阅读说明：本技术 咔唑化合物及其使用方法 (Carbazole compounds and methods of use thereof ) 是由 R·J·帕里萨 M·O·布拉德利 于 2018-04-11 设计创作，主要内容包括：本文描述了可用作S-亚硝基谷胱甘肽还原酶(GSNOR)抑制剂的化合物、药物组合物和方法。(Described herein are compounds, pharmaceutical compositions and methods useful as S-nitrosoglutathione reductase (GSNOR) inhibitors.)

1. A compound of formula I (a):

or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analog thereof, wherein:

m and n are independently 0 or 1;

each X is independently halo or C_1-3A haloalkyl group;

R²selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, amido, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R¹selected from the group consisting of carboxy, carboxy ester, -arylene-carboxy, -alkylene-carboxy ester, -alkenylene-carboxy, -O-alkylene-carboxy, and heteroaryl; and

R³selected from the group consisting of halo, alkyl, substituted alkyl, amino, substituted amino, alkoxy, substituted alkoxy, heterocycloalkyl, substituted heterocycloalkyl, heterocycloalkoxy, substituted heterocycloalkoxy, heterocycloalkylthio, substituted heterocycloalkylthio, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, and substituted heteroarylthio.

2. A compound of formula II:

wherein:

m and n are independently 0 or 1;

q is 1;

each X is independently F or CF₃；

R²Selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, amido, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R³selected from the group consisting of alkyl, substituted alkyl, amino, substituted amino, alkoxy, substituted alkoxy, heterocycloalkyl, substituted heterocycloalkyl, heterocycloalkoxy, substituted heterocycloalkoxyHeterocyclylalkylthio, substituted heterocyclylalkylthio, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, and substituted heteroarylthio;

W¹is a bond or C₁-C₄An alkyl group; and

Z¹selected from the group consisting of carboxyl or carboxyl ester groups;

or a tautomer, solvate, or pharmaceutically acceptable salt thereof.

3. The compound as recited in claim 1 wherein said compound is of formula iii (a):

wherein:

each X is independently F or CF₃；

R¹Selected from the group consisting of carboxyl, carboxyl ester, -arylene-carboxyl, -alkylene-carboxyl, and-alkylene-carboxyl ester; and

w is selected from the group consisting of alkylene, substituted alkylene, -O-alkylene, substituted-O-alkylene, arylene, substituted arylene, heteroarylene, substituted heteroarylene, -O-heteroarylene, and substituted-O-heteroarylene; and

z is selected from the group consisting of hydrogen, amino, substituted amino and CF₃A group of (a);

or a tautomer, solvate, or pharmaceutically acceptable salt thereof.

4. The compound as recited in claim 1 wherein said compound has formula IV:

wherein:

x is F or CF₃；

W is selected from the group consisting of a bond, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroaryloxy, and substituted heteroaryloxy;

W¹is a bond or C₁-C₄An alkyl group;

z is selected from the group consisting of hydrogen, amino, substituted amino and CF₃A group of (a); and

Z¹selected from the group consisting of carboxyl or carboxyl ester groups;

or a tautomer, solvate, or pharmaceutically acceptable salt thereof.

5. The compound as recited in claim 1 wherein said compound has formula V:

wherein:

X¹and X²Are identical and are selected from H, F and CF₃；

R³Selected from the group consisting of alkyl, substituted alkyl, amino, substituted amino, alkoxy, substituted alkoxy, heterocycloalkyl, substituted heterocycloalkyl, heterocycloalkoxy, substituted heterocycloalkoxy, heterocycloalkylthio, substituted heterocycloalkylthio, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, and substituted heteroarylthio;

R⁴is H, C₁-C₄Alkyl or CF₃；

L is a bond or

Q is CH or N; and

Q¹is CH or N;

provided that Q and Q¹Not all are N;

or a tautomer or pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1 to 5, wherein R²Is a substituted alkyl, substituted aryl, or acyl group.

7. The compound of any one of claims 1 to 5, wherein R²Is a substituted alkyl group.

8. The compound of any one of claims 1 to 5, wherein R²Is that

9. The compound of any one of claims 1 to 5, wherein R²Is a substituted aryl group.

10. The compound of any one of claims 1 to 5, wherein R²Is that

11. The compound of any one of claims 1 to 5, wherein R²Is an acyl group.

12. The compound of any one of claims 1 to 5, wherein R²Is an alkyl group substituted by a cyano group.

13. A compound as claimed in claim 1, wherein R is¹Is a carboxyl group, C₁-C₆Alkylene-carboxyl, C₁-C₆Alkenylene-carboxy, -O-C₁-C₆Alkylene-carboxyl, or heteroaryl.

14. A compound as claimed in claim 1 or claim 13 wherein R is¹Is carboxy or C₁-C₆Alkylene-carboxyl groups.

15. A compound as claimed in claim 5 wherein Q is CH, Q¹Is CH.

16. A compound as claimed in claim 5 or claim 15 wherein L is a bond.

17. A compound as described in the tables provided herein.

18. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and one or more compounds of any one of claims 1 to 17.

19. A method of inhibiting S-nitrosoglutathione reductase, the method comprising contacting a cell with an effective amount of one or more compounds of any one of claims 1 to 17 or a pharmaceutical composition of claim 18.

20. A method of treating a disease or disorder mediated at least in part by S-nitrosoglutathione reductase, the method comprising administering to a subject an effective amount of one or more compounds of any one of claims 1 to 17 or a pharmaceutical composition of claim 18.

Technical Field

The present disclosure relates to compounds, pharmaceutical compositions and methods useful as S-nitrosoglutathione reductase (GSNOR) inhibitors. In some embodiments, the present disclosure provides methods for treating various diseases or disorders involving S-nitrosoglutathione reductase (GSNOR). Such diseases or conditions include diseases mediated at least in part by the cytokines interleukin 6(IL-6), interleukin 17(IL-17), or interleukin 23 (IL-23). In one embodiment, the compounds and compositions of the present disclosure are generally useful for treating disorders, including inhibiting tissue and/or organ inflammation caused by IL-6, IL-17, or IL-23 overexpression. In one embodiment, the compounds and compositions of the present disclosure are generally useful for treating disorders, including inhibiting tissue and/or organ inflammation due to IL-6 overexpression.

Background

The finding that Nitric Oxide (NO) has important physiological roles in many different cells and organs has led to the 1998 nobel prize. Research efforts have attempted to utilize the nitric oxide pathway for disease treatment. For example, it is believed that the synthesis of nitric oxide donors or nitric oxide releasing compounds will provide therapeutic results. Most of those studies failed, in part because of the short in vivo half-life of nitric oxide (in seconds). Furthermore, intracellular delivery of effective doses to target tissues is generally insufficient to achieve therapeutic effects, except in limited applications such as application in premature infants.

However, it is believed that the enzyme GSNOR may be used to produce a benefit similar to nitric oxide. GSNOR decomposes S-nitroso-Glutathione (GSNO). GSNO is a chemical conjugate of glutathione and nitric oxide and is a cell-stable storage form of nitric oxide. The enzyme is capable of effecting the formation of nitrosated proteins, but employs a different chemical mechanism to that used by nitric oxide itself. Thus, inhibition of GSNOR increases intracellular GSNO concentration and its bioavailability. This results in increased nitrosylation of cysteines on proteins that regulate signal transduction pathways important for diseases including diseases mediated at least in part by excess IL-6, IL-17, or IL-23. Accordingly, inhibition of GSNOR is associated with decreased expression of IL-6, IL-17 or IL-23 in vivo. Conversely, overexpression of IL-6, IL-17 or IL-23 has been implicated in a variety of diseases.

Accordingly, inhibition of GSNOR would be effective for those conditions and diseases mediated by IL-6, IL-17 or IL-23. Thus, there is a continuing need for GSNOR inhibitors and methods of treating IL-6, IL-17 or IL-23 related diseases or disorders that may be affected by GSNOR inhibition.

Disclosure of Invention

The present disclosure relates in part to aromatic nitrogen-containing compounds that inhibit GSNOR, thereby increasing endogenous GSNO stores. An increase in the amount of endogenous GSNO affects a range of cellular effects that elicit therapeutic benefits including a decrease in the production of IL-6, IL-17 or IL-23. The aromatic nitrogen-containing compounds of the present disclosure are broadly effective in treating conditions caused by IL-6 overexpression. In some embodiments, the compounds of the present disclosure may be used to treat conditions caused by IL-6, IL-17, or IL-23 overexpression.

Certain embodiments of the present disclosure relate to the use of these aromatic nitrogen-containing compounds to treat conditions in a subject, including those conditions mediated at least in part by IL-6 overexpression. Accordingly, in one embodiment, the disclosure relates to methods of ameliorating or ameliorating a condition or disorder mediated at least in part by GSNOR, including conditions caused by IL-6 overexpression.

Certain embodiments of the present disclosure relate to the use of these aromatic nitrogen-containing compounds to treat conditions in a subject, including those conditions mediated at least in part by IL-17 overexpression. Accordingly, in one embodiment, the disclosure relates to methods of ameliorating or improving a condition or disorder mediated at least in part by GSNOR, including conditions caused by IL-17 overexpression.

Certain embodiments of the present disclosure relate to the use of these aromatic nitrogen-containing compounds to treat conditions in a subject, including those conditions mediated at least in part by IL-23 overexpression. Accordingly, in one embodiment, the disclosure relates to methods of ameliorating or improving a condition or disorder mediated at least in part by GSNOR, including conditions caused by IL-23 overexpression.

In some embodiments, the methods, compounds, and/or compositions of the present disclosure are for prophylactic use.

The disclosure also relates to compounds, pharmaceutical compositions and methods for inhibiting GSNOR. The present disclosure is also generally applicable to the treatment of diseases and disorders that can be treated by inhibition of GSNOR.

In particular, in one embodiment, compounds of formula I are provided:

wherein:

m and n are independently 0 or 1;

p and q are 1;

each X is independently F or CF₃；

R²Selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, amido, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R¹selected from the group consisting of carboxyl, carboxyl ester, -aryl-carboxyl, -alkyl-carboxyl, and-alkyl-carboxyl ester; and

R³selected from the group consisting of alkyl, substituted alkyl, amino, substituted amino, alkoxy, substituted alkoxy, heterocycloalkyl, substituted heterocycloalkyl, heterocycloalkoxy, substituted heterocycloalkoxy, heterocycloalkylthio, substituted heterocycloalkylthio, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, and substituted heteroarylthio;

or a tautomer, solvate, or pharmaceutically acceptable salt thereof.

In a related embodiment, pharmaceutical compositions are provided comprising an effective amount of one or more compounds of formula I and a pharmaceutically acceptable excipient.

In one embodiment, a method of inhibiting GSNOR is provided, the method comprising contacting a cell (including neurons/microglia/invasive macrophages) with an effective amount of one or more compounds of formula I above.

In another embodiment, a method is provided for treating a disease or disorder mediated at least in part by GSNOR, wherein the method comprises administering to a subject an effective amount of one or more compounds of formula I or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of one or more compounds of formula I.

These and other embodiments are described in more detail herein.

Drawings

Figure 1 shows Masson trichrome staining in a bleomycin-induced mouse Idiopathic Pulmonary Fibrosis (IPF) model.

