Carbon monoxide prodrugs for the treatment of medical conditions

Abstract

The present invention provides novel compounds that release carbon monoxide and compositions thereof for use in the treatment of medical conditions responsive to carbon monoxide, such as inflammation, pain, and dermatological conditions.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefits of U.S. Provisional Application No. 62 / 746,410, filed October 16, 2018, and U.S. Application No. 62 / 825,677, filed March 28, 2019. Both applications are incorporated herein by reference in their entirety. Technical Field

[0003] This invention provides organic compounds that release carbon monoxide under physiological conditions and their use in the treatment of medical conditions including inflammation, pain, and skin diseases. Background Technology

[0004] Carbon monoxide (CO) is a colorless, odorless, and tasteless gas that is toxic and potentially fatal to hemoglobin-containing animals when exposed to atmospheric levels exceeding 35 ppm. While high concentrations of CO are known to be toxic, recent research has revealed that CO is also a member of a family of gaseous signaling molecules, comparable in importance to nitric oxide (NO) and hydrogen sulfide (H₂S). CO is continuously produced in the human body during heme catabolism, facilitated by heme oxygenase (HO), which includes inducible HO-1 and constitutively expressed HO-2 and HO-3. Through these enzymatic processes, the human body produces an average of 0.07 mL of CO per hour (see Coburn, RF, “Enhancement by Phenobarbital and Diphenylhydrantoin of Carbon Monoxide Production in Normal Man,” *The New England Journal of Medicine*, 1970, 283: 512-515).

[0005] Initially considered merely a waste byproduct of heme metabolism, CO has been found to play an important role in regulating various physiological processes. At low levels normally present in vivo, CO induces vasodilation (see Morita, T. et al., “Carbon monoxide controls the proliferation of hypoxic vascular smooth muscle cells”, Journal of Biochemistry, 1997, 272: 32804-32809; Durante, W. et al., “Role of carbon monoxide in cardiovascular function”, Journal of Cellular and Molecular Medicine, 2006, 10: 672-686) and inhibits platelet aggregation by activating soluble guanylate cyclase (see Brune, B. et al., “Inhibition of platelet aggregation by carbon monoxide is mediated by activation of guanylate cyclase”, Molecular Pharmacology, 1987, 32: 497-504). Among other processes, CO also plays a role in the regulation of inflammation (see Otterbein, LE et al., “Carbon monoxide has anti-inflammatory effects involving themitogen-activated protein kinase pathway”, *Nature Medicine*, 2000, 6:422), mitochondrial biogenesis (see Suliman, HB et al., “A new activating role for CO in cardiac mitochondrial biogenesis”, *Journal of Cell Science*, 2007, 120:299-308), and autophagy (see Lee, SJ. et al., “Carbon monoxide activates autophagy via mitochondrial reactive oxygen species formation”, *American Journal of Respiratory Cell and Molecular Biology*, 2011, 45:867-873).

[0006] The broad biological effects of CO are evident in disease models such as acute lung injury (see Dolinay, T. et al., “Inhaled Carbon Monoxide Confers Anti-inflammatory Effects Against Ventilator-Induced Lung Injury”, *American Journal of Respiratory and Critical Care Medicine*, 2004, 170:613-620), acetaminophen-induced liver injury (see Zheng, Y. et al., “Enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxide”, *Nature Chemistry*, 2018, 10:787-794), and colitis (see Ji, X. et al., “Click and Release: A Chemical Strategy Toward Developing Gastransmitter Prodrugs”). Prodrugs by Using an Intramolecule Diels-Alder Reaction (Angewandte Chemie International Edition, 2016, 55:15846-15851), sepsis (see MacGarvey, NC et al., "Activation of Mitochondrial Biogenesis by Heme Oxygenase-1-mediated NF-E2-related Factor-2 Induction Rescues Mice from Lethal Staphylococcus aureus Sepsis" (American Journal of Respiratory and Critical Care Medicine, 2012, 185:851-861), and organ transplantation (see Sato, K.).The beneficial therapeutic effects observed after the administration of gaseous CO were noted in the studies of Heme Oxygenase-1 ("Carbon Monoxide Generated by Heme Oxygenase-1 Suppresses the Rejection of Mouse-to-Rate Cardiac Transplants"), *Journal of Immunology*, 2001, 166: 4185-4194; and Song, R. et al. ("Carbon Monoxide Induces Cytoprotection in Rat Orthotopic Lung Transplantation via Anti-Inflammatory and Anti-Apoptotic Effects"), *American Journal of Pathology*, 2003, 163: 231-242.

[0007] Although the therapeutic uses of CO gas have been explored, its administration is hampered by the following: lack of portability, difficulty in controlling the dosage and adjusting it according to the specific needs of patients, and heavy reliance on the patient's respiratory rate to deliver the precise amount (see Ji, X. and Wang, B. "Strategies toward Organic Carbon Monoxide Prodrugs", Chemical Research Reports 2018, 51: 1377-1385).

[0008] These issues have prompted researchers to develop CO-releasing molecules that can be readily administered (see Ji, X. et al., “Toward CO-base Therapeutics: Critical Drug Delivery and Developability Issues,” *Journal of Pharmaceutical Sciences*, 2016, 105: 406-416). Many early CO-releasing molecules were fixed carbonyl compounds that, as metal complexes, release CO upon exposure to light or water (see Ji. X.; Wang, B., “Strategies towards Organic Carbon Monoxide Prodrugs,” *Chemical Research Reports*, 2018, 51, 1377-85; and the references cited therein).

[0009] However, these molecules are generally considered unsuitable for pharmaceutical applications due to the potential toxicity of residual metals (see Motterlini R. et al., “The therapeutic potential of carbon monoxide,” *Nature Reviews Drug Discovery*, 2010, 9: 728-743). Some other organic molecules release CO upon exposure to light, but photocontrolled release is not suitable for systemic application as a therapeutic option.

[0010] In WO 2015 / 191616 and WO 2018 / 093924, Binghe Wang and colleagues disclosed an organic prodrug that releases CO in vivo and in vitro after the completion of an intramolecular Diels-Alder reaction.

[0011] Given the therapeutic importance of carbon monoxide and the problems with current delivery methods, it is clear that new methods need to be developed to administer CO to patients in need. Invention Overview

[0013] This invention provides carbon monoxide prodrugs, compositions, and their use and manufacture for the treatment of medical conditions, including inflammation, pain, and skin diseases. In one aspect, the invention provides compounds for the treatment of neuropathic pain (a condition in dire need of new and effective therapies). The compounds described herein release therapeutic amounts of carbon monoxide under physiological conditions and thus have beneficial effects on medical conditions that have shown benefit from the administration of gaseous carbon monoxide, including inflammatory and pain conditions, and especially neuropathic pain. The use of these compounds allows for controlled and routine dosing of carbon monoxide without the need for special equipment and the careful monitoring required with gaseous carbon monoxide. Furthermore, the compounds provided herein do not contain expensive or toxic heavy metals that release CO gas. These compounds spontaneously release carbon monoxide under physiological conditions, along with small molecule byproducts, most of which have known safety or are known sufficiently non-toxic to deliver the drug.

[0014] In another aspect, the present invention provides a highly advantageous solid dispersion formulation comprising selected compounds of the present invention for systemic CO release, adhered to activated charcoal. As described in Example 12, the solid dispersion formulation comprising activated charcoal and compound 5 releases CO from the compound within minutes. Activated charcoal also has the additional benefit of retaining pharmaceutical byproducts such as saccharin and / or acesulfame potassium, thereby reducing their systemic exposure.

[0015] In one aspect, compounds of formulas I, II and III, or pharmaceutically acceptable salts and / or combinations thereof, are described that release carbon monoxide under physiological conditions to treat medical conditions such as inflammation, pain, and inflammatory skin diseases, such as acne vulgaris.

[0016] In one respect, compounds of formula I are provided:

[0017]

[0018] Or its pharmaceutically acceptable salt;

[0019] Where A is selected from:

[0020]

[0021] R 1 Each time it appears, it is independently selected from halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, mercapto, thioalkyl, -(C=O)R S -O(C=O)R S Cyano, -SO3H, -(P=O)(OH)2, -O(P=O)(OH)2, and nitro;

[0022] Or in another implementation, R 1 It is an azide group;

[0023] R 1A Each time it appears, it is independently selected from halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, mercapto, -(C=O)R S -O(C=O)R S Cyano, -SO3H, -(P=O)(OH)2, -O(P=O)(OH)2, and nitro;

[0024] R S Selected from hydrogen, alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, aryl, and heteroaryl;

[0025] m is independently selected from 0, 1, 2, 3, or 4;

[0026] o can be selected from 1, 2, 3, or 4;

[0027] R 2 and R 2’ It is independently selected from hydrogen, alkyl, haloalkyl, aryl, and heteroaryl;

[0028] X 1 It is –C(R) 5 (R) 5’ )-、-N(R 5” -, -O-, or -S-;

[0029] R 3 Each time it appears, it is independently selected from halogen, alkyl, haloalkyl, aryl, heteroaryl, and

[0030] R 4 and R 4’ Independently alkyl;

[0031] R 5 and R 5’ It is independently selected from hydrogen, halogen, hydroxyl, alkyl, haloalkyl, aryl, and heteroaryl;

[0032] R 5” Selected from hydrogen, alkyl, aryl, and heteroaryl;

[0033] R 6 and R 6’ It is independently selected from hydrogen, alkyl, haloalkyl, aryl, and heteroaryl;

[0034] R 7 Each time it appears, it is independently selected from hydrogen, alkyl, haloalkyl, aryl, and heteroaryl;

[0035] Or in another implementation, R 7 It is an azide group;

[0036] R 11 Selected from hydrogen, halogen, alkyl, haloalkyl, aryl, and heteroaryl;

[0037] R 12 Selected from hydrogen, halogen, alkyl, haloalkyl, aryl, and heteroaryl;

[0038] Or in another implementation, R 12 It is an azide group; and

[0039] R 14 It is selected from hydrogen, alkyl, aryl, and heteroaryl.

[0040] In another respect, new compounds of formula II are provided:

[0041]

[0042] Or its pharmaceutically acceptable salt;

[0043] in:

[0044] B is selected from:

[0045]

[0046] B' is selected from:

[0047]

[0048]

[0049] n is independently selected from 0, 1, 2, 3, 4, and 5 each time it appears;

[0050] R 8 and R 8’ Independently selected from alkyl and aryl groups;

[0051] R 9 Selected from alkyl, haloalkyl, aryl, and heteroaryl groups;

[0052] R 10 and R 10’ Independently selected from alkyl, aryl, and heteroaryl groups;

[0053] R 13 and R 13’ It is independently selected from hydrogen, alkyl, haloalkyl, aryl, and heteroaryl;

[0054] R 15 Each time it appears, it is independently selected from hydrogen, halogen, alkyl, haloalkyl, aryl, and heteroaryl;

[0055] R 16 and R 16’ Each time it appears, it is independently selected from alkyl, haloalkyl, aryl, heteroaryl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, amino, alkylamino, and dialkylamino;

[0056] R 17 Selected from halogens, haloalkyl groups, and nitro groups;

[0057] R m R n R o and R p It is independently selected from hydrogen, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, and heteroaryl;

[0058] All other variables are defined here.

[0059] In another respect, new compounds of formula III are provided:

[0060]

[0061] Or its pharmaceutically acceptable salt;

[0062] in:

[0063] R A Selected from hydrogen, alkyl, haloalkyl, aryl, and heteroaryl;

[0064] C is selected from:

[0065]

[0066] All other variables are defined here.

[0067] In another aspect, a pharmaceutical composition is provided that comprises a compound of formula I, II, or III in a pharmaceutically acceptable carrier, or a pharmaceutically acceptable salt thereof.

[0068] In another aspect, a method is provided for treating a medical condition in a subject, such as a human being, that can be treated with carbon monoxide, comprising administering to the subject an effective amount of a compound of formula IV:

[0069]

[0070] Or its pharmaceutically acceptable salt;

[0071] Where A 1 Selected from:

[0072]

[0073]

[0074] All other variables are defined here.

[0075] In one embodiment, the compound of formula IV is selected from:

[0076]

[0077] In another aspect, a method is provided for treating a medical condition in a subject, such as a human being, that can be treated with carbon monoxide, comprising administering to the subject an effective amount of a compound of formula V:

[0078]

[0079] Or its pharmaceutically acceptable salt;

[0080] Among them B 1 Selected from:

[0081]

[0082] All other variables are defined here.

[0083] In one embodiment, the compound of formula V is selected from:

[0084]

[0085] In another aspect, a method is provided for treating a medical condition in a subject, such as a human being, that can be treated with carbon monoxide, comprising administering to the subject an effective amount of a compound of formula VI:

[0086]

[0087] in:

[0088] R B Selected from hydrogen, alkyl, haloalkyl, aryl, and heteroaryl;

[0089] C 1 Selected from:

[0090]

[0091] All other variables are defined here.

[0092] In one embodiment, the compound of formula VI is selected from:

[0093]

[0094] In one aspect, a method is provided for treating a medical disease of a subject, such as a human being, that can be treated with carbon monoxide, comprising administering to the subject an effective amount of a compound of formula I, II, III, IV, V, or VI, or a pharmaceutically acceptable salt thereof.

[0095] In another aspect, a method for treating neuropathic pain in a subject, such as a human, is provided, comprising administering an effective amount of a compound of formula I, II, III, IV, V, or VI, or a pharmaceutically acceptable salt thereof.

[0096] In another aspect, a method is provided for treating an inflammatory condition in a subject, such as a human being, comprising administering to the subject an effective amount of a compound of formula I, II, III, IV, V, or VI, or a pharmaceutically acceptable salt thereof.

[0097] In another aspect, a method is provided for treating a subject, such as a person, a pain condition, comprising administering to the subject an effective amount of a compound of formula I, II, III, IV, V, or VI, or a pharmaceutically acceptable salt thereof.

[0098] In another aspect, a method for treating inflammatory skin diseases, such as acne vulgaris, is provided, comprising administering an effective amount of a topical composition comprising an effective amount of a compound of formula I, II, III, IV, V, or VI, or a pharmaceutically acceptable salt thereof.

[0099] In another aspect, a method for treating inflammatory skin diseases, such as acne vulgaris, is provided, comprising administering an effective amount of a topical composition comprising an effective amount of a compound of formula VII or VIII and an effective amount of a compound of formula IX:

[0100]

[0101] Or its pharmaceutically acceptable salt, wherein:

[0102] Each R 31 R 32 R 33 and R 34 Independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N(R) a1 )2、-SR a1 -S(O)R a1 -S(O)2R a1 -OS(O)OR a1 -OS(O)2OR a1 -OP(OR) a1 )2、-OP(O)HOR a1 -OP(O)(OR) a1 )2、-P(O)(OR a1 )2、-P(O)(OR a1 )2, -ONO, -ONO2, -NO2, -(C=O)R 35 -(C=O)OR 36 , and –(C=O)NR 37 R 38 ;

[0103] Or R 31 and R 32 Independently selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, and together forming optionally bounded by one or more R groups. 39 Partially replaced fused tricyclic portions, wherein each R 39 Independently selected from halogens, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N(R) a1 )2、-SR a1 -S(O)R a1 -S(O)2R a1 -OS(O)OR a1 -OS(O)2OR a1 -OP(OR) a1 )2、-OP(O)HOR a1 -OP(O)(OR) a1 )2、-P(O)(OR a1 )2、-P(O)(OR a1 )2, -ONO, -ONO2, -NO2, -(C=O)R 35-(C=O)OR 36 , and –(C=O)NR 37 R 38 ;

[0104] Each R 35 R 36 R 37 and R 38 Independently selected from hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, ynyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

[0105] R a1 Each time it appears, it is independently selected from hydrogen, alkyl, aryl, cycloalkyl, and heteroaryl;

[0106] Each R 40 R 41 R 42 and R 43 Selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N(R) a1 )2、-SR a1 -S(O)R a1 -S(O)2R a1 -OS(O)OR a1 -OS(O)2OR a1 -OP(OR) a1 )2、-OP(O)HOR a1 -OP(O)(OR) a1 )2、-P(O)(OR a1 )2、-P(O)(OR a1 )2, -ONO, -ONO2, -NO2, -(C=O)R 35 -(C=O)OR 36 , and –(C=O)NR 37 R 38 ;

[0107] Each R 44 R 45 R 46 R 47 R 48 R 49 R 50 and R 51 Independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N(R) a1 )2、-SR a1 -S(O)R a1 -S(O)2Ra1 -OS(O)OR a1 -OS(O)2OR a1 -OP(OR) a1 )2、-OP(O)HOR a1 -OP(O)(OR) a1 )2、-P(O)(OR a1 )2、-P(O)(OR a1 )2, -ONO, -ONO2, -NO2, -(C=O)R 35’ -(C=O)OR 36’ , and –(C=O)NR 37’ R 38’ ;

[0108] Each R 35’ R 36’ R 37’ and R 38’ Independently selected from hydrogen, alkyl, heteroalkyl, alkenyl, heteroalkenyl, ynyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

[0109] Or R 44 or R 45 Optional with R 46 or R 47 Together they form fused cycloalkyl, fused heterocyclic, fused aryl, or fused heteroaryl groups, each optionally being R 39’ replace;

[0110] Or R 48 or R 49 Optional with R 50 or R 51 Together they form fused cycloalkyl, fused heterocyclic, fused aryl, or fused heteroaryl groups, each optionally being R 39’ replace;

[0111] Each R 39’ Independently selected from halogens, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N(R) a1 )2、-SR a1 -S(O)R a1 -S(O)2R a1 -OS(O)OR a1 -OS(O)2OR a1 -OP(OR) a1 )2、-OP(O)HOR a1 -OP(O)(OR) a1 )2、-P(O)(OR a1 )2、-P(O)(ORa1 )2, -ONO, -ONO2, -NO2, -(C=O)R 35 -(C=O)OR 36 , and –(C=O)NR 37 R 38 ;

[0112] Y 1 Selected from CR 52a CR 52b S, O, or NR a1 ;

[0113] X 1 Selected from CR 53a CR 53b S, O, or NR a1 ;

[0114] Each R 52a R 52b R 53a and R 53b For example, R 35’ Defined; and

[0115] t is 0 or 1.

[0116] In another aspect, a method for treating inflammatory skin conditions, such as acne vulgaris, is provided, comprising administering an effective amount of a topical composition comprising an effective amount of a compound of formula X:

[0117]

[0118] Or its pharmaceutically acceptable salt, wherein:

[0119] Each R 61 R 62 R 63 R 64 R 65 and R 66 Independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N(R) a1 )2、-SR a1 -S(O)R a1 -S(O)2R a1 -OS(O)OR a1 -OS(O)2OR a1 -OP(OR) a1 )2、-OP(O)HOR a1 -OP(O)(OR) a1 )2、-P(O)(OR a1)2、-P(O)(OR a1 )2, -ONO, -ONO2, -NO2, -(C=O)R 35 -(C=O)OR 36 , and –(C=O)NR 37 R 38 ;

[0120] Or R 61 and R 62 Independently selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, and together forming optionally bounded by one or more R groups. 39 Partially replaced fused tricyclic portions, wherein each R 39 Independently selected from halogens, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N(R) a1 )2、-SR a1 -S(O)R a1 -S(O)2R a1 -OS(O)OR a1 -OS(O)2OR a1 -OP(OR) a1 )2、-OP(O)HOR a1 -OP(O)(OR) a1 )2、-P(O)(OR a1 )2、-P(O)(OR a1 )2, -ONO, -ONO2, -NO2, -(C=O)R 35 -(C=O)OR 36 , and –(C=O)NR 37 R 38 ;

[0121] Or R 61 and R 62 Independently selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, and together forming optionally bounded by one or more R groups. 39 Partially replaced fused tricyclic portions, wherein each R 39 Independently selected from halogens, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, hydroxyl, -N(R) a1 )2、-SR a1 -S(O)R a1 -S(O)2R a1 -OS(O)OR a1 -OS(O)2OR a1 -OP(OR) a1 )2、-OP(O)HOR a1 -OP(O)(OR)a1 )2、-P(O)(OR a1 )2、-P(O)(OR a1 )2, -ONO, -ONO2, -NO2, -(C=O)R 35 -(C=O)OR 36 , and –(C=O)NR 37 R 38 ;

[0122] X 2 It is CR 72 R 73 S, O, and NR 74 , where each R 72 and R 73 For example, R 61 As defined, and R 74 For example, R 37 Defined;

[0123] Each R 75 Independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, ynyl, aryl, and heteroaryl;

[0124] Or two ORs 75 The groups together form an oxo moiety;

[0125] n1 is 1, 2, or 3;

[0126] All other variables are defined here.

[0127] In another aspect, a method for treating inflammatory skin conditions, such as acne vulgaris, is provided, comprising administering an effective amount of a topical composition comprising an effective amount of a compound of formula XI:

[0128]

[0129] Or its pharmaceutically acceptable salt, wherein:

[0130] A 1 Selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups;

[0131] m1 can be 1, 2, or 3, provided that when m1 is 2 or 3, there is only one X. 2 It is S or O;

[0132] All other variables are defined here.

[0133] In another aspect, a method for treating inflammatory skin conditions, such as acne vulgaris, is provided, comprising administering an effective amount of a topical composition comprising an effective amount of a compound of formula XII:

[0134]

[0135] Or its pharmaceutically acceptable salt, wherein:

[0136] –X 3 -Y 3 - Partially selected from –C(O)-O- and –OC(O-);

[0137] Z 3 Selected from –O- and –S-;

[0138] R 81 Selected from H, C 1-8 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl and –C(O)R 81a ;

[0139] R 81a Selected from C 1-8 Alkyl, C 3-8 cycloalkyl, C 6-10 Aryl, 3- to 8-membered heterocyclic, 5- to 12-membered heteroaryl, -NR 81b R 81c and -OR 81b ;

[0140] R 81b and R 81c Independently selected from H and C 1-8 Alkyl and C 3-8 cycloalkyl;

[0141] R 82 and R 83 Independently selected from C6 -10 aryl, or R 82 and R 83 They can be arbitrarily combined to form a fused three-ring portion;

[0142] R 84 R 85 and R 86 Independently selected from H and C 1-6 alkyl;

[0143] Each R 81 R 82 R 83 R 84 R 85 and R 86 Optionally and independently by one or more R 87 replace;

[0144] Each R 87 Selected from C 1-4Alkyl, halogen, -CN, -OR a2 -C(O)R b2 -C(O)OR a2 -OC(O)R b2 -N(R) a2 )2、-NR a2 C(O)R b2 -C(O)N(R) a2 )2、-S(O)R b2 -S(O)2R b2 -S(O)2OR a2 -S(O)2N(R) a2 )2, and –NR a2 S(O)2R b2 ;

[0145] Each R a2 Independently selected from H and C 1-4 alkyl;

[0146] Each R b2 It is C 1-4 Alkyl; and

[0147] t2 is 0, 1, 2 or 3.

[0148] Another important aspect of the invention is a pharmaceutical formulation comprising at least one CO-releasing molecule of the invention adhered to or adsorbed onto a solid carrier, such as a solid dispersion, for example activated carbon or a polymeric or nonpolymeric solid, having suitable adhesive properties to adsorb the compound of the invention in a stable form. In one aspect, the CO-releasing compound is a compound of formulas I to VI or X to XII, or a pharmaceutically acceptable salt thereof. In another aspect, the CO-releasing compound is a combination of a compound of formula VII or VIII and a compound of formula IX, or a pharmaceutically acceptable salt thereof.

[0149] This solid dispersion pharmaceutical formulation is superior to other pharmaceutical formulations in terms of delivering CO-releasing compounds because it can rapidly release CO while limiting the amount of systemic exposure to unwanted drug byproducts. In one embodiment, the compounds of the invention are adsorbed onto a solid material, such as activated charcoal, and after administration, CO is released while the activated charcoal continues to adsorb drug byproducts, inhibiting their systemic release. In one embodiment, the solid dispersion formulation is suitable for oral delivery and is, for example, in the form of pills or tablets.

[0150] In one embodiment, the solid dispersion formulation comprises activated carbon. In one embodiment, the solid dispersion formulation comprises a polymeric material, such as polyvinylpyrrolidone or a polyvinylpyrrolidone / vinyl acetate copolymer. In one embodiment, the solid dispersion comprises other excipients selected from starch, talc, cellulose, sodium carboxymethyl cellulose, and magnesium stearate. In one embodiment, the solid dispersion formulation is a tablet or capsule. In one embodiment, the solid dispersion formulation is a controlled-release formulation.

[0151] In one embodiment, the ratio of the CO-emitting compound to the solid carrier of the present invention, by weight, is no more than about 35, no more than about 30, no more than about 25, no more than about 20, no more than about 15, no more than about 10, no more than about 5, no more than about 2.5, or no more than about 1. In another embodiment, the ratio of the CO-emitting compound to the solid carrier of the present invention is no more than about 12:1, no more than about 10:1, no more than about 9:1, no more than about 8:1, no more than about 7:1, no more than about 6:1, no more than about 5:1, no more than about 4:1, no more than about 3:1, or no more than about 2:1.

[0152] In one embodiment, the ratio of the CO-emitting compound to the solid carrier of the present invention, by weight, is less than about 35, less than about 30, less than about 25, less than about 20, less than about 15, less than about 10, less than about 5, less than about 2.5, or less than about 1. In another embodiment, the ratio of the CO-emitting compound to the solid carrier of the present invention is less than about 12:1, less than about 10:1, less than about 9:1, less than about 8:1, less than about 7:1, less than about 6:1, less than about 5:1, less than about 4:1, less than about 3:1, or less than about 2:1.

[0153] In one embodiment, the solid dispersion formulation exhibits a carbon monoxide release yield of at least about 99%, at least about 95%, at least about 90%, at least about 85%, at least about 80%, at least about 75%, at least about 70%, at least about 65%, at least about 60%, at least about 55%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, or at least about 10% after administration to a desired subject. In one embodiment, the solid dispersion formulation exhibits a carbon monoxide release yield of at least 75%.

[0154] In one embodiment, the solid dispersion formulation retains up to about 99%, up to about 98%, up to about 95%, up to about 90%, up to about 85%, up to about 75%, up to about 65%, up to about 60%, up to about 50%, or up to about 40% of the pharmaceutical byproduct after administration to a desired subject. In one embodiment, the pharmaceutical byproduct is saccharin, and approximately 98% of the saccharin is retained in the solid dispersion formulation after administration to a desired subject.

[0155] In another aspect of the invention, a topical formulation for treating inflammatory skin conditions, such as acne vulgaris, is provided, comprising an effective amount of a compound of formula I-VI or X-XII and a locally acceptable carrier, wherein the locally acceptable carrier is substantially anhydrous. In some embodiments, the locally acceptable carrier may be selected from an oily matrix, a lipid matrix (including mineral oil), an absorbent matrix, a silica matrix, or a combination thereof.

[0156] In another aspect, a topical preparation for treating inflammatory skin conditions, such as acne vulgaris, is provided, comprising an effective amount of a compound of formula VII or VIII and an effective amount of a compound of formula IX, and a substantially anhydrous, topically acceptable carrier.

[0157] In another aspect, a topical product is provided for treating inflammatory skin conditions, such as acne vulgaris, comprising a first formulation and a second activating formulation, wherein carbon monoxide is released upon mixing the first and second activating formulations. The first formulation comprises an effective amount of a compound of formula I-VI or X-XII and a substantially anhydrous, locally acceptable carrier. The second activating formulation may be aqueous. The first and second activating formulations remain physically separated until application to the skin, wherein the first and second activating formulations are mixed upon application or immediately before application to the skin, and wherein carbon monoxide is released upon mixing the first and second activating formulations and the second activating carrier. In some embodiments, the second activating formulation further comprises an emulsifier.

[0158] In one embodiment, the compositions used in the methods described herein require a substantially anhydrous (e.g., less than about 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.25% by weight of water or alcohol or combinations thereof) carrier to achieve stability of the carbon monoxide-releasing compounds contained therein for long-term storage and handling.

[0159] In one embodiment, at least one hydrogen atom in a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, or XII is substituted with deuterium. In one aspect, the deuterium is located at a metabolic site.

[0160] Therefore, the present invention includes at least the following features:

[0161] (a) A compound of formula I, II or III as described herein, or a pharmaceutically acceptable salt thereof;

[0162] (b) Use of compounds of formula I, II or III as described herein, or pharmaceutically acceptable salts thereof, in the treatment of medical diseases that can be treated with carbon monoxide;

[0163] (c) A pharmaceutical composition comprising an effective amount of a compound of formula I, II or III as described herein, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

[0164] (d) A method for treating a medical disease that can be treated with carbon monoxide, comprising administering to a subject in need an effective amount of a compound of formula I, II, or III, IV, V, or VI or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

[0165] (e) A method for treating neuropathic pain, comprising administering to a subject in need an effective amount of a compound of formula I, II, or III, IV, V, or VI or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

[0166] (f) A method for treating pain symptoms, comprising administering to a subject in need an effective amount of a compound of formula I, II, or III, IV, V, or VI or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

[0167] (g) A method for treating inflammatory conditions, comprising administering to a subject in need an effective amount of a compound of formula I, II, or III, IV, V, or VI or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

[0168] (h) A compound of formula I, II, or III, IV, V, or VI or a pharmaceutically acceptable salt thereof, used to treat a medical condition in a host that is treatable with carbon monoxide, optionally in a pharmaceutically acceptable carrier.

[0169] (i) A compound of formula I, II, or III, IV, V, or VI, or a pharmaceutically acceptable salt thereof, for the treatment of neuropathic pain in a host in need, optionally in a pharmaceutically acceptable carrier.

[0170] (j) A compound of formula I, II, or III, IV, V, or VI, or a pharmaceutically acceptable salt thereof, for the treatment of pain symptoms in a host in need, optionally in a pharmaceutically acceptable carrier.

[0171] (k) A compound of formula I, II, or III, IV, V, or VI, or a pharmaceutically acceptable salt thereof, for the treatment of an inflammatory condition in a host in need, optionally in a pharmaceutically acceptable carrier.

[0172] (l) Use of a compound of formula I, formula II, or formula III, formula IV, formula V, or formula VI, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicine for treating a medical condition in a host that is treatable with carbon monoxide, optionally in a pharmaceutically acceptable carrier.

[0173] (m) Use of a compound of formula I, II, or III, IV, V, or VI, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicine for treating neuropathic pain in a host in need, optionally in a pharmaceutically acceptable carrier.

[0174] (n) Use of a compound of formula I, II, or III, IV, V, or VI, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicine for treating a pain condition in a host in need, optionally in a pharmaceutically acceptable carrier.

[0175] (o) Use of a compound of formula I, II, or III, IV, V, or VI, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicine for treating an inflammatory condition in a host in need, optionally in a pharmaceutically acceptable carrier.

