, NH or H; R3, R 41 , R 51 , R 52 each independently is selected from the group consisting of H, cyano, amino, hydroxy, -C(=0)NH2, -C(=0)CH3, carboxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 epoxyalkyl, which alkyl, alkoxy, cycloalkyl, epoxyalkyl can be substituted with one or more substituents independently selected from halogen, cyano, nitro, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy; R6is selected from: H, -COOH, -C(=0)NH2, -C(=0)CH3or L2is independently selected from: represents a double bond or a single bond; n is 0, 1, 2, 3, 4, 5; preferably when n is 2, R a1 identical or different, when n is 3 or 4, R a1 identical, partially identical or completely different; k is 0, 1, 2, preferably when k is 2, R c3 or R c4 are the same or different; t is 0, 1, 2, 3, 4, preferably when t is 2, R b5 , R b6 , R c5 or R c6 are identical or different, when t is 3 or 4, R b5 , R b6 , R c5 or R c6 are identical, partially identical or completely different; i is 0, 1, 2, 3, 4; preferably when i is 2, R b3 or R b4 are identical or different, when i is 3 or 4, R b3 or R b4 are identical, partially identical or completely different; A3, A4, A5, A6may be each independently selected from: C, or N; X5, X6, X7, X8, can each independently be selected from: C, N, a single bond or a double bond; and when X8is a single bond, R a2 is not carbonyl; G1and G2are each independently selected from the group consisting of: -CH2-, -CH(R d1 )-, -CR e R d2 -, -C(=O)-, -N(R f )-, -S(=O)(=O)-; G3is selected from: -CH2-, -CH(R d1 )-, -CR e R d2 -, -C(=O)-, -NH-, -N(R f )-, -S(=O)(=O)-, -C(R t R v )-; G4is selected from: a single bond, -CH2-, -CH(R d1 )-, -CR e R d2 -, -C(=O)-, -NH-, -N(R f )-, -S(=O)(=O)-, -C(R i R j )-, -C(=CH2)-; R a1 , R a2 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R c1 , R c2 , R c3 , R c4 , R c5 , R c6 , R d1 , R d2 , R e each independently is selected from the group consisting of: H, halogen, -C(=O)-C 1-6 alkyl, hydroxy, cyano, amino, -S(=O)(=O)-C 1-6 alkyl, -C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(CH2) m -aryl or -(CH2) m -arylhetero, m is 0, 1, 2, 3, 4 or 5; wherein any two adjacent R b3 may be C 3-8 carbocyclic, C 3-8 carbocyclic, C 4-9 spirocyclic, phenyl ring, C 5-6 aromatic heterocyclic ring, the aromatic heterocyclic ring can be: The spirocycle can be: The carbocyclic, benzene ring, C 5-6 The aromatic heterocycle or spirocycle can be optionally substituted with any one or more R n substituted; wherein when R e , R d2 are each C 1-6 alkyl, they can be joined to form a C 3-6 carbocyclic ring, which can be substituted with any one or more halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; R f is selected from the group consisting of: H, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, -(CH2) m -aryl, -(CH2) m -arylhetero, or -S(=O)(=O)-C 1-6 alkyl, wherein m is 1, 2, 3, 4, 5, 6, said alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, arylhetero can be substituted by any one or more R n ; wherein R n each independently selected from the group consisting of H, halogen, hydroxyl, cyano, amino, -S(=O)(=O)-C 1-6 alkyl, -C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(CH2) m -aryl or -(CH2) m -arylheteroalkyl, m is 0, 1, 2, 3, 4 or 5; When G3 and G4 are respectively -N(R) f )-、-C(R t R v )-、-C(R i R j When )-, R f R t R v R i R j Each is independently selected from H, halogen, hydroxyl, cyano, amino, carboxyl, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 3-6 Epoxyalkyl, wherein the alkyl, alkoxy, cycloalkyl and epoxyalkyl can be any one or more halogens, C 1-6 Alkyl-substituted; wherein the R on G3 f R t Or R v It can interact with the R on the adjacent G4 atom i Or R j Formation C 3-8 Carbon ring, C 4-9 Spirocyclic rings and benzene rings; spirocyclic rings can be: The carbocyclic or spiro ring can be optionally substituted by any one or more R n substituted; R 61 , R 71 , R 72 , R 73 are each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 epoxyalkyl, aryl, or arahetero; said alkyl or alkoxy can be substituted with one or more independently selected from halogen, cyano, nitro, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or C 3-6 epoxyalkyl; said cycloalkyl, epoxyalkyl, aryl, or arahetero can be substituted with one or more independently selected from halogen, cyano, nitro, hydroxy, amino, C 1-6 alkyl, or C 1-6 alkoxy.

