Anti-inflammatory, anticancer and antiangiogenic compounds, pharmaceutical compositions and methods of making and using the same

Abstract

This application relates to anti-inflammatory, anticancer and anti-angiogenic compounds, pharmaceutical compositions and methods of their preparation and use. Specifically disclosed are compounds of general formula A-D-Y, which have activity in treating diseases associated with inflammation, cancer, neurodegenerative diseases and cardiovascular diseases. Also described are pharmaceutical compositions, methods of their preparation and methods of their use.

Description

[0001] This application is a divisional application of the invention patent application filed on September 28, 2018, with application number 201880077116.1 and entitled "Anti-inflammatory, anti-cancer and anti-angiogenic compounds, pharmaceutical compositions and methods of preparation and use thereof".

[0002] Cross-reference to related applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 564,610, filed on September 28, 2017, the entire contents of which are incorporated herein by reference. Invention Field

[0003] This invention generally relates to compounds of the formula ADY, and methods for preparing and using such compounds as treatments for diseases or conditions. Background of the Invention The global cancer burden is increasing, placing enormous pressure on populations and health systems at all income levels. In May 2017, governments worldwide pledged to further invest in cancer control and make it a public health priority. Every year, tens of millions of people worldwide are diagnosed with cancer, and more than half of these patients eventually die from it. A major reason for the increasing cancer burden is the lack of effective and safe medicines to address this pressing medical need.

[0004] A striking characteristic of cancer cells is their response to chemotherapy by (often rapidly) developing resistance. Ovarian cancer is a prime example. It is a leading cause of death among women with gynecological cancers, causing over 125,000 deaths worldwide each year. Ovarian cancer frequently spreads within the peritoneum; its stage dictates its treatment. Indeed, in 75% of patients, the cancer has spread to the peritoneal cavity (stage III) or further (stage IV) and is treated with surgery plus chemotherapy with platinum and taxanes. The response rate is 80%, but most responders develop resistance (often within 6 months), and subsequent treatment with other agents is rarely successful. The 5-year survival rate for stage III ovarian cancer is 40%, and for stage IV, it is 20%. Survival rates have not changed over the past 20 years.

[0005] Diabetic retinopathy (DR) causes significant vision loss worldwide. The global prevalence of diabetes is projected to increase dramatically over the coming decades, from an estimated 382 million in 2013 to 592 million in 2035. People with diabetes suffer from numerous life-limiting and life-threatening complications, including large vessel-related strokes, ischemic heart disease, and peripheral artery disease and / or microvascular-related retinopathy, neuropathy, and nephropathy. Diabetic retinopathy (DR) is the most common microvascular complication of diabetes. Control of DR remains suboptimal, and currently available injectable eye treatments are expensive, associated with complications, and not optimally effective. DR represents another urgent medical need of global importance.

[0006] Inflammation, a key component of the immune system, plays a role in both defense and pathophysiological events to maintain homeostasis in tissues, organs, and individual cells. Inflammation can be classified as acute or chronic. Acute inflammation is a short-term process characterized by the classic symptoms of inflammation: swelling, redness, pain, fever, and loss of function due to the infiltration of tissues by plasma and leukocytes. This occurs as long as a harmful stimulus is present and ceases once the stimulus is removed. Chronic inflammation is a pathological condition characterized by the simultaneous occurrence of active inflammation, tissue destruction, and attempts at repair. Chronicly inflamed tissues are characterized by the infiltration of mononuclear immune cells (monocytes, macrophages, lymphocytes, and plasma cells), tissue destruction, and attempts at healing, including angiogenesis and fibrosis. Without inflammation, wounds and infections cannot heal, and the progressive destruction of tissues threatens the organism's survival. On the other hand, uncontrolled inflammation can lead to many diseases, such as hay fever, atherosclerosis and other cardiovascular diseases, neurodegenerative diseases such as Alzheimer's disease, cancer, and rheumatoid arthritis. For these reasons, inflammation is strictly controlled by the body. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used anti-inflammatory compounds. Aspirin, a typical NSAID, remains one of the oldest and most widely used drugs in the world. NSAIDs may also prevent cancer, possibly through pleiotropic effects. Invention Overview In one embodiment, the present invention relates to a compound of formula ADY, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In some embodiments, the present invention relates to a compound of formula ADY, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein A is selected from A as defined in Table 1. 1 To A 40 . Table 1

[0007] In one embodiment, the present invention relates to a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein D is selected from D as defined in Table 2. 1 To D 9 In one embodiment, the present invention relates to a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein A is selected from A as defined in Table 1. 1 To A 40 And D is selected from D as defined in Table 2. 1 To D 9 . Table 2 n is an integer between 0 and 12.

[0008] In one embodiment, the present invention relates to a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein Y is selected from Y as defined in Table 3. 1 To Y 7 In one embodiment, the present invention relates to a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein A is selected from A as defined in Table 1. 1 To A 40 And Y is selected from Y as defined in Table 3. 1 To Y 7 In one embodiment, the present invention relates to compounds of formula ADY or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, wherein D is selected from D as defined in Table 2. 1 To D 9 And Y is selected from Y as defined in Table 3. 1 To Y 7 In one embodiment, the present invention relates to a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein A is selected from A as defined in Table 1. 1 To A 40 D is selected from D as defined in Table 2. 1 To D 9 And Y is selected from Y as defined in Table 3. 1 To Y 7 . Table 3 m is an integer between 1 and 12.

[0009] In some embodiments, the present invention relates to compounds of the formula ADY or pharmaceutically acceptable salts, solvates, hydrates, cocrystals or prodrugs thereof, wherein said compounds have anti-inflammatory, anticancer or anti-angiogenic effects.

[0010] In some embodiments, the present invention relates to pharmaceutical compositions comprising compounds of the formula ADY or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. In some embodiments, A is selected from A as defined in Table 1. 1 To A 40 In some implementations, D is selected from D as defined in Table 2. 1 To D 9 In some implementations, Y is selected from Y as defined in Table 3. 1 To Y 7 .

[0011] In one embodiment, the present invention relates to compound 1 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In one embodiment, the present invention relates to a pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0012] In one embodiment, the present invention relates to compound 2 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In another embodiment, the present invention relates to a pharmaceutical composition comprising compound 2 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0013] In one embodiment, the present invention relates to compound 3 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In another embodiment, the present invention relates to a pharmaceutical composition comprising compound 3 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0014] In one embodiment, the present invention relates to compound 4 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In another embodiment, the present invention relates to a pharmaceutical composition comprising compound 4 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0015] In one embodiment, the present invention relates to compound 5 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In another embodiment, the present invention relates to a pharmaceutical composition comprising compound 5 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0016] In one embodiment, the present invention relates to compound 6 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In another embodiment, the present invention relates to a pharmaceutical composition comprising compound 6 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0017] In one embodiment, the present invention relates to compound 7 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In another embodiment, the present invention relates to a pharmaceutical composition comprising compound 7 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0018] In one embodiment, the present invention relates to a method of treating a disease or ailment in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In some embodiments, A is selected from A as defined in Table 1. 1 To A 40 In some implementations, D is selected from D as defined in Table 2. 1 To D 9 In some implementations, Y is selected from Y as defined in Table 3. 1 To Y 7 In some embodiments, the compound or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof is included in a pharmaceutical composition further comprising pharmaceutically acceptable excipients. In some embodiments, the disease or condition is an inflammatory disease or condition, cancer, neurodegenerative disease or condition, cardiovascular disease or condition, eye disease or condition, or angiogenic disease or condition. In some embodiments, the cancer is ovarian cancer, colon cancer, leukemia, gastric cancer, lung cancer, pancreatic cancer, or cancer characterized by a K-Ras mutation. In some embodiments, the cancer is chemoresistant to other therapeutic agents. In some embodiments, treatment comprises inhibiting VEGF expression.

[0019] In some embodiments, the disease or condition is an eye-related disease or condition. The eye consists of the eyeball and its appendages, which include extraocular structures such as the orbit, extraocular muscles, eyelids, eyelashes, conjunctiva, and lacrimal apparatus. The eye and its various structures can be affected by a variety of pathological conditions, including various inflammatory, autoimmune, and metabolic conditions. In some embodiments, the present invention relates to methods for treating various diseases, conditions, and / or conditions of the eye and its related structures, i.e., ophthalmic diseases, conditions, or ailments. In some embodiments, ophthalmic diseases, conditions, or ailments treated by the compounds, compositions, and / or kits of the present invention may include dry eye disease and retinopathy. In some embodiments, retinopathy may include diabetic retinopathy, retinopathy of prematurity, and / or hypertensive retinopathy. In some embodiments, retinopathy may be diabetic retinopathy.

[0020] On the other hand, the present invention relates to compounds of formula ADY as generally described herein and pharmaceutical compositions thereof, which may be used to treat inflammation-related diseases in humans and animals, including but not limited to tumors and cancers; rheumatic diseases such as rheumatoid arthritis and Sjögren's syndrome; cardiovascular diseases such as coronary artery disease, peripheral vascular disease, and hypertension; neurodegenerative diseases such as Alzheimer's disease and its variants or cerebrovascular diseases; autoimmune diseases such as lupus erythematosus; and other conditions characterized by chronic inflammation of organs, such as chronic bronchitis characterized by chronic inflammation of the lungs or chronic sinusitis characterized by chronic inflammation of the sinuses; cardiovascular diseases, such as coronary artery disease, peripheral vascular disease, and hypertension; and various tumors and precancerous diseases, such as benign prostatic hyperplasia, prostate cancer, colonic adenoma and colon cancer, lung cancer, lymphoma, and leukemia. Similarly useful compounds have been described in U.S. Patent No. 8,236,820, the entire contents of which are incorporated herein by reference.

[0021] In one embodiment, the invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, a pharmaceutically acceptable carrier, and one or more solubilizers, such as vitamin E TPGS (d-α-tocopherol polyethylene glycol 1000 succinate), a sugar alcohol (e.g., mannitol), an acid (e.g., boric acid), and a preservative (e.g., polyquad). In some embodiments, after topical application to the eye, such a formulation can be used to deliver a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof to the retina. In some embodiments, such a formulation can be used to deliver an amount sufficient to treat retinopathy (i.e., a therapeutically effective amount) of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof to the retina.

[0022] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising about 0.5% to about 10% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and about 0% to about 25% of vitamin E TPGS (d-α-tocopherol polyethylene glycol 1000 succinate), about 0% to about 10% of mannitol, about 0% to about 10% of boric acid and about 0% to about 1% of polyquad-1.

[0023] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising, by weight, more than 0.5% of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and more than 5% of vitamin E TPGS (d-α-tocopherol polyethylene glycol 1000 succinate), more than 0.5% of mannitol, more than 0.5% of boric acid and more than 0.001% of polyquaternium-1 (polyquad).

[0024] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising less than 10% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, a pharmaceutically acceptable carrier, and less than 25% of vitamin E TPGS (d-α-tocopherol polyethylene glycol 1000 succinate), less than 10% of mannitol, less than 10% of boric acid, and less than 1% of polyquaternium-1 (polyquad).

[0025] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising about 3.5% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, a pharmaceutically acceptable carrier, and about 16% of vitamin E TPGS (d-α-tocopherol polyethylene glycol 1000 succinate), about 3.18% of mannitol, about 1.2% of boric acid, and about 0.005% of one or more of polyquad.

[0026] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, a pharmaceutically acceptable carrier, and one or more of a gelling excipient (e.g., gellan gum or sodium alginate), poloxamer, a solubilizer (e.g., vitamin E TPGS), and cyclodextrin (e.g., (2-hydroxypropyl)-β-cyclodextrin). In some embodiments, such a formulation may allow delivery of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof to the anterior segment of the eye after topical application.

[0027] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and one or more of gellan gum, vitamin E TPGS and (2-hydroxypropyl)-β-cyclodextrin.

[0028] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising about 0.5% to about 10% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and about 0% to about 5% of gellan gum, about 0% to about 20% of vitamin E TPGS and about 0% to about 20% of (2-hydroxypropyl)-β-cyclodextrin.

[0029] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising more than 0.5% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and more than 0.1% of gellan gum, more than 1% of vitamin E TPGS and more than 5% of (2-hydroxypropyl)-β-cyclodextrin.

[0030] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising less than 20% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and less than 5% of gellan gum, less than 20% of vitamin E TPGS, less than 20% of (2-hydroxypropyl)-β-cyclodextrin.

[0031] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising about 2.4% to about 3% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and one or more selected from about 0.5% gellan gum, about 5% vitamin E TPGS, and about 10% (2-hydroxypropyl)-β-cyclodextrin.

[0032] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising about 2.4% to about 3% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and one or more selected from about 0.4% gellan gum, about 10% vitamin E TPGS, and about 5% (2-hydroxypropyl)-β-cyclodextrin.

[0033] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, a pharmaceutically acceptable carrier, and one or more of sodium alginate, vitamin E TPGS, (2-hydroxypropyl)-β-cyclodextrin, Tween (e.g., Tween 80), polyethylene glycol (PEG) (e.g., PEG400), and polyethylene glycol stearate.

[0034] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising about 0.5% to about 10% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and about 0% to about 5% sodium alginate, about 0% to about 20% vitamin E TPGS and about 0% to about 20% (2-hydroxypropyl)-β-cyclodextrin or one or more thereof.

[0035] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising more than 0.5% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and more than 0.1% sodium alginate, more than 1% vitamin E TPGS and more than 5% (2-hydroxypropyl)-β-cyclodextrin.

[0036] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising less than 10% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and less than 5% sodium alginate, less than 20% vitamin E TPGS, and less than 20% (2-hydroxypropyl)-β-cyclodextrin.

[0037] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising about 3% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and one or more of sodium alginate, about 5% vitamin E TPGS, and about 10% (2-hydroxypropyl)-β-cyclodextrin.

[0038] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising about 0.5% to about 10% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and about 0% to about 5% sodium alginate, about 0% to about 25% Tween 80, about 0% to about 20% (2-hydroxypropyl)-β-cyclodextrin, about 0% to about 20% PEG 400 and about 0% to about 10% polyethylene glycol stearate.

[0039] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising, by weight, more than 0.5% of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and more than 1% of sodium alginate, more than 1% of Tween 80, more than 1% of (2-hydroxypropyl)-β-cyclodextrin, more than 1% of PEG400 and more than 1% of polyethylene glycol stearate.

[0040] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising less than 10% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, a pharmaceutically acceptable carrier, and less than 5% sodium alginate, less than 25% Tween 80, less than 20% (2-hydroxypropyl)-β-cyclodextrin, less than 20% PEG 400, and less than 10% polyethylene glycol stearate.

[0041] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising about 3% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and one or more of sodium alginate, about 15% Tween 80, about 10% (2-hydroxypropyl)-β-cyclodextrin, about 10% PEG 400 and about 5% polyethylene glycol stearate.

[0042] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising about 1% to about 5% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and one or more of about 50% to about 90% of (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), about 0.05% to about 1% of cremophor EL (F1) and about 0.5% to about 5% of Tween 80 (F2).

[0043] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising about 1% to about 5% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and about 50% to about 90% of (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) and about 0.05% to about 1% of cremophor EL (F1).

[0044] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising about 1% to about 5% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and about 50% to about 90% of (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) and about 0.5% to about 5% of Tween 80 (F2).

[0045] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising about 3% to about 4% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and one or more of about 80% (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) and about 0.1% cremophor EL (F1).

[0046] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising about 3% to about 4% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and one or more of about 80% (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) and about 1% Tween 80 (F2).

[0047] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising about 1% to about 10% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and one or more of poloxamer 407 and about 1% to about 20% vitamin E TPGS.

[0048] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising more than 1% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and more than 1% of poloxamer 407 and more than 1% of vitamin E TPGS.

[0049] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising less than 10% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and less than 40% of poloxamer 407 and less than 20% of vitamin E TPGS.

[0050] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising about 5.4% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and one or more of about 20% poloxamer 407 and about 12% vitamin E TPGS.

[0051] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising a nanoparticle formulation containing a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a pharmaceutically acceptable carrier. In some embodiments, the nanoparticle formulation may comprise poly(ethylene glycol) (PEG) nanoparticles. In some embodiments, the nanoparticle formulation may comprise methoxylated poly(ethylene glycol)-poly(lactide) (mPEG-PLA) nanoparticles. In some embodiments, such a formulation may allow delivery of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof to the anterior segment of the eye after topical application.

[0052] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising a nanoparticle formulation comprising about 1% to about 5% by weight of a compound of the formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, a pharmaceutically acceptable carrier, and about 90% to about 98% mPEG-PLA.

[0053] In one embodiment, the present invention includes a composition for treating an ophthalmic condition in a patient in need, wherein the ophthalmic condition is selected from dry eye disease and retinopathy, the composition comprising a nanoparticle formulation comprising about 3% to about 3.5% by weight of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, a pharmaceutically acceptable carrier, and about 96.5% to about 97% mPEG-PLA.

[0054] In some implementations, the compound of formula ADY or its pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug is an analgesic.

[0055] In some implementations, the compound of formula ADY or its pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug is an anti-inflammatory agent.

[0056] In some implementations, the compound of formula ADY or its pharmaceutically acceptable salt, solvate, hydrate, eutectic, or prodrug has a reduced risk of corneal melting or does not cause corneal melting when applied to the eye. Brief description of the attached diagram The foregoing overview and the following detailed description of embodiments of the invention will be better understood when read in conjunction with the accompanying drawings.

[0057] Figure 1 The salt of compound 1 is shown. 1 HNMR spectrum.

[0058] Figure 2 MS of the salt of compound 1 is shown.

[0059] Figure 3 The salt of compound 2 is shown. 1 HNMR spectrum.

[0060] Figure 4 MS of the salt of compound 2 is shown.

[0061] Figure 5 The salt of compound 5 is shown. 1 HNMR spectrum.

[0062] Figure 6 MS of the salt of compound 5 is shown.

[0063] Figure 7 Compound 6 is shown. 1 HNMR spectrum.

[0064] Figure 8 MS of compound 6 is shown.

[0065] Figure 9 Images and tumor growth curves of animals treated with compound 5 are shown relative to (vs.) control animals. SKOV-3 cells expressing luciferase were implanted into the peritoneal cavity of nude mice and treated with either compound 5 or the agent. Compound 5 inhibited the growth of intraperitoneal SKOV-3 tumors.

[0066] Figure 10 Tumor growth curves in animals treated with compound 5 are shown relative to control animals. A2780 and HEY were chemosensitive tumors, while A2780cis was resistant to cisplatin, A2780ADR was resistant to doxorubicin (doxorubicin), and HWY-T30 was resistant to paclitaxel. Compound 5 inhibited tumor growth in both chemosensitive and resistant tumors compared to conventional chemotherapeutic agents. Values: mean ± SD.

[0067] Figure 11The mechanism of action of compound 5 against ovarian cancer is shown. The major signal transduction pathway regulated by compound 5 is illustrated. A pointed arrow (→) indicates stimulation; a T-shaped arrow indicates inhibition. (AKT: Ak strain transformation; also known as protein kinase B; ATF4: Activated transcription factor 4; ATF6: Activated transcription factor 6; CHOP: CCAAT-enhancer-binding protein (C / EBP) homolog; COT: Osaka thyroid cancer; ERK: Extracellular signal-regulated kinase; ERS: Endoplasmic reticulum stress response; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase; GCN2: Generalized regulatory repressor protein kinase 2; IRE1α: Inositolase 1α; ISR: Integrated stress response; JNK: c-Jun...) N-terminal kinase; mTOR: mammalian target of rapamycin; MAPK: mitogen-activated protein kinase; MEK: mitogen-activated protein kinase kinase; p-eIF2α: phosphorylated eukaryotic translation initiation factor 2A; PERK: protein kinase RNA (PKR)-like endoplasmic reticulum kinase; PI3K: phosphatidylinositol 3-kinase; Raf: rapidly accelerated fibrosarcoma; Ras: DNA sequence associated with retroviruses; STAT3: signal transducer and transcription activator 3; XBP1: X-box binding protein.