Figure 2 shows the effect of compound 17 on bleomycin-induced pulmonary fibrosis graded by the Ashcroft system in a mouse model of IPF. Data represent mean ± SEM fibrosis fractions. mpk is mg/kg; i.p. ═ intraperitoneally; p.o. ═ oral. P <0.01 compared to controls without any treatment. One-way ANOVA followed by Dunnett's multiple comparison test. n is 7-12.

Figure 3 shows the effect of compound 17 on blood glucose levels as an intragastric insulin tolerance test (IGITT) following intraperitoneal injection of 0.75IU of human insulin per gram of mouse body weight after 6 weeks of drug treatment in db/db diabetic mice.

Figure 4 shows the integral of plasma glucose concentration (mg/dL) over time (AUC) over 45 minutes for compound 17 group as an IGITT.

Figure 5 shows the intragastric glucose tolerance test (IPGTT) for blood glucose levels over 120 minutes for the compound 17 group after intraperitoneal injection of 0.75IU of human insulin per gram of mouse body weight after 6 weeks of drug treatment in db/db diabetic mice.

Figure 6 shows IPGTT for compound 17 group presented as integrated plasma glucose concentration (mg/dL) over time (AUC) over 120 min.

FIG. 7 shows the effect of compound 17 on IL-6 release. The numbered bars refer to the group numbers of table 5 below.

Figure 8 shows a survival comparison of db/db female mice administered compound 17 and vehicle.

Figure 9 shows a comparison of vascular reactivity of db/db female mice administered compound 17 and vehicle.

FIG. 10 shows a comparison of circulating 8-isoprostane and myocardial 8-isoprostane in db/db female mice administered compound 17 and vehicle.

Figure 11 shows the effect of pretreatment on LPS-induced IL-17 release (i.v.). The numbered bars refer to the group numbers of table 6 below.

Figure 12 shows the effect of pretreatment on LPS-induced IL-23 release (i.v.). The numbered bars refer to the group numbers of table 6 below.

Figure 13 shows the effect of compound 17 on arthritis in a mouse model compared to controls.

Figure 14 shows the effect of compound 17 on the amount of anti-collagen antibody production in a mouse model of collagen-induced arthritis compared to controls.

Detailed Description

Throughout this application, various embodiments of the compounds, compositions, and methods of the present invention are referred to herein. The various embodiments described are intended to provide various illustrative examples, and should not be construed as descriptions of alternative materials. Rather, it should be noted that the descriptions of the various embodiments provided herein may have overlapping ranges. The embodiments discussed herein are merely illustrative and are not intended to limit the scope of the present disclosure.

1. Definition of

As used herein, the following definitions shall apply, unless otherwise indicated. Further, any term or symbol used herein shall have its ordinary meaning in the art if it is not defined as described below.

As used herein and in the appended claims, the singular articles such as "a," "an," and "the" and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential.

As used herein, "about" is understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If there is a use of a term that is not clear to one of ordinary skill in the art, "about" will mean plus or minus 10% of the particular term in view of the context in which it is used.

In general, reference to an element such as hydrogen or H is intended to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Thus, containing radioactive isotopes such as tritium, C¹⁴、P³²And S³⁵Are within the scope of the present disclosure. In some embodiments, isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to²H (deuterium, D),³H (tritium),¹¹C、¹³C、¹⁴C、¹⁵N、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I. the various isotopically-labeled compounds of the present disclosure can be, for example, those into which a radioactive isotope such as³H、¹³C and¹⁴a compound of C. Procedures for inserting such labels into the compounds of the present disclosure will be apparent to those skilled in the art based on the disclosure herein. As used herein, "deuterated analog" refers to an analog produced by replacement of at least one hydrogen of a compound with deuterium. "deuterated analogs" of compounds described herein refer to compounds in which one or more hydrogens (e.g., on a carbon atom) are replaced with deuteriumA compound (I) is provided.

"alkyl" means a monovalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. The term includes, for example, straight and branched chain hydrocarbon radicals such as methyl (CH)₃-, ethyl (CH)₃CH₂-), n-propyl (CH)₃CH₂CH₂-, isopropyl ((CH)₃)₂CH-), n-butyl (CH)₃CH₂CH₂CH₂-, isobutyl ((CH)₃)₂CHCH₂-, sec-butyl ((CH)₃)(CH₃CH₂) CH-), tert-butyl ((CH-)₃)₃C-), n-pentyl (CH)₃CH₂CH₂CH₂CH₂-) and neopentyl ((CH)₃)₃CCH₂-)。C_xAlkyl represents an alkyl group having x carbon atoms.

"substituted alkyl" refers to an alkyl having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of: alkoxy, substituted alkoxy, acyl, amido, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, and nitro, wherein the substituents are as defined herein.

In some embodiments, substituted alkyl groups include haloalkyl groups, particularly halomethyl groups, such as trifluoromethyl, difluoromethyl, fluoromethyl and the like. In this example, the term is referred to as "haloalkyl". Haloalkyl refers to an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms (e.g. 1 to 5 hydrogen atoms or 1 to 3 hydrogen atoms) are replaced by a halogen atom.

In some embodiments, substituted alkyl is substituted with-C (O) -NH₂A substituted alkyl group.

"alkenyl" means containing at least one carbon-carbon doubleA bond and having 2 to 20 carbon atoms (i.e. C)_2-20Alkenyl), 2 to 8 carbon atoms (i.e., C)_2-8Alkenyl), 2 to 6 carbon atoms (i.e., C)_2-6Alkenyl), or 2 to 4 carbon atoms (i.e., C)_2-4Alkenyl) alkyl groups. Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1, 2-butadienyl and 1, 3-butadienyl).

"alkoxy" refers to the group-O-alkyl, wherein alkyl is as defined herein. Alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy and n-pentoxy.

"substituted alkoxy" refers to the group-O- (substituted alkyl), wherein substituted alkyl is defined herein. Preferred substituted alkyl groups in the group-O- (substituted alkyl) include haloalkyl groups, particularly halomethyl groups, such as trifluoromethyl, difluoromethyl, fluoromethyl and the like. In one embodiment, the substituted alkoxy is-oxy-alkylene-carboxy or oxy-alkylene carboxy ester. Such substituted alkoxy groups are represented by the formulae-O-alkylene-COOH and-O-alkylene-carboxy esters.

"acyl" refers to the groups alkyl-C (O) -, substituted alkyl-C (O) -, cycloalkyl-C (O) -, substituted cycloalkyl-C (O) -, aryl-C (O) -, substituted aryl-C (O) -, heteroaryl-C (O) -, substituted heteroaryl-C (O) -, heterocycle-C (O) -, and substituted heterocycle-C (O) -, wherein alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. Acyl includes "acyl" CH₃C (O) -. In some embodiments, acyl groups include

"acyloxy" refers to the group-O-acyl, where acyl is defined herein.

"amido" refers to the group-acyl-amino, where acyl is defined herein and amino is defined herein.

"amino" refers to the group-NH₂。

"substituted amino" refers to the group-NR³¹R³²Wherein R is³¹And R³²Each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, and wherein R is³¹And R³²Optionally linked to a nitrogen atom bound thereto to form a heterocyclic group or a substituted heterocyclic group, with the proviso that R³¹And R³²Are not all hydrogen, and wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. When R is³¹Is hydrogen and R³²When alkyl, substituted amino is sometimes referred to herein as alkylamino. When R is³¹And R³²Where both are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it means R³¹Or R³²Is hydrogen but not both. When referring to disubstituted amino, it is meant R³¹Or R³²Are not all hydrogen.

"aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., benzene (Ph)) or multiple fused rings (e.g., naphthyl or anthracenyl) which may or may not be aromatic rings (e.g., 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, etc.), provided that the point of attachment is on an aromatic carbon atom. Preferred aromatic groups include phenyl and naphthyl.

"substituted aryl" refers to aryl substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of: alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, amido, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, and nitro, wherein the substituents are defined herein.

In some embodiments, substituted aryl is substituted with-C (O) -NH₂A substituted aryl group.

"aryloxy" refers to the group-O-aryl, wherein aryl is defined herein.

"substituted aryloxy" refers to the group-O- (substituted aryl), wherein substituted aryl is defined herein.

"carbonyl" refers to the divalent group-C (O) -, which is equivalent to-C (═ O) -.

"carboxy" or "carboxyl" means-COOH or a salt thereof.

"carboxy ester (carboxy ester)" or "carboxy ester (carboxy ester)" refers to the group-C (O) O-alkyl, -C (O) O-substituted alkyl, -C (O) O-aryl, -C (O) O-substituted aryl, -C (O) O-cycloalkyl, -C (O) O-substituted cycloalkyl, -C (O) O-heteroaryloxy, -C (O) O-substituted heteroaryl, -C (O) O-heterocycle, and-C (O) O-substituted heterocycle, wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"cyano" means a group-C.ident.N.

"cycloalkyl" refers to a saturated or unsaturated, but non-aromatic, cyclic alkyl group of 3 to 10 carbon atoms having single or multiple cyclic rings, including fused, bridged, and spiro ring systems. C_xCycloalkyl refers to cycloalkyl groups having x ring carbon atoms. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more of the rings may be aryl, heteroaryl or heterocyclic, provided that the point of attachment is through a non-aromatic, non-heterocyclic saturated carbocyclic ring.

"substituted cycloalkyl" refers to cycloalkyl having 1 to 5, or preferably 1 to 3 substituents selected from the group consisting of: oxo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxy ester, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, and nitro, wherein the substituents are defined herein.

"Cycloalkoxy" refers to-O-cycloalkyl, wherein cycloalkyl is defined herein.

"substituted cycloalkoxy" refers to-O- (substituted cycloalkyl), wherein substituted cycloalkyl is defined herein.

"halo" or "halogen" refers to fluoro, chloro, bromo and iodo, preferably fluoro or chloro.

"Hydroxy" or "hydroxyl" refers to the group-OH.

"heteroaryl" refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms in the ring, the heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple fused rings (e.g., indolizinyl or benzothienyl) wherein the fused rings may or may not be aromatic and/or may not contain heteroatoms, provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, one or more nitrogen and/or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N-oxide (N → O), sulfinyl, or sulfonyl moiety. Preferred heteroaryl groups include 5 or 6 membered heteroaryl groups such as pyridyl, pyrrolyl, indolyl, thiolanyl and furyl. In some embodiments, preferred heteroaryl groups include 5-or 6-membered non-oxygenated heteroaryl groups. In some embodiments, preferred heteroaryl groups include 5-or 6-membered heteroaryl groups excluding oxazoles. In some embodiments, the nitrogen-containing heteroaryl group is attached through the nitrogen of the heteroaryl group.

"substituted heteroaryl" refers to heteroaryl substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents as the group defined for substituted aryl. In some embodiments, a substituted heteroaryl is a heteroaryl with a substituent ═ NH, such as compound 53.

"heteroaryloxy" refers to an-O-heteroaryl group, and "substituted heteroaryloxy" refers to an-O-substituted heteroaryl group.

"heterocyclic compound (heterocyclic)" or "Heterocycle (heterocyclic)" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated but non-aromatic radical having from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen. Heterocyclic compounds include a single ring or multiple fused rings, including fused rings, bridged rings, and spiro ring systems. In fused ring systems, one or more of the rings may be cycloalkyl, aryl or heteroaryl, provided that the point of attachment is through a non-aromatic ring. In one embodiment, one or more of the nitrogen and/or sulfur atoms of the heterocyclic group is optionally oxidized to provide an N-oxide, sulfinyl, or sulfonyl moiety.

