High-potency glucocorticoid compound as well as preparation and application thereof

Abstract

The invention provides a high-potency glucocorticoid compound as well as a preparation method and application thereof. Specifically, the invention provides a high-potency glucocorticoid compound as shown in a formula I as well as a preparation method and application of the high-potency glucocorticoid compound. The glucocorticoid compound of the present invention can achieve the same effect at a lower dose, thereby minimizing side effects. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicine, and particularly relates to a high-potency glucocorticoid compound, its preparation and uses, as well as the uses of a composition containing the above high-potency glucocorticoid compound. Background Art

[0002] Glucocorticoids such as prednisone, dexamethasone (DEX), and budesonide are potent anti-inflammatory drugs. They are widely used in the treatment of inflammatory and autoimmune diseases such as rhinitis, asthma, chronic obstructive pulmonary disease (COPD), dermatitis, arthritis, lupus, and Crohn's disease. These drugs exert their physiological effects by binding to the glucocorticoid receptor (GR), a ligand-activated transcription factor 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 the hormone causes a conformational change in GR, leading to its translocation to the nucleus, where it exerts its transcriptional control activity, i.e., activation (transcriptional activation) or inhibition (transcriptional repression). In transcriptional activation, GR dimerizes, directly binds to specific glucocorticoid response elements, and then recruits coactivators to activate transcription. In transcriptional repression, the general model is as follows: GR binds to other transcription factors (e.g., NF-κB, AP-1) to indirectly tether its binding site through protein-protein interactions. When tethered near the target promoter, GR inhibits downstream gene expression. It is generally believed that transcriptional repression does not require GR dimerization.

[0003] Transcriptional repression is the main mechanism by which glucocorticoids act as anti-inflammatory drugs. The tethering of GR to the NF-κB / AP-1 promoter results in transcriptional repression of major downstream pro-inflammatory factors, including pro-inflammatory cytokines (e.g., TNF-α, IL-1, and IL-6), chemokines (e.g., CCL2, CCL19), and enzymes associated with the onset of inflammation (e.g., COX2, MMP13, and phospholipase A2). Due to the rapid action and sustained effects of glucocorticoids, they remain the treatment of choice for inflammatory diseases. However, long-term use of glucocorticoids, especially at high doses, has many adverse consequences, including diabetes / glucose intolerance, hypertension, obesity, and osteoporosis. Most of these consequences are attributed to the transcriptional activation of GR. For example, glucocorticoids induce genes encoding the rate-limiting enzymes of the glucose production pathway in the liver, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, thereby increasing de novo synthesis of glucose and ultimately leading to weight gain or diabetes. Glucocorticoids also induce the key regulatory gene of bone development, Dickkopf-1 (DKK1), and its upregulation leads to osteoporosis and bone loss. Many side effects of glucocorticoids are commonly observed to be associated with high-dose use 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 "threshold pattern" of prednisone use has been observed: at 7.5 mg per day, it causes glaucoma, depression, and hypertension.These side effects are caused by GR transcriptional activation and off-target activation of other receptors such as the mineralocorticoid receptor (MR), the activation of which causes 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 by a given drug, 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 by GR via DEX requires a glucocorticoid concentration 5 to 6 times higher than gene repression. This differential response provides an opportunity to develop high-potency glucocorticoids that can be used at low doses to achieve complete suppression of inflammatory signals while having minimal transcriptional activation activity and side effects. Finally, the development of insensitivity and resistance to glucocorticoid therapy is a major problem in the treatment of common inflammatory diseases such as chronic obstructive pulmonary disease, rheumatoid arthritis, and inflammatory bowel disease. Glucocorticoid resistance is also an unresolved problem in leukocyte cancers, especially childhood acute leukemia. Several glucocorticoid resistance mechanisms have been identified or proposed, including alterations in kinase pathways, changes in cofactors, and deletions or mutations of receptors. A common observation is a reduced affinity of the ligand for the receptor in glucocorticoid-resistant patients. Such patients treated with high-potency glucocorticoids have shown improvement, but the effect gradually decreases (Gaynon PS, Carrel AL (l999) 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 more high-potency glucocorticoids. Summary of the Invention

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

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

[0008]

[0009] wherein X is O or S;

[0010] is a single bond or a double bond;

[0011] 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 hydrogens in each of the above groups being replaced by R a substituted;

[0012] R2 is -L-R', 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 hydrogens in the above group being replaced by R b substituted;

[0013] R3 is selected from the group consisting of: hydrogen, C 1-6 alkyl, 0, 1, 2 or 3 hydrogens in said C 1-6 alkyl being replaced by R c substituted;

[0014] 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 being replaced by R d substituted;

[0015] Said R a 、R b 、R c 、R d are each independently selected from the group consisting of: hydroxyl, halogen, CN, oxo, carboxyl, amino, sulfonic acid group, C 1-6 alkyl, C 1-6 alkoxy.

[0016] In a preferred embodiment, said R1 is selected from the group consisting of: hydrogen, C 1-6 alkyl; 0, 1, 2 or 3 hydrogens in said C 1-6 alkyl being replaced by halogen;

[0017] Preferably, R1 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, wherein 0, 1, 2, or 3 hydrogens in the above groups are substituted by halogen;

[0018] More preferably, R1 is fluoromethyl.

[0019] In a preferred embodiment, R1 is selected from the group consisting of C 3-7 cycloalkyl, C 6-10 aryl, phenyl, naphthyl, wherein 1, 2, or 3 hydrogens in each of the above groups are substituted by R a substituted.

[0020] In a preferred embodiment, 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), wherein 0, 1, 2, or 3 hydrogens in the above groups are substituted by R b substituted, and the R b is selected from the group consisting of halogen, CN, carboxyl, oxo;

[0021] Preferably, the R2 is selected from the group consisting of:

[0022] In a preferred embodiment, R3 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, wherein 1, 2, or 3 hydrogens in the above groups are substituted by R c substituted.

[0023] In a preferred embodiment, R4 and R5 are each independently -F.

[0024] In a preferred embodiment, it is characterized in that the compound of formula I is selected from the group consisting of:

[0025]

[0026]

[0027] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising: (i) a compound as described in the first aspect of the present invention or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier or adjuvant.

[0028] In a third aspect of the present invention, there is provided a method for modulating the activity of glucocorticoid receptors in a biological sample, comprising the step of contacting the glucocorticoid receptors in the biological sample with a compound as described in the first aspect of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in the second aspect of the present invention.

[0029] In a fourth aspect of the present invention, there is provided the use of a compound as described in the first aspect of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in the second aspect of the present invention in the preparation of a medicament for relieving or treating inflammatory diseases;

[0030] Preferably, the diseases are selected from the group consisting of: rhinitis, asthma, chronic obstructive pulmonary disease (COPD), dermatitis, arthritis, lupus, Crohn's disease, inflammatory bowel disease, celiac disease, glomerulonephritis, acne vulgaris, leukemia, pancreatic cancer.

[0031] In a fifth aspect of the present invention, there is provided a method for treating or reducing the severity of an inflammatory disease in a patient, which comprises the step of administering to the patient a safe and effective amount of a compound as described in the first aspect of the present invention or a pharmaceutical composition as described in the second aspect of the present invention.

[0032] In another preferred embodiment, the disease is rhinitis, asthma, COPD, dermatitis or arthritis.

[0033] 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 specifically described hereinafter (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 Shows the evaluation of the activity of the compounds of the present application in binding to the glucocorticoid receptor.

[0035] Figure 2 Shows the total cell count in the BALF of asthmatic model animals after administration of the compounds of the present application

[0036] Figure 3 Shows the eosinophil count in the BALF of asthmatic model animals after administration of the compounds of the present application.

[0037] Figure 4 Shows the macrophage count in the BALF of asthmatic model animals after administration of the compounds of the present application.

[0038] Figure 5 Shows the neutrophil count in the BALF of asthmatic model animals after administration of the compounds of the present application.

[0039] Figure 6 Shows the lymphocyte count in the BALF of asthmatic model animals after administration of the compounds of the present application. DETAILED DESCRIPTION OF THE INVENTION

[0040] 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. Potency is a very important aspect of this evolution because many adverse side effects are associated with high doses. Administering highly potent glucocorticoids can minimize side effects, and highly potent glucocorticoids can achieve the same therapeutic effect at lower doses. This need has driven the evolution of glucocorticoids from low potency to high potency. Therefore, developing highly potent glucocorticoids to minimize side effects is a key focus of attention.

[0041] Through long-term and in-depth research and extensive screening, the inventors have for the first time developed a highly potent glucocorticoid compound that can achieve the same therapeutic effect at lower doses, thereby minimizing side effects.

[0042] The term

[0043] For the 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, Editors: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0044] For the purposes of the present invention, the carbon numbering of the compounds of formula I is the recognized convention for steroid structures. Thus, the compounds of formula I are numbered as follows:

[0045]

[0046] As described herein, the compounds of the present invention may optionally be substituted with one or more substituents such as those generally described above or as exemplified for the specific classes, subclasses, and species of the present invention.

[0047] As used herein, the term "hydroxy" refers to the -OH moiety.

[0048] As used herein, the term "aliphatic" includes the terms alkyl, alkenyl, alkynyl, each of which is optionally substituted as described below.

[0049] 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-chain. 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 can be substituted with one or more substituents (i.e., optionally substituted), such as halogen, phosphate group, cycloaliphatic group [e.g., cycloalkyl or cycloalkenyl], heteroaliphatic group [e.g., heteroalkyl or heteroalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic group)carbonyl, (cycloaliphatic group)carbonyl, or (heteroaliphatic group)carbonyl], nitro, cyano, amide group [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heteroalkyl)carbonylamino, (heteroalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylaminoalkylaminocarbonyl, cycloalkylaminocarbonyl, heteroalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphatic amino, cycloaliphatic amino, or heteroaliphatic amino], sulfonyl [e.g., aliphatic-S02-], sulfinyl, thioalkyl, thioxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, carboxyl group, carbamoyl, cycloaliphatic oxy, heteroaliphatic oxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. By way of non-limitation, some examples of substituted alkyl groups include carboxy, 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 group)alkyl, or haloalkyl.