[0176] (p) A method for treating inflammatory skin diseases, comprising administering to a subject in need an effective amount of a compound of formula I to VI or formula X to XII or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier;

[0177] (q) Compounds of formulas I to VI or X to XII or pharmaceutically acceptable salts thereof, for the treatment of inflammatory skin diseases in a host in need, optionally in a pharmaceutically acceptable carrier;

[0178] (r) Use of compounds of formulas I to VI or X to XII or pharmaceutically acceptable salts thereof in the manufacture of a medicine for treating an inflammatory skin disease in a host in need, optionally in a pharmaceutically acceptable carrier.

[0179] (s) A method for treating inflammatory skin diseases, comprising administering to a subject in need an effective amount of a combination of a compound of formula VII or VIII and a compound of formula IX or their independent pharmaceutically acceptable salts, optionally in a pharmaceutically acceptable carrier;

[0180] (t) A combination of a compound of formula VII or VIII and a compound of formula IX or their independent pharmaceutically acceptable salts, for the treatment of inflammatory skin diseases in a host in need, optionally in a pharmaceutically acceptable carrier.

[0181] (u) Use of compounds of formulas VII to VIII and IX, or combinations thereof, individually pharmaceutically acceptable salts, in the manufacture of a pharmaceutical product for the treatment of inflammatory skin diseases in a host in need, optionally in a pharmaceutically acceptable carrier;

[0182] (v) Any of the embodiments (p)–(u), wherein the inflammatory skin disease is acne vulgaris;

[0183] (w) Topical formulations comprising compounds of formulas I to VI or X to XII, or pharmaceutically acceptable salts thereof, and locally acceptable carriers.

[0184] (x) A topical formulation comprising compounds of formulas I to VI or X to XII, as well as compounds of formula IX, and a topical formulation of a topically acceptable carrier.

[0185] (y) A topical formulation used in embodiments (w)-(x), wherein the compound or a pharmaceutically acceptable salt thereof is a mixture of enantiomers or diastereomers (as relevant), including racemic derivatives or comprising at least one isotopically rich atom; and

[0186] (z) A topical formulation as used in embodiments (w)-(x), wherein the compound is an enantiomer or diastereomer (as related) enriched form, including as a separated enantiomer or diastereomer (i.e., with a purity greater than 85, 90, 95, 97 or 99%).

[0187] (aa) The compounds used in embodiments (a)-(z) or pharmaceutically acceptable salts thereof, as a mixture of enantiomers or diastereomers (as relevant), including racemic compounds or including at least one isotopically rich atom;

[0188] (bb) The compounds used in embodiments (a)-(z) are in enantiomerically or diastereomeric (as relevant) enriched forms, including as isolated enantiomers or diastereomeric substances (i.e., with a purity greater than 85, 90, 95, 97, or 99%); and

[0189] (cc) A method for preparing a therapeutic product comprising an effective amount of a compound of formula I to XIII or a pharmaceutically acceptable salt thereof;

[0190] (dd) Solid dispersions comprising compounds of formulas I to VI or X to XII or pharmaceutically acceptable salts thereof;

[0191] (ee) A solid dispersion comprising a combination of a compound of formula VII or VIII with a compound of formula IX or a pharmaceutically acceptable salt thereof;

[0192] (ff) Solid dispersion formulation of embodiment (ee), wherein the compound of formula VII or VIII is administered in a solid dispersion formulation separate from the compound of formula IX, wherein the host receives the benefit of the two active agents acting in a synergistic biological manner.

[0193] (gg) The solid dispersion formulation according to any one of embodiments (dd)-(ff) comprises activated carbon;

[0194] (hh) The solid dispersion formulation described in any one of embodiments (dd)-(gg) comprises a polymeric material;

[0195] (ii) The solid dispersion formulation of any one of embodiments (dd)-(hh) comprises other excipients selected from starch, talc, cellulose, sodium carboxymethyl cellulose and magnesium stearate;

[0196] (jj) The solid dispersion formulation described in any one of embodiments (dd)-(ii) is a capsule or tablet; and

[0197] (kk) The solid dispersion formulation described in any one of embodiments (dd)-(jj) is a controlled-release formulation;

[0198] (ll) A formulation for local delivery comprising: a first formulation comprising a compound of formula I-VI or X-XII and a substantially anhydrous locally acceptable carrier, and a second activating formulation, wherein carbon monoxide is released upon mixing the first and second activating formulations.

[0199] (mm) The formulation as described in (ll), wherein the second activator comprises an emulsifier;

[0200] (nn) The formulation as described in (ll) or (mm), wherein the second activator is aqueous. Attached Figure Description

[0201] Figure 1 This is a chemical scheme demonstrating the mechanism of carbon monoxide release from the compounds described herein under physiological conditions.

[0202] Figure 2 It is a chemical scheme that demonstrates competing pathways (CO generation pathway (a) and oxalic acid generation pathway (b), which is the pathway in which the oxalyl-based CO prodrug described in Example 11 can be decomposed in aqueous solution).

[0203] Figure 3 This is a bar graph showing the effect of the pKa of the leaving group of the oxalyl-based CO prodrug described in Example 11 on CO release capacity. The x-axis is labeled with various leaving groups, and the y-axis is labeled with the fluorescence increase and pKa of the leaving groups.

[0204] Figure 4 The UV-Vis fluorescence spectra of the carbon monoxide probe COP-1 in the absence and presence of compound 2 are as described in Example 11. The x-axis shows the wavelength in nanometers, and the y-axis shows the fluorescence index in atomic units.

[0205] Figure 5 The UV-Vis fluorescence spectra of the carbon monoxide probe COP-1 in the absence and presence of compound 5 are as described in Example 11. The x-axis shows the wavelength in nanometers, and the y-axis shows the fluorescence index in atomic units.

[0206] Figure 6A The UV-Vis absorption spectra of deoxymyoglobin in the absence and presence of compound 2 are as described in Example 11. The x-axis represents wavelength measured in nanometers, and the y-axis shows the absorbance level.

[0207] Figure 6B The UV-Vis absorption spectra of deoxymyoglobin in the absence and presence of compound 7 are as described in Example 11. The x-axis represents wavelength measured in nanometers, and the y-axis shows the absorbance level.

[0208] Figure 7 The UV-Vis absorption spectra of deoxymyoglobin in the absence and presence of compound 5 are as described in Example 11. The x-axis represents wavelength measured in nanometers, and the y-axis shows the absorbance level.

[0209] Figure 8A This is the calibration curve for CO release described in Example 11. The x-axis represents mmolCO, and the y-axis represents the peak area of ​​the HPLC curve.

[0210] Figure 8B This is the calibration curve for CO2 release described in Example 11. The x-axis represents mmolCO, and the y-axis represents the peak area of ​​the HPLC curve.

[0211] Figure 9This is a chromatogram measuring the release of CO and CO2 from compound 5 as described in Example 5, as in Example 11. The x-axis represents time in minutes, and the y-axis represents intensity.

[0212] Figure 10 This is a graph showing the CO and CO2 yields of different compounds in ACN:H2O (4:1) at 37°C for 1 hour, as described in Example 11. The x-axis is labeled with the compounds, and the y-axis represents the measured percentage yields of CO and CO2.

[0213] Figure 11 This is a graph showing the effect of pH on the CO and CO2 yields of compound 5 in ACN:H2O (4:1) at 37°C for 1 hour in pH 1 (glycine / NaCl / HCl), pH 3 (citric acid / NaOH / HCl), and pH 7.4 (phosphate buffer), as described in Example 11. The x-axis is labeled with the compounds, and the y-axis is the measured percentage yield of CO and CO2.

[0214] Figure 12 This is a graph showing the effect of pH on the CO and CO2 yields of compound 7 in ACN:H2O (4:1) at 37°C for 1 hour in pH 1 (glycine / NaCl / HCl), pH 3 (citric acid / NaOH / HCl), and pH 7.4 (phosphate buffer), as described in Example 11. The x-axis is labeled with the compounds, and the y-axis is the measured percentage yield of CO and CO2.

[0215] Figure 13 A standard curve for LC-MS determination of oxalic acid produced by compound 5 was prepared as described in Example 11. The x-axis represents the oxalic acid / saccharin ratio measured in μM, and the y-axis represents the peak area ratio of oxalic acid / saccharin.

[0216] Figure 14 It is the decomposition of compound 5 as described in Example 11. 1 HNMR spectrum.

[0217] Figure 15 It is the decomposition of compound 7 as described in Example 11. 1 HNMR spectrum.

[0218] Figure 16A The decomposition of compound 5 was measured by HPLC as described in Example 11. The decomposition was measured over a period of 420 seconds. The x-axis represents the measurement time in minutes, and the y-axis represents the ultraviolet intensity.

[0219] Figure 16BThis is a scatter plot showing the change in the level of compound 5 in 60% PBS at 37°C over time, as measured by HPLC as described in Example 11. The x-axis is time in seconds, and the y-axis is the peak area measured by HPLC.

[0220] Figure 17A The decomposition of compound 7 was measured by HPLC as described in Example 11. The decomposition was measured over a period of 60 minutes. The x-axis represents the measurement time in minutes, and the y-axis represents the ultraviolet light intensity.

[0221] Figure 17B This is a scatter plot showing the change in the level of compound 7 in 60% PBS at 37°C over time, as measured by HPLC as described in Example 11. The x-axis is time in seconds, and the y-axis is the peak area measured by HPLC.

[0222] Figure 18A This is a bar chart showing the decline in TNF-α levels at different concentrations of compound 5 and the control compound saccharin, as described in Example 11. The x-axis represents the micromolar concentration of the carrier, control, compound 5, or saccharin, and the x-axis represents the TNF-α level in nanograms per milliliter.

[0223] Figure 18B This is a bar chart showing the decline in TNF-α levels at different concentrations of compound 7 and the control compound acesulfame, as described in Example 11. The x-axis represents the micromolar concentration of the carrier, control, compound 7, or acesulfame, and the x-axis represents the TNF-α level in nanograms per milliliter.

[0224] Figure 19 This is a bar chart showing the cytotoxicity of compound 5 in HeLa cells compared to saccharin, as described in Example 11. The x-axis represents the micromolar concentration of compound 5 or saccharin, and the x-axis represents the percentage of cell survival.

[0225] Figure 20A This is a scatter plot showing the change in the level of compound 5 in ACN:H2O(4:1) as measured by HPLC as described in Example 11 over time. The x-axis is time in seconds, and the y-axis is the peak area measured by HPLC.

[0226] Figure 20B This is a scatter plot showing the change in the level of compound 7 in ACN:H2O(4:1) as measured by HPLC as described in Example 11 over time. The x-axis is time in seconds, and the y-axis is the peak area measured by HPLC.

[0227] Figure 21This is a standard curve of compound 5 in ACN, used to determine the adsorption capacity of compound 5 on activated carbon, as described in Example 12. The x-axis is the concentration before dilution measured in mg / mL, and the y-axis is the adsorption measured at 280 nm.

[0228] Figure 22 This is the adsorption curve of compound 5 on activated carbon, used to determine the maximum adsorption amount of compound 5, as described in Example 12. The x-axis is the concentration of compound 5 in mg / mL and the y-axis is the adsorbed mass measured in mg. The dashed line at 1.73 mg represents the maximum amount adsorbed.

[0229] Figure 23 This is a CO release kinetics graph of compound 5 as described in Example 12. The x-axis is time measured in minutes, and the y-axis is CO release measured as a percentage. The dashed line at 81% represents the total CO release.

[0230] Figure 24 This is a standard curve of saccharin in the supernatant (PBS) after compound 5 was adsorbed onto activated carbon as described in Example 12. The x-axis is the saccharin concentration measured in mg / mL, and the y-axis is the adsorption measured at 268 nm.

[0231] Figure 25 This is a schematic diagram that summarizes the classification of carbon monoxide as a gas transport agent and details some general biological effects of gas transport agents.

[0232] Figure 26 This is a schematic diagram summarizing the general biological effects of carbon monoxide.

[0233] Figure 27 This is a diagram comparing the concentration of endogenously generated carbon monoxide with the levels present in the exogenous environment (including lethal and FDA clinically restricted levels).

[0234] Figure 28 This is a schematic diagram illustrating a representative example of CO release from an organic carbon monoxide-releasing compound.

[0235] Figure 29 This is a representative example of a compound of formula II.

[0236] Detailed Implementation of the Invention

[0237] I. Definition

[0238] Compounds are described using standard terminology. Unless otherwise stated, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0239] The terms "an" and "a" do not indicate a limitation on quantity, but rather that at least one of the items (a) exists. The term "or" means "and / or". References to numerical ranges are merely shorthand and individually represent each independent value falling within the range unless otherwise stated herein, and each independent value is included within the scope of the specification as if individually referenced. The endpoints of all ranges are included within the range and can be combined independently. All methods described herein may be performed in a suitable order unless otherwise stated herein or clearly indicated by the context. The use of embodiments / examples, or exemplary language (e.g., "for example / as / such as"), is merely for the purpose of better illustrating the invention and is not intended to limit the scope of the invention claimed, unless otherwise indicated.

[0240] A hyphen ("-") not between two letters or symbols is used to indicate the connection point of a substituent. For example, -(C=O)NH2 is connected to the carbon atom of a ketone (C=O) group.

[0241] "Alkyl" is a branched or straight-chain saturated aliphatic hydrocarbon group. In a non-limiting preferred embodiment, the alkyl group typically contains 1 to about 12 carbon atoms, 1 to about 8 carbon atoms, 1 to about 6 carbon atoms, or 1 to about 4 carbon atoms. In some embodiments, the alkyl group is C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, C1-C7, C1-C8, C1-C9, or C1-C 10 In one embodiment, the alkyl group contains about 1 to about 50 carbon atoms or about 1 to about 36 carbon atoms. For example, as used herein, the term C1-C6 alkyl means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, and is intended to indicate that each of these is described as a separate species. For example, as used herein, the term C1-C4 alkyl means a straight-chain or branched alkyl group having 1, 2, 3, or 4 carbon atoms, and is intended to indicate that each of these is described as a separate species. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In some embodiments, the alkyl group is optionally substituted as defined herein.

[0242] In one embodiment, "alkyl" is C1-C 10 Alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl.

[0243] In one implementation, "alkyl" has one carbon atom.

[0244] In one implementation, "alkyl" has two carbon atoms.

[0245] In one implementation, the "alkyl" has three carbon atoms.

[0246] In one implementation, "alkyl" has four carbon atoms.

[0247] In one implementation, the "alkyl" has five carbon atoms.

[0248] In one implementation, the "alkyl" has six carbon atoms.

[0249] Non-limiting examples of "alkyl" include: methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0250] Other non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0251] Other non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[0252] Other non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[0253] Other non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and reactive pentyl.

[0254] In one implementation, "alkyl" means "substituted alkyl".

[0255] When using terms including "alk", it should be understood that "cycloalkyl" or "carbocyclic" may be considered part of the definition unless the context explicitly excludes it. For example, but not limited to, the terms alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkenyloxy, haloalkyl, etc., may all be considered to include cyclic forms of alkyl groups unless the context explicitly excludes it.

[0256] For example, "cycloalkyl" is an alkyl group that forms or includes a ring. When composed of two or more rings, these rings can be linked together in a fused manner. Typical non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0257] As described herein, “aryl” refers to a group in a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in a cyclic array), having 6–14 ring carbon atoms and in the aromatic system (“C6-C”). 14 The aryl group provides zero heteroatoms. In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C6 aryl”).10 Aryl; for example, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 cyclic carbon atoms (“C”). 14 "Aryl" (e.g., anthracene). "Aryl" also includes a ring system in which an aromatic ring as defined above is fused with one or more cycloalkyl or heterocycloalkyl groups, wherein the bonding point is on the aromatic ring, and in this case, the number of carbon atoms continues to represent the number of carbon atoms in the aromatic ring system. The one or more fused cycloalkyl or heterocycloalkyl groups can be 4 to 7 or 5 to 7-membered cycloalkyl or heterocycloalkyl groups, optionally containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron. In a non-limiting embodiment, the aryl group is a side group. An example of a side ring is a phenyl group substituted with a phenyl group. In some embodiments, the aryl group is optionally substituted as defined herein.

[0258] In one embodiment, "aryl" is a 6-carbon aromatic group (phenyl).

[0259] In one embodiment, "aryl" is a 10-carbon aromatic group (naphthyl).

[0260] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a heterocycle, wherein the linking point is an aromatic ring. Non-limiting examples of "aryl" include dihydroindole, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the linking point of each group is on an aromatic ring.

[0261] For example It is an "aryl" group.

[0262] However, It is a "heterocyclic" group.

[0263] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a cycloalkyl group, wherein the linking point is an aromatic ring. Non-limiting examples of "aryl" include dihydroindene and tetrahydronaphthalene, wherein the linking point of each group is on an aromatic ring.

[0264] For example It is an "aryl" group.

[0265] However, It is a "cycloalkyl" group.

[0266] In one implementation, "aryl" means "substituted aryl".

[0267] In one embodiment, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 carbon atoms.

[0268] Non-limiting examples of 5-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetraazole, isoxazole, oxazole, oxadiazole, oxtriazole, isothiazole, thiazole, thiazolium, and thiatriazole.

[0269] Other non-limiting examples of 5-membered "heteroaryl" groups include:

[0270]

[0271] In one embodiment, "heteroaryl" is a 6-membered aromatic group (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl) containing 1, 2, or 3 nitrogen atoms.

[0272] Non-limiting examples of 6-membered "heteroaryl" groups having one or two nitrogen atoms include:

[0273]

[0274] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[0275] Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazol, benzoxazole, and benzothiazol.

[0276] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0277]

[0278] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0279]

[0280] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0281]

[0282] In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[0283] Non-limiting examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cyclophosphine, and naphthidine.

[0284] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0285]

[0286] In one implementation, "heteroaryl" means "substituted heteroaryl".

[0287] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0288] "Halogenated alkyl" refers to a branched or straight-chain alkyl group substituted with one or more of the aforementioned halogen atoms, up to the maximum permissible number of halogen atoms. Examples of halogenated alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Hyperhalogenated alkyl" refers to an alkyl group in which all hydrogen atoms are substituted with halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0289] In one embodiment, "halogenated alkyl" is a C1-C603 ... 10 Haloalkyl, C1-C9 haloalkyl, C1-C8 haloalkyl, C1-C7 haloalkyl, C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl, and C1-C2 haloalkyl.

[0290] In one embodiment, the "halogenated alkyl" has one carbon atom.

[0291] In one embodiment, the "halogenated alkyl" has one carbon atom and one halogen.

[0292] In one embodiment, the "halogenated alkyl" has one carbon atom and two halogens.

[0293] In one embodiment, the "halogenated alkyl" has one carbon atom and three halogens.

[0294] In one implementation, the "halogenated alkyl" has two carbon atoms.

[0295] In one implementation, the "halogenated alkyl" has three carbon atoms.

[0296] In one implementation, the "halogenated alkyl" has four carbon atoms.

[0297] In one embodiment, the "halogenated alkyl" has five carbons.

[0298] In one embodiment, the "halogenated alkyl" has six carbons.

[0299] Non-limiting examples of “halogenated alkyl” include:

[0300] Other non-limiting examples of “haloalkyl” include:

[0301] Other non-limiting examples of “haloalkyl” include:

[0302] Other non-limiting examples of “haloalkyl” include:

[0303] "Alkoxy" refers to an alkyl group as defined above, covalently bonded via an oxygen bridge (-O-). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexyloxy, 2-hexyloxy, 3-hexyloxy, and 3-methylpentoxy. "Haloalkoxy" refers to a haloalkyl group as defined herein, linked via an oxygen bridge (-O-).

[0304] "Dosage form" refers to the unit of administration of an active ingredient. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, spheres, creams, ointments, suppositories, inhalable dosage forms, transdermal dosage forms, buccal, sublingual, topical, gels, and mucosal dosage forms. "Dosage form" can also include implants, such as optical implants.

[0305] As used in this article, "effective amount" refers to the amount that provides therapeutic or preventative benefits.

[0306] "Parenteral" administration of drug compositions includes techniques such as subcutaneous (sc), intravenous (iv), intramuscular (im), or intrasternal injection or infusion.

[0307] As used herein, the term “treatment” for a disease refers to reducing the frequency or severity of at least one sign or symptom of a disease or condition experienced by the subject (i.e., palliative care) or reducing the cause or effect of the disease or condition (i.e., improving the treatment of the disease).

[0308] As used herein, a “pharmaceutical composition” is a composition comprising at least one active agent and at least one other substance such as a carrier. A “pharmaceutical combination” is a combination of at least two active agents that may be combined in a single dosage form or provided together in separate dosage forms, accompanied by instructions for using the active agents together to treat any of the diseases described herein.

[0309] The term "carrier" used in pharmaceutical compositions / combinations of the present invention refers to a diluent, excipient, or carrier used to deliver the active compound.

[0310] "Pharmaceutically acceptable excipients" refer to excipients that can be used to prepare pharmaceutical compositions / combinations, and are generally safe, non-toxic, and biologically or otherwise unsuitable for administration to a host, typically a human. In one embodiment, excipients suitable for veterinary use are used.

[0311] "Patient," "host," or "object" refers to a human or non-human animal that requires treatment or prevention of any condition specifically described herein. Typically, the host is a human. "Host" may alternatively refer to, for example, mammals, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc.

[0312] The "therapeutic effective amount" of the pharmaceutical composition / combination of the present invention refers to the amount that effectively provides therapeutic benefit when administered to the host, such as improving symptoms or alleviating or reducing the disease itself.

[0313] The compounds in any of the formulas described herein may be racemic, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides or other isomers such as rotational isomers, as if each were specifically described, unless explicitly excluded by the context.

[0314] This invention includes compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, or XII having at least one atom of desired isotope substitution, in amounts exceeding the natural abundance of the isotope, i.e., enriched. An isotope is an atom with the same atomic number but different mass numbers, i.e., atoms with the same number of protons but different numbers of neutrons.

[0315] Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, respectively, for example... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 18 F, 31 P, 32 P, 35 S, 36 CI, and 125 I. In one non-limiting embodiment, the isotope-labeled compound can be used for metabolic studies (using...) 14 C) Reaction kinetic studies (using, for example) 2 H or 3H) including detection or imaging techniques for drug or substrate tissue distribution testing (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)), or in the treatment of patients with radiation. Specifically, it may be particularly necessary 18 F-labeled compounds are used for PET or SPECT studies. The isotope-labeled compounds and their prodrugs of the present invention can generally be prepared by the methods disclosed in the following schemes or examples and preparations, wherein the non-isotope-labeling reagent is replaced with an readily available isotope-labeling reagent.

[0316] As a general example and not a limitation, isotopes of hydrogen, such as deuterium (… 2 H) and tritium ( 3 H) can be used anywhere in the structure to achieve the desired result. Alternatively, or additionally, isotopes of carbon, such as... 13 C and 14 C.

[0317] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen atom is substituted with deuterium. In some embodiments, the isotope is enriched at 90, 95, or 99% or more at any site of interest. In a non-limiting embodiment, deuterium is enriched at 90, 95, or 99% at the desired site.

[0318] In one non-limiting embodiment, the deuterium substitution of one or more hydrogen atoms may be provided in any of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, or Formula XII. In one non-limiting embodiment, the deuterium substitution of hydrogen atoms occurs in a process selected from R... 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 31 R 32 R 33 R34 R 35 R 36 R 37 R 38 R 40 R 41 R 42 R 43 R 44 R 45 R 46 R 47 R 48 R 49 R 50 R 51 R 35’ R 36’ R 37’ R 38’ R 39’ R 61 R 62 R 63 R 64 R 65 R 66 R 72 R 73 R 74 R 75 R a1 and R x Within any of the groups. For example, when any group is, or is contained in, for example by substitution of methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc.). In some other embodiments, the unsubstituted carbon may be deuterated when two substituents combine to form a ring.

[0319] The compounds of the present invention can form solvates with solvents. Therefore, in one non-limiting embodiment, the present invention includes the solvated form of the compounds. The term "solvate" refers to a molecular complex of the compounds of the present invention (including their salts) having one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents. Other non-limiting examples of solvents are dimethylacetamide and N-methyl-2-pyrrolidine. The term "hydrate" refers to a molecular complex comprising the compounds of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent can be substituted with an isotope (e.g., D2O, d6-acetone, d6-DMSO). Solvates can be in liquid or solid form.

[0320] As used herein, a "pharmaceutically acceptable salt" is a derivative of a disclosed compound in which the parent compound is modified by preparing its inorganic or organic, non-toxic acid or base addition salt. Salts of this compound can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods.

[0321] Typically, these salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (e.g., hydroxides of Na, Ca, Mg, or K, carbonates, bicarbonates, etc.), or by reacting the reactive free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in a variety of solvents or solvent mixtures compatible with the compounds. Typically, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where feasible. Salts of this compound also include solvates of the compound and its salt.

[0322] Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid salts with basic residues (such as amines), or alkali metal or organic salts with acidic residues (such as carboxylic acids), etc. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of parent compounds formed from non-toxic organic acids. For example, conventional non-toxic acid salts include those formed from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethanesulfonic acid, and HOOC-(CH2). n -COOH (where n is 0-4), etc., or different acids that produce the same counterion. A list of other suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA, USA, page 1418 (1985).

[0323] II. Compounds of Formula I, Formula II, and Formula III

[0324] The present invention provides compounds of formula I, formula II, or formula III or pharmaceutically acceptable salts thereof, optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition.

[0325] In some embodiments, compounds of formula I are provided:

[0326]

[0327] Or its pharmaceutically acceptable salt;

[0328] A is defined as above.

[0329] In some embodiments of Formula I, the compound has the chemical structure of Formula Ia:

[0330]

[0331] Where R 1A And m is defined as above. In one implementation of equation Ia, m is 0.

[0332] In some embodiments of Formula I, the compound has the chemical structure of Formula Ib:

[0333]

[0334] Where R 1 And m is defined as above. In one implementation of equation Ib, m is 0.

[0335] In some embodiments of Formula I, the compound has the chemical structure of Formula Ic:

[0336]

[0337] Where X 1 R 2 and R 2’ As defined above. In some implementations of equation Ic, X 1 It is CH2. In some embodiments of formula Ic, X 1 It is O. In some implementations of formula Ic, X 1 It is S. In some implementations of formula Ic, X 1 It is NH. In some embodiments of formula Ic, R 2 and R 2’ Both are hydrogen.

[0338] In some embodiments of Formula I, the compound has the chemical structure of Formula Id:

[0339]

[0340] Where R 3 R 4 and R 4’ As defined above. In some implementations of formula Id, R 4 and R 4’ All are methyl groups. In some embodiments of formula Id, R 3 It is methyl. In some embodiments of formula Id, R 3 It is –(C=N-OCH3)-CH3.

[0341] In some embodiments of Formula I, the compound has the chemical structure of Formula Ie:

[0342]

[0343] Where R 1 And o are as defined above. In some implementations of formula Ie, R 1 It is a methyl group. In some embodiments of formula Ie, o is 1.

[0344] In some embodiments of Formula I, the compound has the chemical structure of Formula If:

[0345]

[0346] Where R 7 and R 12 As defined above. In some implementations of the formula If, R... 7 It is a methyl group. In some embodiments of formula If, R 12 It is hydrogen.

[0347] In some embodiments of Formula I, the compound has the chemical structure of Formula Ig:

[0348]

[0349] Where R 2 R 2’ R 11 and X 1 As defined above. In some implementations of formula Ig, X 1 It is CH2. In some embodiments of formula Ig, X 1 It is O. In some embodiments of formula Ig, X 1 It is S. In some embodiments of formula Ig, X 1 It is NH. In some embodiments of formula Ig, R 2 and R 2’ All are hydrogen. In some embodiments of formula Ig, R 2 and R 2’ All are methyl groups. In some embodiments of formula Ig, R 11 It is a methyl group. In some embodiments of formula Ig, R 11 It is hydrogen.

[0350] In some embodiments of Formula I, the compound has the chemical structure of Formula Ih:

[0351]

[0352] Where R 3 R7 and R 14 As defined above.

[0353] In some implementations of formula Ih, R 3 It is a methyl group. In some embodiments of formula Ih, R 7 It is a methyl group. In some embodiments of formula Ih, R 14 It is a methyl group. In some embodiments of formula Ih, R 14 It is a phenyl group. In some embodiments of formula Ih, R 14 It is hydrogen.

[0354] In some embodiments, compounds of formula II are provided:

[0355]

[0356] Or its pharmaceutically acceptable salt;

[0357] B and B' are defined as above.

[0358] In some embodiments, the compound has the chemical structure of formula IIa:

[0359]

[0360] Where R 7 As defined above. In some embodiments of formula IIa, R 7 It is a methyl group.

[0361] In some implementations of formulas II and IIb:

[0362]

[0363] Where R 1 m, R 8 and R 8’ As defined above. In some embodiments of equation IIb, m is 0. 8 and R 8’ All are methyl groups.

[0364] In some embodiments of Formula II, the compound has the chemical structure of Formula IIc:

[0365]

[0366] Where R 1 And n is as defined above. In some implementations of equation IIc, R 9 It is methyl. In some embodiments of formula IIc, R 9 It is a phenyl group. In some embodiments of formula IIc, n is 0.

[0367] In some embodiments of Formula II, the compound has the chemical structure of Formula IId:

[0368]

[0369] Where R 1 And m is defined as above. In one implementation of equation IId, m is 0.

[0370] In some embodiments of Formula II, the compound has the chemical structure of Formula IIe:

[0371]

[0372] Where R 1 m, R 2 and R 2’ As defined above. In some embodiments of equation IIe, m is 0. 2 and R 2’ Both are hydrogen.

[0373] In some embodiments of Formula II, the compound has the chemical structure of Formula IIf:

[0374]

[0375] Where R 3 R 10 and R 10’ As defined above. In some implementations of equation IIf, R 3 It is a methyl group. In some embodiments of formula IIf, R 3 It is –(C=N-OCH3)-CH3. In some embodiments of formula IIf, R 10 and R 10’ All are methyl groups. In some embodiments of formula IIf, R 10 and R 10’ Both are hydrogen.

[0376] In some embodiments of Formula II, the compound has the chemical structure of Formula IIg:

[0377]

[0378] Where X 1 R 2 R 2’ and R 11 As defined above. In some embodiments of formula IIg, X 1 It is CH2. In some embodiments of formula IIg, X 1It is O. In some embodiments of formula IIg, X 1 It is S. In some embodiments of formula IIg, X 1 It is NH. In some embodiments of formula IIg, R 2 and R 2’ All are hydrogen. In some embodiments of formula IIg, R 11 It is hydrogen.

[0379] In some embodiments of Formula II, the compound has the chemical structure of Formula IIh:

[0380]

[0381] Where R 7 and R 12 As defined above. In some embodiments of formula IIh, R 7 It is methyl. In some embodiments of formula IIh, R 12 It is hydrogen.

[0382] In some embodiments of Formula II, the compound has the chemical structure of Formula IIi:

[0383]

[0384] Where R 3 R 13 and R 13’ As defined above. In some embodiments of formula IIi, R 13 and R 13’ All are methyl groups. In some embodiments of formula IIi, R 3 It is methyl. In some embodiments of formula IIi, R 3 It is –(C=N-OCH3)-CH3.