3. The thyroid hormone beta receptor agonist of claim 1, wherein, which is a compound of the structure of formula (III): wherein, X1may be independently selected from CH2, O, S, or a single bond; R is selected from: H, F, Cl, Br, I, OH, NH2, CN, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl or C 3-8 epoxyalkyl; a is 0, 1, 2, 3 or 4, when a is 2, R is the same or different, when a is 3 or 4, R is the same, partially the same or completely different; L1is selected from wherein A1, A2rings are each independently selected from: L4 is selected from: -C(=O)-, -C 1-6 Alkylene-, -C(=O)-C 1-6 Alkylene-, wherein the alkylene group may be partially or wholly selected from one or more independently selected from halogen, cyano, nitro, hydroxy, amino, -C(=O)NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or C 3-6 Substituted with epoxy alkyl groups; X2, X3, X4are each independently selected from: CH2, O, S, NH or H; and when a is 3, X3is not NH; R3, R 41 , R 51 , R 52 are each independently selected from the group consisting of H, cyano, amino, hydroxy, -C(=0)NH2, -C(=0)CH3, carboxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 epoxyalkyl, which alkyl, alkoxy, cycloalkyl, epoxyalkyl can be substituted by one or more substituents independently selected from halogen, cyano, nitro, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy; R6is selected from: H, -COOH, -C(=0)NH2, -C(=0)CH3or G3is selected from: -CH2-, -CH(R d1 )-, -CR e R d2 -, -C(=O)-, -NH-, -N(R f )-, -S(=O)(=O)- or -C(R t R v )-; G4is selected from: a single bond, -CH2-, -CH(R d1 )-, -CR e R d2 -, -C(=O)-, -NH-, -N(R f )-, -S(=O)(=O)-, -C(R i R j )- or -C(=CH2)-; R a1 , R d1 , R d2 , R e are each independently selected from the group consisting of H, halogen, -C(=O)-C 1-6 alkyl, hydroxy, cyano, amino, -S(=O)(=O)-C 1-6 alkyl, -C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(CH2) m -aryl or -(CH2) m -arylheteroalkyl, m is 0, 1, 2, 3, 4 or 5; wherein when R e , R d2 are each C 1-6 alkyl, they can be joined to form a C 3-6 carbocyclic ring, which can be substituted with any one or more halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; R f is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, -(CH2) m -aryl, -(CH2) m -arylhetero, or -S(=O)(=O)-C 1-6 alkyl, wherein m is 1, 2, 3, 4, 5, 6, said alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, arylhetero can be substituted by any one or more R n ; wherein R n each independently is selected from the group consisting of H, halogen, hydroxyl, cyano, amino, -S(=O)(=O)-C 1-6 alkyl, -C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(CH2) m -aryl or -(CH2) m -arylheteroaryl, m is 0, 1, 2, 3, 4 or 5; When G3 and G4 are respectively -N(R) f )-、-C(R t R v )-、-C(R i R j When )-, R f R t R v R i R j Each is independently selected from H, halogen, hydroxyl, cyano, amino, carboxyl, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 3-6 Epoxyalkyl, wherein the alkyl, alkoxy, cycloalkyl and epoxyalkyl can be any one or more halogens, C 1-6 Alkyl-substituted; wherein the R on G3 f R t Or R v It can interact with the R on the adjacent G4 atom i Or R j Formation C 3-8 Carbon ring, C 4-9 Spirocyclic rings and benzene rings; spirocyclic rings can be: The carbocyclic or spiro ring can be substituted with any one or more R n substituted.