[0050] As used herein, "alkenyl" refers to an aliphatic carbonyl group having 2 - 8 (e.g., 2 - 8, 2 - 6, or 2 - 4) carbon atoms and at least one double bond. Similar to alkyl, alkenyl can be straight-chain or branched-chain. Examples of alkenyl include, but are not limited to, allyl, 1- or 2-isopropenyl, 2-butenyl, and 2-hexenyl. The alkenyl may optionally be substituted with one or more substituents such as halogen, phosphate group, cycloaliphatic group [e.g., cycloalkyl or cycloalkenyl], heteroaliphatic group [e.g., heteroalkyl or heteroalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic group)carbonyl, (cycloaliphatic group)carbonyl, or (heteroaliphatic group)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heteroalkyl)carbonylamino, (heteroalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylaminoalkylaminocarbonyl, cycloalkylaminocarbonyl, heteroalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphatic amino, cycloaliphatic amino, heteroaliphatic amino, or aliphatic sulfonylamino], sulfonyl [e.g., alkyl-SO2-, cycloaliphatic-SO2-, or aryl-SO2-], sulfinyl, thioalkyl, thioxy, urea, thiourea, aminosulfonyl, sulfonamide, oxo, carboxyl, carbamoyl, cycloaliphatic oxy, heteroaliphatic oxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Non-limiting examples of substituted alkenyl include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl, (sulfonylamino)alkenyl (such as (alkyl-SO2-amino)alkenyl), aminoalkenyl, amidalkenyl, (cycloaliphatic group)alkenyl, or haloalkenyl.

[0051] As used herein, "alkynyl" refers to an aliphatic carbon group having 2 - 8 (e.g., 2 - 12, 2 - 6 or 2 - 4) carbon atoms and having at least one triple bond. The alkynyl group can be straight-chain or branched-chain. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl. The alkynyl group can 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, thioalkyl [e.g., aliphatic thioalkyl or cycloaliphatic thioalkyl], sulfinyl [e.g., aliphatic sulfinyl or cycloaliphatic sulfinyl], sulfonyl [e.g., aliphatic -S02-, aliphatic amino -S02-, or cycloaliphatic -S02-], amido [e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino, heteroarylcarbonylamino or heteroarylaminocarbonyl], urea, thiourea, sulfamoyl, sulfonamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic group, heterocycloaliphatic group, aryl, heteroaryl, acyl [e.g., (cycloaliphatic group)carbonyl or (heterocycloaliphatic group)carbonyl], amino [e.g., aliphatic amino], thioxy, oxo, carboxyl, carbamoyl, (cycloaliphatic group)oxy, (heterocycloaliphatic group)oxy, or (heteroaryl)alkoxy.

[0052] As used herein, "amido" includes "aminocarbonyl" and "carbonylamino". When used alone or in combination with another group, these terms refer to amido, e.g., when used at the terminus it refers to -N(R X )-C(O)R y -C(O)-N(R X )2, and when used internally it refers to -C(O)-N(R X )- or -N(R X )-C(O)-, where R X and R Y can be hydrogen, an aliphatic group, a cycloaliphatic group, an aryl, an araliphatic group, a heterocycloaliphatic group, a heteroaryl or a heteroaraliphatic group. Examples of amido include alkylamido (such as alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic group)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.

[0053] As used herein, "amino" refers to -NR X R Y where R X and R YEach of which is independently hydrogen, an aliphatic group, a cycloaliphatic group, a (cycloaliphatic group)aliphatic group, an aryl group, an araliphatic group, a heterocycloaliphatic group, a (heterocycloaliphatic group)aliphatic group, a heteroaryl group, a carboxyl group, a thioalkyl group, a sulfinyl group, a sulfonyl group, an (aliphatic group)carbonyl group, a (cycloaliphatic group)carbonyl group, a ((cycloaliphatic group)aliphatic group)carbonyl group, an arylcarbonyl group, an (araliphatic group)carbonyl group, a (heterocycloaliphatic group)carbonyl group, a ((heterocycloaliphatic group)aliphatic group)carbonyl group, a (heteroaryl)carbonyl group, or a (heteroaraliphatic group)carbonyl group, 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 -, where R X has the same meaning as defined above.

[0054] As used herein, "aryl", used alone or as part of a larger moiety such as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to a monocyclic (e.g., phenyl) ring system; a bicyclic (e.g., indenyl, naphthyl, tetrahydronaphthyl, tetrahydroindenyl) ring system; and a tricyclic (e.g., fluorenyl, tetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring system, where the monocyclic ring system is aromatic, or at least one ring 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 phenyl fused to two or more C 4－8 carbocyclic moieties. The aryl group is optionally substituted by one or more substituents, which include aliphatic groups [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic group)aliphatic; heterocycloaliphatic; (heterocycloaliphatic group)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic group)oxy; (heterocycloaliphatic group)oxy; aryloxy; heteroaryloxy; (araliphatic group)oxy; (heteroaraliphatic group)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of a benzo-fused bicyclic or tricyclic aryl); nitro; carboxyl; amido; acyl [e.g., (aliphatic group)carbonyl; (cycloaliphatic group)carbonyl; ((cycloaliphatic group)aliphatic group)carbonyl; (araliphatic group)carbonyl; (heterocycloaliphatic group)carbonyl; ((heterocycloaliphatic group)aliphatic group)carbonyl; or (heteroaraliphatic group)carbonyl]; sulfonyl [e.g., aliphatic -SO2- or amino -SO2-]; sulfinyl [e.g., aliphatic -S(O)- or cycloaliphatic -S(O)-]; thioalkyl [e.g., aliphatic -S-]; cyano; halogen; hydroxy; mercapto; thioxy; urea, thiourea; aminosulfonyl; sulfonamide; or carbamoyl. Alternatively, the aryl group may be unsubstituted.

[0055] Non-limiting examples of substituted aryls include haloaryl [e.g., mono-, di- (such as para-, meta-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl [e.g., (alkoxycarbonyl)aryl, ((aralkyl)carbonyloxy)aryl, and (alkoxycarbonyl)aryl]; (amido)aryl [e.g., (aminocarbonyl)aryl, ((((alkylamino)alkyl)amino)carbonyl)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 [e.g., (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.

[0056] As used herein, "araliphatic", such as "aralkyl", refers to an aliphatic group substituted with an aryl group (e.g., C 1－4 alkyl). "Aliphatic", "alkyl", and "aryl" are as defined herein. Examples of araliphatic groups such as aralkyl are benzyl.

[0057] As used herein, "aralkyl" refers to an alkyl group substituted with an aryl group (e.g., C 1－4alkyl). Both "alkyl" and "aryl" have been defined above. Examples of aralkyl are benzyl. The aralkyl is optionally substituted with one or more substituents such as aliphatic groups [e.g., alkyl, alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl], cycloaliphatic groups [e.g., cycloalkyl or cycloalkenyl], (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, or heteroaralkylcarbonylamino], cyano, halogen, hydroxy, acyl, mercapto, alkylthio, thioxo, urea, thiourea, sulfamoyl, sulfonamide, oxo, or carbamoyl.

[0058] 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., bicycloalkyl or bicycloalkenyl), bicyclic heteroaliphatic groups, bicyclic aryls, and bicyclic heteroaryls.

[0059] As used herein, "cycloaliphatic" groups include "cycloalkyl" and "cycloalkenyl", each of which is optionally substituted as described below.

[0060] 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 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.

[0061] As used herein, "cycloalkenyl" refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds. Examples of cycloalkenyl include cyclopentenyl, 1,4-cyclohexadienyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl.

[0062] The cycloalkyl or cycloalkenyl may optionally be substituted with one or more substituents such as a phosphate group, an aliphatic group [e.g., an alkyl, alkenyl, or alkynyl group], a cycloaliphatic group, a (cycloaliphatic group)aliphatic group, a heterocycloaliphatic group, a (heterocycloaliphatic group)aliphatic group, an aryl group, a heteroaryl group, an alkoxy group, a (cycloaliphatic group)oxy group, a (heterocycloaliphatic group)oxy group, an aryloxy group, a heteroaryloxy group, an (arylaliphatic group)oxy group, a (heteroarylaliphatic group)oxy group, an aroyl group, a heteroaroyl group, an amino group, an amide group [e.g., an (aliphatic group)carbonylamino group, a (cycloaliphatic group)carbonylamino group, a ((cycloaliphatic group)aliphatic group)carbonylamino group, an (aryl)carbonylamino group, an (arylaliphatic group)carbonylamino group, a (heterocycloaliphatic group)carbonylamino group, a ((heterocycloaliphatic group)aliphatic group)carbonylamino group, a (heteroaryl)carbonylamino group, or a (heteroarylaliphatic group)carbonylamino group], a nitro group, a carboxyl group [e.g., HOOC-, an alkoxycarbonyl group, or an alkylcarbonyloxy group], an acyl group [e.g., a (cycloaliphatic group)carbonyl group, a ((cycloaliphatic group)aliphatic group)carbonyl group, an (arylaliphatic group)carbonyl group, a (heterocycloaliphatic group)carbonyl group, a ((heterocycloaliphatic group)aliphatic group)carbonyl group, or a (heteroarylaliphatic group)carbonyl group], a cyano group, a halogen, a hydroxyl group, a mercapto group, a sulfonyl group [e.g., an alkyl-SO2- and an aryl-SO2-], a sulfinyl group [e.g., an alkyl-S(O)-], a thioalkyl group [e.g., an alkyl-S-], a thiooxy group, a urea, a thiourea, a sulfamoyl group, a sulfonamide, an oxo group, or a carbamoyl group.

[0063] As used herein, the term "heterocycloaliphatic" includes heterocycloalkyl and heterocycloalkenyl, each of which is optionally substituted as described below.