[0385] In some embodiments of Formula II, the compound has the chemical structure of Formula IIj:

[0386]

[0387] Where R 3 R 7 and R 14 As defined above. In some embodiments of equation IIj, R 3 It is methyl. In some embodiments of formula IIj, R 13 It is methyl. In some embodiments of formula IIj, R 7 It is a methyl group.

[0388] In some embodiments of Formula II, the compound has the chemical structure of Formula IIk:

[0389]

[0390] Where R 2 R 2’ and X 1 As defined above. In some embodiments of equation IIk, R 2 and R 2’ All are hydrogen. In some embodiments of formula IIk, X 1 It is –CH2-. In some embodiments of formula IIk, X 1 It is O. In some embodiments of formula IIk, X 1 It is NH. In some embodiments of formula IIk, X 1 It is S.

[0391] In some embodiments of Formula II, the compound has the chemical structure of Formula II1:

[0392]

[0393] Where R 1 R 7 R 12 , and m are defined as above. In some embodiments of equation II1, m is 0. In some embodiments of equation II1, R 7 It is methyl. In some embodiments of formula IIl, R 12 It is hydrogen.

[0394] In some embodiments of Formula II, the compound has the chemical structure of Formula IIm:

[0395]

[0396] Where R 1 And o as defined above.

[0397] In some embodiments of Formula II, the compound has the chemical structure of Formula IIn:

[0398]

[0399] Where R 1 R s And n is defined as above.

[0400] In some embodiments, compounds of formula III are provided:

[0401]

[0402] Or its pharmaceutically acceptable salt;

[0403] Among them, C and R AAs defined above.

[0404] In some embodiments of Formula III, the compound has the chemical structure of Formula IIIa:

[0405]

[0406] Where R 7 and R A As defined above. In some embodiments of equation IIIa, R 7 It is methyl. In some embodiments of formula IIIa, R A It is hydrogen. In some embodiments of formula IIIa, R A It is methyl. In some embodiments of formula IIIa, R A It is phenyl.

[0407] In some embodiments of Formula III, the compound has the chemical structure of Formula IIIb:

[0408]

[0409] Where R 1 m, R 8 R 8’ and R A As defined above. In some embodiments of equation IIIb, m is 0. 8 and R 8’ All are methyl groups. In some embodiments of formula IIIb, R A It is methyl. In some embodiments of formula IIIb, R A It is phenyl.

[0410] In some embodiments of Formula III, the compound has the chemical structure of Formula IIIc:

[0411]

[0412] Where R 1 n, R 9 and R A As defined above. In some embodiments of equation IIIc, n is 0. 9 It is methyl. In some embodiments of formula IIIc, R 9 It is phenyl. In some embodiments of formula IIIc, R A It is methyl. In some embodiments of formula IIIc, R A It is phenyl.

[0413] In some embodiments of Formula III, the compound has the chemical structure of Formula IIId:

[0414]

[0415] Where R 1 m and R A As defined above. In some embodiments of equation IIId, m is 0. A It is methyl. In some embodiments of formula IIId, R A It is phenyl.

[0416] In some embodiments of Formula III, the compound has the chemical structure of Formula IIIe:

[0417]

[0418] Where R 1 m, R 2 R 2’ and R A As defined above. In some embodiments of equation IIIe, m is 0. 2 and R 2’ It is methyl. In some embodiments of formula IIIe, R A It is methyl. In some embodiments of formula IIIe, R A It is phenyl.

[0419] In some embodiments of Formula III, the compound has the chemical structure of Formula IIIf:

[0420]

[0421] Where R 1 m and R A As defined above. In some embodiments of equation IIIf, m is 0. A It is methyl. In some embodiments of formula IIIf, R A It is phenyl.

[0422] In some embodiments of Formula III, the compound has the chemical structure of Formula IIIg:

[0423]

[0424] Where R 2 R 2’ R 11 and R A As defined above. In some embodiments of formula IIIg, X1 It is CH2. In some embodiments of formula IIIg, X 1 It is O. In some embodiments of formula IIIg, X 1 It is S. In some embodiments of formula IIIg, X 1 It is NH. In some embodiments of formula IIIg, R 2 and R 2’ All are hydrogen. In some embodiments of formula IIIg, R 11 It is hydrogen. In some embodiments of formula IIIg, R A It is methyl. In some embodiments of formula IIIg, R A It is phenyl.

[0425] In some embodiments of Formula III, the compound has the chemical structure of Formula IIIh:

[0426]

[0427] Where R 7 R 12 and R A As defined above. In some embodiments of equation IIIh, R 7 It is methyl. In some embodiments of formula IIIh, R 7 It is hydrogen. In some embodiments of formula IIIh, R A It is methyl. In some embodiments of formula IIIh, R A It is phenyl. In some alternative embodiments of formula IIIh, R 7 It is methyl and R 12 It is hydrogen.

[0428] In some embodiments of Formula III, the compound has the chemical structure of Formula IIIi:

[0429]

[0430] Where R 3 R 13 R 13’ and R A As defined above. In some implementations of equation IIIi, R 3 It is methyl. In some embodiments of formula IIIi, R 3 It is –(C=N-OCH3)-CH3. In some embodiments of formula IIIi, R 13 and R 13’ All are methyl groups. In some embodiments of formula IIIi, R A It is methyl. In some embodiments of formula IIIi, R A It is phenyl.

[0431] In some embodiments of Formula III, the compound has the chemical structure of Formula IIIj:

[0432]

[0433] Where R 1 m and R A As defined above. In some embodiments of equation IIIj, m is 0. A It is methyl. In some embodiments of formula IIIj, R A It is phenyl.

[0434] In some embodiments of Formula III, the compound has the chemical structure of Formula IIIk:

[0435]

[0436] Where R 1 m and R A As defined above. In some embodiments of equation IIIk, m is 0. A It is methyl. In some embodiments of formula IIIk, R A It is phenyl.

[0437] In some embodiments of Formula III, the compound has the chemical structure of Formula IIIl:

[0438]

[0439] Where R 3 R 7 R 14’ and R A As defined above. In some embodiments of formula IIIl, R 3 It is methyl. In some embodiments of formula IIIl, R 3 It is –(C=N-OCH3)-CH3. In some embodiments of formula IIIl, R 7 It is methyl. In some embodiments of formula IIIl, R 14 It is methyl. In some embodiments of formula IIIl, R A It is methyl. In some embodiments of formula IIIl, R A It is phenyl.

[0440] In some embodiments of Formula III, the compound has the chemical structure of Formula IIIm:

[0441]

[0442] Where R 2 R 2’ R A and X 1 As defined above. In some implementations of formula IIIm, X 1 It is CH2. In some embodiments of formula IIIm, X 1 It is O. In some embodiments of formula IIIm, X 1 It is NH. In some embodiments of formula IIIm, m is 0. In some embodiments of formula IIIm, R 2 and R 2’ All are methyl groups. In some embodiments of formula IIIm, R 2 and R 2’ All are hydrogen. In some embodiments of formula IIIm, R A It is methyl. In some embodiments of formula IIIm, R A It is phenyl.

[0443] In some embodiments of Formula III, the compound has the chemical structure of Formula IIIn:

[0444]

[0445] Where R 1 R s R A And n is defined as above.

[0446] In any one of the embodiments of formula I, II, or III Selected from:

[0447]

[0448] In one embodiment of either formula II or III Selected from:

[0449]

[0450] In any one of the embodiments of formula I, II, or III, R 1 It is a halogen. In any one embodiment of formula I, II, or III, R 1 It is fluorine. In any one embodiment of formula I, II, or III, R 1 It is chlorine. In any one embodiment of formula I, II, or III, R 1 It is bromine. In any embodiment of formula I, II, or III, R 1It is iodine. In any embodiment of formula I, II, or III, R 1 It is a hydroxyl group. In any one embodiment of formula I, II, or III, R 1 It is an alkyl group. In any one embodiment of formula I, II, or III, R 1 It is methyl. In any one embodiment of formula I, II, or III, R 1 It is a haloalkyl group. In any one embodiment of formula I, II, or III, R 1 It is trifluoromethyl. In any one embodiment of formula I, II, or III, R 1 It is trichloromethyl. In any one embodiment of formula I, II, or III, R 1 It is an alkoxy group. In any one embodiment of formula I, II, or III, R 1 It is a methoxy group. In any one embodiment of formula I, II, or III, R 1 It is a haloalkoxy group. In any one embodiment of formula I, II, or III, R 1 It is trifluoromethoxy. In any one embodiment of formula I, II, or III, R 1 It is aryl. In any embodiment of formula I, II, or III, R 1 It is phenyl. In any one embodiment of formula I, II, or III, R 1 It is naphthyl. In any one embodiment of formula I, II, or III, R 1 It is a heteroaryl group. In any one embodiment of formula I, II, or III, R 1 It is a thiol group. In any one embodiment of formula I, II, or III, R 1 It is a thioalkyl group. In any one embodiment of formula I, II, or III, R 1 It is a thiomethyl group. In any one embodiment of formula I, II, or III, R 1 It is –SO3H. In any one embodiment of formula I, II, or III, R 1 It is –(P=O)(OH)2. In any one embodiment of formula I, II, or III, R 1 It is –(P=O)(OH)2. In any one embodiment of formula I, II, or III, R 1 It is a formyl group. In any one embodiment of formula I, II, or III, R 1It is an acetyl group. In any one embodiment of formula I, II, or III, R 1 It is an acetoxy group. In any one embodiment of formula I, II, or III, R 1 It is cyano. In an alternative embodiment of any of formulas I, II, or III, R 1 It is an azide group.

[0451] In any one of the embodiments of formula I, II, or III, R 1A It is a halogen. In any one embodiment of formula I, II, or III, R 1A It is fluorine. In any one embodiment of formula I, II, or III, R 1A It is chlorine. In any one embodiment of formula I, II, or III, R 1A It is bromine. In any embodiment of formula I, II, or III, R 1A It is iodine. In any embodiment of formula I, II, or III, R 1A It is a hydroxyl group. In any one embodiment of formula I, II, or III, R 1A It is an alkyl group. In any one embodiment of formula I, II, or III, R 1A It is methyl. In any one embodiment of formula I, II, or III, R 1A It is a haloalkyl group. In any one embodiment of formula I, II, or III, R 1A It is trifluoromethyl. In any one embodiment of formula I, II, or III, R 1A It is trichloromethyl. In any one embodiment of formula I, II, or III, R 1A It is an alkoxy group. In any one embodiment of formula I, II, or III, R 1A It is a methoxy group. In any one embodiment of formula I, II, or III, R 1A It is a haloalkoxy group. In any one embodiment of formula I, II, or III, R 1A It is trifluoromethoxy. In any one embodiment of formula I, II, or III, R 1A It is aryl. In any embodiment of formula I, II, or III, R 1A It is phenyl. In any one embodiment of formula I, II, or III, R 1A It is naphthyl. In any one embodiment of formula I, II, or III, R 1AIt is a heteroaryl group. In any one embodiment of formula I, II, or III, R 1A It is a thiol group. In any one embodiment of formula I, II, or III, R 1A It is a thioalkyl group. In any one embodiment of formula I, II, or III, R 1A It is a thiomethyl group. In any one embodiment of formula I, II, or III, R 1A It is –SO3H. In any one embodiment of formula I, II, or III, R 1A It is –(P=O)(OH)2. In any one embodiment of formula I, II, or III, R 1A It is –(P=O)(OH)2. In any one embodiment of formula I, II, or III, R 1A It is an acetyl group. In any one embodiment of formula I, II, or III, R 1A It is an acetoxy group. In any one embodiment of formula I, II, or III, R 1A It is a cyano group.

[0452] In any one of the embodiments of formula I, II, or III, R S It is hydrogen. In any embodiment of formula I, II, or III, R S It is methyl. In any one embodiment of formula I, II, or III, R S It is trifluoromethyl. In any one embodiment of formula I, II, or III, R S It is a methoxy group. In any one embodiment of formula I, II, or III, R S It is ethoxylated. In any one embodiment of formula I, II, or III, R S It is –NH2. In any one embodiment of formula I, II, or III, R S It is –NHCH3. In any one embodiment of formula I, II, or III, R S It is –N(CH3)2. In any one embodiment of formula I, II, or III, R S It is phenyl. In any one embodiment of formula I, II, or III, R S It is a heteroaryl group.

[0453] In any one embodiment of formula I, II, or III, m is 0. In any one embodiment of formula I, II, or III, m is 1. In any one embodiment of formula I, II, or III, m is 2. In any one embodiment of formula I, II, or III, m is 3. In any one embodiment of formula I, II, or III, m is 4.

[0454] In one embodiment of either Formula II or III, n is 0. In one embodiment of either Formula II or III, n is 1. In one embodiment of either Formula II or III, n is 2. In one embodiment of either Formula II or III, n is 3. In one embodiment of either Formula II or III, n is 4. In one embodiment of either Formula II or III, n is 5.

[0455] In one embodiment of Equation I, o is 1. In one embodiment of Equation I, o is 2. In one embodiment of Equation I, o is 3. In one embodiment of Equation I, o is 4.

[0456] In any one of the embodiments of formula I, II, or III, R 2 It is hydrogen. In any embodiment of formula I, II, or III, R 2 It is an alkyl group. In any one embodiment of formula I, II, or III, R 2 It is methyl. In any one embodiment of formula I, II, or III, R 2 It is a haloalkyl group. In any one embodiment of formula I, II, or III, R 2 It is trifluoromethyl. In any one embodiment of formula I, II, or III, R 2 It is trichloromethyl. In any one embodiment of formula I, II, or III, R 2 It is aryl. In any embodiment of formula I, II, or III, R 2 It is phenyl. In any one embodiment of formula I, II, or III, R 2 It is naphthyl. In any one embodiment of formula I, II, or III, R 2 It is a heteroaryl group.

[0457] In any one of the embodiments of formula I, II, or III, R 2’ It is hydrogen. In any embodiment of formula I, II, or III, R 2’It is an alkyl group. In any one embodiment of formula I, II, or III, R 2’ It is methyl. In any one embodiment of formula I, II, or III, R 2’ It is a haloalkyl group. In any one embodiment of formula I, II, or III, R 2’ It is trifluoromethyl. In any one embodiment of formula I, II, or III, R 2’ It is trichloromethyl. In any one embodiment of formula I, II, or III, R 2’ It is aryl. In any embodiment of formula I, II, or III, R 2’ It is phenyl. In any one embodiment of formula I, II, or III, R 2’ It is naphthyl. In any one embodiment of formula I, II, or III, R 2’ It is a heteroaryl group.

[0458] In any one of the embodiments of formula I, II, or III, X 1 It is –C(R) 5 (R) 5’ In any one embodiment of formula I, II, or III, X 1 It is CH2. In any one embodiment of formula I, II, or III, X 1 It is –N(R) 5 In any one embodiment of formula I, II, or III, X 1 It is NH. In any one embodiment of formula I, II, or III, X 1 It is N(CH3). In any one embodiment of formula I, II, or III, X 1 It is O. In any one embodiment of formula I, II, or III, X 1 It is S.

[0459] In any one of the embodiments of formula I, II, or III, R 3 It is a halogen. In any one embodiment of formula I, II, or III, R 3 It is fluorine. In any one embodiment of formula I, II, or III, R 3 It is chlorine. In any one embodiment of formula I, II, or III, R 3 It is bromine. In any embodiment of formula I, II, or III, R 3 It is iodine. In any embodiment of formula I, II, or III, R3 It is an alkyl group. In any one embodiment of formula I, II, or III, R 3 It is methyl. In any one embodiment of formula I, II, or III, R 3 It is a haloalkyl group. In any one embodiment of formula I, II, or III, R 3 It is trifluoromethyl. In any one embodiment of formula I, II, or III, R 3 It is trichloromethyl. In any one embodiment of formula I, II, or III, R 3 It is aryl. In any embodiment of formula I, II, or III, R 3 It is phenyl. In any one embodiment of formula I, II, or III, R 3 It is naphthyl. In any one embodiment of formula I, II, or III, R 3 It is a heteroaryl group. In any one embodiment of formula I, II, or III, R 3 It is –(C=N-OCH3)-CH3.

[0460] In one embodiment of formula I, R 4 It is a methyl group. In one embodiment of Formula I, R 4’ It is a methyl group.

[0461] In any one of the embodiments of formula I, II, or III, R 5 It is hydrogen. In any embodiment of formula I, II, or III, R 5 It is a halogen. In any one embodiment of formula I, II, or III, R 5 It is fluorine. In any one embodiment of formula I, II, or III, R 5 It is chlorine. In any one embodiment of formula I, II, or III, R 5 It is bromine. In any embodiment of formula I, II, or III, R 5 It is iodine. In any embodiment of formula I, II, or III, R 5 It is a hydroxyl group. In any one embodiment of formula I, II, or III, R 5 It is an alkyl group. In any one embodiment of formula I, II, or III, R 5 It is methyl. In any one embodiment of formula I, II, or III, R 5 It is a haloalkyl group. In any one embodiment of formula I, II, or III, R 5It is trifluoromethyl. In any one embodiment of formula I, II, or III, R 5 It is trichloromethyl. In any one embodiment of formula I, II, or III, R 5 It is aryl. In any embodiment of formula I, II, or III, R 5 It is phenyl. In any one embodiment of formula I, II, or III, R 5 It is naphthyl. In any one embodiment of formula I, II, or III, R 5 It is a heteroaryl group.

[0462] In any one of the embodiments of formula I, II, or III, R 5’ It is hydrogen. In any embodiment of formula I, II, or III, R 5’ It is a halogen. In any one embodiment of formula I, II, or III, R 5’ It is fluorine. In any one embodiment of formula I, II, or III, R 5’ It is chlorine. In any one embodiment of formula I, II, or III, R 5’ It is bromine. In any embodiment of formula I, II, or III, R 5’ It is iodine. In any embodiment of formula I, II, or III, R 5’ It is a hydroxyl group. In any one embodiment of formula I, II, or III, R 5’ It is an alkyl group. In any one embodiment of formula I, II, or III, R 5’ It is methyl. In any one embodiment of formula I, II, or III, R 5’ It is a haloalkyl group. In any one embodiment of formula I, II, or III, R 5’ It is trifluoromethyl. In any one embodiment of formula I, II, or III, R 5’ It is trichloromethyl. In any one embodiment of formula I, II, or III, R 5’ It is aryl. In any embodiment of formula I, II, or III, R 5’ It is phenyl. In any one embodiment of formula I, II, or III, R 5’ It is naphthyl. In any one embodiment of formula I, II, or III, R 5’ It is a heteroaryl group.

[0463] In any one of the embodiments of formula I, II, or III, R5” It is hydrogen. In any embodiment of formula I, II, or III, R 5” It is an alkyl group. In any one embodiment of formula I, II, or III, R 5” It is methyl. In any one embodiment of formula I, II, or III, R 5” It is aryl. In any embodiment of formula I, II, or III, R 5” It is phenyl. In any one embodiment of formula I, II, or III, R 5” It is naphthyl. In any one embodiment of formula I, II, or III, R 5” It is a heteroaryl group.

[0464] In any one of the embodiments of formula I, II, or III, R 6 It is hydrogen. In any embodiment of formula I, II, or III, R 6 It is an alkyl group. In any one embodiment of formula I, II, or III, R 6 It is methyl. In any one embodiment of formula I, II, or III, R 6 It is a haloalkyl group. In any one embodiment of formula I, II, or III, R 6 It is trifluoromethyl. In any one embodiment of formula I, II, or III, R 6 It is trichloromethyl. In any one embodiment of formula I, II, or III, R 6 It is aryl. In any embodiment of formula I, II, or III, R 6 It is phenyl. In any one embodiment of formula I, II, or III, R 6 It is naphthyl. In any one embodiment of formula I, II, or III, R 6 It is a heteroaryl group.

[0465] In any one of the embodiments of formula I, II, or III, R 6’ It is hydrogen. In any embodiment of formula I, II, or III, R 6’ It is an alkyl group. In any one embodiment of formula I, II, or III, R 6’ It is methyl. In any one embodiment of formula I, II, or III, R 6’ It is a haloalkyl group. In any one embodiment of formula I, II, or III, R 6’It is trifluoromethyl. In any one embodiment of formula I, II, or III, R 6’ It is trichloromethyl. In any one embodiment of formula I, II, or III, R 6’ It is aryl. In any embodiment of formula I, II, or III, R 6’ It is phenyl. In any one embodiment of formula I, II, or III, R 6’ It is naphthyl. In any one embodiment of formula I, II, or III, R 6’ It is a heteroaryl group.

[0466] In any one of the embodiments of formula I, II, or III, R 7 It is hydrogen. In any embodiment of formula I, II, or III, R 7 It is an alkyl group. In any one embodiment of formula I, II, or III, R 7 It is methyl. In any one embodiment of formula I, II, or III, R 7 It is a haloalkyl group. In any one embodiment of formula I, II, or III, R 7 It is trifluoromethyl. In any one embodiment of formula I, II, or III, R 7 It is trichloromethyl. In any one embodiment of formula I, II, or III, R 7 It is aryl. In any embodiment of formula I, II, or III, R 7 It is phenyl. In any one embodiment of formula I, II, or III, R 7 It is naphthyl. In any one embodiment of formula I, II, or III, R 7 It is a heteroaryl group. In an alternative embodiment of any of formulas I, II, or III, R 7 It is an azide group.

[0467] In any one embodiment of formula II or III, R 8 It is an alkyl group. In one embodiment of any of formula II or III, R 8 It is methyl. In any embodiment of formula II or III, R 8 It is an aryl group. In one embodiment of either formula II or III, R 8 It is phenyl. In one embodiment of any of formula II or III, R 8 It is a naphthyl group.

[0468] In any one embodiment of formula II or III, R 8’ It is an alkyl group. In one embodiment of any of formula II or III, R 8’ It is methyl. In any embodiment of formula II or III, R 8’ It is an aryl group. In one embodiment of either formula II or III, R 8’ It is phenyl. In one embodiment of any of formula II or III, R 8’ It is a naphthyl group.

[0469] In any one embodiment of formula II or III, R 9 It is an alkyl group. In one embodiment of any of formula II or III, R 9 It is methyl. In any embodiment of formula II or III, R 9 It is an aryl group. In one embodiment of either formula II or III, R 9 It is phenyl. In one embodiment of any of formula II or III, R 9 It is naphthyl. In one embodiment of either formula II or III, R 9 It is a heteroaryl group.

[0470] In one embodiment of formula II, R 10 It is an alkyl group. In one embodiment of formula II, R 10 It is methyl. In one embodiment of formula II, R 10 It is an aryl group. In one embodiment of formula II, R 10 It is phenyl. In one embodiment of formula II, R 10 It is a naphthyl group. In one embodiment of formula II, R 10 It is a heteroaryl group.

[0471] In one embodiment of formula II, R 10’ It is an alkyl group. In one embodiment of formula II, R 10’ It is methyl. In one embodiment of formula II, R 10’ It is an aryl group. In one embodiment of formula II, R 10’ It is phenyl. In one embodiment of formula II, R 10’ It is a naphthyl group. In one embodiment of formula II, R 10’ It is a heteroaryl group.

[0472] In any one embodiment of formula II or III, R 11 It is hydrogen. In any embodiment of formula II or III, R 11It is a halogen. In one embodiment of either Formula II or III, R 11 It is fluorine. In one embodiment of either Formula II or III, R 11 It is chlorine. In one embodiment of either formula II or III, R 11 It is bromine. In one embodiment of either formula II or III, R 11 It is iodine. In one embodiment of either Formula II or III, R 11 It is an alkyl group. In one embodiment of any of formula II or III, R 11 It is methyl. In any embodiment of formula II or III, R 11 It is a haloalkyl group. In one embodiment of any of formula II or III, R 11 It is trifluoromethyl. In one embodiment of any of formula II or III, R 11 It is trichloromethyl. In one embodiment of any of formula II or III, R 11 It is an aryl group. In one embodiment of either formula II or III, R 11 It is phenyl. In one embodiment of any of formula II or III, R 11 It is naphthyl. In one embodiment of either formula II or III, R 11 It is a heteroaryl group.

[0473] In any one of the embodiments of formula I, II, or III, R 12 It is hydrogen. In any embodiment of formula I, II, or III, R 12 It is a halogen. In any one embodiment of formula I, II, or III, R 12 It is fluorine. In any one embodiment of formula I, II, or III, R 12 It is chlorine. In any one embodiment of formula I, II, or III, R 12 It is bromine. In any embodiment of formula I, II, or III, R 12 It is iodine. In any embodiment of formula I, II, or III, R 12 It is an alkyl group. In any one embodiment of formula I, II, or III, R 12 It is methyl. In any one embodiment of formula I, II, or III, R 12 It is a haloalkyl group. In any one embodiment of formula I, II, or III, R 12It is trifluoromethyl. In any one embodiment of formula I, II, or III, R 12 It is trichloromethyl. In any one embodiment of formula I, II, or III, R 12 It is aryl. In any embodiment of formula I, II, or III, R 12 It is phenyl. In any one embodiment of formula I, II, or III, R 12 It is naphthyl. In any one embodiment of formula I, II, or III, R 12 It is a heteroaryl group.

[0474] In any one embodiment of formula II or III, R 13 It is hydrogen. In any embodiment of formula II or III, R 13 It is an alkyl group. In one embodiment of any of formula II or III, R 13 It is methyl. In any embodiment of formula II or III, R 13 It is methyl. In any embodiment of formula II or III, R 13 It is a haloalkyl group. In one embodiment of any of formula II or III, R 13 It is trifluoromethyl. In one embodiment of any of formula II or III, R 13 It is trichloromethyl. In one embodiment of any of formula II or III, R 13 It is an aryl group. In one embodiment of either formula II or III, R 13 It is naphthyl. In one embodiment of either formula II or III, R 13 It is a heteroaryl group.

[0475] In any one embodiment of formula II or III, R 13’ It is hydrogen. In any embodiment of formula II or III, R 13’ It is an alkyl group. In one embodiment of any of formula II or III, R 13’ It is methyl. In any embodiment of formula II or III, R 13’ It is methyl. In any embodiment of formula II or III, R 13’ It is a haloalkyl group. In one embodiment of any of formula II or III, R 13’ It is trifluoromethyl. In one embodiment of any of formula II or III, R 13’ It is trichloromethyl. In one embodiment of any of formula II or III, R 13’It is an aryl group. In one embodiment of either formula II or III, R 13’ It is naphthyl. In one embodiment of either formula II or III, R 13’ It is a heteroaryl group.

[0476] In any one embodiment of formula II or III, R 14 It is hydrogen. In any embodiment of formula II or III, R 14 It is an alkyl group. In one embodiment of any of formula II or III, R 14 It is methyl. In any embodiment of formula II or III, R 14 It is an aryl group. In one embodiment of either formula II or III, R 14 It is phenyl. In one embodiment of any of formula II or III, R 14 It is naphthyl. In one embodiment of either formula II or III, R 14 It is a heteroaryl group.

[0477] In one embodiment of formula II, R 15 It is hydrogen. In one embodiment of Formula II, R 15 It is a halogen. In one embodiment of Formula II, R 15 It is fluorine. In one embodiment of Formula II, R 15 It is chlorine. In one embodiment of Formula II, R 15 It is bromine. In one embodiment of formula II, R 15 It is iodine. In one embodiment of Formula II, R 15 It is an alkyl group. In one embodiment of formula II, R 15 It is methyl. In one embodiment of formula II, R 15 It is a haloalkyl group. In one embodiment of formula II, R 15 It is trifluoromethyl. In one embodiment of formula II, R 15 It is trichloromethyl. In one embodiment of formula II, R 15 It is an aryl group. In one embodiment of formula II, R 15 It is phenyl. In one embodiment of formula II, R 15 It is a naphthyl group. In one embodiment of formula II, R 15 It is a heteroaryl group.

[0478] In one embodiment of formula II, R 16 It is an alkyl group. In one embodiment of formula II, R 16 It is methyl. In one embodiment of formula II, R 16It is a haloalkyl group. In one embodiment of formula II, R 16 It is trifluoromethyl. In one embodiment of formula II, R 16 It is trichloromethyl. In one embodiment of formula II, R 16 It is an aryl group. In one embodiment of formula II, R 16 It is phenyl. In one embodiment of formula II, R 16 It is a heteroaryl group. In one embodiment of formula II, R 16 It is an alkoxy group. In one embodiment of formula II, R 16 It is a methoxy group. In one embodiment of formula II, R 16 It is an ethoxylated compound. In one embodiment of formula II, R 16 It is a haloalkoxy group. In one embodiment of formula II, R 16 It is trichloromethoxy. In one embodiment of formula II, R 16 It is an aryloxy group. In one embodiment of formula II, R 16 It is a phenoxy group. In one embodiment of formula II, R 16 It is a heteroaryloxy group. In one embodiment of formula II, R 16 It is an amino group. In one embodiment of Formula II, R 16 It is an alkylamino group. In one embodiment of formula II, R 16 It is a methylamino group. In one embodiment of formula II, R 16 It is a dialkylamino group. In one embodiment of formula II, R 16 It is dimethylamino.

[0479] In one embodiment of formula II, R 16’ It is an alkyl group. In one embodiment of formula II, R 16’ It is methyl. In one embodiment of formula II, R 16’ It is a haloalkyl group. In one embodiment of formula II, R 16’ It is trifluoromethyl. In one embodiment of formula II, R 16’ It is trichloromethyl. In one embodiment of formula II, R 16’ It is an aryl group. In one embodiment of formula II, R 16’ It is phenyl. In one embodiment of formula II, R 16’ It is a heteroaryl group. In one embodiment of formula II, R 16’ It is an alkoxy group. In one embodiment of formula II, R 16’ It is a methoxy group. In one embodiment of formula II, R 16’ It is an ethoxylated compound. In one embodiment of formula II, R 16’It is a haloalkoxy group. In one embodiment of formula II, R 16’ It is trichloromethoxy. In one embodiment of formula II, R 16’ It is an aryloxy group. In one embodiment of formula II, R 16’ It is a phenoxy group. In one embodiment of formula II, R 16’ It is a heteroaryloxy group. In one embodiment of formula II, R 16’ It is an amino group. In one embodiment of Formula II, R 16’ It is an alkylamino group. In one embodiment of formula II, R 16’ It is a methylamino group. In one embodiment of formula II, R 16’ It is a dialkylamino group. In one embodiment of formula II, R 16’ It is dimethylamino.

[0480] In one embodiment of formula II, R 17 It is a halogen. In one embodiment of Formula II, R 17 It is fluorine. In one embodiment of Formula II, R 17 It is chlorine. In one embodiment of Formula II, R 17 It is bromine. In one embodiment of formula II, R 17 It is iodine. In one embodiment of Formula II, R 17 It is a haloalkyl group. In one embodiment of formula II, R 17 It is trifluoromethyl. In one embodiment of formula II, R 17 It is trichloromethyl. In one embodiment of formula II, R 17 It is a nitro group.