[0068] Figures 12A-12C and Figures 13A-13C This study reveals key findings related to the mechanism of action of compound 5 against ovarian cancer. The research shown here was conducted in SKOV-3 human ovarian cancer cells. Figure 12A Left panel: Compound 5 increased the percentage of cells stained with acridine orange as determined by flow cytometry (4% → 38% after treatment with compound 5) and indicates the induction of autophagy. Right panel: Electron micrographs showing the morphological characteristics of cells undergoing autophagy. Yellow arrows: vacuoles; white arrows: autophagosomes. Figure 12B Transmission electron microscopy confirmed the induction of endoplasmic reticulum (ER) stress by compound 5. N: nucleus; ER: endoplasmic reticulum with visible ribosomes. The left photomicrograph shows a normal ER in a cell treated with the medium (circled). The right photomicrograph shows a greatly expanded ER lumen in a cell treated with compound 5 at 1.5x IC50 (arrow). The latter finding is diagnostic of ER stress. Magnification: 6,800x. Figure 12C Compound 5 inhibits the activation of STAT3, mTOR and JNK by phosphorylation, and also inhibits COT levels.

[0069] Figure 13ACompound 5 induces phosphorylation of eIF2α, confirming an integration stress response. p-eIF2α induces inhibition of 5'-cap-dependent translation initiation of ATF4, as shown below. Figure 13B Compound 5 primarily inhibits 5'-cap-dependent translation initiation. The translation assay (Pierce) TM The levels of the reporter proteins used in the Renilla-Firefly Luciferase Dual Assay Kit (ThermoScientific, Grand Island, NY) were normalized to intracellular FLUC-RLUC transcript levels and expressed as a percentage of untreated control cells. RLU = relative light units. 5'-cap-dependent translation initiation was much less frequent and occurred later. Values: mean ± SEM; *, p < 0.05 and **, p < 0.01, relative to control. Figure 13C Compound 5 activated by phosphorylation of PERK and GCN2 has an IC50 of 1.5x. Internal references: β-actin and GADPH.

[0070] Figure 14 This study illustrates the key mechanistic steps by which compound 6 induces oxidative stress and signal transduction via redox-sensitive pathways in SKOV-3 ovarian cancer cells. (AKT: Ak strain transformation; also known as protein kinase B; ASK1: apoptosis signal-regulated kinase 1; C6: compound 6; JNK: c-Jun N-terminal kinase; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GSH: glutathione; MAPK: mitogen-activated protein kinase; mTOR: mammalian target of rapamycin; NADPH: nicotinamide adenine dinucleotide phosphate; NF-κB: nuclear factor κ light chain enhancer activated in B cells; p38: mitogen-activated protein kinase; Prx1: peroxide reductase 1; Prx-SO3: peroxide reductase-sulfur trioxide; ROS: reactive oxygen species; Trx1: thioredoxin 1; TrxR: thioredoxin reductase; TTFA: thiophenecarboxylic acid trifluoroacetone) Figures 15A-15E This study reveals key findings related to the mechanism of action of compound 6 against ovarian cancer. The research shown here was conducted in SKOV-3 human ovarian cancer cells. Figure 15A Using flow cytometry and the MitoSox Red molecular probe, strong induction of mitochondrial superoxide anion was detected. TTFA (mitochondrial ROS blocker) reversed the effect of compound 6 (C6). Figure 15B In cells treated for 3 hours, compound 6 inhibited the level of GSH (the major cytoplasmic chemical antioxidant) (*p<0.01). Figure 15CLevels of Prx-1 and Prx-SO3 in cells treated with compound 6 for 24 hours (immunoblotting). Figure 15D After 1 hour of treatment, compound 6 inhibited the enzyme activity of TrxR in a concentration-dependent manner (*p<0.01). Figure 15E As shown, with or without DTT 1 mM for 30 minutes, cell protein lysates were treated with compound 6 for 1 h and then subjected to immunoprecipitation (IP) and Western blot (IB). Internal reference: Trx-1.

[0071] Figure 16A Compound 6 inhibited the activation of NF-κB-DNA in the nuclear fraction of cells as determined by electrophoretic mobility shift assay. To determine the specificity of the NF-κB transcription factor-DNA complex, control nuclear fractions were incubated in a 100-fold molar excess of unlabeled oligonucleotides containing a common sequence targeting specific (+NF-κB) or non-specific (+AP-1) transcription factors. Figure 16B As indicated, MAPK activation of the response compound 6 was determined by immunoblotting cell lysates. Figure 16C As indicated, AKT and mTOR activation of compound 6 was determined by immunoblotting cell lysates.

[0072] Figure 17 The synergistic effect between compound 5 and cyclophosphamide (CPA) in inhibiting paclitaxel-resistant human ovarian cancer cell (HEY-T30) xenografts was demonstrated. Animals treated with one or both compounds responded similarly to compounds 5 and CPA at the doses used. Their combination produced a tumor-suppressive effect greater than the sum of the effects of the individual drugs used alone, i.e., synergistic inhibition.

[0073] Figure 18 shows the effects of compounds 5 and 6 on K-Ras. Figure 18A Compound 6 inhibits K-Ras activation. At various time points, compound 6 showed an IC50 concentration of 1.5x. 50 Cells with mutant K-Ras were treated. K-Ras activity was determined by Ras pull-down (Thermo Scientific; follow the supplier’s instructions). K-Ras activation was inhibited by 37% at 1 hour and by 88% at 2 hours, compared to their respective controls. Figure 18BCompound 5 inhibited palmitoylation of Ras in A2780 and A2780cis (cisplatin-resistant) ovarian cancer cells. Palmitoylation was detected using a commercial kit (Badrilla, Leeds, UK) by removing the S-palmitate group from the protein, generating a new free thiol group (at the site of the former palmitic acid group), and capturing the previously S-palmitoylated protein on resin. Ras was detected in the eluent by immunoblotting.

[0074] Figure 19 shows how compound 6 normalizes the retinal vascular system in an oxygen-induced mouse model of retinopathy. Figure 19A Under oxygen-induced retinopathy conditions, retinal patches from C57Bl / 6 mice at day 17 (P17) were stained with isolectin B4 to mark the vascular system. Mice treated with the medium (left) show a central avascular region (blue arrow) and peripheral neovascularization (red arrow). Compound 6 (right) normalized both. Figure 19B : The quantification of avascular and neovascular regions of the retina, expressed as a percentage of the total retinal surface area.

[0075] Figure 20 The effect of compound 6 on angiogenesis is illustrated. Compound 6 was applied at various concentrations to appropriate extracellular matrix supports containing cultured HUVEC human endothelial cells to form capillary-like structures (also known as tubes). Images of the chorioallantoic membrane show that treatment with compound 6 (placed in a sponge at the center of each image, from which it is slowly released into the surrounding tissue) significantly inhibited the formation of new blood vessels, while the already formed major vessels remained unchanged.

[0076] Figure 21 shows that compound 2 normalizes the retinal vascular system in a mouse model of oxygen-induced retinopathy. Figure 21A Under oxygen-induced retinopathy conditions, retinal patches from C57Bl / 6 mice on day 17 were stained with isolectin B4 to mark the vascular system. Mice treated with the medium (left) show a central avascular region (blue arrow) and surrounding neovascularization (red arrow). Compound 2 (right) normalized both. Figure 21B Quantification of avascular and neovascular regions of the retina, expressed as a percentage of the total retinal surface area (n = 8 / group). Values ​​are mean ± SEM. Compared with the medium, ***, p < 0.0001; **, p < 0.029.

[0077] Although the accompanying drawings illustrated above depict the embodiments of the present disclosure, other embodiments are also contemplated as noted in the discussion. This disclosure shows illustrative embodiments by way of example rather than limitation. Many other modifications and embodiments can be devised by those skilled in the art, all falling within the scope and spirit of the principles of the embodiments of the present disclosure. Invention Details Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications mentioned herein are incorporated herein by reference in their entirety.

[0078] definition As used herein, the terms “administer”, “administration”, or “administering” mean (1) being provided, given, administered, and / or prescribed by a health practitioner or their authorized agency or on his or her instructions, and / or (2) being placed, ingested, or consumed by an object such as a mammal (including a human) in accordance with the present disclosure.

[0079] As used herein, the terms “co-administration,” “co-administering,” “administered in combination with,” “administered in combination with,” “simultaneously,” and “concurrently” cover the application of two or more active pharmaceutical ingredients to a subject, such that the two active pharmaceutical ingredients and / or their metabolites are simultaneously present in the subject. Co-administration includes simultaneous administration in separate compositions, administration in separate compositions at different times, or administration in a composition in which two or more active pharmaceutical ingredients are present. In some embodiments, simultaneous administration in separate compositions and administration in compositions in which both agents are present are preferred.

[0080] The terms “active pharmaceutical ingredient” and “medicine” include compounds of formula ADY, including but not limited to all instances described herein.

[0081] The term "isostere" refers to a group or molecule whose chemical and / or physical properties are similar to those of another group or molecule. "Bioisostere" is a type of isostere that refers to a group or molecule whose biological properties are similar to those of another group or molecule. For example, for compounds of formula ADY described herein, a carboxylic acid may be replaced by one of the following carboxylic acid bioisosteres, including but not limited to, alkyl esters (COOR), acylsulfonamides (CONR-SO2R), isohydroxyoxime acids (CONR-OH), isohydroxyoxime esters (CONR-OR), tetrazolium, hydroxyisoxazole, isoxazol-3-one, and sulfonamides (SO2NR), wherein each R may independently represent hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl, or heteroarylalkyl.

[0082] The term "body" refers to events that occur within the body of an object.

[0083] The term "in vitro" refers to events that occur outside the body of the subject. In vitro assays include cell-based assays that use live or dead cells, and may also include cell-free assays that do not use intact cells.

[0084] The term "effective amount" or "therapeutic effective amount" refers to an amount of a compound or combination of compounds as described herein that is sufficient to achieve the intended application (including, but not limited to, the treatment of a disease). Therapeutic effective amounts can vary depending on the intended application (in vitro or in vivo) or the subject and the disease condition being treated (e.g., the subject's weight, age, and sex), the severity of the disease condition, the method of administration, etc., which can be readily determined by those skilled in the art. The term also applies to doses that will induce a specific response (e.g., reduced platelet adhesion and / or cell migration) in target cells. Specific doses will vary depending on the particular compound selected, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

[0085] As used herein, the term "therapeutic effect" encompasses therapeutic benefits and / or preventive benefits. Preventive effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, preventing its recurrence, or any combination thereof.

[0086] As used herein, the terms “treat,” “treatment,” and / or “treating” can refer to the management of a disease, condition, pathological condition, or its symptoms that aims to cure, improve, stabilize, and / or control the disease, condition, or pathological condition. Regarding the control of a disease, condition, or pathological condition, more specifically, “control” can include the absence of disease progression, as assessed by a response to the methods described herein, where such a response can be complete (e.g., disease remission) or partial (e.g., reduction or improvement of any symptoms associated with the condition). As used herein, the terms “prevent,” “preventing,” and / or “prevention” can refer to reducing the risk of developing a disease, condition, or pathological condition.

[0087] As used herein, the terms “modulate” and “modulation” refer to alterations in the biological activity of biomolecules (e.g., proteins, genes, peptides, antibodies, etc.), where such alterations may involve an increase in the biological activity of the biomolecule (e.g., increased activity, agonism, activation, expression, upregulation, and / or increased expression) or a decrease in the biological activity (e.g., decreased activity, antagonism, inhibition, inactivation, downregulation, and / or decreased expression). Without being limited to any particular theory, the compounds described herein can, for example, regulate (i.e., inhibit) VEGF expression and / or K-Ras expression.

[0088] The terms "QD", "qd", or "qd" mean once a day, once daily, or once daily. The terms "BID", "bid", or "bid" mean twice a day, twice daily, or twice daily. The terms "TID", "tid", or "tid" mean three times a day, three times daily, or three times daily. The terms "QID", "qid", or "qid" mean four times a day, four times daily, or four times daily.

[0089] The term "pharmaceutically acceptable salt" refers to a salt derived from a variety of organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can form with both inorganic and organic acids. Preferred inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Preferred organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, acetic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can form with both inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts. The term "cocrystal" refers to a molecular complex derived from many cocrystal forming agents known in the art. Unlike salts, cocrystals generally do not involve hydrogen transfer between the cocrystal and the drug, but rather involve intermolecular interactions between the cocrystal forming agent and the drug within the crystal structure, such as hydrogen bonding, aromatic ring stacking, or dispersion forces.

[0090] The terms "pharmaceutically acceptable carrier," "pharmaceuticalally acceptable excipient," or "physiologically compatible" carrier or carrier medium are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption-delaying agents, and inert components. The use of such pharmaceutically acceptable carriers or excipients for the active pharmaceutical ingredient is well known in the art. Unless any conventional pharmaceutically acceptable carrier or excipient is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the present invention may be considered. Additional active pharmaceutical ingredients, such as other drugs, may also be incorporated into the described compositions and methods.

[0091] "Prodrug" refers to a derivative of the compound described herein whose pharmacological action is achieved through conversion into the active compound via in vivo chemical or metabolic processes. Prodrugs include compounds in which an amino acid residue or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is covalently linked via an amide or ester bond to a free amino, hydroxyl, or carboxylic acid group of the formula ADY. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids typically represented by one or three letter symbols, but also include, for example, 4-hydroxyproline, hydroxylysine, desmodium, isodesmodium, 3-methylhistidine, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Other types of prodrugs are also included. For example, the free carboxyl group can be derived into an amide or alkyl ester (e.g., methyl ester and acetoxymethyl ester). Prodrug esters as used herein include esters and carbonates, which are formed by reacting one or more hydroxyl groups of a compound of the method of the present invention with an acylating agent that is substituted with an alkyl, alkoxy, or aryl group using a procedure known to those skilled in the art to produce acetates, neopentyl esters, methyl carbonates, benzoates, etc. As another example, the free hydroxyl group can be derivatized using groups including, but not limited to, hemisuccinates, phosphates, dimethylaminoacetate, and phosphoryloxymethyloxycarbonyl groups, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs containing hydroxyl and amino groups are also included, as well as carbonate prodrugs, sulfonate prodrugs, sulfonates, and sulfates containing hydroxyl groups. Free amines can also be derivatized into amides, sulfonamides, or phosphoramides. All said prodrug moieties can incorporate groups including, but not limited to, ether, amine, and carboxylic acid functional groups. Furthermore, any compound that can be converted in vivo to provide a bioactive agent (e.g., a compound of formula ADY) is a prodrug within the scope of this invention. Various forms of prodrugs are well known in the art. A comprehensive description of prodrugs and prodrug derivatives can be found in: (a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., (Academic Press, 1996); (b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); and (c) A Textbook of Drug Design and Development, edited by P. Krogsgaard-Larson and H. Bundgaard, (Harwood Academic Publishers, 1991).Typically, prodrugs can be designed to improve drug permeability across biological membranes, thereby achieving improved drug absorption, prolonged drug duration of action (slow release of the parent drug from the prodrug, reduced first-pass metabolism), targeted drug action (e.g., targeting organs or tumors, targeting lymphocytes), modification or improvement of drug water solubility (e.g., intravenous formulations and eye drops), improved local drug delivery (e.g., skin and ocular drug delivery), improved chemical / enzymatic stability of the drug, or reduced off-target drug effects, and more generally, to improve the therapeutic efficacy of the compounds used in this invention.

[0092] Unless otherwise stated, the chemical structures described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, one or more hydrogen atoms may be replaced by deuterium or tritium, or one or more carbon atoms may be... 13 C-enrichment or 14 C-enriched carbon-substituted compounds are within the scope of this invention.

[0093] When ranges are used herein to describe physical or chemical properties such as molecular weight or chemical formula, it is intended to include all combinations and sub-combinations of ranges, as well as specific embodiments thereof. When referring to numerical values ​​or ranges, the term “about” means that the value or range referred to is an approximation within experimental variability (or within statistical experimental error), and therefore the value or range may vary. Such variations are typically 0% to 15%, 0% to 10%, 0% to 5%, etc., of the value or range.

[0094] As used herein, the term “about” means that quantities, sizes, formulations, parameters, shapes, and other quantities and characteristics are not and need not be precise, but may be approximately and / or larger or smaller as required, reflecting tolerances, conversion factors, rounding, measurement errors, and other factors known to those skilled in the art. Generally, whether explicitly stated or not, quantities, sizes, formulations, parameters, shapes, or other quantities or characteristics are “about” or “approximate”.

[0095] When used in the appended claims in both the original and modified forms, the transitional terms “comprising,” “substantially consisting of,” and “consisting of” define the scope of the claims, excluding any additional claim elements or steps (if any) not stated. The term “comprising” is intended to be inclusive or open-ended and does not exclude any additional, unstated elements, methods, steps, or materials. The term “consisting of” excludes any element, step, or material other than those specified in the claim, and in the latter case, excludes common impurities associated with the element, step, or material specified in the claim. The phrase “substantially consisting of” limits the scope of the claims to the specified elements, steps, or materials and those that do not substantially affect the essential and novel features of the claimed invention. In alternative embodiments, all compounds, compositions, formulations, and methods embodying the invention described herein may be more specifically defined by any of the transitional terms “comprising,” “substantially consisting of,” and “consisting of.” The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) includes embodiments such as, for example, any material composition, method or process embodiment that is “composed of the described features” or “substantially composed of the described features”.

[0096] "alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without unsaturation, and having one to ten carbon atoms (e.g., (C10, ... 1-10 )alkyl or C 1-10Alkyl groups. Wherever they appear in this document, numerical ranges such as “1 to 10” refer to each integer within a given range; for example, “1 to 10 carbon atoms” means that an alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the definition is also intended to cover the presence of the term “alkyl” where no specific numerical range is specified. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl. The alkyl moiety can be linked to the rest of the molecule by a single bond, such as, for example, methyl (Me), ethyl (Et), n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), and 3-methylhexyl. Unless otherwise specified in the specification, the alkyl group is optionally substituted with one or more substituents, which are independently heteroalkyl, acylsulfonamide, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -S(O) t R a -(where t is 1 or 2), -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3 (R a )2, where each R aIt can be hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0097] "alkylaryl" refers to a -(alkyl)aryl group, wherein the aryl and alkyl groups are as disclosed herein, and are optionally substituted by one or more substituents that are respectively described as aryl and alkyl substituents.

[0098] "alkylhetaryl" refers to a -(alkyl)hetaryl group, wherein the heteroaryl and alkyl groups are as disclosed herein, and are optionally substituted by one or more substituents described respectively as aryl and alkyl.

[0099] "alkyl heterocyclic alkyl" refers to a -(alkyl)heterocyclic group, wherein the alkyl and heterocyclic alkyl are as disclosed herein, and are optionally substituted by one or more substituents described respectively as heterocyclic alkyl and alkyl.

[0100] The "olefin" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and the "alkyne" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, can be branched, straight-chain, or cyclic.

[0101] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one double bond, and having two to ten carbon atoms (i.e., C2O4 ... 2-10 alkenyl or C 2-10 Alkenyl). Whenever it appears herein, numerical ranges such as “2 to 10” refer to each integer within a given range—for example, “2 to 10 carbon atoms” means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkenyl moiety can be linked to the rest of the molecule by a single bond, such as, for example, ethylene (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, and pent-1,4-dienyl. Unless otherwise specifically stated in the specification, the alkenyl group is optionally substituted with one or more substituents, which are independently alkyl, heteroalkyl, acylsulfonamide, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, isohydroxyoxime, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -S(O) t R a -(where t is 1 or 2), -OC(O)-R a -N(R)a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3 (R a )2, where each R a It can be hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0102] "Alkenyl-cycloalkyl" refers to a -(alkenyl)cycloalkyl group, wherein the alkenyl and cycloalkyl groups are as disclosed herein, and are optionally substituted by one or more substituents described respectively as alkenyl and cycloalkyl groups.

[0103] "Alkyne" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one triple bond, and having two to ten carbon atoms (i.e., C2O4 ... 2-10 ) acetylene or C 2-10 (Alynyl group). Wherever it appears herein, numerical ranges such as "2 to 10" refer to every integer within a given range; for example, "2 to 10 carbon atoms" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkynyl group can be linked to the rest of the molecule via a single bond, such as ethynyl, propynyl, butynyl, pentylyl, and hexynyl. Unless otherwise specifically stated in the specification, the alkynyl group is optionally substituted with one or more substituents, which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, isohydroxyoxime, acylsulfonamide, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SRa -S(O) t R a -(where t is 1 or 2), -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3 (R a )2, where each R a It can be hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0104] "Alynyl-cycloalkyl" refers to a -(alkynyl)cycloalkyl group, wherein the alkynyl and cycloalkyl groups are as disclosed herein, and are optionally substituted by one or more substituents described as suitable substituents of the alkynyl and cycloalkyl groups, respectively.

