Receptor inhibitors, pharmaceutical compositions containing the inhibitors and uses thereof

Abstract

To provide a composition for the prophylaxis or treatment of an AT2 receptor-mediated disorder or a symptom associated therewith.SOLUTION: The present invention discloses a receptor inhibitor of formula (I), a composition comprising the same and the usage thereof.SELECTED DRAWING: None

Description

FIELD OF THE INVENTION

[0001] The present invention relates to angiotensin II type 2 (AT2) receptor inhibitors, pharmaceutical compositions containing the same, and their use for preventing or treating AT2 receptor-mediated disorders or conditions associated therewith.

[0002] There are two known subtypes of angiotensin II (A-II) receptors: AT1 and AT2. In rat brain, A-II receptors are predominantly of the AT2 subtype. AT2-specific inhibitors are useful for the treatment of various cerebrovascular, cognitive, and central nervous system (CNS) disorders. Furthermore, AT2 receptors are found in neuronal tumor cells and transformed human neurons.

[0003] The AT2 receptor is also involved in the differentiation and regeneration of neuronal tissue and the maintenance of bone mass.

[0004] Some studies have shown that AT2 receptor antagonism is related to the treatment of pain, especially inflammatory pain and neuropathic pain, which are two types of pain that are difficult to treat or alleviate.Nerve conduction velocity disorder is also related to nerve damage, and is related to peripheral neuropathy, carpal tunnel syndrome, ulnar neuropathy, Guillain-Barre syndrome, facioscapulohumeral muscular dystrophy and herniated disc.Nerve conduction velocity disorder can lead to reduced reflex response and peripheral sensation changes, such as paraesthesia, and in some cases, pain.AT2 receptor inhibitors have been shown to restore nerve conduction velocity.

[0005] Cell proliferation and angiogenesis are important biological functions in normal tissues.However, uncontrolled cell proliferation and angiogenesis can lead to tumors and other proliferative disorders.AT2 receptor inhibitors have been shown to have antiproliferative activity.

[0006] Osteoporosis is a serious problem in elderly people, especially in postmenopausal women. Current treatment for osteoporosis involves calcium supplementation. However, the control of bone formation and bone resorption is complex. AT2 receptor inhibitors have been shown to increase bone mass.

[0007] The role of the AT2 receptor in regulating neuronal processes and the associated effect of AT2 receptor inhibitors on the loss of neuronal processes indicates that AT2 receptor inhibitors may be useful therapeutic agents in diseases characterized by abnormal nerve regeneration.

[0008] AT2 receptors are also found in the reproductive organs of female mammals, including the uterus and ovaries. A role for angiotensin II in the process leading to ovulation has been reported. Summary of the Invention

[0009] The present invention provides compounds for use as AT2 receptor inhibitors that exhibit excellent inhibitory activity against the AT2 receptor, as well as superior properties such as better physicochemical properties (e.g., solubility, physical and / or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, adequate half-life and duration of action), and improved safety (low toxicity and / or fewer side effects in the therapeutic concentration range). More particularly, the compounds of the present invention have selective inhibitory activity against the AT2 receptor compared to the AT1 receptor.

[0010] An embodiment of the present invention is a compound having the structure of formula (I): [ka] (In the formula, R 1a , R 1b , X 1 , R 2a , R 2b and X 2 has the definition set forth in (1), (2), (3) or (4) below: (1)R 1a , R 1b and X 1together, (i) [ka] or (ii) [ka] (In the formula, ring [ka] is saturated or partially unsaturated C 3~10 a cyclic hydrocarbyl group or a saturated or partially unsaturated 3- to 10-membered heterocyclic group; X is C, CR 10 or N; R 1c is saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, saturated or partially unsaturated 3- to 10-membered heterocyclic groups, C 6~10 Aryl and 5- to 14-membered heteroaryl, -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group, -C 1~6 Alkylene-C 6~10 Aryl, and -C 1~6 alkylene-(5-14 membered heteroaryl) represents; X 2 is CR 10 or N; R 2a is C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); R 2b is H, C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); Optionally, R 2a and R 2b are each independently, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 When R is aryl or 5- to 14-membered heteroaryl, 2a The available ring atoms of R 2a and R 2b However, these are bonded to X 2 together with an optionally substituted saturated or partially unsaturated fused ring system Q containing three or more rings 2 R through the Z group to form2b is connected to an available ring atom of; or (2)R 1a , R 2a , R 1b and R 2b are each independently, C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); X 1 is CR 10 or N; X 2 is CR 15 and; R 15 is halogen, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 -OH, -C(=O)NR 11 R12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y R 11 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 S(=O) z OR 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -NR 11 R 12 , -NR 11 -C(=O)R 12 , -NR 11 -C(=O)OR 12 , -NR 11 -S(=O) y -R 12 , -NR 11 -C(=O)-NR 11 R 12 , -C 1~6 Alkylene-OR 11 , -C 1~6 Alkylene-OC(=O)R 11 , -C 1~6 Alkylene-C(=O)OR 11 , -C 1~6 Alkylene-S(=O) x R 11 , -C 1~6 Alkylene-S(=O) y OR 11 , -C 1~6 Alkylene-OC(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 R 12 , -C 1~6Alkylene-C(=O)NR 11 -S(=O) y R 12 , -C 1~6 Alkylene-NR 11 -C(=O)NR 11 R 12 , -C 1~6 Alkylene-OS(=O) y R 11 , -C 1~6 Alkylene-OS(=O) y NR 11 R 12 , -C 1~6 Alkylene-S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 -S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 R 12 and -OC 1~6 Alkylene-NR 11 R 12 selected from the group consisting of: or (3)R 1a -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 alkylene-saturated or partially unsaturated 3- to 10-membered heterocyclic group, and -C 1~6 alkylene-(5-14 membered heteroaryl); R 1b , R 2a and R 2b are each independently: OH;C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); X 1 is CR 10 , N, O or S; provided that X 1 is O or S, R 1b does not exist; X 2 is CR 10 or N; or (4)X 1 and X 2 are independently 10 or N; R 1a and R 2a are each independently, C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); R1b and R 2b are independently H, C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); however, R 1a and R 1b are each independently, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 aryl or 5- to 14-membered heteroaryl, and R 1a The available ring atoms of R 1a and R 1b However, these are bonded to X 1 together with an optionally substituted saturated or partially unsaturated fused ring system Q containing three or more rings 1 R is bonded to the Y group via the Y group so as to form 1b is connected to an available ring atom of 2a and R 2b are each independently, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 aryl or 5- to 14-membered heteroaryl, and R 2a The available ring atoms of R 2a and R 2b However, these are bonded to X 2together with an optionally substituted saturated or partially unsaturated fused ring system Q containing three or more rings 2 R through the Z group to form 2b is connected to an available ring atom of; R 1a , R 1b , X 1 , R 2a , R 2b and X 2 has the definition set forth in any one of meanings (1), (2), (3) and (4), Y and Z each independently represent a single bond; NR 10 ;C 1~3 Alkylene (wherein one or two CH moieties are O, S, or NR 10 and C 2~3 alkenylene, wherein any one of the CH moieties forming the C═C double bond is optionally replaced with N; C 1~3 Alkylene and C 2~3 Each alkenylene is optionally halogen, OH, -NR 11 R 12 , cyano, nitro, C 1~6 Alkyl, C 1~6 substituted by one, two, three or more groups selected from the group consisting of alkyl-O-, epoxy and oxo; X 3 and X 4 are each independently C(=O);S(=O) y ; and -OC(=O)-, -SC(=O)-, -OS(=O) y -, -NR 10 -C(=O)- and -NR 10 -S(=O) y -(In the formula, O, S, NR 10 is X 1 or X 2 and preferably, X 3 and X 4 are each independently C(=O), -OC(=O)- or -NR 10-C(=O)-; R 3 , R 4 and R 10 are each independently H, halogen, cyano, nitro, or C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -OR 11 , -SR 11 , -OC(=O)R 11、 -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 -OH, -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12、 -C(=O)NR 11 S(=O) y R 12 , -S(=O) y R 11 , -S(=O) y OR 11、 -S(=O) y NR 11 R 12 , -S(=O) y NR 11 S(=O) z OR 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -NR 11 R 12 , -NR 11 -C(=O)R 12 , -NR 11 -C(=O)OR 12 , -NR 11 -S(=O) y -R 12 , -NR 11-C(=O)-NR 11 R 12 , -C 1~6 Alkylene-OR 11 , -C 1~6 Alkylene-OC(=O)R 11 , -C 1~6 Alkylene-C(=O)OR 11 , -C 1~6 Alkylene-S(=O) x R 11 , -C 1~6 Alkylene-S(=O) y OR 11 , -C 1~6 Alkylene-OC(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 -S(=O) y R 12 , -C 1~6 Alkylene-NR 11 -C(=O)NR 11 R 12 , -C 1~6 Alkylene-OS(=O) y R 11 , -C 1~6 Alkylene-OS(=O) y NR 11 R 12 , -C 1~6 Alkylene-S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 -S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 R 12 and -OC 1~6 Alkylene-NR 11 R 12 selected from the group consisting of: R 11 and R 12 are, in each occurrence, independently, H, C1~6 Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl; The alkyl, alkylene, alkenyl, alkenylene, alkynyl, cyclic hydrocarbyl group, heterocyclic group, aryl, heteroaryl, and aralkyl, at each occurrence, may each optionally be one, two, three, or more R 13 is replaced by R 13 is, in each occurrence, a halogen, cyano, nitro, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y R 11 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 S(=O) z OR 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -NR 11 R 12 , -NR11 -C(=O)R 12 , -NR 11 -C(=O)OR 12 , -NR 11 -S(=O) y -R 12 , -NR 11 -C(=O)-NR 11 R 12 , -C 1~6 Alkylene-OR 11 , -C 1~6 Alkylene-OC(=O)R 11 , -C 1~6 Alkylene-C(=O)OR 11 , -C 1~6 Alkylene-S(=O) x R 11 , -C 1~6 Alkylene-S(=O) y OR 11 , -C 1~6 Alkylene-OC(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 -S(=O) y R 12 , -C 1~6 Alkylene-NR 11 -C(=O)NR 11 R 12 , -C 1~6 Alkylene-OS(=O) y R 11 , -C 1~6 Alkylene-OS(=O) y NR 11 R 12 , -C 1~6 Alkylene-S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 -S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 R 12 and -OC1~6 Alkylene-NR 11 R 12 and the substituents R are independently selected from the group consisting of 13 Alkyl, alkylene, cyclic hydrocarbyl groups, heterocyclic groups, aryl, heteroaryl and aralkyl as defined above are substituted with halogen, OH, oxo, amino, cyano, nitro, C 1~6 Alkyl, halogenated C 1~6 Alkyl, C 3~6 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl; heterocyclic group, aryl or heteroaryl, when a substituent, is connected to the remainder of the molecule via a ring C atom or, if possible, via a ring N atom; x, in each occurrence, is independently 0, 1, or 2; y and z, in each occurrence, are each independently 1 or 2; however, R 1a , R 1b , X 1 , R 2a , R 2b and X 2 has the definition set forth in meaning (4), then R 1a and R 1b are each independently, C 1~8 When R is alkyl, Z is not -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-; or R 2a and R 2b are each independently, C 1~8 When Y is alkyl, Y is not -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-. or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

[0011] Another aspect of the present invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers, preferably in the form of a solid, semi-solid, liquid, or gaseous preparation.

[0012] Another aspect of the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for use as an AT2 receptor inhibitor.

[0013] Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, for use as an AT2 receptor inhibitor.

[0014] Another aspect of the present invention provides a method for preventing or treating an AT2 receptor-mediated disorder or a condition associated therewith, comprising the step of administering to a subject in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention.

[0015] Another aspect of the present invention provides a method of modulating AT2 receptor-related reproductive function in a female patient, comprising the step of administering to a subject in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.

[0016] definition Unless otherwise defined by the context, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations on these techniques or substitutions of equivalent techniques as would be apparent to those skilled in the art. While the following terms are believed to be readily understood by those skilled in the art, the following definitions are set forth to better illustrate the present invention.

[0017] The terms "contain," "include," "comprise," "have," or "relate," and other variations as used herein, are inclusive and open-ended and do not exclude additional, unrecited elements or method steps.

[0018] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbyl, preferably having 1, 2, 3, 4, 5, or 6 carbon atoms, such as methylene, ethylene, propylene, or butylene.

[0019] As used herein, the term "alkyl" is defined as a straight-chain or branched saturated aliphatic hydrocarbon. In some embodiments, alkyl has 1 to 12 carbon atoms, particularly 1 to 8 carbon atoms ("C 1~8 alkyl") carbon atoms, e.g., 1 to 6 ("C 1~6 alkyl"), 1 to 4 ("C 1~4 alkyl) carbon atoms, more particularly 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. For example, as used herein, "C 1~8The term "alkyl" refers to a straight or branched chain group having 1 to 8 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, etc.), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogen (in which case the group may be referred to as a "halogenated alkyl") (e.g., CHF, CHF, CF, CCl, CF, CCl, CHCF, CHCl, or -CHCHCF, etc.). "C 1~4 The term "alkyl" refers to a straight or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0020] As used herein, the term "alkenyl" refers to an alkyl group having a double bond and 2 to 8 carbon atoms ("C 2~6 "C" such as alkenyl 2~8 "Alkenyl" refers to a linear or branched monovalent hydrocarbyl having an alkenylene group ("alkenyl"). Alkenyl is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, heptenyl, and octenyl. When the compounds of the present invention contain an alkenylene group, the compounds may exist as the pure E (entgegen) form, the pure Z (zusammen) form, or any mixture thereof.

[0021] As used herein, the term "alkynyl" refers to a monovalent hydrocarbyl containing one or more triple bonds and preferably having 2, 3, 4, 5, 6, 7, or 8 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl.

[0022] As used herein, the terms "cyclic hydrocarbylene," "cyclic hydrocarbyl," and "hydrocarbon ring" refer to saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings, for example, having 3 to 10 (suitably having 3 to 8, more suitably having 3 to 6, e.g., 5 to 6 or 5 to 7) ring carbon atoms, including, but not limited to, cyclopropyl(ene)(ring), cyclobutyl(ene)(ring), cyclopentyl(ene)(ring), cyclohexyl(ene)(ring), cycloheptyl(ene)(ring), cyclooctyl(ene)(ring), cyclononyl(ene)(ring), cyclohexenyl(ene)(ring), and the like.

[0023] As used herein, the terms "heterocyclyl," "heterocyclylene," and "heterocycle" refer to saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double and / or triple bonds within the ring) monocyclic or bicyclic groups having, for example, 3 to 10 (suitably 3 to 8, more suitably 3 to 6; or suitably 8 to 10, more suitably 9 or 10) ring atoms, in which at least one ring atom is a heteroatom selected from the group consisting of N, O, and S, and the remaining ring atoms are C. For example, a "3- to 10-membered heterocyclyl(ene)" or "3- to 10-membered heterocycle" refers to a saturated or partially unsaturated monocyclic or bicyclic heterocyclyl(ene) or heterocycle having 2 to 9 (e.g., 2, 3, 4, 5, 6, 7, 8, or 9) ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from the group consisting of N, O, and S. Examples of monocyclic heterocyclylenes, heterocyclyls, and heterocycles include, but are not limited to, oxiranyl(ene), aziridinyl(ene), azetidinyl(ene), oxetanyl(ene), tetrahydrofuranyl(ene), dioxolinyl(ene), pyrrolidinyl(ene), pyrrolidonyl(ene), imidazolidinyl(ene), pyrazolidinyl(ene), pyrrolinyl(ene), tetrahydropyranyl(ene), piperidinyl(ene), morpholinyl(ene), dithianyl(ene), thiomorpholinyl(ene), piperazinyl(ene), or trithianyl(ene). Bicyclic heterocyclylenes, heterocyclyls, and heterocycles include spirocyclic, fused (e.g., benzofused), or bridged systems. Benzo-fused heterocyclylene, heterocyclyl and heterocycle refers to the above monocyclic heterocyclylene, heterocyclyl and heterocycle having 3 to 6 (suitably 4 to 6, more suitably 5 to 6) ring atoms, in which 1, 2, 3 or 4 ring atoms are heteroatoms selected from N, O and S, and the remaining ring atoms are C, fused to benzene, for example, benzo derivatives of saturated or partially unsaturated monocyclic groups (i.e., "7-10 membered benzo-fused heterocyclylene, heterocyclyl and heterocycle"), for example, 2,3-dihydrobenzofuranyl(ene) ( [ka] ), 1,3-dihydroisobenzofuranyl(ene)( [ka] ), 2,3-dihydrobenzo[c]thienyl(ene)( [ka] ), 1,3-dihydrobenzo[c]thienyl(ene)( [ka] ), dihydroindolyl(ene)( [ka] ), dihydroisoindolyl(ene)( [ka] ), benzo[d][1,3]dioxolyl(ene)( [ka] ), benzo[d][1,3]dithiolyl(ene)( [ka] ), benzo[d][1,3]oxathiolyl(ene)( [ka] ), 3H-benzo[c][1,2]oxathiolyl(ene)( [ka] ), 3H-benzo[d][1,2]oxathiolyl(ene)( [ka] ), 2,3-dihydrobenzo[d]oxazolyl(ene)( [ka] ), 2,3-dihydrobenzo[d]thiazolyl(ene)( [ka] ), 2,3-dihydro-1H-benzo[d]imidazolyl(ene)( [ka] ), 2,3-dihydrobenzo[d]isoxazolyl(ene)( [ka] ), 2,3-dihydrobenzo[d]isothiazolyl(ene)( [ka] ), 1,3-dihydrobenzo[c]isoxazolyl(ene)( [ka] ), 1,3-dihydrobenzo[c]isothiazolyl(ene)( [ka] ), 2,3-dihydro-1H-indazolyl(ene)( [ka] ), chromanyl(ene)( [ka] ), 2H-chromenyl(ene)( [ka] ), 4H-chromenyl(ene)( [ka] ), dihydrobenzothiopyranyl(ene)( [ka] ), 2H-thiochromenyl(ene) (2H-thiochromene, [ka] ), 4H-benzothiopyranyl(ene) (4H-thiochromene, [ka] ), 1,2,3,4,4a,8a-hexahydroquinolinyl(ene)( [ka] ), 1,2,4a,8a-tetrahydroquinolinyl(ene)( [ka] ), 1,4,4a,8a-tetrahydroquinolinyl(ene)( [ka] ), 1,2,3,4,4a,8a-hexahydroisoquinolinyl(ene)( [ka] ), 1,2,3,4,4a,8a-hexahydroquinoxalinyl(ene)( [ka] ), 1,4,4a,8a-tetrahydroquinoxalinyl(ene)( [ka] ), 1,2,3,4,4a,8a-hexahydroquinazolinyl(ene)( [ka] ), 2,4,4a,8a-tetrahydro-1H-benzo[d][1,3]oxazinyl(ene)( [ka] ), 3,4,4a,8a-tetrahydro-2H-benzo[b][1,4]oxazinyl(ene)( [ka] ), 3,4,4a,8a-tetrahydro-2H-benzo[e][1,3]oxazinyl(ene)( [ka] ), 2,4,4a,8a-tetrahydro-1H-benzo[d][1,3]thiazinyl(ene)( [ka] ), 3,4,4a,8a-tetrahydro-2H-benzo[b][1,4]thiazinyl(ene)( [ka] ), 3,4,4a,8a-tetrahydro-2H-benzo[e][1,3]thiazinyl(ene)( [ka] ) Bridged systems also include, for example, 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, and 2-azabicyclo[2.2.2]octane. Heterocyclylene, heterocyclyl, and heterocycle may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0024] As used herein, the terms "aryl(ene)" and "aromatic ring" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. For example, as used herein, "C 6~10 Aryl(ene) and C 6~10 The term "aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as a phenyl(ene) (benzene ring) or a naphthyl(ene) (naphthalene ring). The aryl(ene) or aromatic ring may contain one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO, and C). 1~6 alkyl, etc., and is optionally substituted.

[0025] As used herein, the terms "heteroaryl(ene)" and "heteroaromatic ring" refer to a monocyclic, bicyclic, or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13, or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and containing at least one heteroatom (such as O, N, or S), which may be the same or different. Furthermore, in each case, this can be benzo-fused. In particular, the "heteroaryl(ene)" or "heteroaromatic ring" is selected from the group consisting of thienyl(ene), furyl(ene), pyrrolyl(ene), oxazolyl(ene), thiazolyl(ene), imidazolyl(ene), pyrazolyl(ene) (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl and 5-pyrazolyl), isoxazolyl(ene), isothiazolyl(ene), oxadiazolyl(ene), triazolyl(ene), tetrazolyl(ene) (e.g., 1-tetrazolyl or 5-tetrazolyl), thiadiazolyl(ene), and the like, and benzo derivatives thereof; or pyridinyl(ene), pyridazinyl(ene), pyrimidinyl(ene), pyrazinyl(ene), triazinyl(ene), and the like, and benzo derivatives thereof.

[0026] As used herein, the term "aralkyl" refers to an alkyl substituted with an aryl or heteroaryl, preferably wherein the aryl, heteroaryl, and alkyl are as defined herein. Typically, an aryl group can have 6 to 14 carbon atoms, a heteroaryl group can have 5 to 14 ring atoms, and an alkyl group can have 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0027] As used herein, the term "halo" or "halogen" is defined to include F, Cl, Br, or I.

[0028] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and at least one nitrogen atom in the ring, and optionally further including one or more (e.g., 1, 2, 3, or 4) ring members selected from the group consisting of N, O, C=O, S, S=O, and S(=O)2. The nitrogen-containing heterocycle is bonded to the rest of the molecule through the nitrogen atom in the nitrogen-containing heterocycle and any other ring atoms. The nitrogen-containing heterocycle is optionally benzo-fused, and is preferably bonded to the rest of the molecule through the nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzene ring.

[0029] The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) hydrogens of a specified atom have been replaced with a selection from the indicated group, provided that the replacement does not exceed the normal valence of the specified atom under the existing circumstances, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0030] When a substituent is described as "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. When a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to some extent) may be replaced separately and / or together with independently selected optional substituents.

[0031] When substituents are described as being "independently selected" from a group, each substituent is selected independently of the other substituent(s), and therefore each substituent can be the same as or different from the other substituent(s).

[0032] As used herein, the term "one or more" means one or reasonably more than one (eg, 2, 3, 4, 5, or 10).

[0033] As used herein, unless specified, the point of attachment of a substituent can be at any suitable position on the substituent.

[0034] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may also be bonded to any of the substitutable ring-forming atoms in that ring.

[0035] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds identical to those of the present invention, except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in compounds of the present invention include, but are not limited to: 2 H, 3 Isotopes of hydrogen such as H; 11 C. 13 C and 14 isotopes of carbon such as C; 36 isotopes of chlorine such as Cl; 18 isotopes of fluorine such as F; 123 I and 125 isotopes of iodine such as I; 13 N and 15 isotopes of nitrogen such as N; 15 O. 17 O and 18 isotopes of oxygen such as O; 32 Isotopes of phosphorus, such as P; and 35 Certain isotopically labeled compounds of the present invention, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium, i.e. 3 H and carbon-14, i.e. 14 C is particularly useful for this purpose given its ease of incorporation and rapid means of detection. 11 C. 18 F, 15 O and 13Substitution with positron-emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by methods similar to those described in the accompanying schemes and / or examples and preparations, by substituting the appropriate isotopically labeled reagent for the previously used non-labeled reagent. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent of crystallization may be isotopically substituted, for example, DO, acetone-d6, or DMSO-d6.

