High-efficacy glucocorticoid compound, and preparation and use thereof

Abstract

The present invention provides a high-efficacy glucocorticoid compound, and a preparation method therefor and the use thereof. Specifically, the present invention provides a high-efficacy glucocorticoid compound as shown in formula I, and a preparation method therefor and the use thereof. The glucocorticoid compound of the present invention can achieve the same effect at a lower dose, thereby minimizing side effects.

Description

A high-potency glucocorticoid compound and its preparation and use Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a high-potency glucocorticoid compound, its preparation and use, and use of a composition containing the high-potency glucocorticoid compound. Background Art

[0002] Glucocorticoids such as prednisone, dexamethasone (DEX) and budesonide are highly effective anti-inflammatory drugs. They are widely used to treat inflammatory and autoimmune diseases such as rhinitis, asthma, chronic obstructive pulmonary disease, dermatitis, arthritis, lupus and Crohn's disease. These drugs exert their physiological effects by binding to the glucocorticoid receptor (GR), a transcription factor activated by a ligand of the nuclear receptor superfamily. In the absence of glucocorticoids, GR is present in the cytoplasm and binds to chaperone proteins such as hsp90 and hsp70. The binding of hormones causes a conformational change in GR, causing it to translocate to the nucleus, where it exerts its transcriptional control activity, i.e., activation (transcriptional activation) or inhibition (transcriptional inhibition). In transcriptional activation, GR dimerizes, directly binds to a specific glucocorticoid response element, and then recruits coactivators to activate transcription. In transcriptional inhibition, the general model is as follows: GR binds to other transcription factors (e.g., NF-KB, AP-1) to indirectly tether its binding site through protein-protein interactions. When tethered near target promoters, GR represses downstream gene expression. It is generally believed that transcriptional repression does not require GR dimerization.

[0003] Transcriptional inhibition is the main mechanism that glucocorticoid serves as anti-inflammatory drug.The tethering of GR and NF-KB / AP-1 promoter causes the transcriptional inhibition of major downstream proinflammatory factors, and these downstream proinflammatory factors include proinflammatory cytokines (for example, TNF-α, IL-1 and IL-6), chemokines (for example, CCL2, CCL19) and enzymes (for example, COX2, MMP13 and phosphatidylserine A2) relevant to inflammatory attack.Due to the rapid action and sustainable effect of glucocorticoid, it remains the first choice for treating inflammatory diseases.However, long-term use of glucocorticoid, especially high dose, has many adverse consequences, including diabetes / glucose intolerance, hypertension, obesity and osteoporosis.The major part in these consequences is due to the transcriptional activation of GR.For example, glucocorticoid induces the gene of the rate-limiting enzyme of glucose generation pathway in coding liver, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, thereby increases the de novo synthesis of glucose and finally causes weight gain or diabetes. Glucocorticoids also induce Dickkopf-1 (DKK1), a key regulator of bone development, whose upregulation leads to osteoporosis and bone loss. Many side effects of glucocorticoids are generally observed to be associated with the use of high doses of glucocorticoids (Hoes JN, et al. (2009) Adverse events of low-to-medium-dose oral glucocorticoids in inflammatory diseases: a meta-analysis. Ann Rheum Dis 68(12): 1833-1838; Spies CM, et al. (2011) Glucocorticoids. Best Pract Res Cl Rh 25(6): 891-900; Hoes JN, Jacobs JW, Buttgereit F, Bijlsma JW (2010) Current view of glucocorticoid co-therapy with DMARDs in rheumatoid arthritis. Nat Rev Rheumatol 6(12): 693-702.). For example, a "read-off pattern" has been observed with the use of prednisone: at 7.5 mg per day, it can cause glaucoma, depression, and hypertension.These side effects are caused by GR transcriptional activation as well as non-target activation of other receptors such as the mineralocorticoid receptor (MR), whose activation can cause hypertension (Frey FJ, Odermatt A, Frey BM (2004) Glucocorticoid-mediated mineralocorticoid receptor activation and hypertension. Curr Opin Nephrol Hypertens 13(4):451-458.). Therefore, it is important to develop highly potent and selective glucocorticoids to reduce unwanted side effects.

[0004] Potency and efficacy are two key pharmacokinetic parameters of glucocorticoids. While efficacy is the maximum activity achievable for a given drug, usually at the maximum concentration, potency is the concentration of a given drug required to achieve half-maximal activity (EC 50). For two glucocorticoids with the same efficacy, a high-potency glucocorticoid will require a lower dose to achieve the same therapeutic effect (Hoes JN, Jacobs JW, Buttgereit F, Bijlsma JW (2010) Current view of glucocorticoid co-therapy with DMARDs in rheumatoid arthritis. Nat Rev Rheumatol 6(12): 693-702; Frey FJ, Odermatt A, Frey BM (2004) Glucocorticoid-mediated mineralocorticoid receptor activation and hypertension. Curr Opin Nephrol Hypertens 13(4): 451-458.). Importantly, glucocorticoids may have different potencies for transcriptional activation and transcriptional repression; for example, gene induction of GR via DEX requires 5- to 6-fold higher glucocorticoid concentrations than gene repression. This differential reaction provides the opportunity to develop the following high-efficiency glucocorticoid, which can be used in low doses to achieve complete suppression of inflammatory signals with minimal transcriptional activation activity and side effects. Finally, the development of insensitivity and resistance to glucocorticoid therapy is a major problem in treating common inflammatory diseases such as chronic obstructive pulmonary disease, rheumatoid arthritis and inflammatory bowel disease. Glucocorticoid resistance is also an unsolved problem for leukocyte cancer, especially childhood acute leukemia. Several glucocorticoid resistance mechanisms have been identified or proposed, including changes in kinase pathways, changes in cofactors, and deletions or mutations of receptors. A common observation is that the affinity of ligands to receptors is reduced in glucocorticoid-resistant patients. This type of patient treated with high-efficiency glucocorticoids has been shown to improve, but the effect gradually decreases (Gaynon PS, Carrel AL (1999) Glucocorticosteroid therapy in childhood acute lymphoblastic leukemia. Adv Exp Med Biol 457:593-605).

[0005] Therefore, there is an urgent need to develop a new generation of glucocorticoids with higher potency. Summary of the Invention

[0006] To solve the above problems, the present application provides a high-potency glucocorticoid compound and its preparation method and use. The glucocorticoid compound of the present invention can achieve the same effect at a lower dose, thereby minimizing side effects.

[0007] In the first aspect of the present invention, there is provided a compound as shown in Formula I, or a pharmaceutically acceptable salt thereof,

[0008] Wherein, X is O or S;

[0009] is a single bond or a double bond;

[0010] R1 is selected from the group consisting of hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-12 Aryl, 5-15 membered heteroaryl, C 5-15 Aralkyl, heteroaralkyl, 3-10 membered heterocycloalkyl, 0, 1, 2 or 3 hydrogen atoms in each of the above groups are replaced by R a replace;

[0011] R2 is -LR', wherein L is a bond or -C(O)-, and R' is selected from the group consisting of hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-12 Aryl, 5-15 membered heteroaryl, C 5-15 Aralkyl, heteroaralkyl, 3-10 membered heterocycloalkyl, 0, 1, 2 or 3 hydrogen atoms in the above groups are replaced by R b replace;

[0012] R3 is selected from the group consisting of hydrogen, C 1-6 Alkyl, the above C 1-6 0, 1, 2 or 3 hydrogen atoms in the alkyl group are replaced by R c replace;

[0013] R4 and R5 are each independently selected from the group consisting of hydrogen, halogen, C 1-4 Alkyl; the above C 1-4 0, 1, 2 or 3 hydrogen atoms in the alkyl group are replaced by R d replace;

[0014] The R a 、R b 、R c 、R d Each independently selected from the group consisting of hydroxy, halogen, CN, oxo, carboxyl, amino, sulfonic acid, C 1-6 Alkyl, C 1-6 Alkoxy.

[0015] In a preferred embodiment, the R1 is selected from the following group: hydrogen, C 1-6 Alkyl; the above C 1-6 0, 1, 2 or 3 hydrogen atoms in the alkyl group are replaced by halogen atoms;

[0016] Preferably, R1 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, wherein 0, 1, 2, or 3 hydrogen atoms in the above groups are replaced by halogen atoms;

[0017] More preferably, the R1 is fluoromethyl.

[0018] In a preferred embodiment, the R1 is selected from the following group: C 3-7 Cycloalkyl, C 6-10 Aryl, phenyl, naphthyl, 1, 2 or 3 hydrogen atoms in the above groups are replaced by R a replace.

[0019] In a preferred embodiment, the R2 is -C(O)-R', and R' is selected from the following group: hydrogen, C 1-6 Alkyl, C 6-10 Aryl (C 1-6 alkyl), 5- to 15-membered heteroaryl, 5- to 15-membered heteroaryl (C 1-6 alkyl), wherein 0, 1, 2 or 3 hydrogen atoms are replaced by R b substituted, and the R b Selected from the group consisting of halogen, CN, carboxyl, and oxo;

[0020] Preferably, said R2 is selected from the following group:

[0021] In a preferred embodiment, the R3 is selected from the following group: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and 1, 2 or 3 hydrogen atoms in the above groups are replaced by R c replace.

[0022] In a preferred embodiment, R4 and R5 are each independently -F.

[0023] In a preferred embodiment, it is characterized in that the compound of formula I is selected from the following group:

[0024] The second aspect of the present invention provides a pharmaceutical composition comprising: (i) the compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier or adjuvant.

[0025] The third aspect of the present invention provides a method for regulating the activity of a glucocorticoid receptor in a biological sample, comprising the following steps: contacting the glucocorticoid receptor in the biological product with the compound or pharmaceutically acceptable salt thereof as described in the first aspect of the present invention, or the pharmaceutical composition as described in the second aspect of the present invention.

[0026] The fourth aspect of the present invention provides a use of the compound or pharmaceutically acceptable salt thereof according to the first aspect of the present invention, or the pharmaceutical composition according to the second aspect of the present invention, in the preparation of a medicament for alleviating or treating inflammatory diseases;

[0027] Preferably, the disease is selected from the group consisting of rhinitis, asthma, chronic obstructive pulmonary disease, dermatitis, arthritis, lupus, Crohn's disease, inflammatory bowel disease, celiac disease, glomerulonephritis, acne vulgaris, leukemia, and pancreatic cancer.

[0028] The fifth aspect of the present invention provides a method for treating an inflammatory disease in a patient or reducing its severity, comprising the following steps: administering to the patient a safe and effective amount of the compound as described in the first aspect of the present invention or the pharmaceutical composition as described in the second aspect of the present invention.

[0029] In another preferred embodiment, the disease is rhinitis, asthma, chronic obstructive pulmonary disease, dermatitis or arthritis.

[0030] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] FIG1 shows the activity evaluation of the compounds of the present application binding to the glucocorticoid receptor.