"substituted heterocyclic group" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to a heterocyclic group that is substituted with 1 to 5, or preferably 1 to 3, substituents as defined for substituted cycloalkyl.

Examples of heterocyclic compounds and heteroaryl groups include, but are not limited to: azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indoline, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3, 4-tetrahydroisoquinoline, 4,5,6, 7-tetrahydrobenzo [ b ] thiacene, thiazole, thiazolidine, thiacene, benzo [ b ] thiacene, morpholinyl, thiomorpholinyl, 1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, tetrahydrofuranyl and the like.

"heterocyclyloxy" or "heterocycloalkoxy" refers to the group-O- (heterocyclyl), where heterocyclyl is defined herein.

"substituted heterocyclyloxy" or "substituted heterocycloalkoxy" refers to the group-O- (substituted heterocyclyloxy), wherein substituted heterocyclyloxy is defined herein.

"Heterocyclylthio" or "heterocycloalkylthio" refers to the group-S- (heterocyclyl), wherein heterocyclyl is defined herein.

"substituted heterocyclylthio" or "substituted heterocyclylthio" refers to the group-S- (substituted heterocyclyl), wherein heterocyclyl is defined herein.

"heteroarylthio" refers to the group-S- (heteroaryl), wherein heteroaryl is defined herein.

"substituted heteroarylthio" refers to the group-S- (substituted heteroaryl), wherein substituted heteroaryl is defined herein.

"Nitro" means the radical-NO₂。

"oxo" refers to an atom (═ O) or (-O)^-)。

"Spirocyclic system" refers to bicyclic systems in which two rings share a single ring carbon atom.

Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms and prodrugs of the compounds described herein. "pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. Furthermore, if the compounds described herein are obtained in the form of acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is the free base, the acid addition salts can be prepared according to conventional procedures for preparing acid addition salts with base compounds by reactingAddition salts, particularly pharmaceutically acceptable addition salts, are prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will recognize various synthetic methods that may be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared with inorganic and organic acids. Salts derived from inorganic acids include hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like. Salts derived from organic acids include salts such as acetate, propionate, glycolate, pyruvate, oxalate, malate, malonate, succinate, maleate, fumarate, tartrate, citrate, benzoate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared with inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkylamines (i.e., NH)₂(alkyl)), dialkylamine (i.e., HN (alkyl)₂) Trialkylamine (i.e. N (alkyl)₃) Substituted alkylamines (i.e. NH)₂(substituted alkyl)), di (substituted alkyl) amine (i.e., HN (substituted alkyl)₂) Tri (substituted alkyl) amines (i.e., N (substituted alkyl)₃) Alkenylamines (i.e. NH)₂(alkenyl)), a dienylamine (i.e., HN (alkenyl)₂) Triallylamine (i.e. N (alkenyl)₃) Substituted alkenylamines (i.e. NH)₂(substituted alkenyl)), di (substituted alkenyl) amine (i.e., HN (substituted alkenyl)₂) Tris (substituted alkenyl) amines (i.e., N (substituted alkenyl)₃Mono-, di-or tricyclic alkylamines (i.e. NH)₂(cycloalkyl), HN (cycloalkyl)₂N (cycloalkyl)₃) Mono-, di-or triarylamines (i.e. NH)₂(aryl), HN (aryl)₂N (aryl)₃) Or mixed amines, and the like. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri (isopropyl) amine, tri (N-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

Stereoisomers (also referred to as optical isomers) of compounds include all chiral, dl, stereoisomers and racemic forms of the structure, unless the specific stereochemistry is explicitly indicated. Thus, the compounds used in the present disclosure include enriched or resolved optical isomers at any or all asymmetric atoms as is evident from the description. Both racemic and diastereomeric mixtures and individual optical isomers can be separated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and such stereoisomers are within the scope of the disclosure.

The compounds of the present disclosure may exist as solvates, particularly hydrates. A "solvate" is formed by the interaction of a solvent with a compound. Solvates of salts of the compounds described herein are also provided. Hydrates can form during the manufacture of a compound or composition comprising the compound, or hydrates can form over time due to the hygroscopic nature of the compound. The compounds of the present disclosure may also exist in the form of organic solvates including DMF, ether and alcohol solvates, and the like. The identification and preparation of any particular solvate is within the skill of one of ordinary skill in synthetic organic or pharmaceutical chemistry.

"tautomers" refer to alternative forms of compounds that differ in the position of the proton, such as enol-ketone and imine-enamine tautomers, or tautomeric forms of heteroaryl groups that contain ring atoms attached to a ring-NH-moiety and a ring-N-moiety, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

"Treating (Treating) a disease or disorder" in a subject refers to: 1) preventing the disease or disorder from occurring in a subject susceptible to or not yet exhibiting symptoms of the disease or disorder; 2) inhibiting or arresting the development of the disease or disorder; or 3) ameliorating or causing regression of the disease or condition.

"subject" refers to a mammal. The mammal may be a human or non-human mammalian organism.

The naming of a substituent not explicitly defined herein is made by naming the terminal part of the functional group, followed by naming the adjacent functional group towards the point of attachment, unless otherwise stated. For example, the substituent "alkoxycarbonylalkyl" refers to the group (alkoxy) -C (O) - (alkyl) -.

It is to be understood that, of all substituted groups defined above, polymers resulting from defining the substituents as having further substituents per se (e.g., substituted aryl having substituted aryl as a substituent, the substituted aryl being substituted with substituted aryl per se, etc.) are not intended to be incorporated herein. In such cases, the maximum number of such substituents is three. That is, each of the above definitions is constrained by the following limitations: for example, substituted aryl groups are limited to-substituted aryl- (substituted aryl) -substituted aryl groups.

It is to be understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled person.

2. Compounds of the present disclosure

The present disclosure relates to compounds, compositions, and methods of using the compounds or compositions to inhibit GSNOR. Also provided are methods useful for treating diseases or disorders that are at least partially affected by GSNOR.

In some embodiments, compounds of formula I are provided:

wherein:

m、n、p、q、X、R¹、R²and R³As defined above;

or a tautomer or pharmaceutically acceptable salt thereof.

Some embodiments herein provide compounds of formula i (a):

or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analog thereof, wherein:

m and n are independently 0 or 1;

each X is independently halo or C_1-3A haloalkyl group;

R²selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, amido, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R¹selected from the group consisting of carboxy, carboxy ester, -arylene-carboxy, -alkylene-carboxy ester, -alkenylene-carboxy, -O-alkylene-carboxy, and heteroaryl; and

R³selected from the group consisting of halo, alkyl, substituted alkyl, amino, substituted amino, alkoxy, substituted alkoxy, heterocycloalkyl, substituted heterocycloalkyl, heterocycloalkoxy, substituted heterocycloalkoxy, heterocycloalkylthio, substituted heterocycloalkylthio, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, and substituted heteroarylthio;

some embodiments herein provide compounds of formula i (a):

or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analog thereof, wherein:

m and n are independently 0 or 1;

each X is independently halo or C_1-3A haloalkyl group;

R²selected from the group consisting of hydrogen, alkyl, acyl, acylamino, aryl and heteroaryl, wherein R is²Each alkyl, aryl and heteroaryl of (a) is optionally substituted with 1 to 3R¹⁰Substitution;

R¹selected from the group consisting of carboxyl, carboxyl esterArylene-carboxy, -alkylene-carboxy ester, -alkenylene-carboxy, -O-alkylene-carboxy, and heteroaryl; and

R³selected from the group consisting of halo, alkyl, amino, alkoxy, heterocycloalkyl, heterocycloalkoxy, heterocycloalkylthio, heteroaryl, heteroaryloxy, and heteroarylthio, wherein R is³Each alkyl, amino, alkoxy, heterocycloalkyl, heterocycloalkoxy, heterocycloalkylthio, heteroaryl, heteroaryloxy and heteroarylthio of (a) is optionally substituted with 1 to 3R¹⁰Substitution;

each R¹⁰Are each independently halo, cyano, nitro, oxo, ═ NH, -OR²⁰、-SR²⁰、-NR²⁰R²¹、C_1-12Alkyl radical, C_2-12Alkenyl radical, C_2-12Alkynyl, C_3-10Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R²⁰、-C(O)OR²⁰、-OC(O)OR²⁰、-OC(O)R²⁰、-C(O)NR²⁰R²¹、-OC(O)NR²⁰R²¹、-NR²⁰C(O)NR²¹R²²、-S(O)_1-2R²⁰、-S(O)_1-2NR²⁰、-NR²⁰S(O)_1-2R²¹、-NR²⁰S(O)_1-2NR²¹R²²、-NR²⁰C(O)R²¹or-NR²⁰C(O)OR²¹Wherein R is¹⁰Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of (a) is independently optionally substituted with 1 to 3R¹¹Substitution;

each R¹¹Are all independently halo, cyano, nitro, oxo, -OR²⁵、-SR²⁵、-NR²⁵R²⁶、C_1-12Alkyl radical, C_2-12Alkenyl radical, C_2-12Alkynyl, C_3-10Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R²⁵、-C(O)OR²⁵、-OC(O)OR²⁵、-OC(O)R²⁵、-C(O)NR²⁵R²⁶、-OC(O)NR²⁵R²⁶、-NR²⁵C(O)NR²⁵R²⁶、-S(O)_1-2R²⁵、-S(O)_1-2NR²⁵、-NR²⁵S(O)_{1- 2}R²⁶、-NR²⁵S(O)_1-2NR²⁵R²⁶、-NR²⁵C(O)R²⁶or-NR²⁵C(O)OR²⁶Wherein R is¹¹Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of (a) is independently optionally substituted with 1 to 3 halo or C_1-12Alkyl substitution, said C_1-12Alkyl is independently optionally substituted with 1-3 oxo, halo, hydroxy or amino groups;

R²⁰、R²¹and R²²Each independently is hydrogen, C_1-12Alkyl radical, C_2-12Alkenyl radical, C_2-12Alkynyl, C_3-10Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R⁴⁰、-C(O)OR⁴⁰、-C(O)NR⁴⁰R⁴¹、-S(O)_1-2R⁴⁰or-S (O)_1-2NR⁴⁰Wherein R is²⁰、R²¹And R²²Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of (a) is independently optionally substituted with 1 to 3R¹¹Substitution; or

R²⁰、R²¹And R²²Together with the atom to which they are attached form a heterocyclyl, which is independently optionally substituted by 1 to 3 halo, oxo or C_1-12Alkyl substitution, said C_1-12Alkyl is independently optionally substituted with 1 to 3 oxo, halo, hydroxy or amino groups;

R²⁵and R²⁶Each independently is hydrogen or C_1-12Alkyl radical, said C_1-12Alkyl is independently optionally substituted with 1 to 3 oxo, halo, hydroxy or amino groups; or

R²⁵And R²⁶Together with the atoms to which they are attached form a heterocyclyl, which heterocyclyl is independently optionally substituted by 1 to 3 halo or C_1-12Alkyl substitution, said C_1-12Alkyl is independently optionally substituted with 1 to 3 oxo, halo, hydroxy or amino groups; and

R⁴⁰and R⁴¹Each of which isIndependently is hydrogen or C_1-12Alkyl radical, said C_1-12Alkyl is independently optionally substituted with 1 to 3 oxo, halo, hydroxy or amino groups; or

R⁴⁰And R⁴¹Together with the atoms to which they are attached form a heterocyclyl, which heterocyclyl is independently optionally substituted by 1 to 3 halo or C_1-12Alkyl substitution, said C_1-12Alkyl is independently optionally substituted with 1 to 3 oxo, halo, hydroxy or amino groups;

some embodiments herein provide compounds of formula i (b):

wherein:

m and n are independently 0 or 1;

each X is independently F, Cl or CF₃；

R¹Selected from the group consisting of alkyl, substituted alkyl, amino, substituted amino, alkoxy, substituted alkoxy, heterocycloalkyl, substituted heterocycloalkyl, heterocycloalkoxy, substituted heterocycloalkoxy, heterocycloalkylthio, substituted heterocycloalkylthio, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, and substituted heteroarylthio;

R²selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, amido, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and

R³selected from the group consisting of carboxyl, carboxyl ester, -arylene-carboxyl ester, -oxyalkylene-carboxyl ester, -alkylene-carboxyl ester, -alkenylene-carboxyl, and-alkenylene carboxyl ester;

or a tautomer, solvate, or pharmaceutically acceptable salt thereof.