[0064] As used herein, "heterocycloalkyl" refers to a 3- to 10-membered monocyclic or bicyclic (fused or bridged) (e.g., 5- to 10-membered monocyclic or bicyclic) saturated ring structure in which one or more ring atoms are heteroatoms (e.g., N, O, S, or a combination thereof). Examples of heterocycloalkyl include piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, octahydrobenzofuranyl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyridyl, 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 may be fused to a phenyl moiety to form a structure such as tetrahydroisoquinoline, which would be classified as a heteroaryl.

[0065] As used herein, "heterocyclenyl" 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 of the ring atoms are heteroatoms (e.g., N, O, or S). Monocyclic and bicyclic heterocyclic aliphatic groups are numbered according to standard chemical nomenclature.

[0066] The heterocycloalkyl or heterocyclenyl may optionally be substituted with one or more substituents such as a phosphate group, an aliphatic group [e.g., an alkyl, alkenyl, or alkynyl group], a cycloaliphatic group, a (cycloaliphatic group)aliphatic group, a heterocycloaliphatic group, a (heterocycloaliphatic group)aliphatic group, an aryl group, a heteroaryl group, an alkoxy group, a (cycloaliphatic group)oxy group, a (heterocycloaliphatic group)oxy group, an aryloxy group, a heteroaryloxy group, an (arylaliphatic group)oxy group, a (heteroarylaliphatic group)oxy group, an aroyl group, a heteroaroyl group, an amino group, an amide group [e.g., an (aliphatic group)carbonylamino group, a (cycloaliphatic group)carbonylamino group, a ((cycloaliphatic group)aliphatic group)carbonylamino group, an (aryl)carbonylamino group, an (arylaliphatic group)carbonylamino group, a (heterocycloaliphatic group)carbonylamino group, a ((heterocycloaliphatic group)aliphatic group)carbonylamino group, a (heteroaryl)carbonylamino group, or a (heteroarylaliphatic group)carbonylamino group], a nitro group, a carboxyl group [e.g., HOOC-, an alkoxycarbonyl group, or an alkylcarbonyloxy group], an acyl group [e.g., a (cycloaliphatic group)carbonyl group, a ((cycloaliphatic group)aliphatic group)carbonyl group, an (arylaliphatic group)carbonyl group, a (heterocycloaliphatic group)carbonyl group, a ((heterocycloaliphatic group)aliphatic group)carbonyl group, or a (heteroarylaliphatic group)carbonyl group], a nitro group, a cyano group, a halogen, a hydroxyl group, a mercapto group, a sulfonyl group [e.g., an alkylsulfonyl group or an arylsulfonyl group], a sulfinyl group [e.g., an alkylsulfinyl group], a thioalkyl group [e.g., an alkylthioalkyl group], a thioxy group, a urea, a thiourea, a sulfamoyl group, a sulfonamide, an oxo group, or a carbamoyl group.

[0067] 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 are heteroatoms (e.g., N, O, S, or combinations 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 benzyl groups fused to one or two 4- to 8-membered heteroaliphatic moieties (e.g., indolizinyl, indolyl, isoindolyl, 3H-indolyl, dihydroindolyl, benzo[b]furanyl, benzo[b]thienyl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl are azetidinyl, pyridyl, 1H-indolyl, furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuranyl, isoquinolinyl, benzothiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxolyl, benzo[b]furanyl, benzo[b]thienyl, indolyl, benzimidazolyl, benzothiazolyl, purinyl, cinnolinyl, quinolinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, isoquinolinyl, 4H-quinolizinyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridinyl.

[0068] Non-limiting examples of monocyclic heteroaryl include furanyl, thienyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl, or 1,3,5-triazinyl. Monocyclic heteroaryl is numbered according to standard chemical nomenclature.

[0069] Non-limiting examples of bicyclic heteroaryl include indolizinyl, indolyl, isoindolyl, 3H-indolyl, dihydroindolyl, 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 is numbered according to standard chemical nomenclature.

[0070] The heteroaryl is optionally substituted with one or more substituents such as an aliphatic group [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic group)aliphatic; heterocycloaliphatic; (heterocycloaliphatic group)aliphatic; aryl; heteroaryl; alkoxy; (cycloaliphatic group)oxy; (heterocycloaliphatic group)oxy; aryloxy; heteroaryloxy; (arylalkyl group)oxy; (heteroarylalkyl group)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxyl; amido; acyl [e.g., aliphatic carbonyl; (cycloaliphatic group)carbonyl;

[0071] ((cycloaliphatic group)aliphatic group)carbonyl; (arylalkyl group)carbonyl; (heterocycloaliphatic group)carbonyl; ((heterocycloaliphatic group)aliphatic group)carbonyl; or (heteroarylalkyl group)carbonyl]; sulfonyl [e.g., aliphatic sulfonyl or aminosulfonyl]; sulfinyl [e.g., aliphatic sulfinyl]; thioalkyl [e.g., aliphatic thioalkyl]; nitro; cyano; halogen; hydroxy; mercapto; thiooxy; urea; thiourea; aminosulfonyl; sulfonamide; or carbamoyl. Alternatively, the heteroaryl may be unsubstituted.

[0072] Non-limiting examples of the substituted heteroaryl 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 group)carbonyl)heteroaryl, and ((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl; (alkoxy)heteroaryl; (aminosulfonyl)heteroaryl [e.g., (aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g., (alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl; (alkoxyalkyl)heteroaryl; (hydroxy)heteroaryl;

[0073] ((carboxy)alkyl)heteroaryl; ((((dialkyl)amino)alkyl]heteroaryl; (heterocycloaliphatic group)heteroaryl; (cycloaliphatic group)heteroaryl; (nitroalkyl)heteroaryl; ((((alkylsulfonyl)amino)alkyl)heteroaryl;

[0074] ((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl; (acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl]; (alkyl)heteroaryl; or (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryl].

[0075] As used herein, "heteroarylalkyl" (such as heteroarylalkyl) refers to an aliphatic group substituted with a heteroaryl (e.g., C1-4 (alkyl). "Aliphatic", "alkyl", and "heteroaryl" have been defined above.

[0076] As used herein, "heteroarylalkyl" means an alkyl group substituted with a heteroaryl group (e.g., C 1-4 alkyl). "Alkyl" and "heteroaryl" have both been defined above. The heteroarylalkyl 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, arylalkyloxy, heteroarylalkyloxy, arylcarbonyl, heteroarylcarbonyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, arylalkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroarylalkylcarbonylamino, cyano, halogen, hydroxy, acyl, mercapto, alkylthio, sulfinyl, urea, thiourea, sulfamoyl, sulfonamide, oxo, or carbamoyl.

[0077] As used herein, "ring moiety" and "ring group" mean mono-, bi- and tricyclic ring systems, including cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl, each of which has been defined previously.

[0078] As used herein, "bridged bicyclic ring system" refers to a bicyclic heterocyclic aliphatic ring system or a bicyclic cycloaliphatic ring system, wherein 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-dioxatricyclo[3.3.1.03,7]nonyl. The bridged bicyclic ring system may optionally be 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, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halogen, hydroxy, acyl, thio, alkylthio, thioxo, urea, thiourea, sulfamoyl, sulfonamide, oxo, or carbamoyl.

[0079] 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 previously. Acetyl and pivaloyl are examples of acyl.

[0080] As used herein, "aroyl" or "heteroaroyl" refers to aryl-C(O)- or heteroaryl-C(O)-. The aryl and heteroaryl moieties of aroyl or heteroaroyl are optionally substituted as defined previously.

[0081] As used herein, an "alkoxy" group refers to an alkyl-O- group, where "alkyl" has been defined previously.

[0082] As used herein, "carbamoyl" refers to a group having the structure -O-CO-NR X R Y or -NR X -CO-O-R Z where R X and R Y have been defined above, and R Z can be an aliphatic group, aryl, araliphatic group, heterocycloaliphatic group, heteroaryl, or heteroaraliphatic group.

[0083] 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-.

[0084] As used herein, a "haloaliphatic" group refers to an aliphatic group substituted with 1-3 halogens. For example, the term haloalkyl includes the groups -CF3, -CHF2, and —CH2F.

[0085] As used herein, "sulfhydryl" refers to -SH.

[0086] As used herein, "sulfonic" when used at the end refers to -SO3H or -SO3R X or when used internally refers to -S(O)3-O.

[0087] As used herein, a "sulfonamide" group when used at the end refers to -S(O)2-NR X R Y and when used internally refers to -NRX-S(O)2-NR Y -, where R X R Y and R Z are defined above.

[0088] As used herein, "sulfamoyl" refers to -O-S(O)2-NR X R Y structure, where R Y and R Y are defined above.

[0089] As used herein, a "sulfonamide" group when used at the end refers to -S(O)2-NR Y R Z or -NR X -S(O)2-R Z structure; or when used internally refers to -S(O)2-NR X - or -NR X -S(O)2-, where R X R Y and R Z are as defined above.

[0090] As used herein, "thioalkyl" when used at the end refers to -S-R X , and when used internally refers to -S-, where R X is defined above. Examples of thioalkyl include aliphatic -S-, cycloaliphatic -S-, aryl -S-, etc.

[0091] As used herein, "sulfinyl", when used at the terminus, refers to -S(O)-R X , and when used internally, refers to -S(O)-, where R X has been defined above. Exemplary sulfinyl groups include aliphatic -S(O)-, aryl -S(O)-, (cycloaliphatic(aliphatic))-S(O)-, cycloalkyl -S(O)-, heterocycloaliphatic -S(O)-, heteroaryl -S(O)-, etc.

[0092] As used herein, "sulfonyl", when used at the terminus, refers to -S(O)2-R X , and when used internally, refers to -S(O)2-, where R X has been defined above. 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-, etc.

[0093] As used herein, when used at the terminus, "sulfonyloxy" refers to -O-S(O)-R X or -S(O)-R X , and when used internally, refers to -O-S(O) or -S(O)-O, where R X has been defined above.

[0094] As used herein, the term "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine.

[0095] As used herein, the "alkoxycarbonyl" encompassed by the term carboxyl, when used alone or in combination with another group, refers to a group such as alkyl -O-C(O)-.

[0096] As used herein, "alkoxyalkyl" refers to an alkyl group such as alkyl -O-alkyl-, where alkyl has been defined above.