[0036] The term "stereoisomer" refers to an isomer having at least one asymmetric center. Compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers can result in racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Certain individual molecules may exist as geometric isomers (cis / trans). Similarly, compounds of the present invention may exist as mixtures of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium. Typical examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to be understood that all such isomers and mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%) are within the scope of the present invention.

[0037] Carbon-carbon bonds in the compounds of the present invention are represented by solid lines ( [ka] ), solid wedge ( [ka] ) or dotted wedge ( [ka] ) can be depicted herein. The use of a solid line to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers of that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.) are included. The use of either a solid line or a dotted wedge to depict bonds to asymmetric carbon atoms is intended to indicate that the depicted stereoisomer exists. When present in a racemic compound, solid and dotted wedges are used to define relative stereochemistry rather than absolute stereochemistry. Unless otherwise stated, it is intended that the compounds of the present invention can exist as stereoisomers, including cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention can exhibit more than one type of isomerism and can consist of mixtures thereof (e.g., racemates and diastereomeric pairs).

[0038] The present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, either as single polymorphs or as mixtures of two or more polymorphs in any ratio.

[0039] It should also be understood that certain compounds of the present invention can be used in therapy in free form or, where appropriate, in the form of a pharmaceutically acceptable derivative. In the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, a pharmaceutically acceptable salt, ester, solvate, N-oxide, metabolite, or prodrug that can directly or indirectly provide a compound of the present invention or a metabolite or residue thereof after administration to a patient in need thereof. Therefore, references herein to "a compound of the present invention" are meant to encompass various derivative forms of the compounds referenced above.

[0040] Pharmaceutically acceptable salts of the compounds of the present invention include the acid addition and base salts thereof.

[0041] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Specific examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, malate, malonate ... These include phosphate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate.

[0042] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts, particular examples of which include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0043] For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0044] As used herein, the term "ester" refers to compounds derived from the various formulae of the present application and includes physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the invention in the free acid or alcohol form). The compounds of the invention themselves can also be esters.

[0045] The compounds of the present invention can exist as solvates (preferably hydrates) in which the compounds of the present invention contain polar solvents, particularly water, methanol or ethanol, as structural elements of the crystalline lattice of the compounds. The amount of polar solvent, particularly water, can be present in a stoichiometric or non-stoichiometric ratio.

[0046] As can be understood by those skilled in the art, not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires an available lone electron pair for oxidation to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, and these methods include oxidation of heterocycles and tertiary amines with peracids such as peracetic acid and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see, for example, T. L. Gilchrist, Comprehensive Organic Synthesis, Vol. 7, pp. 748-750; A. R. Katrittzky and A. J. Boulton, eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk, Advances in Heterocyclic Chemistry, Vol. 22, pp. 390-392, A. R. Katrittzky and A. J. Boulton, eds., Academic Press.

[0047] Also included within the scope of the present invention are metabolic products of the compounds of the present invention, i.e., substances formed in vivo upon administration of a compound of the present invention. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic degradation, etc. of the administered compound. Accordingly, the present invention includes metabolic products of the compounds of the present invention, including compounds produced by a process comprising contacting a compound of the present invention with a mammal for a period of time sufficient to yield a metabolic product thereof.

[0048] Also within the scope of the present invention are prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that have little or no pharmacological activity themselves but can be converted, for example, by hydrolytic cleavage, into compounds of the present invention having the desired activity upon administration to or on the body. Generally, such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into compounds having the desired therapeutic activity. Further information regarding the use of prodrugs can be found in "Prodrugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). Prodrugs according to the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties," as described, for example, in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985).

[0049] The present invention further encompasses compounds of the present invention having protecting groups. During any of the methods for preparing compounds of the present invention, it may be necessary and / or desirable to protect any sensitive or reactive groups of the molecule in question, thereby obtaining chemically protected forms of the compounds of the present invention. This can be achieved by conventional protecting groups, such as those described in T.W. Greene & P. ​​G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which is incorporated herein by reference. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0050] The term "about" refers to a range within ±10%, preferably within ±5%, and more preferably within ±2% of the specified value.

[0051] Specific Embodiments

[0052] compound Generally, the present invention provides a compound having the structure of formula (I): [ka] (In the formula, R 1a , R 1b , X 1 , R 2a , R 2b and X 2 has the definition set forth in (1), (2), (3) or (4) below: (1)R 1a , R 1b and X 1 together, (i) [ka] or (ii) [ka] (In the formula, ring [ka] is saturated or partially unsaturated C 3~10 a cyclic hydrocarbyl group or a saturated or partially unsaturated 3- to 10-membered heterocyclic group; X is C, CR 10 or N; R 1c is saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, saturated or partially unsaturated 3- to 10-membered heterocyclic groups, C 6~10 Aryl and 5- to 14-membered heteroaryl, -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group, -C 1~6 Alkylene-C 6~10 Aryl, and -C 1~6 alkylene-(5-14 membered heteroaryl) represents; X 2 is CR 10 or N; R 2a is C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); R 2b is H, C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); Optionally, R 2a and R 2b are each independently, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 When R is aryl or 5- to 14-membered heteroaryl, 2a The available ring atoms of R 2a and R 2b However, these are bonded to X 2 together with an optionally substituted saturated or partially unsaturated fused ring system Q containing three or more rings 2 R through the Z group to form 2b is connected to an available ring atom of; or (2)R 1a , R 2a , R 1b and R 2b are each independently, C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); X 1 is CR 10 or N; X 2 is CR 15 and; R 15 is halogen, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 -OH, -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y R 11 , -S(=O) y OR 11, -S(=O) y NR 11 R 12 , -S(=O) y NR 11 S(=O) z OR 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -NR 11 R 12 , -NR 11 -C(=O)R 12 , -NR 11 -C(=O)OR 12 , -NR 11 -S(=O) y -R 12 , -NR 11 -C(=O)-NR 11 R 12 , -C 1~6 Alkylene-OR 11 , -C 1~6 Alkylene-OC(=O)R 11 , -C 1~6 Alkylene-C(=O)OR 11 , -C 1~6 Alkylene-S(=O) x R 11 , -C 1~6 Alkylene-S(=O) y OR 11 , -C 1~6 Alkylene-OC(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 -S(=O) y R 12 , -C 1~6 Alkylene-NR 11 -C(=O)NR 11 R 12 , -C 1~6 Alkylene-OS(=O) y R 11 , -C 1~6Alkylene-OS(=O) y NR 11 R 12 , -C 1~6 Alkylene-S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 -S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 R 12 and -OC 1~6 Alkylene-NR 11 R 12 selected from the group consisting of: or (3)R 1a -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 alkylene-saturated or partially unsaturated 3- to 10-membered heterocyclic group, and -C 1~6 alkylene-(5-14 membered heteroaryl); R 1b , R 2a and R 2b are each independently: OH;C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6alkylene-(5-14 membered heteroaryl); X 1 is CR 10 , N, O or S; provided that X 1 is O or S, R 1b does not exist; X 2 is CR 10 or N; or (4)X 1 and X 2 are independently 10 or N; R 1a and R 2a are each independently, C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); R 1b and R 2b are independently H, C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); however, R 1a and R 1b are each independently, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 aryl or 5- to 14-membered heteroaryl, and R 1a The available ring atoms of R 1a and R 1b However, these are bonded to X 1 together with an optionally substituted saturated or partially unsaturated fused ring system Q containing three or more rings 1 R is bonded to the Y group via the Y group so as to form 1b is connected to an available ring atom of 2a and R 2b are each independently, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 aryl or 5- to 14-membered heteroaryl, and R 2a The available ring atoms of R 2a and R 2b However, these are bonded to X 2 together with an optionally substituted saturated or partially unsaturated fused ring system Q containing three or more rings 2 R through the Z group to form 2b is connected to an available ring atom of; R 1a , R 1b , X 1 , R 2a , R 2b and X 2has the definition set forth in any one of meanings (1), (2), (3) and (4), Y and Z each independently represent a single bond; NR 10 ;C 1~3 Alkylene (wherein one or two CH moieties are O, S, or NR 10 and C 2~3 alkenylene, wherein any one of the CH moieties forming the C═C double bond is optionally replaced with N; C 1~3 Alkylene and C 2~3 Each alkenylene is optionally halogen, OH, -NR 11 R 12 , cyano, nitro, C 1~6 Alkyl, C 1~6 substituted by one, two, three or more groups selected from the group consisting of alkyl-O-, epoxy and oxo; X 3 and X 4 are each independently C(=O);S(=O) y ; and -OC(=O)-, -SC(=O)-, -OS(=O) y -, -NR 10 -C(=O)- and -NR 10 -S(=O) y -(In the formula, O, S, NR 10 is X 1 or X 2 and preferably, X 3 and X 4 are each independently C(=O), -OC(=O)- or -NR 10 -C(=O)-; R 3 , R 4 and R 10 are each independently H, halogen, cyano, nitro, or C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -OR 11 , -SR 11 , -OC(=O)R 11、 -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 -OH, -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12、 -C(=O)NR 11 S(=O) y R 12 , -S(=O) y R 11 , -S(=O) y OR 11、 -S(=O) y NR 11 R 12 , -S(=O) y NR 11 S(=O) z OR 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -NR 11 R 12 , -NR 11 -C(=O)R 12 , -NR 11 -C(=O)OR 12 , -NR 11 -S(=O) y -R 12 , -NR 11 -C(=O)-NR 11 R 12 , -C 1~6 Alkylene-OR 11 , -C 1~6 Alkylene-OC(=O)R 11 , -C 1~6 Alkylene-C(=O)OR 11 , -C 1~6 Alkylene-S(=O) x R 11 , -C1~6 Alkylene-S(=O) y OR 11 , -C 1~6 Alkylene-OC(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 -S(=O) y R 12 , -C 1~6 Alkylene-NR 11 -C(=O)NR 11 R 12 , -C 1~6 Alkylene-OS(=O) y R 11 , -C 1~6 Alkylene-OS(=O) y NR 11 R 12 , -C 1~6 Alkylene-S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 -S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 R 12 and -OC 1~6 Alkylene-NR 11 R 12 selected from the group consisting of: R 11 and R 12 are, in each occurrence, independently, H, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl; The alkyl, alkylene, alkenyl, alkenylene, alkynyl, cyclic hydrocarbyl group, heterocyclic group, aryl, heteroaryl, and aralkyl, at each occurrence, may each optionally be one, two, three, or more R 13 is replaced by R 13 is, in each occurrence, a halogen, cyano, nitro, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y R 11 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 S(=O) z OR 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -NR 11 R 12 , -NR 11 -C(=O)R 12 , -NR 11 -C(=O)OR 12 , -NR 11 -S(=O) y -R 12 , -NR11 -C(=O)-NR 11 R 12 , -C 1~6 Alkylene-OR 11 , -C 1~6 Alkylene-OC(=O)R 11 , -C 1~6 Alkylene-C(=O)OR 11 , -C 1~6 Alkylene-S(=O) x R 11 , -C 1~6 Alkylene-S(=O) y OR 11 , -C 1~6 Alkylene-OC(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 -S(=O) y R 12 , -C 1~6 Alkylene-NR 11 -C(=O)NR 11 R 12 , -C 1~6 Alkylene-OS(=O) y R 11 , -C 1~6 Alkylene-OS(=O) y NR 11 R 12 , -C 1~6 Alkylene-S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 -S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 R 12 and -OC 1~6 Alkylene-NR 11 R 12 and the substituents R are independently selected from the group consisting of 13The alkyl, alkylene, cyclic hydrocarbyl groups, heterocyclic groups, aryl, heteroaryl and aralkyl listed for 1~6 Alkyl, halogenated C 1~6 Alkyl, C 3~6 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl; heterocyclic group, aryl or heteroaryl, when a substituent, is connected to the remainder of the molecule via a ring C atom or, if possible, via a ring N atom; x, in each occurrence, is independently 0, 1, or 2; y and z, in each occurrence, are each independently 1 or 2; however, R 1a , R 1b , X 1 , R 2a , R 2b and X 2 has the definition set forth in meaning (4), then R 1a and R 1b are each independently, C 1~8 When R is alkyl, Z is not -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-; or R 2a and R 2b are each independently, C 1~8 When Y is alkyl, Y is not -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-. or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

[0053] A first aspect of the embodiment of the compounds according to the invention is R 1a , R 1b , X 1 , R 2a , R2b and X 2 has the definition set forth in meaning (4) above, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

[0054] Thus, a first aspect of the compound of the present invention is X 1 and X 2 are independently, CR 10 or N; R 1a and R 2a are each independently, C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); R 1b and R 2b are independently H, C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); however, R 1a and R 1b are each independently, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 aryl or 5- to 14-membered heteroaryl, and R 1a The available ring atoms of R 1a and R 1b However, these are bonded to X 1 together with an optionally substituted saturated or partially unsaturated fused ring system Q containing three or more rings 1 R is bonded to the Y group via the Y group so as to form 1b is connected to an available ring atom of 2a and R 2b are each independently, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 aryl or 5- to 14-membered heteroaryl, and R 2a The available ring atoms of R 2a and R 2b However, these are bonded to X 2 together with an optionally substituted saturated or partially unsaturated fused ring system Q containing three or more rings 2 R through the Z group to form 2b is connected to an available ring atom of; Y and Z each independently represent a single bond; NR 10 ;C 1~3 Alkylene (wherein one or two CH moieties are O, S, or NR 10and C 2~3 alkenylene, wherein any one of the CH moieties forming the C═C double bond is optionally replaced with N; C 1~3 Alkylene and C 2~3 each alkenylene optionally represents a halogen, OH, or -NR 11 R 12 , cyano, nitro, C 1~6 Alkyl, C 1~6 substituted by one, two, three or more groups selected from the group consisting of alkyl-O-, epoxy and oxo; X 3 and X 4 are each independently C(=O);S(=O) y ; and -OC(=O)-, -SC(=O)-, -OS(=O) y -, -NR 10 -C(=O)- and -NR 10 -S(=O) y -(In the formula, O, S, NR 10 is X 1 or X 2 and preferably, X 3 and X 4 are each independently C(=O), -OC(=O)- or -NR 10 -C(=O)-; R 3 , R 4 and R 10 are each independently H, halogen, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR11 -OH, -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y R 11 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 S(=O) z OR 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -NR 11 R 12 , -NR 11 -C(=O)R 12 , -NR 11 -C(=O)OR 12 , -NR 11 -S(=O) y -R 12 , -NR 11 -C(=O)-NR 11 R 12 , -C 1~6 Alkylene-OR 11 , -C 1~6 Alkylene-OC(=O)R 11 , -C 1~6 Alkylene-C(=O)OR 11 , -C 1~6 Alkylene-S(=O) x R 11 , -C 1~6 Alkylene-S(=O) y OR 11 , -C 1~6 Alkylene-OC(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 -S(=O) y R 12 , -C 1~6 Alkylene-NR 11 -C(=O)NR 11 R 12 , -C 1~6 Alkylene-OS(=O) y R 11 , -C 1~6 Alkylene-OS(=O) y NR 11 R 12 , -C 1~6 Alkylene-S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 -S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 R 12 and -OC 1~6 Alkylene-NR 11 R 12 selected from the group consisting of: R 11 and R 12 However, in each existence, independently, H, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl; The alkyl, alkylene, alkenyl, alkenylene, alkynyl, cyclic hydrocarbyl group, heterocyclic group, aryl, heteroaryl, and aralkyl, each at each occurrence, may each optionally be one, two, three, or more R 13 is replaced by R 13 However, in each occurrence, halogen, cyano, nitro, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y R 11 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 S(=O) z OR 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -NR 11 R 12 , -NR 11 -C(=O)R 12 , -NR 11 -C(=O)OR 12 , -NR 11 -S(=O) y -R 12 , -NR 11 -C(=O)-NR 11 R 12 , -C 1~6 Alkylene-OR 11 , -C 1~6 Alkylene-OC(=O)R 11 , -C 1~6 Alkylene-C(=O)OR 11 , -C 1~6 Alkylene-S(=O) x R 11 , -C 1~6Alkylene-S(=O) y OR 11 , -C 1~6 Alkylene-OC(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 -S(=O) y R 12 , -C 1~6 Alkylene-NR 11 -C(=O)NR 11 R 12 , -C 1~6 Alkylene-OS(=O) y R 11 , -C 1~6 Alkylene-OS(=O) y NR 11 R 12 , -C 1~6 Alkylene-S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 -S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 R 12 and -OC 1~6 Alkylene-NR 11 R 12 and the substituents R are independently selected from the group consisting of 13 The alkyl, alkylene, cyclic hydrocarbyl groups, heterocyclic groups, aryl, heteroaryl and aralkyl groups are listed below, and halogen, OH, oxo, amino, cyano, nitro, C 1~6 Alkyl, halogenated C 1~6 Alkyl, C 3~6 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12aralkyl; when a heterocyclic group, aryl or heteroaryl is a substituent, it is connected to the remainder of the molecule via a ring C atom or, if possible, via a ring N atom; x, in each occurrence, is independently 0, 1, or 2; y and z, in each occurrence, are each independently 1 or 2; however, R 1a and R 1b are each independently, C 1~8 When R is alkyl, Z is not -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-; or R 2a and R 2b are each independently, C 1~8 When Y is alkyl, it is not -CH2-, -CH2-CH2- or -CH2-CH2-CH2-; The present invention relates to a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

[0055] Embodiments of the compounds according to the first aspect are further described below.

[0056] In some embodiments, the present invention provides X 1 and X 2 are independently, CR 10 or N; R 1a and R 2a are each independently, C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); R 1b and R 2b are independently H, C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); however, R 1a and R 1b are each independently, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 aryl or 5- to 14-membered heteroaryl, and R 1a The available ring atoms of R 1a and R 1b However, these are bonded to X 1and R are bonded together through the Y group so as to form an optionally substituted saturated or partially unsaturated fused ring system containing three or more rings. 1b is connected to an available ring atom of 2a and R 2b are each independently, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 aryl or 5- to 14-membered heteroaryl, and R 2a The available ring atoms of R 2a and R 2b However, these are bonded to X 2 and R are bonded together through the Z group to form an optionally substituted saturated or partially unsaturated fused ring system containing three or more rings. 2b is connected to an available ring atom of; Y and Z each independently represent a single bond; NR 10 ;C 1~3 Alkylene (wherein one or two CH moieties are O, S, or NR 10 and C 2~3 alkenylene, wherein any one of the CH moieties forming the C═C double bond is optionally replaced with N; C 1~3 Alkylene and C 2~3 each alkenylene optionally represents a halogen, OH, or -NR 11 R 12 , cyano, nitro, C 1~6 Alkyl, C 1~6 substituted by one, two, three or more groups selected from the group consisting of alkyl-O-, epoxy and oxo; Preferably, Y and Z are each independently NR 10 C substituted with one, two, three or more epoxy or oxo groups 1~3 Alkylene; one or two CH2 are O, S or NR 10 C replaced by a group independently selected from 1~3 Alkylene (wherein C 1~3 Alkylene is halogen, OH, -NR11 R 12 , cyano, nitro, C 1~6 Alkyl, C 1~6 optionally substituted with one, two, three or more groups selected from the group consisting of alkyl-O-, epoxy and oxo; and C 2~3 Alkenylene (wherein any one of the CH moieties forming the C=C double bond is optionally substituted with N, and C 2~3 Alkenylene is halogen, OH, -NR 11 R 12 , cyano, nitro, C 1~6 Alkyl, C 1~6 optionally substituted with one, two, three or more groups selected from the group consisting of alkyl-O-, epoxy and oxo; X 3 and X 4 are each independently C(=O);S(=O) y ; and -OC(=O)-, -SC(=O)-, -OS(=O) y -, -NR 10 -C(=O)- and -NR 10 -S(=O) y -(In the formula, O, S, NR 10 is X 1 or X 2 and preferably, X 3 and X 4 are each independently C(=O), -OC(=O)- or -NR 10 -C(=O)-; R 3 , R 4 and R 10 are each independently H, halogen, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -OR 11 , -SR 11、-OC(=O)R 11 、-C(=O)R 11 、-C(=O)OR 11 、-C(=O)NR 11 R 12 、-C(=O)NR 11 S(=O) y NR 11 R 12 、-C(=O)NR 11 S(=O) y R 12 、-S(=O) y R 11 、-S(=O) y OR 11 、-S(=O) y NR 11 R 12 、-S(=O) y NR 11 S(=O) z OR 12 、-S(=O) y NR 11 C(=O)R 12 、-S(=O) y NR 11 C(=O)OR 12 、-NR 11 R 12 、-NR 11 -C(=O)R 12 、-NR 11 -C(=O)OR 12 、-NR 11 -S(=O) y -R 12 、-NR 11 -C(=O)-NR 11 R 12 、-C 1~6 アルキレン-OR 11 、-C 1~6 アルキレン-OC(=O)R 11 、-C 1~6 アルキレン-C(=O)OR 11 、-C 1~6 アルキレン-S(=O) x R 11 、-C 1~6 アルキレン-S(=O) y OR 11 、-C 1~6 アルキレン-OC(=O)NR 11R 12 , -C 1~6 Alkylene-C(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 -S(=O) y R 12 , -C 1~6 Alkylene-NR 11 -C(=O)NR 11 R 12 , -C 1~6 Alkylene-OS(=O) y R 11 , -C 1~6 Alkylene-OS(=O) y NR 11 R 12 , -C 1~6 Alkylene-S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 -S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 R 12 and -OC 1~6 Alkylene-NR 11 R 12 selected from the group consisting of: R 11 and R 12 However, in each existence, independently, H, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl; The alkyl, alkylene, alkenyl, alkenylene, alkynyl, cyclic hydrocarbyl group, heterocyclic group, aryl, heteroaryl, and aralkyl, each at each occurrence, may each optionally be one, two, three, or more R 13 is replaced by R 13 However, in each occurrence, halogen, cyano, nitro, C 1~6Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y R 11 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 S(=O) z OR 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -NR 11 R 12 , -NR 11 -C(=O)R 12 , -NR 11 -C(=O)OR 12 , -NR 11 -S(=O) y -R 12 , -NR 11 -C(=O)-NR 11 R 12 , -C 1~6 Alkylene-OR 11 , -C 1~6 Alkylene-OC(=O)R 11 , -C 1~6 Alkylene-C(=O)OR 11 , -C 1~6Alkylene-S(=O) x R 11 , -C 1~6 Alkylene-S(=O) y OR 11 , -C 1~6 Alkylene-OC(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 -S(=O) y R 12 , -C 1~6 Alkylene-NR 11 -C(=O)NR 11 R 12 , -C 1~6 Alkylene-OS(=O) y R 11 , -C 1~6 Alkylene-OS(=O) y NR 11 R 12 , -C 1~6 Alkylene-S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 -S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 R 12 and -OC 1~6 Alkylene-NR 11 R 12 and the substituents R are independently selected from the group consisting of 13 The alkyl, alkylene, cyclic hydrocarbyl groups, heterocyclic groups, aryl, heteroaryl and aralkyl defined for 1~6 Alkyl, halogenated C 1~6 Alkyl, C 3~6 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12aralkyl; when a heterocyclic group, aryl or heteroaryl is a substituent, it is connected to the remainder of the molecule via a ring C atom or, if possible, via a ring N atom; x, in each occurrence, is independently 0, 1, or 2; y and z, in each occurrence, are each independently 1 or 2; however, R 1a and R 1b are each independently, C 1~8 When R is alkyl, Z is not -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-; or R 2a and R 2b are each independently, C 1~8 When Y is alkyl, it is not -CH2-, -CH2-CH2- or -CH2-CH2-CH2-; Provided are compounds having the structure of Formula (I) as described above, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof.