[0032] Figure 2 shows the total cell number in BALF of asthma model animals after administration of the compound of the present application

[0033] FIG3 shows the number of eosinophils in BALF of asthma model animals after administration of the compound of the present application.

[0034] FIG4 shows the number of macrophages in BALF of asthma model animals after administration of the compound of the present application.

[0035] FIG5 shows the number of neutrophils in BALF of asthma model animals after administration of the compound of the present application.

[0036] FIG6 shows the number of lymphocytes in BALF of asthma model animals after administration of the compound of the present application. DETAILED DESCRIPTION

[0037] Glucocorticoids have been used for nearly 60 years, and they remain the first choice for treating many inflammatory and autoimmune diseases. However, long-term use of glucocorticoids can cause many adverse reactions. Therefore, the evolution of glucocorticoid drugs is driven by the need to reduce unwanted side effects while maintaining beneficial anti-inflammatory effects. Efficacy is a very important aspect of this evolution because many adverse side effects are associated with high doses. The administration of high-potency glucocorticoids can minimize side effects, and high-potency glucocorticoids can achieve the same therapeutic effect at lower doses. This demand has driven the evolution of glucocorticoids from low potency to high potency. Therefore, developing high-potency glucocorticoids to minimize side effects is a focus of attention.

[0038] After long and in-depth research and extensive screening, the inventors have developed for the first time a highly potent glucocorticoid compound that can achieve the same therapeutic effect at a lower dose, thereby minimizing side effects.

[0039] the term

[0040] For purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics 75th Edition. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausolito: 1999 and "March's Advanced Organic Chemistry", 5th Edition, eds.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0041] For the purposes of this invention, the carbon numbering of the compounds of Formula I follows the recognized convention for steroid structures. Thus, the compounds of Formula I are numbered as follows:

[0042] As described herein, compounds of the invention may be optionally substituted with one or more substituents such as are described generally above, or as exemplified by particular classes, subclasses, and species of the invention.

[0043] As used herein, the term "hydroxy" refers to an -OH moiety.

[0044] As used herein, the term "aliphatic" includes the terms alkyl, alkenyl, alkynyl, each of which is optionally substituted as described below.

[0045] As used herein, "alkyl" refers to a saturated aliphatic hydrocarbon group containing 1-12 (e.g., 1-8, 1-6, or 1-4) carbon atoms. The alkyl group can be straight-chain or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. The alkyl group may be substituted (i.e., optionally substituted) with one or more substituents such as halogen, phosphate, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amide [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphatic amino, cycloaliphatic amino, or heterocycloaliphatic amino], sulfonyl [e.g., aliphatic -SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, carboxyl, carbamoyl, cycloaliphatic oxy, heterocycloaliphatic oxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxyl. Without limitation, some examples of substituted alkyl groups include carboxyl, alkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-SO2-amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, or haloalkyl.

[0046] As used herein, "alkenyl" refers to an aliphatic carbonyl group containing 2-8 (e.g., 2-8, 2-6, or 2-4) carbon atoms and at least one double bond. Like alkyl groups, alkenyl groups can be straight or branched. Examples of alkenyl groups include, but are not limited to, allyl, 1- or 2-isopropenyl, 2-butenyl, and 2-hexenyl. The alkenyl group may be optionally substituted with one or more substituents such as halogen, phosphate, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amide [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino], alkyl] [e.g., alkyl-SO2-, cycloaliphatic-SO2-, or aryl-SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, carboxyl, carbamoyl, cycloaliphatic oxy, heterocycloaliphatic oxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxyl. Without limitation, some examples of substituted alkenyl groups include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, arylalkenyl, (alkoxyaryl)alkenyl, (sulfonylamino)alkenyl (such as (alkyl-SO2-amino)alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic)alkenyl, or haloalkenyl.

[0047] As used herein, "alkynyl" refers to an aliphatic carbon group containing 2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and having at least one triple bond. Alkynyl groups can be straight or branched. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl. Alkynyl groups may be optionally substituted with one or more substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxyl, cyano, halogen, hydroxyl, sulfo, mercapto, sulfanyl [e.g., aliphatic sulfanyl or cycloaliphatic sulfanyl], sulfinyl [e.g., aliphatic sulfinyl or cycloaliphatic sulfinyl], sulfonyl [e.g., aliphatic -SO2-, aliphatic amino-SO2-, or cycloaliphatic -SO2-], amide [e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylamino] [e.g., (cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl], amino [e.g., aliphatic amino], sulfoxy, oxo, carboxy, carbamoyl, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaryl)alkoxy.

[0048] As used herein, "acylamino" includes "aminocarbonyl" and "carbonylamino". When used alone or in conjunction with another group, these terms refer to acylamino groups, for example, when used at the end, it refers to -N(R X )-C(O)R y -C(O)-N(R X )2, and when used internally refers to -C(O)-N(R X )-or-N(R X )-C(O)-, where R X and R Y It can be hydrogen, aliphatic, cycloaliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl or heteroaraliphatic. Examples of acylamino groups include alkylacylamino (such as alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic)acylamino, (heteroaralkyl)acylamino, (heteroar)acylamino, (heterocycloalkyl)alkylacylamino, arylacylamino, aralkylacylamino, (cycloalkyl)alkylacylamino, or cycloalkylacylamino.

[0049] As used herein, "amino" refers to -NR X R Y , where R X and R YEach of the amino radicals is independently hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxyl, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or (heteroaraliphatic)carbonyl, each of which is as defined herein and is optionally substituted. Examples of amino groups include alkylamino, dialkylamino, or arylamino. When the term "amino" is not a terminal group (e.g., alkylcarbonylamino), it is represented by -NR X - indicates that R X has the same meaning as defined above.

[0050] As used herein, "aryl" used alone or as part of a larger moiety as in "aralkyl," "aralkyloxy," or "aryloxyalkyl" refers to monocyclic (e.g., phenyl) ring systems; bicyclic (e.g., indenyl, naphthyl, tetrahydronaphthyl, tetrahydroindenyl) ring systems; and tricyclic (e.g., fluorenyl, tetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systems, wherein the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring system is aromatic. Bicyclic and tricyclic groups include benzo-fused 2-3 membered carbocyclic rings. For example, benzo-fused groups include benzo-fused 2-3 membered carbocyclic rings with two or more C 4－8 A phenyl group fused to a carbocyclic moiety. Aryl is optionally substituted with one or more substituents including aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (aroaliphatic)oxy; (heteroaroaliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on the non-aromatic carbocyclic ring of the benzo-fused bicyclic or tricyclic aryl group); nitro; carboxyl; amide; acyl [e.g., For example, (aliphatic)carbonyl; (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (aromatic)carbonyl; (heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl; or (heteroaromatic)carbonyl]; sulfonyl [e.g., aliphatic -SO2- or amino-SO2-]; sulfinyl [e.g., aliphatic -S(O)- or cycloaliphatic -S(O)-]; sulfanyl [e.g., aliphatic -S-]; cyano; halogen; hydroxyl; mercapto; sulfoxyl; urea, thiourea; sulfamoyl; sulfonamide; or carbamoyl. Alternatively, the aryl group can be unsubstituted.

[0051] Non-limiting examples of substituted aryl groups include halogenaryl [e.g., mono-, di- (such as para-, meta-dihalogenaryl), and (trihalogenated)aryl]; (carboxy)aryl [e.g., (alkoxycarbonyl)aryl, ((aralkyl)carbonyloxy)aryl, and (alkoxycarbonyl)aryl]; (amido)aryl [e.g., (aminocarbonyl)aryl, (((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl]; aminoaryl [e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl]; (cyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl [ For example, (aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl; (hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl, ((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl; (((alkylsulfonyl)amino)alkyl)aryl; ((heterocycloaliphatic)carbonyl)aryl; ((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl; (hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl; p-amino-m-alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or (m-(heterocycloaliphatic)-o-(alkyl))aryl.

[0052] As used herein, "araliphatic," such as "aralkyl," refers to an aliphatic group (e.g., C1 －4 "Alkyl" and "aliphatic" are defined herein. An example of an aromatic aliphatic group such as an aralkyl group is benzyl.

[0053] As used herein, "aralkyl" refers to an alkyl group (e.g., C 1－4"alkyl" and "aryl" are both defined above. An example of an aralkyl group is benzyl. An aralkyl group is optionally substituted with one or more substituents such as an aliphatic group [e.g., an alkyl, alkenyl, or alkynyl group, including carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl], a cycloaliphatic group [e.g., a cycloalkyl or cycloalkenyl group], a (cycloalkyl)alkyl group, a heterocycloalkyl group, a (heterocycloalkyl)alkyl group, an aryl, a heteroaryl, an alkoxy group, a cycloalkyloxy group, a heterocycloalkyloxy group, an aryloxy group, a heteroaryloxy group, an aralkyloxy group, a heteroaralkyloxy group, an aroyl group, a heteroaroyl group, a nitro ... alkyl)carbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, or heteroaralkylcarbonylamino], cyano, halogen, hydroxy, acyl, thiol, alkylsulfanyl, thioxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, or carbamoyl.

[0054] As used herein, "bicyclic ring system" includes 6-12 (e.g., 8-12 or 9, 10 or 11) membered structures forming two rings, wherein the two rings have at least one common atom (e.g., 2 common atoms). Bicyclic ring systems include bicyclic aliphatic groups (e.g., bicyclic alkyl or bicycloalkenyl), bicyclic heteroaliphatic groups, bicyclic aryl groups, and bicyclic heteroaryl groups.

[0055] As used herein, "cycloaliphatic" groups include "cycloalkyl" and "cycloalkenyl," each of which is optionally substituted as described below.

[0056] As used herein, "cycloalkyl" refers to a saturated carbocyclic mono- or bi- (fused or bridged) ring of 3-10 (e.g., 5-10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cycloheptyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, bicyclo[2.2.2]octyl, adamantyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl.

[0057] As used herein, "cycloalkenyl" refers to a non-aromatic carbocyclic ring of 3 to 10 (e.g., 4 to 8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohex-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl.

[0058] The cycloalkyl or cycloalkenyl group may be optionally substituted with one or more substituents such as phosphate, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic) [e.g., (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, (aroaliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaroaliphatic)carbonyl], cyano, halogen, hydroxy, mercapto, sulfonyl [e.g., alkyl-SO2- and aryl-SO2-], sulfinyl [e.g., alkyl-S(O)-], sulfanyl [e.g., alkyl-S-], sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, or carbamoyl.

[0059] As used herein, the term "heterocycloaliphatic" includes heterocycloalkyl and heterocycloalkenyl, each of which is optionally substituted as described below.

[0060] As used herein, "heterocycloalkyl" refers to a 3-10 membered mono- or bicyclic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic) saturated ring structure in which one or more ring atoms is a heteroatom (e.g., N, O, S, or a combination thereof). Examples of heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, octahydrobenzofuranyl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyridinyl, decahydroquinolinyl, octahydrobenzo[b]thienyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. Monocyclic heterocycloalkyl groups may be fused with a phenyl moiety to form structures such as tetrahydroisoquinoline, which would be classified as heteroaryl groups.