[0097] As used herein, "carbonyl" refers to -C(O)-.

[0098] As used herein, "oxo" refers to =O.

[0099] As used herein, the term "phospho group" refers to phosphonates and phosphates. Examples of phosphonates and phosphates include -P(O)(RP)2, where RP is an aliphatic group, alkoxy, aryloxy, heteroaryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy aryl, heteroaryl, cycloaliphatic or amino.

[0100] As used herein, aminoalkyl refers to the (R X )2N-alkyl- structure.

[0101] As used herein, "cyanoalkyl" refers to the (NC)-alkyl- structure.

[0102] As used herein, "ureido" refers to -NR X -CO-NR X R Y structure, and "thioureido" when used at the end 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 have been defined above.

[0103] 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 R X and R Y are defined above.

[0104] As used herein, the term "amidinyl" refers to -C=(NR X )N(R X R Y ) structure where R X and R Y have been defined above.

[0105] As used herein, the term "plurality" refers to a positive integer of 2, 3, 4, 5, or greater than 5.

[0106] The terms "at the end" and "internally" refer to the position of a group within a substituent. When a group is present at the end of a substituent and is not further bonded to the remainder of the chemical structure, the group is terminal. Carboxyalkyl, i.e., R X O(O)C-alkyl, is an example of a carboxy group used at the end. When a group is present in the middle of a substituent of a chemical structure, the group is internal. Alkyl carboxy (e.g., alkyl-C(O)O- or alkyl-OC(O)-) and alkyl carboxyaryl (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally.

[0107] As used herein, "aliphatic chain" refers to a branched or straight-chain aliphatic group (e.g., alkyl, alkenyl, or alkynyl). In some embodiments, the straight-chain aliphatic chain has -[CH2] V - structure, where v is 1 - 12. In some embodiments, the branched aliphatic chain is a straight-chain aliphatic chain substituted with one or more aliphatic groups. The branched aliphatic chain has -[CQQ] V , — structure, where Q is independently hydrogen or an aliphatic group; however, in at least one instance, Q should be an aliphatic group. The term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are as defined above.

[0108] The phrase "optionally substituted" can be used interchangeably with the phrase "substituted or unsubstituted". As described herein, the compounds of the present invention may optionally be substituted with one or more substituents such as those generally described above, or as exemplified for the specific classes, subclasses, and species of the present invention. As described herein, the variant R1, R2, R3, R4, R5, and X and other variables contained in the formulas described herein encompass specific groups such as alkyl and aryl. Unless otherwise noted, each specific group of these variables may optionally be substituted with one or more substituents described herein. Each substituent of a specific group is further optionally substituted with 1 to 3 halogens, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl, and alkyl. For example, an alkyl can be substituted with an alkylthio group, and the alkylthio group can optionally be substituted with 1 to 3 halogens, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, heteroaryl, haloalkyl, and alkyl. As another example, the cycloalkyl moiety of (cycloalkyl)carbonylamino can optionally be substituted with 1 to 3 halogens, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bonded to the same atom or adjacent atoms, the two alkoxy groups can together with one or more atoms to which they are bonded form a ring.

[0109] Generally, the term "substituted", whether preceded by the term "optionally" or not, refers to the replacement of a hydrogen group in a given structure with a given substituent. Specific substituents are described in the definitions above and in the descriptions of its compounds and examples below. Unless otherwise indicated, an optionally substituted group can have substituents at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a particular group, the substituents can be the same or different at each position. Ring substituents, such as heterocycloalkyl, can be bonded to another ring, such as cycloalkyl, to form a spiro-bicyclic ring system; for example, the two rings share a common atom. As will be recognized by those of ordinary skill in the art, the combinations of substituents contemplated by the present invention are those that result in the formation of stable or chemically viable compounds. Unless otherwise stated, the structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations of each asymmetric center, the (Z)(E) double bond isomers, and the (Z) and (E) conformational isomers. Thus, both the individual stereoisomers and mixtures of enantiomers, diastereomers, and geometric (or conformational) isomers of the compounds of the present invention are within the scope of the present invention.

[0110] In addition, unless otherwise stated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention (except for the replacement of hydrogen with deuterium or tritium or the replacement of carbon with carbon enriched in 13 C or 14 C) are within the scope of the present invention. Such compounds can be used, for example, as analytical tools or probes in biological assays or as therapeutic agents.

[0111] Active ingredient

[0112] As used herein, "compounds of the present invention" refers to compounds of formula I or their pharmaceutically acceptable salts.

[0113]

[0114] Wherein,

[0115] X is -O- or -S-;

[0116] --- is a bond or absent;

[0117] R1 is selected from hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl or heterocycloalkyl, any of which is optionally substituted;

[0118] R2 is -L-R'- where L is a bond or -C(O)- and R' is selected from hydrogen, C 1-6 alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl or heterocycloalkyl, where R' is optionally substituted;

[0119] R3 is hydrogen or optionally substituted C 1-6 alkyl;

[0120] R4 and R5 are each independently hydrogen, halogen, or C 1-4 alkyl.

[0121] In some embodiments, R1 is hydrogen, C 1-6 alkyl, cycloalkyl, or aryl, where the alkyl, cycloalkyl or aryl is optionally substituted. For example, R1 is alkyl, cycloalkyl or aryl, any one of which is optionally substituted by halogen.

[0122] In other embodiments, R1 is hydrogen or C 1-6 alkyl, where the C 1-6 alkyl is optionally substituted by 1 - 3 halogens.

[0123] In some embodiments, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert - butyl, any one of which is optionally substituted by 1 - 3 halogens. For example, R1 is fluoromethyl.

[0124] In other embodiments, R1 is unsubstituted C 1-6 alkyl. For example, R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert - butyl. In certain cases, R1 is ethyl. In certain cases, R1 is isopropyl. In certain cases, R1 is tert - butyl. In certain cases, R1 is hydrogen.

[0125] In some embodiments, R1 is optionally substituted 3 - 7 - membered cycloalkyl, phenyl, or naphthyl, any one of which is optionally substituted.

[0126] In some embodiments, L is -C(O)- and R' is hydrogen, C 1-6 alkyl, aralkyl, heteroaryl, or heteroaralkyl, where R2 is optionally substituted by halogen, CN, carboxyl or oxo group. For example, L is -C(O)- and R2 is heteroaryl.

[0127] In other embodiments, R2 is

[0128] In some embodiments, R3 is optionally substituted C 1-6 alkyl. For example, R3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert - butyl, any one of which is optionally substituted.

[0129] In other embodiments, R3 is hydrogen.

[0130] In some embodiments, X is -O-.

[0131] In some embodiments, X is -S-.

[0132] In some embodiments, --- is a bond.

[0133] In some embodiments, --- is absent.

[0134] In some embodiments, R4 and R5 are each independently hydrogen or halogen. For example, both R4 and R5 are F.

[0135] In some embodiments, the compounds of Formula I are selected from the compounds in Table 1 below.

[0136] Table 1: Compounds of Formula I.

[0137]

[0138]

[0139] Pharmaceutical Compositions

[0140] In one aspect of the invention, there are provided pharmaceutically acceptable compositions, namely pharmaceutical compositions, wherein these compositions comprise any of the compounds 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.

[0141] It should also be understood that certain compounds of the invention may be in the free form for use in therapy or, where appropriate, as their pharmaceutically acceptable derivatives or prodrugs. According to the invention, pharmaceutically acceptable derivatives or prodrugs include, but are not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adducts or derivatives which, upon administration to a patient in need, are capable of directly or indirectly providing the compounds described herein or their metabolites or residues.

[0142] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc. and which are commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" 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 directly or indirectly providing the compound of the invention or its metabolite or residue having inhibitory activity.

[0143] Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (which is 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 reacting an amino group with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with an organic acid 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.

[0144] Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanedisulfonates, esulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. Salts derived from appropriate bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 (alkyl)4 salts. 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, etc. When appropriate, additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0145] As described above, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant or vehicle, which as used herein includes any and all solvents, diluents, or other liquid vehicles, dispersing or suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc. suitable for the particular dosage form desired. Remington's Pharmaceutical Sciences, 16th Edition, E.W. Martin (Mack Publishing Co., Easton, Pa, 1980) discloses various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation. Unless any conventional carrier medium is incompatible with the compounds of the present invention, e.g., by producing any undesirable biological effects or otherwise interacting in a harmful manner with one or more other components of the pharmaceutically acceptable composition, 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 exchange agents, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid or potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polypropylene-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 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; diols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, and phosphate buffer solutions, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and coloring agents, release agents, coating agents, sweetening agents, flavoring agents and fragrances, and, according to the judgment of the formulator, preservatives and antioxidants may also be present in the composition.

[0146] Use and Administration of Compounds and Pharmaceutical Compositions

[0147] In another aspect, the present invention provides a method for treating or reducing the severity of inflammation in a subject, the method comprising administering to a subject in need thereof, 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 reducing the severity of an inflammatory disease in a subject, the method comprising administering to a subject in need thereof, preferably a mammal, an effective amount of a composition comprising a compound of Formula I.

[0148] In another aspect, the present invention provides a method for treating or reducing the severity of a disorder, disease or condition involving the glucocorticoid receptor. In certain embodiments, the present invention provides a method for treating a disorder, disease or condition involving a deficiency of glucocorticoid receptor activity, the method comprising administering to a subject in need thereof, preferably a mammal, an effective amount of a composition comprising a compound of Formula I. In certain embodiments, the present invention provides a method for treating an inflammatory disorder, disease or condition in a subject having normal glucocorticoid receptor activity, the method comprising administering to a subject in need thereof, preferably a mammal, an effective amount of a composition comprising a compound of Formula I.

[0149] In another aspect, the present invention provides a method for treating or reducing the severity of a disorder, disease or condition involving the glucocorticoid receptor, wherein the disorder, disease or condition is selected from rhinitis, asthma, chronic obstructive pulmonary disease (COPD), dermatitis, arthritis, lupus, Crohn's disease, inflammatory bowel disease, celiac disease, glomerulonephritis, acne vulgaris, leukemia and pancreatic cancer.