[0057] In some embodiments, the compound of formula (I) further satisfies the following conditions: R 1a and R 1b independently, one, two, three or more R 13 When Z is phenyl optionally substituted by, then Z is not -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-; or R 2a and R 2b are each independently one, two, three or more R 13 When Y is phenyl optionally substituted by, then Y is not -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-.

[0058] Preferably, in any of the above embodiments, the compound of formula (I) has the structure of formula (II): [ka] (In the formula, R 1b and R 2b are each independently, C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl) It has.

[0059] In some further embodiments, R 1a and R 1b are each independently, or R 2a and R 2b are each independently, C such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-hexyl, 1-heptyl, and 1-octyl 1~6 alkyl; C such as vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, and 2-hexenyl 2~6 Alkenyl; C such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, and 3-hexynyl 2~6 Alkynyl; C such as cyclopropyl, cyclopentyl, and cyclohexyl 5~7 C such as cyclic hydrocarbyl groups 3~7 cyclic hydrocarbyl groups; 5- to 7-membered monocyclic heterocyclic groups; [ka] , preferably [ka] , more preferably [ka] 8-10 membered benzo-fused heterocyclic groups such as; phenyl; and 5-6 membered heteroaryl such as thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, more preferably thienyl or furyl, more preferably thienyl. selected from the group consisting of: The alkyl, alkenyl, alkynyl, cyclic hydrocarbyl group, heterocyclic group, aryl, and heteroaryl, each occurrence, may optionally be one, two, or three R 13 has been replaced by

[0060] In other further embodiments, R 1a and R 1b are each independently, or R 2a and R 2b are each independently, -C 1~6Alkylene-C 6~10 Aryl, preferably -C 1~4 Alkylene-C 6~10 aryl, more preferably phenylmethylene- or phenylethylene-; and -C 1~6 Alkylene-(5-14 membered heteroaryl), preferably -C 1~4 alkylene-(5-10 membered heteroaryl), more preferably -methylene-(5-10 membered heteroaryl) and -ethylene-(5-10 membered heteroaryl), wherein heteroaryl is preferably selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl, and benzo derivatives thereof, more preferably selected from the group consisting of thienyl and furanyl, and benzo derivatives thereof, and more preferably selected from the group consisting of thienyl and benzo derivatives thereof. selected from the group consisting of: The alkylene, aryl, and heteroaryl, at each occurrence, each optionally contain one, two, or three R 13 has been replaced by

[0061] In some further embodiments, R 1a and R 1b are each independently, or R 2a and R 2b are each independently, Methyl, ethyl, n-propyl, n-pentyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, [ka] is selected from the group consisting of:

[0062] In other embodiments, the compound of formula (I) has the structure of formula (III): [ka] (In the formula, R 1b is H; X 3 -OC(=O)-, -SC(=O)-, -OS(=O) y -, -NR 10 -C(=O)- or -NR 10 -S(=O) y -, preferably -OC(=O)- or -NR 10 -C(=O)-; R 1a , X 1 , R 2a , R 2b , X 2 , R 3 and R 4 is as defined in any of the above embodiments) It has.

[0063] In some further embodiments, X 1 is CH; and / or R 1a C 5~7 It is a cyclic hydrocarbyl group, a 5- to 7-membered monocyclic heterocyclic group, phenyl or a 5- to 6-membered heteroaryl, preferably phenyl.

[0064] Preferably, in any of the above embodiments, the fused ring system Q 1 has the structure of formula (a): [ka] (In the formula, Ring A and ring B each independently represent C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl or 5-14 membered heteroaryl, preferably C 5~7 a cyclic hydrocarbyl group (such as cyclopentyl or cyclohexyl), a 5- to 7-membered monocyclic heterocyclic group, phenyl, or a 5- to 6-membered heteroaryl; [ka] means a single or double bond) It has.

[0065] More preferably, the fused ring system Q has the structure of formula (a) 1 has a structure of formula (1) or formula (2): [ka] (In the formula, R 5a and R 5b is, in each occurrence, independently, R 10 and; R 7 does not exist, or R 10 and; X 1 , R 10 and Y is as defined in any of the above embodiments; m and n are each independently 0, 1, 2, or 3. is a group having the formula:

[0066] Preferably, in any of the above embodiments, the fused ring system Q 2 but the structure of formula (b): [ka] (In the formula, Ring C and ring D each independently represent C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl or 5-14 membered heteroaryl, preferably C 5~7 a cyclic hydrocarbyl group, a 5- to 7-membered monocyclic heterocyclic group (such as cyclopentyl or cyclohexyl), phenyl, or a 5- to 6-membered heteroaryl; [ka] means a single or double bond) It has.

[0067] More preferably, the fused ring system Q has the structure of formula (b) 2 has a structure of formula (3) or formula (4): [ka] (In the formula, R 6a and R 6b is, in each occurrence, independently, R 10 and; R 8 does not exist, or R 10 and; X 2 , R 10 and Z is as defined in any of the above embodiments; p and q are each independently 0, 1, 2, or 3. is a group having the formula:

[0068] In some further embodiments, Y and Z, in each occurrence, are a single bond; NR 10 ;O;S; and halogens, OH, -NR 11 R 12 , cyano, nitro, C 1~6 Alkyl, C 1~6 From the group consisting of alkyl-O-, epoxy and oxo, in particular F, Cl, C 1~4 methylene, ethylene, -CH2-O-, -O-CH2-, -CH2-S-, -S-CH2-, -CH2-NR optionally substituted with one, two, three or more groups selected from the group consisting of alkyl-O- (such as CH3-O-), epoxy and oxo; 10 -, -NR 10 -CH2-, -CH=CH-, -CH=N-, or -N=CH-; preferably, Y and Z, in each occurrence, are each independently selected from the group consisting of: -NR 10 ;O;S; methylene and ethylene optionally substituted with one, two, three or more epoxy or oxo groups; and halogen, OH, -NR 11 R 12 , cyano, nitro, C 1~6Alkyl, C 1~6 From the group consisting of alkyl-O-, epoxy and oxo, in particular F, Cl, C 1~4 -CH2-O-, -O-CH2-, -CH2-S-, -S-CH2-, -CH2-NR optionally substituted with one, two, three or more groups selected from the group consisting of alkyl-O- (such as CH3-O-), epoxy and oxo 10 -, -NR 10 It is selected from the group consisting of -CH2-, -CH=CH-, -CH=N- or -N=CH-.

[0069] In some preferred embodiments, the group of formula (1) is [ka] TIFF0007814359000063.tif84149 The structure is selected from:

[0070] In some preferred embodiments, the group of formula (2) is [ka] TIFF0007814359000065.tif226149 The structure is selected from:

[0071] In some preferred embodiments, the group of formula (3) is [ka] TIFF0007814359000067.tif84149 The structure is selected from:

[0072] In some preferred embodiments, the group of formula (4) is [ka] TIFF0007814359000069.tif226149 (In the formula, R 5a , R 5b , R 6a , R 6b , R 7 , R 8 , R 10 , m, n, p, and q, in each occurrence, are each independently as defined in any of the above embodiments. The structure is selected from:

[0073] Preferably, the group of formula (1) and the group of formula (3) are each [ka] The structure is selected from:

[0074] Preferably, the group of formula (2) and the group of formula (4) are each [ka] The structure is selected from:

[0075] In another preferred embodiment, the group of formula (1) is [ka] having a structure selected from: In another preferred embodiment, the group of formula (2) is [ka] having a structure selected from: In another preferred embodiment, the group of formula (3) is [ka] having a structure selected from: In another preferred embodiment, the group of formula (4) is [ka] having a structure selected from: (In the formula, R 5a , R 5b , R 6a , R 6b , R 7 , R 8 , m, n, p and q, in each occurrence, are each independently as defined in any of the above embodiments; Preferably, the group of formula (1) and the group of formula (3) are each [ka] The structure is selected from:

[0076] In another preferred embodiment, the fused ring system Q has the structure of formula (a) 1 However, the structure of formula (5): [ka] wherein the bonds identified by a, b, and c [ka] One or two of these represent double bonds, and the rest represent single bonds. is a group having the formula:

[0077] In another preferred embodiment, the fused ring system Q has the structure of formula (b) 2 However, the structure of formula (6): [ka] wherein the bonds identified by t, u, and v are [ka] One or two of these represent double bonds, and the rest represent single bonds. is a group having the formula:

[0078] In some further preferred embodiments, the group having the structure of formula (5) is a group having the structure of formula (7): [ka] is a group having the formula:

[0079] In some further preferred embodiments, the group having the structure of formula (6) is a group having the structure of formula (8): [ka] is a group having the formula:

[0080] In some of the above embodiments of formula (5), formula (6), formula (7) and formula (8), Y and Z, in each occurrence, are each independently a single bond; NR 10 ;O;S; and halogens, OH, -NR 11 R 12 , cyano, nitro, C 1~6 Alkyl, C 1~6 From the group consisting of alkyl-O-, epoxy and oxo, in particular F, Cl, C 1~4 methylene, ethylene, -CH2-O-, -O-CH2-, -CH2-S-, -S-CH2-, -CH2-NR optionally substituted with one, two, three or more groups selected from the group consisting of alkyl-O- (such as CH3-O-), epoxy and oxo; 10 -, -NR 10 It is selected from the group consisting of -CH2-, -CH=CH-, -CH=N- or -N=CH-.

[0081] In some more preferred embodiments, the group of formula (7) is [ka] TIFF0007814359000084.tif226149 TIFF0007814359000085.tif113149 having a structure selected from: In some more preferred embodiments, the group of formula (8) is [ka] TIFF0007814359000087.tif226149 TIFF0007814359000088.tif110149 having a structure selected from (In the formula, R 5a , R 5b , R 6a , R 6b , R 7 , R 8 , R 10 , m, n, p and q, in each occurrence, are each independently as defined in any of the above embodiments).

[0082] Preferably, the group of formula (7) and the group of formula (8) are each [ka] is.

[0083] In some embodiments, the present invention provides [ka] Preferably, [ka] (In the formula, f and g, in each occurrence, are each independently 0, 1, 2, or 3; C 1~8 Alkyl, in each occurrence, may be one, two, or three R 13is optionally replaced by; Above R 1a , R 1b , R 2a , R 2b , X 1 , X 2 , R 3 , R 4 , R 10 , R 13 , Y and Z, in each occurrence, are each independently as defined in any of the above embodiments; Above R 5a , R 5b , R 6a , R 6b , R 7 , R 8 , m, n, p and q, in each occurrence, are each independently as defined in any of the above embodiments; Preferably, Y and Z, in each occurrence, are each independently a single bond; NR 10 ;O;S; and halogens, OH, -NR 11 R 12 , cyano, nitro, C 1~6 Alkyl, C 1~6 From the group consisting of alkyl-O-, epoxy and oxo, in particular F, Cl, C 1~4 methylene, ethylene, -CH2-O-, -O-CH2-, -CH2-S-, -S-CH2-, -CH2-NR optionally substituted with one, two, three or more groups selected from the group consisting of alkyl-O- (such as CH3-O-), epoxy and oxo; 10 -, -NR 10 -CH2-, -CH=CH-, -CH=N- or -N=CH- or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, having the structure:

[0084] Preferably, in any of the above embodiments, R 3 F, Cl, Br, I, amino, cyano, nitro, C 1~4Alkyl, C 5~7 Cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, 5- to 6-membered heteroaryl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -C 1~4 Alkylene-OR 11 , -C 1~4 Alkylene-OC(=O)R 11 , -C 1~4 Alkylene-C(=O)OR 11 , -C 1~4 Alkylene-S(=O) y OR 11 , -C 1~4 Alkylene-OC(=O)NR 11 R 12 , -C 1~4 Alkylene-C(=O)NR 11 R 12 , -C 1~4 Alkylene-OS(=O) y R 11 or -C 1~4 Alkylene-S(=O) y NR 11 R 12 ; preferably 5-6 membered heteroaryl, -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)NR 11S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -C 1~3 Alkylene-OC(=O)R 11 , -C 1~3 Alkylene-C(=O)OR 11 , -C 1~3 Alkylene-S(=O) y OR 11 , -C 1~3 Alkylene-C(=O)NR 11 R 12 or -C 1~3 Alkylene-S(=O) y NR 11 R 12 more preferably 5- to 6-membered heteroaryl (thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, such as 1-tetrazolyl or 5-tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl), -C(=O)OR 11 (COOH, etc.), -C(=O)NR 11 S(=O) y NR 11 R 12 ( [ka] etc.), -C(=O)NR 11 S(=O) y R 12 ( [ka] etc.), -C(=O)NR 11 R 12 , -S(=O) y OR 11 or -S(=O) y NR 11 R 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 ( [ka] etc.) and R 11 , R 12 and y is as defined in any of the above embodiments.

[0085] In another preferred embodiment, R 3 -C(=O)NR 11 -OH.

[0086] Preferably, in any of the above embodiments, R 4 H, F, Cl, Br, I, amino, cyano, nitro, C 1~4 Alkyl, C 5~7 Cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, 5- to 6-membered heteroaryl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y OR 11 , -S(=O) yNR 11 R 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -C 1~4 Alkylene-OR 11 , -C 1~4 Alkylene-OC(=O)R 11 , -C 1~4 Alkylene-C(=O)OR 11 , -C 1~4 Alkylene-S(=O) y OR 11 , -C 1~4 Alkylene-OC(=O)NR 11 R 12 , -C 1~4 Alkylene-C(=O)NR 11 R 12 , -C 1~4 Alkylene-OS(=O) y R 11 or -C 1~4 Alkylene-S(=O) y NR 11 R 12 ; preferably H; R 11 , R 12 and y is as defined in any of the above embodiments.

[0087] In another preferred embodiment, R 4 -C(=O)NR 11 -OH.

[0088] Preferably, in any of the above embodiments, R 10 H, F, Cl, Br, I, amino, cyano, nitro, C 1~4 Alkyl, C 3~7 Cyclic hydrocarbyl group (C 5~7 cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, 5- to 6-membered heteroaryl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)OR 11, -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -C 1~4 Alkylene-OR 11 , -C 1~4 Alkylene-OC(=O)R 11 , -C 1~4 Alkylene-C(=O)OR 11 , -C 1~4 Alkylene-S(=O) y OR 11 , -C 1~4 Alkylene-OC(=O)NR 11 R 12 , -C 1~4 Alkylene-C(=O)NR 11 R 12 , -C 1~4 Alkylene-OS(=O) y R 11 or -C 1~4 Alkylene-S(=O) y NR 11 R 12 and;R 11 , R 12 and y is as defined in the above embodiment.

[0089] In some preferred embodiments, R 10 H, F, Cl, Br, I, OH, -OC 1~6 Alkyl (such as methoxy, ethoxy, or isopropoxy), amino, cyano, nitro, C 1~4It is alkyl (such as methyl, ethyl or isopropyl) or cyclopropyl.

[0090] In some preferred embodiments, R 10 is H, F, Cl, Br, I, OH, amino, cyano, nitro or C 1~4 It is alkyl (such as methyl, ethyl or isopropyl).

[0091] In some preferred embodiments, R 10 is H, OH, amino, methyl or ethyl.

[0092] In some preferred embodiments, R 10 H, F, Cl, Br, I, OH, -OC 1~6 Alkyl (such as methoxy, ethoxy, or isopropoxy), amino, C 1~4 Alkyl (such as methyl, ethyl, or isopropyl) or C 3~7 A cyclic hydrocarbyl group (such as cyclopropyl); more preferably F, Cl, OH, methoxy, ethoxy, amino, methyl, ethyl, isopropyl or cyclopropyl.

[0093] Preferably, in any of the above embodiments, R 11 and R 12 However, in each existence, independently, H, C 1~4 Alkyl, C 5~7 selected from the group consisting of cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, and 5- to 6-membered heteroaryl; preferably H and C 1~4 alkyl.

[0094] Preferably, in any of the above embodiments, R 13 In each occurrence, F, Cl, Br, I, amino, cyano, nitro, C 1~4 Alkyl, C 5~7 Cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, 5- to 6-membered heteroaryl, -OR 11 , -SR 11, -OC(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -C 1~4 Alkylene-OR 11 , -C 1~4 Alkylene-OC(=O)R 11 , -C 1~4 Alkylene-C(=O)OR 11 , -C 1~4 Alkylene-S(=O) y OR 11 , -C 1~4 Alkylene-OC(=O)NR 11 R 12 , -C 1~4 Alkylene-C(=O)NR 11 R 12 , -C 1~4 Alkylene-OS(=O) y R 11 or -C 1~4 Alkylene-S(=O) y NR 11 R 12 are independently selected from the group consisting of: F, Cl, Br, I, amino, cyano, nitro, C 1~4 Alkyl, -OR 11 and -SR 11 and; Preferably, the substituent R 13Alkyl, alkylene, cyclic hydrocarbyl groups, heterocyclic groups, phenyl and heteroaryl as defined above are not limited to F, Cl, Br, I, OH, oxo, amino, cyano, nitro, C 1~4 Alkyl, halogenated C 1~4 Alkyl, C 5~6 The group consisting of cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, and 5- to 6-membered heteroaryl; preferably F, Cl, OH, amino, cyano, nitro, C 1~4 Alkyl and halogenated C 1~4 optionally further substituted with one, two, three or more substituents independently selected from the group consisting of alkyl; R 11 , R 12 and y is as defined in any of the above embodiments, and in some further preferred embodiments, R 11 and R 12 C defined for 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 The aralkyl is not further substituted.

[0095] More preferably, in any of the above embodiments, R 5a , R 5b , R 6a , R 6b and R 7 and R 8 are each independently, H, halogen, cyano, nitro, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl, -OR 11 and -NR 11 R 12 ; Preferably, H, F, Cl, Br, I, OH, -OC 1~6 Alkyl (such as methoxy, ethoxy, or isopropoxy), amino, C 1~4Alkyl (such as methyl, ethyl, or isopropyl) or C 3~7 cyclic hydrocarbyl groups (such as cyclopropyl), 5- to 7-membered monocyclic heterocyclic groups, phenyl, and 5- to 6-membered heteroaryl; Preferably, H, F, Cl, Br, I, OH, methoxy, ethoxy, isopropoxy, amino, methyl, ethyl, isopropyl or cyclopropyl; More preferably, F, Cl, OH, methoxy, ethoxy, amino, methyl, ethyl, isopropyl or cyclopropyl is selected from the group consisting of:

[0096] A second aspect of the embodiment of the compounds according to the invention is R 1a , R 1b , X 1 , R 2a , R 2b and X 2 has the definition set forth in Meaning (1) above, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

[0097] Thus, a second aspect of the embodiment of the compounds according to the invention is R 1a , R 1b and X 1 Together, (i) [ka] or (ii) [ka] (In the formula, ring [ka] is saturated or partially unsaturated C 3~10a cyclic hydrocarbyl group or a saturated or partially unsaturated 3- to 10-membered heterocyclic group; X is C, CR 10 or N; R 1c is saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, saturated or partially unsaturated 3- to 10-membered heterocyclic groups, C 6~10 Aryl and 5- to 14-membered heteroaryl, -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group, -C 1~6 Alkylene-C 6~10 Aryl, and -C 1~6 alkylene-(5-14 membered heteroaryl) represents; X 2 is CR 10 or N; R 2a But C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); R 2b But H, C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); Optionally, R 2a and R 2b are each independently, C 3~10 Cyclic hydrocarbyl groups; 3- to 10-membered heterocyclic groups, C 6~10 When R is aryl or 5- to 14-membered heteroaryl, 2a The available ring atoms of R 2a and R 2b However, these are bonded to X 2 together with an optionally substituted saturated or partially unsaturated fused ring system Q containing three or more rings 2 R through the Z group to form 2b is connected to an available ring atom of; Z is a single bond; NR 10 ;C 1~3 Alkylene (wherein one or two CH2 are O, S or NR 10 and C 2~3 alkenylene, wherein any one of the CH moieties forming the C═C double bond is optionally replaced with N; C 1~3 Alkylene and C 2~3 each alkenylene optionally represents a halogen, OH, or -NR 11 R 12 , cyano, nitro, C 1~6Alkyl, C 1~6 substituted by one, two, three or more groups selected from the group consisting of alkyl-O-, epoxy and oxo; X 3 and X 4 are each independently C(=O);S(=O) y ; and -OC(=O)-, -SC(=O)-, -OS(=O) y -, -NR 10 -C(=O)- and -NR 10 -S(=O) y -(In the formula, O, S, NR 10 is X 1 or X 2 and preferably, X 3 and X 4 are each independently C(=O), -OC(=O)- or -NR 10 -C(=O)-; R 3 , R 4 and R 10 are each independently H, halogen, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 -OH, -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y R 11 , -S(=O) yOR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 S(=O) z OR 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -NR 11 R 12 , -NR 11 -C(=O)R 12 , -NR 11 -C(=O)OR 12 , -NR 11 -S(=O) y -R 12 , -NR 11 -C(=O)-NR 11 R 12 , -C 1~6 Alkylene-OR 11 , -C 1~6 Alkylene-OC(=O)R 11 , -C 1~6 Alkylene-C(=O)OR 11 , -C 1~6 Alkylene-S(=O) x R 11 , -C 1~6 Alkylene-S(=O) y OR 11 , -C 1~6 Alkylene-OC(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 -S(=O) y R 12 , -C 1~6 Alkylene-NR 11 -C(=O)NR 11 R 12 , -C 1~6 Alkylene-OS(=O) y R 11 , -C1~6 Alkylene-OS(=O) y NR 11 R 12 , -C 1~6 Alkylene-S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 -S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 R 12 and -OC 1~6 Alkylene-NR 11 R 12 selected from the group consisting of: R 11 and R 12 However, in each existence, independently, H, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl; The alkyl, alkylene, alkenyl, alkenylene, alkynyl, cyclic hydrocarbyl group, heterocyclic group, aryl, heteroaryl, and aralkyl, each at each occurrence, may each optionally be one, two, three, or more R 13 is replaced by R 13 However, in each occurrence, halogen, cyano, nitro, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y R 11 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 S(=O) z OR 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -NR 11 R 12 , -NR 11 -C(=O)R 12 , -NR 11 -C(=O)OR 12 , -NR 11 -S(=O) y -R 12 , -NR 11 -C(=O)-NR 11 R 12 , -C 1~6 Alkylene-OR 11 , -C 1~6 Alkylene-OC(=O)R 11 , -C 1~6 Alkylene-C(=O)OR 11 , -C 1~6 Alkylene-S(=O) x R 11 , -C 1~6 Alkylene-S(=O) y OR 11 , -C 1~6 Alkylene-OC(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 -S(=O) y R 12, -C 1~6 Alkylene-NR 11 -C(=O)NR 11 R 12 , -C 1~6 Alkylene-OS(=O) y R 11 , -C 1~6 Alkylene-OS(=O) y NR 11 R 12 , -C 1~6 Alkylene-S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 -S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 R 12 and -OC 1~6 Alkylene-NR 11 R 12 and the substituents R are independently selected from the group consisting of 13 The alkyl, alkylene, cyclic hydrocarbyl groups, heterocyclic groups, aryl, heteroaryl and aralkyl defined for 1~6 Alkyl, halogenated C 1~6 Alkyl, C 3~6 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl; when a heterocyclic group, aryl or heteroaryl is a substituent, it is connected to the remainder of the molecule via a ring C atom or, if possible, via a ring N atom; x, in each occurrence, is independently 0, 1, or 2; y and z, in each occurrence, are each independently 1 or 2; The present invention relates to a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

[0098] Embodiments of the compounds according to the second aspect are further described below.