Some embodiments herein provide compounds of formula i (c):

or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analog thereof, wherein:

m and n are independently 0 or 1;

each X is independently halo or C_1-3A haloalkyl group;

R²selected from the group consisting of hydrogen, alkyl, acyl, acylamino, aryl and heteroaryl, wherein R is²Each alkyl, aryl and heteroaryl of (a) is optionally substituted with 1 to 3R¹⁰Substitution;

R¹selected from the group consisting of carboxy, carboxy ester, -arylene-carboxy, -alkylene-carboxy ester, -alkenylene-carboxy, -O-alkylene-carboxy, and heteroaryl; and

R³selected from the group consisting of halo, alkyl, amino, alkoxy, heterocycloalkyl, heterocycloalkoxy, heterocycloalkylthio, heteroaryl, heteroaryloxy, and heteroarylthio, wherein R is³Each alkyl, amino, alkoxy, heterocycloalkyl, heterocycloalkoxy, heterocycloalkylthio, heteroaryl, heteroaryloxy and heteroarylthio of (a) is optionally substituted with 1 to 3R¹⁰Substitution;

each R¹⁰Are all independently halo, cyano, nitro, oxo, -OR²⁰、-SR²⁰、-NR²⁰R²¹、C_1-12Alkyl radical, C_2-12Alkenyl radical, C_2-12Alkynyl, C_3-10Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R²⁰、-C(O)OR²⁰、-OC(O)OR²⁰、-OC(O)R²⁰、-C(O)NR²⁰R²¹、-OC(O)NR²⁰R²¹、-NR²⁰C(O)NR²¹R²²、-S(O)_1-2R²⁰、-S(O)_1-2NR²⁰、-NR²⁰S(O)_{1- 2}R²¹、-NR²⁰S(O)_1-2NR²¹R²²、-NR²⁰C(O)R²¹or-NR²⁰C(O)OR²¹Wherein R is¹⁰Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of (a) is independently optionally substituted with 1 to 3R¹¹Substitution;

each R¹¹Independently halo, cyano, nitro, oxo, -OR²⁵、-SR²⁵、-NR²⁵R²⁶、C_1-12Alkyl radical, C_2-12Alkenyl radical, C_2-12Alkynyl, C_3-10Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R²⁵、-C(O)OR²⁵、-OC(O)OR²⁵、-OC(O)R²⁵、-C(O)NR²⁵R²⁶、-OC(O)NR²⁵R²⁶、-NR²⁵C(O)NR²⁵R²⁶、-S(O)_1-2R²⁵、-S(O)_1-2NR²⁵、-NR²⁵S(O)_{1- 2}R²⁶、-NR²⁵S(O)_1-2NR²⁵R²⁶、-NR²⁵C(O)R²⁶or-NR²⁵C(O)OR²⁶Wherein R is¹¹Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of (a) is independently optionally substituted with 1 to 3 halo or C_1-12Alkyl substitution, said C_1-12Alkyl is independently optionally substituted with 1-3 oxo, halo, hydroxy or amino groups;

R²⁰、R²¹and R²²Each independently is hydrogen, C_1-12Alkyl radical, C_2-12Alkenyl radical, C_2-12Alkynyl, C_3-10Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R⁴⁰、-C(O)OR⁴⁰、-C(O)NR⁴⁰R⁴¹、-S(O)_1-2R⁴⁰or-S (O)_1-2NR⁴⁰Wherein R is²⁰、R²¹And R²²Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of (a) is independently optionally substituted with 1 to 3R¹¹Substitution; or

R²⁰、R²¹And R²²Together with the atom to which they are attached form a heterocyclyl, which is independently optionally substituted by 1 to 3 halo, oxo or C_1-12Alkyl substitution, said C_1-12Alkyl is independently optionally substituted with 1 to 3 oxo, halo, hydroxy or amino groups;

R²⁵and R²⁶Each independently is hydrogen or C_1-12Alkyl radical, said C_1-12Alkyl is independently optionally substituted with 1 to 3 oxo, halo, hydroxy or amino groups; or

R²⁵And R²⁶Together with the atoms to which they are attached form a heterocyclyl, which heterocyclyl is independently optionally substituted by 1 to 3 halo or C_1-12Alkyl substitution, said C_1-12Alkyl is independently optionally substituted with 1 to 3 oxo, halo, hydroxy or amino groups; and

R⁴⁰and R⁴¹Each independently is hydrogen or C_1-12Alkyl radical, said C_1-12Alkyl is independently optionally substituted with 1 to 3 oxo, halo, hydroxy or amino groups; or

R⁴⁰And R⁴¹Together with the atoms to which they are attached form a heterocyclyl, which heterocyclyl is independently optionally substituted by 1 to 3 halo or C_1-12Alkyl substitution, said C_1-12Alkyl is independently optionally substituted with 1 to 3 oxo, halo, hydroxy or amino groups;

in some embodiments, provided herein are compounds of formula II:

wherein:

m、n、q、X、R²and R³As defined above;

W¹is a bond or C₁-C₄An alkyl group;

Z¹selected from the group consisting of carboxyl or carboxyl ester groups;

or a tautomer or pharmaceutically acceptable salt thereof.

In some embodiments, provided herein are compounds of formula III:

m、n、p、X、R¹and R²As defined above;

w is selected from the group consisting of a bond, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroaryloxy, and substituted heteroaryloxy;

z is selected from the group consisting of hydrogen, amino, substituted amino and CF₃A group of (a);

or a tautomer or pharmaceutically acceptable salt thereof.

In some embodiments, provided herein are compounds of formula iii (a):

m、n、p、X、R¹and R²As defined above;

w is selected from the group consisting of alkylene, substituted alkylene, -O-alkylene, substituted-O-alkylene, arylene, substituted arylene, heteroarylene, substituted heteroarylene, -O-heteroarylene, and substituted-O-heteroarylene;

z is selected from the group consisting of hydrogen, amino, substituted amino and CF₃A group of (a);

or a tautomer or pharmaceutically acceptable salt thereof.

In some embodiments, provided herein are compounds of formula IV:

wherein:

m、n、W、W¹、X、Z、Z¹and R²As defined above; or a tautomer and/or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein are compounds of formula V:

wherein:

R²and R³As defined above;

R⁴is H, C₁-C₄Alkyl or CF₃；

X¹And X²Are identical and are selected from H, F and CF₃；

L is a bond or

Q is CH or N; and

Q¹is CH or N;

provided that Q and Q¹Not all are N;

or a tautomer or pharmaceutically acceptable salt thereof.

In some embodiments, Q is CH, and Q is CH¹Is CH. In some embodiments, L is a bond.

It is to be understood that references herein to compounds of formula I also include compounds of formulae II, III, IV and V.

In one aspect, the present disclosure provides one or more compounds of carbazole (benzo [ b ] indole) core structure having the numbering scheme shown below:

in some embodiments, the compound has formula I, wherein R is³Is that

n is 0.

In some embodiments, the compound has formula I, wherein R is³Is that

n is 0.

In some embodiments, the compound has formula I, wherein R is³Is that

q is 1.

In some embodiments, the compound has formula I, wherein R is³Is that

q is 1.

In some embodiments, the compound has formula III, wherein R is³Is that

q is 1.

In some embodiments, the compound has formula III, wherein R is³Is OMe, q is 1 and n is 1.

In some embodiments, the compound has formula III, wherein R is³Is that

q is 1.

In some embodiments, the compound has formula III, wherein R is³Is that

q is 1.

In some embodiments, the compound has formula III, wherein R is³Is that

q is 1.

In some embodiments, the compound has formula III, wherein R is³Is thatq is 1.

In some embodiments, the compound has formula I, wherein R is³Is that

q is 1.

In some embodiments, the compound has formula I, wherein R is³Is that

q is 1.

In some embodiments, the compound has formula I, wherein R is³Is thatq is 1.

In some embodiments, the compound has formula I, wherein R is³Is that

q is 1.

In some embodiments, the compound has formula I, wherein R is³Is that

q is 1.

In some embodiments, the compound has formula I, wherein R is³Is that

q is 1.

In some embodiments, the compound has formula I, wherein R is³Is that

q is 1.

In some embodiments, the compound has formula I, wherein R is³Is that

q is 1.

In some embodiments, the compound has formula I, wherein R is³Is that

R¹Is CO₂H and q are 1.

In some embodiments, the compound has formula I, wherein R is³Is that

And R is¹Is CO₂H and q are 1.

In some embodiments, the compound has formula I, wherein R is³Is that

R¹Is CO₂H，R²Contains aminocarbonyl, q is 1, m is 0 and n is 0.

In some embodiments, the compound has formula I, wherein R is³Is that

R¹Is CO₂H，R²Is a substituted aryl group, q is 1, m is 0, and n is 0.

In some embodiments, the compound has formula I, wherein R is³Is that

R¹Is- (CH)₂)₂CO₂H，R²Contains aminocarbonyl, q is 1, m is 0 and n is 0.

In some embodiments, the compound has formula I, wherein R is³Is that

R¹Is- (CH)₂)₂CO₂H，R₂Contains aminocarbonyl, q is 1, m is 1 and n is 0.

In some embodiments, the compound has formula I, wherein R is³Is that

R¹Is- (CH)₂)₂CO₂H，R₂Contains aminocarbonyl, q is 1, m is 0 and n is 1.

In some embodiments, the compound has formula I, wherein R is³Is that

R¹Is- (CH)₂)₂CO₂H，R²Contains aminocarbonyl and q is 1.

In some embodiments, the compound has formula III, wherein R is³Is that

n is 0.

In some embodiments, R³Selected from the group consisting of:

in some embodiments, the compound has the formula disclosed herein, wherein R is¹Is substituted C₁-C₅An alkyl carboxyl group. In some embodiments, the compound has the formula disclosed herein, wherein R is³Is substituted C₁-C₃An alkyl carboxyl group. In some embodiments, the compound has the formula disclosed herein, wherein R is³Is that

Or an ester thereof.