[0061] As used herein, "heterocycloalkenyl" refers to a mono- or bicyclic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more ring atoms is a heteroatom (e.g., N, O, or S). Monocyclic and bicyclic heterocycloaliphatic groups are numbered according to standard chemical nomenclature.

[0062] The heterocycloalkyl or heterocycloalkenyl group may be optionally substituted with one or more substituents such as phosphate, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic)carbonylamino)] [e.g., (cycloaliphatic)aliphatic)carbonyl, (aroaliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaroaliphatic)carbonyl], nitro, cyano, halogen, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g., alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, or carbamoyl.

[0063] As used herein, "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms, wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or a combination thereof), and wherein the monocyclic ring system is aromatic, or at least one of the bicyclic or tricyclic ring systems is aromatic. Heteroaryl includes benzo-fused ring systems having 2 to 3 rings. For example, benzo-fused groups include benzo (e.g., indolizinyl, indolyl, isoindolyl, 3H-indolyl, dihydroindole, benzo[b]furanyl, benzo[b]thienyl, quinolinyl, or isoquinolinyl) fused to one or two 4- to 8-membered heterocyclic aliphatic moieties. Some examples of heteroaryl groups are azetidinyl, pyridinyl, 1H-indolyl, furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuranyl, isoquinolinyl, benzothiazolyl, xanthene, thioxanthene, phenothiazine, indoline, benzo[1,3]dioxole, benzo[b]furanyl, benzo[b]thienyl, indolyl, benzimidazolyl, benzothiazolyl, purinyl, cinnolinyl, quinolyl, quinazolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, isoquinolinyl, 4H-quinolizinyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridinyl.

[0064] Without limitation, monocyclic heteroaryl groups include furanyl, thienyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl, or 1,3,5-triazinyl. Monocyclic heteroaryl groups are numbered according to standard chemical nomenclature.

[0065] Without limitation, bicyclic heteroaryl groups include indolizinyl, indolyl, isoindolyl, 3H-indolyl, dihydroindolinyl, benzo[b]furanyl, benzo[b]thienyl, quinolinyl, isoquinolinyl, indolizinyl, isoindolyl, indolyl, benzo[b]furanyl, bexo[b]thienyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazoline, quinoxalinyl, 1,8-naphthyridinyl, or pteridinyl. Bicyclic heteroaryl groups are numbered according to standard chemical nomenclature.

[0066] The heteroaryl group is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (aroaliphatic)oxy; (heteroaroaliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl group); carboxyl; amide The heteroaryl group may be unsubstituted.

[0067] Non-limiting examples of substituted heteroaryl groups include (halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl]; (carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl]; cyanoheteroaryl; aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl and ((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e.g., aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl, (((heteroaryl)amino)carbonyl)heteroaryl, ((heterocycloaliphatic)carbonyl)heteroaryl, and ((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl; (alkoxy)heteroaryl; (aminosulfonyl)amino)heteroaryl; (alkyl)heteroaryl; ...

[0068] As used herein, "heteroaromatic aliphatic" (such as heteroaralkyl) refers to an aliphatic group (e.g., C 1-4 "Alkyl" and "heteroaryl" are defined above.

[0069] As used herein, "heteroaralkyl" refers to an alkyl group (e.g., C 1-4 "Alkyl" and "heteroaryl" are defined above. The heteroaralkyl group is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, thiol, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, or carbamoyl.

[0070] As used herein, "cyclic moiety" and "cyclic group" refer to mono-, bi- and tricyclic ring systems, including cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl groups, each of which has been previously defined.

[0071] As used herein, "bridged bicyclic ring system" refers to a bicyclic heterocyclic aliphatic ring system or a bicyclic cycloaliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantyl, norbornyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. The bridged bicyclic ring system can be optionally substituted with one or more substituents such as alkyl (including carbonylalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aralkyloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxyl, alkoxycarboxyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, thio, alkylsulfanyl, thiooxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, or carbamoyl.

[0072] As used herein, acyl refers to formyl or R X -C(O)- (such as alkyl-C(O)-, also known as alkylcarbonyl), where R X and alkyl have been defined above. Acetyl and pivaloyl are examples of acyl groups.

[0073] As used herein, "aroyl" or "heteroaroyl" refers to aryl-C(O)- or heteroaryl-C(O)-. The aryl and heteroaryl portions of the aroyl or heteroaroyl groups are optionally substituted as defined above.

[0074] As used herein, an "alkoxy" group refers to an alkyl-O- group, where "alkyl" has been previously defined.

[0075] As used herein, "carbamoyl" refers to a group having -O-CO-NR X R Y or -NR X -CO-OR Z A group of structure, where R X and R Y As defined above, R Z It may be an aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl or heteroaraliphatic group.

[0076] As used herein, "carboxyl" when used as a terminal group refers to -COOH, -COOR X ,-OC(O)H、-OC(O)R X ; or when used as an internal group refers to -OC(O) or -C(O)O-.

[0077] As used herein, a "haloaliphatic" group refers to an aliphatic group substituted with 1 to 3 halogens. For example, the term haloalkyl includes the groups -CF3, -CHF2, and -CH2F.

[0078] As used herein, "thio" refers to -SH.

[0079] As used herein, "sulfo" when used terminally refers to -SO3H or -SO3R X Or when used internally, it refers to -S(O)3-O.

[0080] As used herein, a "sulfonamide" group refers to -S(O)2-NR when used terminally. X R Y and when used as internal refers to -NRX-S(O)2-NR Y -, where R X R Y and R Z Already defined above.

[0081] As used herein, "sulfamoyl" refers to -OS(O)2-NR X R Y Structure, where R Y and R Y Already defined above.

[0082] As used herein, a "sulfonamide" group when used in conjunction with an endosmotic pump refers to -S(O)2-NR Y R Z or -NR X -S(O)2-R Z structure; or when used internally, -S(O)2-NR X -or-NR X -S(O)2-, where R X R Y and R Z is defined above.

[0083] As used herein, "sulfanyl" when used terminally refers to -SR X , and when used internally refers to -S-, where R X Examples of sulfanyl groups include aliphatic-S-, cycloaliphatic-S-, aryl-S-, and the like.

[0084] As used herein, "sulfinyl" when used terminally refers to -S(O)-R X , and when used internally refers to -S(O)-, where R X Exemplary sulfinyl groups include aliphatic-S(O)-, aryl-S(O)-, (cycloaliphatic(aliphatic))-S(O)-, cycloalkyl-S(O)-, heterocycloaliphatic-S(O)-, heteroaryl-S(O)-, and the like.

[0085] As used herein, "sulfonyl" when used terminally refers to -S(O)2-R X , and when used internally refers to -S(O)2-, where R X Exemplary sulfonyl groups include aliphatic-S(O)2-, aryl-S(O)2-, (cycloaliphatic(aliphatic))-S(O)2-, cycloaliphatic-S(O)2-, heterocycloaliphatic-S(O)2-, heteroaryl-S(O)2-, (cycloaliphatic(amido(aliphatic))-S(O)2-, and the like.

[0086] As used herein, "sulfonyloxy" when used terminally refers to -OS(O)-R X or -S(O)-R X , and when used internally refers to -OS(O) or -S(O)-O, where R X Already defined above.

[0087] As used herein, a "halogen" or "halo" group refers to fluoro, chloro, bromo, or iodo.

[0088] As used herein, "alkoxycarbonyl" encompassed by the term carboxy, used alone or in combination with another group, refers to a group such as alkoxy-OC(O)-.

[0089] As used herein, "alkoxyalkyl" refers to an alkyl group, such as alkyl-O-alkyl-, where alkyl is defined above.

[0090] As used herein, "carbonyl" refers to -C(O)-.

[0091] As used herein, "oxo" refers to =0.

[0092] As used herein, the term "phosphate group" refers to phosphite and phosphate. Examples of phosphite and phosphate include -P(O)(RP)2, where RP is aliphatic, alkoxy, aryloxy, heteroaryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxyaryl, heteroaryl, cycloaliphatic, or amino.

[0093] As used herein, aminoalkyl refers to (R X )2N-alkyl-structure.

[0094] As used herein, "cyanoalkyl" refers to a (NC)-alkyl- structure.

[0095] As used herein, "urea group" refers to -NR X -CO-NR X R Y structure, and "thiourea" when used at the terminal refers to -NR X CS-NR X R Y structure and when used internally refers to -NR X -CO-NR Y -or-NR X -CS-NR Y -, where R X R Y and R Z Already defined above.

[0096] As used herein, "guanidino" refers to -N=C(N(R X R Y ))N(R X R Y ) or -NR X -C(=NR X )NR X R Y Structure, where RX and R Y Defined above.

[0097] As used herein, the term "amidino" refers to a -C=(NR X )N(R X R Y ) structure where R X and R Y Already defined above.

[0098] As used herein, the term "plurality" refers to a positive integer of 2, 3, 4, 5 or more.

[0099] The terms "terminally" and "internally" refer to the position of a group within a substituent. A group is terminal when it is present at the end of a substituent without being further bonded to the rest of the chemical structure. X O(O)C-alkyl is an example of a carboxyl group used at a terminal end. When a group is present within a substituent in a chemical structure, the group is internal. Alkylcarboxyl (e.g., alkyl-C(O)O- or alkyl-OC(O)-) and alkylcarboxyaryl (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxyl groups used internally.

[0100] As used herein, "aliphatic chain" refers to a branched or straight-chain aliphatic group (e.g., an alkyl, alkenyl, or alkynyl group). In some embodiments, a straight-chain aliphatic chain has -[CH2] V -structure, wherein v is 1-12. In some embodiments, the branched aliphatic chain is a straight aliphatic chain substituted with one or more aliphatic groups. The branched aliphatic chain has -[CQQ] V ,—structure, wherein Q is independently hydrogen or an aliphatic group; however, in at least one embodiment, Q is an aliphatic group. The term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, wherein alkyl, alkenyl, and alkynyl are as defined above.

[0101] The phrase "optionally substituted" can be used interchangeably with the phrase "substituted or unsubstituted." As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as those specifically described above, or as exemplified by specific classes, subclasses, and species of the present invention. As described herein, the variables R1, R2, R3, R4, R5, and X, as well as other variables contained in the formulae described herein, encompass specific groups, such as alkyl and aryl. Unless otherwise noted, each specific group of these variables may be optionally substituted with one or more substituents described herein. Each substituent of a specific group is further optionally substituted with 1 to 3 halogen, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl, and alkyl. For example, an alkyl group may be substituted with an alkylsulfanyl group, and the alkylsulfanyl group may be optionally substituted with 1 to 3 halogen, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, heteroaryl, haloalkyl, and alkyl. As another example, the cycloalkyl portion of the (cycloalkyl)carbonylamino group can be optionally substituted with 1 to 3 halogens, cyano groups, alkoxy groups, hydroxyl groups, nitro groups, haloalkyl groups, and alkyl groups. When two alkoxy groups are bonded to the same atom or adjacent atoms, the two alkoxy groups can form a ring together with the one or more atoms to which they are bonded.