[0481] In one embodiment of formula II, R m It is hydrogen. In one embodiment of Formula II, R m It is a halogen. In one embodiment of Formula II, R m It is fluorine. In one embodiment of Formula II, R m It is chlorine. In one embodiment of Formula II, R m It is bromine. In one embodiment of formula II, R m It is iodine. In one embodiment of Formula II, R m It is a hydroxyl group. In one embodiment of Formula II, R m It is an alkyl group. In one embodiment of formula II, R m It is methyl. In one embodiment of formula II, R m It is a haloalkyl group. In one embodiment of formula II, R m It is trifluoromethyl. In one embodiment of formula II, R mIt is trichloromethyl. In one embodiment of formula II, R m It is an alkoxy group. In one embodiment of formula II, R m It is a methoxy group. In one embodiment of formula II, R m It is a haloalkoxy group. In one embodiment of formula II, R m It is a trifluoromethoxy group. In one embodiment of formula II, R m It is an aryl group. In one embodiment of formula II, R m It is phenyl. In one embodiment of formula II, R m It is a naphthyl group. In one embodiment of formula II, R m It is a heteroaryl group.

[0482] In one embodiment of formula II, R n It is hydrogen. In one embodiment of Formula II, R n It is a halogen. In one embodiment of Formula II, R n It is fluorine. In one embodiment of Formula II, R n It is chlorine. In one embodiment of Formula II, R n It is bromine. In one embodiment of formula II, R n It is iodine. In one embodiment of Formula II, R n It is a hydroxyl group. In one embodiment of Formula II, R n It is an alkyl group. In one embodiment of formula II, R n It is methyl. In one embodiment of formula II, R n It is a haloalkyl group. In one embodiment of formula II, R n It is trifluoromethyl. In one embodiment of formula II, R n It is trichloromethyl. In one embodiment of formula II, R n It is an alkoxy group. In one embodiment of formula II, R n It is a methoxy group. In one embodiment of formula II, R n It is a haloalkoxy group. In one embodiment of formula II, R n It is a trifluoromethoxy group. In one embodiment of formula II, R n It is an aryl group. In one embodiment of formula II, R n It is phenyl. In one embodiment of formula II, R n It is a naphthyl group. In one embodiment of formula II, R n It is a heteroaryl group.

[0483] In one embodiment of formula II, R o It is hydrogen. In one embodiment of Formula II, R oIt is a halogen. In one embodiment of Formula II, R o It is fluorine. In one embodiment of Formula II, R o It is chlorine. In one embodiment of Formula II, R o It is bromine. In one embodiment of formula II, R o It is iodine. In one embodiment of Formula II, R o It is a hydroxyl group. In one embodiment of Formula II, R o It is an alkyl group. In one embodiment of formula II, R o It is methyl. In one embodiment of formula II, R o It is a haloalkyl group. In one embodiment of formula II, R o It is trifluoromethyl. In one embodiment of formula II, R o It is trichloromethyl. In one embodiment of formula II, R o It is an alkoxy group. In one embodiment of formula II, R o It is a methoxy group. In one embodiment of formula II, R o It is a haloalkoxy group. In one embodiment of formula II, R o It is a trifluoromethoxy group. In one embodiment of formula II, R o It is an aryl group. In one embodiment of formula II, R o It is phenyl. In one embodiment of formula II, R o It is a naphthyl group. In one embodiment of formula II, R o It is a heteroaryl group.

[0484] In one embodiment of formula II, R p It is hydrogen. In one embodiment of Formula II, R p It is a halogen. In one embodiment of Formula II, R p It is fluorine. In one embodiment of Formula II, R p It is chlorine. In one embodiment of Formula II, R p It is bromine. In one embodiment of formula II, R p It is iodine. In one embodiment of Formula II, R p It is a hydroxyl group. In one embodiment of Formula II, R p It is an alkyl group. In one embodiment of formula II, R p It is methyl. In one embodiment of formula II, R p It is a haloalkyl group. In one embodiment of formula II, R p It is trifluoromethyl. In one embodiment of formula II, R p It is trichloromethyl. In one embodiment of formula II, R pIt is an alkoxy group. In one embodiment of formula II, R p It is a methoxy group. In one embodiment of formula II, R p It is a haloalkoxy group. In one embodiment of formula II, R p It is a trifluoromethoxy group. In one embodiment of formula II, R p It is an aryl group. In one embodiment of formula II, R p It is phenyl. In one embodiment of formula II, R p It is a naphthyl group. In one embodiment of formula II, R p It is a heteroaryl group.

[0485] Representative examples of compounds of formula I include:

[0486]

[0487] Representative examples of compounds of formula II include:

[0488]

[0489]

[0490] Other representative examples of Formula II include

[0491]

[0492] Representative examples of compounds of formula III include:

[0493]

[0494]

[0495] III. Compounds of Formulas IV, V, and VI

[0496] In another aspect, the present invention also provides compounds of formula IV, V, or VI, or pharmaceutically acceptable salts or combinations thereof, for use in the methods described herein.

[0497] In another aspect, a method of treating a medical condition (e.g., an inflammatory condition or a pain condition) in a subject (e.g., a person) includes administering an effective amount of a compound of formula IV to the subject:

[0498]

[0499] Or a pharmaceutically acceptable salt thereof, wherein A 1 As defined above.

[0500] In some embodiments of Formula IV, the compound has the chemical structure of Formula IVa:

[0501]

[0502] Where R 7 As defined above.

[0503] In one aspect of the invention, a compound of formula IVa is provided, wherein R 7 It is a haloalkyl, aryl, or heteroaryl group.

[0504] In some embodiments of formula IV, the compound has the chemical structure of formula IVb:

[0505]

[0506] Where R 1 R 8 R 8’ And m are defined as above.

[0507] In one aspect of the invention, compounds of formula IVb are provided, wherein m is 1, 2, 3, or 4; and R 1 R 8 and R 8’ As defined above.

[0508] In some embodiments of formula IV, the compound has the chemical structure of formula IVc:

[0509]

[0510] Where R 1 R 9 , and n are defined as above.

[0511] In one aspect of the invention, a compound of formula IVc is provided, wherein n is 1, 2, 3, or 4; and R 1 and R 9 As defined above. In another aspect, compounds of formula IVc are provided, wherein R... 9 It is a haloalkyl, aryl, or heteroaryl group; and R 1 And n is defined as above.

[0512] In some embodiments of formula IV, the compound has the chemical structure of formula IVd:

[0513]

[0514] Where R 1 R 2 R 2’ , and m are defined as above.

[0515] In one aspect of the invention, a compound of formula IVd is provided, wherein R 2 It is hydrogen; and R 1 R 2’ , and m are as defined above. In another aspect, compounds of formula IVd are provided, wherein R 1 It is R 1A And R 1A R 2 R 2’ , and m are defined as above.

[0516] In some embodiments of formula IV, the compound has the chemical structure of formula IVe:

[0517]

[0518] Where R 3 R 13 and R 13’ As defined above.

[0519] In one aspect of the invention, compounds of formula IVe are provided, wherein R 3 It is an alkyl, haloalkyl, aryl, heteroaryl, or And R 6 R 6’ R 13 and R 13’ As defined above.

[0520] In some embodiments of formula IV, the compound has the chemical structure of formula IVf:

[0521]

[0522] Where R 1 And m are defined as above.

[0523] In one aspect of the invention, a compound of formula IVf is provided, wherein m is 1, 2, 3, or 4; and R 1 As defined above.

[0524] In some embodiments of formula IV, the compound has the chemical structure of formula IVg:

[0525]

[0526] Where R 3 R 10 and R 10’ As defined above.

[0527] In one aspect of the invention, a compound of formula IVg is provided, wherein R 3 It is a halogen, a haloalkyl, an aryl, a heteroaryl, or And R6 R 6’ R 10 and R 10’ As defined above.

[0528] In some embodiments of Formula IV, the compound has the chemical structure of Formula IVh:

[0529]

[0530] Where R 1 And m are defined as above.

[0531] In one aspect of the invention, a compound of formula IVh is provided, wherein m is 1, 2, 3, or 4; and R 1 It is hydroxyl, haloalkoxy, mercapto, thioalkyl, -SO3H, -(P=O)(OH)2, and -O(P=O)(OH)2.

[0532] In some embodiments of Formula IV, the compound has the chemical structure of Formula IVi.

[0533]

[0534] Where R m R n R o and R p As defined above.

[0535] In some embodiments of Formula IV, the compound has the chemical structure of Formula IVj:

[0536]

[0537] Where R 15 As defined above.

[0538] In some embodiments of formula IV, the compound has the chemical structure of formula IVk:

[0539]

[0540] Where R 15 R 16 and R 16’ As defined above.

[0541] In some embodiments of Formula IV, the compound has the chemical structure of Formula IV1:

[0542]

[0543] Where R 2 R 2’ and X 1As defined above.

[0544] In some embodiments of Formula IV, the compound has the chemical structure of Formula IVm:

[0545]

[0546] Where R 17 And n is defined as above.

[0547] In another aspect, a method for treating a medical condition (e.g., an inflammatory condition or a pain condition) in a subject (e.g., a person) includes administering an effective amount of a compound of formula V to the subject:

[0548]

[0549] Or its pharmaceutically acceptable salt;

[0550] Among them B 1 As defined above.

[0551] In some embodiments of formula V, the compound has the chemical structure of formula Va:

[0552]

[0553] Where R 1 And m are defined as above.

[0554] In one aspect of the invention, compounds of formula Va are provided, wherein m is 1, 2, 3, or 4; and R 1 Selected from R 1 It can be halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, mercapto, thioalkyl, -SO3H, -(P=O)(OH)2, or -O(P=O)(OH)2.

[0555] In some embodiments of formula V, the compound has the chemical structure of formula Vb:

[0556]

[0557] Where R 1 And m are defined as above.

[0558] In one aspect of the invention, a compound of formula Vb is provided, wherein m is 1, 2, 3, or 4; and R 1 As defined above.

[0559] In some embodiments of formula V, the compound has the chemical structure of formula Vc:

[0560]

[0561] Where R m R n R o and R p As defined above.

[0562] In some embodiments of formula V, the compound has the chemical structure of formula Vd:

[0563]

[0564] Where R 15 As defined above.

[0565] In one aspect of the invention, a compound of formula Vd is provided, wherein R 15 It is hydrogen, alkyl, haloalkyl, aryl, or heteroaryl.

[0566] In some embodiments of formula V, the compound has the chemical structure of formula Ve:

[0567]

[0568] Where R 15 R 16 and R 16’ As defined above.

[0569] In some embodiments of formula V, the compound has the chemical structure of formula Vf:

[0570]

[0571] Where R 17 And n is defined as above.

[0572] In another aspect, a method for treating a medical condition (e.g., an inflammatory condition or a pain condition) in a subject (e.g., a person) includes administering an effective amount of a compound of formula VI to the subject:

[0573]

[0574] Or its pharmaceutically acceptable salt;

[0575] Where C 1 and R B As defined above.

[0576] In some embodiments of formula VI, the compound has the chemical structure of formula VIa:

[0577]

[0578] Where R B R 3 R 10 and R10’ As defined above.

[0579] In one aspect of the invention, a compound of formula VIa is provided, wherein R 3 It is a halogen, a haloalkyl, an aryl, a heteroaryl, or And R 10 R 10’ and R B As defined above.

[0580] In some embodiments of formula VI, the compound has the chemical structure of formula VIb:

[0581]

[0582] Where R B R m R n R o and R p As defined above.

[0583] In some embodiments of formula VI, the compound has the chemical structure of formula VIc:

[0584]

[0585] Where R B and R 15 As defined above.

[0586] In some embodiments of formula VI, the compound has the chemical structure of formula VId:

[0587]

[0588] Where R B R 15 R 16 and R 16’ As defined above.

[0589] In some embodiments of formula VI, the compound has the chemical structure of formula VIe:

[0590]

[0591] Where R B R 17 , and n are defined as above.

[0592] In any one of the embodiments of formula IV or V Selected from:

[0593]

[0594] In any one of formulas IV, V or VI Selected from:

[0595]

[0596] In any one of the embodiments of formula IV or V, R 1 It is a halogen. In any embodiment of formula IV or V, R 1 It is fluorine. In any embodiment of formula IV or V, R 1 It is chlorine. In any embodiment of formula IV or V, R 1 It is bromine. In any embodiment of formula IV or V, R 1 It is iodine. In any embodiment of formula IV or V, R 1 It is a hydroxyl group. In any embodiment of formula IV or V, R 1 It is an alkyl group. In one embodiment of any of formula IV or V, R 1 It is methyl. In any embodiment of formula IV or V, R 1 It is a haloalkyl group. In any embodiment of formula IV or V, R 1 It is trifluoromethyl. In any embodiment of formula IV or V, R 1 It is trichloromethyl. In any embodiment of formula IV or V, R 1 It is an alkoxy group. In any embodiment of formula IV or V, R 1 It is a methoxy group. In any embodiment of formula IV or V, R 1 It is a haloalkoxy group. In any one embodiment of formula IV or V, R 1 It is trifluoromethoxy. In any embodiment of formula IV or V, R 1 It is aryl. In any embodiment of formula IV or V, R 1 It is phenyl. In any embodiment of formula IV or V, R 1 It is naphthyl. In one embodiment of any of formula IV or V, R 1 It is a heteroaryl group. In any embodiment of formula IV or V, R 1 It is a thiol group. In any embodiment of formula IV or V, R 1 It is a thioalkyl group. In any embodiment of formula IV or V, R 1 It is a thiomethyl group. In any embodiment of formula IV or V, R 1It is –SO3H. In any embodiment of formula IV or V, R 1 It is –(P=O)(OH)2. In any embodiment of formula IV or V, R 1 It is –(P=O)(OH)2. In any embodiment of formula IV or V, R 1 It is a formyl group. In any embodiment of formula IV or V, R 1 It is an acetyl group. In any embodiment of formula IV or V, R 1 It is an acetoxy group. In any one embodiment of formula I, II, or III, R 1 It is a cyano group.

[0597] In any one of the embodiments of formula IV or V, R S It is hydrogen. In any embodiment of formula IV or V, R S It is methyl. In any embodiment of formula IV or V, R S It is trifluoromethyl. In any embodiment of formula IV or V, R S It is a methoxy group. In any embodiment of formula IV or V, R S It is ethoxylated. In any embodiment of formula IV or V, R S It is –NH2. In any embodiment of formula IV or V, R S It is –NHCH3. In any embodiment of formula IV or V, R S It is –N(CH3)2. In any embodiment of formula IV or V, R S It is phenyl. In any embodiment of formula IV or V, R S It is a heteroaryl group.

[0598] In any one embodiment of formulas IV, V, or VI, m is 0. In any one embodiment of formulas IV, V, or VI, m is 1. In any one embodiment of formulas IV, V, or VI, m is 2. In any one embodiment of formulas IV, V, or VI, m is 3. In any one embodiment of formulas IV, V, or VI, m is 4.

[0599] In any one embodiment of formula IV or V, n is 0. In any one embodiment of formula IV or V, n is 1. In any one embodiment of formula IV or V, n is 2. In any one embodiment of formula IV or V, n is 3. In any one embodiment of formula IV or V, n is 4. In any one embodiment of formula IV or V, n is 5.

[0600] In any one of the embodiments of formula IV or VI, R 2 It is hydrogen. In any embodiment of formula IV or VI, R 2 It is an alkyl group. In one embodiment of any of formula IV or VI, R 2 It is methyl. In any embodiment of formula IV or VI, R 2 It is a haloalkyl group. In one embodiment of any of formula IV or VI, R 2 It is trifluoromethyl. In one embodiment of any of formula IV or VI, R 2 It is trichloromethyl. In one embodiment of any of formula IV or VI, R 2 It is aryl. In any embodiment of formula IV or VI, R 2 It is phenyl. In any embodiment of formula IV or VI, R 2 It is naphthyl. In any embodiment of formula IV or VI, R 2 It is a heteroaryl group.

[0601] In any one of the embodiments of formula IV or VI, R 2’ It is hydrogen. In any embodiment of formula IV or VI, R 2’ It is an alkyl group. In one embodiment of any of formula IV or VI, R 2’ It is methyl. In any embodiment of formula IV or VI, R 2’ It is a haloalkyl group. In one embodiment of any of formula IV or VI, R 2’ It is trifluoromethyl. In one embodiment of any of formula IV or VI, R 2’ It is trichloromethyl. In one embodiment of any of formula IV or VI, R 2’ It is aryl. In any embodiment of formula IV or VI, R 2’ It is phenyl. In any embodiment of formula IV or VI, R 2’ It is naphthyl. In any embodiment of formula IV or VI, R 2’ It is a heteroaryl group.

[0602] In any one of the embodiments of formula IV or VI, X 1 It is –C(R) 5 (R) 5’ In one embodiment of either formula IV or VI, X 1 It is CH2. In any embodiment of formula IV or VI, X 1 It is –N(R)5” In one embodiment of either formula IV or VI, X 1 It is NH. In any embodiment of formula IV or VI, X 1 It is N(CH3). In any embodiment of formula IV or VI, X 1 It is O. In any embodiment of formula IV or VI, X 1 It is S.

[0603] In any one of the embodiments of formula IV or VI, R 3 It is a halogen. In any embodiment of formula IV or VI, R 3 It is fluorine. In any embodiment of formula IV or VI, R 3 It is chlorine. In any embodiment of formula IV or VI, R 3 It is bromine. In any embodiment of formula IV or VI, R 3 It is iodine. In any embodiment of formula IV or VI, R 3 It is an alkyl group. In one embodiment of any of formula IV or VI, R 3 It is methyl. In any embodiment of formula IV or VI, R 3 It is a haloalkyl group. In one embodiment of any of formula IV or VI, R 3 It is trifluoromethyl. In one embodiment of any of formula IV or VI, R 3 It is trichloromethyl. In one embodiment of any of formula IV or VI, R 3 It is aryl. In any embodiment of formula IV or VI, R 3 It is phenyl. In any embodiment of formula IV or VI, R 3 It is naphthyl. In any embodiment of formula IV or VI, R 3 It is a heteroaryl group. In any embodiment of formula IV or VI, R 3 It is –(C=N-OCH3)-CH3.

[0604] In one embodiment of formula IV, R 7 It is hydrogen. In one embodiment of Formula IV, R 7 It is an alkyl group. In one embodiment of formula IV, R 7 It is methyl. In one embodiment of formula IV, R 7 It is a haloalkyl group. In one embodiment of formula IV, R 7 It is trifluoromethyl. In one embodiment of formula IV, R 7It is trichloromethyl. In one embodiment of formula IV, R 7 It is an aryl group. In one embodiment of formula IV, R 7 It is phenyl. In one embodiment of formula IV, R 7 It is naphthyl. In one embodiment of formula IV, R 7 It is a heteroaryl group.

[0605] In one embodiment of formula IV, R 8 It is an alkyl group. In one embodiment of formula IV, R 8 It is methyl. In one embodiment of formula IV, R 8 It is an aryl group. In one embodiment of formula IV, R 8 It is phenyl. In one embodiment of formula IV, R 8 It is a naphthyl group.

[0606] In any one of the embodiments of formula IV or VI, R 10 It is an alkyl group. In one embodiment of any of formula IV or VI, R 10 It is methyl. In any embodiment of formula IV or VI, R 10 It is aryl. In any embodiment of formula IV or VI, R 10 It is phenyl. In any embodiment of formula IV or VI, R 10 It is naphthyl. In any embodiment of formula IV or VI, R 10 It is a heteroaryl group.

[0607] In any one of the embodiments of formula IV or VI, R 10’ It is an alkyl group. In one embodiment of any of formula IV or VI, R 10’ It is methyl. In any embodiment of formula IV or VI, R 10’ It is aryl. In any embodiment of formula IV or VI, R 10’ It is phenyl. In any embodiment of formula IV or VI, R 10’ It is naphthyl. In any embodiment of formula IV or VI, R 10’ It is a heteroaryl group.

[0608] In one embodiment of formula IV, R 11 It is hydrogen. In one embodiment of Formula IV, R 11 It is a halogen. In one embodiment of Formula IV, R 11 It is fluorine. In one embodiment of formula IV, R 11 It is chlorine. In one embodiment of formula IV, R 11It is bromine. In one embodiment of formula IV, R 11 It is iodine. In one embodiment of Formula IV, R 11 It is an alkyl group. In one embodiment of formula IV, R 11 It is methyl. In one embodiment of formula IV, R 11 It is a haloalkyl group. In one embodiment of formula IV, R 11 It is trifluoromethyl. In one embodiment of formula IV, R 11 It is trichloromethyl. In one embodiment of formula IV, R 11 It is an aryl group. In one embodiment of formula IV, R 11 It is phenyl. In one embodiment of formula IV, R 11 It is naphthyl. In one embodiment of formula IV, R 11 It is a heteroaryl group.

[0609] In one embodiment of formula IV, R 13 It is hydrogen. In one embodiment of Formula IV, R 13 It is an alkyl group. In one embodiment of formula IV, R 13 It is methyl. In one embodiment of formula IV, R 13 It is methyl. In one embodiment of formula IV, R 13 It is a haloalkyl group. In one embodiment of formula IV, R 13 It is trifluoromethyl. In one embodiment of formula IV, R 13 It is trichloromethyl. In one embodiment of formula IV, R 13 It is an aryl group. In one embodiment of formula IV, R 13 It is naphthyl. In one embodiment of formula IV, R 13 It is a heteroaryl group.

[0610] In one embodiment of formula IV, R 13’ It is hydrogen. In one embodiment of Formula IV, R 13’ It is an alkyl group. In one embodiment of formula IV, R 13’ It is methyl. In one embodiment of formula IV, R 13’ It is methyl. In one embodiment of formula IV, R 13’ It is a haloalkyl group. In one embodiment of formula IV, R 13’ It is trifluoromethyl. In one embodiment of formula IV, R 13’ It is trichloromethyl. In one embodiment of formula IV, R 13’ It is an aryl group. In one embodiment of formula IV, R 13’ It is naphthyl. In one embodiment of formula IV, R 13’It is a heteroaryl group.

[0611] In one embodiment of formula IV, R 14 It is hydrogen. In one embodiment of Formula IV, R 14 It is an alkyl group. In one embodiment of formula IV, R 14 It is methyl. In one embodiment of formula IV, R 14 It is an aryl group. In one embodiment of formula IV, R 14 It is phenyl. In one embodiment of formula IV, R 14 It is naphthyl. In one embodiment of formula IV, R 14 It is a heteroaryl group.

[0612] In any one of the embodiments of formulas IV, V, or VI, R 15 It is hydrogen. In any one embodiment of formula IV, V, or VI, R 15 It is a halogen. In any one embodiment of formula IV, V, or VI, R 15 It is fluorine. In any one embodiment of formula IV, V, or VI, R 15 It is chlorine. In any one embodiment of formula IV, V, or VI, R 15 It is bromine. In any embodiment of formula IV, V, or VI, R 15 It is iodine. In any one embodiment of formula IV, V, or VI, R 15 It is an alkyl group. In any one embodiment of formula IV, V, or VI, R 15 It is methyl. In any one embodiment of formula IV, V, or VI, R 15 It is a haloalkyl group. In any one embodiment of formula IV, V, or VI, R 15 It is trifluoromethyl. In any one embodiment of formula IV, V, or VI, R 15 It is trichloromethyl. In any one embodiment of formula IV, V, or VI, R 15 It is aryl. In any one embodiment of formula IV, V, or VI, R 15 It is phenyl. In any one embodiment of formula IV, V, or VI, R 15 It is naphthyl. In any one embodiment of formula IV, V, or VI, R 15 It is a heteroaryl group.

[0613] In any one of the embodiments of formulas IV, V, or VI, R 16 It is an alkyl group. In any one embodiment of formula IV, V, or VI, R 16It is methyl. In any one embodiment of formula IV, V, or VI, R 16 It is a haloalkyl group. In any one embodiment of formula IV, V, or VI, R 16 It is trifluoromethyl. In any one embodiment of formula IV, V, or VI, R 16 It is trichloromethyl. In any one embodiment of formula IV, V, or VI, R 16 It is aryl. In any one embodiment of formula IV, V, or VI, R 16 It is phenyl. In any one embodiment of formula IV, V, or VI, R 16 It is a heteroaryl group. In any one embodiment of formula IV, V, or VI, R 16 It is an alkoxy group. In any one embodiment of formula IV, V, or VI, R 16 It is a methoxy group. In any one embodiment of formula IV, V, or VI, R 16 It is ethoxylated. In any one embodiment of formula IV, V, or VI, R 16 It is a haloalkoxy group. In any one embodiment of formula IV, V, or VI, R 16 It is trichloromethoxy. In any one embodiment of formula IV, V, or VI, R 16 It is an aryloxy group. In any one embodiment of formula IV, V, or VI, R 16 It is a phenoxy group. In any one embodiment of formula IV, V, or VI, R 16 It is a heteroaryloxy group. In any one embodiment of formula IV, V, or VI, R 16 It is an amino group. In any one embodiment of formula IV, V, or VI, R 16 It is an alkylamino group. In any one embodiment of formula IV, V, or VI, R 16 It is a methylamino group. In any one embodiment of formula IV, V, or VI, R 16 It is a dialkylamino. In any one embodiment of formula IV, V, or VI, R 16 It is dimethylamino.

[0614] In any one of the embodiments of formulas IV, V, or VI, R 16’ It is an alkyl group. In any one embodiment of formula IV, V, or VI, R 16’ It is methyl. In any one embodiment of formula IV, V, or VI, R 16’ It is a haloalkyl group. In any one embodiment of formula IV, V, or VI, R 16’It is trifluoromethyl. In any one embodiment of formula IV, V, or VI, R 16’ It is trichloromethyl. In any one embodiment of formula IV, V, or VI, R 16’ It is aryl. In any one embodiment of formula IV, V, or VI, R 16’ It is phenyl. In any one embodiment of formula IV, V, or VI, R 16’ It is a heteroaryl group. In any one embodiment of formula IV, V, or VI, R 16’ It is an alkoxy group. In any one embodiment of formula IV, V, or VI, R 16’ It is a methoxy group. In any one embodiment of formula IV, V, or VI, R 16’ It is ethoxylated. In any one embodiment of formula IV, V, or VI, R 16’ It is a haloalkoxy group. In any one embodiment of formula IV, V, or VI, R 16’ It is trichloromethoxy. In any one embodiment of formula IV, V, or VI, R 16’ It is an aryloxy group. In any one embodiment of formula IV, V, or VI, R 16’ It is a phenoxy group. In any one embodiment of formula IV, V, or VI, R 16’ It is a heteroaryloxy group. In any one embodiment of formula IV, V, or VI, R 16’ It is an amino group. In any one embodiment of formula IV, V, or VI, R 16’ It is an alkylamino group. In any one embodiment of formula IV, V, or VI, R 16’ It is a methylamino group. In any one embodiment of formula IV, V, or VI, R 16’ It is a dialkylamino. In any one embodiment of formula IV, V, or VI, R 16’ It is dimethylamino.

[0615] In any one of the embodiments of formulas IV, V, or VI, R 17 It is a halogen. In any one embodiment of formula IV, V, or VI, R 17 It is fluorine. In any one embodiment of formula IV, V, or VI, R 17 It is chlorine. In any one embodiment of formula IV, V, or VI, R 17 It is bromine. In any embodiment of formula IV, V, or VI, R 17 It is iodine. In any one embodiment of formula IV, V, or VI, R 17It is a haloalkyl group. In any one embodiment of formula IV, V, or VI, R 17 It is trifluoromethyl. In any one embodiment of formula IV, V, or VI, R 17 It is trichloromethyl. In any one embodiment of formula IV, V, or VI, R 17 It is a nitro group.

[0616] In any one of the embodiments of formulas IV, V, or VI, R m It is hydrogen. In any one embodiment of formula IV, V, or VI, R m It is a halogen. In any one embodiment of formula IV, V, or VI, R m It is fluorine. In any one embodiment of formula IV, V, or VI, R m It is chlorine. In any one embodiment of formula IV, V, or VI, R m It is bromine. In any embodiment of formula IV, V, or VI, R m It is iodine. In any one embodiment of formula IV, V, or VI, R m It is a hydroxyl group. In any one embodiment of formula IV, V, or VI, R m It is an alkyl group. In any one embodiment of formula IV, V, or VI, R m It is methyl. In any one embodiment of formula IV, V, or VI, R m It is a haloalkyl group. In any one embodiment of formula IV, V, or VI, R m It is trifluoromethyl. In any one embodiment of formula IV, V, or VI, R m It is trichloromethyl. In any one embodiment of formula IV, V, or VI, R m It is an alkoxy group. In any one embodiment of formula IV, V, or VI, R m It is a methoxy group. In any one embodiment of formula IV, V, or VI, R m It is a haloalkoxy group. In any one embodiment of formula IV, V, or VI, R m It is trifluoromethoxy. In any one embodiment of formula IV, V, or VI, R m It is aryl. In any one embodiment of formula IV, V, or VI, R m It is phenyl. In any one embodiment of formula IV, V, or VI, R m It is naphthyl. In any one embodiment of formula IV, V, or VI, R m It is a heteroaryl group.

[0617] In any one of the embodiments of formulas IV, V, or VI, R n It is hydrogen. In any one embodiment of formula IV, V, or VI, R n It is a halogen. In any one embodiment of formula IV, V, or VI, R n It is fluorine. In any one embodiment of formula IV, V, or VI, R n It is chlorine. In any one embodiment of formula IV, V, or VI, R n It is bromine. In any embodiment of formula IV, V, or VI, R n It is iodine. In any one embodiment of formula IV, V, or VI, R n It is a hydroxyl group. In any one embodiment of formula IV, V, or VI, R n It is an alkyl group. In any one embodiment of formula IV, V, or VI, R n It is methyl. In any one embodiment of formula IV, V, or VI, R n It is a haloalkyl group. In any one embodiment of formula IV, V, or VI, R n It is trifluoromethyl. In any one embodiment of formula IV, V, or VI, R n It is trichloromethyl. In any one embodiment of formula IV, V, or VI, R n It is an alkoxy group. In any one embodiment of formula IV, V, or VI, R n It is a methoxy group. In any one embodiment of formula IV, V, or VI, R n It is a haloalkoxy group. In any one embodiment of formula IV, V, or VI, R n It is trifluoromethoxy. In any one embodiment of formula IV, V, or VI, R n It is aryl. In any one embodiment of formula IV, V, or VI, R n It is phenyl. In any one embodiment of formula IV, V, or VI, R n It is naphthyl. In any one embodiment of formula IV, V, or VI, R n It is a heteroaryl group.