[0150] According to the present invention, an "effective amount" of the compound or pharmaceutically acceptable composition is an amount effective to treat one or more of the diseases, disorders or conditions described above or reduce their severity.

[0151] The compounds and compositions of the method according to the present invention can be administered using any dosage amount and any route of administration effective to treat one or more of the diseases, disorders or conditions described above or reduce their severity.

[0152] 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 exact amount required will vary from subject to subject. Preferably, the compounds of the present invention are formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the expression "dosage unit form" refers to physically discrete units of medicament 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 dosage 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 particular compound used; the specific composition used; the age, weight, general health, sex and diet of the patient; the time of administration, route of administration and excretion rate of the particular compound used; the duration of the treatment; drugs used in combination with or concurrently with the particular compound used, and similar factors well known in the medical arts. As used herein, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

[0153] Depending on the severity of the infection being treated, the pharmaceutically acceptable compositions of the present invention can be administered orally, rectally, parenterally, intrathecally, vaginally, intraperitoneally, topically (such as by powder, ointment, drops or patch), buccally, as an oral or nasal spray, etc. to humans and other animals. In certain embodiments, the compounds of the present invention can be administered orally or parenterally once or more times a 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 the subject's body weight, to obtain the desired therapeutic effect.

[0154] 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, solubilizing agents and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butanediol, dimethylformamide, oils (especially 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 the inert diluent, these oral compositions may also contain adjuvants, such as wetting agents, emulsifying agents and suspending agents, sweetening agents, flavoring agents and aromatic agents.

[0155] Injectable formulations can be prepared according to known techniques using suitable dispersing or wetting agents and suspending agents, such as sterile injectable aqueous or oily suspensions. The sterile injectable formulation can also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be employed include water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. Additionally, a sterile fixed oil is commonly used as a solvent or suspending medium. For this purpose, any mild fixed oil can be employed, including synthetic mono- or di-glycerides of fatty acids. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0156] The injectable preparation can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0157] To prolong the effect of the compounds of the present invention, it is generally desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous material. The rate of absorption of the compound then depends on its rate of dissolution, which in turn can depend on crystal size and crystal form. Alternatively, delayed absorption of the compound in a form suitable for parenteral administration is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are made by forming a microcapsule matrix of the compound in a biodegradable polymer such as poly(lactide-co-glycolide). Depending on the ratio of the compound to the polymer and the nature of the particular polymer used, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions compatible with body tissues.

[0158] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and thus melts in the rectal or vaginal cavity and releases the active compound.

[0159] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or calcium phosphate dibasic and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginate, 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 retardants such as paraffin wax; f) absorption promoters such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol 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 contain buffering agents.

[0160] Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They may optionally contain opacifying agents and may also have a composition such that they release only one or more active ingredients, or preferentially in a certain part of the intestine, preferably in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0161] The active compound can also be in microencapsulated form with one or more of the 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 well known in the art of pharmaceutical formulation. In such solid dosage forms, the active compound can be admixed with at least one inert diluent such as sucrose, lactose, or starch. These dosage forms may also contain (as is common practice) additional substances in addition to the inert diluent such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. They may optionally contain opacifying agents and may also have a composition such that they release only one or more active ingredients, or preferentially in a certain part of the intestine, preferably in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0162] Dosage forms for the topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed with a pharmaceutically acceptable carrier and any desired preservatives or buffering agents as may be required, under sterile conditions. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in a suitable medium. Penetration enhancers may also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymeric matrix or gel.

[0163] The activity of the compounds used as glucocorticoid receptor modulators in the present invention can be determined according to the methods generally described in the art and in the examples herein.

[0164] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0165] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (such as a human) in need of treatment, wherein the dosage administered is a pharmaceutically effective dosage. For a person weighing 60 kg, the daily dosage is generally 1 - 2000 mg, preferably 5 - 500 mg. Of course, the specific dosage should also consider factors such as the route of administration and the health status of the patient, which are within the scope of the skills of a skilled physician.

[0166] Preparation methods

[0167] Method 1:

[0168]

[0169] Method 2:

[0170]

[0171] Advantages of the present invention:

[0172] Compared with conventional and up-to-date glucocorticoid drugs, the glucocorticoid compounds of the present invention show stronger glucocorticoid receptor affinity and stronger anti-inflammatory effects in vivo, and can achieve the same therapeutic effect at a lower dose, thereby minimizing side effects.

[0173] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0174] Example 1: Synthesis of Compound PA7200

[0175] First Step: Synthesis of Intermediate Compound 1-B

[0176]

[0177] Under a nitrogen atmosphere, commercially available compound 1-A (50 g, 122 mmol) and anhydrous ethanol (150 mL) were added to 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 while controlling the temperature below 30 °C. After the addition was complete, the temperature was controlled at 25 - 30 °C and stirring was continued for 3 hours. Monitoring by LC-MS showed that compound 1-A had basically disappeared. 150 mL of drinking water was added to the reaction system and stirred for 1 hour. The mixture was filtered, and the filter cake was washed with a mixture of ethanol and water (1:1). The solid was placed in an oven to dry to obtain 48.1 g of compound 1-B, with a yield of 99.6%, LC-MS: [M+1] + = 397.2.

[0178] NMR: 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 7.29 (d, J = 10.4 Hz, 1H), 6.31 (dd, J = 10.2, 1.7 Hz, 1H), 6.12 (s, 1H), 5.65 (ddd, J = 48.7, 10.0, 6.8 Hz, 1H), 5.36 (d, J = 2.1 Hz, 1H), 4.72 (s, 1H), 4.16 (d, J = 9.4 Hz, 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 = 7.1 Hz, 3H).

[0179] Second Step: Synthesis of Intermediate Compound 1-C

[0180]

[0181] Under a nitrogen atmosphere, compound 1-B (48 g, 121 mmol) and methanol (190 mL) were added to a 500 mL reaction flask. The system was cooled to 5 - 15 °C and stirred, with the temperature controlled below 20 °C. Thionyl chloride (21.41 g, 182 mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to 60 °C and the reaction was carried out overnight. Monitoring the reaction progress, compound 1-B had basically disappeared. The organic solvent was evaporated under reduced pressure. The crude product of compound 1-C obtained was slurried with a mixed solution of ethyl acetate (48 mL) and petroleum ether (144 mL) and stirred for 2 hours. After filtration, the solid was dried in an oven to obtain 48.7 g of compound 1-C, with a yield of 97.76%, LC-MS: [M + 1] + = 411.1.

[0182] NMR: 1 H NMR (400 MHz, DMSO-d6) δ 7.34 (dd, J = 28.3, 10.2 Hz, 1H), 6.32 (dd, J = 10.1, 1.5 Hz, 1H), 6.14 (s, 1H), 5.66 (ddd, J = 48.8, 10.5, 7.0 Hz, 1H), 5.37 (t, J = 19.9 Hz, 1H), 5.04 (s, 1H), 4.17 (d, J = 10.1 Hz, 1H), 3.67 (s, 3H), 2.62 - 2.37 (m, 2H), 2.22 (dd, J = 20.8, 16.1 Hz, 1H), 2.20 - 1.95 (m, 2H), 1.70 (q, J = 11.8 Hz, 1H), 1.63 - 1.41 (m, 5H), 1.21 - 1.02 (m, 1H), 1.02 - 0.81 (m, 6H).

[0183] Step 3: Synthesis of intermediate compound 1-D

[0184]

[0185] Compound 1-C (48.5 g, 118 mmol), methanol (170 mL) and tetrahydrofuran (72 mL) were added to a 500 mL reaction flask. After stirring evenly, 6.3 g of Pd / C (10%) was added, and the system was purged with hydrogen three times. The reaction was stirred at room temperature under a hydrogen atmosphere for 2 days. Monitoring the reaction progress, compound 1-C and the intermediate states had basically disappeared. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with tetrahydrofuran (72 mL). The filtrate was concentrated to dryness under reduced pressure, and the solid was dried in an oven to obtain 50 g of compound 1-D, with a yield of 98.61%, LC-MS: [M + H2O] + = 432.5.

[0186] NMR: 11H NMR (400 MHz, DMSO-d6) δ 5.14 (ddd, J = 17.8, 11.6, 5.4 Hz, 1H), 5.03 - 4.91 (m, 2H), 4.23 (s, 1H), 3.66 (s, 3H), 2.90 (dd, J = 12.5, 5.5 Hz, 1H), 2.66 - 2.55 (m, 2H), 2.35 (dd, J = 24.5, 13.7 Hz, 2H), 2.28 - 2.03 (m, 5H), 1.81 (d, J = 3.4 Hz, 1H), 1.73 - 1.58 (m, 3H), 1.52 (d, J = 13.9 Hz, 1H), 1.27 (s, 3H), 1.10 (dd, J = 15.0, 11.4 Hz, 1H), 0.98 - 0.88 (m, 6H).

[0187] Step 4: Synthesis of Intermediate Compound 1-E

[0188]

[0189] Under a nitrogen atmosphere, compound 1-D (49.5 g, 119 mmol) and dichloromethane (1500 mL) were added to a 5 L reaction flask. The system was cooled to 0 - 10 °C and stirred, and pyridine tribromide (41.3 g, 262 mmol) was added in batches. After the addition was complete, the reaction was carried out at room temperature for 3 hours. Monitoring the reaction, compound 1-D had 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) and then washed with saturated brine (1500 mL), and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness, and the solid was dried in an oven to obtain 69.4 g of crude compound 1-E. LC-MS: [M + H2O] + = 589.9

[0190] Nuclear magnetic resonance: 1 1H NMR (400 MHz, DMSO-d6) δ 5.14 (ddd, J = 17.8, 11.6, 5.4 Hz, 1H), 5.03 - 4.91 (m, 2H), 4.23 (s, 1H), 3.67 (s, 3H), 2.90 (dd, J = 12.5, 5.5 Hz, 1H), 2.66 - 2.55 (m, 1H), 2.35 (dd, J = 24.5, 13.7 Hz, 1H), 2.20 - 2.07 (m, 5H), 1.84 (d, J = 3.4 Hz, 1H), 1.58 (m, 3H), 1.50 (d, J = 13.9 Hz, 1H), 1.33 (s, 3H), 1.20 (dd, J = 15.0, 11.4 Hz, 1H), 0.99 - 0.88 (m, 6H).