[0105] "Acylsulfonamide" refers to the group -C(=O)NR a -S(=O)R a , where each R a It can be hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0106] "Formaldehyde" refers to the -(C=O)H group.

[0107] "Carbonyl" refers to the group -C(=O)-. The carbonyl group can be substituted with the following exemplary substituents: alkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, isohydroxyoxime ester, acylsulfonamide, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -S(O) t R a -(where t is 1 or 2), -OC(O)-R a -N(R) a )2、-C(O)R a -N(R) a )-OR a -、-C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3 (R a )2, where each R a It can be hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0108] "Carboxyl group" refers to the -(C=O)OH group.

[0109] “Cyano” refers to the -CN group.

[0110] "Cycloalkyl" refers to a monocyclic or polycyclic group containing only carbon and hydrogen, and may be saturated or partially unsaturated. Cycloalkyl groups include groups having 3 to 10 ring atoms (i.e., C1, C2, C3, C4, C5, C6, C7, C83-10 )cycloalkyl or C 3-10(Cycloalkyl). Wherever it appears herein, numerical ranges such as “3 to 10” refer to each integer within a given range; for example, “3 to 10 carbon atoms” means that a cycloalkyl group can consist of 3 carbon atoms, up to and including 10 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, etc. Unless otherwise specifically stated in the specification, cycloalkyl groups are optionally substituted with one or more substituents, which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, acylsulfonamide, heterocycloalkyl, isohydroxyoxime, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -S(O) t R a -(where t is 1 or 2), -S(O) t R a -(where t is 1 or 2), -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3 (R a )2, where each R a It can be hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0111] "Cycloalkyl-alkenyl" refers to a -(cycloalkyl)alkenyl group, wherein the cycloalkyl and alkenyl groups are as disclosed herein, and are optionally substituted by one or more substituents described respectively as cycloalkyl and alkenyl groups.

[0112] "Cycloalkyl-heterocycloalkyl" refers to a -(cycloalkyl)heterocycloalkyl group, wherein the cycloalkyl and heterocycloalkyl are as disclosed herein, and are optionally substituted by one or more substituents described respectively as suitable substituents of the cycloalkyl and heterocycloalkyl groups.

[0113] "Cycloalkyl-heteroaryl" refers to a -(cycloalkyl)heteroaryl group, wherein the cycloalkyl and heteroaryl groups are as disclosed herein, and are optionally substituted by one or more substituents described respectively as cycloalkyl and heteroaryl groups.

[0114] The term "alkoxy" refers to a straight-chain, branched, cyclic, or combined group consisting of 1 to 8 carbon atoms connected to a parent structure via oxygen. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, and cyclohexyloxy. "Lower alkoxy" refers to an alkoxy group containing one to six carbon atoms.

[0115] The term "substituted alkoxy" refers to an alkoxy group in which the alkyl component is substituted (i.e., -O-(substituted alkyl)). Unless otherwise specifically stated in the specification, the alkyl portion of the alkoxy group is optionally substituted by one or more substituents, which are independently: alkyl, heteroalkyl, alkenyl, acylsulfonamide, alkynyl, cycloalkyl, heterocycloalkyl, isohydroxyoxime, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -S(O) t R a -(where t is 1 or 2), -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(Ra S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3 (R a )2, where each R a It can be hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0116] The term "alkoxycarbonyl" refers to a group of the formula (alkoxy) (C=O)- linked by a carbonyl carbon, wherein the alkoxy group has a specified number of carbon atoms. Therefore, (C... 1-6 An alkoxycarbonyl group is an alkoxy group having 1 to 6 carbon atoms, in which its oxygen atom is attached to a carbonyl linker. "Lower alkoxycarbonyl" refers to an alkoxycarbonyl group in which the alkoxy group is a lower alkoxy group.

[0117] The term "substituted alkoxycarbonyl" refers to a group (substituted alkyl) -OC(O)-, wherein the group is linked to the parent structure via a carbonyl functional group. Unless otherwise specified in the specification, the alkyl group of the alkoxycarbonyl is optionally substituted with one or more substituents, which are independently: alkyl, heteroalkyl, acylsulfonamide, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, isohydroxyoxime, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -S(O) t R a -(where t is 1 or 2), -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(R aS(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3 (R a )2, where each R a It can be hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0118] "Acyl" refers to the groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C(O)-, and (heterocyclic alkyl)-C(O)-, wherein the groups are linked to the parent structure via a carbonyl functional group. If the R group is a heteroaryl or heterocyclic alkyl, the heterocyclic or chain atoms contribute to the total number of chain or ring atoms. Unless otherwise specified in the specification, the alkyl, aryl, or heteroaryl portion of the acyl group is optionally substituted with one or more substituents, which are independently alkyl, heteroalkyl, acylsulfonamide, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, isohydroxyoxime ester, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -S(O) t R a -(where t is 1 or 2), -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O)t N(R a )2 (where t is 1 or 2) or PO3 (R a )2, where each R a It can be hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0119] "Acyloxy group" refers to an R(C=O)O- group, where R is an alkyl, aryl, heteroaryl, heteroalkyl, or heterocyclic alkyl group as described herein. If the R group is a heteroaryl or heterocyclic alkyl group, the heterocyclic or chain atom contributes to the total number of chain or ring atoms. Unless otherwise specifically stated in the specification, the R of the acyloxy group is optionally substituted with one or more substituents, which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, isohydroxyoxime ester, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -S(O) t R a -(where t is 1 or 2), -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3 (R a )2, where each R a It can be hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0120] "Amino" or "amine" refers to -N(R) a )2 groups, wherein each R a Independently, it is hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl, or heteroarylalkyl, unless otherwise specified in the specification. When -N(R a The )2 group has two R groups other than hydrogen. a When substituents are present, they can combine with nitrogen atoms to form 4-, 5-, 6-, or 7-membered rings. For example, -N(R a )2 is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Unless otherwise specifically stated in the specification, the amino group may optionally be substituted with one or more substituents, which are independently: alkyl, acylsulfonamide, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, isohydroxyoxime ester, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -S(O) t R a -(where t is 1 or 2), -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3 (R a )2, where each R a It can be hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0121] The term "substituted amino" also refers to the respective groups as described above -NHR d and NR d R d N-oxides. N-oxides can be prepared by treating the corresponding amino groups with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.

[0122] "Amide" or "amide group" refers to a group with the formula -C(O)NR a R b or -NR a C(O)R b The chemical part, in which R a and R b The moiety is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (by cyclic carbon bonding), and heterocyclic (by cyclic carbon bonding), and each moiety may optionally be substituted. -C(O)NR a R b R of amide a and R b The amides may optionally form 4-, 5-, 6-, or 7-membered rings together with the nitrogen to which they are attached. Unless otherwise specifically stated in the specification, the amide group may optionally be independently substituted by one or more substituents as described herein for alkyl, amino, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl groups. The amide may be an amino acid or peptide molecule linked to a compound disclosed herein, thereby forming a prodrug. Procedures and specific groups for preparing such amides are known to those skilled in the art and can be readily described in publications such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd The entire contents of Ed., John Wiley & Sons, New York, NY, 1999, are incorporated herein by reference.

[0123] "Aromatic" or "aryl" or "Ar" refers to an aromatic group having six to ten ring atoms (e.g., C6-C). 10 Aroma or C6-C 10Aryl groups (e.g., phenyl, fluorenyl, and naphthyl) have at least one carbon ring with a conjugated π-electron system. Divalent groups formed from substituted benzene derivatives and having free valences on the ring atoms are called substituted phenylene groups. Divalent groups derived from monovalent polycyclic hydrocarbon groups whose names end in "-yl" by removing a hydrogen atom from a carbon atom with a free valence are named by adding "-idene" to the name of the corresponding monovalent group; for example, naphthyl with two bonding points is called naphthylene. Wherever it appears herein, numerical ranges such as "6 to 10" refer to each integer within a given range; for example, "6 to 10 ring atoms" means that an aryl group can consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. The terminology includes monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of ring atoms) groups. Unless otherwise specifically stated in the specification, the aryl moiety is optionally substituted with one or more substituents, which are independently alkyl, heteroalkyl, acylsulfonamide, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, isohydroxyoxime, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -S(O) t R a -(where t is 1 or 2), -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3 (R a )2, where each R aIt can be hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0124] "Arylalkyl" or "arylalkyl" refers to an (aryl)alkyl group, wherein the aryl and alkyl groups are as disclosed herein, and are optionally substituted by one or more substituents that are respectively described as aryl and alkyl substituents.

[0125] "Ester" refers to a chemical group of the formula -COOR, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (by cyclic carbon bonding), and heterocyclic (by cyclic carbon bonding). Procedures for preparing esters and the specific groups involved are known to those skilled in the art and can be readily described in works such as Greene and Wuts, *Protective Groups in Organic Synthesis*, 3... rd Ed., John Wiley & Sons, New York, NY, 1999. The entire contents of this article are incorporated herein by reference. Unless otherwise specifically stated in the specification, the ester group may optionally be substituted with one or more substituents, which are independently: alkyl, acylsulfonamide, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, isohydroxyoxime, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, -OR a -SR a -S(O) t R a -(where t is 1 or 2), -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t OR a(where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3 (R a )2, where each R a It can be hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0126] "Fluoroalkyl" refers to an alkyl group as defined above that is substituted with one or more fluorine groups as defined above, such as trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. The alkyl portion of a fluoroalkyl group may be optionally substituted as defined above for alkyl groups.

[0127] The terms “halogenated,” “halide,” or alternatively “halogen” are intended to mean fluorinated, chlorinated, brominated, or iodinated. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl,” and “haloalkoxy” include alkyl, alkenyl, alkynyl, and alkoxy structures substituted with one or more halogenated groups or combinations thereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” respectively include halogenated alkyl and haloalkoxy groups, wherein the halogenation is fluorination.

[0128] "Heteroalkyl," "heteroalkenyl," and "heteroynyl" refer to optionally substituted alkyl, alkenyl, and ynyl groups having one or more skeletal chain atoms selected from atoms other than carbon (e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof). Numerical ranges may be given, such as C1-C4 heteroalkyl, referring to the total chain length, which is 4 atoms in the example. Heteroalkyl groups may be substituted with one or more substituents, which are independently: alkyl, heteroalkyl, alkenyl, ynylsulfonamide, cycloalkyl, heterocycloalkyl, isohydroxyoxime, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, nitro, oxo, thioxo, trimethylsilyl, -OR a -SR a -S(O) t R a -(where t is 1 or 2), -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a)C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3 (R a )2, where each R a It can be hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0129] "Heteroalkylaryl" refers to a -(heteroalkyl)aryl group, wherein the heteroalkyl and aryl groups are as disclosed herein, and are optionally substituted by one or more substituents described respectively as heteroalkyl and aryl groups.

[0130] "Heteroalkylheteroaryl" refers to a -(heteroalkyl)heteroaryl group, wherein the heteroalkyl and heteroaryl groups are as disclosed herein, and are optionally substituted by one or more substituents described respectively as heteroalkyl and heteroaryl groups.

[0131] "Heteroalkylheterocyclic alkyl" refers to a -(heteroalkyl)heterocyclic alkyl group, wherein the heteroalkyl and heterocyclic alkyl are as disclosed herein, and are optionally substituted by one or more substituents that are respectively described as heteroalkyl and heterocyclic alkyl.

[0132] "Heteroalkylcycloalkyl" refers to a -(heteroalkyl)cycloalkyl group, wherein the heteroalkyl and cycloalkyl are as disclosed herein, and are optionally substituted by one or more substituents described respectively as heteroalkyl and cycloalkyl.

[0133] "Heteroaryl" or "heteroary group" or "HetAr" refers to 5- to 18-benzyl aryl groups (e.g., C5-C6). 13A heteroaryl group comprises one or more cyclic heteroatoms selected from nitrogen, oxygen, and sulfur, and can be a monocyclic, bicyclic, tricyclic, or tetracyclic system. Wherever it appears herein, numerical ranges such as “5 to 18” refer to each integer within a given range; for example, “5 to 18 ring atoms” means that a heteroaryl group can consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. A divalent group derived from a monovalent heteroaryl group whose name ends with “-aryl” by removing a hydrogen atom from an atom with a free valence is named by adding “-pyridyl” to the name of the corresponding monovalent group; for example, a pyridyl group with two connection points is a pyridylene group. The N-containing “heteroaryl” or “heteroaryl” part refers to an aromatic group in which at least one skeletal atom of the ring is a nitrogen atom. Polycyclic heteroaryl groups can be fused or unfused. The heteroatoms in a heteroaryl group are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. Heteroaryl groups can be attached to the rest of the molecule via any atom of the ring. Examples of heteroaryl groups include, but are not limited to, aza-aryl groups. 1,3-benzodioxane-1, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzo[b][1,4]dioxane Benz[b][1,4]oxazinyl, 1,4-benzodioxane, benzonaphthylfuranyl, benzooxazolyl, benzodioxacyclopentenyl, benzodioxacyclohexenyl, benzooxazolyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzofuranyl, benzothiazolyl, benzothienyl (benzothienyl) othiophenyl), benzothiophene[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenolinyl, cyclopentadien[d]pyrimidinyl, 6,7-dihydro-5H-cyclopentadien[4,5]thiophene[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrophenyl [h]-Pyrolinyl, 6,7-dihydro-5H-benzo[6,7]cycloheptatrien[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanoneyl, furan[3,2-c]pyridyl, 5,6,7,8,9,10-hexahydrocyclooctatetraen[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctatetraen[d]pyridazinyl 5,6,7,8,9,10-hexahydrocyclooctatetraen[d]pyridyl, isothiazolyl, imidazolyl, indazole, indole, indazole, isoindole, indolinyl, isoindolinyl, isoquinolinyl, indazinyl, isoxazolyl, isoxazol-3-one, 5,8-methylbridged-5,6,7,8-tetrahydroquinazolinyl, naphridyl, 1,6-naphridinone, oxadiazolyl, 2-oxoazapyridine alkyl, oxazolyl, ethylene oxide, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purine, pyranyl, pyrroleyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyridine [3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroloyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cycloheptatrien[4,5]thieno[2, [3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiaranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated in the specification, the heteroaryl moiety is optionally substituted by one or more substituents, which are independently: alkyl, acylsulfonamide, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, isohydroxyoxime, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, nitro, oxo, thiocarbonyl, trimethylsilyl, -OR a -SR a -S(O) t R a -(where t is 1 or 2), -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O)t N(R a )2 (where t is 1 or 2) or PO3 (R a )2, where each R a It can be hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0134] Substituted heteroaryl groups also include ring systems substituted with one or more oxidized (-O-) substituents, such as pyridyl N-oxides.

[0135] "Heteroarylalkyl" refers to a portion having an aryl moiety as described herein and a alkylene moiety as described herein, wherein the connection to the rest of the molecule is via the alkylene moiety.

[0136] "Heterocyclic alkyl" refers to a stable 3- to 18-membered non-aromatic cyclic group containing two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Whenever it appears herein, numerical ranges such as "3 to 18" refer to each integer within a given range; for example, "3 to 18 ring atoms" means that a heterocyclic alkyl group can consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. Unless otherwise specified in the specification, a heterocyclic alkyl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocyclic alkyl group may optionally be oxidized. If present, one or more nitrogen atoms may optionally be quaternized. The heterocyclic alkyl group is partially or fully saturated. A heterocyclic alkyl group can be attached to the remainder of the molecule by any atom of the ring. Examples of such heterocyclic alkyl groups include, but are not limited to, dioxacyclopentyl, thieno[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolinyl, isoxazolinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolinyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolyl, pyrazolyl, quininecycloyl, thiazolinyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specified in the specification, the heterocyclic alkyl portion is optionally substituted with one or more substituents, which are independently: alkyl, acylsulfonamide, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, isohydroxyoxime, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyl, halogen, cyano, nitro, oxo, thiocarbonyl, trimethylsilyl, -OR a -SR a -S(O) t Ra -(where t is 1 or 2), -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -OC(O)N(R) a )2、-C(O)N(R a )2、-N(R a )C(O)OR a -N(R) a )C(O)R a -N(R) a )C(O)N(R a )2、N(R a )C(NR a )N(R a )2、-N(R a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t N(R a )2 (where t is 1 or 2) or PO3 (R a )2, where each R a It can be hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0137] "Heterocyclic alkyl" also includes bicyclic systems in which one non-aromatic ring (typically having 3 to 7 ring atoms) contains at least 2 carbon atoms in addition to 1 to 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and combinations containing at least one of the aforementioned heteroatoms, and the other ring (typically having 3 to 7 ring atoms) optionally contains 1 to 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and is not aromatic.

[0138] "Isohydroxyoxime ester" refers to -C(O)NR a OR a Part, where each R a It can be hydrogen, alkyl, fluoroalkyl, carbocyclic, carbocyclic alkyl, aryl, arylalkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl.

[0139] "Nitro" refers to the -NO2 group.

[0140] "O-" refers to the -O- group.

[0141] "Oxo" refers to the =O group.

[0142] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the spatial arrangement of their atoms, i.e., they have different stereochemical configurations. "Enantiomers" are a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the term "(±)" is used to denote racemic mixtures. "Diadiaomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry of each chiral carbon can be specified by (R) or (S). A resolved compound with an unknown absolute configuration can be indicated as (+) or (-) according to the direction (dextrorotatory or levorotatory) of its plane-polarized light at the wavelength of the sodium D line. Some of the compounds described herein contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers, and other stereoisomers that can be defined as (R) or (S) according to absolute stereochemistry. The chemical entities, pharmaceutical compositions, and methods of the present invention are intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0143] As used herein, “enantiomer purity” refers to the relative amount of a particular enantiomer present relative to other enantiomers, expressed as a percentage. For example, if the compound is present in a racemic mixture other than a compound that may potentially have (R)- or (S)- isomer configurations, the enantiomer purity is about 50% for the (R)- or (S)- isomer. If the compound has one isomer form preferred over the other, for example, 80% (S)- isomer and 20% (R)- isomer, the enantiomer purity of the compound for the (S)- isomer form is 80%. The enantiomer purity of a compound can be determined by a variety of methods known in the art, including but not limited to chromatography using chiral supports, polarization measurements by polarization rotation, nuclear magnetic resonance spectroscopy using chiral shift reagents (including but not limited to chiral complexes containing lanthanides or Pirkle reagents), or derivatization of the compound using chiral compounds such as Mosher's acids followed by chromatography or nuclear magnetic resonance spectroscopy.

[0144] In some embodiments, the enantiomer-enriched composition has a higher potency per unit mass of therapeutic effect than a racemic mixture of the composition. Enantiomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred enantiomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York (1981); E.L. Liel, Stereochemistry of Carbon Compounds, McGraw-Hill, New York (1962); and E.L. Liel and S.H. Wilen, Stereochemistry of Organic Compounds, Wiley-Interscience, New York (1994).

[0145] As used herein, the terms “enantiomer-enriched” and “non-racemic” refer to compositions in which the weight percentage of one enantiomer is greater than the amount of that enantiomer in a control mixture of racemic compositions (e.g., a weight ratio greater than 1:1). For example, an enantiomer-enriched formulation of the (S)-enantiomer means a formulation of a compound having more than 50% by weight of the (S)-enantiomer relative to the (R)-enantiomer, such as at least 75% by weight, or such as at least 80% by weight. In some embodiments, enrichment may be significantly greater than 80% by weight, providing a “substantially enantiomer-enriched” or “substantially non-racemic” formulation, which means a formulation of a composition having at least 85% by weight of one enantiomer relative to the other enantiomers, such as at least 90% by weight, or such as at least 95% by weight. The terms “enantiomer-pure” or “substantially enantiomer-pure” refer to a composition containing at least 98% of a single enantiomer and less than 2% of opposite enantiomers.

[0146] A "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is usually a recognized chemical entity that is embedded in or attached to a molecule.

[0147] "Tautomers" are structurally different isomers that interconvert through tautomerism. Tautomerism is a form of isomerization and includes proton shift or proton transfer tautomerism, which is considered a subset of acid-base chemistry. Proton shift or proton transfer tautomerism involves the migration of protons accompanied by a change in bond order, often the exchange of a single bond with an adjacent double bond. Where tautomerism is possible (e.g., in solution), chemical equilibrium of tautomers can be achieved. An example of tautomerism is keto-enol tautomerism. A specific example of keto-enol tautomerism is the interconversion of the pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of the pyridine-4-ol and pyridine-4(1H)-keto tautomers.