[0618] In any one of the embodiments of formulas IV, V, or VI, R o It is hydrogen. In any one embodiment of formula IV, V, or VI, R o It is a halogen. In any one embodiment of formula IV, V, or VI, R oIt is fluorine. In any one embodiment of formula IV, V, or VI, R o It is chlorine. In any one embodiment of formula IV, V, or VI, R o It is bromine. In any embodiment of formula IV, V, or VI, R o It is iodine. In any one embodiment of formula IV, V, or VI, R o It is a hydroxyl group. In any one embodiment of formula IV, V, or VI, R o It is an alkyl group. In any one embodiment of formula IV, V, or VI, R o It is methyl. In any one embodiment of formula IV, V, or VI, R o It is a haloalkyl group. In any one embodiment of formula IV, V, or VI, R o It is trifluoromethyl. In any one embodiment of formula IV, V, or VI, R o It is trichloromethyl. In any one embodiment of formula IV, V, or VI, R o It is an alkoxy group. In any one embodiment of formula IV, V, or VI, R o It is a methoxy group. In any one embodiment of formula IV, V, or VI, R o It is a haloalkoxy group. In any one embodiment of formula IV, V, or VI, R o It is trifluoromethoxy. In any one embodiment of formula IV, V, or VI, R o It is aryl. In any one embodiment of formula IV, V, or VI, R o It is phenyl. In any one embodiment of formula IV, V, or VI, R o It is naphthyl. In any one embodiment of formula IV, V, or VI, R o It is a heteroaryl group.

[0619] In any one of the embodiments of formulas IV, V, or VI, R p It is hydrogen. In any one embodiment of formula IV, V, or VI, R p It is a halogen. In any one embodiment of formula IV, V, or VI, R p It is fluorine. In any one embodiment of formula IV, V, or VI, R p It is chlorine. In any one embodiment of formula IV, V, or VI, R p It is bromine. In any embodiment of formula IV, V, or VI, R pIt is iodine. In any one embodiment of formula IV, V, or VI, R p It is a hydroxyl group. In any one embodiment of formula IV, V, or VI, R p It is an alkyl group. In any one embodiment of formula IV, V, or VI, R p It is methyl. In any one embodiment of formula IV, V, or VI, R p It is a haloalkyl group. In any one embodiment of formula IV, V, or VI, R p It is trifluoromethyl. In any one embodiment of formula IV, V, or VI, R p It is trichloromethyl. In any one embodiment of formula IV, V, or VI, R p It is an alkoxy group. In any one embodiment of formula IV, V, or VI, R p It is a methoxy group. In any one embodiment of formula IV, V, or VI, R p It is a haloalkoxy group. In any one embodiment of formula IV, V, or VI, R p It is trifluoromethoxy. In any one embodiment of formula IV, V, or VI, R p It is aryl. In any one embodiment of formula IV, V, or VI, R p It is phenyl. In any one embodiment of formula IV, V, or VI, R p It is naphthyl. In any one embodiment of formula IV, V, or VI, R p It is a heteroaryl group.

[0620] Representative examples of compounds of formula IV include:

[0621]

[0622]

[0623] Representative examples of compounds of formula V include:

[0624]

[0625] Representative examples of compounds of formula VI include:

[0626]

[0627]

[0628] IV. Pharmaceutical Compositions

[0629] The CO-releasing compounds described herein can be administered as pure chemicals to a host in need, but more typically as pharmaceutical compositions comprising an effective amount for a subject (typically a human) requiring such treatment with the active compound described herein or a pharmaceutically acceptable salt thereof. Thus, in one embodiment, this disclosure provides pharmaceutical compositions for any of the uses described herein, comprising an effective amount of the compound or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. The pharmaceutical composition may comprise the compound or salt as the sole active agent, or, in alternative embodiments, the pharmaceutical composition may comprise the compound and at least one other active agent.

[0630] In typical pharmaceutical compositions, the pharmaceutically acceptable carrier is anhydrous or substantially anhydrous (e.g., water or alcohol or combinations thereof less than about 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.25% by weight). Pharmaceutical compositions considered herein may optionally include a carrier. The carrier must have sufficiently high purity and sufficiently low toxicity to be suitable for administration to the patient to be treated. The carrier may be inert but must not contain amounts of water or other excipients that could adversely react with the compounds described herein. All compounds must be stored and administered in a manner that prohibits exposure to moisture or other compounds that may react with them. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound. Non-limiting examples of carriers include dimethylacetamide, N-methylpyrrolidone, ethylene glycol, polyethylene glycol, Tween 80, poloxamer, and combinations thereof. Other non-limiting examples of carriers are polypropylene glycol.

[0631] In one embodiment, the pharmaceutically acceptable transporter is a mixture of dimethylacetamide (DMA) and polyethylene glycol or a mixture of N-methylpyrrolidone (NMP) and polyethylene glycol. In one embodiment, the pharmaceutically acceptable transporter is a mixture of dimethylacetamide and a water-soluble solvent selected from ethylene glycol, Tween 80, and poloxamer. In one embodiment, the pharmaceutically acceptable transporter is a mixture of N-methylpyrrolidone and a water-soluble solvent selected from ethylene glycol, Tween 80, and poloxamer. In one embodiment, the ratio of solvent to water-soluble solvent is not higher than about 1:10, not higher than about 1:8, not higher than about 1:5, not higher than about 1:3, not higher than about 1:2, not higher than about 1:1, not higher than about 2:1, not higher than about 3:1, not higher than about 5:1, not higher than about 1:8, or not higher than about 1:10.

[0632] An effective amount of the active compound described herein, or which may be used alone or in combination with or alternately with an activator or another active agent, or before, during or after an activator or another active agent, is sufficient to (a) inhibit the progression of the medical disease described herein; (b) cause the remission of the medical disease described herein; (c) cure the medical disease described herein; or inhibit or prevent the development of the medical disease described herein. Therefore, an effective amount of the active compound described herein, or a salt or combination thereof, when administered to a patient, will provide a sufficient amount of active agent to provide clinical benefit.

[0633] The exact amount of the active compound or pharmaceutical composition described herein delivered to the recipient (usually a person) in need will be determined by the healthcare provider to achieve the desired clinical benefit.

[0634] In some embodiments, the pharmaceutical composition is a dosage form comprising about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of an active compound and optionally about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of other active agents. Examples are dosage forms having at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 15, 20, 25, 10, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 900, 1000, 1100, 1200, 1250, 1300, 1400, 1500, 1600, 1700, or 1800 mg of an active compound or its salt or prodrug. In one embodiment, the dosage form contains at least about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 200 mg, 400 mg, 500 mg, 600 mg, 1000 mg, 1200 mg, or 1600 mg of an active compound or a salt thereof. The amount of the active compound in the dosage form is calculated without reference to the salt. The dosage form can be administered as needed, for example, once a day (qd), twice a day (bid), three times a day (tid), four times a day (qid), every other day (Q2d), every three days (Q3d), or any dosage regimen that provides treatment for the condition described herein.

[0635] The pharmaceutical composition may, for example, comprise an active compound and other active agents in a molar ratio to achieve the desired result. The pharmaceutical composition may comprise a combination of other active agents in a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1, or about 1.5:1 to about 4:1 with the active compound described herein (other active agents: active compound) or a salt thereof.

[0636] In one embodiment, the pharmaceutical composition is administered once, twice, or three times a day at a dose of at least about or no more than 25, 50, 75, 100, 150, 200, 225, or 300 mg. In a non-limiting embodiment, the dosage form is administered at a dose of at least or no more than 150 mg / day, 300 mg / day, 450 mg / day, 600 mg / day, 900 mg / day, 1,200 mg / day, or 1,800 mg / day. In alternative, non-limiting embodiments, the dosage form is administered at a dose of at least or no more than 2,000 mg / day, 3,000 mg / day, 4,000 mg / day, 5,000 mg / day, 6,000 mg / day, 7,000 mg / day, 8,000 mg / day, 9,000 mg / day, 10,000 mg / day, 11,000 mg / day, 12,000 mg / day, 13,000 mg / day, 14,000 mg / day, or 15,000 mg / day.

[0637] In alternative, non-limiting embodiments, the dosage form is administered at a dose based on weight of at least or no more than 2 mg / kg, 5 mg / kg, 15 mg / kg, 30 mg / kg, 45 mg / kg, 60 mg / kg, 85 mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, 130 mg / kg, 140 mg / kg, 150 mg / kg, 160 mg / kg, 170 mg / kg, 180 mg / kg, 190 mg / kg, 200 mg / kg, 210 mg / kg, 220 mg / kg, 230 mg / kg, 240 mg / kg, 250 mg / kg, 260 mg / kg, 270 mg / kg, 280 mg / kg, 290 mg / kg, 300 mg / kg, or 315 mg / kg.

[0638] The compounds disclosed herein or used as described herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, via implants (including ocular implants), percutaneously, orally, rectally, as eye drops, by injection (including ocular injection), intravenously, intra-aortally, intracranially, subcutaneously, intraperitoneally, subcutaneously, via the nose, sublingually, intrathecally, or rectally, or by other means, in the form of dosage units containing conventionally pharmaceutically acceptable carriers. For ocular delivery, the compound may be administered as needed, for example, as a solution, suspension, or other formulation via the vitreous body, stroma, anterior chamber, subtendon, subretinal, retrobulbar, peribulbar, suprachoroidal, subchoroidal, choroidal, conjunctiva, subconjunctival, extrascleral, periocular, transscleral, retrobulbar, posterior scleral, limbal, or as a lacrimal duct injection, or via mucus, mucosal or mucosal barrier in an immediate or controlled-release manner, or via an ocular device, injection, or a topical formulation (e.g., a solution or suspension provided as eye drops).

[0639] Pharmaceutical compositions can be formulated into any pharmaceutically useful form, such as as aerosols, creams, gels, gel capsules, pills, microparticles, nanoparticles, injectable or infusion solutions, capsules, tablets, syrups, transdermal patches, subcutaneous patches, dry powders, inhaled formulations, in medical devices, suppositories, oral or sublingual preparations, parenteral preparations, or ophthalmic solutions or suspensions. Some dosage forms, such as tablets and capsules, are subdivided into appropriately sized unit doses containing an appropriate amount of the active ingredient, such as an effective amount to achieve the desired purpose.

[0640] Suitable pharmaceutical compositions for application as considered herein and methods for manufacturing such compositions are known in the art. Examples of known techniques include, for example, U.S. Patent Nos. 4,983,593, 5,013,557, 5,456,923, 5,576,025, 5,723,269, 5,858,411, 6,254,889, 6,303,148, 6,395,302, 6,497,903, 7,060,296, and 7,078,0 Numbers 57, 7,404,828, 8,202,912, 8,257,741, 8,263,128, 8,337,899, 8,431,159, 9,028,870, 9,060,938, 9,211,261, 9,265,731, 9,358,478, and 9,387,252 are incorporated herein by reference.

[0641] Pharmaceutical compositions suitable for topical application are preferably ointments, creams, lotions, pastes, gels, sprays, aerosols, or oils. Suitable carriers include petroleum jelly, lanolin, polyethylene glycol, alcohols, transdermal enhancers, and combinations of two or more thereof.

[0642] Pharmaceutical compositions suitable for transdermal administration can be adapted into discrete patch forms that maintain prolonged close contact with the recipient's epidermis. In one embodiment, microneedle patches or devices are provided for delivering drugs through or into biological tissues, particularly the skin. Microneedle patches or devices allow for drug delivery across or into skin or other tissue barriers at clinically relevant rates with minimal or no damage, pain, or irritation to the tissue.

[0643] Suitable drug compositions for lung delivery can be delivered via a wide range of passively driven and actively powered single / multi-dose dry powder inhalers (DPIs). The most commonly used devices for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers. Various types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The selection of a suitable lung delivery device depends on parameters such as the nature of the drug and its formulation, the site of action, and the pathophysiology of the lungs.

[0644] Other non-limiting examples of inhalation delivery devices and methods include, for example: US 7,383,837 entitled "Inhalation device" (SmithKline Beecham Corporation); WO / 2006 / 033584 entitled "Powder inhaler" (Glaxo SmithKline Pharmaceuticals SA); WO / 2005 / 044186 entitled "Inhalable pharmaceutical formulations employing desiccating agents and methods of administering the same" (Glaxo Group Ltd and SmithKline Beecham Corporation); US 9,095,670 entitled "Inhalation device and method of dispensing medicament"; US 8,205,611 entitled "Dry powder inhaler" (Astrazeneca AB); WO / 2013 / 038170 entitled "Inhaler" (Astrazeneca AB and Astrazeneca UK). Ltd.); US / 2014 / 0352690 entitled "Inhalation Device with Feedback System", US 8,910,625 and US / 2015 / 0165137 entitled "Inhalation Device for Use in Aerosol Therapy" (Vectura GmbH);US 6,948,496 is titled "Inhalers"; US / 2005 / 0152849 is titled "Powders comprising anti-adherent materials for use in dry powder inhalers"; US 6,582,678, US 8,137,657, US / 2003 / 0202944, and US / 2010 / 0330188 are titled "Carrier particles for use in dry powder inhalers"; US 6,221,338 is titled "Method of producing particles for use in dry powder inhalers"; US 6,989,155 is titled "Powders"; US / 2007 / 0043030 is titled "Pharmaceutical compositions for treating premature ejaculation by pulmonary inhalation"; US 7,845,349 is titled "Inhaler"; and US / 2012 / 0114709 and US... US / 2013 / 0287854 is titled "Compositions and Uses," US / 2014 / 0037737 and US / 8,580,306 are titled "Particles for Use in a Pharmaceutical Composition," US / 2015 / 0174343 is titled "Mixing Channel for an Inhalation Device," US / 7,744,855 and US / 2010 / 0285142 are titled "Method of making particles for use in a pharmaceutical composition," and US / 7,541,022, US / 2009 / 0269412 and US / 2015 / 0050350 are titled "Pharmaceutical formulations for dry powder inhalers" (Vectura Limited).

[0645] Pharmaceutical compositions suitable for rectal administration are typically unit-dose suppositories. These suppositories can be prepared by mixing the active compound with one or more conventional solid carriers, such as cocoa butter, and then shaping the resulting mixture.

[0646] Solid dispersion pharmaceutical formulations

[0647] In another aspect of the invention, a solid dispersion formulation is provided comprising an effective amount of a compound of formula I to VI or formula X to XII or a pharmaceutically acceptable salt thereof.

[0648] In one aspect of the invention, a solid dispersion formulation is provided comprising an effective amount of a combination of a compound of formula VII or VIII and a compound of formula IX, or a pharmaceutically acceptable salt thereof. This solid dispersion formulation may also be provided as two separate solid dispersion formulations, such that the host receives the benefit of two active agents acting in a synergistic biological manner.

[0649] This solid dispersion formulation allows for the release of CO from the CO-releasing compounds of the present invention while retaining pharmaceutical byproducts such as saccharin and / or acesulfame potassium. This provides an advantageous pharmaceutical formulation that reduces systemic exposure to unwanted pharmaceutical byproducts.

[0650] In one embodiment, the solid dispersion formulation carrier comprises activated carbon. In one embodiment, the solid dispersion formulation carrier comprises a polymeric material. In one embodiment, the solid dispersion formulation carrier comprises activated carbon coated with a polymeric material. In one embodiment, the solid dispersion formulation carrier comprises a surfactant. In one embodiment, the solid dispersion formulation carrier comprises other excipients selected from starch, talc, cellulose, sodium carboxymethyl cellulose, and magnesium stearate.

[0651] Non-limiting examples of polymeric materials used for solid dispersions include poloxamer, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone polyvinyl acetate (PVP-VA), hydroxypropyl methylcellulose (HPMC), ethyl cellulose, hydroxypropyl cellulose (HPC), polyethylene glycol (PEG), hydroxypropyl methylcellulose acetate succinate (HPMC AS), polyvinyl acetate, polymethacrylate, polyacrylate, crosspovidone (PVP-CL), starch derivatives such as cyclodextrin, and copolymers thereof. In one embodiment, the solid dispersion comprises polyvinylpyrrolidone (PVP). In one embodiment, the solid dispersion comprises polyvinylpyrrolidone polyvinyl acetate (PVP-VA). In one embodiment, the solid dispersion formulation comprises activated carbon and a polymeric material.

[0652] In one embodiment, the activated carbon is granular activated carbon. In one embodiment, the granular activated carbon has a particle size of less than about 3 mm, less than about 2.5 mm, less than about 2 mm, less than about 1.5 mm, less than about 1 mm, less than about 0.08 mm, less than about 0.05 mm, less than about 0.03 mm, or less than about 0.01 mm.

[0653] In one embodiment, the activated carbon is pharmaceutical-grade powdered activated carbon, such as extra-pure Millipore Sigma pharmaceutical-grade powder. In one embodiment, the powdered activated carbon has a particle size of less than about 150 μm, less than about 140 μm, less than about 130 μm, less than about 120 μm, less than about 110 μm, less than about 100 μm, less than about 90 μm, less than about 80 μm, less than about 70 μm, less than about 60 μm, less than about 50 μm, or less than about 40 μm.

[0654] Crystallization carriers for solid dispersion formulations include sugars and polyols such as glucose, galactose, sucrose, mannitol, maltose, sorbitol, xylitol, isomaltitol, lactitol, maltitol, trehalose, glucosamine, and combinations thereof. In one embodiment, the solid dispersion formulation includes sugars and polymeric materials such as PEG.

[0655] In one embodiment, the solid dispersion further includes a surfactant. Typical, non-limiting examples of surfactants include inulin, inutec SP1, compritol 888ATO, gelucire 44 / 14, and poloxamer 407. In one embodiment, the solid dispersion comprises a polymeric material and a surfactant. In one embodiment, the solid dispersion comprises an organic acid, such as nicotinamide, citric acid, or succinic acid.

[0656] The methods for preparing solid dispersion formulations are well known in the art, including solvent evaporation, melting, co-milling, co-precipitation, hot melt extrusion, lyophilization / freeze-drying, electrospinning, and spray drying (see Meng, F. et al., Drug Development and Industrial Pharmacy, 2015 41: 9, 1401; Tran, P. et al., Pharmaceutics, 2019, 11, 132; and Zhang et al., Pharmaceutics, 2018, 10, 74).

[0657] In one embodiment, the active compound as described herein is administered to a patient in need as a spray-dried dispersion (SDD). In another embodiment, the present invention provides a spray-dried dispersion (SDD) comprising the compound of the present invention and one or more pharmaceutically acceptable excipients, as described herein. In another embodiment, the SDD comprises the compound of the present invention and other therapeutic agents. In yet another embodiment, the SDD comprises the compound of the present invention, other therapeutic agents, and one or more pharmaceutically acceptable excipients. In yet another embodiment, any of the described spray-dried dispersions may be coated to form a coated tablet. In an alternative embodiment, the spray-dried dispersion is formulated as a tablet but is not coated.

[0658] In a typical embodiment, an effective amount of the compound of the present invention is absorbed onto a solid dispersion carrier, such as activated carbon or a polymeric material, using a solvent evaporation method.

[0659] In one embodiment, a solid dispersion formulation is provided comprising an effective amount of a compound of formula I to VI or formula X to XII or a pharmaceutically acceptable salt thereof and activated charcoal.

[0660] In one embodiment, a solid dispersion formulation is provided comprising an effective amount of a compound of formula I to VI or formula X to XII or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone.

[0661] In one embodiment, a solid dispersion formulation is provided comprising an effective amount of a compound of formula I to VI or formula X to XII or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone polyvinyl acetate.

[0662] In one embodiment, a solid dispersion formulation is provided comprising an effective amount of a compound of formula I to VI or formula X to XII or a pharmaceutically acceptable salt thereof, activated charcoal, and polyvinylpyrrolidone.

[0663] In one embodiment, a solid dispersion formulation is provided comprising an effective amount of a compound of formula I to VI or formula X to XII or a pharmaceutically acceptable salt thereof, activated charcoal, and polyvinylpyrrolidone polyvinyl acetate.

[0664] In an alternative embodiment, the invention also includes a solid dispersion formulation comprising activated carbon for local delivery and an effective amount of a compound of formula I to VI or formula X to XII or a pharmaceutically acceptable salt thereof, wherein the activated carbon is activated carbon cloth or fiber.

[0665] In one embodiment, the solid dispersion formulation comprises about 0.1% to 0.5%, about 0.1% to 1.0%, about 1.0% to 5.0% of the compound of the present invention, about 5.0% to 10% of the compound of the present invention, about 10% to 30%, about 30% to 50%, about 40% to 60%, about 50% to 70%, about 60% to 80%, about 70% to 90%, or about 80% to 95% of the compound of the present invention. In one embodiment, the solid dispersion comprises more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, or more of the CO-releasing compound of the present invention.

[0666] The compounds of the present invention are adsorbed onto a carrier of the solid dispersion formulation until administration, at which point CO is released, and the carrier retains pharmaceutical byproducts such as saccharin or acesulfame potassium. In one embodiment, the solid dispersion formulation retains up to about 99%, up to about 98%, up to about 95%, up to about 90%, up to about 85%, up to about 75%, up to about 65%, up to about 60%, up to about 50%, or up to about 40% of the pharmaceutical byproducts. In one embodiment, the pharmaceutical byproduct is saccharin, and after administration, approximately 98% of the saccharin remains in the solid dispersion formulation.

[0667] In one embodiment, the solid dispersion formulation exhibits a carbon monoxide release yield of at least about 99%, at least about 95%, at least about 90%, at least about 85%, at least about 80%, at least about 75%, at least about 70%, at least about 65%, at least about 60%, at least about 55%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, or at least about 10% after administration to a desired subject. In one embodiment, the solid dispersion formulation exhibits a carbon monoxide release yield of at least 75%.

[0668] Topical preparations for the treatment of inflammatory skin diseases

[0669] In one embodiment, the CO-releasing compound used in this invention is formulated as a topical preparation for treating inflammatory skin conditions, such as acne vulgaris. Acne vulgaris is a disease caused in part by the overgrowth of Propionibacterium acnes and inflammation in response to the bacteria. Acne is a common skin condition that occurs when hair follicles become clogged with dead skin cells and sebum. Clogged follicles develop due to increased sebum production influenced by androgens, leading to comedone formation and blockage. The earliest pathological changes involve the formation of microcomedones due to the accumulation of skin cells in the hair follicle, which mix with oily sebum to clog the follicle; the presence of a Propionibacterium acnes biofilm further exacerbates this process. If the microcomedone is superficial, the melanin within the plug oxidizes upon exposure to air, forming a blackhead or comedone. If the microcomedone is located deep within the hair follicle, it forms a whitehead or closed comedone.

[0670] Propionibacterium acnes (reclassified as *Dermatobacterium acnes* in 2016) is a Gram-positive (bamboo rod) bacterium associated with acne, belonging to the genus *Dermatobacter* and family *Propionibacterium*. It typically grows slowly and is an aerobic anaerobic bacterium, meaning it can tolerate the presence of oxygen but does not utilize it for growth. While the bacterium is involved in maintaining healthy skin, it can also cause many common skin conditions, such as acne vulgaris. This bacterium primarily lives deep within hair follicles and pores, where it uses sebum, cellular debris, and metabolic byproducts of surrounding skin tissue as a source of energy and nutrients. Increased sebum production or clogged hair follicles can lead to bacterial overgrowth, and this rapid growth can trigger inflammation, resulting in symptoms of common skin conditions such as folliculitis and acne vulgaris.

[0671] Although less common, *Staphylococcus epidermidis* can cause acne. It is a Gram-positive bacterium belonging to the genus *Staphylococcus* and family *Staphylococci*, and is part of the normal human flora, typically the skin or mucous membrane flora. It is a facultative anaerobe, so it can grow in both aerobic and anaerobic conditions. It is usually not pathogenic, but in patients with complex immune systems, the bacteria can cause infection. *Staphylococcus epidermidis* has the ability to form biofilms on plastic, and infections are often associated with ducts or surgical implants.

[0672] Because bacteria can bind to Toll-like receptors (TLRs), particularly TLR2 and TLR4, and alter the fatty composition of oily sebum by oxidizing squalene, the presence of Propionibacterium acnes can trigger skin inflammation. The subsequent inflammatory cascade leads to the formation of inflammatory acne lesions such as papules, pustules, or nodules. If the inflammation is severe, hair follicles can penetrate into the dermis and subcutaneous tissue, forming deep nodules, resulting in local tissue destruction and scarring.

[0673] Traditionally, acne is classified as non-inflammatory (open / closed comedones) or inflammatory (papules, pustules, or nodules). Increasing evidence suggests that inflammation is present throughout the entire lifecycle of acne lesions, identifying its crucial role in acne pathology. In the earliest stages of acne lesion development, the numbers of CD3+ T cells, CD4+ T cells, and macrophages are elevated, while the level of the pro-inflammatory cytokine interleukin-1 is also upregulated. The onset of inflammatory events has been documented even before acne lesions are clinically detected.

[0674] This invention provides topical compositions and methods for treating inflammatory skin conditions such as acne vulgaris, comprising an effective amount of the carbon monoxide (“CO”)-releasing compounds described herein. The CO-releasing compounds used in the compositions and methods have anti-inflammatory and / or antimicrobial effects, which help alleviate symptoms of acne vulgaris and / or treat the potential overgrowth of bacteria that cause acne, such as *Propionibacterium acnes* or *Staphylococcus epidermidis*. The treatment options provided by this invention can complement or replace those currently available for treating this very common skin condition. Furthermore, the compositions and methods described herein can actually enhance the immune response against *Propionibacterium acnes* or *Staphylococcus epidermidis*.

[0675] The topical composition and method provide an anti-inflammatory effect due to the spontaneous release of carbon monoxide under physiological conditions present in the skin or when activated by a second composition.

[0676] Active CO-releasing compounds are generally sensitive to water or other agents that, under conditions of use, would attack carbonyl groups, such as hydroxyl groups in alcohols or potential amines. Therefore, in a preferred embodiment, the CO-releasing compound is provided in a substantially anhydrous topical composition, for example, which does not contain water (or reactive alcohols or amines) in amounts that react with the active agent to reduce the amount of the active agent to below the effective amount required to treat acne. Anhydrous, pharmaceutically acceptable topical materials are known and include silicone-based oils, aliphatic-based compositions, oily materials, gels, mineral oils, polydimethylsiloxanes, and other substantially anhydrous lipophilic carriers.

[0677] The active compounds described herein may be given to people in need as pure chemicals, but more commonly as topical preparations containing an effective amount of the compounds described herein or their pharmaceutically acceptable salts, for people who need treatment for inflammatory skin conditions such as acne vulgaris.

[0678] Therefore, in one embodiment, this disclosure provides a topical formulation for any of the uses described herein, comprising an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof, and at least one locally acceptable transporter. The topical formulation may comprise the compound or salt as the sole active ingredient, or, in alternative embodiments, the pharmaceutical composition may comprise the compound and at least one other active agent.

[0679] Additives or excipients are used as inactive ingredients in topical formulations for structuring. The main uses of topical formulation additives are to control the absorption of the active compound, maintain viscosity, improve stability and sensory properties, and increase the volume of the formulation. The primary goal of topical formulations is to confine the desired effect to the skin or within the skin. Such formulations are preferred because they are protective, emollient, and deliver the active agent to exert its local activity when applied to the skin or mucous membranes.

[0680] The topical formulations considered herein typically include a locally acceptable carrier. The carriers used in the topical formulations described herein may be inert, but must not contain amounts of water or other excipients that could adversely react with the compounds described herein. All compounds must be stored and administered in a manner that prohibits exposure to moisture or other compounds that may react with them. The amount of carrier bound to the compound is sufficient to provide a practical amount of material for administration of the topical formulation to the skin or mucous membranes.

[0681] In some embodiments, the topical formulation includes a carrier selected from oily bases, absorbent bases, and silicone bases. Oily bases are composed entirely of lipophilic materials. They are anhydrous, insoluble in water, and not easily removed with water. Oily bases are inexpensive, non-reactive, non-irritating, good emollients, have protective and occlusive properties, and are not washable. Representative examples of oily matrices include hydrocarbons (such as petrolatum, paraffin, liquid paraffin, microcrystalline wax, plastibase, or mineral wax), vegetable and animal fats (such as coconut oil, beeswax, olive oil, lanolin, peanut oil, cetearyl, sesame oil, or almond oil), hydrogenated and sulfated oils (such as hydrogenated castor oil, hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated corn oil, or hydrogenated sulfated castor oil), alcohols / acids / esters (such as cetyl alcohol, stearic acid, stearyl alcohol, oleic acid, oleyl alcohol, palmitic acid, lauryl alcohol, lauric acid, myristyl alcohol, ethyl oleate, isopropyl myristate, or ethylene glycol), and organosilicones (such as dimethylpropylsiloxane, methylphenyl polysiloxane, and sterol esters of dimethyl polysiloxane).

[0682] It is known that absorbent alkalis can absorb several times their own weight in water, but the absorption of pharmaceuticals from alkalis is not permitted. The advantages of absorbent matrices are their protective, occlusive, and emollient properties, their ability to absorb liquids, and their resistance to washing away, thus allowing them to maintain adequate contact between the incorporated compound and the skin. Representative examples of absorbent matrices include activated petrolatum and anhydrous lanolin.

[0683] When used for skin application, silicone matrices are typically composed of siloxane oligomers, polymers, or derivatives thereof. Silicone matrices have good emollient and occlusive properties, are generally non-reactive and non-irritating, but are sometimes preferred over other oil-based matrices due to their breathability and water vapor permeability on the skin. Representative silicon matrices may be composed of siloxanes, including but not limited to hexamethyldisiloxane, octamethyltrisiloxane, decamethylcyclopentasiloxane, cyclopentasiloxane, cyclohexasiloxane, dimethicone, hydroxyl-terminated dimethicone (dimethicone alcohol), mixtures of dimethicone and dimethicone alcohol, dimethicone crosslinked polymers, dimethicone crosslinked polymers in dimethicone, dimethicone crosslinked polymers in decamethylcyclopentasiloxane, mixtures of stearoxytrimethylsilane and stearyl alcohol, alkylmethylsiloxane copolyols, organosilicon polyethers, octylmethylsiloxane, trimethylsiloxysilicate, trimethylsiloxysilicate in dimethicone, C30-C45 alkyldimethylsilyl polypropylsilsesquioxane, PEG-10 dimethicone, or combinations thereof. Various silicon substrates suitable for local application are available from commercial suppliers, such as Dow Corning.

[0684] In another aspect, a localized product is provided, comprising a first formulation and a second activating formulation. The first formulation comprises an effective amount of the compound described herein, as defined herein, in a substantially anhydrous carrier, and the second activating formulation contains water. Examples of the first formulation include locally acceptable carriers selected from oily matrices, absorbent matrices, and silica matrices, or combinations thereof.

[0685] In some embodiments, the first formulation and the second activating formulation remain physically separated until application to the skin. Alternatively, the first formulation and the second activating formulation are mixed upon application to the skin. In different embodiments, carbon monoxide is released during mixing of the first formulation and the second activating carrier. This topical product allows the active compound to be stably stored in an anhydrous carrier when not in use. The mixing of the first formulation and the second activating formulation produces an emulsion that has properties that may be more appealing to the end user when applied to the skin, while ensuring that the compound is activated with only a single application to the skin. In a typical embodiment, the activating carrier further includes an emulsifier to further ensure proper mixing of the first formulation and the second activating formulation.