[0099] In some embodiments, the compound of Formula (I) has the structure of Formula (IV) or Formula (V): [ka] It has.

[0100] In some further embodiments, X is C or N.

[0101] In some still further embodiments, the compound of Formula (I) has the structure of Formula (VI) or Formula (VII): [ka] (In the formula, ring [ka] represents a saturated or partially unsaturated 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group, more preferably a 3- to 6-membered heterocyclic group; Preferably, said heterocyclic group optionally further contains 1, 2 or 3 heteroatoms independently selected from N, O and S; more preferably, said heterocyclic group is [ka] and more preferably selected from the group consisting of [ka] and more preferably selected from the group consisting of [ka] is) It has.

[0102] In other still further embodiments, the compound of formula (I) has the structure of formula (VIII) or formula (IX): [ka] (In the formula, ring [ka] teeth, Saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, preferably C 3~7 Cyclic hydrocarbyl groups, more preferably C 3~6 is a cyclic hydrocarbyl group; preferably, the cyclic hydrocarbyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, preferably selected from the group consisting of cyclopentyl and cyclohexyl; or A saturated or partially unsaturated 3- to 10-membered heterocyclic group, preferably a 3- to 7-membered heterocyclic group, more preferably a 3- to 6-membered heterocyclic group; said heterocyclic group contains 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; preferably, said heterocyclic group is [ka] and more preferably selected from the group consisting of [ka] and more preferably selected from the group consisting of [ka] and * The C atom identified by R1c and X 3 connected to It has.

[0103] Preferably, in any of the above embodiments, R 1c But C 3~7 Cyclic hydrocarbyl groups, 3- to 7-membered heterocyclic groups, C 6~10 Aryl, 5-6 membered heteroaryl, -C 1~4 Alkylene-C 3~7 Cyclic hydrocarbyl groups, -C 1~4 Alkylene-(3- to 7-membered heterocyclic group), -C 1~4 Alkylene-C 6~10 Aryl and -C 1~4 alkylene-(5-6 membered heteroaryl); Preferably, C 3~6 Cyclic hydrocarbyl groups, 4- to 6-membered heterocyclic groups, phenyl, 5- to 6-membered heteroaryl, -C 1~4 Alkylene-C 3~6 Cyclic hydrocarbyl groups, -C 1~4 Alkylene-(4- to 6-membered heterocyclic group), -C 1~4 Alkylene-phenyl and -C 1~4 alkylene-(5-6 membered heteroaryl); Preferably, C 3~6 Cyclic hydrocarbyl groups, phenyl, -C 1~4 -Alkylene-C 3~6 Cyclic hydrocarbyl groups and -C 1~4 selected from the group consisting of alkylene-phenyl; Preferably, it is selected from the group consisting of cyclopentyl, cyclohexyl, phenyl, cyclopentylmethylene, cyclopentylethylene, cyclohexylmethylene, cyclohexylethylene, phenylmethylene- and phenylethylene-; More preferably, it is phenyl.

[0104] Preferably, in any of the above embodiments, R 10 H, F, Cl, Br, I, amino, cyano, nitro, C 1~4 Alkyl, C 3~7Cyclic hydrocarbyl group (C 5~7 cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, 5- to 6-membered heteroaryl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -C 1~4 Alkylene-OR 11 , -C 1~4 Alkylene-OC(=O)R 11 , -C 1~4 Alkylene-C(=O)OR 11 , -C 1~4 Alkylene-S(=O) y OR 11 , -C 1~4 Alkylene-OC(=O)NR 11 R 12 , -C 1~4 Alkylene-C(=O)NR 11 R 12 , -C 1~4 Alkylene-OS(=O) y R 11 or -C 1~4 Alkylene-S(=O) y NR 11 R 12 and R 11 , R 12 and y is as defined in the embodiment of the first aspect above.

[0105] In some preferred embodiments, R 10 H, F, Cl, Br, I, OH, -OC 1~6 Alkyl (such as methoxy, ethoxy, or isopropoxy), amino, cyano, nitro, C 1~4 It is alkyl (such as methyl, ethyl or isopropyl) or cyclopropyl.

[0106] In some preferred embodiments, R 10 is H, F, Cl, Br, I, OH, amino, cyano, nitro or C 1~4 It is alkyl (such as methyl, ethyl or isopropyl).

[0107] In some preferred embodiments, R 10 is H, OH, amino, methyl or ethyl.

[0108] In some preferred embodiments, R 10 H, F, Cl, Br, I, OH, -OC 1~6 Alkyl (such as methoxy, ethoxy, or isopropoxy), amino, C1-4 alkyl (such as methyl, ethyl, or isopropyl), or C 3~7 A cyclic hydrocarbyl group (such as cyclopropyl); more preferably F, Cl, OH, methoxy, ethoxy, amino, methyl, ethyl, isopropyl or cyclopropyl.

[0109] In some preferred embodiments, R 10 is H, methyl or ethyl.

[0110] Preferably, in any of the above embodiments, [ka] but, [ka] , preferably [ka] ( [ka] It has a structure including

[0111] Preferably, in any of the above embodiments, [ka] but, [ka] , preferably [ka] It has the following structure.

[0112] Preferably, in any of the above embodiments, X 2 is CH or N.

[0113] Preferably, in any of the above embodiments, R 2a and R 2b are each independently, C such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-hexyl, 1-heptyl, and 1-octyl 1~6 alkyl; C such as vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, and 2-hexenyl 2~6 Alkenyl; C such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, and 3-hexynyl 2~6 Alkynyl; C 5~7 C such as cyclic hydrocarbyl groups 3~7 cyclic hydrocarbyl groups, such as cyclopropyl, cyclopentyl, cyclohexyl; 5- to 7-membered monocyclic heterocyclic groups; [ka] , preferably [ka] , more preferably [ka] 8-10 membered benzo-fused heterocyclic groups such as; phenyl; and 5-6 membered heteroaryl such as thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, more preferably thienyl or furyl, more preferably thienyl; -C 1~6 Alkylene-C 6~10 Aryl, preferably -C 1~4 Alkylene-C 6~10 aryl, more preferably phenylmethylene- or phenylethylene-; and -C 1~6 Alkylene-(5-14 membered heteroaryl), preferably -C 1~4alkylene-(5-10 membered heteroaryl), more preferably -methylene-(5-10 membered heteroaryl) and -ethylene-(5-10 membered heteroaryl), wherein the heteroaryl group is preferably selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl, and benzo derivatives thereof, more preferably selected from the group consisting of thienyl and furanyl, and benzo derivatives thereof, and more preferably selected from the group consisting of thienyl and benzo derivatives thereof. selected from the group consisting of: The alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbyl group, heterocyclic group, aryl, and heteroaryl, each occurrence, may optionally be one, two, or three R 13 has been replaced by

[0114] In some more preferred embodiments, R 2a But C 1~6 Alkyl, phenyl and -C 1~6 alkylene-phenyl, preferably C 1~4 Alkyl, phenyl and C 1~4 It is selected from the group consisting of alkylene-phenyl, preferably selected from the group consisting of methyl, ethyl, isopropyl, phenyl, phenylmethylene- and phenylethylene-, more preferably selected from the group consisting of methyl, phenyl and phenylmethylene-.

[0115] In other embodiments, R 2b can also be H.

[0116] In some more preferred embodiments, R 2b But H, C 1~6 Alkyl, phenyl and -C 1~6 alkylene-phenyl, preferably H, C 1~4Alkyl, phenyl and -C 1~4 It is selected from the group consisting of alkylene-phenyl, preferably selected from the group consisting of H, methyl, ethyl, isopropyl, phenyl, phenylmethylene- and phenylethylene-, more preferably selected from the group consisting of H, methyl, phenyl and phenylmethylene-.

[0117] Alternatively, in any of the above embodiments, R 2a and R 2b are preferably each independently 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 aryl or 5- to 14-membered heteroaryl; R 2a The available ring atoms of R 2a and R 2b However, these are bonded to X 2 together with an optionally substituted saturated or partially unsaturated fused ring system Q containing three or more rings 2 R through the Z group to form 2b is connected to an available ring atom.

[0118] Preferably, the fused ring system Q 2 is a group having a structure represented by any one selected from formula (b), formula (3), formula (4), formula (6), formula (8), formula (3a-1) to formula (3a-22), formula (3b-1) to formula (3b-22), formula (4a-1) to formula (4a-32), and formula (4b-1) to formula (4b-32), wherein formula (b), formula (3), formula (4), formula (6), formula (8), formula (3a-1) to formula (3a-22), formula (3b-1) to formula (3b-22), formula (4a-1) to formula (4a-32), and formula (4b-1) to formula (4b-32) are as defined in the first aspect above. Therefore, the fused ring system Q 2 However, in some preferred embodiments, the group has the structure of formula (b); in some more preferred embodiments, the group has the structure of formula (3); in other more preferred embodiments, the group has the structure of formula (4); and in other more preferred embodiments, the group has the structure of formula (6), preferably formula (8).

[0119] In some embodiments of any one of Formula (b), Formula (3), Formula (4), Formula (6), and Formula (8), Z, in each occurrence, is a single bond; NR 10 ;O;S; and halogens, OH, -NR 11 R 12 , cyano, nitro, C 1~6 Alkyl, C 1~6 From the group consisting of alkyl-O-, epoxy and oxo, in particular F, Cl, C 1~4 methylene, ethylene, -CH2-O-, -O-CH2-, -CH2-S-, -S-CH2-, -CH2-NR optionally substituted with one, two, three or more groups selected from the group consisting of alkyl-O- (such as CH3-O-), epoxy and oxo; 10 -, -NR 10 Independently selected from the group consisting of -CH2-, -CH=CH-, -CH=N- or -N=CH-.

[0120] Preferably, R 10 , R 11 and R 12 are each as defined in the first aspect above.

[0121] In some further preferred embodiments, the group having the structure of formula (3) has a structure represented by formula (3a-1) to formula (3a-22) and formula (3b-1) to formula (3b-22).

[0122] In some further preferred embodiments, the group having the structure of formula (4) has structures represented by formulas (4a-1) to (4a-32) and (4b-1) to (4b-32).

[0123] In some further preferred embodiments, the group having the structure of formula (8) has structures represented by formulas (8a-1) to (8a-32) and (8b-1) to (8b-32).

[0124] Preferably, the group of formula (3) is [ka] The structure is selected from:

[0125] Preferably, the group of formula (4) is [ka] The structure is selected from:

[0126] Preferably, the group of formula (8) is [ka] is.

[0127] More preferably, the fused ring system Q 2 but, [ka] is.

[0128] Preferably, in any of the above embodiments, R 3 F, Cl, Br, I, amino, cyano, nitro, C 1~4 Alkyl, C 5~7 Cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, 5- to 6-membered heteroaryl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 -OH, -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y OR 11 , -S(=O) y NR11 R 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -C 1~4 Alkylene-OR 11 , -C 1~4 Alkylene-OC(=O)R 11 , -C 1~4 Alkylene-C(=O)OR 11 , -C 1~4 Alkylene-S(=O) y OR 11 , -C 1~4 Alkylene-OC(=O)NR 11 R 12 , -C 1~4 Alkylene-C(=O)NR 11 R 12 , -C 1~4 Alkylene-OS(=O) y R 11 or -C 1~4 Alkylene-S(=O) y NR 11 R 12 ; preferably 5-6 membered heteroaryl, -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -C 1~3 Alkylene-OC(=O)R 11 , -C 1~3Alkylene-C(=O)OR 11 , -C 1~3 Alkylene-S(=O) y OR 11 , -C 1~3 Alkylene-C(=O)NR 11 R 12 or -C 1~3 Alkylene-S(=O) y NR 11 R 12 more preferably 5- to 6-membered heteroaryl (thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, such as 1-tetrazolyl or 5-tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl), -C(=O)OR 11 (COOH, etc.), -C(=O)NR 11 S(=O) y NR 11 R 12 ( [ka] etc.), -C(=O)NR 11 S(=O) y R 12 ( [ka] etc.), -C(=O)NR 11 R 12 , -S(=O) y OR 11 or -S(=O) y NR 11 R 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 ( [ka] etc.) and R 11 , R 12 and y is as defined in any of the embodiments according to the first aspect above.

[0129] More preferably, R 3 is COOH.

[0130] Preferably, in any of the above embodiments, R 4 H, F, Cl, Br, I, amino, cyano, nitro, C 1~4 Alkyl, C 5~7 Cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, 5- to 6-membered heteroaryl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 -OH, -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -C 1~4 Alkylene-OR 11 , -C 1~4 Alkylene-OC(=O)R 11 , -C 1~4 Alkylene-C(=O)OR 11 , -C 1~4 Alkylene-S(=O) y OR 11 , -C 1~4 Alkylene-OC(=O)NR11 R 12 , -C 1~4 Alkylene-C(=O)NR 11 R 12 , -C 1~4 Alkylene-OS(=O) y R 11 or -C 1~4 Alkylene-S(=O) y NR 11 R 12 and R 11 , R 12 and y is as defined in any of the embodiments according to the first aspect above.

[0131] More preferably, R 4 is H.

[0132] Preferably, in any of the above embodiments, R 11 and R 12 However, in each existence, independently, H, C 1~4 Alkyl, C 5~7 selected from the group consisting of cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, and 5- to 6-membered heteroaryl; preferably H and C 1~4 alkyl.

[0133] Preferably, in any of the above embodiments, R 13 In each occurrence, F, Cl, Br, I, amino, cyano, nitro, C 1~4 Alkyl, C 5~7 Cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, 5- to 6-membered heteroaryl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12, -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -C 1~4 Alkylene-OR 11 , -C 1~4 Alkylene-OC(=O)R 11 , -C 1~4 Alkylene-C(=O)OR 11 , -C 1~4 Alkylene-S(=O) y OR 11 , -C 1~4 Alkylene-OC(=O)NR 11 R 12 , -C 1~4 Alkylene-C(=O)NR 11 R 12 , -C 1~4 Alkylene-OS(=O) y R 11 and -C 1~4 Alkylene-S(=O) y NR 11 R 12 ; preferably F, Cl, Br, I, amino, cyano, nitro, C 1~4 Alkyl, -OR 11 and -SR 11 independently selected from the group consisting of: Preferably, the substituent R 13 Alkyl, alkylene, cyclic hydrocarbyl groups, heterocyclic groups, phenyl and heteroaryl as defined above are not limited to F, Cl, Br, I, OH, oxo, amino, cyano, nitro, C 1~4 Alkyl, halogenated C 1~4 Alkyl, C 5~6 Cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, 5- to 6-membered heteroaryl; preferably F, Cl, OH, amino, cyano, nitro, C 1~4 Alkyl and halogenated C 1~4optionally further substituted with one, two, three or more substituents independently selected from the group consisting of alkyl; R 11 , R 12 and y is as defined in any of the embodiments according to the first aspect above, and in some further preferred embodiments, R 11 and R 12 C defined for 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 The aralkyl is not further substituted.

[0134] Preferably, in any of the above embodiments, X 3 is C(=O).

[0135] Preferably, in any of the above embodiments, X 4 is C(=O) or -OC(=O)-.

[0136] A third aspect of the embodiment of the compounds according to the invention is R 1a , R 1b , X 1 , R 2a , R 2b and X 2 has the definition set forth in Meaning (2) above, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

[0137] Thus, a third aspect of the embodiment of the compounds according to the invention is R 1a , R 2a , R 1b and R 2b are each independently, C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); X 1 is CR 10 or N; X 2 is CR 15 and; R 15 But halogen, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 -OH, -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y R 11 , -S(=O) y OR 11 , -S(=O) y NR11 R 12 , -S(=O) y NR 11 S(=O) z OR 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -NR 11 R 12 , -NR 11 -C(=O)R 12 , -NR 11 -C(=O)OR 12 , -NR 11 -S(=O) y -R 12 , -NR 11 -C(=O)-NR 11 R 12 , -C 1~6 Alkylene-OR 11 , -C 1~6 Alkylene-OC(=O)R 11 , -C 1~6 Alkylene-C(=O)OR 11 , -C 1~6 Alkylene-S(=O) x R 11 , -C 1~6 Alkylene-S(=O) y OR 11 , -C 1~6 Alkylene-OC(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 -S(=O) y R 12 , -C 1~6 Alkylene-NR 11 -C(=O)NR 11 R 12 , -C 1~6 Alkylene-OS(=O) y R 11 , -C 1~6 Alkylene-OS(=O) y NR11 R 12 , -C 1~6 Alkylene-S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 -S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 R 12 and -OC 1~6 Alkylene-NR 11 R 12 selected from the group consisting of: X 3 and X 4 are each independently C(=O);S(=O) y ; and -OC(=O)-, -SC(=O)-, -OS(=O) y -, -NR 10 -C(=O)- and -NR 10 -S(=O) y -(In the formula, O, S, NR 10 is X 1 or X 2 and preferably, X 3 and X 4 are each independently C(=O), -OC(=O)- or -NR 10 -C(=O)-; R 3 , R 4 and R 10 are each independently H, halogen, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11-OH, -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y R 11 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 S(=O) z OR 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -NR 11 R 12 , -NR 11 -C(=O)R 12 , -NR 11 -C(=O)OR 12 , -NR 11 -S(=O) y -R 12 , -NR 11 -C(=O)-NR 11 R 12 , -C 1~6 Alkylene-OR 11 , -C 1~6 Alkylene-OC(=O)R 11 , -C 1~6 Alkylene-C(=O)OR 11 , -C 1~6 Alkylene-S(=O) x R 11 , -C 1~6 Alkylene-S(=O) y OR 11 , -C 1~6 Alkylene-OC(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 R12 , -C 1~6 Alkylene-C(=O)NR 11 -S(=O) y R 12 , -C 1~6 Alkylene-NR 11 -C(=O)NR 11 R 12 , -C 1~6 Alkylene-OS(=O) y R 11 , -C 1~6 Alkylene-OS(=O) y NR 11 R 12 , -C 1~6 Alkylene-S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 -S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 R 12 and -OC 1~6 Alkylene-NR 11 R 12 selected from the group consisting of: R 11 and R 12 However, in each existence, independently, H, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl; The alkyl, alkylene, alkenyl, alkenylene, alkynyl, cyclic hydrocarbyl group, heterocyclic group, aryl, heteroaryl, and aralkyl, each at each occurrence, may each optionally be one, two, three, or more R 13 is replaced by R 13 However, in each occurrence, halogen, cyano, nitro, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y R 11 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 S(=O) z OR 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -NR 11 R 12 , -NR 11 -C(=O)R 12 , -NR 11 -C(=O)OR 12 , -NR 11 -S(=O) y -R 12 , -NR 11 -C(=O)-NR 11 R 12 , -C 1~6 Alkylene-OR 11 , -C 1~6 Alkylene-OC(=O)R 11 , -C 1~6 Alkylene-C(=O)OR 11 , -C 1~6 Alkylene-S(=O) x R 11 , -C 1~6Alkylene-S(=O) y OR 11 , -C 1~6 Alkylene-OC(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 -S(=O) y R 12 , -C 1~6 Alkylene-NR 11 -C(=O)NR 11 R 12 , -C 1~6 Alkylene-OS(=O) y R 11 , -C 1~6 Alkylene-OS(=O) y NR 11 R 12 , -C 1~6 Alkylene-S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 -S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 R 12 and -OC 1~6 Alkylene-NR 11 R 12 and the substituents R are independently selected from the group consisting of 13 The alkyl, alkylene, cyclic hydrocarbyl groups, heterocyclic groups, aryl, heteroaryl and aralkyl defined for 1~6 Alkyl, halogenated C 1~6 Alkyl, C 3~6 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12aralkyl; when a heterocyclic group, aryl or heteroaryl is a substituent, it is connected to the remainder of the molecule via a ring C atom or, if possible, via a ring N atom; x, in each occurrence, is independently 0, 1, or 2; y and z, in each occurrence, are each independently 1 or 2; The present invention relates to a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

[0138] Embodiments of compounds according to the third aspect are further described below.

[0139] In some embodiments, the present invention provides R 1a and R 1b are each independently, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl (wherein C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~7 Cyclic hydrocarbyl group; saturated or partially unsaturated 5- to 7-membered monocyclic heterocyclic group; C 6~10 Aryl; 5-6 membered heteroaryl; -C 1~4 Alkylene-saturated or partially unsaturated C 3~7 Cyclic hydrocarbyl groups, -C 1~4 Alkylene - saturated or partially unsaturated 5- to 7-membered heterocyclic group; -C 1~4 Alkylene-C 6~10 aryl; and -C 1~4 alkylene-(5-6 membered heteroaryl); Preferably, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4Alkynyl, C 6~10 Aryl, 5-6 membered heteroaryl, -C 1~4 Alkylene-C 6~10 Aryl and -C 1~4 alkylene-(5-6 membered heteroaryl), Provided are compounds having the structure of Formula (I) above, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof.

[0140] More preferably, R 1a phenyl, 5-6 membered heteroaryl, -C 1~4 Alkylene-phenyl and -C 1~4 alkylene-(5-6 membered heteroaryl).

[0141] Preferably, in the above embodiment, the 5- to 6-membered heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, more preferably thienyl or furyl, more preferably thienyl.

[0142] More preferably, R 1a is selected from the group consisting of phenyl and -CH2-phenyl.

[0143] More preferably, R 1b But C 1~4 It is selected from the group consisting of alkyl and phenyl; more preferably, it is selected from the group consisting of methyl, ethyl, isopropyl, and phenyl.