In some embodiments, R³Is that

In some embodiments, R¹Is a carboxyl group, C₁-C₆Alkylene-carboxyl, C₁-C₆Alkenylene-carboxy, -O-C₁-C₆Alkylene-carboxyl or heteroAnd (4) an aryl group.

In some embodiments, R¹Is a carboxyl group.

In some embodiments, R¹Is C₁-C₆Alkylene-carboxyl groups. In some embodiments, R¹Is substituted C₁-C₆Alkylene-carboxyl groups. In some embodiments, R¹Is C substituted by 1 to 5 halogen groups₁-C₆Alkylene-carboxyl groups. In some embodiments, R¹Is C substituted by 1 to 5 fluorine₁-C₆Alkylene-carboxyl groups. In some embodiments, R¹Is that

In some embodiments, R¹Is C₁-C₆Alkenylene-carboxy.

In some embodiments, R¹is-O-C₁-C₆Alkylene-carboxyl groups. In some embodiments, R¹Is that

In some embodiments, R¹Is a heteroaryl group. In some embodiments, R¹Is a 5 to 6 membered heteroaryl ring. In some embodiments, R¹Is a 5-to 6-membered nitrogen-containing heteroaryl ring. In some embodiments, R¹Is a tetrazole ring.

In some embodiments, R²Is hydrogen.

In some embodiments, R²Is C_1-6An alkyl group. In some embodiments, R²Is C_1-C₆A substituted alkyl group. In some embodiments, R²Is represented by-C (O) -NH₂Substituted C_1-6An alkyl group. In some embodiments, R²Is an alkyl group substituted by a cyano group. In some embodiments, R²Is C substituted by cyano_1-4An alkyl group. In some embodiments, R²Is- (CH)₂)₄-CN。

In some embodiments, R²Is an aryl ring. In some embodiments, R²Is a substituted aryl ring. In some embodiments, R²Is an aryl ring substituted with 1 to 3 groups independently selected from halo, C_1-3Alkyl radical, C_1-3Alkoxy, -CO-NH₂Cyano and nitro.

In some embodiments, R²Is a substituted alkyl, substituted aryl or acyl group. In some embodiments, R²Is a substituted alkyl group. In some embodiments, R²Is that

In some embodiments, R²Is a substituted aryl group. In some embodiments, R²Is that

In some embodiments, R²Is an acyl group.

In certain embodiments, X is halo. In some embodiments, X is C_1-3A haloalkyl group. In some embodiments, X is CF₃。

In some embodiments, each R is¹⁰Are each independently halo, cyano, nitro, -OR²⁰、-SR²⁰、-NR²⁰R²¹、C_1-12Alkyl radical, C_2-12Alkenyl radical, C_2-12Alkynyl, C_3-10Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R²⁰、-C(O)OR²⁰、-OC(O)OR²⁰、-OC(O)R²⁰、-C(O)NR²⁰R²¹、-OC(O)NR²⁰R²¹、-NR²⁰C(O)NR²¹R²²、-S(O)_1-2R²⁰、-S(O)_{1- 2}NR²⁰、-NR²⁰S(O)_1-2R²¹、-NR²⁰S(O)_1-2NR²¹R²²、-NR²⁰C(O)R²¹or-NR²⁰C(O)OR²¹Wherein R is¹⁰Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of (a) is independently optionally substituted with 1 to 3R¹¹Substitution;

in some embodiments, each R is¹¹Are each independently halo, cyano, nitro, -OR²⁵、-SR²⁵、-NR²⁵R²⁶、C_1-12Alkyl radical, C_2-12Alkenyl radical, C_2-12Alkynyl, C_3-10Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R²⁵、-C(O)OR²⁵、-OC(O)OR²⁵、-OC(O)R²⁵、-C(O)NR²⁵R²⁶、-OC(O)NR²⁵R²⁶、-NR²⁵C(O)NR²⁵R²⁶、-S(O)_1-2R²⁵、-S(O)_{1- 2}NR²⁵、-NR²⁵S(O)_1-2R²⁶、-NR²⁵S(O)_1-2NR²⁵R²⁶、-NR²⁵C(O)R²⁶or-NR²⁵C(O)OR²⁶Wherein R is¹¹Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of (a) is independently optionally substituted with 1 to 3 halo or C_1-12Alkyl substitution, said C_1-12Alkyl is independently optionally substituted with 1-3 oxo, halo, hydroxy or amino groups;

some embodiments provided herein relate to a compound in table 1, wherein the compound is selected from the group consisting of:

TABLE 1

Or a tautomer, solvate, or pharmaceutically acceptable salt thereof.

Some embodiments provided herein relate to compounds of the formula:

or a tautomer, solvate, or pharmaceutically acceptable salt thereof.

Some embodiments provided herein relate to compounds of the formula:

or a tautomer, solvate, or pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure relates to a compound disclosed herein, and is selected from the group consisting of:

or a tautomer, solvate, and/or pharmaceutically acceptable salt thereof.

In some embodiments, the compound is:

additional compounds X, Y, Z, AA, AB, AC, AD, and AE are included within the scope of the present disclosure:

compounds X, Y and Z

Compound AA-AE

Some embodiments herein provide a compound selected from the group consisting of:

6- [5- (2-methyl-1H-imidazol-1-yl) thiophen-2-yl ] -9H-carbazole-2-carboxylic acid;

9- (3-amino-3-oxopropyl) -7- [ (1H-imidazol-1-yl) methyl ] -9H-carbazole-2-carboxylic acid;

9- (3-amino-3-oxopropyl) -6- (1H-imidazol-1-yl) -9H-carbazole-2-carboxylic acid;

9- (4-aminocarbonyl-2-nitrophenyl) -6- [ (1H-imidazol-1-yl) methyl ] -9H-carbazole-2-carboxylic acid;

9- (3-amino-3-oxopropyl) -6- (1H-imidazol-1-yl) -2- (2-carboxyethyl) -9H-carbazole;

7-methoxy-9H-carbazole-2-carboxylic acid;

9- (3-amino-3-oxopropyl) -7-methoxy-9H-carbazole-2-carboxylic acid;

9- (4-aminocarbonylphenyl) -7-methoxy-9H-carbazole-2-carboxylic acid;

9- (3-amino-3-oxopropyl) -6- [5- (2-methyl-1H-imidazol-1-yl) thiophen-2-yl ] -9H-carbazole-2-carboxylic acid;

9- (4-aminocarbonyl-2-methylphenyl) -6- [5- (2-methyl-1H-imidazol-1-yl) thiophen-2-yl ] -9H-carbazole-2-carboxylic acid;

7- [ (1H-imidazol-1-yl) methyl ] -9H-carbazole-2-carboxylic acid;

6- (1H-imidazol-1-yl) -9H-carbazole-2-carboxylic acid;

9- (4-aminocarbonylphenyl) -6- (1H-imidazol-1-yl) -9H-carbazole-2-carboxylic acid;

9- (4-aminocarbonyl-2-methylphenyl) -6- (1H-imidazol-1-yl) -9H-carbazole-2-carboxylic acid;

9- (3-amino-3-oxopropyl) -7- (1H-imidazol-1-yl) -9H-carbazole-2-carboxylic acid;

9- (4-aminocarbonylphenyl) -7- (1H-imidazol-1-yl) -9H-carbazole-2-carboxylic acid;

9- (4-aminocarbonyl-2-methylphenyl) -7- (1H-imidazol-1-yl) -9H-carbazole-2-carboxylic acid;

9- (3-amino-3-oxopropyl) -3-fluoro-6- (1H-imidazol-1-yl) -9H-carbazole-2-carboxylic acid;

7- (5- (2-methyl-1H-imidazol-1-yl) thia-cyclopent-2-yl) -9H-carbazole-2-carboxylic acid;

9- (4-cyano-2-nitrophenyl) -7- ((thiazol-2-ylamino) methyl) -9H-carbazole-2-carboxylic acid;

9- (4-cyano-2-nitrophenyl) -7- ((oxazol-2-ylamino) methyl) -9H-carbazole-2-carboxylic acid;

9- (4-carbamoyl-2-nitrophenyl) -7- ((oxazol-2-ylamino) methyl) -9H-carbazole-2-carboxylic acid; and

9- (4-carbamoyl-2-nitrophenyl) -7- ((thiazol-2-ylamino) methyl) -9H-carbazole-2-carboxylic acid;

or a tautomer, solvate, and/or pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure also relates to pharmaceutical compositions comprising one or more compounds disclosed herein and a pharmaceutically acceptable excipient.

In one embodiment, a compound of the present disclosure or a pharmaceutical composition comprising the one or more compounds may be administered in combination with a NO donor. NO donor means nitric oxide itself or a related redox active agent and more generally provides an activity determined by nitric oxide. Examples of S-nitroso compounds (including S-nitrosothiols useful herein) include S-nitrosoglutathione, S-nitroso-N-acetylpenicillamine, S-nitroso- γ -thio-L-leucine, S-nitroso- δ -thio-L-leucine, S-nitrosocysteine and its ethyl ester, S-nitroso- γ -methyl-L-homocysteine, S-nitroso-L-homocysteine, S-nitrosoalbumin, and S-nitrosocysteinyl glycine. Examples of other NO donors useful herein are carriers including perfluorocarbons, nitroglycerin, isosorbide, sodium nitroprusside, ethyl nitrite, molsidomine, furanosamine (furoxamine), and N-hydroxy (N-nitrosamine) groups that have been saturated with NO or a hydrophobic NO donor. Accordingly, in one embodiment, the present disclosure provides a combination of one or more compounds of formula I, or tautomers, solvates, and/or pharmaceutically acceptable salts thereof, and a GSNOR inhibitor of the known NO releasing agent R- (+) amlodipine.

3. Compositions and methods

Compounds represented by formula I, or tautomers and/or pharmaceutically acceptable salts thereof, can effectively act as GSNOR inhibitors and can treat conditions that are at least partially affected by increased nitrosylation due to GSNOR inhibition. In one aspect of the disclosure, pharmaceutical compositions are provided comprising one or more compounds of formula I and a pharmaceutically acceptable excipient. In another aspect of the disclosure, methods of inhibiting GSNOR using an effective amount of one or more compounds of formula I provided herein, and/or methods of treating diseases treatable by inhibition of GSNOR using an effective amount of one or more compounds of formula I provided herein are provided.

In some embodiments, the present disclosure provides methods for treating various diseases or disorders that can be treated by inhibiting GSNOR. These diseases include diseases mediated at least in part by proinflammatory cytokines (including but not limited to: IL-4, -5, -6, -10, -12, 13, -17, and-23) and proinflammatory chemokines (including but not limited to CCL-2 and CCL-11) and proinflammatory infiltrating cells (including but not limited to: neutrophils, eosinophils, basophils, lymphocytes, and monocytes) (collectively: proinflammatory mediators). In one embodiment, the compounds and compositions of the present invention are generally useful for treating conditions, including inhibiting tissue and/or organ inflammation caused by proinflammatory mediators.

Certain embodiments of the present disclosure relate to the use of aromatic nitrogen-containing compounds, such as those described herein, to treat conditions in a subject, including those conditions mediated at least in part by the overexpression of proinflammatory mediators. Accordingly, in one embodiment, the present disclosure relates to methods of ameliorating or improving a condition or disorder mediated at least in part by GSNOR, including conditions caused by overexpression of pro-inflammatory mediators.