[0686] The second activating agent may, for example, comprise an aqueous solution containing an emulsifier, but more typically comprises a topical formulation containing at least a portion of water or other activating ingredients, such as a cream, lotion, gel, or liniment. The second activating agent may be an additional activating diluent, including but not limited to water, lower monohydric alcohols (e.g., C2-C4), propylene glycol, polyethylene glycol, polypropylene glycol, glycerin, butylene glycol, 1,2,3-butanetriol, sorbitol esters, 1,2,6-hexanetriol, ethanol, isopropanol, sorbitol esters, butylene glycol, ether propanol, ethoxylated ethers, propoxylated ethers, or combinations thereof.

[0687] The second activated formulation may contain an emulsifier to help the two formulations mix completely when applied to the skin. These materials may be ionic or nonionic and are typically selected based on their ability to provide wetting, emulsification, low irritation, foaming (or lack thereof), or other desired properties. Representative examples of emulsifiers include, but are not limited to: alkyl sulfates; alkyl ether sulfates; alkyl monoglyceride sulfates; alkyl sulfonates; alkyl aryl sulfonates; alkyl sulfosuccinates; alkyl carboxylates; alkyl amide ether carboxylates; alkyl succinates; fatty acyl sarcosines; fatty acyl amino acids; fatty acyl taurine; fatty alkyl sulfonate acetates; alkyl phosphates; polyoxyethylene derivatives of polyol esters (1) derived from (a) fatty acids containing about 8 to about 22, preferably about 10 to about 14 carbon atoms, and (b) selected from sorbitol, dehydrated sorbitol, glucose, α-methyl glucoside, polydextrose having an average of about 1 to about 3 glucose residues per molecule, glycerol, Pentaerythritol and mixtures thereof, (2) containing an average of about 10 to about 120, preferably about 20 to about 80, oxyethylene units, (3) having an average of about 1 to about 3 fatty acid residues per mole of polyoxyethylene derivative of polyol ester; amphoteric carboxylates such as alkyl amphoteric acetates; alkyl betaines; amide alkyl betaines; amide alkyl sulfobetaine; amphoteric phosphates; phosphorylated imidazolines, such as phosphate betaines and pyrophosphate betaines; carboxyalkyl alkyl polyamines; alkyl iminodipropionates; alkyl diglycinates; alkyl amphoteric propionates; N-alkyl β-aminopropionic acid; alkyl polyaminocarboxylates; alkyl quaternary ammonium salts; benzyl quaternary ammonium salts; ester quaternary ammonium salts; ethoxylated quaternary ammonium salts; alkylamines; and combinations thereof.

[0688] In one embodiment, the second activating agent comprises a water-soluble ointment base. A water-soluble base, also known as an oil-free ointment base, is composed of water-soluble ingredients such as polyethylene glycol polymers (carbowax). Polyethylene glycol is water-soluble, non-volatile, and inert. Other water-soluble bases include glyceryl monostearate, cellulose derivatives, sodium alginate, bentonite, and carbomer 934.

[0689] In one embodiment, the second activated formulation is a gel formulation. A gel is a transparent or translucent semi-solid formulation in which one or more active ingredients are contained in a suitable activated matrix. The gel can be transparent or opaque. The gel is prepared through a fusion process or a specific procedure requiring gelling agents, wetting agents, and preservatives. The gelling agent exhibits pseudoplasticity, giving the formulation thixotropic properties. The gelling agent is typically used at a concentration of 0.5-10% to allow for easy addition of the active pharmaceutical ingredient before gel formation. Representative examples of reagents used in gel formulations include tragacanth gum, fenugreek mucilage, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carbomer, pectin, poloxamer, alginates (such as sodium alginate, potassium alginate, or ammonium alginate), gelatin, starch, polyvinyl alcohol, povidone, propylene glycol, and ethylenediaminetetraacetic acid.

[0690] In one embodiment, the second activating agent is an emulsion formulation. The emulsion is a low- to medium-viscosity formulation suitable for unbroken skin. The emulsion is applied to the external skin using bare hands, a clean cloth, cotton wool, or gauze. The emulsion provides a cooling effect to the skin through the evaporation of the solvent in which it is formulated. Typical additives in emulsion formulations include bentonite, sodium carboxymethyl cellulose, alcohols, and glycerin.

[0691] In one embodiment, the second activating agent is a cream formulation. A cream is a semi-solid emulsion formulation for use on the skin or mucous membranes. Creams can be formulated as water-in-oil (w / o) emulsions or oil-in-water (o / w) emulsions. Compared to ointments, water-in-oil emulsion creams are less greasy and have good spreadability. Oil-in-water emulsion creams are commonly referred to as cold creams, as they are easily applied to the skin and easily removed with water.

[0692] Water-in-oil emulsion formulations typically consist of an active component, such as water or other active diluent, and a hydrophobic component, such as lipids, oils, or oily substances. The active component is typically dispersed within the hydrophobic component, i.e., present as small particles and droplets. Water-in-oil emulsions typically contain about 1% to about 98% of a dispersed active phase and about 1% to about 50% of a hydrophobic phase. Common additives used in water-in-oil emulsion formulations include lanolin (containing sterols, cholesterol, hydroxycholesterol, triterpenes, or fatty alcohols), waxes, divalent soaps, sorbitan esters, borax, and oleic acid. In some embodiments, a water-in-oil emulsion refers to a silicone oil-in-water emulsion.

[0693] Oil-in-water emulsion formulations typically consist of an active component, such as water or other active diluent, and a hydrophobic component, such as lipids, oils, or oily substances. The hydrophobic component is usually dispersed within the active component, i.e., it exists as small particles and droplets. Oil-in-water emulsions typically contain about 1% to about 98% of the active phase and about 1% to about 50% of the dispersed hydrophobic phase. Common additives used in oil-in-water emulsion formulations include polysorbates (e.g., Tween 80, Tween 21, and Tween 40), methylcellulose, gum arabic, tragacanth gum, triethanolamine oleate, peanut oil, and cetearyl alcohol.

[0694] Various optional components / ingredients may be included in any of the above-described topical formulations, including but not limited to absorbents, abrasives, anticaking agents, defoamers, antimicrobial agents, adhesives, bioactive agents, buffers, fillers, chemical additives, cosmetic bactericides, denaturants, cosmetic astringents, medicated astringents, topical analgesics, film-forming agents, moisturizers, sunscreens, fragrances, pigments, colorants, essential oils, skin-sensing agents, emollients, skin soothing agents, skin healing agents, pH adjusters, plasticizers, and preservatives. Agents, preservatives, enhancers, propellants, reducing agents, additional skin conditioning agents, skin penetration enhancers, skin protectants, solvents, suspending agents, emulsifiers, thickeners, solubilizers, sunscreens, UV absorbers or scattering agents, sun-free tanning agents, antioxidants and / or free radical scavengers, chelating agents, oil / sebum control agents, sweat control agents, chelating agents, antioxidants, anti-androgens, depilatory agents, desquamating / exfoliating agents, organic hydroxy acids, vitamins and their derivatives, and natural extracts.

[0695] Micron and nanoparticle formulations

[0696] The CO-emitting compound of the present invention can be formulated into particles, such as micron-sized particles or nanoparticles. In one embodiment, the particles are or comprise micron-sized particles. In an alternative embodiment, the particles are or comprise nanoparticles. The particles can be polymeric or non-polymeric, for example, activated carbon particles.

[0697] Common techniques that can be used to prepare particles using the compounds described herein include, but are not limited to, solvent removal, spray drying, phase inversion, agglomeration, and cryogenic casting. Suitable particle formulation methods are briefly described below. Pharmaceutically acceptable excipients, including disintegrants, preservatives, and antioxidants, may optionally be incorporated into the particles during particle formation.

[0698] Solvent removal can also be used to prepare particles from hydrolyzed unstable compounds. In this method, the compound (or a polymer matrix and one or more compounds) is dispersed or dissolved in a volatile organic solvent such as dichloromethane. The mixture is then suspended in an organic oil (e.g., silicone oil) to form an emulsion.

[0699] In one embodiment, the active compound as described herein is administered to a patient in need as particles formed by solvent removal. In another embodiment, the invention provides particles formed by solvent removal comprising the compound of the invention and one or more pharmaceutically acceptable excipients as described herein. In another embodiment, the particles formed by solvent removal comprise the compound of the invention and additional therapeutic agents. In yet another embodiment, the particles formed by solvent removal comprise the compound of the invention, other therapeutic agents, and one or more pharmaceutically acceptable excipients. In another embodiment, any of the particles formed by solvent removal can be formulated into tablets and then coated to form coated tablets. In an alternative embodiment, the particles formed by solvent removal are formulated into tablets, but the tablets are not coated.

[0700] In one embodiment, the particles are obtained by spray drying. In this method, a compound (or a polymer matrix and one or more compounds) is dissolved in an organic solvent such as dichloromethane. The solution is pumped through a micronizing nozzle driven by a compressed gas stream, and the resulting aerosol is suspended in a heated air cyclone, causing the solvent to evaporate from the droplets and form particles. Micron-sized and nano-sized particles can be obtained using this method.

[0701] A method for casting controlled-release microspheres at extremely low temperatures is described in U.S. Patent No. 5,019,400 to Gombotz et al. In this method, a compound is dissolved in a solvent. The mixture is then atomized into a container containing a liquid non-solvent at a temperature below the freezing point of the drug solution, causing the compound droplets to solidify. As the droplets of the compound and the non-solvent are heated, the solvent in the droplets thaws and is extracted into the non-solvent, thereby hardening the microspheres.

[0702] In one embodiment, the compound of the invention is given to a patient in need as particles formed by cryogenic casting. In another embodiment, the invention provides particles formed by cryogenic casting comprising the compound of the invention and one or more pharmaceutically acceptable excipients described herein. In another embodiment, the particles formed by cryogenic casting comprise the compound of the invention and additional therapeutic agents. In yet another embodiment, the particles formed by cryogenic casting comprise the compound of the invention, other therapeutic agents, and one or more pharmaceutically acceptable excipients. In another embodiment, any of the particles formed by cryogenic casting can be formulated into tablets and then coated to form coated tablets. In an alternative embodiment, the particles formed by cryogenic casting are formulated into tablets, but the tablets are not coated.

[0703] In one aspect of the invention, an effective amount of the active compound described herein is incorporated into nanoparticles, for example, to facilitate delivery and / or prolong release delivery. The use of nanoscale materials provides the ability to alter fundamental physical properties, such as solubility, diffusivity, blood circulation half-life, drug release characteristics, and / or immunogenicity. Many nanoparticle-based therapeutic and diagnostic agents have been developed for the treatment of cancer, diabetes, pain, asthma, allergies, and infections. These nanoscale drugs can provide more efficient and / or more convenient routes of administration, reduce therapeutic toxicity, extend product lifecycles, and ultimately reduce healthcare costs. As a therapeutic delivery system, nanoparticles can achieve targeted delivery and controlled release.

[0704] Furthermore, nanoparticle-based compound delivery can be used to release compounds at sustained rates, thereby reducing dosing frequency, to deliver drugs in a targeted manner to reduce systemic side effects, or to deliver two or more drugs simultaneously for combination therapy to produce synergistic effects and inhibit drug resistance. Many nanotechnology-based therapeutic products have been approved for clinical use. Among these products, liposomal drugs and polymer-based conjugates account for a large proportion. See Zhang, L. et al., "Nanoparticles in Medicine: Therapeutic Applications and Developments," Clinical Pharmacy and Therapeutics, 83(5):761-769, 2008.

[0705] Methods for preparing nanoparticles are known in the art. For example, see Muller, RH, et al., Solid lipid nanoparticles (SLN) for controlled drug delivery – a review of the state of the art, Eur. H. Pharm. Biopharm., 50: 161-177, 2000; Consien et al., US 8,691,750; Kanwar, WO 2012 / 145801; Armes, S. et al., US 8,580,311; Petros, RA and DeSimone, JM, Strategies in the design of nanoparticles for therapeutic applications, Nature Reviews / Drug Discovery, Vol. 9: 615-627, 2010; US 8,465,775; US 8,444,899; US 8,420,124; US 8,263,129; US 8,158,728; 8,268,446; Pellegrino et al., 2005, Small, 1:48; Murray et al., 2000, Ann. Rev. Mat. Sci., 30:545; and Trindade et al., 2001, Chem. Mat., 13:3843; all are incorporated herein by reference. Other methods have been described in the literature (see, for example, Doubrow, Ed., “Microcapsules and Nanoparticles in Medicine and Pharmacy”, CRC Press, Boca Raton, 1992; Mathiowitz et al., 1987, J. Control. Release, 5:13; Mathiowitz et al., 1987, Reactive Polymers, 6:275; and Mathiowitz et al., 1988, J. Appl. Polymer Sci., 35:755; U.S. Patent Nos. 5,578,325 and 6,007,845; P.Paolicelli et al., “Surface-modified PLGA-based nanoparticles that can efficiently associate and deliver virus-like particles” Nanomedicine. 5(6):843-853 (2010), Gref et al., U.S. Patent No. 5,543,158, or Von Andrian et al., WO Publication WO2009 / 051837; Zauner et al., 1998, Adv. Drug Del. Rev., 30:97; and Kabanov et al., 1995, Bioconjugate Chem., 6:7; (PEI; Boussif et al., 1995, Proc. Natl. Acad. Sci., USA, 1995, 92:7297), and poly(amide) dendritic polymers (Kukowska-Latallo et al., 1996, Proc. Natl. Acad. Sci., USA, 93:4897; Tang et al., 1996, Bioconjugate Chem., 7:703; and Haensler et al., 1993, Bioconjugate Chem., 4:372; Putnam et al., 1999, Macromolecules, 32:3658; Barrera et al., 1993, J. Am. Chem. Soc., 115:11010; Kwon et al., 1989, Macromolecules, 22:3250; Lim et al., 1999, J. Am. Chem. Soc., 121:5633; and Zhou et al., 1990, Macromolecules, 23:3399). Examples of these polyesters include poly(L-lactide-co-L-lysine) (Barrera et al., 1993, J. Am. Chem. Soc., 115:11010), poly(serine ester) (Zhou et al., 1990, Macromolecules, 23:3399), poly(4-hydroxy-L-proline ester) (Putnam et al., 1999, Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem. Soc., 121:5633), and poly(4-hydroxy-L-proline ester) (Putnam et al., 1999, Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem. Soc.).,121:5633; US Patent No. 6,123,727; US Patent No. 5,804,178; US Patent No. 5,770,417; US Patent No. 5,736,372; US Patent No. 5,716,404; US Patent No. 6,095,148; US Patent No. 5,837,752; US Patent No. 5,902,599; US Patent No. 5,696,175; US Patent No. 5,514,378; US Patent No. 5,512,600; US Patent No. 5,399,665; US Patent No. 5,019,379; US Patent No. 5,010,167; US Patent No. US Patent No. 4,806,621; US ​​Patent No. 4,638,045; and US Patent No. 4,946,929; Wang et al., 2001, J. Am. Chem. Soc., 123:9480; Lim et al., 2001, J. Am. Chem. Soc., 123:2460; Langer, 2000, Acc. Chem. Res., 33:94; Langer, 1999, J. Control. Release, 62:7; and Uhrich et al., 1999, Chem. Rev., 99:3181; Concise Encyclopedia of Polymer Science and Polyamines and Ammonium Salts (Concise Encyclopedia of Polymer Science and Polymeric Amines and Ammonium Salts, edited by Goethals, Pergamon Press, 1980; Odian, Principles of Polymerization, John Willie & Sons, 4th edition, 2004; Allcock et al., Contemporary Polymer Chemistry, Prentice-Hall, 1981; Deming et al., Nature, 1997, 390:386; and in U.S. Patent Nos. 6,506,577, 6,632,922, 6,686,446, and 6,818,732; C. Astete et al., Synthesis and characterization of PLGA nanoparticles, J. Biomater. Sci. Polymer Edn, Vol. 17, No. 3, pp. 247-289 (2006); K.Avgoustakis, “Pegylated Poly(Lactide) and Poly(Lactide-Co-Glycolide) Nanoparticles: Preparation, Properties and Possible Applications in Drug Delivery,” Current Drug Delivery 1:321-333 (2004); C. Reis et al., “Nanoencapsulation I. Methods for preparation of drug-loaded polymeric nanoparticles,” Nanomedicine 2:8-21 (2006); P. Paolicelli et al., “Surface-modified PLGA-based nanoparticles that can Efficiently Associate and Deliver Virus-like Particles.” Virus-like Particles” Nanomedicine. 5(6):843-853 (2010); Unger’s U.S. Patent No. 6,632,671, October 14, 2003, all contents of which are incorporated herein by reference.

[0706] In one embodiment, the particles are about 0.1 nm to about 10,000 nm, about 1 nm to about 1,000 nm, about 10 nm to 1,000 nm, about 1 to 100 nm, about 1 to 10 nm, about 1 and 50 nm, about 100 nm to 800 nm, about 400 nm to 600 nm, or about 500 nm. In one embodiment, the micron-sized particles are no larger than 0.1 nm, 0.5 nm, 1.0 nm, 5.0 nm, 10 nm, 25 nm, 50 nm, 75 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, 1000 nm, 1250 nm, 1500 nm, 1750 nm, or 2000 nm. In some embodiments, the compounds described herein may be covalently coupled to polymers used in the nanoparticles (e.g., polystyrene particles, PLGA particles, PLA particles, or other nanoparticles).

[0707] The pharmaceutical compositions can be formulated for oral administration. These compositions may contain any amount of the active compound to achieve the desired results, such as 0.1 to 99 wt.% and typically at least about 5 wt%. Some embodiments contain at least about 10%, 15%, 20%, 25 wt% to about 50 wt%, or about 5 wt% to about 75 wt% of the compound.

[0708] The pharmaceutical composition can be formulated for delayed release. Delayed-release formulations can be prepared by coating solid dosage forms with a polymer film that is insoluble in the acidic environment of the stomach but soluble in the neutral environment of the small intestine. Delayed-release dosage forms can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material. Drug-containing compositions can be, for example, tablets for incorporation into capsules, tablets used as the core in a coated core dosage form, or multiple drug-containing beads, particles, or granules for incorporation into tablets or capsules. Typical coating materials include bio-erosive, gradually hydrolyzable, gradually water-soluble, or enzymatically degradable polymers. Coating materials can be polymers commonly used in the manufacture of enteric coatings. As understood by those skilled in the art, enteric polymers become soluble in the higher pH environment of the lower gastrointestinal tract or are slowly eroded as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes in the lower gastrointestinal tract, particularly the colon. Examples of coating materials for achieving delayed release include, but are not limited to, cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl succinate, hydroxypropyl methyl cellulose phthalate, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose trimellitate acetate, and sodium carboxymethyl cellulose; acrylic polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, or ethyl methacrylate, and other commercially available methacrylic resins under trade names. (Rohm Pharma, Weststadt, Germany) includes Eudragit L30D-55 and L100-55 (soluble at pH 5.5 and above), Eudragit L-100 (soluble at pH 6.0 and above), Eudragit S (soluble at pH 7.0 and above), and Eudragit NE, Eudragit RL, and Eudragit RS (water-insoluble polymers with different permeability and swelling properties); vinyl polymers and copolymers such as polyvinylpyrrolidone, vinyl acetate, vinyl acetate phthalate, vinyl acetate-crotonic acid copolymer, and ethyl-vinyl acetate copolymer; enzyme-degradable polymers such as azo polymers, pectin, chitosan, amylose, and guar gum; corn gluten and shellac. Combinations of different coating materials can also be used. Multilayer coatings using different polymers can also be applied.

[0709] The preferred coating weight of a particular coating material can be readily determined by those skilled in the art by evaluating the individual release profiles of tablets, beads, and granules prepared with different amounts of various coating materials. The desired release characteristics are the result of a combination of materials, methods, and administration methods, which can only be determined through clinical studies.

[0710] Coating compositions may include conventional additives such as plasticizers, pigments, colorants, stabilizers, and flow aids. Plasticizers are typically present to reduce the brittleness of the coating and generally constitute from about 10 wt% to about 50 wt% of the polymer dry weight. Typical examples of plasticizers include polyethylene glycol, propylene glycol, trace amounts of tin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, castor oil, and acetylated glycerol monoester. Stabilizers are preferably used to stabilize the particles in the dispersion. Typical stabilizers are nonionic emulsifiers such as sorbitan esters, polysorbates, and polyvinylpyrrolidone. Flow aids are generally used to reduce adhesion effects during film formation and drying and generally constitute from about 25 wt% to about 75 wt% of the polymer weight in the coating solution. Representative flow aids include talc, magnesium stearate, and glyceryl monostearate. Pigments such as titanium dioxide can also be used. In some embodiments, a small amount of defoamer, such as dimethyl silicone oil, can be added to the coating composition.

[0711] Particles, including nanoparticles and microparticles, are common for ocular drug delivery. Numerous methods and apparatuses for delivering drugs to the eye, including polymer delivery, are known in the art. Non-limiting examples are described in the following patents and patent applications (which are incorporated herein by reference in their entirety). Examples include US 8,192,408 titled "Ocular trocarassembly" (Psivida Us, Inc.); US 7,585,517 titled "Transcleral delivery" (Macusight, Inc.); US 5,710,182 and US 5,795,913 titled "Ophthalmic composition" (Santen OY); US 8,663,639 titled "Formulations for treating ocular diseases and conditions"; US 8,486,960 titled "Formulations and methods for vascularpermeability-related diseases or conditions"; US 8,367,097 and US 8,927,005 titled "Liquid formulations for treatment of diseases or conditions"; and US 7,455,855 titled "Delivering substance and drug delivery system using the same" (Santen Pharmaceutical). Co., Ltd.; WO / 2011 / 050365 entitled "Conformable Therapeutic Shield For Vision and Pain" and WO / 2009 / 145842 entitled "Therapeutic Device for Pain Management and Vision" (Forsight Labs, LLC); US 9,066,779 and US 8,623,395 entitled "Implantable therapeutic device"; WO / 2014 / 160884 entitled "Ophthalmic Implant for Delivering Therapeutic Substances"; US 8,399,006; US 8,277,830; US 8,795,712; US 8,808,727; US 8,298...578, and WO / 2010 / 088548 entitled "Posterior segment drug delivery"; WO / 2014 / 152959 and US20140276482 entitled "Systems for Sustained Intraocular Delivery of Low Solubility Compounds from a Port Delivery System Implant"; US 8,905,963 and US 9,033,911 entitled "Injector apparatus and method for drug delivery"; WO / 2015 / 057554 entitled "Formulations and Methods for Increasingor Reducing Mucus"; US 8,715,712 and US 8,939,WO / 2013 / 116061, titled "Ocular insert apparatus and methods"; WO / 2014 / 066775, titled "Ophthalmic System for Sustained Release of Drug to the Eye"; WO / 2015 / 085234 and WO / 2012 / 019176, titled "Implantable Therapeutic Device"; WO / 2012 / 065006, titled "Methods and Apparatus to determine Porous Structures for Drug Delivery"; WO / 2010 / 141729, titled "Anterior Segment Drug Delivery"; WO / 2011 / 050327, titled "Corneal Denervation for Treatment of Ocular Pain"; and WO / 2013 / 022801, titled "Small Molecule Delivery with..." The following are listed as patent titles: "Implantable Therapeutic Device", WO / 2012 / 019047 "Subconjunctival Implant for Posterior Segment Drug Delivery", WO / 2012 / 068549 "Therapeutic Agent Formulations for Implanted Devices", WO / 2012 / 019139 "Combined Delivery Methods and Apparatus", WO / 2013 / 040426 "Ocular Insert Apparatus and Methods", WO / 2012 / 019136 "Injector Apparatus and Method for Drug Delivery", and WO / 2013 / 040247 "Fluid Exchange Apparatus and Methods" (For SightVision4, Inc.).

[0712] The following are other non-limiting examples of how to deliver active compounds: WO / 2015 / 085251 entitled "Intracameral Implant for Treatment of an Ocular Condition" (Envisia Therapeutics, Inc.); WO / 2011 / 008737 entitled "Engineered Aerosol Particles, and Associated Methods"; WO / 2013 / 082111 entitled "Geometrically Engineered Particles and Methods for Modulating Macrophage or Immune Responses"; WO / 2009 / 132265 entitled "Degradable compounds and methods of use thereof, particularly with particle replication in non-wetting templates"; WO / 2010 / 099321 entitled "Interventional drug delivery system and associated methods"; WO / 2008 / 100304 entitled "Polymerparticle composite having high fidelity order, size, and shape". particles", WO / 2007 / 024323 is titled "Nanoparticle fabrication methods, systems, and materials" (Liquidia Technologies, Inc. and the University of North Carolina at Chapel Hill); WO / 2010 / 009087 is titled "Iontophoretic Delivery of a Controlled-ReleaseFormulation in the Eye" (Liquidia Technologies, Inc. and Eyegate Pharmaceuticals, Inc.The following documents are relevant: WO / 2009 / 132206, titled "Compositions and Methods for Intracellular Delivery and Release of Cargo"; WO / 2007 / 133808, titled "Nano-particles for cosmetic applications"; WO / 2007 / 056561, titled "Medical device, materials, and methods"; WO / 2010 / 065748, titled "Method for producing patterned materials"; and WO / 2007 / 081876, titled "Nanostructured surfaces for biomedical / biomaterial applications and processes thereof" (Liquidia Technologies, Inc.).

[0713] Other non-limiting examples of methods and devices for delivering drugs to the eye include, for example, WO2011 / 106702 and US 8,889,193 entitled “Sustained delivery of therapeutic agents to an eyecompartment”, WO2013 / 138343 and US 8,962,577 entitled “Controlled release formulations for the delivery of HIF-1 inhibitors”, WO / 2013 / 138346 and US2013 / 0272994 entitled “Non-Linear Multiblock Copolymer-Drug Conjugates for the Delivery of Active Agents”, WO2005 / 072710 and US 8,957,034 titled "Drug and GeneCarrier Particles that Rapidly Move Through Mucus Barriers", WO2008 / 030557, US2010 / 0215580, US2013 / 0164343 titled "Compositions and Methods for Enhancing Transport Through Mucous", WO2012 / 061703, US2012 / 0121718, and US2013 / 0236556 titled "Compositions and Methods Relating to Reduced Mucoadhesion", WO2012 / 039979 and US2013 / 0183244 titled "Rapid Diffusion of Large Polymeric Nanoparticles in the Mammalian Brain", WO2012 / 109363 and US2013 / 0323313 titled "Mucus Penetrating GeneCarriers", WO The following patents are listed: 2013 / 090804 and US2014 / 0329913, titled "Nanoparticles with enhanced mucosal penetration or decreased inflammation"; WO2013 / 110028, titled "Nanoparticle formulations with enhanced mucosal penetration"; WO2013 / 166498 and US2015 / 0086484, titled "Lipid-based drug carriers for rapid penetration through mucus linings" (The Johns Hopkins University); WO2013 / 166385, titled "Pharmaceutical Nanoparticles Showing Improved Mucosal Transport"; and US2013 / 0323179, titled "Nanocrystals, Compositions,And Methods that Aid Particle Transport in Mucus”(The Johns Hopkins University and Kala Pharmaceuticals, Inc.); WO / 2015 / 066444 titled “Compositions and methods for ophthalmic and / or other applications”, WO / 2014 / 020210 and WO / 2013 / 166408 titled “Pharmaceutical nanoparticles showing improved mucosal transport” (Kala Pharmaceuticals, Inc.); US 9,022,970 titled “Ophthalmic injection device including dosage control device”, WO / 2011 / 153349 titled “Ophthalmic compositions comprising pbo - peo - pb block copolymers”, WO / 2011 / 140203 titled “Stabilized ophthalmic galactomannan formulations”, WO / 2011 / 068955 titled “Ophthalmic emulsion”, WO / 2011 / 037908 titled “Injectable aqueous ophthalmic composition and method of use therefor”, US 2007 / 0149593 titled “Pharmaceutical Formulation for Delivery of Receptor Tyrosine Kinase Inhibiting (RTKi) Compounds to the Eye”, US 8,632,809 titled “Water insoluble polymer matrix for drug delivery” (Alcon, Inc.).,

[0714] Other non-limiting examples of drug delivery devices and methods include, for example, US20090203709 entitled "Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor" (Abbott Laboratories); US20050009910 entitled "Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of a prodrug"; US 20130071349 entitled "Biodegradable polymers for lowering intraocular pressure"; US 8,481,069 entitled "Tyrosine kinase microspheres"; US 8,465,778 entitled "Method of making tyrosine kinase microspheres"; US 8,409,607 entitled "Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods"; and US... 8,512,738 and US2014 / 0031408 are titled “Biodegradable intravitreal tyrosine kinase implants”, US2014 / 0294986 is titled “Micosphere Drug Delivery System for Sustained IntraocularRelease”, US 8,911,768 is titled “Methods For Treating Retinopathy With ExtendedTherapeutic Effect" (Allergan, Inc.); US 6,495,164 is titled "Preparation of injectable suspensions having improved injectability" (Alkermes ControlledTherapeutics, Inc.);WO 2014 / 047439 titled "Biodegradable Microcapsules Containing Filling Material" (Akina, Inc.); WO 2010 / 132664 titled "Compositions And Methods For Drug Delivery" (Baxter International Inc., Baxter Healthcare SA); US 20120052041 titled "Polymeric nanoparticles with enhanced drugloading and methods of use thereof" (The Brigham and Women’s Hospital, Inc.); US 20140178475, US 20140248358, and US 20140249158 titled "Therapeutic Nanoparticles Comprising a Therapeutic Agent and Methods of Making and Using Same" (BIND Therapeutics, Inc.); US 5,869,103 titled "Polymer microparticles for drug delivery" (Danbiosyst UK Ltd.); US 8628801 titled "Pegylated Nanoparticles" (Universidad de Navarra); US 2014 / 0107025 titled "Ocular drug delivery system" (Jade Therapeutics, LLC); US 6,287,588 titled "Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof", US 6,589,549 titled "Bioactive agent delivering system comprised of microparticles within a biodegradable to improve release profiles" (Macromed, Inc.US 6,007,845 and US 5,578,325 are titled "Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers" (Massachusetts Institute of Technology); US 20040234611, US 20080305172, US 20120269894, and US 20130122064 are titled "Ophthalmic depot formulations for periocular or subconjunctival administration" (Novartis Ag); US 6,413,539 is titled "Blockpolymer" (Poly-Med, Inc.); US 20070071756 is titled "Delivery of an agent toameliorate inflammation" (Peyman); US 20080166411 is titled "Injectable Depot Formulations And Methods For Providing Sustained Release of Poorly Soluble Drugs Comprising Nanoparticles" (Pfizer, Inc.); US 6,706,289 titled "Methods and compositions for enhanced delivery of bioactive molecules" (PR Pharmaceuticals, Inc.); and US 8,663,674 titled "Microparticle containing matrices for drug delivery" (Surmodics).