[0144] Preferably, in any of the above embodiments, R 2a and R 2b are each independently, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6Alkynyl (wherein C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~7 Cyclic hydrocarbyl group; saturated or partially unsaturated 5- to 7-membered monocyclic heterocyclic group; C 6~10 Aryl; 5-6 membered heteroaryl; -C 1~4 Alkylene-saturated or partially unsaturated C 3~7 Cyclic hydrocarbyl groups, -C 1~4 Alkylene - saturated or partially unsaturated 5- to 7-membered monocyclic heterocyclic group; -C 1~4 Alkylene-C 6~10 aryl; and -C 1~4 alkylene-(5-6 membered heteroaryl); Preferably, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 6~10 Aryl, 5-6 membered heteroaryl, -C 1~4 Alkylene-C 6~10 Aryl and -C 1~4 alkylene-(5-6 membered heteroaryl).

[0145] More preferably, R 2a phenyl, 5-6 membered heteroaryl, -C 1~4 Alkylene-phenyl and -C 1~4 alkylene-(5-6 membered heteroaryl).

[0146] Preferably, in the above embodiment, the 5- to 6-membered heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, more preferably thienyl or furyl, more preferably thienyl.

[0147] More preferably, R 2a is phenyl.

[0148] More preferably, R 2b But C 1~4 It is selected from the group consisting of alkyl and phenyl; more preferably, it is selected from the group consisting of methyl, ethyl, isopropyl, and phenyl.

[0149] Preferably, in any of the above embodiments, X 1 is CR 10 is.

[0150] Preferably, in the other embodiments above, X 1 is N.

[0151] Preferably, in any of the above embodiments, R 15 But halogen, cyano, nitro, C 1~4 Alkyl, C 3~7 Cyclic hydrocarbyl groups, 5- to 7-membered heterocyclic groups, phenyl, 5- to 6-membered heteroaryl, C 6~12 Aralkyl, -OR 11 , -SR 11 , -NR 11 R 12 , -C 1~4 Alkylene-OR 11 , -C 1~4 Alkylene-NR 11 R 12 and -OC 1~6 Alkylene-NR 11 R 12 preferably C such as methyl, ethyl and isopropyl 1~4 It is preferably alkyl, more preferably methyl.

[0152] Preferably, in any of the above embodiments, X 3 and X 4 are each independently C(=O) and S(=O) y and each is preferably C(=O).

[0153] Preferably, in any of the above embodiments, R 10 H, F, Cl, Br, I, amino, cyano, nitro, C 1~4 Alkyl, C 3~7 Cyclic hydrocarbyl group (C 5~7 cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, 5- to 6-membered heteroaryl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -C 1~4 Alkylene-OR 11 , -C 1~4 Alkylene-OC(=O)R 11 , -C 1~4 Alkylene-C(=O)OR 11 , -C 1~4 Alkylene-S(=O) y OR 11 , -C 1~4 Alkylene-OC(=O)NR 11 R 12 , -C 1~4 Alkylene-C(=O)NR 11 R 12 , -C 1~4 Alkylene-OS(=O) y R 11 or -C 1~4 Alkylene-S(=O) y NR 11 R12 and;R 11 , R 12 and y is as defined in any of the embodiments according to the first aspect above.

[0154] In some such embodiments, R 10 H, F, Cl, Br, I, OH, -OC 1~6 Alkyl (such as methoxy, ethoxy, or isopropoxy), amino, cyano, nitro, C 1~4 It is alkyl (such as methyl, ethyl or isopropyl) or cyclopropyl.

[0155] In some such embodiments, R 10 is H, F, Cl, Br, I, OH, amino, cyano, nitro or C 1~4 It is alkyl (such as methyl, ethyl or isopropyl).

[0156] In some such embodiments, R 10 is H, OH, amino, methyl or ethyl.

[0157] In some such embodiments, R 10 H, F, Cl, Br, I, OH, -OC 1~6 Alkyl (such as methoxy, ethoxy, or isopropoxy), amino, C 1~4 Alkyl (such as methyl, ethyl, or isopropyl) or C 3~7 A cyclic hydrocarbyl group (such as cyclopropyl); more preferably F, Cl, OH, methoxy, ethoxy, amino, methyl, ethyl, isopropyl or cyclopropyl.

[0158] In some such embodiments, R 10 is H, methyl or ethyl.

[0159] Preferably, in any of the above embodiments, R 11 and R 12 However, in each existence, independently, H, C 1~4Alkyl, C 5~7 selected from the group consisting of cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, and 5- to 6-membered heteroaryl; preferably H and C 1~4 alkyl.

[0160] Preferably, in any of the above embodiments, R 13 In each occurrence, F, Cl, Br, I, amino, cyano, nitro, C 1~4 Alkyl, C 5~7 Cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, 5- to 6-membered heteroaryl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -C 1~4 Alkylene-OR 11 , -C 1~4 Alkylene-OC(=O)R 11 , -C 1~4 Alkylene-C(=O)OR 11 , -C 1~4 Alkylene-S(=O) y OR 11 , -C 1~4 Alkylene-OC(=O)NR 11 R 12 , -C 1~4 Alkylene-C(=O)NR 11 R12 , -C 1~4 Alkylene-OS(=O) y R 11 and -C 1~4 Alkylene-S(=O) y NR 11 R 12 ; preferably F, Cl, Br, I, amino, cyano, nitro, C 1~4 Alkyl, -OR 11 and -SR 11 may be independently selected from the group consisting of: Substituent R 13 Alkyl, alkylene, cyclic hydrocarbyl groups, heterocyclic groups, phenyl and heteroaryl as defined above are not limited to F, Cl, Br, I, OH, oxo, amino, cyano, nitro, C 1~4 Alkyl, halogenated C 1~4 Alkyl, C 5~6 Cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, 5- to 6-membered heteroaryl; preferably F, Cl, OH, amino, cyano, nitro, C 1~4 Alkyl and halogenated C 1~4 optionally further substituted with one, two, three or more substituents independently selected from the group consisting of alkyl; R 11 , R 12 and y is as defined in any of the embodiments according to the first aspect above, and in some further preferred embodiments, R 11 and R 12 C defined for 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 The aralkyl is not further substituted.

[0161] A fourth aspect of the embodiment of the compounds according to the invention is R 1a , R 1b , X 1 , R 2a , R 2b and X 2has the definition set forth in Meaning (3) above, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

[0162] Thus, a fourth aspect of the embodiment of the compounds according to the invention is R 1a But -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 alkylene-saturated or partially unsaturated 3- to 10-membered heterocyclic group, and -C 1~6 alkylene-(5-14 membered heteroaryl); R 1b , R 2a and R 2b are independently OH;C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Alkynyl (wherein C 1~8 Alkyl, C 2~8 Alkenyl and C 2~8 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl group; saturated or partially unsaturated 3- to 10-membered heterocyclic group; C 6~10 Aryl; 5-14 membered heteroaryl; -C 1~6 Alkylene-saturated or partially unsaturated C 3~10 Cyclic hydrocarbyl groups, -C 1~6 Alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; -C 1~6 Alkylene-C 6~10 aryl; and -C 1~6 alkylene-(5-14 membered heteroaryl); X 1 is CR 10 , N, O or S; provided that X 1 is O or S, R 1b does not exist; X 2 is CR 10or N; X 3 and X 4 are each independently C(=O);S(=O) y ; and -OC(=O)-, -SC(=O)-, -OS(=O) y -, -NR 10 -C(=O)- and -NR 10 -S(=O) y -(In the formula, O, S, NR 10 is X 1 or X 2 and preferably, X 3 and X 4 are each independently C(=O), -OC(=O)- or -NR 10 -C(=O)-; R 3 , R 4 and R 10 are each independently H, halogen, cyano, nitro, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 -OH, -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y R 11 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O)y NR 11 S(=O) z OR 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -NR 11 R 12 , -NR 11 -C(=O)R 12 , -NR 11 -C(=O)OR 12 , -NR 11 -S(=O) y -R 12 , -NR 11 -C(=O)-NR 11 R 12 , -C 1~6 Alkylene-OR 11 , -C 1~6 Alkylene-OC(=O)R 11 , -C 1~6 Alkylene-C(=O)OR 11 , -C 1~6 Alkylene-S(=O) x R 11 , -C 1~6 Alkylene-S(=O) y OR 11 , -C 1~6 Alkylene-OC(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 -S(=O) y R 12 , -C 1~6 Alkylene-NR 11 -C(=O)NR 11 R 12 , -C 1~6 Alkylene-OS(=O) y R 11 , -C 1~6 Alkylene-OS(=O) y NR 11 R 12 , -C1~6 Alkylene-S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 -S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 R 12 and -OC 1~6 Alkylene-NR 11 R 12 selected from the group consisting of: R 11 and R 12 However, in each existence, independently, H, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl; The alkyl, alkylene, alkenyl, alkenylene, alkynyl, cyclic hydrocarbyl group, heterocyclic group, aryl, heteroaryl, and aralkyl, each at each occurrence, may each optionally be one, two, three, or more R 13 is replaced by R 13 However, in each occurrence, halogen, cyano, nitro, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R12 , -S(=O) y R 11 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 S(=O) z OR 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -NR 11 R 12 , -NR 11 -C(=O)R 12 , -NR 11 -C(=O)OR 12 , -NR 11 -S(=O) y -R 12 , -NR 11 -C(=O)-NR 11 R 12 , -C 1~6 Alkylene-OR 11 , -C 1~6 Alkylene-OC(=O)R 11 , -C 1~6 Alkylene-C(=O)OR 11 , -C 1~6 Alkylene-S(=O) x R 11 , -C 1~6 Alkylene-S(=O) y OR 11 , -C 1~6 Alkylene-OC(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 R 12 , -C 1~6 Alkylene-C(=O)NR 11 -S(=O) y R 12 , -C 1~6 Alkylene-NR 11 -C(=O)NR 11 R12 , -C 1~6 Alkylene-OS(=O) y R 11 , -C 1~6 Alkylene-OS(=O) y NR 11 R 12 , -C 1~6 Alkylene-S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 -S(=O) y NR 11 R 12 , -C 1~6 Alkylene-NR 11 R 12 and -OC 1~6 Alkylene-NR 11 R 12 and the substituents R are independently selected from the group consisting of 13 The alkyl, alkylene, cyclic hydrocarbyl groups, heterocyclic groups, aryl, heteroaryl and aralkyl defined for 1~6 Alkyl, halogenated C 1~6 Alkyl, C 3~6 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 aralkyl; when a heterocyclic group, aryl or heteroaryl is a substituent, it is connected to the remainder of the molecule via a ring C atom or, if possible, via a ring N atom; x, in each occurrence, is independently 0, 1, or 2; y and z, in each occurrence, are each independently 1 or 2; The present invention relates to a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

[0163] Embodiments of compounds according to the fourth aspect are further described below.

[0164] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 1a But -C 1~4 Alkylene-saturated or partially unsaturated C 3~7 Cyclic hydrocarbyl groups, -C 1~4 Alkylene - saturated or partially unsaturated 5- to 7-membered heterocyclic group and -C 1~4 The present invention provides a compound having the structure of formula (I) above, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound is selected from the group consisting of alkylene-(5- to 10-membered heteroaryl).

[0165] Preferably, in such embodiments, said heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl and benzo derivatives thereof, more preferably selected from the group consisting of thienyl and furyl and benzo derivatives thereof (such as benzothienyl and benzofuryl), more preferably selected from the group consisting of thienyl and benzo derivatives thereof (such as benzothienyl).

[0166] Preferably, in such embodiments, the heteroaryl is selected from one or two R 13 is optionally replaced by

[0167] Preferably, in such embodiments, R 13 In each occurrence, F, Cl, Br, I, amino, cyano, nitro, C 1~4 Alkyl, -OR 11 and -SR 11 are independently selected from the group consisting of: and preferably selected from the group consisting of Cl, methyl and ethyl.

[0168] More preferably, in such embodiments, R 1a but, [ka] is selected from.

[0169] Preferably, in any of the above embodiments, R 1b , R 2a and R 2b are independently OH;C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl (wherein C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Any one of the CH2 moieties of the alkynyl is optionally replaced with O or S); saturated or partially unsaturated C 3~7 Cyclic hydrocarbyl group; saturated or partially unsaturated 5- to 7-membered heterocyclic group; C 6~10 Aryl; 5-7 membered heteroaryl; -C 1~4 Alkylene-saturated or partially unsaturated C 3~7 Cyclic hydrocarbyl groups, -C 1~4 Alkylene - saturated or partially unsaturated 5- to 7-membered heterocyclic group; -C 1~4 Alkylene-C 6~10 aryl; and -C 1~4 alkylene-(5-10 membered heteroaryl); Preferably, OH, C 1~4 Alkyl, saturated or partially unsaturated C 3~7 Cyclic hydrocarbyl groups and C 6~10 aryl.

[0170] More preferably, R 1b But, OH, C 1~4 Alkyl, saturated or partially unsaturated C 3~5 Cyclic hydrocarbyl groups and C 6~10 It is selected from the group consisting of aryl; more preferably, it is selected from the group consisting of OH, methyl, ethyl, isopropyl, cyclopropyl, and phenyl.

[0171] More preferably, R 2a is phenyl.

[0172] More preferably, R 2b But C 1~4 It is selected from the group consisting of alkyl and phenyl; more preferably, it is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, and phenyl.

[0173] Preferably, in any of the above embodiments, X 1 is N, O or S; preferably N or O.

[0174] Preferably, in any of the above embodiments, X 2 is CH or N.

[0175] Preferably, in any of the above embodiments, X 3 and X 4 are each independently C(=O) and S(=O) y are each preferably C(=O).

[0176] Preferably, in any of the above embodiments, R 10 H, F, Cl, Br, I, amino, cyano, nitro, C 1~4 Alkyl, C 3~7 Cyclic hydrocarbyl group (C 5~7 cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, 5- to 6-membered heteroaryl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR 11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y OR11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -C 1~4 Alkylene-OR 11 , -C 1~4 Alkylene-OC(=O)R 11 , -C 1~4 Alkylene-C(=O)OR 11 , -C 1~4 Alkylene-S(=O) y OR 11 , -C 1~4 Alkylene-OC(=O)NR 11 R 12 , -C 1~4 Alkylene-C(=O)NR 11 R 12 , -C 1~4 Alkylene-OS(=O) y R 11 or -C 1~4 Alkylene-S(=O) y NR 11 R 12 and R 11 , R 12 and y is as defined in any of the embodiments according to the first aspect above.

[0177] In some embodiments, R 10 H, F, Cl, Br, I, OH, -OC 1~6 Alkyl (such as methoxy, ethoxy, or isopropoxy), amino, cyano, nitro, C 1~4 It is alkyl (such as methyl, ethyl or isopropyl) or cyclopropyl.

[0178] In some embodiments, R 10 is H, F, Cl, Br, I, OH, amino, cyano, nitro or C 1~4 It is alkyl (such as methyl, ethyl or isopropyl).

[0179] In some embodiments, R 10 is H, OH, amino, methyl or ethyl.

[0180] In some embodiments, R 10 H, F, Cl, Br, I, OH, -OC 1~6 Alkyl (such as methoxy, ethoxy, or isopropoxy), amino, C 1~4 Alkyl (such as methyl, ethyl, or isopropyl) or C 3~7 A cyclic hydrocarbyl group (such as cyclopropyl); more preferably F, Cl, OH, methoxy, ethoxy, amino, methyl, ethyl, isopropyl or cyclopropyl.

[0181] In some embodiments, R 10 is H, methyl or ethyl.

[0182] Preferably, in any of the above embodiments, R 11 and R 12 However, in each existence, independently, H, C 1~4 Alkyl, C 5~7 selected from the group consisting of cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, and 5- to 6-membered heteroaryl; preferably H and C 1~4 alkyl.

[0183] Preferably, in any of the above embodiments, R 13 In each occurrence, F, Cl, Br, I, amino, cyano, nitro, C 1~4 Alkyl, C 5~7 Cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, 5- to 6-membered heteroaryl, -OR 11 , -SR 11 , -OC(=O)R 11 , -C(=O)OR 11 , -C(=O)NR 11 R 12 , -C(=O)NR 11 S(=O) y NR11 R 12 , -C(=O)NR 11 S(=O) y R 12 , -S(=O) y OR 11 , -S(=O) y NR 11 R 12 , -S(=O) y NR 11 C(=O)R 12 , -S(=O) y NR 11 C(=O)OR 12 , -C 1~4 Alkylene-OR 11 , -C 1~4 Alkylene-OC(=O)R 11 , -C 1~4 Alkylene-C(=O)OR 11 , -C 1~4 Alkylene-S(=O) y OR 11 , -C 1~4 Alkylene-OC(=O)NR 11 R 12 , -C 1~4 Alkylene-C(=O)NR 11 R 12 , -C 1~4 Alkylene-OS(=O) y R 11 and -C 1~4 Alkylene-S(=O) y NR 11 R 12 ; preferably F, Cl, Br, I, amino, cyano, nitro, C 1~4 Alkyl, -OR 11 and -SR 11 may be independently selected from the group consisting of: Preferably, the substituent R 13 Alkyl, alkylene, cyclic hydrocarbyl groups, heterocyclic groups, phenyl and heteroaryl as defined above are not limited to F, Cl, Br, I, OH, oxo, amino, cyano, nitro, C 1~4 Alkyl, halogenated C 1~4 Alkyl, C 5~6Cyclic hydrocarbyl groups, 5- to 7-membered monocyclic heterocyclic groups, phenyl, 5- to 6-membered heteroaryl; preferably F, Cl, OH, amino, cyano, nitro, C 1~4 Alkyl and halogenated C 1~4 optionally further substituted with one, two, three or more substituents independently selected from the group consisting of alkyl; R 11 , R 12 and y is as defined in any of the embodiments according to the first aspect above, and in some further preferred embodiments, R 11 and R 12 C defined for 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl groups, 3- to 10-membered heterocyclic groups, C 6~10 Aryl, 5-14 membered heteroaryl and C 6~12 The aralkyl is not further substituted.

[0184] Compounds obtained by any combination of the various embodiments described above are encompassed by the present invention.

[0185] In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, having the following structure and characterization data:

[0186] [Table 1] TIFF0007814359000128.tif198149 TIFF0007814359000129.tif195149 TIFF0007814359000130.tif190149 TIFF0007814359000131.tif206149 TIFF0007814359000132.tif204149 TIFF0007814359000133.tif197149 TIFF0007814359000134.tif203149 TIFF0007814359000135.tif190149 TIFF0007814359000136.tif195149 TIFF0007814359000137.tif185149 TIFF0007814359000138.tif202149 TIFF0007814359000139.tif204149 TIFF0007814359000140.tif205149 TIFF0007814359000141.tif211149 TIFF0007814359000142.tif207149

[0187] In some embodiments, compounds of the present invention have selective inhibitory activity for the AT2 receptor compared to the AT1 receptor.

[0188] In some embodiments, the present invention provides a method of preparing a compound of formula (I), comprising the steps of: [ka] (In the formula, PG is an amino protecting group, preferably tert-butoxycarbonyl (Boc); Hal 1 and Hal 2 are the same or different and are halogens such as F, Cl, Br or I; the remaining groups are as defined in any of the above embodiments); Step 1: Reacting compound IN-1 with compound SM-1 to obtain compound IN-2 The reaction is preferably carried out in a suitable organic solvent, which is preferably a halogenated hydrocarbon such as a halogenated methane, including methylene chloride, dichloromethane, chloroform, etc. The reaction is preferably carried out in the presence of a suitable base, which is preferably an organic base, such as an organic amine, including diethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, and pyridine. The reaction is preferably carried out at a suitable temperature, preferably 0-10°C, for example 0-8°C, 1-6°C, or 2-5°C. Step 2: Deprotecting compound IN-2 under conditions suitable for PG (preferably in an organic solvent such as 1,4-dioxane and in the presence of an acid such as HCl) to give compound IN-3; Step 3: Reacting compound IN-3 with compound SM-II under the same conditions as in Step 1 to obtain a compound of formula (I).

[0189] In another embodiment, the present invention provides a method of preparing a compound of formula (I'), comprising the steps of: [ka] (In the formula, R' is C 1~4 C such as alkyl 1~6 alkyl, preferably methyl or ethyl; the remaining groups are as defined in Reaction Scheme 1 above); Step 1: reacting compound IN-1′ with compound SM-I to obtain compound IN-2, as described in Step 1 of Reaction Scheme 1 above; Step 2: Deprotecting compound IN-2′ under conditions suitable for PG (preferably in an organic solvent such as 1,4-dioxane and in the presence of an acid such as HCl) as described in Step 2 of Reaction Scheme 1 above to give compound IN-3′; Step 3: Esterification of compound IN-3′ with a suitable alcohol to obtain compound IN-4′; The reaction is preferably carried out in the presence of a suitable catalyst, for example in the presence of SOCl. Suitable alcohols include C1~6 Alkanols, e.g., C 1~4 It may be an alkanol, preferably methanol or ethanol. Step 4: reacting compound IN-4′ with compound SM-II under the same conditions as in Step 1 to obtain compound IN-5′; and Step 5: Hydrolysis of ester IN-5' under appropriate conditions to give compound of formula I'.

[0190] Pharmaceutical compositions and methods of treatment

[0191] In some embodiments, the present invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers, preferably in the form of a solid, semi-solid, liquid, or gaseous preparation. In some embodiments, the pharmaceutical composition can further comprise one or more additional therapeutic agents.

[0192] In some embodiments, the present invention provides use of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for use as an angiotensin II type 2 (AT2) receptor inhibitor.

[0193] In some embodiments, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention, for use as an angiotensin II type 2 (AT2) receptor inhibitor.

[0194] In some embodiments, the present invention provides a method for preventing or treating an AT2 receptor-mediated disorder or a symptom associated therewith, comprising administering to a subject in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention.

[0195] In some embodiments, the AT2 receptor-mediated disorder is selected from the group consisting of cerebrovascular disorders (including cerebral vasospasm and cerebral ischemia); cognitive disorders (including amnesia, senile dementia, AIDS-related dementia, and Down's syndrome); central nervous system diseases or disorders (including addictions such as alcoholism, anxiety, depressive, or dysthymic disorders, epilepsy, hyperkinesia, pain, Parkinson's disease, psychosis, sleep disorders, autonomic dysfunction, and demyelinating diseases such as tardive dyskinesia, schizophrenia, multiple sclerosis, and amyotrophic lateral sclerosis); respiratory diseases (including bronchospasm, asthma, and chronic obstructive airway disease); neurological tumors; inflammatory diseases (including inflammatory bowel disease and osteoarthritis). ); gastrointestinal (GI) diseases or disorders (including ulcerative colitis, Crohn's disease and incontinence); disorders of blood flow caused by vasodilation; hypersensitivity disorders (including allergies such as eczema, rhinitis and contact dermatitis); vasospastic diseases (including angina, migraine and Raynaud's disease); fibrotic and collagen diseases (including scleroderma and eosinophilic fascioliasis); reflex sympathetic dystrophies (including shoulder / hand syndrome); stress-related physical disorders; peripheral neuropathy; neuralgia; autoimmune diseases (including systemic lupus erythematosus, rheumatoid arthritis, psoriasis and graft-versus-host disease); and rheumatic diseases (including fibromyalgia).