In one embodiment, a method is provided for treating a disease or disorder that is mediated at least in part by GSNOR expression or overexpression and that is treatable by inhibiting GSNOR, wherein the method comprises administering to a subject an effective amount of one or more compounds of formula I or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of one or more compounds of formula I.

The compounds of the present disclosure are useful for inhibiting GSNOR and/or treating disorders associated with IL-6 overexpression. In some embodiments, the compounds of the present disclosure may be used to inhibit GSNOR and/or treat disorders associated with IL-17 overexpression. In some embodiments, the compounds of the present disclosure may be used to inhibit GSNOR and/or treat disorders associated with IL-23 overexpression. In some embodiments, the compounds of the present disclosure may be used to inhibit GSNOR and/or treat disorders associated with overexpression of IL6, IL-17, or IL-23.

In one of its method aspects, the disclosure relates to methods of inhibiting GSNOR comprising contacting a cell (including neurons/microglia/invasive macrophages) containing GSNOR with an effective amount of one or more compounds of formula I as described herein.

In one aspect, methods of inhibiting GSNOR are provided, wherein the methods comprise contacting a cell in vivo or in vitro with an effective amount of one or more compounds of formula I.

In another aspect, there is provided a method for prophylactically treating or treating a subject having a disorder treatable by inhibition of GSNOR, wherein the method comprises administering to a subject in need thereof an effective amount of one or more compounds of formula I.

In another aspect, there is provided a method of increasing nitrosylation of a protein, wherein the method comprises contacting a cell with an effective amount of one or more compounds of formula I disclosed herein under conditions wherein GSNOR inhibition results in increased nitrosylation of the protein. In one aspect, the method of increasing the nitrosylation of a protein is performed in vitro or in vivo.

In some embodiments, the present disclosure relates to a method for treating a proinflammatory mediator-related condition selected from the group consisting of respiratory tract, cardiovascular, tumor, aging, metabolism, kidney, liver, skin, autoimmune, oxidant-based, inflammatory, fibrotic, inflammatory bowel disease, wherein the method comprises administering to a subject in need thereof an effective amount of one or more compounds of formula I.

Some embodiments provide a method of treating an IL-6, IL-17, or IL-23 related condition in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a compound described herein, and the condition is selected from the group consisting of respiratory, cardiovascular, tumor, aging, metabolic, renal, liver, skin, autoimmune, oxidant-based, inflammatory, fibrotic, and inflammatory bowel disease. In some embodiments, the present disclosure relates to methods of treating an IL-6-related condition selected from the group consisting of respiratory, cardiovascular, tumor, aging, metabolic, renal, hepatic, dermal, autoimmune, oxidant-based, inflammatory, fibrotic, and inflammatory bowel disease, wherein the method comprises administering to a subject in need thereof an effective amount of one or more compounds of formula I. Some embodiments provide a method of treating an IL-17-associated condition in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a compound described herein, and the condition is selected from the group consisting of respiratory, cardiovascular, tumor, aging, metabolic, renal, liver, skin, autoimmune, oxidant-based, inflammatory, fibrotic, and inflammatory bowel disease. Some embodiments provide a method of treating an IL-23-associated condition in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a compound described herein, and the condition is selected from the group consisting of respiratory, cardiovascular, tumor, aging, metabolic, renal, liver, skin, autoimmune, oxidant-based, inflammatory, fibrotic, and inflammatory bowel disease.

In some embodiments, the present disclosure relates to methods for treating conditions treatable by inhibition of GSNOR, the conditions resulting from radio toxicity. The radiotoxicity induced the overexpression of IL-6, IL-17 and IL-23. Accordingly, inhibition of GSNOR results in the inhibition of IL-6, IL-17 and IL-23 overexpression. Such methods can be administered in a therapeutic or prophylactic setting to a subject receiving radiation therapy or to a soldier or other first responder at risk of or having been exposed to toxic levels of radiation. The method comprises administering one or more compounds of formula I to a subject in need thereof to reduce radiation-induced IL-6 levels. In some embodiments, provided herein are methods comprising administering a compound described herein to a subject in need thereof to reduce radiation-induced IL-6, IL-17, or IL-23 levels. In some embodiments, the method comprises administering to a subject in need thereof one or more compounds of formula I to reduce radiation-induced levels of proinflammatory mediators. In one embodiment, the condition is radiation proctitis, radiation colitis, radiation fibrosis, radiation dermatitis or radiation damage of the lungs.

In another aspect, the disclosure also relates to a method wherein one or more compounds of formula I may be administered with other GSNOR inhibitors, such as anti-GSNOR antibodies or antibody fragments, GSNOR antisense irnas, or other small molecule GSNOR inhibitors, or in combination with other agents described in detail herein.

Diseases and/or disorders that are at least partially affected by GSNOR inhibition of IL-6 production include diseases and/or disorders selected from the group consisting of: asthma, exercise-induced asthma, COPD, idiopathic pulmonary fibrosis, lung injury due to cystic fibrosis, type I and type II diabetes, atherosclerosis, ischemic heart disease, myocardial infarction, myocarditis, endocarditis, coronary artery disease, heart failure, ischemia reperfusion injury, septic shock, toxic shock syndrome, pulmonary hypertension, coronary restenosis, cardiomyopathy, congestive heart failure, arrhythmia, peripheral artery disease, sickle cell anemia, embolic disease, cerebrovascular accident, rheumatoid arthritis, osteoarthritis, arteriosclerosis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, chronic kidney disease, autoimmune disease, glomerulonephritis, psoriasis, cutaneous lupus erythematosus, systemic sclerosis, dermatitis, acne, atopic dermatitis, psoriasis, systemic lupus erythematosus, rheumatoid arthritis, and the like, Radiodermatitis, radioproctitis, ischemic stroke, traumatic brain injury, convulsive episodes, alzheimer's disease, parkinson's disease, myasthenia gravis, chronic pain, aging and aging diseases, alcoholic liver disease, cirrhosis, liver fibrosis, fatty liver disease (non-alcoholic fatty liver disease (NAFLD), hepatitis, and Primary Sclerosing Cholangitis (PSC), and/or complications thereof.

In some embodiments, methods are provided for treating a disease or disorder that is affected, at least in part, by GSNOR inhibition of the amount of IL-6, IL-17, or IL-23 production, comprising administering a therapeutically effective amount of a compound as described herein. In some embodiments, such diseases or conditions that are at least partially affected by GSNOR inhibition of the amount of IL-6, IL-17, or IL-23 produced are asthma, exercise-induced asthma, COPD, idiopathic pulmonary fibrosis, lung injury due to cystic fibrosis, type I and type II diabetes, atherosclerosis, ischemic heart disease, myocardial infarction, myocarditis, endocarditis, coronary artery disease, heart failure, ischemic reperfusion injury, septic shock, toxic shock syndrome, pulmonary hypertension, coronary restenosis, cardiomyopathy, congestive heart failure, arrhythmia, peripheral artery disease, sickle cell anemia, embolic disease, cerebrovascular accident, rheumatoid arthritis, osteoarthritis, arteriosclerosis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, chronic kidney disease, and the like, Autoimmune diseases, glomerulonephritis, psoriasis, cutaneous lupus erythematosus, systemic sclerosis, dermatitis, acne, atopic dermatitis, radiodermatitis, radiation proctitis, ischemic stroke, traumatic brain injury, convulsive episodes, alzheimer's disease, parkinson's disease, myasthenia gravis, chronic pain, aging and aging diseases, alcoholic liver diseases, cirrhosis, liver fibrosis, fatty liver diseases (non-alcoholic fatty liver disease-NAFLD), non-alcoholic steatohepatitis (NASH), hepatitis or Primary Sclerosing Cholangitis (PSC) or complications thereof.

In some embodiments, there is provided a method of treating NASH in a subject in need thereof comprising administering a therapeutically effective amount of a compound as described herein. In some embodiments, relief from the symptoms and condition of NASH is achieved by administering one or more compounds described herein.

In some embodiments, a compound as described herein is administered with another therapeutic agent for alleviating one or more symptoms of NASH, including, but not limited to, agents for controlling blood glucose levels, agents for controlling lipid levels, such as agents for lowering control of cholesterol, antioxidants, appetite suppressants, anti-obesity agents, antibiotics, or anti-inflammatory agents. Non-limiting examples of such agents include agents for controlling blood glucose levels, for example sulfonylureas such as chlorpropamide (trade name: Diabinese), glipizide (trade name: Glucotrol and Glucotrol XL), glyburide (trade name: Micronase, Glynase and Diabeta), and glimepiride(Amaryl); meglitinides such as repaglinide (trade name: Prandin) and nateglinide (trade name: Starlix); biguanides, such as metformin (trade name:

) And acarbose (Precose); thiazolidinediones, such as rosiglitazone (trade name:

) Troglitazone (trade name:) And pioglitazone (trade name:

) α -glucosidase inhibitors, e.g. acarbose (trade name)

) And magitol (trade name: glyset); and insulin such as pramlintide (trade name: Symlin), exenatide (trade name: Byetta), eugenol (trade name: Lispro), noratheli (trade name: Aspart), eucrine (humulin), norathalin, ultralente and lefluidex (trade name: Glargine); agents for controlling lipid levels, e.g. vytorin, LXR agonists, clofibrate and gemfibrozil, plasma HDL-raising agents, cholesterol-lowering agents such as ursodeoxycholic acid (synthetic bile salts)

Or

) Cholesterol biosynthesis inhibitors such as HMG-CoA reductase inhibitors (e.g., statins such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Altocor, Mevacor), pravastatin (Pravachol), rosuvastatin (Crestor), simvastatin (Zocor) and rosuvastatin calcium, HMG-CoA synthase inhibitors, squalene epoxidase inhibitors or squalene synthase inhibitorsInhibitors of enzyme formation (also known as squalene synthase inhibitors), acyl-CoA cholesterol acyltransferase (ACAT) inhibitors such as toluylene, probucol, nicotinic acid (niacin, vitamin B-3), niacin and salts and niacinamide, cholesterol absorption inhibitors such as β -sitosterol and ezetimibe (Zatia), bile acid sequestrants such as cholestyramine (Questran), colestipol (Colestid) and colesevelam (WelChol) or dialkylaminoalkyl derivatives of cross-linked dextran, and LDL (low density lipoprotein) receptor inducers, fibrates (such as clofibrate, fenofibrate and gemfibrozole, etc.), vitamin B₆(also known as pyridoxine) and physiologically acceptable salts thereof such as hydrochloride; vitamin B₁₂(also known as cyanocobalamin) and angiotensin II antagonist invertase inhibitors, platelet aggregation inhibitors such as fibrinogen receptor antagonists (i.e., glycoprotein IIb/IIIa fibrinogen receptor antagonists), antibiotics such as polymyxin B, and antioxidants such as selenium, betaine, vitamin C, vitamin E and β -carotene β receptor blockers, agents for reducing body weight or suppressing appetite such as sibutramine (Meridia), orlistat (Xenicamid), anorectic (Anorexigenin), dexamphetamine (dexamprine), digoxin, cannabinoid (CB 1) receptor antagonists, rimonabant, amphetamine, lipase inhibitors, bupropion, topiramate, zonisamide, fenfluramine, phentermine (adix-P, Fastin, lonamin, Oby-trim, Pro-Fast, Zantryl), phenmetrexed (Plutralil, bolux-2, pterothricin, propidine, pteridine/benzthiazine), and other therapeutic regimens described in the literature, are additional examples of oxybutyrin/benzthiazine.