[0715] V. Treatment Methods

[0716] In one embodiment, an effective amount of the formulas I to VI described herein, or their salts or compositions, is used to treat or prevent a medical condition. The compounds described herein can be used to treat conditions that show improvement upon administration of gaseous carbon monoxide. The compounds of the present invention release carbon monoxide in vivo, allowing administration in a form that does not require specialized equipment and allows for controlled dosage. In one embodiment, the compounds of the present invention can be used to treat conditions that have previously shown improvement upon treatment with gaseous carbon monoxide. In one embodiment, a method is provided comprising administering an effective amount of the compounds described herein or pharmaceutically acceptable salts or compositions to a subject (generally a person) suffering from the medical condition described herein.

[0717] In some embodiments, compounds of formulas I to VI, or pharmaceutically acceptable salts thereof, may be used to treat inflammatory conditions. Examples of inflammatory conditions include, but are not limited to: inflammation associated with asthma; arteritis including polyarteritis, temporal arteritis, periarteritis nodosa, and high-pressure arteritis; arthritis including crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, and Reiter's arthritis; ankylosing spondylitis; amyloidosis; amyotrophic lateral sclerosis; autoimmune diseases; allergies or allergic reactions; atherosclerosis; bronchitis; bursitis; chronic prostatitis; conjunctivitis; Chagas disease; and chronic obstructive pulmonary disease. Diseases; myometritis; diverticulitis; diabetes including type 1 and type 2 diabetes; skin diseases including psoriasis, eczema, burns, dermatitis, and pruritus; endometriosis; Guillain-Barré syndrome; infections; ischemic heart disease; Kawasaki disease; glomerulonephritis; gingivitis; hypersensitivity reactions; headaches including migraines and tension headaches; intestinal obstruction including postoperative intestinal obstruction and intestinal obstruction during sepsis; idiopathic thrombocytopenic purpura; interstitial cystitis; gastrointestinal diseases including peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilia. Eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis, gastritis, diarrhea, gastroesophageal reflux disease, constipation-related enteropathy, Crohn's disease, Behcet's syndrome, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, shunt colitis, indeterminate colitis, microscopic colitis, chemical colitis, infectious colitis, fulminant colitis, and inflammatory bowel syndrome; lupus; multiple sclerosis, scleroderma; myasthenia gravis; myocardial ischemia; nephrotic syndrome; pemphigus vulgaris; pernicious anemia; Peptic ulcers; polymyositis; primary biliary cirrhosis; neuroinflammatory diseases including Parkinson's disease, Huntington's disease, and Alzheimer's disease; prostatitis; chronic inflammation associated with craniocerebral radiation injury; inflammatory pelvic diseases; reperfusion injury; regional enteritis; rheumatic fever; systemic lupus erythematosus; scleroderma; sarcoidosis; spondyloarthritis; Sjögren's syndrome; thyroiditis; transplant rejection; tendinitis; trauma or injury, including frostbite, chemical irritants, toxins, scars, burns, or bodily injury; vasculitis; leukoplakia; and Wegener's granulomatosis.

[0718] In some embodiments, compounds of formulas I to VI, or pharmaceutically acceptable salts thereof, may be used to treat pain conditions. Pain conditions may be acute or chronic. Examples of treatable pain conditions include, but are not limited to, inflammatory pain, postoperative pain, osteoarthritis, pain associated with metastatic cancer, trigeminal neuralgia, acute herpes and postherpetic neuralgia, diabetic neuropathy, burning pain, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, and phantom limb pain.

[0719] In one embodiment, a method is provided for treating inflammatory pain caused by infection, including but not limited to pain caused by influenza, SARS, or the common cold, comprising administering an effective amount of a compound of formula I to VI or a pharmaceutically acceptable salt thereof.

[0720] In one embodiment, a method for treating inflammatory pain in a subject is provided, comprising administering an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0721] In one embodiment, a method for treating postoperative pain in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof.

[0722] In one embodiment, a method for treating osteoarthritis in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof.

[0723] In one embodiment, a method for treating pain associated with metastatic cancer in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof.

[0724] In some embodiments, compounds of formulas I to VI, or pharmaceutically acceptable salts thereof, may be used to treat neuropathic pain. Neuropathic pain is pain caused by damage or disease affecting the somatosensory nervous system. Neuropathic pain is typically characterized by abnormal sensation (sensory disturbance) or pain elicited by normal, non-painful stimuli (abnormal pain). Neuropathic pain can be caused by diseases of the peripheral system or the central nervous system (e.g., the brain or spinal cord). Central neuropathic pain is found in cases of spinal cord injury, multiple sclerosis, and stroke. Peripheral neuropathic pain can be seen in patients with diabetes (diabetic neuropathy), herpes zoster infection, HIV infection, nutritional deficiencies, exposure to toxins, remote manifestations of malignancies, immune-mediated diseases, and physical trauma to the nerve trunk. Neuropathic pain may occur in cancer cases due to direct compression of peripheral nerves by tumors, or as a side effect of chemotherapy (chemotherapy-induced peripheral neuropathy), radiation therapy, or surgery.

[0725] In one embodiment, a method for treating central nervous system pain in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof.

[0726] In one embodiment, a method for treating peripheral neuropathic pain in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof.

[0727] In one embodiment, a method for treating trigeminal neuralgia in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof.

[0728] In one embodiment, a method for treating acute herpes zoster neuralgia in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof.

[0729] In one embodiment, a method for treating postherpetic neuralgia in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof.

[0730] In one embodiment, a method is provided for treating neuropathic pain associated with diabetic peripheral neuropathy in a subject, comprising administering an effective amount of a compound of formulas I to VI described herein or a pharmaceutically acceptable salt thereof.

[0731] In one embodiment, a method is provided for treating neuropathic pain in a subject associated with injury or trauma, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof.

[0732] In one embodiment, a method for treating burning pain in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof.

[0733] In one embodiment, a method for treating brachial plexus avulsion in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof.

[0734] In one embodiment, a method for treating occipital neuralgia in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof.

[0735] In one embodiment, a method for treating reflex sympathetic dystrophy in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof.

[0736] In one embodiment, a method for treating fibromyalgia in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof.

[0737] In one embodiment, a method for treating gout in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof.

[0738] In one embodiment, a method for treating phantom limb pain in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof.

[0739] In one embodiment, a method for treating rheumatoid arthritis in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof. CO has been shown to improve collagen-induced arthritis in mice (Takagi, T. et al., Inflammation 2009, 32, 2, 83-88; Bonelli, M. et al., Clin Exp Rheumatol. 2012, 30, 1, 73-8).

[0740] In an alternative embodiment, an effective amount of a compound of formulas I to VI or a pharmaceutically acceptable salt thereof is provided for analgesic effect. Colic, whether generated endogenously from HO or administered via exogenous colic, has been shown to be effective in managing nociceptive pain (Castany, S. et al., Psychopharmacol. 2016, 233, 2209-2219; Fan, W. et al., J. Neurosci. Res. 2011, 89, 802-807; Gou, G. et al., Eur. J. Pharmacol. 2014, 737, 41-46) and neuropathic pain (Hervera, A. et al., Anesthesiology 2013, 118, 1180-1197; Hervera, A. et al., PLOS ONE 2012, 7, e43693; Jurga, AM et al., Pharmacolog. Rep. 2016, 68, 206-213; Méndez-Lara, KA et al., PLOS ONE). It is effective in animal models (2018, 13, e0204841; Wang, H. et al., J.Mol.Neurosci. 2017, 63, 58-69; Bijjem, KRV et al., Naunyn-Schmiedeberg's Arch.Pharmacol. 2013, 386, 79-90).

[0741] Furthermore, coliforms (CO) are known to have synergistic effects with opioids, cannabinoids, and gabapentin in pain management (Godai, K. et al. Pain Rep. 2018, 3, e677; Carcolé, M. et al. J. Pharmacol. Exp. Therap. 2014, 351, 224) and may be involved in the anti-nociceptive effects of some NSAIDs (Grangeiro, NMG et al. Pharmacolog. Rep. 2011, 63, 112-119). The cytoprotective, anti-inflammatory, and neuroprotective effects of CO may also be beneficial in pain management, especially nociceptive pain.

[0742] In an alternative embodiment, a method for treating atherosclerosis in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof. CO has been shown to alleviate atherosclerosis in animal models (Hou, M. et al., Shanghai Journal of Stomatology 2014, 23, 531-538; Liu, DN et al., Cardiovasc. J. Afr. 2010, 21, 257-262; Liu, D. et al., J. Pharmacol. Sci. 2012, 118, 14-24; Liu, DN et al., Chinese Journal of Pathology 2011, 40, 397-402; Durante, W. et al., J. Cell. Mol. Med. 2006, 10, 672-686; Morita, T. Arterioscler. Thromb. Vasc. Biol. 2005, 25, 1786-1795; Siow, RC et al., Cardiovasc. Res. 1999, 41, 385-394).

[0743] In an alternative embodiment, a method for treating organ injury in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the organ is selected from the kidney, heart, liver, brain, and gastrointestinal tract.

[0744] CO has been extensively studied as a therapeutic agent for inflammation, including in the kidneys (Correa-Costa, M. et al., Proc. Natl. Acad. Sci. USA). 2018, 115, E2302; Uddin, MJ et al., Korean J. Physiol. Pharmacol. 2018, 22, 567-575; Cheng, Y. et al., Curr. Pharm. Des. 2017, 23, 3884-3898; Abe, T., Lab. Invest. 2017, 97, 468-477), heart (Suliman, HB et al., J. Clin. Invest. 2007, 117, 3730-3741; Kim, HH et al., Int. J. Mol. Sci. 2019, 19, doi:10.3390 / ijms19082381), liver (Zheng, Y. et al., Nature Chem. 2018, 10, 787-794; Sun, J. et al., Liver Transpl.2017,23,510-526; Upadhyay, KK et al., Toxicology and appliedpharmacology 2018, 360, 99-108), brain (Che, X. et al., Front. Neurosci. 2018, 12, 392; Choi, YK et al., Nat. Med. 2016, 22, 1335-1341; Wang, P. et al., Int. J. Biol. Sci. 2016, 12, 1000-1009), and gastrointestinal tract (Ji, X. et al., Angew. Chem. Int. Ed. Engl. 2016, 55, 15846-15851; Hegazi, RAF et al., J. Exp. Med. 2005, 202, 1703; Sheikh, SZ et al., J. Immunol. 2011, 186, 5506-5513; Steiger, C. et al., J. Control. Release 2016, 239, 128-136; Takagi, T. et al., Digest. Dis. Sci. 2010, 55, 2797-2804; Takagi, T. et al., Digest. Dis. Sci. 2011, 56, 1663-1671; Uddin, MJ et al., Oxid. Med. Cell. Longev. 2013, 210563, and others (Motterlini, R. et al., Nat. Rev. Drug Discov. 2010, 9, 728-743; Ji, X. et al., J. Pharm. Sci.).It provides cellular protection in various organ injury models, including 2016, 105, 406-416.

[0745] In an alternative embodiment, a method for treating or preventing ischemia-reperfusion injury (IRI) in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof. In one embodiment, ischemia-reperfusion injury is a result of surgery or organ transplantation.

[0746] The efficacy of coagulation (CO) has been widely demonstrated in organ transplantation. In multiple organ transplantation studies, the similarities in the datasets are that they all indicate that CO can prevent ischemia-reperfusion injury (Hanto, DW et al., Am. J. Transplant. 2010, 10, 2421-2430; Nakao, A. et al., Am. J. Transplant. 2005, 5, 282-291; Neto, JS et al., Am. J. Physiol. Renal. Physiol. 2004, 287, F979-989; Nakao, A., Surgery 2003, 134, 285-292; Nakao, A. et al., Am. J. Pathol. 2003, 163, 1587-1598).

[0747] In an alternative embodiment, a method for treating acute kidney injury in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the acute kidney injury is a result of chemotherapy. In one embodiment, the acute kidney injury is cisplatin-induced acute kidney injury. In one embodiment, the acute kidney injury is methotrexate-induced. In one embodiment, the acute kidney infection is caused by ischemia-reperfusion injury.

[0748] CO has been shown to have protective effects in areas such as chemotherapy-mediated damage seen with the use of cisplatin or methotrexate (Holditch, SJ et al. Int. J. Mol. Sci. 2019, 20, doi:10.3390 / ijms20123011; Severin, MJ et al. Clin. Exp. Pharmacol. Physiol. 2019, doi:10.1111 / 1440-1681.13122), and numerous studies have described the biological activities of CO, including its role as an anti-inflammatory and anti-apoptotic agent for renal endothelial cells, hepatocytes, and cardiomyocytes, as well as its pro-apoptotic effects under pathological conditions such as cancer cells, dysregulated fibroblasts, and invasive T cells (Motterlini, R. et al. Nat Rev Drug Discov 2010, 9, 728-743).

[0749] In an alternative embodiment, a method for improving renal microcirculation in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof. The effects of CO on renal microcirculation and renal protective activity were investigated (Botros, FT et al. Am. J. Physiol. Heart Circ. Physiol. 2006, 291, H2772-2778).

[0750] In an alternative embodiment, a method for treating heavy metal poisoning in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof. In an animal study using rats poisoned with 100 mg / kg lead acetate, CORM-A1 treatment for 3 months restored serum urea levels to levels similar to those in the unpoisoned control group. Intracellular glutathione (GSH) in kidney tissue also returned to levels comparable to those in the unpoisoned control group. Serum creatinine and malondialdehyde levels were also significantly reduced in the CORM-A1 treatment group compared to the poisoned group. CORM-A1 has also been shown to prevent the elevation of inflammatory cytokines (TNF, IL-1β) and caspase-3 (Southam, HM, et al. Redox Biol. 2018, 18, 114-123). Among all the renal function-related biochemical markers tested, CORM-A1 showed comparable improvement to 10 mg / kg / d L-NAME and 3 mg / kg / d NaHS (Abdel-Zaher, AO et al. Toxicol Lett 2019, 310, 39-50).

[0751] In an alternative embodiment, a method is provided for preventing chemotherapy-induced cardiotoxicity and / or sensitizing cancer cells to chemotherapy in a subject, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the chemotherapy is doxorubicin. In one embodiment, the chemotherapy is cisplatin.

[0752] CO has been shown to protect against doxorubicin-induced cardiotoxicity and to sensitize cancer cells to chemotherapy. Low doses of CO have been shown to protect cardiomyocytes from cell death and maintain overall cardiovascular health (Soni, H. et al. Toxicol. Appl. Pharmacol. 2011, 253, 70-80; Soni, HM et al. Indian J. Pharm. Sci. 2012, 74, 281-291; Suliman, HB et al. J. Clin. Invest. 2007, 117, 3730-3741; Clark, JE et al. Circ. Res. 2003, 93, e2-8; Musameh, MD et al. Med. Gas. Res. 2016, 6, 122-129; Zhao, S. et al. Mol. Med. Rep. 2014, 9, 754-762; Zhou, PY, Transplant Proc. 2015, 47, 2746-2751).

[0753] Cardiotoxicity of DXR is a major limiting factor for this standard treatment, and identifying methods to mitigate DXR damage could be of great significance given CO's potent cardioprotective effects. CO also sensitizes cancer cells and could have far-reaching implications for dose reduction, thereby minimizing chemotherapy toxicity. Furthermore, existing resistance, particularly multidrug resistance associated with efflux, is unlikely to impact the effectiveness of CO-based approaches, as CO can diffuse across membranes and is highly unlikely to act as an efflux substrate. It is well known that CO can also control inflammation closely related to cancer (Roxburgh, CSD et al., British J. Cancer 2014, 110, 1409-1412; Rayburn, ER et al., Mol. Cell. Pharmacol. 2009, 1, 29–43; Balkwill, F. et al., Lancet 2001, 357, 539–545; Grivennikov, SI et al., Cell 2010, 140, 883-899; Coussens, LM; Werb, Z. Nature 2002, 420, 860-867).

[0754] In an alternative embodiment, a method for treating pancreatitis in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the pancreatitis is severe acute pancreatitis (SAP).

[0755] In severe acute pancreatitis (SAP), HO-1 gene expression was significantly upregulated in the rat pancreas and liver, alleviating pancreatic damage and subsequent organ damage caused by a strong systemic inflammatory response. The protective effect of HO-1 in pancreatitis was reproduced by one of its metabolites, CO. CO delivered in different forms has been shown to be effective in controlling pancreatitis (Chen, P. et al., Cytokine 2010, 49, 15-23; Nagao, S. et al., International, J. Nanoded. 2016, 11, 5611-5620; Makhija, R. et al., J. Hepato-Biliary-Pancr. Surg. 2002, 9, 401-410; Xue, J.; Habtezion, J. Clin. Investig. 2014, 124, 437-447; Taguchi, K. et al., Drug Delivery 2018, 25, 1266-1274).

[0756] In an alternative embodiment, a method for treating malaria in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof. CO can prevent severe malaria associated with Plasmodium infection (Jeney, V. et al., Cell Rep. 2014, 8, 1, 126-36; Pamplona, ​​A. et al., Nat. Med. 2007, 13, 6, 703-10; Pena, AC., Antimicrob Agents Chemother. 2012, 56, 3, 1281-90).

[0757] In an alternative embodiment, a method for treating traumatic brain injury in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof. CO, similar to NO, acts as a second messenger and neuromodulator. Therefore, the expression of CO and HO has been shown to promote neurogenesis in traumatic brain injury (Choi, YK. et al., Nat Med. 2016, 22, 11, 1335-1341; Chang, EF. et al., J Neurosci. 2003, 23, 9, 3689-96; Liu, Y. et al., Neuroreport. 2013, 24, 6, 281-6; Fukuda, K. et al., Neurosci Lett. 1995, 199, 2, 127-30; Schallner, N. et al., J Clin Invest 2015, 125, 7, 2609-2625; Wood, H. et al., Nat Rev Neurology 2016, 12, 615; Che, X. et al., Front Neurosci 2018, 12, 392).

[0758] In an alternative embodiment, a method for treating sickle cell disease in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof. Low concentrations of CO provide strong cytoprotection against sickle cell disease (Belcher, J. et al., Plos One 2018, 13, 10, e0205194; Gomperts, E. et al., Am J Hematol 2017, 92, 6, 569-582; Araujo, J., Blood, 2013, 122, 15, 2535-2536).

[0759] In an alternative embodiment, a method for treating autoimmune neuroinflammation in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof. HO-1 expression or exogenous CO inhibits the pathological outcome of autoimmune neuroinflammation (Chora, A. et al., J Clin Invest 2007, 117, 2, 438-447).

[0760] In an alternative embodiment, a method for treating angiogenesis in a therapeutic subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof. CO exposure in mice has been shown to inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis (Ahmad, S. et al., Thromb Haemost 2015, 113, 2, 329-37; Kourti, M. et al., Oncotarget 2019, 10, 10, 1132-1148).

[0761] In an alternative embodiment, a method for treating a metabolic disorder in a subject is provided, comprising administering an effective amount of a compound of formulas I to VI described herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the metabolic disorder is selected from familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabby disease, maple syrup diabetes, metachromatic leukodystrophy, mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS), Niemann-Pick, phenylketonuria (PKU), porphyria, Tessachus disease, and Wilson's disease.

[0762] In one embodiment, the active compound or its salt or composition as described herein may be combined with, alternate with, or be administered before, concurrently with, or after an effective amount of at least one other therapeutic agent, for example, to treat the conditions listed herein. Non-limiting examples of other active agents for such combination therapies are provided below. In the general descriptions herein, whenever any term referring to the active compound or its salt or composition described herein is used, it should be understood to include pharmaceutically acceptable salts, prodrugs, or compositions, unless otherwise stated or inconsistent with the text.

[0763] In one embodiment, the active compound described herein, or its salt or composition, may be used in combination with or alternate with a nonsteroidal anti-inflammatory drug (NSAID). Representative examples of NSAIDs that may be used include, but are not limited to, aspirin, diflunisal, salicylic acid and other salicylates, disalicylate, ibuprofen, dextro-ibuprofen, naproxen, fenofofen, ketoprofen, dextro-ketoprofen, flurbiprofen, oxpromethazine, loxoprofen, indomethacin, tometetin, sulindac, etodoxacin, ketoroxyprofen, diclofenac, aceclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tofenamic acid, celecoxib, rofecoxib, vardicoxib, parecoxib, romecoxib, etodoxacin, fenofoxacin, nimesulide, clonidine, ricofolone, and harbazoside.

[0764] In one embodiment, the active compound described herein, or its salt or composition, may be used in combination with or alternate with corticosteroids. Representative examples of corticosteroids include, but are not limited to, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, ancinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone, beclomethasone, betamethasone, dexamethasone, flucolone, halometasone, mometasone, aclomethasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasol butyrate, fluprednisolone acetate, mometasone furoate, cyclosonepine, cortisone acetate, hydrocortisone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone valerate, prenicarbate, and teicotor neovalerate.

[0765] In one embodiment, the active compound described herein, or its salt or composition, may be used in combination with or alternate with opioids. Representative examples of opioids include, but are not limited to, codeine, fentanyl, hydrocodone, hydromorphone, pethidine, methadone, morphine, oxycodone, alfentanil, remifentanil, sufentanil, etorphine, carfentanil, buprenorphine, pentazocine, propoxyphene, tapentadol, tramadol, and butorphanol.

[0766] In one embodiment, the active compound described herein, or its salt or composition, may be used in combination with or alternately with tricyclic antidepressants, such as nortriptyline or amitriptyline.

[0767] In one embodiment, the active compound described herein, or its salt or composition, may be used in combination with or alternately with duloxetine.

[0768] In one embodiment, the active compound described herein, or its salt or composition, may be used in combination with or alternately with an antiepileptic drug, such as gabapentin, pregabalin, or sodium valproate.

[0769] VI. Methods for treating inflammatory skin diseases

[0770] Effective amounts of the selective CO-releasing compound of the present invention, or its salts, or compositions as described herein, may also be used to treat or prevent inflammatory skin conditions, such as acne vulgaris caused by any bacteria that cause such acne, including Propionibacterium acnes and Staphylococcus epidermidis. In one embodiment, a method is provided comprising administering an effective amount of the compound, or its pharmaceutically acceptable salts, or compositions, alone or in combination with an effective amount of another active agent / e.g., an antibiotic or an anti-inflammatory agent, to treat acne vulgaris.

[0771] Acne vulgaris can be classified as mild, moderate, or severe. The classic definition of mild acne is the presence of blocked hair follicles (called comedones) limited to the face, with occasional inflammatory lesions. Moderate acne occurs when numerous inflammatory papules and pustules appear on the face, some of which may also appear on the trunk. Severe acne occurs when nodules are characteristic facial lesions and the trunk is extensively affected.

[0772] This method involves identifying a target portion of skin affected by an inflammatory skin condition, such as acne vulgaris, requiring treatment and applying the compound described herein, or its salts or compositions, to the target portion of the skin. In some cases, the target portion of the skin may not appear to have an inflammatory skin condition, meaning the compound described herein, or its salts or compositions, can be used as a preventative treatment for the inflammatory skin condition. During treatment, the compound, or its salts or compositions, may be applied to the target skin portion and, if desired, to the surrounding skin at least once daily, twice daily, or more frequently. Typically, the compound, or its salts or compositions, are applied in the morning and / or at bedtime.

[0773] Ideally, the treatment period is a sufficient time for the active compound to reduce or eliminate the appearance of inflammatory skin conditions, such as acne vulgaris on the target area of ​​the skin. The treatment period can last at least one week, about two weeks, about four weeks, about eight weeks, or about 12 weeks. It can also be extended to several months (about 3-12 months) or years. The application of the compound or its salts or compositions can be accomplished through topical application, i.e., by applying it to the target area while minimizing delivery to skin surfaces that do not require treatment, or by applying it more generally or more extensively to one or more skin surfaces.

[0774] Propionibacterium acnes (reclassified as *Dermatobacterium acnes* in 2016) is a Gram-positive (bamboo rod) bacterium associated with acne, belonging to the genus *Dermatobacter* and family *Propionibacterium*. It typically grows slowly and is an aerobic anaerobic bacterium, meaning it can tolerate the presence of oxygen but does not utilize it for growth. While the bacterium is involved in maintaining healthy skin, it can also cause many common skin conditions, such as acne vulgaris. This bacterium primarily lives deep within hair follicles and pores, where it uses sebum, cellular debris, and metabolic byproducts of surrounding skin tissue as a source of energy and nutrients. Increased sebum production or clogged hair follicles can lead to bacterial overgrowth, and this rapid growth can trigger inflammation, resulting in symptoms of common skin conditions such as folliculitis and acne vulgaris.

[0775] Staphylococcus epidermidis is a Gram-positive bacterium belonging to the genus Staphylococcus and family Staphylococci. It is part of the normal human flora, typically found in the skin or mucous membrane flora. It is a facultative anaerobe, thus it can grow in both aerobic and anaerobic conditions. It is usually not pathogenic, but in patients with complex immune systems, the bacteria can cause infection. Staphylococcus epidermidis has the ability to form biofilms on plastics, and infections are often associated with catheters or surgical implants.

[0776] In one embodiment, the active compound described herein, or a salt thereof, or a combination thereof, may be used in combination with or alternately with benzoyl peroxide. In the hair follicles of the skin, benzoyl peroxide kills Propionibacterium acnes by forming oxygen free radicals and oxidizing its proteins with benzoic acid. These free radicals are believed to interfere with the bacteria's metabolism and ability to produce proteins. Furthermore, benzoyl peroxide has a mild effect in breaking down acne and suppressing inflammation. In one embodiment, the active compound, or a salt thereof, is formulated in combination with benzoyl peroxide in the topical formulation described herein.

[0777] In one embodiment, the active compound or its salt or composition described herein may be used in combination with or alternately with retinoids. Retinoids are drugs that reduce inflammation, normalize the life cycle of hair follicle cells, and reduce sebum production. They are structurally related to vitamin A. Retinoids appear to affect the cell life cycle within the inner wall of the hair follicle; this helps prevent skin cells from accumulating within the follicle and causing blockage. Commonly used topical retinoids include adapalene, isotretinoin, retinol, tazarotene, and retinoic acid. In one embodiment, the active compound or its salt is formulated in combination with a retinoid in a topical formulation described herein.

[0778] In one embodiment, the active compounds described herein, or their salts or compositions, may be used in combination with or alternate with antibiotics. Antibiotics are frequently used topically or orally to treat acne and are considered effective due to their antibacterial activity against Propionibacterium acnes and their ability to reduce inflammation. Commonly used antibiotics, whether applied topically or orally, include clindamycin, erythromycin, metronidazole, sulfacetamide, and tetracyclines such as doxycycline and minocycline. Other representative topical antibiotics include bacitracin, polymyxin B, neomycin, retamoline, mupirocin, promoxin, gentamicin, mefenidone, and oxifenesin. The compounds described herein are particularly effective when combined with antibiotics because they enhance the antimicrobial activity of the antibiotics.

[0779] In one embodiment, the active compound or its salt is formulated in combination with an antibiotic in the topical formulation described herein.

[0780] In one embodiment, the active compound or its salt or composition described herein may be used in combination with or alternately with azelaic acid. Azelaic acid is considered an effective treatment for acne because it can reduce the accumulation of skin cells in hair follicles and has antibacterial and anti-inflammatory properties. In one embodiment, the active compound or its salt is formulated in combination with azelaic acid in the topical formulation described herein.

[0781] In one embodiment, the active compound or its salt or composition described herein may be used in combination with or alternately with salicylic acid. Salicylic acid is a topically applied β-hydroxy acid that, in addition to inhibiting bacterial growth, also has keratin-removing properties. In one embodiment, the active compound or its salt is formulated in combination with salicylic acid in the topical formulation described herein.

[0782] In one embodiment, the active compound or its salt or composition described herein may be used in combination with or alternately with nicotinamide. Nicotinamide can improve acne by reducing inflammation, inhibiting sebum production, and promoting wound healing. In one embodiment, the active compound or its salt is formulated in combination with nicotinamide in the topical formulation described herein.

[0783] VII. Method for preparing the compounds of the present invention

[0784] The compounds described herein can be prepared by methods known to those skilled in the art. In a non-limiting example, the disclosed compounds can be prepared using the methods provided below.

[0785] General synthetic route

[0786]

[0787] Route 1

[0788] In some embodiments, compounds of formula I or IV can be formed by the method shown in route 1. Compounds of formula I can be synthesized by reacting AH with formic anhydride. Similarly, compounds of formula IV can be synthesized by reacting DH with formic anhydride. Formic anhydride can be formed by reacting acetic anhydride with formic acid at 0°C or by reacting sodium formate with acetyl chloride in anhydrous diethyl ether at 23-27°C (see Krimen, LI, *Organic Syntheses*, 1970, 50:1). As is known to those skilled in the art, reagents similar to formic anhydride can be substituted.

[0789]

[0790] Route 2

[0791] In other embodiments, compounds of formula I or IV can be synthesized by the method shown in route 2. Compounds of formula I can be synthesized by reacting AH with formic acid and N,N'-dicyclohexylcarbodiimide (DCC) at 0°C. Similarly, compounds of formula IV can be synthesized by reacting DH with formic acid and DCC at 0°C. As is known to those skilled in the art, reagents similar to DCC can be substituted.

[0792]

[0793] Route 3

[0794] In other embodiments, compounds of formula II or V can be synthesized by the method shown in route 3. Compound II can be formed by reacting at least two equivalents of BH with one equivalent of oxalyl chloride in the presence of triethylamine. Alternatively, formula II can also be synthesized from a salt of BH without a base such as triethylamine. Similarly, compounds of formula V can be synthesized by reacting at least two equivalents of DH with one equivalent of oxalyl chloride in the presence of triethylamine. As known to those skilled in the art, reagents similar to triethylamine, such as diisopropylethylamine or sodium carbonate, can be substituted. In one embodiment, the reaction is carried out at 0°C and then heated to room temperature.

[0795]

[0796] Route 4

[0797] In other embodiments, compounds of formula III or VI can be synthesized by the method shown in route 4. Compounds of formula III are synthesized by approximately one equivalent of R... A -OH reacts with approximately one equivalent of oxalyl chloride to synthesize crude R. A -O-(C=O)-(C=O)-Cl, then reacted with approximately one equivalent of CH in the presence of triethylamine. Similarly, by causing approximately one equivalent of R... A -OH reacts with approximately one equivalent of oxalyl chloride to synthesize compound VI, yielding crude R. A -O-(C=O)-(C=O)-Cl, then reacted with approximately one equivalent of DH in the presence of triethylamine. To prepare R... A For compounds containing H, oxalyl chloride is first reacted with tert-butanol to give crude tBu-O-(C=O)-(C=O)-Cl, and then reacted with approximately one equivalent of CH in the presence of triethylamine. The tert-butyl group is then removed using trifluoroacetic acid.