[0102] Typically, the term "substituted", whether or not preceded by the term "optionally", refers to the replacement of a hydrogen radical in a given structure with a given substituent. Specific substituent descriptions are provided in the above definitions and in the description of its compounds and examples below. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a particular group, the substituent may be the same or different at each position. Ring substituents, such as heterocycloalkyls, may be bonded to another ring (such as a cycloalkyl) to form a spiral-bicyclic ring system, for example, two rings share a common atom. As will be appreciated by those of ordinary skill in the art, the combination of substituents contemplated by the present invention is those that result in the formation of stable or chemically feasible compounds. Unless otherwise indicated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, (Z)(E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present invention.

[0103] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or by an enriched gas, are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. 13 C or 14 Such compounds are useful, for example, as analytical tools or probes in biological assays, or as therapeutic agents.

[0104] Active ingredient

[0105] As used herein, "a compound of the present invention" refers to a compound represented by Formula I or a pharmaceutically acceptable salt thereof.

[0106] in,

[0107] X is -O- or -S-;

[0108] --- is a key or does not exist;

[0109] R1 is selected from hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocycloalkyl, any of which is optionally substituted;

[0110] R2 is -LR'-, wherein L is a bond or -C(O)-, and R' is selected from hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocycloalkyl, wherein R' is optionally substituted;

[0111] R3 is hydrogen or optionally substituted C 1-6 alkyl;

[0112] R4 and R5 are each independently hydrogen, halogen, or C 1-4 alkyl.

[0113] In some embodiments, R1 is hydrogen, C 1-6 alkyl, cycloalkyl, or aryl, wherein the alkyl, cycloalkyl, or aryl is optionally substituted. For example, R 1 is alkyl, cycloalkyl, or aryl, any of which is optionally substituted with halogen.

[0114] In other embodiments, R1 is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1-3 halogens.

[0115] In some embodiments, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, any of which is optionally substituted with 1-3 halogens. For example, R1 is fluoromethyl.

[0116] In other embodiments, R1 is unsubstituted C 1-6 In some cases, R1 is alkyl. For example, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl. In some cases, R1 is ethyl. In some cases, R1 is isopropyl. In some cases, R1 is tert-butyl. In some cases, R1 is hydrogen.

[0117] In some embodiments, R1 is optionally substituted 3-7 membered cycloalkyl, phenyl, or naphthyl, any of which is optionally substituted.

[0118] In some embodiments, L is -C(O)-, and R' is hydrogen, C 1-6 Alkyl, aralkyl, heteroaryl, or heteroaralkyl, wherein R2 is optionally substituted by halogen, CN, carboxyl or oxo. For example, L is -C(O)-, and R2 is heteroaryl.

[0119] In other embodiments, R2 is

[0120] In some embodiments, R3 is optionally substituted C 1-6 For example, R3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, any of which is optionally substituted.

[0121] In other embodiments, R3 is hydrogen.

[0122] In some embodiments, X is -O-.

[0123] In some embodiments, X is -S-.

[0124] In some embodiments, --- is a bond.

[0125] In some embodiments, --- is not present.

[0126] In some embodiments, R4 and R5 are each independently hydrogen or halogen. For example, R4 and R5 are both F.

[0127] In some embodiments, the compound of Formula I is selected from the compounds in Table 1 below.

[0128] Table 1: Compounds of formula I.

[0129] Pharmaceutical composition

[0130] In one aspect of the present invention, pharmaceutically acceptable compositions, i.e., pharmaceutical compositions, are provided, wherein these compositions comprise any compound as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0131] It will also be understood that certain compounds of the present invention may be in free form for therapeutic use or, where appropriate, as pharmaceutically acceptable derivatives or prodrugs thereof. Pharmaceutically acceptable derivatives or prodrugs according to the present invention include, but are not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adducts or derivatives that, upon administration to a patient in need thereof, are capable of providing, directly or indirectly, a compound as further described herein or a metabolite or residue thereof.

[0132] As used herein, the term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, and commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salts" means any non-toxic salt or salt of an ester of a compound of the invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the invention or an inhibitory metabolite or residue thereof.

[0133] Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid) or by using other methods used in the art (such as ion exchange).

[0134] Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, edisulphonate (ethanedisulfonate), ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1-4 The present invention also contemplates quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water-soluble or oil-soluble or dispersible products can be obtained by such quaternization. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate.

[0135] As mentioned above, the pharmaceutically acceptable compositions of the present invention additionally comprise pharmaceutically acceptable carriers, adjuvants or vehicles, which, as used herein, include any and all solvents, diluents or other liquid vehicles suitable for the desired particular dosage form, dispersion or suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. Remington's Pharmaceutical Sciences, sixteenth edition, EW Martin (Mack Publishing Co., Easton, Pa, 1980) discloses various carriers for preparing pharmaceutically acceptable compositions and known techniques for their preparation. Unless any conventional carrier medium is incompatible with the compounds of this invention, for example, by producing any undesirable biological effect or otherwise interacting with one or more of any other components of the pharmaceutically acceptable compositions in a harmful manner, its use is contemplated within the scope of the present invention. Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, Cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, and phosphate buffered solutions, and other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring agents and perfuming agents, preservatives and antioxidants may also be present in the composition according to the judgment of the formulator.

[0136] Use and Administration of Compounds and Pharmaceutical Compositions

[0137] In another aspect, the present invention provides a method for treating or lessening the severity of inflammation in a subject, comprising administering to a subject, preferably a mammal, an effective amount of a composition comprising a compound of Formula I. The present invention also provides a method for treating or lessening the severity of an inflammatory disease in a subject, comprising administering to a subject, preferably a mammal, an effective amount of a composition comprising a compound of Formula I.

[0138] On the other hand, the present invention provides a method for treating a condition, disease or disorder involved in a glucocorticoid receptor or reducing its severity. In certain embodiments, the present invention provides a method for treating a condition, disease or disorder involved in a lack of glucocorticoid receptor activity, the method comprising administering an effective amount of a composition comprising a compound of Formula I to a subject in need, preferably a mammal. In certain embodiments, the present invention provides a method for treating an inflammatory condition, disease or disorder in a subject, wherein the subject has normal glucocorticoid receptor activity, the method administering an effective amount of a composition comprising a compound of Formula I to a subject in need, preferably a mammal.

[0139] In another aspect, the present invention provides a method for treating or lessening the severity of a condition, disease or disorder involving the glucocorticoid receptor, wherein the condition, disease or disorder is selected from rhinitis, asthma, chronic obstructive pulmonary disease, dermatitis, arthritis, lupus, Crohn's disease, inflammatory bowel disease, celiac disease, glomerulonephritis, acne vulgaris, leukemia and pancreatic cancer.

[0140] According to the present invention, an "effective amount" of the compound or pharmaceutically acceptable composition is an amount effective to treat or lessen the severity of one or more diseases, disorders or conditions as described above.

[0141] The compounds and compositions according to the methods of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the diseases, disorders, or conditions as described above.

[0142] The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the specific agent, its mode of administration, etc. The compounds of the present invention are preferably formulated in dosage unit form to facilitate administration and uniformity of the dosage. The expression "dosage unit form" as used herein refers to physically discrete dosage units suitable for the patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, overall health, sex and diet; the time of administration, route of administration and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or concurrently with the specific compound used, and similar factors well known in the medical field. As used herein, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

[0143] Depending on the severity of the infection being treated, the pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneal, topically (e.g., by powders, ointments, drops, or patches), buccally, as an oral or nasal spray, etc. In certain embodiments, the compounds of this invention can be administered orally or parenterally once or more per day at a dosage level of about 0.01 mg / Kg to about 0.5 mg / Kg, preferably from about 0.5 mg / Kg to 20 mg / Kg of subject body weight per day to achieve the desired therapeutic effect.

[0144] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, these liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, these oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, and aromatics.

[0145] Suitable dispersants or wetting agents and suspending agents can be used to prepare injectable preparations according to known technology, such as sterile injectable aqueous or oily suspensions. This sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a nontoxic parenteral acceptable diluent or solvent, for example, as a solution in 1,3-butylene glycol. Acceptable vehicles and solvents that can be adopted include water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oil is usually used as solvent or suspension medium. For this purpose, any gentle fixed oil can be adopted, including synthetic monoglyceride or diglyceride. In addition, fatty acids (such as oleic acid) are used to prepare injections.

[0146] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0147] In order to prolong the effect of the compounds of the present invention, it is generally desirable to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility. The absorption rate of the compound then depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, delayed absorption of the compound form administered parenterally can be achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are manufactured by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by embedding the compound in liposomes or microemulsions compatible with body tissues.

[0148] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0149] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceryl monostearate; h) absorbents such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0150] The solid composition of similar type also can be used as filler for the soft and hard filled gelatin capsules of using such as excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.The solid dosage form of tablet, dragee, capsule, pill and granule can be prepared with coating and shell, and these coatings and shell are such as other coatings known in enteric coating and pharmaceutical formulation field.They can optionally contain sunscreen, and can also have following composition, and promptly they only discharge one or more active components, or preferentially in a certain part of intestinal tract, preferably in a delayed mode.The example of operable embedded composition comprises polymeric substance and wax.The solid composition of similar type also can be used as filler for the soft and hard filled gelatin capsules of using such as excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0151] Active compound can also be in the form of microencapsulation with one or more excipients as indicated above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, controlled release coatings and other coatings known in the field of pharmaceutical formulations. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. These dosage forms can also include (as common practice) other substances other than inert diluents such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of gelatin, tablets and pills, the dosage form can also include a buffer. They can optionally contain an opacifier and can also have a composition such that they only release one or more active ingredients, or preferentially in a certain part of the intestinal tract, preferably in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0152] The dosage form for topical or transdermal administration of the compounds of this invention includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. Under aseptic conditions, active ingredient is mixed with a pharmaceutically acceptable carrier and any required preservative or buffer as may be needed. Ophthalmic preparations, ear drops and eye drops are also expected to be within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the added advantage of providing compound control delivery to the body. Such dosage forms are prepared by dissolving or distributing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. Rate control can be achieved by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0153] The activity of the compounds useful as glucocorticoid receptor modulators in the present invention can be determined according to methods generally described in the art and in the Examples herein.

[0154] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0155] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 5 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0156] Preparation method

[0157] Method 1:

[0158] Method 2:

[0159] Advantages of the present invention:

[0160] Compared with conventional and latest glucocorticoid drugs, the glucocorticoid compound of the present invention shows stronger glucocorticoid receptor affinity and stronger in vivo anti-inflammatory effect, and can achieve the same therapeutic effect at a lower dose, thereby minimizing side effects.

[0161] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are percentages by weight and parts by weight.