[0196] In some embodiments, the AT2 receptor-mediated disorder is selected from the following: Neuropathic conditions (primary and secondary neuropathies, e.g., peripheral neuropathy) or symptoms associated with the same (including hyperesthesia, hyperalgesia, allodynia, sudden burning pain, numbness, weakness, burning pain, tingling pain, and loss of reflexes), preferably neuropathic pain; secondary neuropathies include diabetic neuropathy, shingles-associated neuropathy, uremia-associated neuropathy, amyloidosis neuropathy, HIV sensory neuropathy, hereditary motor and sensory neuropathy, hereditary sensory neuropathy, hereditary sensory and autonomic neuropathy, hereditary neuropathy with ulcer resection, nitrofurantoin neuropathy, neuropathies caused by nutritional deficiencies; neuropathies caused by renal failure and complex regional pain syndrome; neuropathies caused by repetitive activities (such as typing or assembly line work); peripheral neuropathies caused by antiretroviral drugs (such as zalcitabine and didanosine), antibiotics (such as metronidazole and isoniazid), gold compounds, chemotherapy drugs (such as vincristine), alcohol, lead, arsenic, mercury, and organophosphate pesticides; and peripheral neuropathies associated with infectious processes (such as Guillain-Barré syndrome). conditions characterized by neuronal hypersensitivity, including hyperalgesic conditions such as fibromyalgia and irritable bowel syndrome; Disorders associated with abnormal nerve regeneration, including neuronal hypersensitivity, mastalgia, interstitial cystitis, vulvodynia, and cancer chemotherapy-induced neuropathy; Inflammatory pain that may be due to conditions characterized by inflammation (including burns such as chemical burns, friction burns or thermal burns; autoimmune diseases such as rheumatoid arthritis; inflammatory bowel diseases such as Crohn's disease and colitis; osteoarthritis, carditis, dermatitis, myositis, neuritis and collagen vascular diseases); Nerve conduction velocity disorders that may be associated with the neuropathic conditions listed above (such as peripheral neuropathy) as well as carpal tunnel syndrome, ulnar neuropathy, Guillain-Barré syndrome, facioscapulohumeral muscular dystrophy, and herniated discs; Cell proliferative disorders, including cancer (including leukemia, melanoma, prostate cancer, breast cancer, ovarian cancer, basal cell carcinoma, squamous cell carcinoma, sarcoma, fibrosarcoma, colon cancer, and lung cancer); and non-cancerous proliferative disorders (including dermatological disorders such as warts, keloids, psoriasis, and granulation disorders, as well as the reduction and cosmetic remodeling of scar tissue); Disorders associated with an imbalance between bone resorption and bone formation, including osteoporosis.

[0197] In some embodiments, the present invention provides a method of modulating AT2 receptor-associated reproductive function in a female patient, comprising administering to a subject in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention. In some embodiments, the reproductive function is selected from menstrual cycle, fertility, and hormonal balance of the sexual cycle.

[0198] The term "pharmaceutically acceptable carrier" as used herein refers to a diluent, adjuvant, excipient, or vehicle with which a therapeutic is administered, which is suitable, within the scope of sound medical judgment, to come into contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0199] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include sterile liquids such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as, but not limited to, peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat dry milk, glycerol, propylene glycol, water, ethanol, and the like. Pharmaceutical compositions can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutical carriers are described, for example, in Remington's Pharmaceutical Sciences (1990).

[0200] The pharmaceutical compositions of the present invention can act systemically and / or locally, and to this end, the compositions can be administered by any suitable route, such as through injection (intravenous, including instillation, intraarterial, subcutaneous, intraperitoneal, intramuscular injection) or transdermal administration, or can be administered orally, bucally, intranasally, intramuscularly, topically, in an ophthalmic formulation, or via inhalation.

[0201] For these administration routes, the pharmaceutical composition of the present invention can be administered in an appropriate dosage form.

[0202] Suitable dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, salves, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups. As used herein, the term "effective amount" refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.

[0203] Dosage regimens can be adjusted to provide the optimum desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated and can include single or multiple doses. It should further be understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition.

[0204] The amount of a compound of the invention administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the discretion of the prescribing physician. Generally, an effective dosage ranges from about 0.0001 to about 50 mg / kg of body weight per day, e.g., from about 0.01 to about 10 mg / kg per day, in single or divided doses. For a 70 kg human, this would be from about 0.007 mg to about 3500 mg per day, e.g., from about 0.7 mg to about 700 mg per day. In some instances, dosage levels below the lower end of the range may be more than sufficient, while in other instances, even higher doses may be used without causing adverse side effects, provided that such higher doses are initially divided into several smaller doses for administration throughout the day.

[0205] The content or dosage of the compound of the present invention in the pharmaceutical composition is about 0.01 mg to about 1000 mg, appropriately 0.1 to 500 mg, preferably 0.5 to 300 mg, more preferably 1 to 150 mg, particularly preferably 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.

[0206] Unless otherwise indicated, the terms "treating" or "treatment" as used herein means to reverse, alleviate, inhibit the progression of, or prevent the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0207] As used herein, the term "subject" includes a human or a non-human animal. Exemplary human subjects include human subjects (referred to as patients) with a disease (such as those described herein) or normal subjects. As used herein, the term "non-human subject" includes all vertebrates, such as mammals, including non-mammals (e.g., birds, amphibians, reptiles) and non-human primates, domestic and / or farm animals (sheep, dogs, cats, cows, pigs, etc.).

[0208] In some embodiments, pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents. [Example]

[0209] The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention.

[0210] The structure of the compound was confirmed by nuclear magnetic resonance spectroscopy ( 1 The results were confirmed by 1 H NMR or mass spectrometry (MS).

[0211] Chemical shifts (δ) are expressed in parts per million (ppm). 1 H NMR was recorded on a Bruker 400 spectrometer, the test solvents were deuterated methanol (CD3OD), deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-d6), and the internal standard was tetramethylsilane (TMS).

[0212] LC-MS assays were performed on an Agilent LC-MS-1110 liquid chromatography-mass spectrometer, an Agilent LC-MS-6110 liquid chromatography-mass spectrometer, an Agilent LC-MS-6120 liquid chromatography-mass spectrometer (manufacturer: Agilent) or a Shimadzu LC-MS-2020.

[0213] Preparative high-performance liquid chromatography was performed using an MS-guided AutoPurification system (Waters), a Gilson GX-281 (Gilson), or a semi-preparative liquid chromatograph (Tong Heng Innovation Technology Co., Ltd., LC3000 (Ddlsogel, C18, 30 mm × 250 mm 10 μm)).

[0214] Thin-layer chromatography (TLC) was performed on Huanghai HSGF 254 (5 × 20 cm) silica gel plates, and preparative thin-layer chromatography was performed on GF254 (0.4–0.5 nm) silica gel plates manufactured by Yantai.

[0215] The reaction was monitored by thin-layer chromatography (TLC) or LC-MS. The developing solvent systems included dichloromethane and methanol, n-hexane and ethyl acetate, and petroleum ether and ethyl acetate, and were adjusted (by adjusting the volume ratio of the solvents or by adding triethylamine, etc.) according to the polarity of the compounds to be separated.

[0216] Microwave reactions were carried out in a CEM Discovery Sp (400 W, RT-300° C.) microwave reactor.

[0217] Typically, silica gel (200-300 mesh) manufactured by Yucheng Chemical Co., Ltd. was used as the stationary phase for column chromatography. The eluent system included a dichloromethane and methanol system and an n-hexane and ethyl acetate system, and was adjusted (by adjusting the volume ratio of the solvents or adding triethylamine, etc.) according to the polarity of the compounds to be separated.

[0218] In the following examples, unless otherwise specified, the reaction temperature was room temperature (20°C to 30°C).

[0219] Reagents used in the examples were purchased from companies such as Aldrich Chemical Company, Shanghai Bide Pharmatech Co. Ltd., Beijing Greenchem Co. Ltd., Shanghai Shaoyuan Co. Ltd., or Ables Technology Co. Ltd.

[0220] The abbreviations used in this invention have the following meanings:

[0221] [Table 2]

[0222] Example 1: Preparation of (S)-4-(5H-dibenzo[b,f]azepine-5-carbonyl)-1-(diphenylcarbamoyl)piperazine-2-carboxylic acid (C1) [ka]

[0223] Step 1: Compound C1-1 (1015 mg, 5 mmol) was dissolved in 1,4-dioxane (20 mL) and water (20 mL), and Na2CO3 (795 mg, 1.08 mol) and (Boc)2O (136 mg, 0.81 mol) were added sequentially. The reaction solution was allowed to react at room temperature for 16 hours. LC-MS analysis showed that the reaction of the starting material was essentially complete. The reaction solution was concentrated under reduced pressure to remove 1,4-dioxane, followed by the addition of purified water (20 mL) and extraction with ethyl acetate (40 mL). The aqueous phase was adjusted to pH 4-5 by dropwise addition of 2N HCl solution, and then extracted with n-butanol (40 mL × 2). The n-butanol was combined, followed by the addition of anhydrous sodium sulfate (10 g), drying for 30 minutes, filtering, and concentration under reduced pressure to give compound C1-2 (1.07 g, white solid, yield: 95%). MS m / z (ESI): 231.0 [M+H] + .

[0224] Step 2: Compound C1-2 (460 mg, 2 mmol) was dissolved in anhydrous dichloromethane (20 mL). After the temperature was lowered to 0-5°C, triethylamine (808 mg, 8 mmol) and SM2 (462 mg, 2 mmol) were added sequentially. The reaction solution was allowed to react at room temperature for 3 hours. LC-MS showed that the reaction of the starting material was complete. The reaction was quenched by adding water (50 mL) and extracted with dichloromethane (30 mL × 2). The combined organic phases were washed once with saturated brine (50 mL), then dried over anhydrous sodium sulfate (20 g) for 30 minutes, filtered, and concentrated. The crude product was separated by column chromatography [dichloromethane:methanol = 15:1 to 10:1 (0.1% formic acid)] to give compound C1-3 (700 mg, white solid, yield: 83%). MS m / z (ESI): 448.0 [M+Na] + .

[0225] Step 3: Compound C1-3 (700 mg, 1.65 mmol) was dissolved in 1,4-dioxane (10 mL), and a solution of HCl in 1,4-dioxane (5 mL, 4.0 M in 1,4-dioxane) was added. The reaction solution was reacted at room temperature for 3 hours. LC-MS showed that the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure to give compound C1-4 (535 mg, white solid, yield: 100%). MS m / z (ESI): 326.0 [M+H] + .

[0226] Step 4: Compound C1-4 (535 mg, 1.65 mmol) was dissolved in anhydrous dichloromethane (20 mL). After the temperature was lowered to 0-5°C, triethylamine (667 mg, 6.6 mmol) and SM1 (420 mg, 1.65 mmol) were added sequentially. The reaction solution was allowed to react at room temperature for 3 hours. LC-MS showed that the reaction of the starting material was complete. The reaction was quenched by adding water (50 mL) and extracted with dichloromethane (30 mL × 2). The combined organic phases were washed once with saturated brine (50 mL), then dried over anhydrous sodium sulfate (20 g) for 30 minutes, filtered, concentrated, and then separated by preparative high-performance liquid chromatography [CHCN / HO, 5%-40%, (0.1% CFCOOH)] to obtain compound C1 (350 mg, white solid, yield: 39%). 1 H NMR(400 MHz, DMSO-d6) δ 13.05 (s, 1H), 7.56 (d, J = 7.9Hz, 2H), 7.40 (dd, J = 16.9, 7.9 Hz, 4H), 7.33 - 7.25 (m, 6H), 7.13 (t, J = 7.3Hz, 2H), 7.04 (s, 2H), 6.89 (d, J = 7.9 Hz, 4H), 4.19 (s, 1H), 3.93 (d, J = 13.1Hz, 1H), 3.31 (d, J = 12.4 Hz, 1H), 2.92 (d, J = 12.8 Hz, 1H), 2.76 - 2.63 (m,2H), 2.39 (t, J = 10.8 Hz, 1H). MS m / z (ESI): 545.0 [M+H] + .

[0227] The compounds in Table 1 were prepared by methods similar to those described in Example 1.

[0228] [Table 3] TIFF0007814359000148.tif173149 TIFF0007814359000149.tif129149

[0229] Example 2: Preparation of (S)-1-(5H-dibenzo[b,f]azepine-5-carbonyl)-4-(diphenylcarbamoyl)piperazine-2-carboxylic acid (C2) [ka]

[0230] Step 1: Compound C1-1 (4.06 g, 20 mmol) was dissolved in 1,4-dioxane (80 mL) and water (40 mL), and Na2CO3 (3.18 g, 30 mol) and (Boc)2O (4.76 g, 22 mol) were added sequentially. The reaction solution was allowed to react at room temperature for 16 hours. LC-MS analysis showed that the reaction of the starting material was essentially complete. The reaction solution was concentrated under reduced pressure to remove 1,4-dioxane, followed by the addition of purified water (60 mL) and extraction with ethyl acetate (80 mL). The aqueous phase was adjusted to pH 4-5 by dropwise addition of 2N HCl solution, and then extracted with n-butanol (80 mL × 2). The n-butanol was combined, dried by adding anhydrous sodium sulfate (20 g) for 30 minutes, filtered, and concentrated under reduced pressure to give compound C1-2 (4.05 g, white solid, yield: 87%). MS m / z (ESI): 231.0 [M+H] + .

[0231] Step 2: Compound C1-2 (3.24 g, 13.9 mmol) was dissolved in anhydrous dichloromethane (50 mL). After the temperature was lowered to 0-5°C, triethylamine (5.62 g, 55.6 mmol) and SM1 (3.55 g, 13.9 mmol) were added sequentially. The reaction solution was allowed to react at room temperature for 16 hours. LC-MS showed that the reaction of the starting material was complete. The reaction was quenched by adding water (50 mL) and extracted with dichloromethane (60 mL × 2). The combined organic phases were washed once with saturated brine (60 mL), then dried over anhydrous sodium sulfate (20 g) for 30 minutes, filtered, and concentrated to give compound C2-1 (3.62 g, white solid, yield: 60%). MS m / z (ESI): 394.0 [M+H-56] + .

[0232] Step 3: Compound C2-1 (3.62 g, 8.24 mmol) was dissolved in anhydrous methanol (40 mL). After the temperature was lowered to 0-5°C, SOCl2 (1.47 g, 12.4 mmol) was added dropwise. The reaction solution was allowed to react at room temperature for 3 hours. LC-MS showed that the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure, and the methanol was removed by rotary evaporation. The residue was then dissolved in dichloromethane (80 mL), washed once with saturated brine (50 mL), and then dried over anhydrous sodium sulfate (20 g) for 30 minutes, followed by filtration and concentration. The crude product was separated by column chromatography (dichloromethane:methanol = 15:1 to 10:1) to give compound C2-2 (2.90 g, white solid, yield: 95%). MS m / z (ESI): 364.0 [M+H] + .

[0233] Step 4: Compound C2-2 (2.90 g, 8.0 mmol) was dissolved in anhydrous dichloromethane (60 mL). After the temperature was lowered to 0-5°C, triethylamine (3.23 g, 32 mmol) and SM2 (1.84 g, 8.0 mmol) were added sequentially. The reaction solution was allowed to react at room temperature for 3 hours. LC-MS showed that the reaction of the starting material was complete. The reaction was quenched by adding water (50 mL) and extracted with dichloromethane (60 mL × 2). The combined organic phases were washed once with saturated brine (60 mL), then dried over anhydrous sodium sulfate (20 g) for 30 minutes, filtered, and concentrated. The crude product was separated by column chromatography (dichloromethane:methanol = 15:1 to 10:1) to give compound C2-3 (2.80 g, white solid, yield: 64%). MS m / z (ESI): 559.0 [M+H] + .

[0234] Step 5: Compound C2-3 (2.80 g, 5.0 mmol) was dissolved in anhydrous methanol (30 mL) and water (10 mL), and sodium hydroxide (1.6 g, 40 mmol) was added. The reaction solution was reacted at 40 °C for 16 hours. LC-MS showed that the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure, and the methanol was removed by rotary evaporation. Water (60 mL) was added to dissolve the residue, and the pH was adjusted to 4-5 by dropwise addition of 2N HCl solution to obtain a white precipitate. The mixture was filtered, and the white solid was rinsed with water (50 mL) and then concentrated under reduced pressure. The white solid was dried by rotary evaporation to remove the water, yielding compound C2 (2.5 g, white solid, yield: 93%). 1HNMR(400 MHz, DMSO-d6) δ 13.31 - 12.74 (s, 1H), 7.39 - 7.27(m, 12H), 7.14 (t, J = 7.0 Hz, 2H), 7.03 - 6.93 (m, 6H), 4.39 (s, 1H), 3.92 (d,J = 12.8 Hz, 1H), 3.12 (d, J = 8.8 Hz, 1H), 2.93 (d, J = 9.2 Hz, 1H), 2.67 (s,1H), 2.42 (t, J = 10.2 Hz, 2H). MS m / z (ESI): 544.9 [M+H] + .

[0235] The compounds in Table 2 were prepared by methods similar to those described in Example 2.

[0236] [Table 4] TIFF0007814359000152.tif210149 TIFF0007814359000153.tif153149 TIFF0007814359000154.tif153149 TIFF0007814359000155.tif168149 TIFF0007814359000156.tif207149 TIFF0007814359000157.tif153149 TIFF0007814359000158.tif130149 TIFF0007814359000159.tif147149 TIFF0007814359000160.tif173149 TIFF0007814359000161.tif153149 TIFF0007814359000162.tif192149 TIFF0007814359000163.tif178149 TIFF0007814359000164.tif207149 TIFF0007814359000165.tif138149 TIFF0007814359000166.tif139149 TIFF0007814359000167.tif142149 TIFF0007814359000168.tif136149 TIFF0007814359000169.tif141149 TIFF0007814359000170.tif136149 TIFF0007814359000171.tif130149 TIFF0007814359000172.tif139149 TIFF0007814359000173.tif136149 TIFF0007814359000174.tif137149 TIFF0007814359000175.tif140149 TIFF0007814359000176.tif112149 TIFF0007814359000177.tif137149 TIFF0007814359000178.tif131149

[0237] Example 3: Preparation of (S)-1-(5H-dibenzo[b,f]azepine-5-carbonyl)-4-(dipentylcarbamoyl)piperazine-2-carboxylic acid (C7) [ka]

[0238] Step 1: Compound C2-2 (100 mg, 0.27 mmol) and triethylamine (82 mg, 0.81 mmol) were added to anhydrous dichloromethane (10 mL). After cooling to 0 °C, triphosgene (80 mg, 0.27 mmol) was added. After stirring for an additional 0.5 h, dipentylamine (43 mg, 0.27 mmol) was slowly added. The reaction solution was allowed to react at room temperature for 16 h. LC-MS showed that the reaction of the starting material was complete. After adding dichloromethane (30 mL), it was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate (20 g) for 30 min, and then filtered. The filtrate was concentrated under reduced pressure to give the crude compound. The crude product was separated by preparative plate chromatography (petroleum ether:ethyl acetate = 3:1) to give compound C7-1 (80 mg, white solid, yield: 53%). MS m / z (ESI): 546.4 [M+H] + .

[0239] Step 2: Compound C7-1 (80 mg, 0.15 mmol) was dissolved in methanol (8 mL) and water (6 mL), and sodium hydroxide (59 mg, 1.5 mmol) was added at room temperature. The mixture was then heated to 40 °C and stirred for 16 hours, followed by concentration under reduced pressure. The residue was dissolved in water (20 mL), adjusted to pH 5 with 1N diluted hydrochloric acid, and then extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate (20 g) for 30 minutes, and then filtered. The filtrate was concentrated under reduced pressure to obtain the crude compound. The crude product was separated by preparative high-performance liquid chromatography (CHCN:HO (0.1% TFA) = 30% to 70%) to obtain compound C7 (10 mg, white solid, yield: 12.8%). 1H NMR(400 MHz, -DMSO-d6): δ 12.81 (brs, 1H), 7.57 (d, J =7.6, 2H), 7.45 - 7.35 (m, 4H), 7.31 - 7.28 (m, 2H), 7.06 (s, 1H), 4.20 (s, 1H),3.55 - 3.52 (m, 1H), 3.13 - 2.92 (m, 3H), 2.64 - 2.60 (m, 1H), 2.23 - 2.17 (m,1H), 1.39 - 1.31 (m, 4H), 1.25 - 1.18 (m, 4H), 1.14 - 1.08 (m, 4H), 0.82 (t, J= 7.6 Hz, 6H). MS m / z (ESI): 532.8 [M+H] + .

[0240] Example 4: Preparation of (S)-4-(diphenylcarbamoyl)-1-(10-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carbonyl)piperazine-2-carboxylic acid (C77) [ka]

[0241] Step 1: Compound C77-1 (10 g, 44.8 mmol) and triethylamine (13.6 g, 133.4 mmol) were dissolved in 1,2-dichloroethane (150 mL), and triphosgene (13.2 g, 44.8 mmol) was added portionwise at 0 °C. The reaction solution was allowed to react at room temperature for 16 hours. LC-MS analysis showed that the reaction of the starting material was essentially complete. The reaction solution was then washed with saturated brine (60 mL × 3) and then dried by adding anhydrous sodium sulfate (20 g) for 30 minutes. The mixture was then filtered and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (dichloromethane:petroleum ether = 1:10) to obtain compound C77-2 (7.2 g, yellow solid, yield: 57%). 1HNMR(400 MHz, CDCl3) δ 7.78 (d, J = 8 Hz, 1H),7.52 - 7.41 (m, 4H), 7.34 - 7.32 (m, 3H), 7.26 (s, 1H), 6.19 (s, 1H), 3.93 (d,J = 5.2Hz, 3H). MS m / z (ESI): 285.7 [M+H] + .

[0242] Step 2: Compound 1-2 (5.8 g, 25 mmol) was dissolved in anhydrous dichloromethane (100 mL). After the temperature was lowered to 0-5°C, triethylamine (7.6 g, 75 mmol) and C77-2 (7.2 g, 25 mmol) were added sequentially. The reaction solution was allowed to react at room temperature for 16 hours. LC-MS showed that the reaction of the starting material was complete. The reaction was quenched by adding water (100 mL) and extracted with dichloromethane (100 mL × 2). The combined organic phases were washed once with saturated brine (100 mL), then dried over anhydrous sodium sulfate (40 g) for 30 minutes, filtered, and concentrated to give compound C77-3 (10 g, yellow solid, yield: 83%). MS m / z (ESI): 424.1 [M+H-56] + .

[0243] Step 3: Compound C77-3 (10 g, 20.9 mmol) was dissolved in anhydrous methanol (100 mL). After the temperature was lowered to 0-5°C, SOCl2 (10 mL) was added dropwise. The reaction solution was reacted at 70°C for 48 hours. LC-MS showed that the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure and dried by rotary evaporation, and then saturated aqueous sodium bicarbonate solution (100 mL) was added thereto. It was then extracted with ethyl acetate (60 mL x 3), washed with saturated brine (80 mL x 2), and then dried over anhydrous sodium sulfate (40 g) for 30 minutes. It was then filtered and concentrated. The crude product was separated by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain compound C77-4 (4 g, pale yellow solid, yield: 50.6%). 1 HNMR(400 MHz, CDCl3) δ 8.12 (d, J = 8.0 Hz, 1H),7.85 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 3.2 Hz, 2H), 7.31 - 7.22 (m, 4H), 5.30(s, 1H), 4.81 (brs, 1H), 4.17 - 4.05 (m, 2H), 3.79 (s, 3H), 3.51 - 3.42 (m,2H), 3.14 (s, 1H), 2.93 - 2.89 (m, 2H), 2.55 (t, J =10.8 Hz, 1H ). MS m / z (ESI): 379.7 [M+H] + .