[0798] Experimental Examples of the Invention

[0799] Unless otherwise specified, reactions were carried out under a nitrogen atmosphere using glassware that had been pre-oven-dried overnight with magnetic stirring. Unless otherwise specified, all reagents were obtained from commercial suppliers (Sigma-Aldrich, VWR International, and Oakwood Chemicals) and were ready for use without further purification. Thin-layer chromatography was performed on glass-backed silica gel TLC plates using a mixture of hexane and ethyl acetate as eluent, and visualized using UV light, iodine powder, or potassium permanganate staining. Column chromatography was performed using Silica Flash P60 silica gel (230-400 mesh). 1 H and 13 C10 NMR spectra were recorded on a Bruker-400 spectrometer (400 MHz and 100 MHz, respectively). Chemical shifts are reported in ppm relative to the residual solvent peak. 1 H is δ7.26. 13 C is δ77.1, CHCl3 / CDCl3) and ( 1 H is δ2.49, 13 C = δ 39.1 (DMSO / DMSO-d6). Data are reported as follows: bs = broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, ddd = doublet of doublet, ddt = doublet of doublet, td = doublet of doublet; coupling constant in Hz; integrated. Accurate mass measurements were obtained at the mass spectrometry facility at Georgia State University. For spectrophotometric studies, the Shimadzu PharmaSpecUV-1700 was used as a UV-Vis spectrophotometer; while the Shimadzu RF-5301PC fluorometer was used for fluorescence studies. An Agilent 7820A equipped with a TCD detector was used for CO and CO2 quantification.

[0800] Example 1. Synthesis of 3-oxobenzo[d]isothiazol-2(3H)-formaldehyde 1,1-dioxide (1)

[0801]

[0802] A mixture of formic acid (1.21 g, 26.3 mmol) and acetic anhydride (2.67 g, 26.2 mmol) was heated to 55 °C for 2 hours, and then benzo[d]isothiazol-3(2H)-one 1,1-dioxide (1.7 g, 9.3 mmol) was added in one part. The resulting mixture was stirred at 60 °C for another 5 hours. The reaction mixture was then cooled to room temperature and 20 mL of deionized water was added. The resulting white precipitate was filtered and dried under vacuum to give a white solid, 3-oxobenzo[d]isothiazol-2(3H)-formaldehyde 1,1-dioxide (1.65 g, 84%). 1 H NMR (400MHz, DMSO-d6) 9.15 (s, 1H), 8.35 (d, J = 8.0Hz, 1H), 8.22 (d, J = 8.0Hz, 1H), 8.14 (t, J = 7.6Hz, 1H), 8.04 (t, J = 8.0Hz, 1H).

[0803] Example 2. Synthesis of 5-methyl-2-thio-1,3,4-thiadiazole-3(2H)-formaldehyde (2)

[0804]

[0805] Acetic formic anhydride (670 mg, 7.6 mmol) was added to an anhydrous THF (10 mL) solution of 5-methyl-1,3,4-thiadiazole-2(3H)-thione (500 mg, 3.8 mmol) at 0 °C. The resulting mixture was stirred for 15 minutes and cooled to -20 °C for 2 hours. The precipitate was filtered to produce 5-methyl-2-thio-1,3,4-thiadiazole-3(2H)-formaldehyde (480 mg, 80%) as yellow needle-like crystals. 1 H NMR (400MHz, DMSO-d6)9.45(s,1H),2.58(s,3H).

[0806] Example 3. Synthesis of 2-oxopyridine-1(2H)-formaldehyde (3)

[0807]

[0808] DCC (2.27 g, 11.0 mmol) was added fractionally to a CH₂Cl₂ (50 mL) solution of pyridine-2-ol (1 g, 10.5 mmol) and formic acid (485 mg, 10.5 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for another 30 minutes. The reaction mixture was then filtered, and the filtrate was cooled to -80 °C. The resulting pale yellow precipitate was filtered to give 2-oxopyridine-1(2H)-formaldehyde (450 mg, 35%). ¹H NMR (400 MHz, DMSO-d₆) 9.65 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 6.39 (t, J = 8.0 Hz, 1H).

[0809] Example 4. Synthesis of N-(1-formylpyridin-4(1H)-yl)-N-methylmethylamine bromide (4)

[0810]

[0811] Trimethylsilyl bromide (752 mg, 4.92 mmol) was added dropwise to a solution of N,N-dimethylpyridin-4-amine (600 mg, 4.92 mmol) in CH₂Cl₂ (10 mL) at room temperature, and the resulting solution was stirred for another 30 minutes. The reaction mixture was then added to a solution of formic acid acetic anhydride (476 mg, 5.4 mmol) at -20 °C. The resulting white precipitate was filtered and washed with CH₂Cl₂ to give a white solid N-(1-formylpyridin-4(1H)-yl)-N-methylmethylamine bromide (790 mg, 70%). 1 H NMR (400MHz, CD3CN), 8.56 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 3.41 (s, 6H).

[0812] Example 5. Synthesis of 1,2-bis(1,1-dioxo-3-oxobenzo[d]isothiazo-2(3H)-yl)ethane-1,2-dione (5)

[0813]

[0814] At 0 °C, oxalyl chloride (190 μL, 2.73 mmol) dissolved in THF was added dropwise to a solution of benzo[d]isothiazo-3(2H)-one 1,1-dioxide (1 g, 5.46 mmol) and triethylamine (766 μL, 5.46 mmol) in THF. After the addition of oxalyl chloride, the reaction mixture was stirred at room temperature for 3 hours. Then, THF was removed by rotary evaporation. The residue was dissolved in dichloromethane and washed with water (2 × 10 mL), saturated NaHCO3 (3 × 10 mL), and brine. The organic layer was then concentrated in a rotary evaporator at <30 °C to give a white solid. The separated solid was recrystallized in acetonitrile to give a white solid 1,2-bis(1,1-dioxide-3-oxobenzo[d]isothiazo-2(3H)-yl)ethane-1,2-dione. 1 HNMR(400MHz,CD3CN)8.13-8.22(m,6H),8.01-8.05(m,2H). 13 C NMR (100MHz, CD3CN)159.5,156.8,139.8,139.6,137.4,128.4,125.2,123.3.

[0815] Example 6. Synthesis of 2,2'-oxalylbis(isodihydroindole-1,3-dione) (6)

[0816]

[0817] Oxaloyl chloride (37.5 μL, 0.539 mmol) was added dropwise to a THF (10 mL) suspension of potassium phthalimide (200 mg, 1.08 mmol). The reaction mixture was stirred at room temperature for 45 minutes. After 1 hour, the reaction mixture was diluted with DCM and filtered. The filtrate was concentrated in a rotary evaporator to give 2,2'-oxalylbis(isodihydroindole-1,3-dione) (260 mg, 70%) as a white solid.

[0818] Example 7. Synthesis of 1,2-bis(6-methyl-2,2-dioxo-4-oxo-1,2,3-oxathiazin-3(4H)-yl)ethane-1,2-dione (7)

[0819]

[0820] Acesulfame potassium (1 g, 4.97 mmol) was stirred at 0 °C in a suspension of acesulfame potassium in 10 mL of THF, and oxalyl chloride (173 μL, 2.49 mmol) dissolved in 5 mL of THF was added dropwise. The reaction mixture was stirred in an ice bath for 10 min, and then stirred at room temperature for 3 h. The reaction mixture was then concentrated in a rotary evaporator. The crude residue was dissolved in DCM and washed with water (2 × 20 mL), saturated NaHCO3 (2 × 20 mL), and brine. The organic layer was dried with Na2SO4 and concentrated in a rotary evaporator to give a pale yellow solid. The crude residue was suspended in diethyl ether and filtered to give 1,2-bis(6-methyl-2,2-dioxo-4-oxo-1,2,3-oxathiazin-3(4H)-yl)ethane-1,2-dione as a white solid. 1 H NMR(400MHz,CD3CN)6.12(m,1H),2.31(m,3H). 13 C NMR(100MHz,CD3CN)167.9,160.8,156.4,104.4,20.4.

[0821] Example 8.N 1 N 2 -Dibenzoyl-N 1 N 2 Synthesis of bis(methylsulfonyl)oxalamide (9)

[0822]

[0823] To a THF solution of N-(methanesulfonyl)benzamide (350 mg, 1.76 mmol) and triethylamine (247 μL, 1.76 mmol), oxalyl chloride dissolved in THF (61 μL, 0.88 mmol) was added dropwise while stirring at 0 °C. After addition, the reaction mixture was stirred at room temperature. THF was then removed by rotary evaporation. The residue was redissolved in dichloromethane and washed with water (2 × 10 mL), saturated NaHCO3 (3 × 10 mL), and brine. The organic layer was then concentrated in a rotary evaporator at <30 °C to give a solid. The separated solid was purified by silica gel column chromatography using dichloromethane as the elution solvent to give a white solid. 1 H NMR(CD3CN)8.04-8.06(2H,m),7.77-7.81(1H,m),7.58-7.62(2H,m),3.62(3H,s). 13 C NMR(CD3CN)169.2,137,132.9,131.6,130.5,44.5.

[0824] Example 9. 2-(1,1-dioxo-3-oxobenzo[d]isothiazolyl-2(3H)-yl)-2-glyoxylic acid tert-butyl ester (8) and 2-(1,1-dioxo-3-oxobenzo[d]isothiazolyl-2(3H)-yl)-2-glyoxylic acid (10)

[0825]

[0826] A solution of tert-butanol in ether (3 mL) was added dropwise to a solution of oxaloyl chloride (1.8 mL) in ether (10 mL) with stirring at 0 °C. The mixture was stirred at room temperature for 20 hours and then concentrated in a rotary evaporator to obtain crude tert-butyl 2-chloro-2-glyoxylate, a clear, colorless liquid.

[0827] Crude 2-chloro-2-oxobutyl acetate was added dropwise to a solution of saccharin (1.3 g) and triethylamine (3.0 mL) and stirred at room temperature for 3 hours. The reaction mixture was then diluted with dichloromethane and washed with saturated NaHCO3 (2 × 15 mL). The organic layer was dried over sodium sulfate and concentrated in a rotary evaporator. The residue was suspended in diethyl ether and filtered to give tert-butyl 2-(1,1-dioxo-3-oxobenzo[d]isothiazo-2(3H)-yl)-2-glyoxylate (8) as a white solid. 1 H NMR (400MHz, CD3CN)8.17-8.16(m,1H),8.0-7.94(m,3H),1.62(s,9H). 13 C NMR (100MHz, CD3CN)157.0,156.8,156.7,138.9,137.3,135.5,126.7,124.5,121.7,87.2,27.9.

[0828] While stirring at 0°C, 1 mL of trifluoroacetic acid was added to a dichloromethane solution of tert-butyl 2-(1,1-dioxo-3-oxobenzo[d]isothiazol-2(3H)-yl)-2-glyoxylic acid (8) (50 mg). The reaction was then stirred at room temperature. After 5 hours, the reaction mixture was dried in a rotary evaporator to give 2-(1,1-dioxo-3-oxobenzo[d]isothiazol-2(3H)-yl)-2-glyoxylic acid (10) as a white solid. 1 HNMR(CD3CN)8.04-8.06(2H,m),7.77-7.81(1H,m),7.58-7.62(2H,m),3.62(3H,s). 13 C NMR(CD3CN)169.2,137,132.9,131.6,130.5,44.5.

[0829] Example 10. Non-limiting embodiment of the present invention

[0830] Table 1 illustrates non-limiting examples of the present invention.

[0831]

[0832]

[0833] Example 11. Evaluation of carbon monoxide release

[0834] Evaluation of CO fluorescent probe COP-1

[0835] Oxaloyl-based compounds with suitable leaving groups are readily hydrolyzed, expelling a leaving group and generating a keto acid intermediate. Figure 2 Once the ketoacid intermediate undergoes subsequent decarboxylation and decarbonylation reactions, CO is produced. For oxalyl chloride, this pathway is dominant, so only CO, CO2, and HCl are formed upon exposure to water. However, when the chloride leaving group is replaced by a weaker leaving group (such as saccharin), another decomposition pathway may compete with the CO formation pathway. The ketoacid intermediate can undergo hydrolysis to expel a second leaving group and form oxalic acid without producing CO. Therefore, the pKa of the leaving group must be carefully selected to favor the CO formation pathway.

[0836] COP-1 is a commonly used CO probe in the literature for detecting CO, used to evaluate the ability of different oxalyl compounds to release CO in aqueous solution at room temperature. Various leaving groups with different pKa values ​​were used instead of chlorides to study the effect of pKa on CO release.

[0837] To prepare a final solution concentration of 100 μM, DMSO solution of 1,2-bis(1,1-dioxo-3-oxobenzo[d]isothiazo-2(3H)-yl)ethane-1,2-dione was added to a 3% DMSO solution of the CO probe COP-1 (0.5 μM) in PBS. The resulting mixture was incubated at 37 °C, and fluorescence emission intensity was recorded at different time points from 430 to 460 nm, with an excitation wavelength of 475 nm.

[0838] like Figure 3 As shown, when the pKa of the leaving group is below 4, the fluorescence on-off intensity is observed to increase by 4 to 6 times, while increasing the pKa of the leaving group to above 4 results in the compound failing to release CO (except for a moderate increase of 0.1 times with imidazole).

[0839] like Figure 4 As shown, a 2.3-fold increase in fluorescence was observed after compound 2 was incubated with the COP-1 probe for 10 minutes. A 4-fold increase in fluorescence intensity was observed after 3 hours for compound 5. Figure 5 ).

[0840]

[0841] The reactions of a range of oxalyl-based CO donors in COP-1 fluorescence assays were examined. The results in Table 2 show that the best CO donors are compounds with pKa values ​​typically less than 4.0 for the leaving group's conjugate acid.

[0842] Table 2. COP-1 fluorescence response based on oxalyl-based CO donors

[0843]

[0844] CO-myoglobin assay

[0845] Direct detection of carbon monoxide (CO) release was performed using a dual-compartment Mb-CO assay. This apparatus is assembled by placing a smaller vial inside a larger one and sealing the system. The larger vial contains a deoxy-MB solution, while the smaller vial contains CO-releasing molecules in DMSO / PBS. The deoxy-MB solution was prepared by degassing a myoglobin-in-PBS (1 mg / mL, pH 7.4) solution with nitrogen for at least 20 minutes, followed by conversion to deoxy-MB by adding a freshly prepared sodium dithionite (1 mL, 22 mg / mL) solution. The CO-releasing molecules in DMSO were added to the inner vial containing PBS using a syringe. The entire apparatus was then incubated at 37°C. After 25 minutes, the apparatus was cooled in an ice bath for 10 minutes to increase CO gas solubility, and the incubated solution was immediately transferred to a cuvette for UV-Vis spectroscopy analysis.

[0846] like Figure 6A , Figure 6B and Figure 7 As shown, compounds 2, 7 and 5 exhibit characteristic spectral features of CO-myoglobin formation, confirming the release of CO from these molecules under physiological conditions.

[0847]

[0848] Quantitative CO analysis

[0849] An Agilent 7820A GC system equipped with a thermal conductivity detector was used to detect and quantify the CO release yield of a CO prodrug. A specific volume of headspace sample from a 20 mL headspace vial was sampled using a hermetically sealed syringe and transferred to an inlet maintained at 125°C. Helium was used as the carrier gas at a flow rate of 30 mL / min. The gaseous components in the headspace were separated using a packed column with a 60 / 80 Carboxen-1000 matrix support, L×OD×ID 15.0 ft (4.6 m) × 1 / 8 inch × 2.1 mm (Supelco). The column was heated at 35°C for 5 min, then to 225°C at a rate of 20°C / min, while the detector was maintained at 125°C. Under these conditions, the elution time for CO was approximately 7.4 min, while the elution time for CO2 was 13.4 min.

[0850] When dissolved in a 4:1 acetonitrile:water mixture and incubated at 37°C for 1 hour, compound 5 released 76% ± 6% CO, and compound 7 released 92% ± 3% CO. Figure 10 ). Figure 9 This is the chromatogram of compound 5. On the other hand, CO was not detected in compound 9, possibly because it is more likely to undergo secondary hydrolysis compared to the CO formation pathway.

[0851]

[0852] To investigate the requirement that CO compounds must first undergo hydrolysis to expose the keto acid intermediates that serve as the CO source, compound 10 was synthesized from compound 8 (Example 9 above). No CO or CO2 was detected from compound 8, while approximately 40% CO and CO2 were produced from compound 10. Figure 10 These results indicate that attaching two saccharin groups to the oxalyl core prevents hydrolysis and favors a reaction pathway that produces CO.

[0853]

[0854] The effect of pH was also investigated. As the pH decreased, the yield of CO from compound 5 decreased from 60% to 30%. Figure 11 The CO release yield of compound 7 is pH-independent, remaining constant at approximately 90% over a wide pH range. Figure 12 ).

[0855] Figure 8A and Figure 8B These are calibration curves for CO and CO2 release, respectively.

[0856] LC-MS Study: CO Generation and Non-CO Generation Pathways

[0857] LCMS analysis was performed in negative mode on an Agilent 1200 HPLC and 3200 API triple quadrupole mass spectrometer with an electrospray ionization source. The selected ion mode was used to detect ions of saccharin at m / z 182 and oxalic acid at m / z 89. 5 μL of sample solution (compound 5) was directly fed into the ionization source of the mass spectrometer equipped with an Agilent autosampler and HPLC by mixing with 1% ACN aqueous solution at a flow rate of 200 μL / min. No column was used. Recordings were taken for three minutes, and peak areas were integrated. A standard curve was plotted as the ratio of PA (oxalic acid) / PA (saccharin) to the concentration ratio (C(saccharin) / C(oxalic acid)). A linear regression equation was generated to calculate the ratio of unknowns.

[0858] Using this method, 47 μM of oxalic acid was produced from a 200 μM compound 5 sample. Figure 13 Therefore, the estimated CO yield is approximately 75%, which is in very good agreement with the results obtained from the GC-TCD experiment (the quantitative CO analysis described above).

[0859] NMR CO release experiment of formyl compounds

[0860] CO release from compounds 1–4 was determined by NMR. Each compound was placed in deuterated PBS or 20% DMSO-d6 deuterated PBS. The CO release yield was indirectly determined by calculating the ratio of formic acid formed as a competitive hydrolysis byproduct. The CO release yields of these compounds are summarized in Table 3 below.

[0861] Table 3. Carbon monoxide release yield of formyl CO donors

[0862]

[0863] Approximately 5 mg of compound 5 was dissolved in 450 μL of deuterated acetonitrile, and proton and carbon NMR were then run. Next, 250 μL of deuterated water was added to the NMR tube, and proton and carbon NMR were run at different time points. The experiment was repeated with compound 7. These two studies indicate that the products after gas release are primarily benign carriers saccharin and acesulfame potassium. Figure 14 Decomposition of compound 5 1 HNMR spectrum, Figure 15 Decomposed from compound 7 1 HNMR image.

[0864] HPLC kinetics experiment

[0865] The degradation rate of compound 5 under physiological conditions was tested. The following samples were injected into the HPLC instrument: i) saccharin (200 μM) dissolved in 40% acetonitrile in PBS; b) a solution of CO-releasing compound 5 dissolved in 40% acetonitrile in PBS, incubated at 37°C at different time points. 200 μL aliquots of the incubated sample were placed in 0.5 mL vials and diluted with 200 μL of acetonitrile. This study was performed using a Shimadzu Prominence UFLC HPLC system equipped with a reversed-phase analytical column (Waters C18 3.5 μM, 4.6 x 100 mm) at 25°C. The flow rate was set to 1 mL / min. Gradient elution was performed using acetonitrile and deionized water containing 0.05% TFA to elute the components in the sample. Elution conditions: 0–7 min 50% to 70% acetonitrile; injection volume 10 μL; detection wavelengths 254 and 280 nm. The experiment was performed in triplicate.

[0866] Figure 16A This is the decomposition curve of compound 5 in 60% PBS. (Example:) Figure 16B As shown, compound 5 has a half-life of 1.28 ± 0.03 minutes in 60% PBS at 37 °C. In contrast, compound 5 is stable as a solid for at least 24 days and as an acetonitrile solution for at least 7 days.

[0867] Compound 7 was tested in the same manner. Figure 17A This is the decomposition curve of compound 7 in 60% PBS. Figure 17B This indicates that the half-life of compound 7 is 9.5 ± 0.1 minutes. Figure 17A In this study, the decomposition was measured over a period of 0 to 60 minutes.

[0868] Anti-inflammatory test

[0869] The effects of the compounds of this invention on CO-related anti-inflammatory activity were investigated. The pro-inflammatory cytokine TNF-α in RAW264.7 cell cultures stimulated with lipopolysaccharide (LPS) from *E. coli* was measured using EILSA assay. Figure 18A and Figure 18BThe results showed that pretreatment of RAW264.7 cells with the representative CO prodrug compounds 5 and 7, respectively, inhibited LPS-induced TNF-α production in a dose-dependent manner, and the released products did not exhibit anti-inflammatory activity. Due to the rapid release kinetics of compound 5, a repeated-dose regimen was used. The specified concentration of compound 5 was added to the culture medium before cell addition, and the freshly prepared drug-loaded medium was replaced 5 times every 1 hour. Compound 7 has a longer half-life, so a single addition of the drug is sufficient to exert an anti-inflammatory effect. A total of 5 hours of pretreatment was used throughout the experiment, and the reported CO prodrug (Ji, X. et al., Angew Chem Int Ed Engl 2016, 55(51), 15846-15851) was used as a positive control:

[0870]

[0871] Cytotoxicity test

[0872] For the CCK-8 assay, HeLa cells were cultured at 37°C and 5% CO2 in DMEM (Dulbecco's Modified Eagle's medium) supplemented with 10% fetal bovine serum (MidSci; SO1520HI) and 1% penicillin-streptomycin (Sigma-Aldrich; P4333). Fresh medium was added every other day. Cells were treated with the compound (0-100 μM) in 1% DMSO in the DMEM for 24 hours.

[0873] like Figure 19 As shown, compound 5 is not toxic to HeLa cells at concentrations up to 100 μM.

[0874] Stability Study

[0875] RP-HPLC studies showed that compounds 5 and 7, as solids, were stable for at least 24 days after exposure to ambient light and temperature. These prodrugs were also stable as acetonitrile solutions stored at room temperature for at least 7 days. Kinetic experiments using HPLC revealed that compound 5 (… Figure 20A ) and compound 7 ( Figure 20B The half-lives in 60% phosphate buffered saline were 1.28 ± 0.03 minutes and 9.5 ± 0.14 minutes, respectively.

[0876] Example 12. Formulation of Compound 5

[0877] In one embodiment, the compounds of the present invention are formulated in a manner that allows them to be readily miscible with water and not exposed to water content during storage. For administration, one method is to dissolve the prodrug in an organic excipient that is miscible or partially miscible with water. CO is released from this homogeneous mixture upon contact with water. In one embodiment, dimethylacetamide (DMA) is used to dissolve compound 5 in DMA to form a 10 mg / ml solution, which is then further diluted three-fold with polyethylene glycol (PEG) 300. The resulting mixture can be used as a liquid formulation of compound 5. N-methylpyrrolidone (NMP) can also be used in place of DMA, or other non-nucleophilic solvents miscible with water can be used for the same purpose. Ethylene glycol, Tween 80, poloxamer, and other similar water-soluble cosolvents can also be used instead of PEG. A mixture of solvent and cosolvent in a specific ratio can be used.

[0878] Another approach is to achieve uniform dispersion in a solid matrix. The adsorption of saccharin-based compound 5 on activated carbon is described below. Various ratios and conditions investigated are also described. In all cases, the activated carbon was preheated overnight at 120°C to remove adsorbed water. This represents an advantageous method for dispersing agents under physiologically relevant aqueous conditions to induce CO2 release.

[0879]

[0880] Determination of the adsorption rate of compound 5 on activated carbon

[0881] The saturated adsorption test was used to determine the adsorption capacity of compound 5 on activated carbon. Compound 5 was dissolved in anhydrous acetonitrile to form calibration samples with concentrations ranging from 0.019 to 0.3 mg / ml. The absorbance at 280 nm was measured using a UV-Vis spectrophotometer, and a calibration curve was plotted against concentration to provide a calibration curve. Figure 21 ).

[0882] At room temperature (25°C), 1-6 mg of compound 5 was mixed with 10 mg of activated carbon, and then 0.5 ml of ACN was added. The mixture was shaken for 1 hour, then centrifuged at 12000 × g for 5 minutes. The supernatant was diluted 50-fold with ACN, and the concentration of compound 5 in the supernatant was measured at 280 nm using a UV / Vis spectrophotometer. The adsorbed mass of compound 5 was calculated using Formula I:

[0883] Adsorbed mass = (initial mass) - 0.5 * (supernatant concentration) (Equation I)

[0884] Adsorption mass = Y0 + (stationary - Y0) * (1 - e -KX (Formula II)

[0885] Plotting adsorption mass against concentration ( Figure 22 The constant calculated from Formula II is 1.73 mg, which represents the maximum adsorption capacity of compound 5 at 25°C that can be adsorbed by 10 mg of activated carbon.

[0886] Formulation of activated carbon and compound 5

[0887] The following describes two typical procedures for formulations using activated charcoal and compound 5.

[0888] Method A: 10 mg of compound 5 was mixed with 100 mg of activated charcoal and 1 ml of anhydrous ACN and shaken at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The resulting black powder was dried overnight using a lyophilizer (vacuum 1 mbar, condenser -70°C) to remove residual ACN. The dried black powder was used as an activated CO prodrug formulation.

[0889] Method B: 10 mg of compound 5 was mixed with 60 mg of activated charcoal and 1 ml of anhydrous ACN and shaken at room temperature for 1 hour. The slurry was filtered and the solid was dried overnight using a lyophilizer (vacuum 1 mbar, condenser -70°C) to remove residual ACN. The dried black powder was used as a CO prodrug formulation. The actual loading was determined by gas chromatography.

[0890] In an alternative embodiment, polyvinylpyrrolidone (PVP) or polyvinylpyrrolidone polyvinyl acetate (PVP-VA) is used as an excipient for preparing the solid dispersion. In a typical embodiment, the solvent is anhydrous and non-nucleophilic, such as ACN, THF, acetone, or dichloromethane.

[0891] Determination of CO release curves of CO prodrug formulations on activated carbon

[0892] Activated carbon (100 mg) containing compound 5, prepared according to method A, was placed in a GC headspace vial. 3 mL of PBS preheated to 37°C was added, the vial was sealed, and incubated at 37°C. At different time points, 250 μL of headspace gas was extracted and injected into a gas chromatograph (Agilent 7820) equipped with a RESETK packed molecular sieve column and a TCD detector. CO release kinetics and yield plots were constructed based on the CO peak area and calibration curve. Figure 23 ).

[0893] The results showed that the adsorption of compound 5 on activated carbon resulted in a rapid release rate with a half-life of 2.2 minutes and a total CO release yield of 81%, which was higher than that under homogeneous conditions in the ACN / water system.

[0894] Quantitative analysis of saccharin in the supernatant after CO release

[0895] The byproduct of compound 5's release of CO is saccharin. Due to the adsorption effect of activated charcoal, the byproduct may still be adsorbed onto the activated charcoal, thus reducing systemic exposure to saccharin. Although saccharin is considered safe, reducing systemic absorption is still beneficial.

[0896] The standard curve for saccharin in PBS was established by ultraviolet spectrophotometry by plotting the adsorption at 268 nm against saccharin concentrations ranging from 0.0078 to 0.25 mg / ml. Figure 24 After CO was released from a 100 mg activated charcoal formulation containing compound 5 (incubated at 37°C for 4 hours), the liquid phase was filtered through a 0.45 μm syringe filter, diluted 5-fold, and tested using a UV spectrophotometer. The Abs reading was 0.1575, corresponding to a saccharin concentration of 0.1 mg / ml in the supernatant PBS. This represents only 1.5% of the total input saccharin. Therefore, most of the saccharin byproducts remain adsorbed on the activated charcoal used, and the amount of free saccharin after CO release is significantly reduced by using this formulation method.

[0897] All publications and patent applications cited in this specification are incorporated herein by reference as if each publication or patent application were specifically and individually incorporated herein by reference.

[0898] Although the invention has been described in detail by way of illustration and example for purposes of explanation, it will be readily apparent to those skilled in the art, based on the teachings of the invention, that certain changes and modifications may be made without departing from the spirit and scope of the appended claims.

Claims

1. Compounds selected from the following formula or pharmaceutically acceptable salts thereof:

2. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating medical diseases treatable with carbon monoxide in subjects of need.

3. The application as described in claim 2, wherein the object is a person.

4. The application as described in claim 2, wherein the medical condition is: pain syndrome; inflammatory syndrome; ischemia-reperfusion injury; acute kidney injury; heavy metal poisoning; pancreatitis; or chemotherapy-induced cardiotoxicity.

5. The application as described in claim 4, wherein the pain condition is neuropathic pain; inflammatory pain; postoperative pain; osteoarthritis; pain associated with metastatic cancer; trigeminal neuralgia; acute herpes zoster neuralgia; postherpetic neuralgia; diabetic neuropathy; burning pain; brachial plexus avulsion; occipital neuralgia; reflex sympathetic dystrophy; fibromyalgia; gout; or phantom limb pain.

6. The application as described in claim 5, wherein the neuropathic pain is central or peripheral neuropathic pain.

7. The application as described in claim 5, wherein the inflammatory pain is inflammatory pain caused by infection.

8. The application as described in claim 4, wherein the inflammatory condition is acne vulgaris or atherosclerosis.

9. The application as described in claim 4, wherein the acute kidney injury is chemotherapy-induced acute kidney injury.

10. A pharmaceutical composition comprising the compound of claim 1 on a pharmaceutically acceptable carrier, wherein the composition is a solid dispersion.

11. The pharmaceutical composition of claim 10, wherein the composition is a solid dispersion and comprises activated charcoal.

12. The pharmaceutical composition of claim 11, wherein the composition further comprises a polymer selected from polyvinylpyrrolidone and polyvinylpyrrolidone / vinyl acetate copolymer.

13. The pharmaceutical composition of claim 10, wherein the composition is a solid dispersion and is suitable for oral delivery.

14. The pharmaceutical composition of claim 13, wherein the composition is a tablet or capsule.

15. The pharmaceutical composition of claim 10, wherein the compound is of formula [formula missing]. Or its pharmaceutically acceptable salt.

16. A solid dispersion pharmaceutical composition comprising compounds selected from the following formula: Or its pharmaceutically acceptable salt.

17. The solid dispersion pharmaceutical composition of claim 16, wherein the composition comprises activated charcoal.

18. The solid dispersion pharmaceutical composition of claim 17, wherein the composition further comprises a polymer selected from polyvinylpyrrolidone and polyvinylpyrrolidone / vinyl acetate copolymer.

19. The solid dispersion pharmaceutical composition of claim 16, wherein the composition is suitable for oral delivery.

20. The solid dispersion pharmaceutical composition of claim 19, wherein the composition is a tablet or capsule.

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