[0148] "Leaving group or atom" is any group or atom that will cleave the starting material under selected reaction conditions, thereby promoting a reaction at a specific site. Unless otherwise stated, examples of such groups include halogen atoms and methanesulfonyloxy, p-nitrobenzenesulfonyloxy, and toluenesulfonyloxy.

[0149] The term "protecting group" is intended to refer to a group that selectively blocks one or more reaction sites in a multifunctional compound, thereby allowing a chemical reaction to occur selectively at another unprotected reaction site, after which the protecting group can be readily removed or deprotected. Various protecting groups are disclosed, for example, in TH Greene and PGM Watts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York (1999).

[0150] A "solvent" is a compound that is physically associated with one or more pharmaceutically acceptable solvent molecules.

[0151] "Substituted" means that the mentioned group may have one or more additional groups, radicals, or moiety connected to it, which are individually and independently selected from, for example, acyl, alkyl, alkylaryl, cycloalkyl, arylalkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, isohydroxamic acid ester, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, ester, thiocarbonyl, isocyanate, thiocyanate, isothiocyanate, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate ester, silyl, sulfinyl, sulfonyl, sulfonamide, sulfonic acid, sulfonate, urea, and amino, including monosubstituted and disubstituted amino groups, and their protected derivatives. The substituent itself may be substituted; for example, a cycloalkyl substituent itself may have halogen substituents on one or more of its ring carbons. The term "optionally substituted" means that it is substituted by a specified group, radical, or moiety.

[0152] "Thioalkyl" refers to groups including -S- (optionally substituted alkyl), -S- (optionally substituted aryl), -S- (optionally substituted heteroaryl), and -S- (optionally substituted heterocyclic alkyl).

[0153] "Sylenyl group" refers to a group including -S(O)-H, -S(O)- (optionally substituted alkyl), -S(O)- (optionally substituted amino), -S(O)- (optionally substituted aryl), -S(O)- (optionally substituted heteroaryl), and -S(O)- (optionally substituted heterocyclic alkyl).

[0154] "Sulfoyl" refers to a group including -S(O2)-H, -S(O2)- (optionally substituted alkyl), -S(O2)- (optionally substituted amino), -S(O2)- (optionally substituted aryl), -S(O2)- (optionally substituted heteroaryl), and -S(O2)- (optionally substituted heterocyclic alkyl).

[0155] "Sulfonamidyl" or "sulfonamido" refers to a -S(=O)2-NRR group, wherein each R is independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (by cyclic carbon bonding), and heterocyclic (by cyclic carbon bonding). The R group in the -NRR of the -S(=O)2-NRR group may form a 4-, 5-, 6-, or 7-membered ring with the nitrogen to which it is attached. The sulfonamidyl group may optionally be substituted by one or more substituents as described for alkyl, cycloalkyl, aryl, and heteroaryl groups, respectively.

[0156] "Sulfonic acid group" refers to the -S(=O)2OH group.

[0157] "Sulfonate" refers to the -S(=O)2-OR group, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (by cyclic carbon bonding), and heterocyclic (by cyclic carbon bonding). The sulfonate group may optionally be substituted on R by one or more substituents described for alkyl, cycloalkyl, aryl, and heteroaryl groups, respectively.

[0158] The compounds of the present invention also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvable polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. The terms "crystalline form" and "polymorph" are intended to include all crystalline and amorphous forms of the compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvable polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a specific crystalline or amorphous form is mentioned.

[0159] Compounds of formula ADY This invention provides novel compounds with biological properties that can be used to treat any of a variety of conditions or diseases typically characterized by abnormal inflammation, or to prevent such conditions or diseases in the presence of a risk of developing them.

[0160] In one embodiment, the present invention relates to a compound of formula ADY, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In some embodiments, the present invention relates to a compound of formula ADY, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein A is selected from A as defined in Table 1. 1 To A 40 . Table 1

[0161] In one embodiment, the present invention relates to a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein D is selected from D as defined in Table 2. 1 To D 9 In one embodiment, the present invention relates to a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein A is selected from A as defined in Table 1. 1 To A 40And D is selected from D as defined in Table 2. 1 To D 9 . Table 2 n is an integer between 0 and 12.

[0162] In one embodiment, the present invention relates to a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein Y is selected from Y as defined in Table 3. 1 To Y 7 In one embodiment, the present invention relates to a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein A is selected from A as defined in Table 1. 1 To A 40 And Y is selected from Y as defined in Table 3. 1 To Y 7 In one embodiment, the present invention relates to compounds of formula ADY or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, wherein D is selected from D as defined in Table 2. 1 To D 9 And Y is selected from Y as defined in Table 3. 1 To Y 7 In one embodiment, the present invention relates to a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein A is selected from A as defined in Table 1. 1 To A 40 D is selected from D as defined in Table 2. 1 To D 9 And Y is selected from Y as defined in Table 3. 1 To Y 7 . Table 3 m is an integer between 1 and 12.

[0163] In some embodiments, the present invention relates to compounds of the formula ADY or pharmaceutically acceptable salts, solvates, hydrates, cocrystals or prodrugs thereof, wherein said compounds have anti-inflammatory, anticancer or anti-angiogenic effects.

[0164] In some embodiments, the present invention relates to pharmaceutical compositions comprising compounds of the formula ADY or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. In some embodiments, A is selected from A as defined in Table 1. 1 To A 40 In some implementations, D is selected from D as defined in Table 2. 1To D 9 In some implementations, Y is selected from Y as defined in Table 3. 1 To Y 7 .

[0165] In one embodiment, the present invention relates to compound 1 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In one embodiment, the present invention relates to a pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0166] In one embodiment, the present invention relates to compound 2 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In another embodiment, the present invention relates to a pharmaceutical composition comprising compound 2 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0167] In one embodiment, the present invention relates to compound 3 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In another embodiment, the present invention relates to a pharmaceutical composition comprising compound 3 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0168] In one embodiment, the present invention relates to compound 4 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In another embodiment, the present invention relates to a pharmaceutical composition comprising compound 4 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0169] In one embodiment, the present invention relates to compound 5 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In another embodiment, the present invention relates to a pharmaceutical composition comprising compound 5 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0170] In one embodiment, the present invention relates to compound 6 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In another embodiment, the present invention relates to a pharmaceutical composition comprising compound 6 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0171] In one embodiment, the present invention relates to compound 7 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In another embodiment, the present invention relates to a pharmaceutical composition comprising compound 7 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0172] In some embodiments, the present invention relates to compounds 10 to 107 as described in Table 4, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. In some embodiments, the present invention relates to pharmaceutical compositions comprising one or more of compounds 10 to 107, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, and one or more pharmaceutically acceptable excipients. Table 4 11 A19-D1-Y2 31 A19-D4-Y1 51 A19-D6-Y7 71 A30-D2-Y6 91 A30-D5-Y5 12 A19-D1-Y3 32 A19-D4-Y2 52 A19-D7-Y1 72 A30-D2-Y7 92 A30-D5-Y6 13 A19-D1-Y4 33 A19-D4--Y3 53 A19-D7-Y2 73 A30-D3-Y1 93 A30-D5-Y7 14 A19-D1-Y5 34 A19-D4-Y4 54 A19-D7-Y3 74 A30-D3-Y2 94 A30-D6-Y1 15 A19-D1-Y6 35 A19-D4-Y5 55 A19-D7-Y4 75 A30-D3-Y3 95 A30-D6-Y2 16 A19-D1-Y7 36 A19-D4-Y6 56 A19-D7-Y5 76 A30-D3-Y4 96 A30-D6-Y3 17 A19-D2-Y1 37 A19-D4-Y7 57 A19-D7-Y6 77 A30-D3-Y5 97 A30-D6-Y4 18 A19-D2-Y2 38 A19-D5-Y1 58 A19-D7-Y7 78 A30-D3-Y6 98 A30-D6-Y5 19 A19-D2-Y3 39 A19-D5-Y2 59 A30-D1-Y1 79 A30-D3-Y7 99 A30-D6-Y6 20 A19-D2-Y4 40 A19-D5-Y3 60 A30-D1-Y2 80 A30-D4-Y1 100 A30-D6-Y7 21 A19-D2-Y5 41 A19-D5-Y4 61 A30-D1-Y3 81 A30-D4-Y2 101 A30-D7-Y1 22 A19-D2-Y6 42 A19-D5-Y5 62 A30-D1-Y4 82 A30-D4-Y3 102 A30-D7-Y2 23 A19-D2-Y7 43 A19-D5-Y6 63 A30-D1-Y5 83 A30-D4-Y4 103 A30-D7-Y3 24 A19-D3-YI 44 A19-D5-Y7 64 A30-D1-Y6 84 A30-D4-Y5 104 A30-D7-Y4 25 A19-D3-Y2 45 A19-D6-Y1 65 A30-D1-Y7 85 A30-D4-Y6 105 A30-D7-Y5 26 A19-D3-Y3 46 A19-D6-Y2 66 A30-D2-Y1 86 A30-D4-Y7 106 A30-D7-Y6 27 A19-D3-Y4 47 A19-D6-Y3 67 A30-D2-Y2 87 A30-D5-Y1 107 A30-D7-Y7 28 A19-D3-Y5 48 A19-D6-Y4 68 A30-D2-Y3 88 A30-D5-Y2 29 A19-D3-Y6 49 A19-D6-Y5 69 A30-D2-Y4 89 A30-D5-Y3

[0173] Treatment The compounds and compositions described herein can be used in methods of treating diseases. In one embodiment, the present invention relates to a method of treating a disease or symptom in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In one embodiment, the patient or object is a mammal, such as a human. In one embodiment, the patient or object is a human. In one embodiment, the patient or object is an animal, such as a farm animal or companion animal. In one embodiment, the patient or object is a canine, feline, or equine animal.

[0174] In some embodiments, the present invention relates to a method of treating a disease or condition in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein A is selected from A as defined in Table 1. 1 To A 40 .

[0175] In some embodiments, the present invention relates to a method of treating a disease or condition in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein D is selected from D as defined in Table 2. 1 To D 9 .

[0176] In some embodiments, the present invention relates to a method of treating a disease or condition in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein Y is selected from Y as defined in Table 3. 1 To Y 7 .

[0177] In some embodiments, the present invention relates to a method of treating a disease or condition in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein the compound or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof is included in a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

[0178] In some embodiments, the present invention relates to a method of treating a disease or condition in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein the disease or condition is an inflammatory disease or condition, cancer, neurodegenerative disease or condition, cardiovascular disease or condition, eye disease or condition, or angiogenic disease or condition.

[0179] In some embodiments, the present invention relates to a method of treating cancer in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein the cancer is ovarian cancer, colon cancer, leukemia, gastric cancer, lung cancer, pancreatic cancer, or cancer characterized by K-Ras mutations.

[0180] In some embodiments, the present invention relates to a method of treating cancer in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein the cancer is chemoresistant to other therapeutic agents.

[0181] In some embodiments, the present invention relates to a method of treating a disease or condition in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein the treatment comprises inhibiting VEGF expression.

[0182] In some embodiments, the present invention relates to a method of treating diabetic retinopathy in patients in need, comprising administering to the patient a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

[0183] In some embodiments, the present invention relates to a method of treating inflammation of the eye in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

[0184] In some embodiments, the present invention relates to a method of treating dry eye disease in patients in need, comprising administering to the patient a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, eutectic or prodrug thereof.

[0185] In some embodiments, the present invention relates to a method of treating an anterior segment disease or ailment in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, eutectic or prodrug thereof.

[0186] In some embodiments, the present invention relates to a method of treating a disease or condition of the posterior part of the eye in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of the formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, eutectic or prodrug thereof.

[0187] In some embodiments, the compounds and compositions described herein can be used for methods of treating diseases associated with upregulation and / or downregulation of VEGF expression and / or K-Ras expression.

[0188] In one embodiment, the present invention relates to a method of treating a disease relieved by administration of a compound of the formula ADY in a patient in need, comprising administering a therapeutically effective amount of the compound of the formula ADY to the patient in the form of a dose unit. In one embodiment, the dose unit comprises a physiologically compatible carrier medium.

[0189] In one embodiment, the present invention relates to a method of treating a disease relieved by administering a compound of the formula ADY to a patient in need, comprising administering a therapeutically effective amount of the compound of the formula ADY to said patient, wherein said disease is cancer or an inflammatory disease. In some embodiments, the disease is rheumatoid arthritis, cardiovascular disease, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), asthma, acute respiratory distress syndrome (ARDS), or acute lung injury (ALI). In one embodiment, the disease is a hyperproliferative disease. In some embodiments, the hyperproliferative disease is cancer. In some implementation schemes, cancers include pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain cancer, head and neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck cancer, breast cancer, ovarian cancer, lung cancer, small cell lung cancer, Wilms' tumor, cervical cancer, testicular cancer, bladder cancer, pancreatic cancer, stomach cancer, colon cancer, prostate cancer, genitourinary cancer, thyroid cancer, esophageal cancer, myeloma, multiple myeloma, adrenal cancer, renal cell carcinoma, endometrial cancer, adrenocortical carcinoma, malignant pancreatic insulinoma, and malignant carcinoid tumors. (carcinoma), choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocythemia, Hodgkin's disease, non-Hodgkin's lymphoma, soft tissue sarcoma, osteosarcoma, primary macroglobulinemia, or retinoblastoma, etc.In other implementation schemes, the cancers include acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endothelial carcinoma, ependymoma, epithelial carcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, renal cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendothelioma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, and papillary carcinoma. Pineal gland tumor, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, gastric cancer, sweat gland carcinoma, synovial sarcoma, testicular cancer, small cell lung cancer, laryngeal cancer, uterine cancer, Wilms' tumor, leukemia, acute erythroleukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia, acute myelomonocytic leukemia, acute non-lymphocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma, polycythemia vera, or Waldenström macroglobulinemia.

[0190] In some embodiments, the hyperproliferative diseases (e.g., cancers) treated by the compounds and compositions described herein include cells expressing VEGF and / or K-Ras-related proteins.

[0191] In one embodiment, the present invention relates to a method of treating a disease or condition in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and one or more additional therapeutic agents, including chemotherapeutic agents and / or immunotherapeutic agents.

[0192] In one embodiment, the present invention relates to a method of treating a disease or condition in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and one or more additional therapeutic agents, including antibiotics. In some embodiments, the antibiotic may include one or more of tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, brevicin, oxytetracycline, chloramphenicol, gentamicin, and erythromycin. Other antibiotics include aminoglycosides, ampicillin, carbenicillin, cefazolin, cephalosporins, chloramphenicol, clindamycin, gentamicin, kanamycin, lipopeptides, methicillin, nafcillin, neomycin, oxazolidinones, penicillins, quinolones, rifampin, streptomycin, streptomycin, sulfamethoxazole, sulfonamides, trimethoprim, and vancomycin. In some embodiments, the compound of formula ADY does not inhibit, impede, or otherwise delay or prevent the efficacy of antibiotics (e.g., co-administered antibiotics). In some implementations, the antibiotic does not inhibit, hinder, or otherwise delay or prevent the efficacy of compounds of the ADY formula (e.g., compounds of the ADY formula administered together).

[0193] In one embodiment, the present invention relates to a method of treating a disease or condition in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and one or more additional therapeutic agents, including antibiotics, for the topical treatment of ocular inflammatory conditions. Ocular inflammatory conditions occur frequently. Often, when the eye is inflamed, it is clinically difficult to assess whether the inflammation is due to an infectious agent, a non-infectious cause, or both. Because the treatments for these two causes differ, timely treatment is required in some embodiments, as these diseases or conditions can have catastrophic consequences for the eye if left untreated. In some embodiments, when there is a risk of infection and / or the possible presence of bacteria in the eye, the medication is instructed to be used in combination with an anti-infective ingredient. In some embodiments, an effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof is combined with one or more additional therapeutic agents in an eye drop formulation or an eye ointment formulation. In some embodiments, the additional therapeutic agent is neomycin sulfate. In some embodiments, the additional therapeutic agent is polymyxin B sulfate. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent. In some embodiments, the additional therapeutic agent is dexamethasone. In some embodiments, the additional therapeutic agent is cortisone or other corticosteroids. In some embodiments, the additional therapeutic agent is tobramycin. In some embodiments, an effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof is combined with one or more additional therapeutic agents in an eye drop or ointment formulation, excluding dexamethasone.

[0194] The term "compound with reduced risk of corneal melting" refers to a compound that, at approximately the same dose, is unlikely to cause corneal melting in treated patients compared to NSAIDs known to cause corneal melting (e.g., diclofenac (see, for example, Julianne, C. et al., "Corneal Melting Associated with Use of Topical Nonsteroidal Anti-Inflammatory Drugs after Ocular Surgery," (2000) 118:1129-1132)). In some embodiments, compounds of formula ADY or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof are compounds with reduced risk of corneal melting.

[0195] The compounds and compositions described herein can be used in methods for treating eye diseases. One example is ovarian cancer. Ovarian cancer is the deadliest gynecological cancer, affecting women of all ages. Approximately 95% are epithelial ovarian cancers (referred to herein as OvCa); germ cell tumors and sex cord-stromal tumors make up the remainder. The 5-year survival rate for patients with advanced cancer is only 17%–28%.

[0196] For a small percentage of ovarian cancer patients, surgery is effective. All other patients were treated with cytoreductive surgery plus chemotherapy in combination with cisplatin and paclitaxel, achieving a response rate of approximately 80%. Approximately 70% of patients with stage III or IV ovarian cancer relapse within 5 years and develop resistance. Patients with a recurrence-free interval >6 months are considered "cisplatin-sensitive," while those who progress or relapse within 6 months of initial treatment are considered "cisplatin-resistant." Patients with resistant disease are treated with other agents such as liposomal doxorubicin, gemcitabine, topotecan, or etoposide. The overall response rate for these drugs is 10%–25%, and the duration of response is short.

[0197] Available treatments have reached their therapeutic limit. Over the past 20 years, improvements in overall survival have been slow. Regrettably, recent targeted therapies for ovarian cancer, such as PARP inhibitors, anti-TNF antibodies, and folic acid antagonists, have provided minimal or no improvement in overall survival. Therefore, novel agents are needed to improve outcomes in advanced ovarian cancer.

[0198] The compounds and compositions described herein can be used in methods for treating eye diseases. In some embodiments, the eye diseases treated by the compounds, compositions, methods, and kits described herein include dry eye disease and retinopathy. In some embodiments, retinopathy may include diabetic retinopathy, retinopathy of prematurity, VEGF retinopathy, age-related macular degeneration, retinal vein occlusion, and / or hypertensive retinopathy. In some embodiments, the retinopathy may be diabetic retinopathy.

[0199] Dry eye disease (DED) is a multifactorial disease of the ocular surface characterized by the loss of tear film homeostasis, accompanied by ocular symptoms. The tear film in DED is abnormal, caused by one or more of three factors: reduced tear production; increased tear evaporation; or abnormalities in the mucus or lipids of the tears. The clinical manifestations of DED vary in severity: from very mild to a degree that significantly impacts a patient's quality of life by reducing their ability to perform activities requiring visual attention, such as reading and driving. Given its global distribution and the lack of a single, definitive diagnostic test or standard, prevalence data for DED vary. The best estimate of its prevalence is 15% (17.9% in women and 10.5% in men); some authors believe even 15% is an underestimate.

[0200] DED is an inflammatory disease whose pathogenesis is under extensive investigation. For example, lacrimal gland dysfunction, chronic irritant stress, or systemic autoimmune diseases can lead to ocular inflammation. Subsequently, the inflammation causes dysfunction or death of cells responsible for tear secretion, thus establishing a vicious cycle that leads to ocular surface disease regardless of whether the initial damage has occurred. Important contributors to the inflammatory process in DED are: (1) activation of pro-inflammatory cytokines; tear hyperosmolarity, which stimulates inflammatory mediators via MAPK; (2) matrix metalloproteinases (MMPs), which cleave components of the corneal epithelial basement membrane and tight junction proteins; (3) chemokines, which recruit nearby responsive cells; and (4) T cells, which amplify the cascade reaction by attracting inflammatory cells (e.g., in Sjögren's syndrome).

[0201] Treatment for DED depends on its clinical severity. Symptoms of very mild disease are usually treated with artificial tears, which provide partial relief but do not suppress inflammation. Advanced disease is treated with immunosuppressants such as cyclosporine, the recently approved integrin antagonist lifitegrast, lacrimal duct plugs, or (rarely) corticosteroids. Nonsteroidal anti-inflammatory drugs (NSAIDs) are ineffective in DES.