[0244] Step 4: Compound C77-4 (4 g, 10.5 mmol) was dissolved in anhydrous dichloromethane (100 mL). After the temperature was lowered to 0-5 °C, triethylamine (3.2 g, 31.5 mmol) and SM2 (2.43 g, 8.0 mmol) were added sequentially. The reaction solution was allowed to react at room temperature for 16 hours. LC-MS showed that the reaction of the starting material was complete. The reaction was quenched by adding water (100 mL) and extracted with dichloromethane (80 mL × 2). The combined organic phases were washed twice with saturated brine (60 mL), then dried over anhydrous sodium sulfate (30 g) for 30 minutes, filtered, and concentrated. The crude product was separated by silica gel column chromatography (ethyl acetate:petroleum ether = 1:1) to give compound C77-5 (5.4 g, pale yellow solid, yield: 90%). 1 HNMR(400 MHz, CDCl3) δ 8.10 (d, J = 8 Hz, 1H),7.82 (d, J = 7.6 Hz, 1H), 7.56 - 7.53 (m, 2H), 7.29 - 7.21 (m, 8H), 7.12 (t, J= 7.2 Hz, 2H), 6.96 (d, J = 8 Hz, 2H), 4.76 (s, 1H), 4.22 (d, J = 13.6 Hz, 1H),4.08 (brs, 2H), 3.77 (s, 3H), 3.55 (d, J = 12.4 Hz, 1H), 3.27 (d, J = 12.8Hz,1H), 3.05 - 3.01 (m, 2H), 2.66 (t, J = 11.2 Hz, 1H). MS m / z (ESI): 574.5 [M+H] + .

[0245] Step 5: Compound C77-5 (5.3 g, 9.2 mmol) was dissolved in anhydrous methanol (100 mL) and water (40 mL), and sodium hydroxide (2.2 g, 55.2 mmol) was added. The reaction solution was allowed to react at room temperature for 3 hours. LC-MS showed that the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure, dissolved in water (150 mL), and then adjusted to pH 4-5 by dropwise addition of 1N HCl solution until a white precipitate formed, which was then filtered. The white solid was washed with water (50 mL) and then dried in vacuo to give compound C77 (4.5 g, pale yellow solid, yield: 88%). 1 HNMR(400 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.92 (d, J = 8 Hz,1H), 7.79 (d, J = 7.2 Hz, 1H), 7.68 - 7.66 (m, 2H), 7.61 - 7.55 (m, 1H), 7.37 -7.25 (m, 8H), 7.09 (t, J = 7.6 Hz, 2H), 6.94 (d, J = 8 Hz, 2H), 4.31 - 3.89 (m,4H), 3.58 (s, 1H), 3.34 (brs, 1H), 2.82 - 2.60 (m, 3H). MS m / z (ESI): 560.7 [M+H] + .

[0246] The compounds in Table 3 were prepared by methods similar to those described in Example 4.

[0247] [Table 5] TIFF0007814359000182.tif187149 TIFF0007814359000183.tif201149 TIFF0007814359000184.tif192149 TIFF0007814359000185.tif167149 TIFF0007814359000186.tif160149 TIFF0007814359000187.tif201149 TIFF0007814359000188.tif74149

[0248] Example 5: (S)-4-(5H-dibenzo[b,f]azepine-5-carbonyl)-N 3 -(N,N-dimethylsulfamoyl)-N 1 ,N 1 Preparation of -diphenylpiperazine-1,3-dicarboxamide (C33) [ka]

[0249] Compound C2 (55 mg, 0.1 mmol) and SM3 (25 mg, 0.2 mmol) were dissolved in anhydrous dichloromethane (20 mL), and dicyclohexylcarbodiimide (31 mg, 0.15 mmol) and 4-dimethylaminopyridine (7 mg, 0.075 mmol) were added sequentially. The reaction solution was allowed to react at room temperature for 16 hours. LC-MS showed the reaction of the starting material was complete. The reaction was quenched by adding water (30 mL) and extracted with dichloromethane (30 mL × 2). The combined organic phases were washed once with saturated brine (30 mL), then dried over anhydrous sodium sulfate (20 g) for 30 minutes, filtered, and concentrated. The crude product was separated by preparative plate chromatography (dichloromethane:methanol = 30:1) to give compound C33 (30 mg, white solid, yield: 48%). 1H NMR(400 MHz, DMSO-d6) δ 11.62 (s, 1H), 7.57 (m, 2H), 7.40(m, 4H), 7.28 (m, 6H), 7.12 (t, J = 7.1 Hz, 2H), 7.04 (m, 2H), 6.91 (m, 4H),4.28 (s, 1H), 3.96 (m, 1H), 3.07 (m, 2H), 2.90 (m, 1H), 2.81 (s, 6H), 2.70 (m,1H), 2.36 (m, 1H). MS m / z (ESI): 651.1 [M+H] + .

[0250] The compounds in Table 4 were prepared by methods similar to those described in Example 5.

[0251] [Table 6] TIFF0007814359000191.tif208149

[0252] Example 6: Preparation of (S)-1-(10-chloro-5H-dibenzo[b,f]azepine-5-carbonyl)-4-(diphenylcarbamoyl)piperazine-2-carboxylic acid (C51) [ka]

[0253] Step 1: Compound C77-5 (80 mg, 0.14 mmol) was dissolved in phosphorus oxychloride (10 mL), and the reaction solution was then reacted at 100° C. for 16 hours. LC-MS showed that the reaction of the starting material was essentially complete. The reaction solution was then concentrated, ethyl acetate (50 mL) was added, and then washed with saturated brine (40 mL×2). Anhydrous sodium sulfate (10 g) was added to dry it for 30 minutes, and then filtered and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel preparative thin-layer chromatography (ethyl acetate:petroleum ether=1:1) to obtain compound C51-1 (20 mg, pale red solid, yield: 24%). MS m / z (ESI): 592.4 [M+H] + .

[0254] Step 2: Compound C51-1 (20 mg, 0.38 mmol) was dissolved in anhydrous methanol (6 mL) and water (3 mL), and sodium hydroxide (15 mg, 3.8 mmol) was added. The reaction solution was allowed to react at room temperature for 16 hours. LC-MS showed that the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure, dissolved by adding water (150 mL), and adjusted to pH 4-5 by dropwise addition of 1N HCl solution. The mixture was then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 2), and then dried by adding anhydrous sodium sulfate (10 g) for 30 minutes. The mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (acetonitrile:water (0.1% trifluoroacetic acid), gradient: 30%-60%) to obtain compound C51 (2.5 mg, white solid, yield: 13%). 1H NMR(400 MHz, DMSO-d6) δ 13.14 (s, 1H), 7.70 - 7.51 (m,6H), 7.48 - 7.38 (m, 2H), 7.31 - 7.27 (m, 4H), 7.16 - 7.10 (m, 2H), 6.89(d, J = 7.2 Hz, 4H), 6.53 (s, 1H), 4.21 (d, J = 22 Hz, 2H), 4.02 - 3.93 (m,2H), 3.02 - 2.95 (m, 3H). MS m / z (ESI): 578.7 [M+H] + .

[0255] Example 7: Preparation of (S)-4-(diphenylcarbamoyl)-1-(11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine-5-carbonyl)piperazine-2-carboxylic acid (C53) [ka]

[0256] Step 1: Compound C53-1 (2.16 g, 20 mmol), C53-2 (5.5 g, 20 mmol), Pd(dppf)Cl (1.46 g, 2 mmol), and cesium carbonate (13 g, 40 mmol) were dissolved in dioxane (100 mL). The reaction mixture was heated at 100 °C for 16 hours. LC-MS showed that the reaction of the starting material was essentially complete. It was then cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (ethyl acetate:petroleum ether = 1:8) to obtain compound C53-3 (2.5 g, yellow solid, yield: 49%). 1HNMR(400 MHz, CDCl3) δ 9.02 (s, 1H), 7.97 (d, J= 8.0 Hz, 1H), 7.26 (t, J = 7.2 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.10 (t, J =7.6 Hz, 1H), 6.91 (d, J = 7.2 Hz, 1H), 6.84 (t, J = 7.6 Hz, 1H), 6.70 - 6.62(m, 2H), 4.34 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H). MS m / z (ESI): 257.0 [M+H] + .

[0257] Step 2: Compound C53-3 (2.5 g, 9.8 mmol) and potassium phosphate (3.1 g, 14.6 mmol) were dissolved in ethylene glycol (50 mL) and then reacted at 100 °C for 16 hours. After cooling and adding water (100 mL), ethyl acetate (50 mL × 3) was added for extraction, followed by washing with saturated brine (80 mL × 2) and drying over anhydrous sodium sulfate (20 g) for 30 minutes. After filtration and concentration, crude compound C53-4 was obtained (2 g, black solid, yield: 100%). 1 HNMR(400 MHz, DMSO-d6) δ 9.83 (s, 1H), 7.84 (s, 1H), 7.68(dd, J = 8.0 Hz, 1.5 Hz, 1H), 7.35 - 7.31 (m, 1H), 7.01 - 6.87 (m, 6H). MS m / z (ESI): 211.0 [M+H] + .

[0258] Step 3: Compound 53-4 (1.9 g, 9 mmol) and triethylamine (1.8 g, 18 mmol) were dissolved in 1,2-dichloroethane (50 mL), and triphosgene (2.9 g, 10 mmol) was added portionwise at 0 °C. The reaction solution was reacted at room temperature for 16 hours. LC-MS showed that the reaction of the starting material was essentially complete. The reaction solution was then washed with saturated brine (50 mL × 2) and dried by adding anhydrous sodium sulfate (20 g) for 30 minutes, then filtered and concentrated under reduced pressure to give crude compound C53-5 (1.5 g, black solid, yield: 61%). MS m / z (ESI): 272.8 [M+H] + .

[0259] Step 4: Compound C1-2 (127 mg, 0.55 mmol) was dissolved in anhydrous dichloromethane (20 mL). After the temperature was lowered to 0-5°C, triethylamine (112 mg, 1.1 mmol) and C53-5 (150 mg, 0.55 mmol) were added sequentially. The reaction solution was reacted at room temperature for 16 hours. LC-MS showed that the reaction of the starting material was complete. The reaction was quenched by adding water (30 mL) and extracted with dichloromethane (30 mL × 2). The organic phases were combined, washed twice with saturated brine (30 mL), and then dried over anhydrous sodium sulfate (10 g) for 30 minutes, filtered, and concentrated to give compound C53-6 (150 mg, pale yellow solid, yield: 58%). MS m / z (ESI): 489.0 [M+Na] + .

[0260] Step 5: Compound C53-6 (150 mg, 0.32 mmol) was dissolved in anhydrous methanol (10 mL). After the temperature was lowered to 0-5°C, SOCl (0.5 mL) was added dropwise. The reaction solution was reacted at 50°C for 16 hours. LC-MS showed that the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate solution (10 mL). It was then extracted with ethyl acetate (20 mL x 3), washed with saturated brine (30 mL x 2), and then dried over anhydrous sodium sulfate (10 g) for 30 minutes. It was then filtered and concentrated. The crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to give compound C53-7 (50 mg, pale yellow solid, yield: 41%). MS m / z (ESI): 381.1[M+H] + .

[0261] Step 6: Compound 53-7 (50 mg, 0.13 mmol) was dissolved in anhydrous dichloromethane (10 mL). After the temperature was lowered to 0-5 °C, triethylamine (27 mg, 0.26 mmol) and SM2 (30 mg, 0.13 mmol) were added sequentially. The reaction solution was reacted at 35 °C for 16 h. LC-MS showed that the reaction of the starting material was complete. The reaction was quenched by adding water (10 mL) and extracted with dichloromethane (20 mL × 2). The combined organic phases were washed twice with saturated brine (30 mL), then dried over anhydrous sodium sulfate (10 g) for 30 min, filtered, and concentrated. The crude product was separated by column chromatography (ethyl acetate:petroleum ether = 1:1) to give compound C53-8 (60 mg, pale yellow solid, yield: 79%). MS m / z (ESI): 576.0 [M+H] + .

[0262] Step 7: Compound 53-8 (60 mg, 0.1 mmol) was dissolved in anhydrous methanol (4 mL) and water (2 mL), and sodium hydroxide (40 mg, 1 mmol) was added. The reaction solution was reacted at 30 °C for 16 hours. LC-MS showed that the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure, dissolved in water (10 mL), and then 1N HCl solution was added dropwise to adjust the pH to 4-5 until a white precipitate formed. The white solid was filtered, washed with water (10 mL), and then dried in vacuo to give compound C53 (25 mg, white solid, yield: 42%). 1 HNMR(400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.83 (d, J = 7.6 Hz,1H), 7.37 - 7.24 (m, 8H), 7.14 (t, J = 7.2 Hz, 3H), 7.04 - 6.97 (m, 5H), 6.69(d, J = 7.2 Hz, 1H), 4.63 (s, 1H), 4.21 (d, J = 13.2 Hz, 1H), 3.71 - 3.63 (m,2H), 2.91 - 2.80 (m, 3H). MS m / z (ESI): 561.8[M+H] + .

[0263] Example 8: Preparation of (S)-4-(diphenylaminomethyl)-1-(10-methyl-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine-5-carbonyl)piperazine-2-carboxylic acid (C96) [ka]

[0264] Step 1: Compound C53-4 (100 mg, 0.48 mmol) was dissolved in anhydrous DMF (10 mL). After the temperature was lowered to 0 °C, NaH (19 mg, 0.48 mmol) was added and stirred for 0.5 hours. Iodomethane (68 mg, 0.48 mmol) was added to the reaction solution, and the mixture was allowed to react at room temperature for 1 hour. LC-MS showed that the reaction of the starting material was complete. The reaction was quenched by adding ice water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed twice with saturated brine (20 mL), and then dried over anhydrous sodium sulfate (5 g) for 30 minutes, filtered, and concentrated. The resulting crude product was separated by column chromatography (ethyl acetate:petroleum ether = 1:1) to give compound C96-1 (80 mg, pale yellow solid, yield: 74.7%). 1 HNMR(400 MHz, CDCl3) δ 7.90 (s, 1H), 7.64 (d, J= 7.6 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 7.29 - 7.27 (m, 1H), 7.14 - 7.05 (m,4H), 6.94 (t, J = 7.6 Hz, 1H), 3.37 (s, 3H). MS m / z (ESI): 225.0 [M+H] + .

[0265] Step 2: Compound C96-1 (80 mg, 0.36 mmol) and pyridine (1.8 g, 18 mmol) were dissolved in 1,2-dichloroethane (10 mL), and triphosgene (106 mg, 0.36 mmol) was added portionwise at 0 °C. The reaction solution was reacted at room temperature for 16 hours. LC-MS showed that the reaction of the starting material was essentially complete. DCM (20 mL) was added. The reaction solution was then washed with saturated brine (20 mL × 2), dried by adding anhydrous sodium sulfate (10 g) for 30 minutes, filtered, and concentrated under reduced pressure to give crude compound C96-2 (100 mg, pale red solid, yield: 97%). MS m / z (ESI): 287.0 [M+H] + .

[0266] Step 3: Compound C1-2 (80 mg, 0.35 mmol) was dissolved in anhydrous dichloromethane (20 mL). After the temperature was lowered to 0-5°C, triethylamine (106 mg, 1.05 mmol) and C96-2 (100 mg, 0.35 mmol) were added sequentially. The reaction solution was reacted at room temperature for 16 hours. LC-MS showed that the reaction of the starting material was complete. The reaction was quenched by adding water (30 mL) and extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), and then dried over anhydrous sodium sulfate (10 g) for 30 minutes, filtered, and concentrated to give compound C96-3 (140 mg, pale yellow solid, yield: 83%). MS m / z (ESI): 425.0 [M-56+H] + .

[0267] Step 4: Compound C96-3 (140 mg, 0.29 mmol) was dissolved in anhydrous methanol (5 mL). After the temperature was lowered to 0-5°C, SOCl2 (0.5 mL) was added dropwise. The reaction solution was reacted at 50°C for 16 hours. LC-MS showed that the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure, followed by the addition of saturated aqueous sodium bicarbonate solution (10 mL). It was then extracted with ethyl acetate (20 mL x 3), washed with saturated brine (30 mL x 2), and then dried over anhydrous sodium sulfate (10 g) for 30 minutes. It was then filtered and concentrated. The crude product was separated by preparative plate chromatography (dichloromethane:methanol = 20:1) to give compound C96-4 (60 mg, pale yellow solid, yield: 52%). MS m / z (ESI): 395.0 [M+H] + .

[0268] Step 5: Compound C96-4 (60 mg, 0.15 mmol) was dissolved in anhydrous dichloromethane (10 mL). After the temperature was lowered to 0-5 °C, triethylamine (46 mg, 0.26 mmol) and SM2 (35 mg, 0.15 mmol) were added sequentially. The reaction solution was reacted at 35 °C for 16 hours. LC-MS showed that the reaction of the starting material was complete. The reaction was quenched by adding water (10 mL) and extracted with dichloromethane (20 mL × 2). The combined organic phases were washed twice with saturated brine (30 mL), then dried over anhydrous sodium sulfate (10 g) for 30 minutes, filtered, and concentrated. The resulting crude product was separated by silica gel preparative thin-layer chromatography (ethyl acetate:petroleum ether = 1:1) to give compound C96-5 (50 mg, pale yellow solid, yield: 55%). MS m / z (ESI): 589.0 [M+H] + .

[0269] Step 6: Compound C96-5 (50 mg, 0.085 mmol) was dissolved in anhydrous methanol (5 mL) and water (2 mL), and sodium hydroxide (40 mg, 1 mmol) was added. The reaction solution was allowed to react at room temperature for 16 hours. LC-MS showed that the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure, dissolved in water (10 mL), and then 1N HCl solution was added dropwise to adjust the pH to 4-5 until a white precipitate formed. The white solid was then filtered, washed with water (10 mL), and dried in vacuo to give compound C96 (35 mg, white solid, yield: 71%). 1HNMR(400 MHz, DMSO-d6) δ 13.26 (s, 1H), 7.67 - 7.62 (m,2H), 7.58 - 7.46 (m, 3H), 7.33 - 7.28 (m, 6H), 7.24 - 7.20 (m, 2H), 7.13 (t, J= 7.2 Hz, 2H), 6.90 (d, J = 7.6 Hz, 4H), 4.29 (d, J = 26.4 Hz, 1H), 4.00 (d, J= 13.2 Hz, 1H), 3.47 (s, 3H), 3.43 (s, 1H), 3.12 - 3.05 (m, 1H), 2.87 - 2.77(m, 2H), 2.63 - 2.60 (m, 1H). MS m / z (ESI): 576.0 [M+H] + .

[0270] The compounds in Table 5 were prepared by methods similar to those described in Example 8.

[0271] [Table 7] TIFF0007814359000196.tif78149

[0272] Example 9: Preparation of (S)-4-(5H-dibenzo[b,f]azepine-5-carbonyl)-N,N-diphenyl-3-(1H-tetrazol-5-yl)piperazine-1-carboxamide (C31) [ka]

[0273] Step 1: Compound C2-1 (550 mg, 1.22 mmol) and triethylamine (247 mg, 2.44 mmol) were dissolved in tetrahydrofuran (20 mL), and butyl chloroformate (183 mg, 1.34 mmol) was added at 0 °C. The reaction solution was reacted at 0 °C for 0.5 hours. Aqueous ammonia (1 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction of the starting material was essentially complete. After adding ethyl acetate (30 mL), the reaction solution was washed with saturated brine (30 mL × 3), dried by adding anhydrous sodium sulfate (20 g) for 30 minutes, and then filtered and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain compound C31-1 (500 mg, yellow oil, yield: 91%). MS m / z (ESI): 448.7 [M+H] + .

[0274] Step 2: Compound C31-1 (450 mg, 1 mmol) and triethylamine (202 mg, 2 mmol) were dissolved in anhydrous dichloromethane (20 mL). After the temperature was lowered to 0-5 °C, trifluoroacetic anhydride (231 mg, 1.1 mmol) was slowly added. The reaction solution was reacted at room temperature for 16 hours. LC-MS showed that the reaction of the starting material was complete. The reaction was quenched by adding water (20 mL) and extracted with dichloromethane (20 mL × 2). The organic phases were combined, washed three times with saturated brine (30 mL), dried over anhydrous sodium sulfate (10 g) for 30 minutes, then filtered and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain compound C31-2 (400 mg, yellow solid, yield: 92%). 1H NMR(400 MHz, CDCl3) δ 7.49 (brs, 2H), 7.43(brs, 2H), 7.36 - 7.26 (m, 4H), 6.98 (s, 2H), 4.89 (s, 1H), 4.21 (m, 1H), 3.86- 3.78 (m, 1H), 3.15 (d, J = 13.2 Hz, 1H), 2.97 (m, 1H), 2.78 (m, 1H), 2.33 (m,1H), 1.43 (s, 9H). MS m / z (ESI): 430.7 [M+H] + .

[0275] Step 3: Compound C31-2 (300 mg, 0.7 mmol) was dissolved in anhydrous dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was slowly added at room temperature. The reaction solution was allowed to react at room temperature for 16 hours. LC-MS showed that the reaction of the starting material was complete. The reaction solution was concentrated to dryness, followed by the addition of saturated aqueous sodium bicarbonate (10 mL) and extraction with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 2), and then dried over anhydrous sodium sulfate (10 g) for 30 minutes, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (dichloromethane:methanol = 20:1) to obtain compound C31-3 (240 mg, pale yellow solid, yield: 99%). MS m / z (ESI): 348.8 [M+H] + .

[0276] Step 4: Compound 31-3 (240 mg, 0.69 mmol) and triethylamine (139 mg, 1.38 mmol) were dissolved in dichloromethane (20 mL), and SM2 (159 mg, 0.69 mmol) was added at room temperature. The reaction solution was reacted at 30 °C for 16 hours. LC-MS showed that the reaction of the starting material was essentially complete. Dichloromethane (20 mL) was added to the reaction solution, which was then washed with saturated brine (20 mL × 3). The organic phase was dried by adding anhydrous sodium sulfate (10 g) for 30 minutes, then filtered and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (dichloromethane:ethyl acetate = 2:1) to obtain compound C31-4 (200 mg, yellow oil, yield: 53%). MS m / z (ESI): 544.0 [M+H] + .