[0162] Example 1: Synthesis of compound PA7200

[0163] Step 1: Synthesis of intermediate compound 1-B

[0164] Under a nitrogen atmosphere, commercially available compound 1-A (50 g, 122 mmol) and anhydrous ethanol (150 mL) were put into a 500 mL reaction flask. The system was cooled to 10-15 ° C and stirred, and periodic acid (36.1 g, 159 mmol) was slowly added to the reaction system with the temperature controlled to less than 30 ° C. After the addition was completed, the temperature was controlled at 25-30 ° C and continued to stir for 3 hours. The LC-MS control showed that compound 1-A basically disappeared. 150 mL of drinking water was added to the reaction system and stirred for 1 hour. Filter and wash the filter cake with a mixture of ethanol and water (1: 1). The solid was placed in an oven and dried to obtain 48.1 g of compound 1-B with a yield of 99.6%. LC-MS: [M+1] + =397.2.

[0165] NMR: 1 H NMR(400MHz,DMSO-d6)δ12.49(s,1H),7.29(d,J=10.4Hz,1H),6.31(dd,J=10.2,1.7Hz,1H), 6.12(s,1H),5.65(ddd,J=48.7,10.0,6.8Hz,1H),5.36(d,J=2.1Hz,1H),4.72(s,1H),4.16(d ,J=9.4Hz,1H),2.94-2.79(m,1H),2.48-2.37(m,1H),2.28-2.18(m,1H),2.16-1.97(m,2H), 1.73-1.60(m,1H),1.60-1.39(m,5H),1.18-1.06(m,1H),1.01(s,3H),0.89(d,J=7.1Hz,3H).

[0166] Step 2: Synthesis of intermediate compound 1-C

[0167] Under a nitrogen atmosphere, compound 1-B (48 g, 121 mmol) and methanol (190 mL) were put into a 500 mL reaction flask. The system was cooled to 5-15 ° C and stirred, and the temperature was controlled to be less than 20 ° C, and dichlorothionyl (21.41 g, 182 mmol) was slowly added dropwise. After the dropwise addition, the temperature was raised to 60 ° C and the reaction was allowed to proceed overnight. In the middle control, compound 1-B basically disappeared, the organic solvent was spin-dried, and the obtained crude compound 1-C was slurried with a mixed solution of ethyl acetate (48 mL) and petroleum ether (144 mL) and stirred for 2 hours. Filtered, the solid was placed in an oven and dried to obtain 48.7 g of compound 1-C, with a yield of 97.76%, LC-MS: [M+1]+ =411.1.

[0168] NMR: 1 H NMR (400MHz, DMSO-d6) δ7.34 (dd, J=28.3, 10.2Hz, 1H), 6.32 (dd, J=10.1, 1.5Hz, 1H), 6.14 (s,1H),5.66(ddd,J=48.8,10.5,7.0Hz,1H),5.37(t,J=19.9Hz,1H),5.04(s,1H),4.17(d ,J=10.1Hz,1H),3.67(s,3H),2.62-2.37(m,2H),2.22(dd,J=20.8,16.1Hz,1H),2.20-1.9 5(m,2H),1.70(q,J=11.8Hz,1H),1.63-1.41(m,5H),1.21-1.02(m,1H),1.02-0.81(m,6H).

[0169] Step 3: Synthesis of intermediate compound 1-D

[0170] Compound 1-C (48.5 g, 118 mmol), methanol (170 mL) and tetrahydrofuran (72 mL) were put into a 500 mL reaction flask. After stirring evenly, 6.3 g of Pd / C (10%) was added, and the system was replaced with hydrogen three times. The reaction was stirred at room temperature for 2 days under a hydrogen atmosphere. In the control, compound 1-C and the intermediate state basically disappeared. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with tetrahydrofuran (72 mL), the filtrate was decompressed to dryness, and the solid was placed in an oven to dry to obtain 50 g of compound 1-D with a yield of 98.61%. LC-MS: [M+H2O] + =432.5.

[0171] NMR: 1 H NMR(400MHz,DMSO-d6)δ5.14(ddd,J=17.8,11.6,5.4Hz,1H),5.03-4.91(m,2H),4.2 3(s,1H),3.66(s,3H),2.90(dd,J=12.5,5.5Hz,1H),2.66-2.55(m,2H),2.35(dd,J= 24.5,13.7Hz,2H),2.28-2.03(m,5H),1.81(d,J=3.4Hz,1H),1.73-1.58(m,3H),1.5 2(d,J=13.9Hz,1H),1.27(s,3H),1.10(dd,J=15.0,11.4Hz,1H),0.98-0.88(m,6H).

[0172] Step 4: Synthesis of intermediate compound 1-E

[0173] Under a nitrogen atmosphere, compound 1-D (49.5 g, 119 mmol) and dichloromethane (1500 mL) were put into a 5 L reaction flask. The system was cooled to 0-10 ° C and stirred, and tribromopyridine (41.3 g, 262 mmol) was added in batches. After the addition was completed, the reaction was carried out at room temperature for 3 hours. In the middle control, compound 1-D basically disappeared. Drinking water (1500 mL) was added to the reaction system, and the organic phase was separated. The organic phase was washed twice with drinking water (1500 mL), washed with saturated brine (1500 mL), and dried over anhydrous sodium sulfate. Filter, reduce the organic phase to dryness, and put the solid into an oven to dry to obtain 69.4 g of compound 1-E crude product, LC-MS: [M+H2O] + =589.9.

[0174] NMR: 1 H NMR(400MHz,DMSO-d6)δ5.14(ddd,J=17.8,11.6,5.4Hz,1H),5.03-4.91(m,2H),4 .23(s,1H),3.67(s,3H),2.90(dd,J=12.5,5.5Hz,1H),2.66-2.55(m,1H),2.35(dd ,J=24.5,13.7Hz,1H),2.20-2.07(m,5H),1.84(d,J=3.4Hz,1H),1.58(m,3H),1.50 (d,J=13.9Hz,1H),1.33(s,3H),1.20(dd,J=15.0,11.4Hz,1H),0.99-0.88(m,6H).

[0175] Step 5: Synthesis of intermediate compound 1-F

[0176] Under a nitrogen atmosphere, compound 1-E crude product (69 g, 119 mmol) and DMAC (255 mL) were placed in a 500 mL reaction flask. After stirring evenly, the system was heated to 45 ° C, lithium bromide (20.67 g, 238 mmol) was added, and stirred for 5 minutes. Calcium carbonate (23.8 g, 238 mmol) was then added, and the system was heated to 95 ° C and the reaction continued for 3 hours. The system was cooled to room temperature, 4M sodium hydroxide aqueous solution (500 mL) was added to the reaction system, and the reaction was continued at room temperature for 3 hours. The pH was then adjusted to 1-2 with 2 mol / L hydrochloric acid solution, ethyl acetate (500 mL) was added for extraction, and the organic phase was separated. The organic phase was washed twice with drinking water (500 mL), washed once with saturated brine (500 mL), and dried over anhydrous sodium sulfate. Filter, reduce the organic phase to dryness, and place the solid in an oven to dry to obtain 49.7 g of compound 1-F crude product. 49.7 g of the crude product was added to acetonitrile (150 mL), stirred for 2 hours, filtered, and the filter cake was washed with acetonitrile (5 mL). The filter cake was added to a mixture of acetonitrile (100 mL) and methanol (100 mL), stirred for two hours, filtered, and the solid was placed in an oven to dry to obtain 15.7 g of compound 1-F, with a two-step yield of 32.75%. LC-MS: [M+1] + =397.0.

[0177] NMR: 1 H NMR (400MHz, DMSO-d6) δ12.41(s,1H),5.87(s,1H),5.64(d,J=15.1Hz,1H),5.22(d, J=1.9Hz,1H),4.13(s,1H),3.18-2.82(m,2H),2.78-2.59(m,1H),2.37(dd,J=19.8,1 2.5Hz,2H),2.24(td,J=14.0,4.7Hz,1H),2.17-2.02(m,2H),1.76(q,J=11.4Hz,1H) ,1.65-1.41(m,5H),1.36-1.18(m,1H),1.06(d,J=6.3Hz,3H),0.92(d,J=7.1Hz,3H).

[0178] Step 6: Synthesis of intermediate compound 1-G

[0179] Under a nitrogen atmosphere, compound 1-F (900 mg, 2.27 mmol) and dichloromethane (30 mL) were put into a 100 mL reaction flask. After stirring evenly, the system was cooled to 10 ° C. Tribromopyridine (376 mg, 2.38 mmol) was added in batches. After the addition was completed, the reaction was continued for 6 hours. In the control, compound 1-F basically disappeared. 50 mL of water was added to the reaction system, and the organic phase was separated. The organic phase was washed twice with drinking water (50 mL), washed once with saturated brine (50 mL), and dried over anhydrous sodium sulfate. Filter, the organic phase was decompressed to dryness, and the solid was placed in an oven to dry to obtain 1.1 g of compound 1-G crude product. LC-MS: [M+1] + =474.9.

[0180] Step 7: Synthesis of intermediate compound 1-H

[0181] Under nitrogen atmosphere, crude compound 1-G (1.1 g, 2.31 mmol) and DMAC (20 mL) were placed in a 100 mL reaction flask. After stirring evenly, the system was heated to 45 ° C, lithium bromide (400 mg, 4.62 mmol) was added, stirred for 5 minutes, and calcium carbonate (462 mg, 4.62 mmol) was added. The system was heated to 95 ° C and the reaction was continued for 3 hours. The system was cooled to room temperature and the pH was adjusted to 1-2 with 2 mol / L hydrochloric acid solution. Ethyl acetate (50 mL) was added to the reaction system for extraction. The organic phase was separated and washed twice with drinking water (50 mL) and once with saturated brine (50 mL). It was dried over anhydrous sodium sulfate and filtered. The organic phase was reduced to dryness under reduced pressure and the solid was placed in an oven to dry to obtain 890 mg of the compound with a two-step yield of 97%. LC-MS: [M+1] + =395.0.

[0182] NMR: 1 H NMR (400MHz, DMSO-d6) δ14.71-9.60(m,1H),7.42(d,J=10.2Hz,1H),6.35(d,J=10.1Hz,1H),6. 22(s,1H),5.64(d,J=14.9Hz,1H),5.56(s,1H),4.25(s,1H),3.19(s,1H),3.09(dd,J=24.2,9.2 Hz,1H),2.91(d,J=6.9Hz,1H),2.34(dd,J=20.3,12.0Hz,1H),2.18-2.06(m,1H),1.78(q,J=11 .5Hz,1H),1.64-1.50(m,4H),1.26(dd,J=14.1,6.1Hz,1H),1.07(s,3H),0.91(d,J=7.1Hz,3H).