[0202] Diabetic retinopathy refers to retinal changes that occur in people with diabetes. These changes affect the small blood vessels in the retina and can lead to vision loss through several different pathways. Macular edema (defined as thickening of the retina and edema involving the macula) can occur at any stage of diabetic retinopathy. Diabetic retinopathy is one of the most common causes of vision loss. Vascular endothelial growth factor (VEGF) is secreted by the ischemic retina. VEGF causes (a) increased vascular permeability, leading to retinal swelling / edema, and (b) angiogenesis—the formation of new blood vessels. In some implementations, agents that inhibit VEGF can control diabetic retinopathy.

[0203] Besides diabetic retinopathy, several other eye diseases are characterized by abnormal vascular phenomena that rely primarily on VEGF. Given the role of VEGF in these conditions, controlling VEGF is one way to prevent and treat them. The most prominent of these is age-related macular degeneration (AMD), a degenerative disease of the central part of the retina (macula), primarily causing central vision loss. Central vision is required for activities such as driving, reading, watching television, and performing daily living activities. For clinical purposes, AMD is classified as dry (atrophic) or wet (neovascular or exudative). Wet AMD, also known as choroidal neovascularization, is characterized by the growth of abnormal blood vessels (usually from the choroidal circulation and less frequently from the retinal circulation) into the subretinal space. These abnormal vessels leak, leading to a collection of subretinal fluid and / or blood under the retina.

[0204] Retinal vein occlusion (RVO) is a leading cause of vision loss in older adults worldwide. A significant component of RVO is its secondary complications that affect vision, including macular edema, retinal neovascularization, and anterior segment neovascularization. VEGF plays a crucial role in these vision-determining complications. Patients with severe (ischemic) central retinal vein occlusion have a particularly high risk of developing neovascular glaucoma, typically within the first few months of diagnosis, and the development of anterior segment neovascularization should be monitored at least monthly during this period. Indeed, patients with severe (ischemic) central retinal vein occlusion have a particularly high risk of developing neovascular glaucoma and are closely monitored for the development of anterior segment neovascularization. It is hypothesized that VEGF inhibitors in RVO patients limit macular edema and improve vision by reducing vascular permeability.

[0205] Not wishing to be bound by any particular theory, this invention is based, at least in part, on some unexpected observations relating to compounds of formula ADY or combinations of pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs and anti-infective agents. In some embodiments, such combinations can be used to treat ocular conditions. In some embodiments, certain chemical portions of the compounds of formula ADY, such as “A”, are residues associated with nonsteroidal anti-inflammatory compounds (NSAIDs). However, in some embodiments, the compounds of formula ADY do not behave like NSAIDs when applied to the eye. For example, in some embodiments, the compounds of formula ADY do not inhibit the synthesis of prostaglandins in the eye, whereas the use of NSAIDs typically inhibits the synthesis of prostaglandins in the eye. In other embodiments, the compounds of formula ADY do not cause corneal melting, a complication of ocular application of NSAIDs, and which typically prohibits or limits the use of topical ophthalmic NSAIDs. However, the compounds of formula ADY of the present invention unexpectedly possess beneficial analgesic properties similar to those of NSAIDs. In some embodiments, the compounds of formula ADY of the present invention provide corneal analgesia. In some embodiments, the compounds of formula ADY of the present invention provide short-term corneal analgesia. Therefore, in some embodiments, the compounds of formula ADY of the present invention provide symptom relief for ocular discomfort associated with various ophthalmic diseases or conditions. In some embodiments, the compounds of formula ADY of the present invention do not inhibit the antibacterial efficacy of antibiotics administered in combination.

[0206] The efficacy of the compounds and combinations thereof described herein in treating the indicated disease or condition can be tested using various models known in the art and those described herein, which provide guidance for treating human diseases. Any and all treatments described may include medical follow-up to determine the therapeutic or preventative effects in subjects receiving treatment with the compounds and / or compositions described herein.

[0207] Pharmaceutical Composition In one embodiment, an active pharmaceutical ingredient or combination of active pharmaceutical ingredients, such as any compound of formula ADY of the present invention, is provided as a pharmaceutically acceptable composition.

[0208] In one embodiment, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a physiologically compatible carrier medium for treating a disease relieved by administration of a compound of the formula ADY to a patient in need.

[0209] In one embodiment, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula ADY for treating a disease relieved by administration of the compound ADY to a patient in need, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a physiologically compatible carrier medium, wherein the disease is cancer or an inflammatory disease. In one embodiment, the disease is rheumatoid arthritis, cardiovascular disease, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), asthma, acute respiratory distress syndrome (ARDS), or acute lung injury (ALI). In one implementation plan, the disease is cancer, such as acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endothelial carcinoma, ependymoma, epithelial cancer, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, renal cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangiosarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, prostate cancer, transverse... Rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, gastric cancer, sweat gland carcinoma, synovial sarcoma, testicular cancer, small cell lung cancer, laryngeal cancer, uterine cancer, Wilms' tumor, leukemia, acute erythroleukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia, acute myelomonocytic leukemia, acute non-lymphocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma, polycythemia vera, or Waldenström macroglobulinemia.

[0210] In some embodiments, the compositions described herein can be formulated for topical application to the eye and surrounding tissues, particularly to the inner surfaces of the eye and eyelids, including, for example, the cornea, conjunctiva, and sclera. For example, such compositions can be formulated for instillation, application to the conjunctival sac, and conjunctival administration. In particular, the compositions described herein can be formulated as eye drops. Such eye drop formulations may include liquid or semi-solid pharmaceutical compositions suitable for administration to the eye. A typical example of an eye drop composition is an ophthalmic solution administered dropwise to the eye.

[0211] In some embodiments, the concentration of each active pharmaceutical ingredient (such as any compound of formula ADY of the present invention) provided in the pharmaceutical composition of the present invention is less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or 0.09% of the pharmaceutical composition. 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w / w, w / v or v / v.

[0212] In some embodiments, the concentration of each active pharmaceutical ingredient (such as any compound of formula ADY of the present invention) provided in the pharmaceutical composition of the present invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 1... 6%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.2 5%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08% 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w / w, w / v or v / v.

[0213] In some embodiments, the concentration of each active pharmaceutical ingredient (such as any compound of formula ADY of the present invention) provided in the pharmaceutical composition of the present invention is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, and from about [missing information]% of the pharmaceutical composition. The range of 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, or about 1% to about 10% w / w, w / v, or v / v.

[0214] In some embodiments, the concentration of each active pharmaceutical ingredient (such as any compound of formula ADY of the present invention) provided in the pharmaceutical composition of the present invention is in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, w / v, or v / v.

[0215] In some embodiments, the concentration of each active pharmaceutical ingredient (such as any compound of formula ADY of the present invention) provided in the pharmaceutical composition of the present invention is about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, or about 46%. Approximately 47%, approximately 48%, approximately 49%, approximately 50%, approximately 51%, approximately 52%, approximately 53%, approximately 54%, approximately 55%, approximately 56%, approximately 57%, approximately 58%, approximately 59%, approximately 60%, approximately 61%, approximately 62%, approximately 63%, approximately 64%, approximately 65%, approximately 66%, approximately 67%, approximately 68%, approximately 69%, approximately 70%, approximately 71%, approximately 72%, approximately 73% Approximately 74%, approximately 75%, approximately 76%, approximately 77%, approximately 78%, approximately 79%, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100%.

[0216] In some embodiments, the amount of each active pharmaceutical ingredient (such as any of the aforementioned compounds of formula ADY of the present invention) provided in the pharmaceutical composition of the present invention is equal to or less than 10g, 9.5g, 9.0g, 8.5g, 8.0g, 7.5g, 7.0g, 6.5g, 6.0g, 5.5g, 5.0g, 4.5g, 4.0g, 3.5g, 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0. 35g, 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.00 6g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g or 0.0001g.

[0217] In some embodiments, the amount of each active pharmaceutical ingredient (such as any compound of formula ADY of the present invention) provided in the pharmaceutical composition of the present invention is greater than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, etc. g, 0.002g, 0.0025g, 0.003g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.0 2g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0 .075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g , 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g , 2g, 2.5g, 3g, 3.5g, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g or 10g.

[0218] Each active pharmaceutical ingredient according to the invention is effective over a wide dosage range. For example, in the treatment of adults, dosages independently ranging from 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg daily, and 5 to 40 mg daily are examples of dosages that can be used. The exact dosage will depend on the route of administration, the form of the compound administered, the sex and age of the patient being treated, the weight of the patient being treated, and the preferences and experience of the attending physician. If appropriate, the clinically determined dosage of the compound of formula ADY of the invention may also be used.

[0219] In one embodiment, the molar ratio of the two active pharmaceutical ingredients in the pharmaceutical composition is in the range of 10:1 to 1:10, preferably 2.5:1 to 1:2.5, and more preferably about 1:1. In one embodiment, the weight ratio of the molar ratio of the two active pharmaceutical ingredients in the pharmaceutical composition is selected from 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, and 1:20. In one embodiment, the weight ratio of the molar ratio of the two active pharmaceutical ingredients in the pharmaceutical composition is selected from 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, and 1:20.

[0220] In one embodiment, the pharmaceutical composition described herein, such as any compound of formula ADY of the present invention, is used to treat inflammatory diseases or conditions, cancer, neurodegenerative diseases or conditions, cardiovascular diseases or conditions, eye diseases or conditions, or angiogenic diseases or conditions. In one embodiment, the pharmaceutical composition described herein, such as any compound of formula ADY of the present invention, is used to treat ovarian cancer, colon cancer, leukemia, gastric cancer, lung cancer, pancreatic cancer, or cancer characterized by K-Ras mutations. In one embodiment, the pharmaceutical composition described herein, such as any compound of formula ADY of the present invention, is used to treat cancers that are chemoresistant to other therapeutic agents such as cisplatin or paclitaxel. In one embodiment, the pharmaceutical composition described herein, such as any compound of formula ADY of the present invention, is used to treat diabetic retinopathy.

[0221] In one embodiment, the pharmaceutical compositions described herein, such as any compound of formula ADY of the present invention, are used to treat hyperproliferative disorders associated with overexpression or upregulation and / or downregulation of VEGF and / or K-Ras. In some embodiments, the pharmaceutical compositions described herein are used to treat cancers associated with overexpression or upregulation and / or downregulation of VEGF and / or K-Ras, such as pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain cancer, head and neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck cancer, breast cancer, ovarian cancer, lung cancer, small cell lung cancer, Wilms' tumor, cervical cancer, testicular cancer, bladder cancer, pancreatic cancer, gastric cancer, colon cancer, prostate cancer, genitourinary cancer, thyroid cancer, esophageal cancer, myeloma, and multiple lesions. Multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenocortical carcinoma, malignant pancreatic insulinoma, malignant carcinoid, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocythemia, Hodgkin's disease, non-Hodgkin's lymphoma, soft tissue sarcoma, osteosarcoma, primary macroglobulinemia, or retinoblastoma.

[0222] In one embodiment, the present invention includes a composition for treating an ocular condition selected from dry eye disease and retinopathy in a patient in need, the composition comprising a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In some embodiments, the compositions described herein comprise a pharmaceutically acceptable carrier. In some embodiments, the compositions described herein comprise one or more of a solubilizer, alcohol, acid, and preservative.

[0223] In some embodiments, the compositions described herein include a solubilizer and an alcohol. In some embodiments, the compositions described herein include a solubilizer and an acid. In some embodiments, the compositions described herein include a solubilizer and a preservative. In some embodiments, the compositions described herein include a solubilizer, an alcohol, and an acid. In some embodiments, the compositions described herein include a solubilizer, an alcohol, an acid, and a preservative.

[0224] In some embodiments, the compositions of the present invention may comprise, by weight, about 0.5% to about 75%, or about 0.5% to about 70%, or about 0.5% to about 65%, or about 0.5% to about 60%, or about 0.5% to about 55%, or about 0.5% to about 50%, or about 0.5% to about 45%, or about 0.5% to about 40%, or about 0.5% to about 35%, or about 0.5% to about 30%, or about 0.5% to about 25%, or about 0.5% to about A pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug of formula ADY in amounts of 20%, or about 0.5% to about 15%, or about 0.5% to about 10%, or about 0.5% to about 9%, or about 0.5% to about 8%, or about 0.5% to about 7%, or about 0.5% to about 6%, or about 0.5% to about 5%, or about 0.5% to about 4%, or about 0.5% to about 3%, or about 0.5% to about 2%, or about 0.5% to about 1%.

[0225] In some embodiments, the solubilizer is vitamin E TPGS (d-α-tocopherol polyethylene glycol 1000 succinate). In some embodiments, the compositions described herein comprise, by weight, about 0.5% to about 75%, or about 1% to about 70%, or about 1% to about 65%, or about 1% to about 60%, or about 1% to about 55%, or about 1% to about 50%, or about 1% to about 45%, or about 1% to about 40%, or about 1% to about 35%, or about 1% to about 30%, or about 1% to about 25%, or about 1% to about 20%, or about 1% to about 15%, or about 1% to about 10%, or about 1% to about 5%.

[0226] In some embodiments, the alcohol is a sugar alcohol, such as mannitol. In some embodiments, the composition described herein comprises, by weight, about 0.5% to about 75%, or about 0.5% to about 70%, or about 0.5% to about 65%, or about 0.5% to about 60%, or about 0.5% to about 55%, or about 0.5% to about 50%, or about 0.5% to about 45%, or about 0.5% to about 40%, or about 0.5% to about 35%, or about 0.5% to about 30%, or about 0. The amount of alcohol is 5% to about 25%, or about 0.5% to about 20%, or about 0.5% to about 15%, or about 0.5% to about 10%, or about 0.5% to about 9%, or about 0.5% to about 8%, or about 0.5% to about 7%, or about 0.5% to about 6%, or about 0.5% to about 5%, or about 0.5% to about 4%, or about 0.5% to about 3%, or about 0.5% to about 2%, or about 0.5% to about 1%.

[0227] In some embodiments, the acid is boric acid. In some embodiments, the composition described herein comprises, by weight, about 0.5% to about 75%, or about 0.5% to about 70%, or about 0.5% to about 65%, or about 0.5% to about 60%, or about 0.5% to about 55%, or about 0.5% to about 50%, or about 0.5% to about 45%, or about 0.5% to about 40%, or about 0.5% to about 35%, or about 0.5% to about 30%, or about 0. Acid in amounts of 5% to 25%, or about 0.5% to 20%, or about 0.5% to 15%, or about 0.5% to 10%, or about 0.5% to 9%, or about 0.5% to 8%, or about 0.5% to 7%, or about 0.5% to 6%, or about 0.5% to 5%, or about 0.5% to 4%, or about 0.5% to 3%, or about 0.5% to 2%, or about 0.5% to 1%.

[0228] In some embodiments, the preservative is polyquaternium salt 1. In some embodiments, the composition described herein comprises, by weight, about 0.001% to about 5%, or about 0.001% to about 4%, or about 0.001% to about 3%, or about 0.001% to about 2%, or about 0.001% to about 1%, or about 0.001% to about 0.5%, or about 0.001% to about 0.1%, or about 0.001% to about 0.009%, or about 0.001% to about 0.008%, or about 0.007%, or about 0.001% to about 0.006%, or about 0.001% to about 0.005%.

[0229] In some embodiments, the compositions described herein may include a gelling excipient, such as gellan gum or sodium alginate. In some embodiments, the compositions described herein comprise, by weight, an amount of gelling excipient of about 0.5% to about 20%, or about 0.1% to about 15%, or about 0.1% to about 10%, or about 0.1% to about 9%, or about 0.1% to about 8%, or about 0.1% to about 7%, or about 0.1% to about 6%, or about 0.1% to about 5%, or about 0.1% to about 4%, or about 0.1% to about 3%, or about 0.1% to about 2%, or about 0.1% to about 1%, or about 0.1% to about 0.9%, or about 0.1% to about 0.8%, or about 0.1% to about 0.7%, or about 0.1% to about 0.6%, or about 0.1% to about 0.5%.

[0230] In some embodiments, the compositions described herein may include poloxamer. In some embodiments, the compositions described herein comprise poloxamer in amounts of about 1% to about 75%, or about 1% to about 70%, or about 1% to about 65%, or about 1% to about 60%, or about 1% to about 55%, or about 1% to about 50%, or about 1% to about 45%, or about 1% to about 40%, or about 1% to about 35%, or about 1% to about 30%, or about 1% to about 25%, or about 1% to about 20%, or about 1% to about 15%, or about 1% to about 10%, or about 1% to about 9%, or about 1% to about 8%, or about 1% to about 7%, or about 1% to about 6%, or about 1% to about 5%, or about 1% to about 4%, or about 1% to about 3%, or about 1% to about 2%.

[0231] In some embodiments, the compositions described herein include surfactants such as Tween 80 or polyethylene stearate. In some embodiments, the compositions described herein comprise, by weight, amounts of surfactant in amounts of about 0.01% to about 20%, or about 0.01% to about 15%, or about 0.01% to about 10%, or about 0.01% to about 9%, or about 0.01% to about 8%, or about 0.01% to about 7%, or about 0.01% to about 6%, or about 0.01% to about 5%, or about 0.01% to about 4%, or about 0.01% to about 3%, or about 0.01% to about 2%, or about 0.01% to about 1%, or about 0.01% to about 0.5%, or about 0.01% to about 0.1%, or about 0.01% to about 0.09%, or about 0.01% to about 0.08%, or about 0.07%, or about 0.01% to about 0.06%, or about 0.01% to about 0.05%.

[0232] In some embodiments, the compositions described herein comprise cyclodextrin, such as (2-hydroxypropyl)-β-cyclodextrin. In some embodiments, the compositions described herein comprise, by weight, about 0.5% to about 95%, or about 0.5% to about 90%, or about 0.5% to about 85%, or about 0.5% to about 80%, or about 0.5% to about 75%, or about 0.5% to about 70%, or about 0.5% to about 65%, or about 0.5% to about 60%, or about 0.5% to about 55%, or about 0.5% to about 50%, or about 0.5% to about 45%, or about 0.5% to about 40%, or about 0.5% to about 40%. Cyclodextrin in amounts of % to about 35%, or about 0.5% to about 30%, or about 0.5% to about 25%, or about 0.5% to about 20%, or about 0.5% to about 15%, or about 0.5% to about 10%, or about 0.5% to about 9%, or about 0.5% to about 8%, or about 0.5% to about 7%, or about 0.5% to about 6%, or about 0.5% to about 5%, or about 0.5% to about 4%, or about 0.5% to about 3%, or about 0.5% to about 2%, or about 0.5% to about 1%.

[0233] In one embodiment, the composition described herein may include a therapeutically effective amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and one or more of a gelling excipient (e.g., gellan gum or sodium alginate), poloxamer, a solubilizer (e.g., vitamin E TPGS), a surfactant (e.g., Tween 80 or polyethylene glycol stearate), a polyether (e.g., polyethylene glycol, propylene glycol, Cremophor), and a cyclodextrin (e.g., (2-hydroxypropyl)-β-cyclodextrin). In some embodiments, such a formulation may allow PS to be delivered to the anterior segment of the eye after topical application. In some embodiments, such a formulation may be used to deliver PS to the anterior segment of the eye in an amount sufficient to treat the disease described herein associated with such an anterior segment (i.e., a therapeutically effective amount).

[0234] In some embodiments, a substantial portion of the total amount of a compound of formula ADY or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs distributed into tissues after 1 hour, as determined by HPLC, is in a specific or targeted tissue or region. In some embodiments, greater than 30% of the total amount of a compound of formula ADY or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs in the cornea, conjunctiva, aqueous humor, vitreous body, retina, choroid, sclera, lacrimal glands, and lens (referred to as tissues or regions of the eye) may be present in a single tissue or region of the eye. In some embodiments, greater than 30% of the total amount of a compound of formula ADY or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs in the cornea, conjunctiva, aqueous humor, vitreous body, retina, choroid, sclera, lacrimal glands, and lens may be present in a single tissue or region. In some embodiments, greater than 40% of the total amount of a compound of formula ADY or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs in the cornea, conjunctiva, aqueous humor, vitreous body, retina, choroid, sclera, lacrimal gland, and lens may be present in a single tissue or region. In some embodiments, greater than 50% of the total amount of a compound of formula ADY or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs in the cornea, conjunctiva, aqueous humor, vitreous body, retina, choroid, sclera, lacrimal gland, and lens may be present in a single tissue or region. In some embodiments, greater than 60% of the total amount of a compound of formula ADY or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs in the cornea, conjunctiva, aqueous humor, vitreous body, retina, choroid, sclera, lacrimal gland, and lens may be present in a single tissue or region. In some embodiments, greater than 70% of the total amount of a compound of formula ADY or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs in the cornea, conjunctiva, aqueous humor, vitreous body, retina, choroid, sclera, lacrimal gland, and lens may be present in a single tissue or region. In some embodiments, greater than 80% of the total amount of a compound of formula ADY or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs in the cornea, conjunctiva, aqueous humor, vitreous body, retina, choroid, sclera, lacrimal gland, and lens may be present in a single tissue or region. In some embodiments, greater than 90% of the total amount of a compound of formula ADY or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs in the cornea, conjunctiva, aqueous humor, vitreous body, retina, choroid, sclera, lacrimal gland, and lens may be present in a single tissue or region.