4. The thyroid hormone beta receptor agonist of claim 1, wherein, which is a compound of the structure shown in formula (IV): wherein, X1may be independently selected from CH2, O, S, or a single bond; R is selected from: H, F, Cl, Br, I, OH, NH2, CN, NO2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 halocycloalkyl or C 3-8 epoxyalkyl; a is 0, 1, 2, 3 or 4, when a is 2, R is the same or different, when a is 3 or 4, R is the same, partially the same or completely different; R 41 selected from: H, cyano, amino, hydroxy, -C(=O)NH2, -C(=O)CH3, carboxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 epoxyalkyl, which alkyl, alkoxy, cycloalkyl, epoxyalkyl can be substituted by one or more substituents independently selected from halogen, cyano, nitro, hydroxy, amino, C 1-6 alkyl or C 1-6 alkoxy; G3is selected from: -CH2-, -CH(R d1 )-, -CR e R d2 -, -C(=O)-, -NH-, -N(R f )-, -S(=O)(=O)-, -C(R t R v )-; G4is selected from: a single bond, -CH2-, -CH(R d1 )-, -CR e R d2 -, -C(=O)-, -NH-, -N(R f )-, -S(=O)(=O)-, -C(R i R j )-, -C(=CH2)-; R d1 , R d2 , R e are each independently selected from the group consisting of: H, halogen, -C(=O)-C 1-6 alkyl, hydroxy, cyano, amino, -S(=O)(=O)-C 1-6 alkyl, -C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(CH2) m -aryl or -(CH2) m -arylheteroalkyl, m is 0, 1, 2, 3, 4 or 5; wherein when R e , R d2 are each C 1-6 alkyl, they can be joined to form a C 3-6 carbocyclic ring, which can be substituted with any one or more halogen, -C 1-6 alkyl, -C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy; R f is selected from the group consisting of: H, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, -(CH2) m -aryl, -(CH2) m -arylhetero, or -S(=O)(=O)-C 1-6 alkyl, wherein m is 1, 2, 3, 4, 5, 6, said alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, arylhetero can be substituted by any one or more R n ; Among them, R n Each group is independently selected from: H, halogen, hydroxyl, cyano, amino, -S(=O)(=O)-C 1-6 Alkyl, -C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy group, -(CH2) m -aryl or -(CH2) m -Aromatic hexyl group, where m is 0, 1, 2, 3, 4 or 5; When G3 and G4 are respectively -N(R) f )-、-C(R t R v )-、-C(R i R j When )-, R f R t R v R i R j Each is independently selected from H, halogen, hydroxyl, cyano, amino, carboxyl, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 3-6 Epoxyalkyl, wherein the alkyl, alkoxy, cycloalkyl and epoxyalkyl can be any one or more halogens, C 1-6 Alkyl-substituted; wherein the R on G3 f R t Or R v It can interact with the R on the adjacent G4 atom i Or R j Formation C 3-8 Carbon ring, C 4-9 Spirocyclic rings and benzene rings; spirocyclic rings can be: The carbocyclic or spiro ring can be substituted with any one or more R n substituted.

5. The thyroid hormone beta receptor agonist of claim 1 or 2, wherein, In the compound of the structure represented by Formula (I) or (II), L2is: When A3is C, L1is When A3is C, L1is 41 is not hydrogen.

6. The thyroid hormone beta receptor agonist of claim 1, wherein, L2 is: when A3 is C, with L1 being when A3 is C, with L1 being a1 OH, or isopropyl.

7. The thyroid hormone beta receptor agonist of claim 1 or 2, wherein, In the compound of the structure represented by Formula (I) or (II), L2is: L1is wherein R6is not A3is not C when 8. The thyroid hormone beta receptor agonist of claim 1 or 2, wherein, In the compounds of the formula (I) or (II) described above, L2is selected from: wherein n is 2, R a1 At the para and meta positions, L1is wherein X3is N and L4is -C(=O)-, A3is not C.

9. The thyroid hormone beta receptor agonist of claim 1 or 2, wherein, In compounds with the structure shown in formula (I) or (II), when X1 is C or O, R b2 When the carbonyl group is in the ortho position, L2 is... L1 is R 41 When it is -CN, the R 73 It should not be hydrogen.

10. The thyroid hormone beta receptor agonist of claim 1 or 2, wherein, In the compound of the formula (I) or (II) shown above, when X1is C, O or S, L2is L1is wherein R 73 is aryl, or isopropyl, said R b2 is not hydrogen or isopropyl, and said R 73 is not hydrogen.

11. The thyroid hormone beta receptor agonist of claim 1 or 2, wherein, In the compound of the formula (I) or (II), L2is L1is The R b2 is not hydrogen, halogen.

12. The thyroid hormone beta receptor agonist of claim 1 or 2, wherein, In the compound of the formula (I) or (II), when X1is O or N, L2is L1is R 41 is not NH2, -CH3, H, R is not 13. The thyroid hormone beta receptor agonist of claim 1, wherein, In the compounds of the formula (I) shown above, L2is selected from R 72 is H, R c1 is alkyl, L1is R is halogen, R 41 is difluoromethyl or R is cyclopropyl or trifluoromethoxy.

14. The thyroid hormone beta receptor agonist of claim 1, wherein, In the compounds of the formula (I) shown above, L2is selected from L1is When R is cyclopropyl or trifluoromethoxy, or R is halogen, R 41 is difluoromethyl.