[0183] Step 8: Synthesis of compound 1-I:

[0184] Under a nitrogen atmosphere, compound 1-H (445 mg, 1.13 mmol), DCM (5 mL) and triethylamine (303 mg, 2.99 mmol) were added to a 50 mL reaction flask. After stirring evenly, the system was cooled to 5 ° C, and furoyl chloride (366 mg, 2.82 mmol) was slowly added dropwise. After the dropwise addition, the reaction was allowed to proceed at room temperature for 1 hour. TLC control showed that the starting material disappeared and was converted to an intermediate state. The organic solvent was reduced to dryness, and the crude product was added with methanol (8.8 mL), sodium bicarbonate (230 mg, 2.74 mmol) and water (2.3 mL) and stirred. The system was heated to 48 ° C and the reaction was continued for 10 hours. Control showed that all intermediates were converted into products. The pH was adjusted to 1-2 with 1 mol / L hydrochloric acid, filtered, and the filter cake was washed with drinking water (5 mL). The solid was placed in an oven to dry to obtain 490 mg of compound 1-I with a yield of 88.9%. LC-MS: [M+1] + =489.0.

[0185] Step 9: Synthesis of intermediate compound 1-J:

[0186] Under a nitrogen atmosphere, compound 1-I (490 mg, 1 mmol), sodium iodide (179 mg, 1.2 mmol), triethylamine (202 mg, 2 mmol) and 2-butanone (10 mL) were put into a 50 mL reaction flask. After stirring evenly, the system was cooled to 0-5 ° C, dimethylamino-thiocarbonyl chloride (185 mg, 1.5 mmol) was added, and then reacted at room temperature for 16 hours. TLC control, the raw material disappeared, saturated brine (50 mL) was added to the reaction system to quench the reaction, and then ethyl acetate (50 mL) was added to extract. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, the organic phase was reduced to dryness, and the solid was placed in an oven to dry to obtain 507 mg of compound 1-J with a yield of 87.8%.

[0187] Step 11: Synthesis of intermediate compound 1-K

[0188] Under nitrogen, compound 1-J (490 mg, 0.85 mmol), 100-mesh potassium carbonate (351 mg, 2.54 mmol), and ethanol (5 mL) were placed in a 50 mL reaction flask, stirred, and allowed to react at room temperature for 16 hours. TLC indicated that the starting material had essentially disappeared. The mixture was filtered, the filter cake washed with water (5 mL), and the solid was oven-dried to yield 800 mg of compound 1-K. The crude product was used directly in the next step without purification. LC-MS: [MK] --=503.0.

[0189] Step 12: Synthesis of compound PA7200

[0190] Under a nitrogen atmosphere, the crude product of compound 1-K (400 mg, theoretical value 0.43 mmol) and DMF (5 mL) were put into a 50 mL reaction bottle, the system was cooled to 0-5 ° C, and iodomethane (101 mg, 0.64 mmol) was slowly added. After stirring evenly, the reaction was allowed to react at room temperature for 2 hours. TLC control showed that the raw material basically disappeared. Drinking water (50 mL) was added to the reaction system to quench the reaction, and then ethyl acetate (50 mL) was added to extract and separate the organic phase. The organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the organic phase was reduced to dryness. The reverse phase column was prepared and lyophilized to obtain 90 mg of compound PA7200, with a two-step yield of 24.3%, HPLC purity of 95.52%, LC-MS: [M+1] + =537.1.

[0191] NMR: 1 H NMR (400MHz, DMSO-d6) δ8.04(s,1H),7.43(d,J=9.9Hz,1H),7.24(d,J=3.4Hz,1H),6.73(dd,J=3.5 ,1.7Hz,1H),6.39(d,J=10.2Hz,1H),6.26(s,1H),6.05(s,1H),5.92(s,1H),5.86(d,J=2.4Hz,1H), 5.71(d,J=15.0Hz,1H),4.39(s,1H),3.79-3.51(m,3H),2.30(d,J=14.3Hz,1H),2.06(dd,J=21.9, 10.0Hz, 1H), 1.92 (d, J = 13.9Hz, 1H), 1.55 (s, 3H), 1.50 (s, 1H), 1.13 (s, 3H), 0.98 (d, J = 7.1Hz, 3H).

[0192] Example 2: Synthesis of compound PA7201

[0193] Step 1: Synthesis of intermediate compound 1-L

[0194] Under nitrogen atmosphere, compound 1-H (445 mg, 1.13 mmol), DCM (5 mL) and triethylamine (303 mg, 2.99 mmol) were added to a 50 mL reaction flask. After stirring evenly, the system was cooled to 5 ° C and propionyl chloride (260 mg, 2.82 mmol) was slowly added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 1 hour. TLC control showed that the starting material disappeared and converted to an intermediate state. The organic solvent was reduced to dryness, and the crude product was added with methanol (8.8 mL), sodium bicarbonate (230 mg, 2.74 mmol) and water (2.3 mL) and stirred. The system was heated to 48 ° C and the reaction was continued for 10 hours. Control showed that all intermediates were converted into products. The pH was adjusted to 1-2 with 1 mol / L hydrochloric acid, filtered, and the filter cake was washed with drinking water (5 mL). The solid was placed in an oven to dry to obtain 500 mg of compound 1-L with a yield of 98.1%. LC-MS: [M+1] + =451.0.

[0195] Step 2: Synthesis of intermediate compound 1-M

[0196] Under a nitrogen atmosphere, compound 1-L (500 mg, 1.1 mmol), sodium iodide (198 mg, 1.3 mmol), triethylamine (224 mg, 2.2 mmol) and 2-butanone (5 mL) were placed in a 50 mL reaction flask. After stirring evenly, the system was cooled to 0-5 ° C, dimethylamino-thiocarbonyl chloride (185 mg, 1.5 mmol) was added, and then reacted at room temperature for 16 hours. TLC control, the starting material disappeared, saturated brine (50 mL) was added to the reaction system to quench the reaction, and then ethyl acetate (50 mL) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, the organic phase was reduced to dryness, and the solid was placed in an oven to dry to obtain 567 mg of compound 1-M, with a yield of 95%, LC-MS: [M+1] + =538.0.

[0197] Step 3: Synthesis of intermediate compound 1-N:

[0198] Under nitrogen atmosphere, compound 1-M (567 mg, 1.1 mmol), 100-mesh potassium carbonate (456 mg, 3.3 mmol), and ethanol (5 mL) were placed in a 50 mL reaction flask. After stirring, the reaction was allowed to proceed at room temperature for 16 hours. TLC control showed that the starting material had almost disappeared. The product was filtered, the filter cake was washed with anhydrous ethanol (5 mL), and the solid was placed in an oven to dry to obtain 917 mg of compound 1-N. The crude product was used directly in the next reaction without purification. LC-MS: [MK] - =465.0.

[0199] Step 4: Synthesis of compound PA7201

[0200] Under a nitrogen atmosphere, the crude product of compound 1-N (917 mg, theoretical value 1.1 mmol) and DMF (5 mL) were put into a 50 mL reaction bottle. The temperature was lowered to 0-5 ° C, and iodomethane (264 mg, 1.65 mmol) was slowly added. After stirring, the reaction was allowed to react at room temperature for 2 hours. The TLC control showed that the raw material had basically disappeared. Drinking water (50 mL) was added to the reaction system to quench the reaction, and then ethyl acetate (50 mL) was added to extract and separate the organic phase. The organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the organic phase was reduced to dryness. The reverse phase column was prepared and lyophilized to obtain 5 mg of compound PA7201 with an HPLC purity of 94.4% and a two-step yield of 0.55%. LC-MS: [M+1] + =499.1.

[0201] NMR: 1 H NMR(400MHz,DMSO-d6)δ7.41(d,J=10.2Hz,1H),6.37(dd,J=10.2,1.7Hz,1H),6.24(s,1H),6.02(s,1H ),5.90(s,1H),5.81(d,J=2.3Hz,1H),5.68(d,J=14.2Hz,1H),4.34(s,1H),3.67-3.50(m,2H),3.18(d ,J=14.5Hz,1H),2.44-2.29(m,3H),2.20(d,J=14.0Hz,1H),2.00(d,J=12.1Hz,1H),1.88(d,J=14.1Hz ,1H),1.53(s,3H),1.45(t,J=10.3Hz,1H),1.04(dd,J=13.6,6.1Hz,7H),0.91(dd,J=19.0,7.3Hz,4H).

[0202] Example 3: Synthesis of compound PA7202

[0203] Under a nitrogen atmosphere, compound 1-I (160 mg, 0.33 mmol), potassium carbonate (135 mg, 0.97 mmol) and DMF (10 mL) were put into a 100 mL reaction bottle. The temperature was lowered to 0-5 ° C, fluoroiodomethane (78 mg, 0.49 mmol) was slowly added, stirred evenly, and reacted at room temperature for 2 hours. TLC control showed that the raw material basically disappeared. Drinking water (50 mL) was added to the reaction system to quench the reaction, and then ethyl acetate (50 mL) was added for extraction. The organic phase was separated and washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the organic phase was reduced to dryness. The reverse phase column was prepared and lyophilized to obtain 106 mg of compound PA7202 with an HPLC purity of 99.59% and a yield of 58.8%. LC-MS: [M+1] + =521.5.

[0204] NMR: 1 H NMR (400MHz, DMSO-d6) δ8.01(dd,J=1.7,0.8Hz,1H),7.40(d,J=8.4Hz,1H),7.22(dd,J=3.5,0. 7Hz,1H),6.70(dd,J=3.6,1.7Hz,1H),6.36(dd,J=10.2,1.9Hz,1H),6.24(s,1H),5.79(ddd,J=5 6.0,40.0,27.1Hz,4H),4.33(s,1H),3.21(d,J=44.4Hz,3H),2.24(d,J=13.8Hz,1H),2.06-1.9 3(m,1H),1.75(d,J=14.1Hz,1H),1.54(s,3H),1.45(s,1H),1.10(s,3H),0.92(d,J=7.2Hz,3H).

[0205] Example 4: Synthesis of compound PA7203

[0206] Under a nitrogen atmosphere, compound 1-L (144 mg, 0.32 mmol), potassium carbonate (132 mg, 0.96 mmol) and DMF (10 mL) were put into a 100 mL reaction bottle, and fluoroiodomethane (76 mg, 0.47 mmol) was slowly added. After stirring, the reaction was allowed to react at room temperature for 2 hours. TLC control showed that the raw material had basically disappeared. Drinking water (50 mL) was added to the reaction system to quench the reaction, and then ethyl acetate (50 mL) was added to extract the organic phase. The organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the organic phase was reduced to dryness. The reverse phase column was prepared and lyophilized to give 60 mg of compound PA7203 with a yield of 42.3%, HPLC purity of 98.02%, and LC-MS: [M+1].+ =483.7.

[0207] NMR: 1 H NMR(400MHz,DMSO-d6)δ7.38(d,J=10.3Hz,1H),6.35(dd,J=10.2,1.9Hz,1H), 6.21(s,1H),5.93-5.63(m,4H),4.29(s,1H),3.24(s,3H),2.37-2.35(m,2H), 2.14(d,J=14.0Hz,1H),1.94(d,J=11.9Hz,1H),1.70(d,J=14.3Hz,1H),1.52( s, 3H), 1.39 (s, 1H), 1.05 (s, 3H), 1.01 (t, J = 7.5Hz, 3H), 0.88 (d, J = 7.1Hz, 3H).