[0235] As used in this article, an amount described as “about 0%” by weight should be understood as an amount greater than 0%.

[0236] The following describes non-restrictive pharmaceutical compositions and methods for their preparation.

[0237] Pharmaceutical compositions for oral administration In one embodiment, the present invention provides a pharmaceutical composition for oral administration comprising an active pharmaceutical ingredient or a combination of active pharmaceutical ingredients, such as a compound of formula ADY as described herein, and a pharmaceutical excipient suitable for oral administration.

[0238] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising: (i) an effective amount of an active pharmaceutical ingredient or a combination of active pharmaceutical ingredients, and (ii) a pharmaceutical excipient suitable for oral administration. In selected embodiments, the composition further comprises (iii) an effective amount of a third active pharmaceutical ingredient, and optionally (iv) an effective amount of a fourth active pharmaceutical ingredient.

[0239] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral administration. Pharmaceutical compositions of the present invention suitable for oral administration may be presented in discrete dosage forms, such as capsules, sacs, or tablets, or liquids or aerosol sprays, solutions, or suspensions in aqueous or non-aqueous liquids containing predetermined amounts of the active ingredient in powder or granular form, oil-in-water emulsions, water-in-oil liquid emulsions, powders for reconstitution, powders for oral administration, bottles (including powders or bottled liquids), orally dissolving films, lozenges, pastes, tubes, gumms, and packs. Such dosage forms can be prepared by any pharmaceutical method, but all methods include the step of binding the active ingredient with a carrier constituting one or more essential components. Generally, the composition is prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a finely chopped solid carrier, or both, and then, if necessary, shaping the product into the desired presentation form. For example, tablets may be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared by compressing free-flowing active ingredients, such as powders or granules, in a suitable machine, optionally mixed with excipients such as, but not limited to, binders, lubricants, inert diluents, and / or surfactants or dispersants. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0240] This invention also includes anhydrous pharmaceutical compositions and dosage forms because water can promote the degradation of certain compounds. For example, in the pharmaceutical field, water (e.g., 5%) can be added as a means of simulating long-term storage in order to determine characteristics such as shelf life or the stability of the formulation over time. The anhydrous pharmaceutical compositions and dosage forms of this invention can be prepared using anhydrous or low-moisture components and low-moisture or low-humidity conditions. If sufficient contact with moisture and / or humidity is desired during manufacturing, packaging, and / or storage, the pharmaceutical compositions and dosage forms of this invention containing lactose can be made anhydrous. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous properties. Therefore, anhydrous compositions can be packaged using materials known to prevent exposure to water, so that they can be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, airtight foil, plastics, etc., unit-dose containers, blister packs, and strip packs.

[0241] Each active pharmaceutical ingredient can be combined with a drug carrier into a compact mixture using conventional pharmaceutical compounding techniques. The carrier can take many forms, depending on the desired formulation for administration. When preparing compositions for oral dosage forms, any commonly used pharmaceutical medium can be used as a carrier, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., in the case of oral liquid formulations (such as suspensions, solutions, and elixirs) or aerosols, or in the case of oral solid formulations, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulators, lubricants, binders, and disintegrants. In some embodiments, lactose is not used. For example, suitable carriers for solid oral formulations include powders, capsules, and tablets. If desired, tablets can be coated using standard aqueous or non-aqueous techniques.

[0242] Binders suitable for pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as gum arabic, sodium alginate, alginic acid, other alginates, tragacanth powder, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose and mixtures thereof.

[0243] Examples of suitable fillers for the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, glucose dextrorates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0244] Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate upon exposure to an aqueous environment. Too much disintegrant may result in tablets that disintegrate in the bottle. Too little may be insufficient to cause disintegration, thereby altering the rate and extent of release of the active ingredient from the dosage form. Therefore, a sufficient amount of disintegrant, neither too little nor too much, that would adversely alter the release of the active ingredient can be used to form dosage forms of the compounds disclosed herein. The amount of disintegrant used can vary depending on the type of formulation and the method of administration, and can be readily discerned by those skilled in the art. About 0.5 to about 15% by weight of disintegrant, or about 1 to about 5% by weight of disintegrant, can be used in pharmaceutical compositions. Disintegrants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacolin potassium, sodium hydroxyacetic acid starch, potato or cassava starch, other starches, pregelatinized starches, other starches, clay, other alginates, other celluloses, gums, or mixtures thereof.

[0245] Lubricants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, sodium stearyl fumarate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, coagulated aerosols of synthetic silica, silanized microcrystalline cellulose, or mixtures thereof. Lubricants may optionally be added in an amount less than about 0.5% or less than about 1% (by weight) of the pharmaceutical composition.

[0246] When aqueous suspensions and / or elixirs are required for oral administration, the active pharmaceutical ingredient may be combined with various sweeteners or flavorings, colorings or dyes, and, if necessary, emulsifiers and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin, or various combinations thereof.

[0247] Tablets may be uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. For example, delay-release materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oil-based medium such as peanut oil, liquid paraffin, or olive oil.

[0248] Surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, mixtures of hydrophilic surfactants, mixtures of lipophilic surfactants, or mixtures of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0249] Suitable hydrophilic surfactants generally have an HLB value of at least 10, while suitable lipophilic surfactants generally have an HLB value of about 10 or less. The empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLB values ​​are more lipophilic or more hydrophobic and have greater solubility in oils, while surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be compounds with HLB values ​​greater than about 10, as well as anionic, cationic, or zwitterionic compounds that are generally not applicable to HLB scales. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with HLB values ​​equal to or less than about 10. However, the HLB value of a surfactant is only a rough guideline generally used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0250] Hydrophilic surfactants can be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts, fusidates, fatty acid derivatives of amino acids, oligopeptides and polypeptides, glycerol derivatives of amino acids, oligopeptides and polypeptides, lecithin and hydrogenated lecithin, lysophosphatidylcholine and hydrogenated lysophosphatidylcholine, phospholipids and their derivatives, lysophosphatidylcholine and their derivatives, carnitine fatty acid ester salts, alkyl sulfate salts, fatty acid salts, sodium docusate, acyl-lactylates, mono- and di-acetylated monoglycerides and diglycerides of tartrate, succinylated monoglycerides and diglycerides of citric acid, and mixtures thereof.

[0251] In the above group, ionic surfactants include, for example, lecithin, lysophosphatidylcholine, phospholipids, lysophosphatidylcholine and its derivatives, carnitine fatty acid ester salts, salts of alkyl sulfates, fatty acid salts, sodium docusate, acyl lactates, mono- and di-acetylated monoglycerides and diglycerides of tartrate, succinylated monoglycerides and diglycerides of tartrate, monoglycerides and diglycerides of citric acid, and mixtures thereof.

[0252] Ionic surfactants can be ionized forms of lecithin, lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactates, stearoyl 2-lactic acid ester, stearoyl lactate, succinyl monoglyceride, mono / diacetyl tartrate monoglyceride / diglyceride, citric acid monoglyceride / diglyceride, cholycylsarcosine, hexanoate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenic acid ester, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and their salts and mixtures.

[0253] Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides, alkyl maltodextrins, alkyl thioglucosides, lauryl polyethylene glycol glycerides, polyoxyethylene alkyl ethers such as polyethylene glycol alkyl ethers, polyoxyethylene alkylphenols such as polyethylene glycol alkylphenols, polyoxyethylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters, polyethylene glycol glycerol fatty acid esters, polyglycerol fatty acid esters, polyoxyethylene dehydrated sorbitol fatty acid esters such as polyethylene glycol dehydrated sorbitol fatty acid esters, hydrophilic transesterification products of polyols with at least one member of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, polyoxyethylene sterols, their derivatives and analogs, polyoxyethylene vitamins and their derivatives, polyoxyethylene-polyoxypropylene block copolymers and mixtures thereof, polyethylene glycol dehydrated sorbitol fatty acid esters, and hydrophilic transesterification products of polyols with at least one member of triglycerides, vegetable oils and hydrogenated vegetable oils. Polyols can be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or sugars.

[0254] Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG- PEG-30 Glyceryl Oleate, PEG-30 Glyceryl Laurate, PEG-40 Glyceryl Laurate, PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Caprylic / Capric Glyceryl Acetate, PEG-8 Caprylic / Capric Glyceryl Acetate, Polyglycerol-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterol, PEG-30 Soybean Sterol, PEG-20 Trioleate, PEG-40 Sorbitol Oleate, PEG-80 Sorbitol Laurate, Polysorbate 20, Polysorbate 80, POE-9 Lauryl Ether, POE-23 Lauryl Ether, POE-10 Oleyl Ether PEG-100 succinate, PEG-20 stearyl ether, PEG-24 cholesterol, polyglycerol-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series and poloxamer.

[0255] Suitable lipophilic surfactants, by way of example only, include: fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, sterols and sterol derivatives, polyoxyethylene sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugar esters, sugar ethers, lactic acid derivatives of monoglycerides and diglycerides, hydrophobic transesterification products of polyols with at least one member of the following: glycerol esters, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, oil-soluble vitamin / vitamin derivatives, and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophobic transesterification products of polyols with at least one member of the following: vegetable oils, hydrogenated vegetable oils and triglycerides.

[0256] In one embodiment, the composition may include a solubilizer to ensure good solubility and / or dissolution of the compounds of the present invention and to minimize precipitation of the compounds of the present invention. This is particularly important for compositions intended for non-oral use (e.g., compositions for injection). Solubilizers may also be added to increase the solubility of hydrophilic drugs and / or other components such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0257] Examples of suitable solubilizers include, but are not limited to, the following substances: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, diethylene glycol monoethyl ether, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives, polyethylene glycol ethers with an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl PEG ether (glycofurol) or methoxy PEG, amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, ε-caprolactone Amides, N-alkylpyrrolidones, N-hydroxyalkylpyrrolidones, N-alkylpiperidones, N-alkylcaprolactams, dimethylacetamide and polyvinylpyrrolidone, esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl octanoate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers, and other solubilizers known in the art, such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoic acid, diethylene glycol monoethyl ether and water.

[0258] Mixtures of solubilizers may also be used. Examples include, but are not limited to, triacetyl citrate, triethyl citrate, ethyl oleate, ethyl octanoate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, tetrahydrofuran polyethylene glycol ether, diethylene glycol monoethyl ether, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetyl citrate, ethanol, PEG-400, tetrahydrofuran polyethylene glycol ether, and propylene glycol.

[0259] There are no particular limitations on the amount of solubilizer that may be included. A given amount of solubilizer may be limited to a bioacceptable amount, which can be readily determined by those skilled in the art. In some cases, including an amount of solubilizer far exceeding the bioacceptable amount may be advantageous, for example, to maximize the concentration of the drug, removing excess solubilizer using conventional techniques such as distillation or evaporation before administering the composition to the patient. Thus, if present, the weight ratio of solubilizer may be 10% by weight, 25% by weight, 50% by weight, 100% by weight, or up to about 200% by weight, based on the total weight of the drug and other excipients. Very small amounts of solubilizer, such as 5%, 2%, 1%, or even less, may also be used if desired. Typically, the amount of solubilizer present may be from about 1% by weight to about 100% by weight, more typically from about 5% by weight to about 25% by weight.

[0260] The composition may further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to: detackifiers, defoamers, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tension modifiers, flavoring agents, coloring agents, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0261] Additionally, acids or bases may be incorporated into the composition to facilitate processing, enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic calcite dihydrate, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tri(hydroxymethyl)aminomethane (TRIS), etc. Also suitable are bases that are salts of pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanolamine, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc. Polyprotic acid salts, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate, may also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, and alkaline earth metals. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0262] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, and phosphoric acid. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulosic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, quinacrine, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid.

[0263] Pharmaceutical composition for injection In some embodiments, a pharmaceutical composition for injection is provided, comprising an active pharmaceutical ingredient or a combination of active pharmaceutical ingredients, such as a compound of the formula ADY, and a pharmaceutical excipient suitable for injection.

[0264] The compositions of the present invention may be incorporated into aqueous or oily suspensions or emulsions for administration by injection, containing sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical carriers.

[0265] Aqueous solutions in saline solutions are also commonly used for injection. Ethanol, glycerol, propylene glycol, and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Appropriate flowability can be maintained, for example, by using coatings (such as lecithin) to maintain the desired particle size (in the case of dispersions) and by using surfactants. Microbial activity can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.

[0266] Sterile injectable solutions are prepared by incorporating the desired amount of the active pharmaceutical ingredient or combination of active pharmaceutical ingredients, along with various other ingredients listed above (as needed), into a suitable solvent, followed by filtration and sterilization. Generally, dispersions are prepared by incorporating various sterile active ingredients into a sterile medium containing a base dispersion medium and the desired other ingredients listed above. For sterile powders used to prepare sterile injectable solutions, certain desirable preparation methods include vacuum drying and freeze-drying techniques, which produce powders of the active ingredient plus any other desired ingredients from solutions that have been previously sterile filtered.

[0267] Pharmaceutical compositions for local delivery In some embodiments, pharmaceutical compositions for transdermal delivery are provided, comprising an active pharmaceutical ingredient or combination of active pharmaceutical ingredients, such as compounds of the formula ADY described herein, and pharmaceutical excipients suitable for topical (e.g., transdermal or corneal delivery). Any ocular drug delivery system known in the art can be used to deliver the compounds and compositions of the present invention (Patel et al., “Ocular drug delivery systems: An overview,” World J Pharmacol. 2013; 2(2):47–64).

[0268] The compositions of the present invention can be formulated into solid, semi-solid, or liquid forms suitable for topical or local application, such as gels, water-soluble gels, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, salt solutions, and dimethyl sulfoxide (DMSO)-based solutions. Generally, a carrier with higher density provides a region of prolonged exposure to the active ingredient. Conversely, solution formulations allow for more direct exposure of the active ingredient to the selected area.

[0269] Pharmaceutical compositions may also contain suitable solid or gel phase carriers or excipients, which are compounds that increase or facilitate the delivery of therapeutic molecules across the stratum corneum permeability barrier of the skin. Many such penetration-enhancing molecules are known to those skilled in the art of topical formulations. Examples of such carriers and excipients include, but are not limited to, moisturizers (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glyceryl monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0270] Another exemplary formulation used in the method of the present invention employs a transdermal delivery device (“patch”). Such transdermal patches can be used to provide continuous or discontinuous infusion of an active pharmaceutical ingredient or a combination of active pharmaceutical ingredients in controlled amounts, with or without another active pharmaceutical ingredient.

[0271] The construction and use of transdermal patches for drug delivery are well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139, the entire contents of which are incorporated herein by reference. Such patches can be constructed for continuous, pulsed, or on-demand drug delivery.

[0272] Pharmaceutical compositions for inhalation Compositions for inhalation or blowing include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above and compounds of the formula ADY as described herein. Preferably, the compositions are administered via oral or nasal routes for local or systemic action. Compositions in preferred pharmaceutically acceptable solvents can be nebulized using an inert gas. The nebulized solution can be inhaled directly from a nebulizer, or the nebulizer can be connected to a face mask tent or intermittent positive pressure ventilation machine. Solution, suspension, or powder compositions can preferably be administered orally or nasally from a device that delivers the formulation in a suitable manner. Dry powder inhalers can also be used to provide inhaled delivery of the composition.

[0273] Other pharmaceutical compositions and formulations Pharmaceutical compositions of the formula ADY described herein can also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or spinal administration. The preparation of such pharmaceutical compositions is well known in the art. See, for example, Anderson, Philip O.; Knoben, James E.; Troutman, William G. (eds.), *Handbook of Clinical Drug Data*, 10th edition, McGraw-Hill, 2002; and Pratt and Taylor (eds.), *Principles of Drug Action*, 3rd edition, Churchill Livingston, NY, 1990, the entire contents of which are incorporated herein by reference.

[0274] The administration of an active pharmaceutical ingredient or combination of active pharmaceutical ingredients, or a pharmaceutical composition thereof, may be carried out by any method capable of delivering the compound to the site of action. These methods include oral administration, intraduodenal administration, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or infusion), local administration (e.g., transdermal), rectal administration, local delivery via catheter or stent, or inhalation. The active pharmaceutical ingredient or combination of active pharmaceutical ingredients may also be administered intraadiposally or intrathecally. In some embodiments, a compound of formula ADY, or a pharmaceutical composition thereof, may be administered intraperitoneally.

[0275] Exemplary parenteral formulations include solutions or suspensions of the active compound in sterile aqueous solutions, such as propylene glycol or dextrose. Such formulations may be appropriately buffered if desired.

[0276] Exemplary liquid formulations include ophthalmic solutions, microemulsions, and in-situ gel formulations. Various excipients can be used in these formulations, such as those used to adjust the osmotic pressure, pH, and / or viscosity of the formulation. In some embodiments, the formulation is designed to prolong the contact time between the liquid dosage form and ocular tissue and increase tissue uptake of the active pharmaceutical ingredient. In some embodiments, excipients are included to increase viscosity and / or enhance permeability. In some embodiments, cyclodextrin is added. Cyclodextrin is a cyclic oligosaccharide that forms inclusion complexes with the active pharmaceutical ingredient, thereby increasing its water solubility and bioavailability. In some embodiments, such a method can be used to formulate hydrophobic active pharmaceutical ingredients.

[0277] In some embodiments, the present invention relates to a liquid formulation comprising about 0.05% to about 25%, for example about 3.5%, of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In some embodiments, the liquid formulation comprises about 0.05% to about 25%, for example about 16% of vitamin E TPGS. In some embodiments, the liquid formulation comprises about 0.05% to about 25%, for example about 3.18% of mannitol. In some embodiments, the liquid formulation comprises about 0.05% to about 25%, for example about 1.2% of boric acid. In some embodiments, the liquid formulation comprises about 0.001% to about 2.5%, for example about 0.005% of polyquaternium-1. In some embodiments, the liquid formulation comprises about 0.001% to about 2.5%, for example about 0.005% of a preservative. In some embodiments, the formulation can be prepared by dissolving polyquaternium-1 and vitamin E TPGS (D-α-tocopherol polyethylene glycol 1000 succinate) in purified water, adding a compound of formula ADY to the solution, and stirring at 70°C for a period of time (e.g., 30 minutes). The solution is then centrifuged, for example, at 13,200 rpm for a period of time, for example, 10 minutes, and the supernatant is collected. Mannitol and boric acid are added to the collected supernatant. After adjusting the pH to 6.7 ± 0.2 using an alkali such as NaOH, purified water is added to the final solution.

[0278] In some embodiments, the present invention relates to a liquid formulation comprising about 0.05% to about 25%, for example about 3% to about 4%, of a compound of the formula ADY, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In some embodiments, the present invention relates to a liquid formulation comprising about 5% to about 95%, for example about 80%, of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). In some embodiments, the present invention relates to a liquid formulation comprising about 0.05% to about 5%, for example about 0.1% of Cremophor EL (F1). In some embodiments, the present invention relates to a liquid formulation comprising about 0.05% to about 5%, for example about 1% of Tween 80 (F2). In some embodiments, the formulation can be prepared by dissolving about 6 g of HP-β-CD (CAS No. 128446-35-5) in 5 mL of purified water at 55°C (on a water bath). A specific amount of the compound of formula ADY or its pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug is added to the solution, and the mixture is incubated overnight in a water bath at 55°C, or until the compound of formula ADY is completely dissolved. Kolliphor EL or Tween 80 is added to the solution, respectively. The solution is then centrifuged at 3000 rpm for approximately 10 minutes to remove undissolved particles. The supernatant is collected.