[0277] Step 5: Compound 31-4 (180 mg, 0.33 mmol) and triethylamine (100 mg, 1 mmol) were dissolved in anhydrous dichloromethane (20 mL). After the temperature was lowered to 0-5 °C, trifluoroacetic anhydride (77 mg, 0.36 mmol) was slowly added. The reaction solution was allowed to react at room temperature for 16 hours. LC-MS showed that the reaction of the starting material was complete. The reaction was quenched by adding water (100 mL) and extracted with dichloromethane (20 mL × 2). The combined organic phases were washed three times with saturated brine (20 mL), then dried over anhydrous sodium sulfate (10 g) for 30 minutes, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (ethyl acetate:dichloromethane = 1:3) to obtain compound C31-5 (160 mg, yellow solid, yield: 91%). MS m / z (ESI): 525.8 [M+H] + .

[0278] Step 6: Compound C31-5 (100 mg, 0.19 mmol), sodium azide (15 mg, 0.28 mmol), lithium chloride (8 mg, 0.19 mmol), and ammonium chloride (18 mg, 0.28 mmol) were dissolved in anhydrous DMF (3 mL). The reaction solution was reacted at 120 °C for 16 hours. LC-MS showed that the reaction of the starting material was complete. The reaction was quenched by adding water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed three times with saturated brine (30 mL), then dried over anhydrous sodium sulfate (10 g) for 30 minutes, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance liquid chromatography (acetonitrile-water (0.1% trifluoroacetic acid), gradient: 40% to 70%) to obtain compound C31 (45 mg, white solid, yield: 42%). 1 H NMR(400 MHz, DMSO-d6) δ 7.67 (brs, 1H), 7.49 (brs, 1H),7.41 - 7.35 (m, 4H), 7.30 - 7.16 (m, 6H), 7.11 - 7.01 (m, 4H), 6.71 (d, J = 7.6Hz, 4H), 5.25 (s, 1H), 4.10 (d, J = 12.8 Hz, 1H), 3.16 - 3.05 (m, 2H), 2.93 (d,J = 12.4 Hz, 1H), 2.65 - 2.62 (m, 1H), 2.36 (s, 1H). MS m / z (ESI): 568.8 [M+H] + .

[0279] Example 10: Preparation of (S)-4-(10-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carbonyl)-N,N-diphenyl-3-(1H-tetrazol-5-yl)piperazine-1-carboxamide (C104) [ka]

[0280] Step 1: Compound C50 (160 mg, 0.28 mmol) and triethylamine (56 mg, 0.56 mmol) were dissolved in tetrahydrofuran (10 mL), and butyl chloroformate (45 mg, 0.33 mmol) was added at 0° C. The reaction solution was reacted at 0° C. for 30 minutes. Aqueous ammonia (1 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction of the starting material was essentially complete. After adding ethyl acetate (40 mL), the reaction solution was washed with saturated brine (30 mL × 3) and then dried by adding anhydrous sodium sulfate (20 g) for 30 minutes. The mixture was then filtered and concentrated under reduced pressure to obtain crude compound C104-1 (150 mg, pale yellow solid, yield: 94%). MS m / z (ESI): 574.1[M+H] + .

[0281] Step 2: Compound 104-1 (150 mg, 0.26 mmol) and triethylamine (79 mg, 0.78 mmol) were dissolved in anhydrous dichloromethane (20 mL). After the temperature was lowered to 0-5 °C, trifluoroacetic anhydride (231 mg, 1.1 mmol) was slowly added. The reaction solution was reacted at room temperature for 16 hours. LC-MS showed that the reaction of the starting material was complete. The reaction was quenched by adding water (20 mL) and extracted with dichloromethane (20 mL × 2). The organic phases were combined, washed three times with saturated brine (30 mL), dried over anhydrous sodium sulfate (10 g) for 30 minutes, then filtered and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (ethyl acetate:petroleum ether = 1:1) to obtain compound C104-2 (140 mg, pale yellow solid, yield: 96%). MS m / z (ESI): 556.2 [M+H] + .

[0282] Step 3: Compound C104-2 (140 mg, 0.25 mmol), sodium azide (20 mg, 0.38 mmol), lithium chloride (12 mg, 0.28 mmol), and ammonium chloride (18 mg, 0.28 mmol) were dissolved in anhydrous DMF (5 mL). The reaction solution was reacted at 120 °C for 16 hours. LC-MS showed that the reaction of the starting material was complete. The reaction was quenched by adding water (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate (10 g) for 30 minutes, and then filtered and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain compound C104-3 (100 mg, pale yellow solid, yield: 67%). MS m / z (ESI): 599.2 [M+H] + .

[0283] Step 4: Compound C104-3 (90 mg, 0.15 mmol) was dissolved in anhydrous methanol (20 mL). After the temperature was lowered to 0-5°C, SOCl2 (3 mL) was added dropwise. The reaction solution was reacted at 70°C for 48 hours. LC-MS showed that the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure and dried by rotary evaporation, followed by the addition of ethyl acetate (60 mL). This was washed with saturated brine (50 mL × 2), then dried over anhydrous sodium sulfate (10 g) for 30 minutes, filtered, and concentrated. The crude product was separated by high-performance liquid chromatography (acetonitrile-water (0.1% trifluoroacetic acid), gradient: 40%-80%) to give compound C104 (20 mg, white solid, yield: 22.7%). 1H NMR(400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.07 - 8.01 (m,1H), 7.95 (d, J = 7.6 Hz, 1H), 7.77 (s, 1H), 7.67 - 7.58 (m, 2H), 7.45 - 7.18(m, 9H), 7.15 - 7.07 (m, 2H), 6.78 - 6.68 (m, 4H), 5.53 (s, 1H), 4.22 - 4.19(m, 1H), 3.63 - 3.49 (m, 2H), 3.03 - 2.86 (m, 2H), 2.59 (m, 1H). MS m / z (ESI): 585.2 [M+H] + .

[0284] Example 11: Preparation of (S)-1-(10,11-dioxo-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carbonyl)-4-(diphenylcarbamoyl)piperazine-2-carboxylic acid (C116) [ka]

[0285] Step 1: Compound C77-5 (90 mg, 0.15 mmol) and selenium dioxide (352 mg, 0.31 mmol) were dissolved in dioxane (20 mL), and the reaction solution was then reacted at 100 °C for 16 hours. LC-MS showed that the reaction of the starting material was essentially complete. Ethyl acetate (30 mL) was added to the reaction solution, which was then washed with saturated brine (40 mL × 2). The organic phase was then dried by adding anhydrous sodium sulfate (10 g) for 30 minutes, and then filtered and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel preparative thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain crude compound C116-1 (80 mg, yellow solid, yield: 87%). MS m / z (ESI): 589.1 [M+H] + .

[0286] Step 2: Compound C116-1 (80 mg, 0.13 mmol) was dissolved in anhydrous methanol (10 mL) and water (2 mL), and sodium hydroxide (52 mg, 1.3 mmol) was added. The reaction solution was allowed to react at room temperature for 16 hours. LC-MS showed the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure and dissolved by adding water (10 mL). It was then adjusted to pH 4-5 by adding 1N HCl solution, and then extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed twice with saturated brine (30 mL), and then dried over anhydrous sodium sulfate (10 g) for 30 minutes, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by high-performance liquid chromatography (acetonitrile-water (0.1% trifluoroacetic acid), gradient: 30%-50%) to obtain compound C116 (30 mg, yellow solid, yield: 38%). 1 H NMR(400 MHz, CD3OD) δ 8.45 (s, 1H), 7.92 - 7.83(m, 1H), 7.55 - 7.46 (m, 2H), 7.42 - 7.32 (m, 6H), 7.19 (t, J = 7.2 Hz, 2H),7.13 (t, J = 6.8Hz, 2H), 7.08 - 7.03 (m, 4H), 5.23 (s, 1H), 4.52 (d, J = 13.6Hz, 1H), 3.74 - 3.64 (m, 2H), 3.16 - 3.05 (m, 1H), 2.95 - 2.73 (m, 2H). MS m / z (ESI): 574.6 [M+H] + .

[0287] Biological assays

[0288] Experimental Example 1: Measurement of inhibitory activity against AT1 receptor (AT1R) / AT2 receptor (AT2R) The inhibitory activity (IC) of compounds against AT1R / AT2R was measured through the following steps: 50 values) were determined: 1) Prepare an appropriate amount of 1X TLB (Tag-lite buffer) and mix thoroughly for use. 2) Compounds were diluted 10-fold in ddH2O or DMSO. Compounds were then diluted to 4x the working concentration in 1X TLB and mixed well for use. 3) 8600 nM Tag-lite angiotensin receptor red agonist was diluted to 12 nM (4X Kd) in 1X TLB. 4) 5 ml of 1X TLB was placed in a 15 ml centrifuge tube. 5) After thawing one tube of Tb-labeled AT1R / AT2R cells in a 37°C water bath, the cells were quickly transferred to the 1X TLB from step 4), mixed gently, and centrifuged at 1200g for 5 minutes at room temperature. 6) The supernatant was gently aspirated and the cells were resuspended and mixed in 2.7 ml 1× TLB, then left at room temperature until use. 7) 10 μl of cells were added to all test wells, and 5 μl of the 4X working solution of compound from step 2) was added to the corresponding test wells. 5 μl of 4X Tag-lite Angiotensin Receptor Red Agonist, fully diluted in step 3), was added to all test wells. 8) After leaving the reaction plate at room temperature for 1 hour, the data were measured and analyzed using an Envision HTRF Reader. The half-maximal inhibitory concentration (IC) of the compound against AT1R / AT2R was calculated using a GraphPad Prism 4-parameter equation. 50 ) was calculated. Measured IC of compounds 50 The values ​​are shown in Table 6 below.

[0289] [Table 8] TIFF0007814359000201.tif138149

[0290] Experimental Example 2. Pharmacokinetic (PK) study in mice Male ICR mice were intravenously (IV) and intragastrically (PO) administered a solution of Compound C2 (1 mg / mL) of the present invention and a solution of the control Compound A (1 mg / mL), both in a vehicle system of DMSO, solutol, and deionized water (1:2:17, v:v:v). The IV and PO doses for Compound C2 and Compound A were 3 mg / kg and 20 mg / kg, respectively. For IV administration, blood was collected from the ophthalmic venous plexus of the mice at time 0 before administration and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. For PO administration, blood was collected from the ophthalmic venous plexus of the mice at time 0 before administration and 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. For Compound C2, 0.05 mL blood samples were collected at each time point, and for Compound A, 0.03 mL blood samples were collected at each time point. The collected blood samples were placed in clean sample tubes containing EDTA-K2 (4%) and centrifuged at 5000 rpm for 5 minutes at 4°C. The resulting plasma was transferred to another clean sample tube and stored at -20°C. LC-MS / MS analysis was performed on the plasma samples. Pharmacokinetic parameters were calculated using WinNonlin 6.3 software. The results are shown in Table 7. [ka]

[0291] [Table 9]

[0292] Various modifications of the present invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. Each reference, including all patents, applications, journal articles, books, and any other disclosures, referred to herein is hereby incorporated by reference in its entirety.

Claims

1. Structure of formula (I'): 【Chemistry 1】 (In the formula, X １ and X ２ are each independently, CR １０ or N; R １ａ and R １ｂ are each independently phenyl, and R １ａ The available ring atoms of R １ａ and R １ｂ However, these are bonded to X １ together with an optionally substituted partially unsaturated fused ring system Q containing three rings １ R via the Y group so as to form １ｂ is connected to an available ring atom of R ２ａ is C １～８ Alkyl, C ２～８ Alkenyl and C ２～８ Alkynyl (wherein C １～８ Alkyl, C ２～８ Alkenyl and C ２～８ Alkynyl CH ２ any one of the moieties is optionally replaced with O or S); saturated or partially unsaturated C ３～１０ Cyclic hydrocarbyl groups; saturated or partially unsaturated 3- to 10-membered heterocyclic groups; C ６～１０ Aryl; 5- to 14-membered heteroaryl; —C １～６ Alkylene - saturated or partially unsaturated C ３～１０ cyclic hydrocarbyl group, —C １～６ alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; １～６ Alkylene-C ６～１０ aryl; and -C １～６ selected from the group consisting of alkylene-(5- to 14-membered heteroaryl); R ２ｂ is C １～８ Alkyl, C ２～８ Alkenyl and C ２～８ Alkynyl (wherein C １～８ Alkyl, C ２～８ Alkenyl and C ２～８ Alkynyl CH ２ any one of the moieties is optionally replaced with O or S); saturated or partially unsaturated C ３～１０ Cyclic hydrocarbyl groups; saturated or partially unsaturated 3- to 10-membered heterocyclic groups; C ６～１０ Aryl; 5- to 14-membered heteroaryl; —C １～６ Alkylene - saturated or partially unsaturated C ３～１０ cyclic hydrocarbyl group, —C １～６ alkylene - saturated or partially unsaturated 3- to 10-membered heterocyclic group; １～６ Alkylene-C ６～１０ aryl; and -C １～６ selected from the group consisting of alkylene-(5- to 14-membered heteroaryl); The R ２ａ and R ２ｂ The alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbyl group, heterocyclic group, aryl, and heteroaryl in each occurrence may each optionally be one, two, three, or more R １３ and R １３ is, in each occurrence, a halogen, C １～６ Alkyl and -OR １１ (R １１ is H or C １～６ alkyl); Y is a single bond; C １～３ Alkylene (wherein one CH ２ The moiety is O, S or NR １０ and C ２～３ alkenylene, wherein any one of the CH moieties forming the C═C double bond is optionally replaced with N; １～３ Alkylene and C ２～３ Each alkenylene is optionally selected from halogen, OH, —NR １１ R １２ , cyano, nitro, C １～６ Alkyl, C １～６ substituted with one, two, three or more groups selected from the group consisting of alkyl-O-, epoxy and oxo; X ３ and X ４ are each independently C(=O); R ３ is a 5- to 6-membered heteroaryl, —C(═O)OR １１ , —C(═O)NR １１ S (= O) ｙ NR １１ R １２ and —C(═O)NR １１ S (= O) ｙ R １２ selected from the group consisting of: R ４ is H; R １０ is H and C １～６ selected from the group consisting of alkyl; R １１ and R １２ is, in each occurrence, independently H and C １～６ selected from the group consisting of alkyl; y, in each occurrence, is independently 2. or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof.

2. R ２ａ and R ２ｂ are each independently, C １～８ alkyl, phenyl, and 8- to 10-membered benzo-fused heterocyclic groups, １～８ The alkyl, phenyl, and 8- to 10-membered benzo-fused heterocyclic groups each optionally have one, two, or three R １３ 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof, wherein:

3. The R ２ａ and R ２ｂ C in １～８ alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-hexyl, 1-heptyl, and 1-octyl; and / or ２ａ and R ２ｂ The 8- to 10-membered benzo-fused heterocyclic group in 【Chemistry 2】 3. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof, selected from the group consisting of:

4. R ２ａ and R ２ｂ each independently represents methyl, ethyl, n-propyl, n-pentyl, phenyl, 【Transformation 3】 3. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof, selected from the group consisting of:

5. The fused ring system Q １ has the structure of formula (1): 【Chemistry 4】 is a group having (In the formula, R ５ａ and R ５ｂ is, in each occurrence, independently R １０ and R ７ does not exist or R １０ and X １ , R １０ and Y is as defined in any one of claims 1 to 4; m and n are each independently 0; 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof.

6. Y is a single bond; NR １０ ; O; S; and halogen, OH, —NR １１ R １２ , cyano, nitro, C １～６ Alkyl, C １～６ methylene, ethylene, —CH optionally substituted with one, two, three or more groups selected from the group consisting of alkyl-O—, epoxy and oxo; ２ —O—, —O—CH ２ -, -CH ２ -S-, -S-CH ２ -, -CH ２ -NR １０ -, -NR １０ -CH ２ 6. The compound of any one of claims 1 to 5, wherein each of the groups is independently selected from the group consisting of -, -CH=CH-, -CH=N-, or -N=CH-, or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotopically labeled compound thereof.

7. Y is NR １０ O; S; methylene and ethylene optionally substituted with one, two, three or more oxo groups; and —CH optionally substituted with one, two, three or more oxo groups. ２ —O—, —O—CH ２ -, -CH ２ -S-, -S-CH ２ -, -CH ２ -NR １０ -, -NR １０ -CH ２ 7. The compound of claim 6, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof, wherein the compound is selected from the group consisting of -, -CH=CH-, -CH=N-, or -N=CH-.

8. The group of formula (1) is 【Transformation 5】 【change】 having a structure selected from (In the formula, R ５ａ , R ５ｂ , R １０ , m and n, in each occurrence, are each independently as defined in claim 5; 6. The compound of claim 5, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof.

9. The group of formula (1) is 【Transformation 6】 having a structure selected from 6. The compound of claim 5, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof. 【Request Item 10】 【Chemistry 7】 (In the formula, The above R ２ａ , R ２ｂ , X １ , X ２ , R ３ , R ４ and Y, in each occurrence, are each independently as defined in any one of claims 1 to 7; The above R ５ａ , R ５ｂ , R ７ , m and n, in each occurrence, are each independently as defined in claim 5. having the structure 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof. 【Request Item 11】 【Chemistry 8】 (In the formula, f and g, in each occurrence, are each independently 0, 1, 2, or 3; C １～８ Alkyl, in each occurrence, may be one, two, or three R １３ is optionally replaced by The above R ２ａ , R ２ｂ , X １ , X ２ , R ３ , R ４ , R １３ and Y, in each occurrence, are each independently as defined in any one of claims 1 to 7; The above R ５ａ , R ５ｂ , R ７ , m and n, in each occurrence, are each independently as defined in claim 5. having the structure 11. The compound of claim 10, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof.

12. R ３ Tetrazolyl, COOH, 【Chemistry 9】 or 【Chemistry 10】 12. The compound of any one of claims 1 to 11, wherein:

13. 13. The compound of claim 12, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof, wherein said tetrazolyl is 5-tetrazolyl.

14. R １０ The compound of any one of claims 1 to 13, wherein is H, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof.

15. R １１ and R １２ In each occurrence, each independently represents H and C １～４ 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof, wherein the compound is selected from the group consisting of alkyl.

16. R １３ In each occurrence, F, Cl, Br, I, C １～４ Alkyl and —OC １～４ 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof, wherein each of the groups is independently selected from the group consisting of alkyl. 【Request Item 17】 【Table 1】 10. The compound of claim 1, having the structure: or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof. 【Request Item 18】 【Table 2】 or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof.

19. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof, and a pharmaceutically acceptable carrier.

20. Angiotensin II type 2 (AT ２ 20. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutical composition according to claim 19, in the manufacture of a medicament for use as ...

21. The drug is a selective AT ２ 21. The use according to claim 20, which is a medicament for use as a receptor inhibitor.

22. The drug is AT ２ The compounds are useful for the prevention or treatment of receptor-mediated disorders or symptoms associated therewith, such as cerebrovascular disorders (including cerebral vasospasm and cerebral ischemia); cognitive disorders (including amnesia, senile dementia, AIDS-related dementia and Down's syndrome); central nervous system diseases or disorders (including addictions such as alcoholism, anxiety, depression or dysthymic disorders, epilepsy, hyperkinesia, pain, Parkinson's disease, psychosis, sleep disorders, autonomic dysfunction and demyelinating diseases such as tardive dyskinesia, schizophrenia, multiple sclerosis and amyotrophic lateral sclerosis); respiratory diseases (including bronchospasm, asthma and chronic obstructive airway disease); neurological tumors; inflammatory diseases (including inflammatory bowel disease and osteoarthritis).

22. The use of claim 20 or 21, wherein the condition is selected from gastrointestinal (GI) diseases or disorders (including ulcerative colitis, Crohn's disease and incontinence); blood flow disorders caused by vasodilation; hypersensitivity disorders (including allergies such as eczema, rhinitis and contact dermatitis); vasospastic diseases (including angina, migraine and Raynaud's disease); fibrotic and collagen diseases (including scleroderma and eosinophilic fascioliasis); reflex sympathetic dystrophies (including shoulder / hand syndrome); stress-related physical disorders; peripheral neuropathy; neuralgia; autoimmune diseases (including systemic lupus erythematosus, rheumatoid arthritis, psoriasis and graft-versus-host disease); and rheumatic diseases (including fibromyalgia).

23. The drug is AT ２ The present invention is useful for the prevention or treatment of a receptor-mediated disorder or a condition associated therewith, wherein the disorder is Neuropathic conditions (primary and secondary neuropathies, e.g., peripheral neuropathy) or symptoms associated with the same, including hyperesthesia, hyperalgesia, allodynia, sudden burning pain, numbness, weakness, burning pain, tingling pain, and loss of reflexes; secondary neuropathies include diabetic neuropathy, shingles-associated neuropathy, uremia-associated neuropathy, amyloidosis neuropathy, HIV sensory neuropathy, hereditary motor and sensory neuropathy, hereditary sensory neuropathy, hereditary sensory and autonomic neuropathy, hereditary neuropathy with ulcerectomy, nitrofurantoin neuropathy, so These include sage-like neuropathies; neuropathies caused by nutritional deficiencies; neuropathies caused by renal failure and complex regional pain syndrome; neuropathies caused by repetitive activities (such as typing or assembly line work); peripheral neuropathies caused by antiretroviral drugs (such as zalcitabine and didanosine), antibiotics (such as metronidazole and isoniazid), gold compounds, chemotherapy drugs (such as vincristine), alcohol, lead, arsenic, mercury, and organophosphate pesticides; and peripheral neuropathies associated with infectious processes (such as Guillain-Barré syndrome). Conditions characterized by neuronal hypersensitivity, including hyperalgesic conditions such as fibromyalgia and irritable bowel syndrome; Disorders associated with abnormal nerve regeneration, including neuronal hypersensitivity, mastalgia, interstitial cystitis, vulvodynia, and cancer chemotherapy-induced neuropathy; Inflammatory pain that may be due to conditions characterized by inflammation (including burns such as chemical, friction or thermal burns; autoimmune diseases such as rheumatoid arthritis; inflammatory bowel diseases such as Crohn's disease and colitis; osteoarthritis, carditis, dermatitis, myositis, neuritis and collagen vascular disease); Nerve conduction velocity disorders that may be associated with the neuropathic conditions listed above (such as peripheral neuropathy), as well as carpal tunnel syndrome, ulnar neuropathy, Guillain-Barré syndrome, facioscapulohumeral muscular dystrophy, and herniated discs; Cell proliferative disorders, including cancer (including leukemia, melanoma, prostate cancer, breast cancer, ovarian cancer, basal cell carcinoma, squamous cell carcinoma, sarcoma, fibrosarcoma, colon cancer, and lung cancer); and non-cancerous proliferative disorders (including dermatological disorders such as warts, keloids, psoriasis, granulation disorders, and scar tissue reduction and cosmetic remodeling); Disorders associated with an imbalance between bone resorption and bone formation, including osteoporosis 22. The use according to claim 20 or 21, wherein the compound is selected from the group consisting of:

24. 24. The use according to claim 23, wherein the disorder is neuropathic pain.

25. AT for female patients who need it ２ Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopically labeled compound thereof, or a pharmaceutical composition according to claim 19, in the manufacture of a medicament for regulating receptor-related reproductive functions (including menstrual cycle, fertility and hormonal balance of the sexual cycle).

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