[0191] Step 5: Synthesis of Intermediate Compound 1-F

[0192]

[0193] Under a nitrogen atmosphere, the crude product of Compound 1-E (69 g, 119 mmol) and DMAC (255 mL) were charged into a 500 mL reaction flask. After stirring evenly, the temperature of the system was raised to 45 °C, lithium bromide (20.67 g, 238 mmol) was added, and the mixture was stirred for 5 minutes. Then calcium carbonate (23.8 g, 238 mmol) was added, and the temperature of the system was raised to 95 °C and the reaction continued for 3 hours. The system was cooled to room temperature, 4M aqueous sodium hydroxide solution (500 mL) was added to the reaction system, and the reaction was carried out at room temperature for 3 hours. Then the pH was adjusted to 1 - 2 with 2 mol / L hydrochloric acid solution, ethyl acetate (500 mL) was added for extraction, the organic phase was separated, the organic phase was washed twice with drinking water (500 mL) and once with saturated brine (500 mL), and dried over anhydrous sodium sulfate. After filtration, the organic phase was evaporated to dryness under reduced pressure, and the solid was dried in an oven to obtain 49.7 g of the crude product of Compound 1-F. The 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 mixed solution of acetonitrile (100 mL) and methanol (100 mL), stirred for two hours, filtered, and the solid was dried in an oven to obtain 15.7 g of Compound 1-F. The overall yield of the two steps was 32.75%, LC-MS: [M + 1] + = 397.0.

[0194] NMR: 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 5.87 (s, 1H), 5.64 (d, J = 15.1 Hz, 1H), 5.22 (d, J = 1.9 Hz, 1H), 4.13 (s, 1H), 3.18 - 2.82 (m, 2H), 2.78 - 2.59 (m, 1H), 2.37 (dd, J = 19.8, 12.5 Hz, 2H), 2.24 (td, J = 14.0, 4.7 Hz, 1H), 2.17 - 2.02 (m, 2H), 1.76 (q, J = 11.4 Hz, 1H), 1.65 - 1.41 (m, 5H), 1.36 - 1.18 (m, 1H), 1.06 (d, J = 6.3 Hz, 3H), 0.92 (d, J = 7.1 Hz, 3H).

[0195] Step 6: Synthesis of Intermediate Compound 1-G

[0196]

[0197] Under a nitrogen atmosphere, compound 1-F (900 mg, 2.27 mmol) and dichloromethane (30 mL) were added into a 100 mL reaction flask. After stirring evenly, the temperature of the system was cooled to 10 °C, and pyridinium tribromide (376 mg, 2.38 mmol) was added in batches. After the addition was completed, the reaction continued for 6 hours. Monitoring the reaction, 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), once with saturated brine (50 mL), and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure, and the solid was dried in an oven to obtain 1.1 g of crude compound 1-G. LC-MS: [M+1] + = 474.9.

[0198] Step 7: Synthesis of intermediate compound 1-H

[0199]

[0200] Under a nitrogen atmosphere, crude compound 1-G (1.1 g, 2.31 mmol) and DMAC (20 mL) were added into a 100 mL reaction flask. After stirring evenly, the temperature of the system was raised to 45 °C, lithium bromide (400 mg, 4.62 mmol) was added, and the mixture was stirred for 5 minutes. Then calcium carbonate (462 mg, 4.62 mmol) was added, and the temperature of the system was raised to 95 °C and the reaction 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, and the organic phase was separated. The organic phase was washed twice with drinking water (50 mL), once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to dryness under reduced pressure. The solid was dried in an oven to obtain 890 mg of the compound. The overall yield of the two steps was 97%. LC-MS: [M+1] + = 395.0.

[0201] NMR: 11H NMR (400 MHz, DMSO-d6) δ 14.71 - 9.60 (m, 1H), 7.42 (d, J = 10.2 Hz, 1H), 6.35 (d, J = 10.1 Hz, 1H), 6.22 (s, 1H), 5.64 (d, J = 14.9 Hz, 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 = 6.9 Hz, 1H), 2.34 (dd, J = 20.3, 12.0 Hz, 1H), 2.18 - 2.06 (m, 1H), 1.78 (q, J = 11.5 Hz, 1H), 1.64 - 1.50 (m, 4H), 1.26 (dd, J = 14.1, 6.1 Hz, 1H), 1.07 (s, 3H), 0.91 (d, J = 7.1 Hz, 3H).

[0202] Step 8: Synthesis of Compound 1-I:

[0203]

[0204] 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 then 2-furoyl chloride (366 mg, 2.82 mmol) was slowly added dropwise. After the addition was complete, the reaction was carried out at room temperature for 1 hour. Monitored by TLC, the raw materials disappeared and were converted into an intermediate state. The organic solvent was evaporated to dryness under reduced pressure, and the crude product was added to 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 reacted for another 10 hours. Monitored, all the intermediate states were 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 dried in an oven to obtain 490 mg of compound 1-I, with a yield of 88.9%, LC-MS: [M + 1] + = 489.0.

[0205] Step 9: Synthesis of Intermediate Compound 1-J:

[0206]

[0207] 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 added to a 50 mL reaction flask. After stirring evenly, the temperature of the system was lowered to 0-5 °C, and dimethylamino-thiocarbonyl chloride (185 mg, 1.5 mmol) was added. Then the reaction was carried out at room temperature for 16 hours. Monitored by TLC, when the raw materials 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 evaporated to dryness under reduced pressure. The solid was dried in an oven to obtain 507 mg of compound 1-J, with a yield of 87.8%.

[0208] Step 11: Synthesis of intermediate compound 1-K

[0209]

[0210] Under a nitrogen atmosphere, compound 1-J (490 mg, 0.85 mmol), potassium carbonate (351 mg, 2.54 mmol) with a mesh size of 100 and ethanol (5 mL) were added to a 50 mL reaction flask. After stirring evenly, the reaction was carried out at room temperature for 16 hours. Monitored by TLC, when the raw materials basically disappeared, the mixture was filtered, and the filter cake was washed with water (5 mL). The solid was dried in an oven to obtain 800 mg of compound 1-K. The crude product was directly used for the next step without purification. LC-MS: [M - K] -- = 503.0.

[0211] Step 12: Synthesis of compound PA7200

[0212]

[0213] Under a nitrogen atmosphere, the crude product of compound 1-K (400 mg, theoretical value 0.43 mmol) and DMF (5 mL) were added to a 50 mL reaction flask. The temperature of the system was lowered to 0-5 °C, and fluoroiodomethane (101 mg, 0.64 mmol) was slowly added. After stirring evenly, the reaction was carried out at room temperature for 2 hours. Monitored by TLC, when the raw materials 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 the organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. Prepared by reverse-phase column chromatography and freeze-dried to obtain 90 mg of compound PA7200. The two-step yield was 24.3%, the HPLC purity was 95.52%, and LC-MS: [M + 1] + = 537.1.

[0214] NMR:[[]]END]] 11H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.43 (d, J = 9.9 Hz, 1H), 7.24 (d, J = 3.4 Hz, 1H), 6.73 (dd, J = 3.5, 1.7 Hz, 1H), 6.39 (d, J = 10.2 Hz, 1H), 6.26 (s, 1H), 6.05 (s, 1H), 5.92 (s, 1H), 5.86 (d, J = 2.4 Hz, 1H), 5.71 (d, J = 15.0 Hz, 1H), 4.39 (s, 1H), 3.79 - 3.51 (m, 3H), 2.30 (d, J = 14.3 Hz, 1H), 2.06 (dd, J = 21.9, 10.0 Hz, 1H), 1.92 (d, J = 13.9 Hz, 1H), 1.55 (s, 3H), 1.50 (s, 1H), 1.13 (s, 3H), 0.98 (d, J = 7.1 Hz, 3H).

[0215] Example 2: Synthesis of Compound PA7201

[0216] First Step: Synthesis of Intermediate Compound 1-L

[0217]

[0218] 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 propionyl chloride (260 mg, 2.82 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 hour. Monitored by TLC, the raw materials disappeared and were converted into an intermediate state. The organic solvent was evaporated to dryness under reduced pressure, and the crude product was added to 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 reacted for another 10 hours. Monitored, all the intermediate state was converted into the product, and 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 dried in an oven to obtain 500 mg of compound 1-L, with a yield of 98.1%, LC-MS: [M + 1] + = 451.0.

[0219] Second Step: Synthesis of Intermediate Compound 1-M

[0220]

[0221] 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 added to a 50 mL reaction flask. After stirring evenly, the temperature of the system was lowered to 0 - 5 °C, and dimethylamino-thiocarbonyl chloride (185 mg, 1.5 mmol) was added. Then the reaction was carried out at room temperature for 16 hours. Monitored by TLC, when the raw materials 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 evaporated to dryness under reduced pressure. The solid was dried in an oven to obtain 567 mg of compound 1-M, with a yield of 95%, LC-MS: [M+1] + = 538.0.

[0222] Step 3: Synthesis of intermediate compound 1-N:

[0223]

[0224] Under a nitrogen atmosphere, compound 1-M (567 mg, 1.1 mmol), potassium carbonate of 100 mesh (456 mg, 3.3 mmol) and ethanol (5 mL) were added to a 50 mL reaction flask. After stirring evenly, the reaction was carried out at room temperature for 16 hours. Monitored by TLC, when the raw materials basically disappeared, filtration was carried out. The filter cake was washed with anhydrous ethanol (5 mL), and the solid was dried in an oven to obtain 917 mg of compound 1-N. The crude product was directly used for the next step without purification, LC-MS: [M-K] - = 465.0.