[0279] In some embodiments, the present invention relates to a liquid formulation comprising about 0.05% to about 25%, for example about 3% to about 4%, or about 3.5% of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In some embodiments, the present invention relates to a liquid formulation comprising about 90% to about 99%, for example about 96.5% propylene glycol (PG). In some embodiments, propylene glycol is well tolerated by the eyes. The formulation may be applied topically to the eyes of New Zealand white rabbits in the form of eye drops at a concentration of 3.5% of the compound of formula ADY in propylene glycol, and its biodistribution over 1 hour shall be determined by HPLC.

[0280] In some embodiments, each of the various exemplary formulations exemplified herein targets a specific ocular tissue with the compound described herein, such as a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, in a particular manner. In some embodiments, the biodistribution characteristics of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug formulated as described herein are a result of the inherent physicochemical properties of the compound or its pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug. In some embodiments, the biodistribution characteristics of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug formulated as described herein are not a result of the inherent physicochemical properties of the compound or its pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug. In some embodiments, the biodistribution characteristics of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug formulated as described herein are generated by the specific formulation described herein. In some embodiments, the formulations described herein can direct a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof to a target therapeutic tissue, such as the cornea and conjunctiva for treating dry eye disease, or to the retina for treating various retinal diseases.

[0281] Exemplary semi-solid formulations include high-viscosity formulations that enhance bioavailability by increasing the residence time of the active pharmaceutical ingredient in the precorneal region. In-situ gels are viscous liquids that undergo a sol-gel transition upon ocular application due to variations in pH, temperature, or electrolyte concentration. Gelation excipients with favorable mucosal adhesion properties further increase residence time. Polymers used to develop these pharmaceutical formulations include gellan gum, poloxamer, and cellulose acetate phthalate. Poloxamer 407 or gellan gum can be used to generate thermogels.

[0282] In some embodiments, the present invention relates to a gel formulation comprising about 0.05% to about 25%, for example about 2.4% to about 3%, of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In some embodiments, the present invention relates to a gel formulation comprising about 0.05% to about 5%, for example about 0.4% or about 0.5% gellan gum. In some embodiments, the present invention relates to a gel formulation comprising about 0.05% to about 25%, for example about 5% or about 10% vitamin E TPGS. In some embodiments, the present invention relates to a gel formulation comprising about 0.05% to about 25%, for example about 5% or about 10% (2-hydroxypropyl)-β-cyclodextrin. In some embodiments, a gellan gum solution is prepared by adding an appropriate amount of gellan gum to deionized water and heating the mixture to 90°C with rapid stirring (500 rpm). Once the gum is completely dissolved, the solution is filtered through a 0.22 μm filter. Then, the compound of formula ADY or its pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug, along with other excipients, is added to the system to achieve the desired concentration, and then stirred at 500 rpm at 50°C until completely dissolved.

[0283] In some embodiments, the present invention relates to a gel formulation comprising about 0.05% to about 25%, for example about 3%, of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof and an alginate. In some embodiments, the present invention relates to a gel formulation comprising about 0.05% to about 5%, for example about 1.5% sodium alginate. In some embodiments, the present invention relates to a gel formulation comprising about 0.05% to about 25%, for example about 15% Tween 80. In some embodiments, the present invention relates to a gel formulation comprising about 0.05% to about 25%, for example about 10% (2-hydroxypropyl)-β-cyclodextrin. In some embodiments, the present invention relates to a gel formulation comprising about 0.05% to about 25%, for example about 10% polyethylene glycol 400 (PEG400). In some embodiments, the present invention relates to a gel formulation comprising about 0.05% to about 25%, for example about 5% polyethylene glycol stearate. In some embodiments, a sodium alginate solution is prepared by adding an appropriate amount of sodium alginate to deionized water and heating the mixture to 90°C with rapid stirring (500 rpm). Once the sodium alginate is completely dissolved, the solution is filtered through a 0.22 μm filter. Then, a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, along with any additional excipients, is added to achieve any desired concentration, and the mixture is stirred at 50°C and 500 rpm until completely dissolved.

[0284] In some embodiments, the present invention relates to nanoparticle formulations comprising about 0.05% to about 25%, for example about 3% to about 3.5%, of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In some embodiments, the present invention relates to nanoparticle formulations comprising about 75% to about 99%, for example about 96.5% to about 97%, of methoxy-poly(ethylene glycol)-poly(lactide) (mPEG-PLA). In some embodiments, an oil phase is prepared by dissolving a certain amount of a compound of formula ADY or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof and a certain amount of PEG-PLA in 20 mL of dichloromethane (DCM). In some embodiments, an aqueous phase is prepared by dissolving a certain amount of sodium cholate in a certain amount of purified water. A certain amount of the oil phase is then slowly added to a certain amount of the aqueous phase in an Eppendorf conical tube. To produce an emulsion, a probe can be used to sonicate for a period of time, for example, approximately 2 minutes at 75% output (Branson 150, Fisher Scientific). TM(USA; watt output at approximately 12-13). The emulsion was then transferred to a beaker and stirred overnight in a chemical hood at approximately 600 rpm until the DCM was completely evaporated. The mixture was then transferred to an ultrafiltration tube (Amicon Ultra-15) and centrifuged at 5000 rpm for approximately 1 h. PBS was added to the resulting concentrated nanoparticle formulation in the ultrafiltration tube to a specific volume, and the centrifugation step was repeated once. The concentrated nanoparticles were resuspended in PBS to the desired final volume, transferred to an Eppendorf tube, and spun for a short period of time, e.g., a few seconds, to remove aggregates. The supernatant was collected as the final product. The nanoparticles were characterized by effective diameter (nm), particle size distribution (polydispersity index), and drug encapsulation efficiency (EE; calculated as EE% = encapsulated drug / added drug × 100). The compound of formula ADY, formulated as nanoparticles, was administered topically as eye drops to New Zealand white rabbits, and the biodistribution of the compound of formula ADY in ocular tissues at various time points after administration was determined by HPLC. The biodistribution of the compound of formula ADY can also be determined after intravitreal injection. A specific amount of the compound of formula ADY, formulated in nanoparticles and diluted with PBS to a concentration of approximately 0.2% to approximately 2%, was directly injected into the vitreous humor of New Zealand white rabbits, and its biodistribution was determined by HPLC. The biodistribution of the compound of formula ADY in isolated human eyes was determined as described elsewhere herein. The anterior surface of the human eye (corresponding to an area slightly larger than the palpebral fissure) was directly contacted with a nanoparticle solution of the compound of formula ADY at concentrations of approximately 0.2%, approximately 1%, or approximately 2%, and the tissue was then treated as described herein. The biodistribution of the compound of formula ADY can also be determined in isolated pig eyes. The removed pig eyes were exposed to a nanoparticle solution of the compound of formula ADY (at a concentration of approximately 2%) and treated similarly to those used for human eyes.

[0285] In some embodiments, the compounds of formula ADY of the present invention, when applied topically to the anterior surface of the eye, are able to reach the retina. In some embodiments, this unexpected property is achieved when the compounds of formula ADY of the present invention are formulated as described herein. In some embodiments, the property of the compounds of formula ADY being rapidly transported to the posterior segment of the eye can be altered, inhibited, or otherwise modulated by changing their respective formulations. In some embodiments, unexpected characteristics limiting the distribution of the compounds of formula ADY can be used to direct the compounds to specific sites throughout the eye. In some embodiments, the compounds of formula ADY are directed to the anterior segment of the eye. In some embodiments, the compounds of formula ADY are directed to the posterior segment of the eye.

[0286] Exemplary multi-compartment formulations include nanoparticles, liposomes, dendritic polymers, and nanovesicles. Nanoparticles are polymer carriers that enhance bioavailability due to increased corneal penetration and a larger dissolution surface area. Nanovesicles and discos are two-layered carriers that improve the bioavailability of the active pharmaceutical ingredient by prolonging the pre-corneal residence time.

[0287] Reagent test kit The present invention also provides a kit. The kit includes, alone or in combination with suitable packaging, an active pharmaceutical ingredient or a combination of active pharmaceutical ingredients, and written materials that may include instructions for use, clinical study discussions, and a list of side effects. Such a kit may also include information such as scientific literature references, packaging inserts, clinical trial results and / or summaries of these, indicating or identifying the activity and / or benefits of the composition, and / or describing dosage, administration, side effects, drug interactions, or other information useful to a healthcare provider. Such information may be based on the results of various studies, such as studies using laboratory animals involving in vivo models and studies based on human clinical trials. The kit may further contain another active pharmaceutical ingredient. In selected embodiments, the active pharmaceutical ingredient or combination of active pharmaceutical ingredients is provided as a separate composition in a separate container within the kit. In selected embodiments, the active pharmaceutical ingredient or combination of active pharmaceutical ingredients is provided as a single composition within a container of the kit. Suitable packaging and additional items for use (e.g., measuring cups for liquid formulations, foils wrapped to minimize air exposure, etc.) are known in the art and may be included in the kit. The kits described herein can be offered, sold, and / or promoted to healthcare providers, including doctors, nurses, pharmacists, and prescribing personnel. In selected implementation schemes, the kits can also be sold directly to consumers.

[0288] In some embodiments, the present invention provides a kit comprising a composition comprising a therapeutically effective amount of an active pharmaceutical ingredient (e.g., a compound of the formula ADY) or a combination of active pharmaceutical ingredients or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. These compositions are typically pharmaceutical compositions. The kit is intended for simultaneous or separate co-administration of the active pharmaceutical ingredient or a combination of active pharmaceutical ingredients.

[0289] In some embodiments, the present invention provides a kit comprising (1) a composition comprising a therapeutically effective amount of an active pharmaceutical ingredient (e.g., a compound of the formula ADY) or a combination of active pharmaceutical ingredients or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and (2) a diagnostic test for determining whether a patient’s cancer is a specific cancer subtype. Any of the aforementioned diagnostic methods may be used in the kit.

[0290] The above-described kits are preferably used to treat the diseases and conditions described herein. In some embodiments, the kits are used to treat inflammatory diseases. In some embodiments, the kits are used to treat cancer, neurodegenerative diseases or conditions, cardiovascular diseases or conditions, eye diseases or conditions, angiogenic diseases or conditions, ovarian cancer, colon cancer, leukemia, gastric cancer, lung cancer, pancreatic cancer, cancers characterized by K-Ras mutations, cancers chemoresistant to other therapeutic agents (e.g., cisplatin or paclitaxel), or diabetic retinopathy.

[0291] In one specific implementation, the kit is used to treat hyperproliferative disorders, such as cancer. In some implementations, the kit described herein is used to treat cancers selected from the following: pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain cancer, head and neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck cancer, breast cancer, ovarian cancer, lung cancer, small cell lung cancer, Wilms' tumor, cervical cancer, testicular cancer, bladder cancer, pancreatic cancer, gastric cancer, colon cancer, prostate cancer, genitourinary cancer, thyroid cancer, esophageal cancer, myeloma, multiple myeloma, adrenal cancer, and renal cell carcinoma. Endometrial cancer, adrenocortical carcinoma, malignant pancreatic insulinoma, malignant carcinoid tumor, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, piloblastic leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocythemia, Hodgkin's disease, non-Hodgkin's lymphoma, soft tissue sarcoma, osteosarcoma, primary macroglobulinemia, and retinoblastoma. In a specific implementation, the kit described herein is used to treat malignant melanoma.

[0292] Dosage and administration regimen The amount of pharmaceutical composition administered using the methods described herein, such as the dosage of compounds of formula ADY, will depend on the subject, for example, the person or mammal being treated, the severity of the condition or illness, the rate of administration, the formulation of the active pharmaceutical ingredient, and the discretion of the prescribing physician. However, the effective dose is in the range of about 0.001 to about 100 mg per kg body weight per day, either in a single dose or in divided doses, such as about 1 to about 35 mg / kg / day. For a 70 kg person, this would total about 0.05 to 7 g / day, such as about 0.05 to about 2.5 g / day. In some cases, dose levels below the lower limit of the above range may be sufficient, while in others, larger doses may still be used without causing any adverse side effects—for example, by dividing such a larger dose into several smaller doses administered throughout the day. The dosage of the pharmaceutical composition and the active pharmaceutical ingredient can be expressed in mg / kg body weight or mg / m². 2 Body surface area is provided.

[0293] In some embodiments, the compounds described herein are delivered to mammals to treat a disease. Those skilled in the art will understand that in some embodiments, the dosage of such compounds can be adjusted depending on the mammal to be treated. For example, in some embodiments, treatment of rabbits is described herein, and such dosage may or may not be changed when administering the compounds of the invention to humans. However, if desired, those skilled in the art can convert the dosages provided herein as described in Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, USDapartmentofHealth and Human Services,Food and Drug Administration,Center for Drug Evaluation and Research (CDER), July 2005 (the entire contents of which are incorporated herein by reference). In some embodiments, the human equivalent dose (HED) can be determined from the animal dose by multiplying the animal dose by the following conversion factors to provide units in mg / kg: mouse = 0.08, hamster = 0.13, rat = 0.16, ferret = 0.19, guinea pig = 0.22, rabbit = 0.32, dog = 0.54, monkey = 0.32, marmoset = 0.16, squirrel monkey = 0.19, baboon = 0.54, miniature pig = 0.73, and small pig = 0.95. As will be understood by those skilled in the art, the foregoing conversion factors are exemplary and in no way limiting the doses provided herein.

[0294] In some embodiments, the present invention includes a method for treating cancer in a human subject, the method comprising the step of administering to the human subject a therapeutically effective dose of an active pharmaceutical ingredient of the formula ADY.

[0295] In some embodiments, the present invention includes a method of treating cancer in a human subject suffering from cancer in which cancer cells overexpress K-Ras, the method comprising the step of administering to the human subject a therapeutically effective dose of an active pharmaceutical ingredient of the formula ADY to inhibit or reduce K-Ras protein activity.

[0296] In some embodiments, the pharmaceutical composition or active pharmaceutical ingredient is administered in a single dose. Such administration can be by injection, such as intravenous injection, to rapidly deliver the active pharmaceutical ingredient. However, other routes may be used as appropriate, including the preferred oral route. A single dose of the pharmaceutical composition can also be used to treat acute conditions.

[0297] In some embodiments, the pharmaceutical composition or active pharmaceutical ingredient is administered in multiple doses. In one embodiment, the pharmaceutical composition is administered in multiple doses. Administration may be once, twice, three times, four times, five times, six times, or more than six times daily. Administration may be once a month, once every two weeks, once a week, or every other day. In other embodiments, the pharmaceutical composition is administered from about once daily to about six times daily. In some embodiments, the pharmaceutical composition is administered once daily, while in other embodiments, the pharmaceutical composition is administered twice daily, and in other embodiments, the pharmaceutical composition is administered three times daily.

[0298] Administration of the active pharmaceutical ingredient can continue as needed. In selected embodiments, the pharmaceutical composition is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the pharmaceutical composition is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the pharmaceutical composition is continuously administered for a long period—for example, for treating chronic effects. In some embodiments, administration of the pharmaceutical composition continues for less than about 7 days. In another embodiment, administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous administration can be achieved and maintained as needed.

[0299] In some embodiments, the effective dose of the active pharmaceutical ingredient disclosed herein is from about 1 mg to about 500 mg, from about 10 mg to about 300 mg, from about 20 mg to about 250 mg, from about 25 mg to about 200 mg, from about 10 mg to about 200 mg, from about 20 mg to about 150 mg, from about 30 mg to about 120 mg, from about 10 mg to about 90 mg, from about 20 mg to about 80 mg, from about 30 mg to about 70 mg, from about 40 mg to about 60 mg, from about 45 mg to about 55 mg, from about 48 mg to about The effective dose of the active pharmaceutical ingredient disclosed herein is within the range of 52 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, or about 198 mg to about 202 mg. In some embodiments, the effective dose of the active pharmaceutical ingredient disclosed herein is less than about 25 mg, less than about 50 mg, less than about 75 mg, less than about 100 mg, less than about 125 mg, less than about 150 mg, less than about 175 mg, less than about 200 mg, less than about 225 mg, or less than about 250 mg. In some embodiments, the effective dose of the active pharmaceutical ingredient disclosed herein is greater than about 25 mg, greater than about 50 mg, greater than about 75 mg, greater than about 100 mg, greater than about 125 mg, greater than about 150 mg, greater than about 175 mg, greater than about 200 mg, greater than about 225 mg, or greater than about 250 mg.

[0300] In some embodiments, the effective dose of the active pharmaceutical ingredient disclosed herein is in the range of about 0.01 mg / kg to about 200 mg / kg, or about 0.1 to 100 mg / kg, or about 1 to 50 mg / kg.

[0301] In some embodiments, the active pharmaceutical ingredient is administered at doses of 10 to 200 mg BID, including doses of 50, 60, 70, 80, 90, 100, 150, or 200 mg BID. In some embodiments, the active pharmaceutical ingredient is administered at doses of 10 to 500 mg BID, including doses of 1, 5, 10, 15, 25, 50, 75, 100, 150, 200, 300, 400, or 500 mg BID.

[0302] In some cases, dose levels below the lower limit of the aforementioned range may be sufficient, while in others, larger doses may be used without causing any harmful side effects, for example, by dividing such a larger dose into several smaller doses administered throughout the day. As those skilled in the art will understand, the actual dose administered will depend on the condition being treated, the recipient's age, health status, and weight, the type of concurrent treatment (if any), and the frequency of treatment. Furthermore, those skilled in the art can determine an effective dose based on routine empirical activity tests that measure the biological activity of the compound in a bioassay and thereby determine the appropriate dosage.

[0303] An effective amount of the combination of active pharmaceutical ingredients can be administered in single or multiple doses via any acceptable route of administration of agents with similar efficacy, including rectal, buccal, intranasal and transdermal routes, via intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical or as an inhaler.

[0304] In some embodiments, the compositions described herein further include a therapeutic dosage form for administering the compound in a controlled-release, sustained-release, or extended-release manner, comprising incorporating the compound into a suitable delivery system during the formation of certain compositions. The dosage form controls the release of the compound in such a manner that an effective concentration of the compound in the blood can be maintained over a prolonged period, and the blood concentration remains relatively constant, to improve therapeutic outcomes and / or minimize side effects. Additionally, the controlled-release system will provide minimal peak-to-trough fluctuations in the plasma levels of the compound.

[0305] The invention is described in more detail below with reference to the embodiments. These embodiments are provided for illustrative purposes only and should not be construed as limiting the invention. Example

[0306] Materials and Methods General chemical methods: All reactions sensitive to air or moisture were performed under positive nitrogen pressure using dried glassware. Chemical reagents and anhydrous solvents were obtained from commercial sources and used as is. HPLC conditions: Column: Halo C18 4.6 × 150 mm, 2.7 μm, Part #: 92814-702; Flow rate: 0.8 mL / min; Mobile phase A: 0.05% TFA / water; B: 0.05% trifluoroacetic acid / acetonitrile; Gradient: Time (min) - %A / %B: 0 min = 90% / 10%; 8 min = 20% / 80%; 10 min 0% / 100%; 10.1 min = 90% / 10%; 15 min = 90% / 10%.

[0307] Example 1: Synthesis of Compound 1 Option 1 Synthesis of intermediate (c): A mixture of sulindac (9.36 g, 26.2 mmol) and CDI (4.92 g, 30.1 mmol, 1.15 equivalents) in THF (150 mL) was stirred at room temperature for 1–2 hours to produce a thick slurry. After the sulindac was completely consumed, compound (b) (7.83 g, 34.1 mmol, 1.30 equivalents) was added to the slurry. The resulting mixture was stirred overnight at room temperature to obtain a clear, pale yellow solution. After the reaction was completed as monitored by HPLC, the solvent was evaporated under reduced pressure at room temperature. Then, EtOAc (200 mL) and H2O (60.0 mL) were added to the reaction mixture. The organic layer was washed with H2O (40.0 mL × 3) and brine (30.0 mL), dried over MgSO4, and evaporated to give intermediate (c) (17.2 g). This substance was used in the next step without further purification.

[0308] Synthesis of intermediate (d): TFA (35.0 mL) was added to a solution of intermediate (c) (17.2 g) in DCM (90.0 mL) in an ice bath. The resulting solution was stirred overnight. After the reaction was completed as monitored by HPLC, the reaction mixture was evaporated under reduced pressure at room temperature to give intermediate (d) (40.6 g, containing excess TFA residue). This substance was used in the next step without further purification.