[0208] Example 5: Synthesis of compound PA7204

[0209] Under a nitrogen atmosphere, compound 1-H (130 mg, 0.33 mmol), potassium carbonate (136 mg, 0.98 mmol) and DMF (10 mL) were put into a 100 mL reaction bottle. The temperature was lowered to 0-5 ° C, fluoroiodomethane (79 mg, 0.49 mmol) was slowly added, stirred evenly, and reacted at room temperature for 2 hours. TLC control showed that the raw material basically disappeared. Drinking water (50 mL) was added to the reaction system to quench the reaction, and then ethyl acetate (50 mL) was added for extraction. The organic phase was separated and washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the organic phase was reduced to dryness. The reverse phase column was prepared and lyophilized to obtain 72 mg of compound PA7204 with an HPLC purity of 99.53% and a yield of 51.2%. LC-MS: [M+1] + =427.4.

[0210] NMR: 1H NMR (400MHz, DMSO-d6) δ7.39 (dd, J=10.2, 1.8Hz, 1H), 6.34 (dd, J=10.2, 1.9Hz, 1H), 6.20 (s, 1 H),5.98-5.57(m,4H),5.35(s,1H),4.24(s,1H),3.08(dd,J=25.4,8.0Hz,1H),2.99-2.84(m, 1H),2.35(dd,J=15.8,7.0Hz,1H),2.15(d,J=13.9Hz,1H),1.87-1.73(m,1H),1.60(d,J=14.0 Hz, 1H), 1.51 (s, 3H), 1.27 (ddd, J = 12.3, 8.1, 3.8Hz, 1H), 1.01 (s, 3H), 0.92 (d, J = 7.2Hz, 3H).

[0211] Example 6: Synthesis of compound PA7100

[0212] Step 1: Synthesis of intermediate compound 1-O

[0213] Under nitrogen atmosphere, compound 1-F (1.0 g, 2.52 mmol), DCM (7 mL) and triethylamine (663 mg, 6.55 mmol) were placed in a 50 mL reaction flask. After stirring evenly, the temperature was lowered to 0-5 ° C, furoyl chloride (823 mg, 6.31 mmol) was added, and the mixture was stirred at room temperature for 1 hour. TLC control showed that the starting material disappeared and converted to an intermediate state. The organic solvent was reduced to dryness, and the crude product was added with methanol (20 mL), sodium bicarbonate (0.5 g, 6.23 mmol) and water (5.0 mL) and stirred. The system was heated to 48 ° C and the reaction was continued for 10 hours. Control showed that all the intermediates were converted into products. The pH was adjusted to 1-2 with 1 mol / L hydrochloric acid, filtered, and the filter cake was washed with drinking water (5 mL). The solid was placed in an oven to dry to obtain 1023 mg of compound 1-O with a yield of 82.6%. LC-MS: [M+1] + =491.0.

[0214] NMR: 1H NMR (400MHz, DMSO-d6) δ12.92(s,1H),8.02(s,1H),7.17(d,J=3.2Hz,1H),6.73(s,1H),5. 90(s,1H),5.72(d,J=14.7Hz,1H),5.41(s,1H),4.20(s,1H),3.24-2.98(m,2H),2.68(d,J =13.8Hz,1H),2.39-2.17(m,3H),2.10(s,1H),1.95(d,J=11.3Hz,1H),1.73(d,J=15.4Hz, 1H), 1.49 (s, 3H), 1.43 (s, 1H), 1.20 (t, J = 7.2Hz, 1H), 1.11 (s, 3H), 0.94 (d, J = 7.0Hz, 3H).

[0215] Step 2: Synthesis of intermediate compound 1-P

[0216] Under a nitrogen atmosphere, compound 1-O (1.0 g, 2.04 mmol), sodium iodide (366 mg, 2.24 mmol), triethylamine (412 mg, 4.08 mmol) and 2-butanone (10 mL) were put into a 50 mL reaction flask. After stirring evenly, the temperature was lowered to 0-5 ° C, dimethylamino-thiocarbonyl chloride (378 mg, 3.05 mmol) was added, and the reaction was allowed to react at room temperature for 16 hours. TLC control showed that the raw material disappeared. Saturated brine (50 mL) was added to the reaction system to quench the reaction, and then ethyl acetate (50 mL) was added to extract. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic phase was reduced to dryness. The solid was placed in an oven to dry to obtain 931 mg of compound 1-P with a yield of 79.06%.

[0217] NMR: 1 H NMR (400MHz, DMSO-d6) δ8.08(d,J=0.9Hz,1H),7.27(d,J=3.5Hz,1H),6.77(dd,J=3.5,1. 7Hz,1H),5.92(s,1H),5.73(d,J=15.0Hz,1H),5.58(s,1H),4.26(s,1H),3.46(t,J=5.8Hz ,2H),3.16(d,J=23.5Hz,4H),3.01(s,4H),2.77-2.64(m,1H),2.35-2.21(m,2H),2.17-1. 98(m,2H),1.92(d,J=13.8Hz,1H),1.51(s,4H),1.25-1.19(m,3H),0.99(d,J=7.0Hz,3H).

[0218] Step 3: Synthesis of Compound 1-Q

[0219] Under nitrogen atmosphere, compound 1-P (900 mg, 1.56 mmol), 100-mesh potassium carbonate (646 mg, 4.671 mmol), and ethanol (5 mL) were placed in a 50 mL reaction flask. After stirring, the reaction was allowed to proceed at room temperature for 16 hours. TLC control showed that the starting material had almost disappeared. The product was filtered, the filter cake was washed with anhydrous ethanol (5 mL), and the solid was placed in an oven to dry to obtain 1.7 g of compound 1-Q. The crude product was used directly in the next reaction without purification. LC-MS: [MK] - =507.0.

[0220] Step 4: Synthesis of compound PA7100

[0221] Under a nitrogen atmosphere, the crude product of compound 1-Q (1.0 g, theoretical value 0.92 mmol) and DMF (10 mL) were put into a 50 mL reaction bottle, the system was cooled to 0-5 ° C, fluoroiodomethane (219 mg, 1.37 mmol) was slowly added, stirred evenly, and reacted at room temperature for 2 hours. TLC control showed that the raw material basically disappeared. Drinking water (50 mL) was added to the reaction system to quench the reaction, and then ethyl acetate (50 mL) was added to extract and separate the organic phase. The organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the organic phase was reduced to dryness. The reverse phase column was prepared and lyophilized to obtain 80 mg of compound PA7100 with an HPLC purity of 92.11% and a two-step yield of 80.89%. LC-MS: [M+1] + =539.1.

[0222] NMR: 1H NMR (400MHz, DMSO-d6) δ8.05(d,J=5.2Hz,1H),7.42(s,1H),7.25(d,J=3.4Hz,1H),6.80-6.70(m,1H),6 .38(dt,J=8.8,4.4Hz,1H),6.25(d,J=9.8Hz,1H),6.02(d,J=27.8Hz,1H),5.92(d,J=11.7Hz,1H),5.82 (t,J=10.9Hz,1H),5.77-5.64(m,1H),4.39(s,1H),3.43(d,J=7.1Hz,1H),3.30-3.16(m,1H),2.39-2.2 6(m,1H),2.13-1.98(m,1H),1.93(d,J=13.7Hz,1H),1.59-1.45(m,5H),1.13(s,3H),1.04-0.94(m,3H).

[0223] Example 7: Synthesis of Compound PA7101

[0224] Step 1: Synthesis of intermediate compound 1-R

[0225] Under a nitrogen atmosphere, compound 1-F (1.0 g, 2.52 mmol), DCM (7 mL) and triethylamine (663 mg, 6.55 mmol) were placed in a 50 mL reaction flask, stirred evenly, cooled to 0-5 ° C, and propionyl chloride (583 mg, 6.31 mmol) was slowly added and stirred at room temperature for 1 hour. TLC control showed that the starting material disappeared and converted to an intermediate state. The organic solvent was reduced to dryness under reduced pressure, and the crude product was added with methanol (20 mL), sodium bicarbonate (0.5 g, 6.23 mmol) and water (5 mL) and stirred. The system was heated to 48 ° C and the reaction was continued for 10 hours. Control, the intermediate state was completely converted into the product, the pH was adjusted to 1-2 with 1 mol / L hydrochloric acid, filtered, the filter cake was washed with drinking water (5 mL), and the solid was placed in an oven to dry to obtain 930 mg of compound 1-R with a yield of 81.4%, [M+1] + =453.1.

[0226] NMR: 1H NMR (400MHz, DMSO-d6) δ12.61(s,1H),5.88(s,1H),5.69(d,J=14.4Hz,1H),5.37(d,J=2 .3Hz,1H),4.16(s,1H),3.29-3.17(m,1H),3.15-3.00(m,1H),2.74-2.61(m,1H),2.45-2 .31(m,4H),2.29-2.19(m,1H),2.11(t,J=14.6Hz,2H),1.89(q,J=11.7Hz,1H),1.69(d,J =14.1Hz,1H),1.48(s,3H),1.42-1.31(m,1H),1.10-1.01(m,6H),0.89(d,J=7.1Hz,3H).

[0227] Step 2: Synthesis of intermediate compound 1-S

[0228] Under a nitrogen atmosphere, compound 1-R (900 mg, 1.99 mmol), sodium iodide (359 mg, 2.4 mmol), triethylamine (404 mg, 4.0 mmol) and 2-butanone (5 mL) were placed in a 50 mL reaction flask. After stirring evenly, the temperature was lowered to 0-5 ° C. Dimethylamino-thiocarbonyl chloride (369 mg, 3.0 mmol) was added and the reaction was allowed to react at room temperature for 16 hours. TLC control showed that the starting material disappeared. Saturated brine (50 mL) was added to the reaction system to quench the reaction, and then ethyl acetate (50 mL) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic phase was reduced to dryness. The solid was placed in an oven to dry to obtain 891 mg of compound 1-S with a yield of 83.02%.

[0229] Step 3: Synthesis of intermediate compound 1-T

[0230] Under nitrogen atmosphere, compound 1-S (891 mg, 1.65 mmol), 100-mesh potassium carbonate (684 mg, 4.95 mmol), and ethanol (5 mL) were placed in a 50 mL reaction flask, stirred evenly, and reacted at room temperature for 16 hours. TLC control showed that the starting material had almost disappeared. The product was filtered, the filter cake was washed with anhydrous ethanol (5 mL), and the solid was placed in an oven to dry to obtain 1.5 g of compound 1-T. The crude product was used directly in the next reaction without purification. LC-MS: [MK] - =467.1.