In one embodiment, the therapeutically effective amount is the amount that causes the particular physiological effect that results in the amelioration of the condition being treated or the prevention of the risk associated with the condition. For example, for asthma, the therapeutically effective amount is a bronchodilatory effective amount; for cystic fibrosis, a therapeutically effective amount is an amount effective to improve airway obstruction; for ARDS, a therapeutically effective amount is an hypoxemia-ameliorating effective amount; for heart diseases, a therapeutically effective amount is an amount effective to slow angina or induce angiogenesis; for hypertension, a therapeutically effective amount is an effective blood pressure lowering amount; for ischemic coronary disorders, the therapeutic amount is an amount effective to increase blood flow; for atherosclerosis, a therapeutically effective amount is an effective amount to reverse endothelial cell dysfunction; for autoimmune diseases, a therapeutic amount is an effective amount to reduce autoimmunity; for diseases characterized by angiogenesis, a therapeutically effective amount is an amount effective to inhibit angiogenesis; for conditions in which thrombosis may occur, a therapeutically effective amount is an amount effective to prevent thrombosis; for conditions at risk of developing restenosis, the therapeutically effective amount is an effective restenosis-inhibiting amount; for chronic inflammatory diseases, a therapeutically effective amount is an amount effective to reduce inflammation; for conditions in which apoptosis is likely to occur, a therapeutically effective amount is an amount effective to prevent apoptosis; for impotence, a therapeutically effective amount is an amount effective to achieve or maintain an erection; for obesity, a therapeutically effective amount is an amount effective to induce satiety; for stroke, a therapeutically effective amount is an amount effective to increase blood flow or protect TIA; for reperfusion injury, a therapeutically effective amount is an effective amount to increase function; and for pretreatment of the heart and brain, a therapeutically effective amount is a cytoprotective effective amount, e.g., as measured by troponin or CPK.

The compounds of the present disclosure are also useful in the diagnosis and treatment of a variety of human diseases selected from the group consisting of: type I and type II diabetes, oncological diseases and conditions, atherosclerosis, hypertension, ischemic heart disease, myocardial infarction, myocarditis, endocarditis, congenital heart disease, rheumatic heart disease, valvular heart disease, coronary artery disease, heart failure, cardiogenic shock, ischemia-reperfusion injury, septic shock, toxic shock syndrome, pulmonary hypertension, coronary restenosis, cardiomyopathy, congestive heart failure, arrhythmia, peripheral artery disease, sickle cell anemia, embolic disease, and cerebrovascular accidents. For example, the compounds of the present disclosure are particularly useful for treating conditions caused by oxidative stress and its complications.

In another aspect, the disclosure relates to a method wherein one or more compounds of formula I are used as a means to improve β -adrenergic signaling, in particular, GSNOR inhibitors are used, alone or in combination with β -agonists, to treat or prevent heart failure or other vascular disorders such as hypertension and asthma GSNOR inhibitors may also modulate G protein-coupled receptors (GPCRs) by increasing Gs G-protein, leading to smooth muscle relaxation (e.g., in airways and blood vessels), and by attenuating Gq G-protein, thereby preventing smooth muscle contraction (e.g., in airways and blood vessels).

In some embodiments, provided herein are methods of treating a fibrotic disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound described herein. In some embodiments, the fibrotic disease is pulmonary fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis, radiation-induced lung injury following cancer treatment, cirrhosis, biliary atresia, NASH, atrial fibrosis, endocardial fibrosis, old myocardial infarction fibrosis, glial scar, arterial stiffness, joint fibrosis (knee, shoulder, other joints), crohn's disease, Dupuytren's contracture, keloid, mediastinal fibrosis, myelofibrosis, peyronie's disease, nephrogenic systemic fibrosis, progressive massive pulmonary fibrosis, coal dust lung, retroperitoneal fibrosis, scleroderma/systemic sclerosis, or shoulder joint adhesive capsulitis.

In some embodiments, provided herein are methods of treating an autoimmune disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein. In some embodiments, the autoimmune disease is acute disseminated encephalomyelitis, acute motor axis cord neuropathy, Addison's disease, painful obesity, adult-onset stills disease, alopecia areata, ankylosing spondylitis, anti-glomerulobasement membrane nephritis, anti-neutrophil cytoplasmic antibody-associated vasculitis, anti-N-methyl-D-aspartate receptor encephalitis, anti-phospholipid syndrome, anti-synthetase syndrome, aplastic anemia, autoimmune angioedema, autoimmune enteropathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune multiple endocrine syndrome, Autoimmune multiple endocrine syndrome type 2, autoimmune multiple endocrine syndrome type 3, autoimmune progestogenic dermatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura, autoimmune thyroiditis, autoimmune urticaria, autoimmune uveitis, Barlow's concentric sclerosis, Behcet's disease, Bickerstaff's encephalitis, bullous pemphigoid, celiac disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, Kogan syndrome, cold agglutinin disease, complex regional pain syndrome, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, type 1 diabetes, discoid lupus erythematosus, endometriosis, onset (enthestis), arthritis associated with onset of infection, eosinophilic esophagitis, autoimmune retinopathy, autoimmune thyroiditis purpura, autoimmune thyroiditis, autoimmune uveitis, Crohn's disease, multiple sclerosis, Crohn's disease, Crohn, Eosinophilic fasciitis, epidermolysis bullosa acquisita, erythema nodosum, primary mixed cryoglobulinemia, Erwinia syndrome, Fileti syndrome, fibromyalgia, gastritis, pemphigoid pregnancy, giant cell arteritis, Goodpasture's syndrome (goodpasture's syndrome), Graves ' disease, Graves ' ophthalmopathy, Guillain-Barre syndrome (Guillain-Barre syndrome), Hashimoto's encephalopathy, Hashimoto's thyroiditis, Henoch-Schonein purpura, hidradenitis suppurativa, idiopathic inflammatory demyelinating disease, IgG 4-related diseases, inclusion body myositis, inflammatory bowel disease (moss), intermediate uveitis, interstitial cystitis, juvenile arthritis, Kawasaki disease, Lambert-amyotrophy syndrome, Earlacetic leukocythemia, lichen myasthenia gravis, Grave's syndrome, Graves's disease, Graves ' disease, Lichen sclerosis, ligneous conjunctivitis, linear IgA disease, lupus nephritis, lupus vasculitis, Lyme disease (chronic), Meniere's disease, microscopic colitis, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer, scleroderma (Morphea), Mucha-Haemon disease (Mucha-Habermann disease), multiple sclerosis, myasthenia gravis, myocarditis, myositis, neuromyelitis optica, neuromuscular spasticity syndrome, optic neuritis, Alder's thyroiditis, recurrent rheumatism, paraneoplastic cerebellar degeneration, Parrommberg syndrome, Parsonage-Turner syndrome, Streptococcus childhood infection-related autoimmune neuropsychiatric disorder, pemphigus vulgaris, pernicious anemia, acute pimple-like pityriasis, POEMS syndrome, polymyositis, polymyalgia rheumatica, polymyositis, multiple myositis, Post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary immunodeficiency, primary sclerosing cholangitis, progressive inflammatory neuropathy, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, raynaud's phenomenon, reactive arthritis, recurrent polychondritis, restless leg syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, rheumatoid vasculitis, sarcoidosis, senitdler syndrome, scleroderma, Sjogren's syndrome, stiff person syndrome, subacute bacterial endocarditis, susacks's syndrome, Sydenham's chorea, sympathetic ophthalmia, systemic lupus erythematosus, systemic scleroderma, thrombocytopenia, Tolosa-Hunt syndrome, cross-colitis myelitis, ulcerative colitis, scleroderma, Undifferentiated connective tissue disease, urticaria vasculitis, or vitiligo.

In some embodiments, provided herein are methods of treating an inflammatory disease in a subject in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein. In some embodiments, the inflammatory disease is alzheimer's disease, ankylosing spondylitis, arthritis (including but not limited to osteoarthritis, rheumatoid arthritis ("RA"), and psoriatic arthritis), psoriasis, asthma, atherosclerosis, crohn's disease, colitis, atopic dermatitis, diverticulitis, fibromyalgia, hepatitis, NASH, Irritable Bowel Syndrome (IBS), Systemic Lupus Erythematosus (SLE), nephritis, parkinson's disease, ulcerative colitis, endometriosis, pre-eclampsia, acne vulgaris, asthma, autoimmune diseases, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivity, inflammatory bowel disease, interstitial cystitis, lichen planus, mastocytosis, otitis, pelvic inflammatory disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivity, inflammatory bowel disease, interstitial cystitis, lichen planus, mastocytosis, otitis, pelvic inflammatory disease, chronic prostatitis, chronic cystitis, diverticulitis, chronic, Reperfusion injury, rheumatic fever, rhinitis, sarcoidosis, transplant rejection, vasculitis, uterine fibroid, or eosinophilic esophagitis.

Certain compounds of the present disclosure have been shown to have improved safety and efficacy, for example, efficacy in inhibiting GSNOR at nanomolar concentrations. In general, the compounds of the present disclosure have been demonstrated to be efficacious, have an ameliorating effect, and/or have efficacy in treating diseases or conditions that include some form of oxidative stress as a component.

The amount of active compound administered will vary depending upon the disease being treated, the type of mammal and the particular mode of administration, the age, weight and severity of the disease, as well as other factors well known to the attending physician. A suitable dose of a compound of the disclosure may be, for example, 0.1mg to about 1000mg, 1mg to about 500mg, 1mg to about 300mg, or 1mg to about 100mg daily. Such doses may be administered once daily or more than once daily, for example 2,3,4, 5 or 6 times a day, but preferably 1 or 2 times daily. In some embodiments, the total dose for a 70kg adult is in the range of 0.001mg/kg to about 15mg/kg per administration of the subject's body weight, or 0.01mg/kg to about 1.5mg/kg per administration of the subject's body weight, and such treatment may extend for days, weeks, or months, in some cases years. It will be understood, however, that the specific dose level for any particular subject will depend upon a variety of factors, including the activity of the specific compound employed; the age, weight, general health, sex, and diet of the individual being treated; time and route of administration; the rate of excretion; other drugs previously administered; and the severity of the particular disease being treated.

4. General synthetic methods

The compounds of the present disclosure can be prepared using the following general methods and procedures, using readily available starting materials. It should be understood that while typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are listed, other process conditions may be used unless otherwise indicated. Optimal reaction conditions may vary with the particular reactants or solvents used, but such conditions may be determined by one skilled in the art through routine optimization procedures.

In addition, it will be apparent to those skilled in the art that conventional protecting groups may be required to prevent undesirable reactions of certain functional groups. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting a particular functional group are well known in the art. For example, many Protecting Groups are described in t.w.greene and p.g.m.wuts, Protecting Groups in organic Synthesis, 3 rd edition, Wiley, New York,1999 and references cited therein.