[0225] Step 4: Synthesis of compound PA7201

[0226]

[0227] Under a nitrogen atmosphere, the crude product of compound 1-N (917 mg, theoretical value 1.1 mmol) and DMF (5 mL) were added to a 50 mL reaction flask. The temperature was lowered to 0 - 5 °C, and fluoroiodomethane (264 mg, 1.65 mmol) was slowly added. After stirring evenly, the reaction was carried out at room temperature for 2 hours. Monitored by TLC, when the raw materials 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 the organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. Prepared by reverse-phase column chromatography and freeze-dried to obtain 5 mg of compound PA7201, HPLC purity 94.4%, two-step yield 0.55%, LC-MS: [M+1] + = 499.1.

[0228] NMR: 11H NMR (400 MHz, DMSO-d6) δ 7.41 (d, J = 10.2 Hz, 1H), 6.37 (dd, J = 10.2, 1.7 Hz, 1H), 6.24 (s, 1H), 6.02 (s, 1H), 5.90 (s, 1H), 5.81 (d, J = 2.3 Hz, 1H), 5.68 (d, J = 14.2 Hz, 1H), 4.34 (s, 1H), 3.67 - 3.50 (m, 2H), 3.18 (d, J = 14.5 Hz, 1H), 2.44 - 2.29 (m, 3H), 2.20 (d, J = 14.0 Hz, 1H), 2.00 (d, J = 12.1 Hz, 1H), 1.88 (d, J = 14.1 Hz, 1H), 1.53 (s, 3H), 1.45 (t, J = 10.3 Hz, 1H), 1.04 (dd, J = 13.6, 6.1 Hz, 7H), 0.91 (dd, J = 19.0, 7.3 Hz, 4H).

[0229] Example 3: Synthesis of Compound PA7202

[0230]

[0231] Under a nitrogen atmosphere, compound 1-I (160 mg, 0.33 mmol), potassium carbonate (135 mg, 0.97 mmol) and DMF (10 mL) were added into a 100 mL reaction flask. The temperature was lowered to 0 - 5 °C, and fluoroiodomethane (78 mg, 0.49 mmol) was slowly added. After stirring evenly, the reaction was carried out at room temperature for 2 hours. Monitored by TLC, the raw materials 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, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, the organic phase was concentrated to dryness under reduced pressure, prepared by reverse-phase column chromatography, and freeze-dried to obtain 106 mg of compound PA7202, HPLC purity 99.59%, yield 58.8%, LC-MS: [M+1] + = 521.5.

[0232] Nuclear magnetic resonance: 11H 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=56.0,40.0,27.1Hz,4H),4.33(s,1H),3.21(d,J=44.4Hz,3H),2.24(d,J=13.8Hz,1H),2.06-1.93(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).

[0233] Example 4: Synthesis of Compound PA7203

[0234]

[0235] Under a nitrogen atmosphere, compound 1-L (144 mg, 0.32 mmol), potassium carbonate (132 mg, 0.96 mmol) and DMF (10 mL) were added into a 100 mL reaction flask. Fluoroiodomethane (76 mg, 0.47 mmol) was slowly added. After stirring evenly, the reaction was carried out at room temperature for 2 hours. Monitored by TLC, the raw materials basically disappeared. Water for injection (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, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, prepared by reverse-phase column chromatography, and freeze-dried to obtain 60 mg of compound PA7203, with a yield of 42.3% and an HPLC purity of 98.02%. LC-MS: [M+1] + = 483.7

[0236] Nuclear magnetic resonance:[[]] 11H NMR (400 MHz, DMSO-d6) δ 7.38 (d, J = 10.3 Hz, 1H), 6.35 (dd, J = 10.2, 1.9 Hz, 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 = 14.0 Hz, 1H), 1.94 (d, J = 11.9 Hz, 1H), 1.70 (d, J = 14.3 Hz, 1H), 1.52 (s, 3H), 1.39 (s, 1H), 1.05 (s, 3H), 1.01 (t, J = 7.5 Hz, 3H), 0.88 (d, J = 7.1 Hz, 3H).

[0237] Example 5: Synthesis of Compound PA7204

[0238]

[0239] Under a nitrogen atmosphere, compound 1-H (130 mg, 0.33 mmol), potassium carbonate (136 mg, 0.98 mmol) and DMF (10 mL) were added to a 100 mL reaction flask. The temperature was lowered to 0 - 5 °C, and iodofluoromethane (79 mg, 0.49 mmol) was slowly added. After stirring evenly, the reaction was carried out at room temperature for 2 hours. Monitored by TLC, the raw materials basically disappeared. Water for injection (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, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, the organic phase was evaporated to dryness under reduced pressure, prepared by reverse-phase column chromatography, and freeze-dried to obtain 72 mg of compound PA7204, HPLC purity 99.53%, yield 51.2%, LC-MS: [M + 1] + = 427.4.

[0240] Nuclear magnetic resonance: 11H 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,1H),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=14.0Hz,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).

[0241] Example 6: Synthesis of Compound PA7100

[0242] Step 1: Synthesis of Intermediate Compound 1-O

[0243]

[0244] Under a nitrogen atmosphere, compound 1-F (1.0 g, 2.52 mmol), DCM (7 mL) and triethylamine (663 mg, 6.55 mmol) were added to a 50 mL reaction flask. After stirring evenly, the temperature was lowered to 0 - 5 °C, and then 2-furoyl chloride (823 mg, 6.31 mmol) was added, followed by stirring at room temperature for 1 hour. Monitored by TLC, the raw materials disappeared and were converted into the intermediate state. The organic solvent was evaporated to dryness under reduced pressure. The crude product was added with methanol (20 mL), sodium bicarbonate (0.5 g, 6.23 mmol) and water (5.0 mL), and the mixture was stirred. The temperature of the system was raised to 48 °C and the reaction was continued for 10 hours. Monitored, the intermediate state was completely converted into the product. 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

[0245] Nuclear magnetic resonance: 11H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.02 (s, 1H), 7.17 (d, J = 3.2 Hz, 1H), 6.73 (s, 1H), 5.90 (s, 1H), 5.72 (d, J = 14.7 Hz, 1H), 5.41 (s, 1H), 4.20 (s, 1H), 3.24 - 2.98 (m, 2H), 2.68 (d, J = 13.8 Hz, 1H), 2.39 - 2.17 (m, 3H), 2.10 (s, 1H), 1.95 (d, J = 11.3 Hz, 1H), 1.73 (d, J = 15.4 Hz, 1H), 1.49 (s, 3H), 1.43 (s, 1H), 1.20 (t, J = 7.2 Hz, 1H), 1.11 (s, 3H), 0.94 (d, J = 7.0 Hz, 3H).

[0246] Step 2: Synthesis of Intermediate Compound 1-P

[0247]

[0248] 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 added into a 50 mL reaction flask. After stirring evenly, the temperature was lowered to 0 - 5 °C, and dimethylamino-thiocarbonyl chloride (378 mg, 3.05 mmol) was added. The reaction was carried out at room temperature for 16 hours. Monitored by TLC, when the raw materials disappeared, the reaction was quenched by adding saturated brine (50 mL) to the reaction system, and then extracted with ethyl acetate (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic phase was evaporated to dryness under reduced pressure. The solid was dried in an oven to obtain 931 mg of compound 1-P, with a yield of 79.06%.

[0249] Nuclear magnetic resonance: 11H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 0.9 Hz, 1H), 7.27 (d, J = 3.5 Hz, 1H), 6.77 (dd, J = 3.5, 1.7 Hz, 1H), 5.92 (s, 1H), 5.73 (d, J = 15.0 Hz, 1H), 5.58 (s, 1H), 4.26 (s, 1H), 3.46 (t, J = 5.8 Hz, 2H), 3.16 (d, J = 23.5 Hz, 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 = 13.8 Hz, 1H), 1.51 (s, 4H), 1.25 - 1.19 (m, 3H), 0.99 (d, J = 7.0 Hz, 3H).

[0250] Step 3: Synthesis of Compound 1-Q

[0251]

[0252] Under a nitrogen atmosphere, compound 1-P (900 mg, 1.56 mmol), potassium carbonate (646 mg, 4.671 mmol) with a mesh size of 100, and ethanol (5 mL) were added to a 50 mL reaction flask. After stirring evenly, the reaction was carried out at room temperature for 16 hours. Monitored by TLC, the raw materials were basically disappeared. After filtration, the filter cake was washed with anhydrous ethanol (5 mL), and the solid was dried in an oven to obtain 1.7 g of compound 1-Q. The crude product was directly used for the next reaction without purification. LC-MS: [M-K] - = 507.0.

[0253] Step 4: Synthesis of Compound PA7100

[0254]

[0255] Under a nitrogen atmosphere, the crude product of compound 1-Q (1.0 g, theoretical value 0.92 mmol) and DMF (10 mL) were added to a 50 mL reaction flask. The temperature of the system was cooled to 0 - 5 °C, and fluoroiodomethane (219 mg, 1.37 mmol) was slowly added. After stirring evenly, the reaction was carried out at room temperature for 2 hours. Monitored by TLC, the raw materials were basically disappeared. Water for drinking (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 the organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, the organic phase was evaporated to dryness under reduced pressure, prepared by reverse-phase column chromatography, and freeze-dried to obtain 80 mg of compound PA7100. The HPLC purity was 92.11%, and the two-step yield was 80.89%. LC-MS: [M+1] + = 539.1.

[0256] Nuclear magnetic resonance: 1 H 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),2.39-2.26(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).

[0257] Example 7: Synthesis of Compound PA7101

[0258] First step: Synthesis of Intermediate Compound 1-R

[0259]

[0260] Under a nitrogen atmosphere, compound 1-F (1.0 g, 2.52 mmol), DCM (7 mL) and triethylamine (663 mg, 6.55 mmol) were added to a 50 mL reaction flask. After stirring evenly, the temperature was lowered to 0-5 °C, and propionyl chloride (583 mg, 6.31 mmol) was slowly added. Stir at room temperature for 1 hour. Monitored by TLC, the raw materials disappeared and were converted into an intermediate state. The organic solvent was evaporated to dryness under reduced pressure. 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 reacted for another 10 hours. Monitored, all the intermediate states were 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 dried in an oven to obtain 930 mg of compound 1-R, with a yield of 81.4%, [M+1] + = 453.1.