15. The thyroid hormone beta receptor agonist of claim 1, wherein, In the compounds of the structure of formula (I), L2is selected from L1is when R is cyclopropyl or trifluoromethoxy, or R is halogen when R 41 is difluoromethyl; The selected from the group consisting of 16. The thyroid hormone beta receptor agonist of claim 1, wherein, In the compounds of the formula (I) shown above, L2is selected from L1is When R 41 is H or C 1-3 alkyl, R is cyclopropyl or trifluoromethoxy, or R is halogen, R 41 is difluoromethyl.

17. The thyroid hormone beta receptor agonist of claim 1, wherein, In the compounds of the formula (I) shown, L2is selected from When R c1 L1is The R 41 is H, -CF2or -CN or where R6is not ​ R is cyclopropyl or trifluoromethoxy, or R is halogen when R 41 is difluoromethyl; said selected from the group consisting of 18. The thyroid hormone beta receptor agonist of claim 1, wherein, In the compounds of the structure of formula (I), L2is selected from L1is when X1is O, R 41 is -CN, R is cyclopropyl or trifluoromethoxy, or R is halogen, R 41 is difluoromethyl.

19. The thyroid hormone beta receptor agonist of claim 1 or 2, wherein, In the compounds of the formula (I) or (II) shown, L2is selected from L1is When X8is not O, it is preferably N.

20. The thyroid hormone beta receptor agonist of claim 1 or 2, wherein, In the compounds of the formula (I) or (II) shown, L2is selected from L1is When R 41 is H or C 1-3 alkyl, L1is When X8is N, the X8is not O, preferably N.

21. The thyroid hormone beta receptor agonist of claim 1 or 2, wherein, In the compounds of the formula (I) or (II) shown, L2is selected from L1is wherein R 41 is H or -CN, or wherein R6is not X8is not O, preferably N.

22. The thyroid hormone beta receptor agonist of claim 1 or 2, wherein, In the compounds of the formula (I) or (II) shown, L2is selected from When X1is O, L1is The R 41 When X8is -CN, X8is not O, but preferably N.

23. The thyroid hormone beta receptor agonist of claim 1 or 2, wherein, In the compound of the formula (I) or (II) shown above, L2 is In the compound of the formula (I) or (II) shown above, L2 is selected from 24. The thyroid hormone beta receptor agonist of claim 1 or 2, wherein, In the compound of the formula (I) or (II), when L1is , the L2is , and R f , R t or R v on G3 forms a C 3-8 carbocyclic ring, C 4-9 spiro ring, benzene ring with R i or R j on the adjacent G4 atom.

25. The thyroid hormone beta receptor agonist of claim 1 or 2, wherein, In the compound of the formula (I) or (II) shown above, L2 is when G1 is N, and L1 is when The selected from the group consisting of 26. The thyroid hormone beta receptor agonist of claim 1 or 2, wherein, In the compound of the formula (I) or (II) shown above, L2is when G1is N, L1is not including or the compound containing a substituent on the above ​ 27. The thyroid hormone beta receptor agonist of any one of claims 1-3, wherein, In the compounds of formula (I), (II) or (III), each R3, R 41 , R 51 , R 52 is independently selected from the group consisting of: H, -CN, -CF3, -CONH2, -CHF2, or COOH.

28. The thyroid hormone beta receptor agonist of any one of claims 1-3, wherein, In the compounds of formula (I), (II) or (III), said L1is:

29. The thyroid hormone beta receptor agonist of claim 1 or 2, wherein, In the compounds of formula (I) or (II), said L2is selected from:

30. The thyroid hormone beta receptor agonist of claim 1, wherein, in the compound of the structure represented by formula (I), R is Cl, Br, cyclopropane, -OCF3.

31. The thyroid hormone beta receptor agonist of claim 2, wherein, in the compound of the structure represented by formula (II), R1or R2is each independently selected from: Cl, Br, cyclopropane, -OCF3.

32. The thyroid hormone beta receptor agonist of any one of claims 1-4, wherein, which is selected from the following compounds:

33. The thyroid hormone beta receptor agonist of claim 1 selected from the group consisting of:

34. A pharmaceutical composition comprising the compound, optical isomer thereof or pharmaceutically acceptable salt thereof according to any one of claims 1-33.

35. Use of the compound, optical isomer or pharmaceutically acceptable salt thereof according to claims 1-33 or the pharmaceutical composition according to claim 34 in the manufacture of a medicament for treating a disease selected from the group consisting of obesity, diabetes, atherosclerosis, hypothyroidism, lipid metabolism disorder, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, nonalcoholic fatty liver disease, liver fibrosis, neurodegenerative disease, hypertension or heart disease.

Images