If a compound of the present disclosure contains one or more chiral centers, such compounds may be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or d (l) stereoisomers, or as stereoisomerically-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

The starting materials for the following reactions are generally known compounds or may be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St.Louis, Missouri, USA). Other materials can be prepared using standard references such as the procedures described in Fieser and Fieser's research for Organic Synthesis, volumes 1-15 (John Wiley, and Sons,1991), Rodd's chemistry of Carbon Compounds, volumes 1-5 and supplements (Elsevier Science Publishers,1989), Organic Reactions, volumes 1-40 (John Wiley, and Sons,1991), March's Advanced Organic chemistry, (John Wiley, and Sons, 5 th edition, 2001), and Larock's Comprehensive Organic transformations (VCH Publishers, Inc.,1989), with obvious modifications thereof.

Synthesis of representative Compounds of the invention

In one general embodiment, the process comprises reacting a suitable nitro-aryl compound as a starting material with a suitable aryl boronic acid coupling partner and palladium to give a 2-nitro-1, 1' -biphenyl adduct (Suzuki reaction), which is then heated in the presence of excess triphenylphosphine to produce the corresponding carbazole. It is understood that the nitroaryl component can be coupled to other suitable aryl compounds by a variety of methods or reactions, including Ullmann, Stille, Negishi, Heck, Sonogashira, Gomberg-Bachmann, and Kumada couplings.

In addition, it should be noted that those skilled in the art will appreciate that these carbazole compounds may also be prepared by other synthetic strategies employing different starting compounds having different functional groups. For example, carbazoles may be prepared by the Graebe-Ullmann reaction using N-phenyl-1, 2-diaminobenzene, by nitrene (nitrene) insertion using 2-nitro-1, 1' -biaryl compounds, or by the Bucherer reaction using arylhydrazines and phenol. In any case, the isolated carbazole compound may be followed by further functionalization using additional reaction steps.

In another general embodiment, the method comprises reacting a suitably functionalized carbazole compound synthesized as above with an electrophilic partner under electrophilic substitution reaction conditions. In another general embodiment, the method comprises reacting an appropriately functionalized carbazole compound synthesized as above with a nucleophilic partner under nucleophilic substitution reaction conditions. It is also understood that electrophilic or nucleophilic partners selectively react with one functional group of the carbazole compound. Thus, the reactants should not be added under any reaction conditions under which the reactants may react with any other functional group.

For example, the compounds disclosed herein can generally be prepared according to representative scheme 1:

scheme 1

Amino, keto, hydroxyl and any other necessary Protecting Groups and their deprotection methods are known in the art, where appropriate, for example those described in t.w.greene and p.g.m.wuts, Protecting Groups in Organic Synthesis, 3 rd edition, Wiley, New York, 1999.

In another example, compound 10 in table 1 is prepared according to scheme 2:

scheme 2

5. Administration and pharmaceutical compositions

The present disclosure provides novel compounds having GSNOR inhibitory activity that reduces proinflammatory mediator activity. Also provided herein are novel compounds having GSNOR inhibitory activity that reduces IL-6, IL-17 or IL-23 activity. Accordingly, these compounds are useful for treating conditions and/or disorders that are affected (or at least partially affected) by GSNOR inhibition. Such conditions include asthma, exercise-induced asthma, COPD, idiopathic pulmonary fibrosis, lung injury due to cystic fibrosis, type I and type II diabetes, atherosclerosis, ischemic heart disease, myocardial infarction, myocarditis, endocarditis, coronary artery disease, heart failure, ischemia reperfusion injury, septic shock, toxic shock syndrome, pulmonary hypertension, coronary restenosis, cardiomyopathy, congestive heart failure, arrhythmia, peripheral artery disease, sickle cell anemia, embolic disease, cerebrovascular accident, rheumatoid arthritis, osteoarthritis, atherosclerosis, multiple sclerosis, inflammatory bowel disease, crohn's disease, ulcerative colitis, chronic kidney disease, autoimmune disease, glomerulonephritis, psoriasis, cutaneous lupus erythematosus, systemic sclerosis, dermatitis, cystic fibrosis, stroke, acne, atopic dermatitis, radiodermatitis, radiation proctitis, ischemic stroke, traumatic brain injury, convulsive episodes, alzheimer's disease, parkinson's disease, myasthenia gravis, chronic pain, aging and aging diseases, alcoholic liver disease, cirrhosis, liver fibrosis, fatty liver disease (non-alcoholic fatty liver disease — NAFLD), hepatitis, and Primary Sclerosing Cholangitis (PSC), and/or complications thereof.

In general, the compounds of the present disclosure will be administered in therapeutically effective amounts by any acceptable mode of administration of the agents that serve similar utilities. The actual amount of the compound of the present disclosure, i.e., the active ingredient, will depend on a number of factors, such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors well known to those skilled in the art. The medicament may be administered at least once daily, preferably once or twice daily.

Effective amounts of such agents, as well as the most effective and convenient route of administration and the most appropriate formulation, can be readily determined by routine experimentation. Various formulations and drug delivery systems are available in the art. See, e.g., Gennaro, A.R., eds. (1995) Remington's Pharmaceutical Sciences, 18 th ed., Mack Publishing Co.

The therapeutically effective dose can be estimated initially using various techniques well known in the art. The initial dose used in animal studies can be based on concentrations established in cell culture assays. Dosage ranges suitable for human subjects can be determined, for example, using data obtained from animal studies and cell culture assays.

An effective or therapeutically effective amount or dose of an agent, e.g., a compound of the present disclosure, refers to the amount of the agent or compound that results in an improvement in the symptoms or an increase in survival of the subject. Toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining LD50 (the dose that causes death in 50% of the population) and the Maximum Tolerated Dose (MTD) and ED50 (the dose that is therapeutically effective in 50% of the population). The dose ratio of toxic to therapeutic effect is the therapeutic index, which can be expressed as the ratio LD50/ED50 or MTD/ED 50. Agents that exhibit high therapeutic indices are preferred.

An effective or therapeutically effective amount is that amount of the compound or pharmaceutical composition that elicits the biological or medical response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. The dose may particularly fall within a circulating concentration range which includes ED50 and which is slightly or non-toxic. The dosage may vary within this range depending upon the dosage form employed and/or the route of administration utilized. The exact formulation, route of administration, dosage and dosage interval should be selected in view of the specifics of the subject's condition according to methods known in the art.

The dose amount and interval can be adjusted individually to provide plasma levels of the active moiety sufficient to achieve the desired effect; i.e. the lowest effective concentration (MEC). The MEC for each compound will vary, but can be estimated from, for example, in vitro data and animal experiments. The dosage required to achieve MEC will depend on the individual characteristics and route of administration. For example, for topical administration or selective uptake, the effective local concentration of the drug may be independent of plasma concentration.

The amount of agent or composition administered may depend on a variety of factors including the sex, age and weight of the subject being treated, the severity of the affliction, the mode of administration and the judgment of the prescribing physician.

The present disclosure is not limited to any particular composition or pharmaceutical carrier, as they may vary. In general, the compounds of the present disclosure will be administered as pharmaceutical compositions by any of the following routes: oral, systemic (e.g., transdermal, intranasal, or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. The preferred mode of administration is oral using a convenient daily dosage regimen which may be adjusted to the degree of affliction. The compositions may take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition. Another preferred mode of administering the compounds of the present disclosure is inhalation.

The choice of formulation depends on various factors such as the mode of administration of the drug and the bioavailability of the drug substance. For delivery by inhalation, the compounds may be formulated as liquid solutions, suspensions, aerosol propellants or dry powders and loaded into a suitable dispenser for administration. There are several types of medicinal inhalation devices-nebulizer inhalers, Metered Dose Inhalers (MDIs) and Dry Powder Inhalers (DPIs). The nebulizer device generates a high velocity air stream that causes the therapeutic agent (formulated in liquid form) to be sprayed in the form of a mist, which is carried into the respiratory tract of the subject. MDIs are generally formulations packaged with compressed gas. Upon activation, the device expels a measured amount of therapeutic agent by compressed gas, thereby providing a reliable method of administering a set amount of agent. The DPI allows the therapeutic agent to be dispensed in the form of a free-flowing powder that can be dispersed in the subject's inhaled air stream during breathing with the device. To obtain a free-flowing powder, the therapeutic agent is formulated with an adjuvant such as lactose. The measured amount of therapeutic agent is stored in capsule form and dispensed upon each actuation.

Pharmaceutical dosage forms of the compounds of the present disclosure may be manufactured by any method well known in the art, for example, by means of conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tabletting, suspending, extruding, spray-drying, levigating, emulsifying, (nano/micro) encapsulating, entrapping or lyophilizing processes. As mentioned above, the compositions of the present invention may comprise one or more physiologically acceptable inactive ingredients which aid in the processing of the active molecule into a pharmaceutical preparation.

Recently, pharmaceutical formulations have been developed especially for drugs exhibiting poor bioavailability based on the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing the particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles with a particle size in the range of 10nm to 1,000nm, wherein the active material is supported on a cross-linked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation wherein a drug substance is pulverized into nanoparticles (average particle size of 400nm) in the presence of a surface modifier, and then dispersed in a liquid medium to give a pharmaceutical formulation exhibiting significantly high bioavailability. Such formulations are encompassed by the present invention.

The compositions are generally composed of a compound of the present disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, facilitate administration, and do not adversely affect the therapeutic benefit of the claimed compounds. Such excipients may be any solid, liquid, semi-solid, or gaseous excipient generally available to those skilled in the art, in the case of aerosol compositions.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk (chalk), silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. The liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol, and various oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Preferred liquid carriers, particularly for injectable solutions, include water, physiological saline, aqueous dextrose, and ethylene glycol.

Compressed gas may be used to disperse the compounds of the invention in the form of an aerosol. Suitable inert gases for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and formulations thereof are described in Remington's pharmaceutical Sciences, E.W. Martin, eds (Mack Publishing Company, 18 th edition, 1990).

The compositions of the present disclosure, if desired, may be presented in the form of a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such packages or devices may, for example, comprise metal or plastic foils (e.g., blister packs) or glass and rubber stoppers (e.g., in vials). The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising the compounds of the present invention, which may be formulated in compatible pharmaceutical carriers, may also be prepared and placed in suitable containers and labeled for treatment of the indicated condition.

The amount of the compound in the formulation may vary over the entire range employed by those skilled in the art. Typically, the formulation will contain from about 0.01 to 99.99 wt% (based on the total formulation) of a compound of the present disclosure, in weight percent (wt%), with the remainder being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt%. Representative pharmaceutical formulations are described below.

Formulation examples

The following are representative pharmaceutical formulations containing compounds of formula I, II, III, IV and/or V.

Formulation example 1 tablet formulation

The following ingredients were intimately mixed and then compressed into individual scored tablets.

Formulation example 2 Capsule formulation

The following ingredients were intimately mixed and then filled into hard shell gelatin capsules.

Formulation example 3 suspension formulation

The following ingredients were mixed to form a suspension for oral administration.

Formulation example 4 injectable formulation

The following ingredients were mixed to form an injectable formulation.

Formulation example 5 suppository formulations

Suppositories with a total weight of 2.5g are prepared by mixing the compounds of the invention with

H-15 (triglycerides of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) and has the following composition:

the following synthetic and biological examples are provided to illustrate the present disclosure and are not to be construed in any way as limiting the scope of the present disclosure. Unless otherwise specified, all temperatures are expressed in degrees Celsius.