[0261] Nuclear magnetic resonance: 11H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H), 5.88 (s, 1H), 5.69 (d, J = 14.4 Hz, 1H), 5.37 (d, J = 2.3 Hz, 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 = 14.6 Hz, 2H), 1.89 (q, J = 11.7 Hz, 1H), 1.69 (d, J = 14.1 Hz, 1H), 1.48 (s, 3H), 1.42 - 1.31 (m, 1H), 1.10 - 1.01 (m, 6H), 0.89 (d, J = 7.1 Hz, 3H).

[0262] Step 2: Synthesis of Intermediate Compound 1-S

[0263]

[0264] 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 added into a 50 mL reaction flask. After stirring evenly, the temperature was lowered to 0 - 5 °C, and dimethylamino-thiocarbonyl chloride (369 mg, 3.0 mmol) was added. The reaction was carried out at room temperature for 16 hours. Monitored by TLC, when the raw materials 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 evaporated to dryness under reduced pressure. The solid was dried in an oven to obtain 891 mg of compound 1-S, with a yield of 83.02%.

[0265] Step 3: Synthesis of Intermediate Compound 1-T

[0266]

[0267] Under a nitrogen atmosphere, compound 1-S (891 mg, 1.65 mmol), potassium carbonate of 100 mesh (684 mg, 4.95 mmol) and ethanol (5 mL) were added into a 50 mL reaction flask. After stirring evenly, the reaction was carried out at room temperature for 16 hours. Monitored by TLC, when the raw materials basically disappeared, the mixture was filtered, and the filter cake was washed with anhydrous ethanol (5 mL). The solid was dried in an oven to obtain 1.5 g of compound 1-T. The crude product was directly used for the next step without purification. LC-MS: [M - K] - = 467.1.

[0268] Step 4: Synthesis of Compound PA7101

[0269]

[0270] Under a nitrogen atmosphere, the crude compound 1-T (750 mg, theoretical value 0.83 mmol) and DMF (5 mL) were charged into a 50 mL reaction flask. The temperature was lowered to 0 - 5 °C, and fluoroiodomethane (198 mg, 1.24 mmol) was slowly added. After stirring evenly, the reaction was carried out at room temperature for 2 hours. Monitored by TLC, the raw materials 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, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, prepared by reverse-phase column chromatography, and freeze-dried 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.

[0271] NMR: 1 H NMR (400 MHz, DMSO-d6) δ 6.02 (s, 1H), 5.89 (d, J = 4.6 Hz, 2H), 5.70 (d, J = 14.8 Hz, 1H), 5.50 (d, J = 3.0 Hz, 1H), 4.17 (d, J = 25.2 Hz, 1H), 3.36 (s, 1H), 3.10 (ddd, J = 16.4, 11.5, 4.0 Hz, 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 = 11.8 Hz, 1H), 1.85 (d, J = 13.8 Hz, 1H), 1.54 - 1.38 (m, 4H), 1.11 - 1.00 (m, 6H), 0.92 (dd, J = 18.8, 7.0 Hz, 3H).

[0272] Example 8: Synthesis of Compound PA7102

[0273]

[0274] Under a nitrogen atmosphere, compound 1-F (100 mg, 0.25 mmol), 100-mesh potassium carbonate (104 mg, 0.76 mmol), and DMF (5 mL) were added to a 50-mL reaction flask. The temperature was lowered to 0 - 5 °C, and iodofluoromethane (60 mg, 0.38 mmol) was slowly added. After stirring evenly, the reaction was carried out at room temperature for 2 hours. Monitored by TLC, the raw materials 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, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure. Prepared by reverse-phase column chromatography and freeze-dried 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.

[0275] NMR: 1 H NMR (500 MHz, DMSO-d6) δ 5.92 (d, J = 2.0 Hz, 1H), 5.85 (s, 1H), 5.80 (dd, J = 11.1, 2.1 Hz, 1H), 5.69 (d, J = 2.1 Hz, 1H), 5.63 (d, J = 14.5 Hz, 1H), 5.31 (d, J = 20.6 Hz, 2H), 4.11 (d, J = 5.2 Hz, 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 = 7.3 Hz, 1H), 1.78 (q, J = 11.2 Hz, 1H), 1.58 - 1.50 (m, 1H), 1.45 (s, 3H), 1.28 (ddd, J = 12.3, 8.1, 4.2 Hz, 1H), 1.04 - 0.98 (m, 3H), 0.92 (d, J = 7.2 Hz, 3H).

[0276] Example 9: Evaluation test of glucocorticoid receptor (hereinafter referred to as "GR") binding activity

[0277] Dexamethasone is a glucocorticoid, first synthesized in 1957. It has pharmacological effects such as anti-inflammatory, anti-endotoxin, immunosuppressive, anti-shock, and enhancing stress response. It is listed in the World Health Organization's List of Essential Medicines and is one of the essential drugs for the basic public health system. Its structural formula is shown below.

[0278]

[0279] Fluticasone furoate is a new type of glucocorticoid that is currently the best in the world. It was developed by GlaxoSmithKline and first marketed 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.

[0280]

[0281] Culture GRC9 / HEK293 cells in a medium containing 88% phenol red-containing DMEM, 10% FBS, 1% P / S, 1% GlutaMax, 900 μg / ml G418, and 75 μg / ml hygromycin. In each well of a 96-well plate, add different concentrations of different candidate compounds (dexamethasone, fluticasone furoate, PA7200, PA7201, PA7202, PA7203, PA7204, PA7100, PA7101, PA7102), and then inoculate the cultured GRC9 / HEK293 cells into this 96-well plate with an inoculation solution containing 89% phenol red-free DMEM, 10% carbon-free FBS, and 1% GlutaMax. Incubate in an environment of 5% CO2 and 37 °C for one day, harvest the cells, and measure the luciferase activity using a luciferase kit. The activity results are shown in Table 2 and Figure 1 as follows.

[0282] Table 2: Summary Table of GR Reporter Gene Detection

[0283] No. Sample ID <![CDATA[EC 50 (nM)]]> 1 Dexamethasone 1.270 2 Fluticasone furoate 0.01711 3 Compound PA7200 0.01408 4 Compound PA7201 0.0629 5 Compound PA7202 0.01339 6 Compound PA7203 0.06446 7 Compound PA7204 0.8863 8 Compound PA7100 0.05767 9 Compound PA7101 0.1947 10 Compound PA7102 5

[0284] Result Analysis

[0285] The experimental results show that the EC 50 value of the commonly used glucocorticoid drug dexamethasone is 1.270 nM, indicating low activity in activating the glucocorticoid receptor; while the EC 50 values of the compounds PA7200 (Example 1) and PA7202 (Example 3) of this application are 0.01408 nM and 0.01339 nM respectively, which are much lower than dexamethasone and also lower than the recently marketed glucocorticoid drug fluticasone furoate. They are reduced by 18% and 22% respectively compared with fluticasone furoate (EC 50 is 0.01711 nM), indicating that the compounds of this application have significantly stronger activity in activating the glucocorticoid receptor than dexamethasone and fluticasone furoate, and have excellent activity in activating the glucocorticoid receptor.

[0286] Example 10: Determination of Anti-Inflammatory Effect

[0287] An OVA-induced mouse asthma model was used to examine the anti-inflammatory effects of candidate compounds. First, 7-9-week-old Balb / c mice were immunized with OVA (ovalbumin). On the first day, the animals were randomly assigned to 5 different treatment groups (blank group, model group, positive drug group, low-dose test substance group, and high-dose test substance group) by the random allocation function of BioBook. On the 28th - 30th day after the first immunization, the mice were challenged with OVA via the airway after nebulizing the attack solution with BUXCO, and different treatment methods were administered simultaneously, namely the blank group (normal saline), the model group (no drug), the positive drug group (0.2 mg / kg fluticasone furoate), the low-dose test substance group (0.067 mg / kg PA7200), and the high-dose test substance group (0.2 mg / kg PA7200). The lung tissues of the experimental animals in each group were lavaged and bronchoalveolar lavage fluid (BALF) was collected. Then, the cells in the lavage fluid were classified and counted and compared. The cell count results are shown in Table 3 and Figures 2-6 as follows.

[0288] Table 3: Cell counts in BALF

[0289]

[0290] Result analysis

[0291] The experimental results showed that compared with the blank group, the total number of cells and the number of white blood cell subtypes in the BALF of the model group animals were significantly increased after OVA sensitization and challenge, showing relatively typical asthma disease manifestations, indicating that the asthma model was successfully constructed.

[0292] Compared with the model group, the low-dose PA7200 group could significantly reduce the total number of cells and eosinophils, and to a certain extent reduce the number of neutrophils and lymphocytes; the high-dose PA7200 group could significantly reduce the total number of cells, eosinophils and lymphocytes, and to a certain extent reduce the number of neutrophils, indicating that PA7200 has a good effect on improving asthma inflammatory symptoms.

[0293] The administration doses of the fluticasone furoate group and the high-dose PA7200 group were the same, but compared with the fluticasone furoate group, the total number of cells, eosinophils and lymphocytes in the high-dose PA7200 group were significantly reduced, indicating that the anti-inflammatory effect of the compound PA7200 of this application was significantly better than that of the newly marketed glucocorticoid drug fluticasone furoate.

[0294] In summary, the compound PA7200 of this application has an excellent effect on improving asthma inflammatory symptoms and is significantly better than the newly marketed glucocorticoid drug fluticasone furoate.

[0295] It should be understood that although the present invention has been described in connection with specific embodiments thereof, the foregoing description is intended to illustrate and not limit the scope of the present 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 ; 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: hydroxyl, halogen, CN, oxo, carboxyl, amino, sulfonic acid group, C 1-6 alkyl, C 1-6 alkoxy group.

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, wherein 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, characterized in that, 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 replaced by R a substituted.

4. The compound according to claim 1, characterized in that, 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 said 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, characterized in that, 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, characterized in that, 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 or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7; 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 or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or the pharmaceutical composition according to claim 8.

10. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or the pharmaceutical composition according to 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.

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