[0231] Step 4: Synthesis of compound PA7101

[0232] Under a nitrogen atmosphere, the crude product of compound 1-T (750 mg, theoretical value 0.83 mmol) and DMF (5 mL) were put into a 50 mL reaction bottle, cooled to 0-5 ° C, and iodomethane (198 mg, 1.24 mmol) was slowly added. After stirring, the reaction was allowed to react at room temperature for 2 hours. TLC control showed that the raw material basically disappeared. Drinking water (50 mL) was added to the reaction system to quench the reaction, and then ethyl acetate (50 mL) was added to extract and separate the organic phase. The organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the organic phase was reduced to dryness. The reverse phase column was prepared and lyophilized to obtain 46 mg of compound PA7101 with an HPLC purity of 95.64% and a two-step yield of 6.2%. LC-MS: [M+1] + =501.3.

[0233] NMR: 1 H NMR (400MHz, DMSO-d6) δ6.02(s,1H),5.89(d,J=4.6Hz,2H),5.70(d,J=14.8Hz,1H),5.50(d,J =3.0Hz,1H),4.17(d,J=25.2Hz,1H),3.36(s,1H),3.10(ddd,J=16.4,11.5,4.0Hz,1H),2.77- 2.62(m,1H),2.47-2.31(m,4H),2.32-2.16(m,2H),2.14-2.02(m,1H),1.98(q,J=11.8Hz,1H) ,1.85(d,J=13.8Hz,1H),1.54-1.38(m,4H),1.11-1.00(m,6H),0.92(dd,J=18.8,7.0Hz,3H).

[0234] Example 8: Synthesis of compound PA7102

[0235] Under nitrogen atmosphere, compound 1-F (100 mg, 0.25 mmol), 100 mesh potassium carbonate (104 mg, 0.76 mmol) and DMF (5 mL) were put into a 50 mL reaction bottle, cooled to 0-5 ° C, and iodomethane (60 mg, 0.38 mmol) was slowly added. After stirring, the reaction was allowed to react at room temperature for 2 hours. TLC control showed that the raw material had basically disappeared. Drinking water (50 mL) was added to the reaction system to quench the reaction, and then ethyl acetate (50 mL) was added for extraction. The organic phase was separated and washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the organic phase was reduced to dryness. The reverse phase column was prepared and lyophilized to obtain 53 mg of compound PA7102 with an HPLC purity of 96.26% and a yield of 49.03%. LC-MS: [M+1] +=429.7.

[0236] NMR: 1 H NMR (500MHz, DMSO-d6) δ5.92(d,J=2.0Hz,1H),5.85(s,1H),5.80(dd,J=11.1,2.1Hz,1H),5.69(d,J=2.1 Hz,1H),5.63(d,J=14.5Hz,1H),5.31(d,J=20.6Hz,2H),4.11(d,J=5.2Hz,1H),3.08-2.90(m,2H),2.71- 2.59(m,1H),2.44-2.32(m,2H),2.26-2.11(m,2H),2.06(d,J=7.3Hz,1H),1.78(q,J=11.2Hz,1H),1.58- 1.50(m,1H),1.45(s,3H),1.28(ddd,J=12.3,8.1,4.2Hz,1H),1.04-0.98(m,3H),0.92(d,J=7.2Hz,3H).

[0237] Example 9: Glucocorticoid receptor (hereinafter referred to as "GR") binding activity evaluation test

[0238] Dexamethasone is a glucocorticoid first synthesized in 1957. It exhibits anti-inflammatory, anti-endotoxin, immunosuppressive, anti-shock, and stress response-enhancing effects. It is listed on the World Health Organization's List of Essential Medicines and is essential for the basic public health system. Its structural formula is shown below.

[0239] Fluticasone furoate is currently the best new glucocorticoid in the world. It was developed by GlaxoSmithKline and first launched in the UK in 1993. It is used to treat asthma, allergic rhinitis, chronic obstructive pneumonia, atopic dermatitis, etc. Compared with other glucocorticoids, it shows stronger receptor affinity and has stronger anti-inflammatory effects. Its structural formula is shown below.

[0240] GRC9 / HEK293 cells were cultured in a medium containing 88% DMEM (phenol red-containing), 10% FBS, 1% P / S, 1% GlutaMax, 900 μg / ml G418, and 75 μg / ml hygromycin. Different candidate compounds (dexamethasone, fluticasone furoate, PA7200, PA7201, PA7202, PA7203, PA7204, PA7100, PA7101, and PA7102) were added to each well of a 96-well plate. The cultured GRC9 / HEK293 cells were then seeded in this 96-well plate with an inoculum containing 89% DMEM (phenol red-free), 10% carbon-free FBS, and 1% GlutaMax. After one day of incubation at 37°C in a 5% CO2 environment, the cells were harvested and luciferase activity was measured using a luciferase assay. The activity results are shown in Table 2 and Figure 1.

[0241] Table 2: Summary of GR reporter gene assay

[0242] Result Analysis

[0243] The experimental results showed that the EC of dexamethasone, a commonly used glucocorticoid drug, 50 The EC value was 1.270 nM, indicating that its activity in activating glucocorticoid receptor was low; while the EC values ​​of the compounds PA7200 (Example 1) and PA7202 (Example 3) of the present application were 50 The values ​​were 0.01408nM and 0.01339nM, respectively, which were much lower than dexamethasone and the latest glucocorticoid drug fluticasone furoate, and were lower than fluticasone furoate (EC 50 The results showed that the activity of the compound of the present invention on the glucocorticoid receptor was significantly stronger than that of dexamethasone and fluticasone furoate, and the compound of the present invention had excellent activity in activating the glucocorticoid receptor.

[0244] Example 10: Determination of anti-inflammatory effect

[0245] The anti-inflammatory effects of candidate compounds were examined using an OVA-induced mouse asthma model. Seven- to nine-week-old Balb / c mice were first immunized with OVA (ovalbumin). On day 1, animals were randomly assigned to five different treatment groups (blank, model, positive drug, low-dose test substance, and high-dose test substance) using the BioBook randomization function. On days 28-30 after the first immunization, mice were challenged with OVA via the airway using a Buxco nebulized challenge solution. Simultaneously, the mice were administered different treatments: blank (normal saline), model (no drug), positive drug (0.2 mg / kg fluticasone furoate), low-dose test substance (0.067 mg / kg PA7200), and high-dose test substance (0.2 mg / kg PA7200). Lung tissue was lavaged from each experimental group, and bronchoalveolar lavage fluid (BALF) was collected. Cells in the BALF were then counted and compared. The cell count results are shown in Table 3 and Figures 2-6.

[0246] Table 3: Cell counts in BALF

[0247] Result Analysis

[0248] The experimental results showed that compared with the blank group, the total cell count and leukocyte typing number in the BALF of the model group animals were significantly increased after OVA sensitization and attack, showing more typical manifestations of asthma disease, indicating that the asthma model was successfully constructed.

[0249] Compared with the model group, the low-dose PA7200 group can significantly reduce the total cell and eosinophil counts, and to a certain extent reduce the neutrophil and lymphocyte counts; the high-dose PA7200 group can significantly reduce the total cell, eosinophil and lymphocyte counts, and to a certain extent reduce the neutrophil count, indicating that PA7200 has a good effect in improving the inflammatory symptoms of asthma.

[0250] The fluticasone furoate group and the PA7200 high-dose group were administered at the same dose, but the total cell, eosinophil, and lymphocyte counts in the PA7200 high-dose group were significantly reduced compared with the fluticasone furoate group, indicating that the anti-inflammatory effect of the compound PA7200 of the present application is significantly superior to that of the newly marketed glucocorticoid drug fluticasone furoate.

[0251] In summary, the compound PA7200 of the present application has an excellent effect in improving the inflammatory symptoms of asthma and is significantly better than the latest glucocorticoid drug fluticasone furoate on the market.

[0252] It should be understood that although the invention has been described in conjunction with specific embodiments thereof, the foregoing description is intended to illustrate rather than limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the claims.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, Among them, X is O or S; is a single bond or a double bond; R1 is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5- to 15-membered heteroaryl, C 5-15 aralkyl, heteroaralkyl, 3- to 10-membered heterocycloalkyl, where 0, 1, 2 or 3 hydrogens in each of the above groups are replaced by R a substituted; R2 is -L-R', where L is a bond or -C(O)-, and R' is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-12 aryl, 5- to 15-membered heteroaryl, C 5-15 aralkyl, heteroaralkyl, 3- to 10-membered heterocycloalkyl, where 0, 1, 2 or 3 hydrogens in the above groups are replaced by R b substituted; R3 is selected from the group consisting of: hydrogen, C 1-6 alkyl, wherein 0, 1, 2 or 3 hydrogens in said C 1-6 alkyl are replaced by R c substituted; R4 and R5 are each independently selected from the group consisting of: hydrogen, halogen, C 1-4 alkyl; 0, 1, 2 or 3 hydrogens in said C 1-4 alkyl are replaced by R d substituted; The said R a , R b , R c , R d are each independently selected from the group consisting of: hydroxy, halogen, CN, oxo, carboxyl, amino, sulfo, C 1-6 alkyl, C 1-6 alkoxy.

2. The compound according to claim 1, wherein The R1 is selected from the following group: hydrogen, C 1-6 alkyl; 0, 1, 2 or 3 hydrogens in the above C 1-6 alkyl are substituted by halogen; Preferably, R1 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and 0, 1, 2, or 3 hydrogens in the above groups are substituted by halogen; More preferably, R1 is fluoromethyl.

3. The compound according to claim 2, wherein The R1 is selected from the following group: C 3-7 cycloalkyl, C 6-10 aryl, phenyl, naphthyl, and 1, 2 or 3 hydrogens in each of the above groups are substituted by R a .

4. The compound according to claim 1, wherein R2 is -C(O)-R', and R' is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 6-10 aryl(C 1-6 alkyl), 5- to 15-membered heteroaryl, 5- to 15-membered heteroaryl(C 1-6 alkyl), 0, 1, 2 or 3 hydrogens in the above groups are replaced by R b , and the R b is selected from the group consisting of: halogen, CN, carboxyl, oxo; Preferably, the R2 is selected from the following group:

5. The compound according to claim 1, wherein R3 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, where 1, 2 or 3 hydrogens in the above groups are replaced by R c substituted.

6. The compound according to claim 1, wherein, R4 and R5 are each independently -F.

7. The compound according to claim 1, wherein The compound of formula I is selected from the group consisting of:

8. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: (i) a compound as claimed in any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier or adjuvant.

9. A method for modulating the activity of glucocorticoid receptors in a biological sample, characterized in that, Comprising the following steps: contacting the glucocorticoid receptor in the biological product with a compound as claimed in any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as claimed in claim 8.

10. Use of a compound as claimed in any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as claimed in claim 8 in the preparation of a medicament for relieving or treating inflammatory diseases; Preferably, the diseases are selected from the group consisting of rhinitis, asthma, chronic obstructive pulmonary disease, dermatitis, arthritis, lupus, Crohn's disease, inflammatory bowel disease, celiac disease, glomerulonephritis, acne vulgaris, leukemia, pancreatic cancer.

Images