[0309] Synthesis of Compound 1: In an ice bath in the presence of Et3N (100 mL), methanesulfonyl chloride (4.5 g, 1.5 equivalents) in DCM (20 mL) was added to a solution of intermediate (d) (36.8 g, containing excess TFA, 23.7 mmol) in DCM (120 mL) via a syringe pump over 4 hours. After the reaction was monitored by HPLC, the reaction mixture was diluted with DCM (150 mL), washed with NaHCO3 (50 mL × 2), H2O (40 mL × 3), and brine (50 mL), and evaporated to obtain a reaction mixture containing excess Et3N residue. The reaction mixture was dissolved in EtOAc (200 mL), and H2O (100 mL) was added to the reaction mixture. The organic layer was washed with H2O (40.0 mL × 4) and brine (40.0 mL × 2), dried over MgSO4, evaporated, and purified by rapid chromatography (0%-5% MeOH / DCM) to give compound 1 (4.86 g) (yield: 34.0% in total for 3 steps).

[0310] Synthesis of the salt of compound 1: A solution of compound 1 (7.86 g) in DCM (100 mL) was stirred at 0 °C, and then methanesulfonic acid (1.38 g, 1.0 equivalent) in DCM (10.0 mL) was slowly added. EtOAc (100 mL) was added very slowly to the above mixture, followed by heptane (200 mL). The resulting suspension was stirred for 2 hours, filtered, and washed with heptane (30.0 mL × 3) to give a yellow solid. The yellow solid was dried under high vacuum, then dissolved in H2O (40 mL) and freeze-dried to provide the salt of compound 1 (8.4 g). Figure 1 The salt of compound 1 is shown 1 HNMR spectrum, and Figure 2 MS of the salt of compound 1 is shown.

[0311] Example 2: Synthesis of Compound 2 Option 2 Synthesis of Compound 2: In an ice bath in the presence of DIPEA (150 mL), diethyl chlorophosphate (6.7 g, 1.5 equivalents) in DCM (20 mL) was added via a syringe pump to a solution of intermediate (d) (40.7 g, containing excess TFA, approximately 26 mmol) in DCM (200 mL) over 4 hours. After the reaction was completed as monitored by HPLC, the reaction mixture was concentrated, diluted with EtOAc (200 mL), washed with NaHCO3 (50 mL × 2), H2O (40 mL × 4), and brine (50 mL × 2), evaporated, and purified by rapid chromatography (0%–5% MeOH / DCM) to give Compound 2 (6.56 g) (yield: 41.8% after 3 steps).

[0312] Synthesis of the salt of compound 2: A solution of compound 2 (8.41 g) in DCM (100 mL) was stirred at 0 °C, and then methanesulfonic acid (1.32 g, 1.0 equivalent) in DCM (10.0 mL) was slowly added. EtOAc (100 mL) was added very slowly to the above mixture, followed by heptane (400 mL). The resulting suspension was stirred for 2 hours, filtered, and washed with heptane (30.0 mL × 3) to give a yellow solid. The yellow solid was dried under high vacuum, then dissolved in H2O (50 mL) and freeze-dried to provide the salt of compound 2 (9.40 g). Figure 3 The salt of compound 2 is shown 1 HNMR spectrum, and Figure 4 MS of the salt of compound 2 is shown.

[0313] Example 3: Synthesis of Compound 5 Option 3 Synthesis of intermediate (k): A mixture of compound (h) (4.90 g, 29.2 mmol) and compound (j) (7.1 g, 29.5 mmol, 1.01 equivalents) in ACN (150 mL) was refluxed for 12 h to produce a slurry. After the reaction was completed by HPLC monitoring, the solvent was evaporated under reduced pressure at room temperature. Then, EtOAc (200 mL) and H2O (60.0 mL) were added to the reaction mixture. The organic layer was washed with H2O (40.0 mL × 2) and brine (30.0 mL), dried over MgSO4, evaporated, and purified by rapid chromatography (5%–10% EtOAc / heptane) to give compound (k) (10.5 g) in 96.7% yield.

[0314] Synthesis of intermediate (m): NaOH (80.0 mL, 1.0 N) was added to a solution of intermediate (k) (17.2 g) in methanol (150 mL) at room temperature. The resulting mixture was refluxed at 60 °C for 3 h. After the reaction was complete as monitored by TLC, the reaction mixture was evaporated under reduced pressure at room temperature and neutralized to pH 5-6 with HCl (2.0 N). The mixture was extracted with EtOAc (50.0 mL × 4). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under vacuum to give (m) in solid form (9.9 g, 98.0%). This substance was used in the next step without further purification.

[0315] Synthesis of Compound 5: A mixture of compound (m) (3.59 g, 11.0 mmol) and CDI (2.33 g, 14.3 mmol, 1.30 equivalents) in THF (40.0 mL) was stirred at 30–40 °C for 2 hours. Compound (m) (2.38 g, 16.5 mmol, 1.5 equivalents) in THF (15 mL) was slowly added to the mixture at room temperature. The resulting mixture was stirred overnight at room temperature to obtain a clear, pale yellow solution. After the reaction was complete as monitored by HPLC, the solvent was evaporated under reduced pressure. Then, DCM (100 mL) and H₂O (30.0 mL) were added to the reaction mixture. The aqueous layer was extracted with DCM (40.0 mL × 3). The combined organic layers were washed with H2O (40.0 mL × 3) and brine (30.0 mL), dried over MgSO4, evaporated, and purified by rapid chromatography (0%-15% MeOH / DCM) to give compound 5 (4.95 g) in 92.7% yield.

[0316] Synthesis of the salt of compound 5: Phosphoric acid (1.05 mL, 1.0 equivalent) in EtOAc (10.0 mL) was slowly added to a solution of compound 5 (7.40 g, 15.3 mmol) in EtOAc (25.0 mL) at 0 °C. Heptane (500 mL) was added very slowly to the mixture. The resulting suspension was stirred for 2 hours, filtered, and washed with heptane (30.0 mL × 3) to give a white solid. The solid was dried under high vacuum, dissolved in H2O (80 mL), and then freeze-dried to provide phosphate of compound 5 as a grayish-white colloidal solid (9.2 g). Figure 5 The salt of compound 5 is shown. 1 HNMR spectrum, and Figure 6 MS of compound 5 salt is shown.

[0317] Example 4: Synthesis of Compound 6 Option 4 Synthesis of compound (q): DCC (3.45 g, 16.74 mmol, 1.2 equivalent) was added to a mixture of intermediate (m) (5.00 g, 13.95 mmol) and HOBt (1.89 g, 13.95 mmol, 1.0 equivalent) in THF (60.0 mL) in an ice bath. The resulting slurry was stirred at room temperature for 2 hours. Compound (p) (3.15 g, 16.74 mmol, 1.2 equivalent) in THF (30.0 mL) was added to the slurry. The reaction mixture was stirred at room temperature overnight, concentrated, diluted with EtOAc (200 mL), filtered, and washed with EtOAc (20 mL × 3). The combined organic layers were treated with NaHCO3 (40.0 mL), NaOH (40 mL, 2.0 N), and brine (40 mL × 2), dried over MgSO4, evaporated, and purified by rapid chromatography (0%-30% EtOAc / heptane) to give compound (q) (6.51 g, 88.2%).

[0318] Synthesis of compound (r): A suspension of compound (q) (3.86 g, 7.3 mmol), NaOtBu (6.92 g, 72.0 mmol, 10 equivalents), and H2O (0.17 mL, 1.0 equivalents) in 2-MeTHF (800 mL) was heated to reflux for 15 hours. After the reaction was complete, the mixture was cooled in an ice bath and quenched with saturated ammonium chloride (50.0 mL) to adjust the pH to 10-11. The aqueous layer was extracted with EtOAc (40.0 mL × 4), washed with H2O (40.0 mL × 2) and brine (30.0 mL), dried over MgSO4, evaporated, and purified by rapid chromatography (5%-50% MeOH / DCM) to give compound (r) (2.64 g) in 84.3% yield.

[0319] Synthesis of Compound 6: Compound (t) (1.92 mL, 1.2 equivalents) was added to a solution of compound (r) (4.73 g, 11.04 mmol) and DIPEA (5.80 mL, 3 equivalents) in DCM (80 mL) in an ice bath. The resulting mixture was stirred at room temperature for 2 hours. The mixture was evaporated, diluted with EtOAc (150 mL), washed with NaHCO3 (40.0 mL), H2O (40.0 mL × 3), and brine (30.0 mL), dried over MgSO4, evaporated, and purified by different solvent systems (0%–5% MeOH / DCM) and (50%–100% EtOAc / heptane) to give product 6 (5.05 g) as a pale yellow oil in yield of 83.7%. Figure 7 Compound 6 is shown 1 HNMR spectrum, and Figure 8 MS of compound 6 is shown.

[0320] Example 5: Synthesis of Compound 7 Option 5 Step 1: Synthesis of tert-butyl (2-(4-(2-propylpentanoyl)piperazin-1-yl)ethyl)carbamate (7b): CDI (28.5 g, 17.56 mmol, 1.0 equivalent) was added to a stirred solution of compound 7a (22.0 g, 15.22 mmol, 1.0 equivalent) in THF (170 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After 2 hours, compound 7d (45.0 g, 19.86 mmol, 1.3 equivalent) in THF (170 mL) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was stirred at room temperature for 18 hours (monitored by TLC). After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give the residue. The residue was suspended in water (300 mL) and extracted with EtOAc (2 × 400 mL). The combined organic layers were dried over sodium sulfate and filtered. The solvent was concentrated under reduced pressure to give the crude product. The crude product was purified by alkaline silica gel column chromatography using ethyl acetate:hexane (30:70) as the eluent to give compound-7b (34.0 g), which was a pale yellow liquid. 1 H-NMR (400MHz, CDCl3): δ5.01(bs,0.8H),3.67(t,J=9.6Hz,2H),3.56(t,J=9.6Hz,2H),3.24(t,J=5.2Hz,2H),2.66-2.52 (m,1H),2.49-2.40(m,6H),1.65-1.62(m,2H),1.47(s,9H),1.41-1.34(m,3H),1.30-1.20(m,4H),0.88(t,J=7.2Hz,6H).

[0321] Step 2: 1-(4-(2-aminoethyl)piperazin-1-yl)-2-propylpentan-1-one (7c) Synthesis: TFA (71.9 mL, 63.09 mmol, 7.0 equivalent) was added dropwise to a stirred solution of compound 7b (32.0 g, 90.14 mmol, 1.0 equivalent) in DCM (425 mL) for 10 minutes at 0 °C. The reaction mixture was stirred at room temperature for 2.5 hours. After 2.5 hours, the reaction mixture was concentrated under reduced pressure to give a residue. The obtained residue was co-distilled with toluene (2 × 60 mL). The obtained residue was washed with diethyl ether and dried under vacuum to give compound -7c, a TFA salt. It was dissolved in a mixture of dichloromethane:water (9:1) and NaHCO3 (64 g, 2 g equivalent) was added, and the mixture was stirred for 30 minutes. After 30 minutes, the reaction mixture was filtered, and the solvent was dried over Na2SO4 and filtered again. The solvent was concentrated under reduced pressure to give compound -7c (32.0 g) as a colorless liquid. 1H-NMR (400MHz, CD3OD): δ3.90-3.80(m,4H),3.37-3.33(m,2H),3.32-3.30(m,2H),3.28-3.10(m,4H) ,2.87-2.83(m,1H),1.62-1.53(m,2H),1.45-1.38(m,2H),1.37-1.17(m,4H),0.90(t,J=7.2Hz,6H).

[0322] Step 3: Synthesis of diethyl (2-(4-(2-propylpentanoyl)piperazin-1-yl)ethyl)aminophosphate (compound 7): DIPEA (18.25 g, 14.11 mmol, 3.0 equivalent) was added to a stirred solution of compound 7c (12.0 g, 47.05 mmol, 1 equivalent) in DCM (384 mL) over a 20-minute period at room temperature. After 20 minutes, the reaction mixture was cooled to 0 °C, and diethyl chlorophosphate (9.97 g, 56.47 mmol, 1.0 equivalent) was added dropwise over a 10-minute period at 0 °C. The reaction mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give the residue. The residue was dissolved in EtOAc (800 mL) and extracted with saturated NaHCO3 solution (2 × 250 mL). The organic layer was dried over sodium sulfate and filtered. The solvent was concentrated under reduced pressure to give the crude product. The crude product was purified by alkaline silica gel column chromatography using MeOH:DCM (2:98) as the eluent to give compound 7 (6.0 g) as a pure light brown liquid. 1 H-NMR (400MHz, CDCl3): δ4.10-4.05(m,4H),3.67-3.55(m,2H),3.40(bs,1H),3.04-2.91(m,2H,),2.54-2.5 2(m,1H),2.50-2.43(m,6H),1.65-1.63(m,2H),1.41-1.29(m,9H),1.28-1.21(m,4H),0.88(t,J=7.2Hz,6H). 31 P-NMR (161.9MHz, CDCl3): δ9.16.

[0323] Example 6: Cancer Growth Inhibition Exemplary compounds inhibit cancer growth. The therapeutic efficacy of compounds 2, 5, and 6 was evaluated in human and mouse cell lines from different tissue sources, and their 24-hour 50% inhibitory concentrations were determined using the following standard methodology. Typical results, demonstrating broad-spectrum anticancer activity, are shown in Table 5. Table 5: 24-hour IC 50 (μM)

[0324] Ovarian cancer cells were studied in more detail using the following ovarian cancer cell lines: SKOV-3, OVCAR3, A2780 (and two derived cell lines, A2870cis, which is resistant to cisplatin, and A2870ADR, which is resistant to doxorubicin), and HEY (sensitive to paclitaxel, and its paclitaxel-resistant derivative HEY-T30). Compounds 5 and 6 effectively inhibited the growth of these cancer cell lines. Table 6 summarizes the results obtained with compound 6. Similar results were obtained with compound 5. Table 6

[0325] Example 7: In vivo cancer growth inhibition The ability of compound 5 to inhibit the growth of human ovarian cancer cell xenografts in nude mice was determined. A mouse model reproducing peritoneal spread, the most clinically relevant manifestation of ovarian cancer, was used. In this model, luciferase-expressing ovarian cancer cells were injected intraperitoneally (ip) into nude mice. Following intraperitoneal administration of luciferin (a substrate for luciferase), multiple tumors grew within the peritoneal cavity, and their growth was monitored periodically using an IVIS Lumina II imaging system. The luciferase gene was transfected into SKOV-3 cells, and 2x10⁻⁶ cells were used. 6 The cells were injected intraperitoneally into mice. Two weeks later, when the tumors had grown, mice were treated with compound 5 (15 mg / kg) or a carrier (corn oil) via intraperitoneal injection once a day for six days a week (n = 10 mice / group).

[0326] like Figure 9 As shown, compound 5 significantly inhibited the growth of IP tumors. On day 24, compound 5 reduced tumor volume by 153% compared to the control (p < 0.001). When the tumor volume of mice treated with compound 5 at the end of the study was compared with the tumor volume on the day treatment began (baseline), compound 5 caused 53% tumor regression, and in 3 out of 10 mice, the tumor was difficult to detect by imaging and no visible tumor was found at necropsy. Compound 6 produced almost the same results.

[0327] Compound 6, administered once daily for six days a week at a dose of 100 mg / kg to the same animal model, produced almost identical results to compound 5. Compound 6 was also effective against chemotherapy-resistant ovarian cancer. This was demonstrated in subcutaneous xenografts of human ovarian cancer cell lines in nude mice. The effects of compound 6 in cisplatin-resistant (A2780cis) and doxorubicin (A2780ADR)-resistant tumors were investigated. Briefly, these cell lines were subcutaneously inoculated into athymic nude mice, and when the tumor size reached 100–200 mm... 3 At that time, compound 6, 150 mg / kg / day or its mediator was administered intraperitoneally. After 11 days of treatment, the tumor volume in the mediator group for cisplatin-resistant tumors was 2388 ± 127 mm. 3 Furthermore, for compound group 6, the tumor volume was 1032±108 mm. 3 (mean ± SEM; P < 0.02); for doxorubicin-resistant tumors, these values ​​were: mediator group = 1369 ± 337 mm 3 , and compound group 6 = 396 ± 182 mm 3 (P<0.02).

[0328] Example 8: In vivo efficacy against chemotherapy-resistant ovarian cancer To determine whether compound 5 was effective against chemotherapy-resistant ovarian cancer, three pairs of sensitive and resistant human ovarian cancer cell lines were cultured as subcutaneous xenografts in nude mice and treated accordingly. Figure 10 The following cell lines are summarized: A2780, sensitive to both cisplatin and doxorubicin (doxorubicin); A2780cis, resistant to cisplatin; A2780ADR, resistant to doxorubicin; HEY, sensitive to paclitaxel; HEY-T30, resistant to paclitaxel. When the tumor volume is approximately 150 mm... 3 Mice were treated as shown in the figure. The treatments administered were: mediator control; compound 5, 15 mg / kg / day, six days a week, intraperitoneally (IP); cisplatin 5.5 mg / kg, once a week, IP; doxorubicin 3 mg / kg, twice a week, IP; and paclitaxel 20 mg / kg, twice a week, IP. Figure 10 As shown, compound 5 and cisplatin inhibited the growth of platinum-sensitive xenografts with the same potency. In platinum-resistant xenografts, compound 5 was as effective as in platinum-sensitive xenografts, while platinum did not significantly inhibit tumor growth. The same response pattern was observed for compound 5 relative to (vs.) doxorubicin and compound 5 relative to paclitaxel. These results, consistent with in vitro data, demonstrate the ability of compound 5 to overcome drug resistance in ovarian cancer, a key determinant of clinical outcomes in this often fatal malignancy.

[0329] Example 9: Mechanism of anticancer action of compounds 5 and 6 Further studies evaluated the mechanisms of action of exemplary compounds 5 and 6, showing that they are different from each other and also different from other known compounds.

[0330] The primary mechanism of action of compound 5 is the induction of integrated stress response (ISR) and endoplasmic reticulum stress (ERS). These stresses are so intense that they exceed the pro-survival threshold, triggering cell death through autophagy and apoptosis—a therapeutically useful outcome. Normal cells can avoid this effect. This mechanism of action works in both sensitive and resistant cells and explains compound 5's ability to overcome chemotherapy resistance. Figure 11 The mechanism was summarized in the text, and Figures 12A-12C 13A-13C revealed key findings supporting this mechanism.

[0331] Compound 6 has a completely different mechanism of action, primarily based on inducing different types of stress in ovarian cancer cells, namely oxidative stress. Depending on its degree, oxidative stress can induce cancer cell death, mainly through apoptosis, thereby mediating the action of the anticancer agent. Figure 14 The mechanism is summarized in Figures 15 and 16, which illustrate key findings that support this mechanism.

[0332] Example 10: Synergistic effect with chemotherapeutic agents Further evidence shows that, at low doses, exemplary compound 5 synergistically works with low doses of cyclophosphamide to inhibit the growth of chemotherapy-resistant ovarian cancer. Figure 17 As shown, subcutaneous xenografts of the paclitaxel-resistant human ovarian cancer cell line HEY-T30 in nude mice were administered via intraperitoneal injection of either the drug or compound 5 at 10 mg / kg / day for six days, or orally with cyclophosphamide at 10 mg / kg / day for six days, or both at the same dose. Compared to the control, neither drug alone produced significant tumor growth inhibition. However, their combination not only significantly inhibited tumor growth (58% on day 21), but the extent of this inhibition established a synergistic effect, exceeding the sum of each drug alone (26% and 23% respectively on day 21).

[0333] Furthermore, in vitro studies using cultured human cancer cells have demonstrated the synergistic effects of exemplary compounds with various anticancer agents. For example, compound 5 synergistically with tamoxifen to substantially eliminate (when tamoxifen is administered before compound 5) or significantly reduce (if tamoxifen is administered concurrently with or before tamoxifen) the growth of MIA PaCa2 human pancreatic cancer cells. Additionally, compounds 5 and 6 have been shown to synergize with several chemotherapeutic agents and other agents, including but not limited to various camptothecins (e.g., camptothecin 11), resveratrol, gemcitabine, docetaxel, curcumin, progesterone, and methotrexate. Such synergistic effects involve the ability of these combinations to significantly inhibit the growth of various human cancer cell lines derived from the pancreas, lung, and other tissues. Furthermore, the combination of compounds 5, 6, and tamoxifen is highly effective in completely inhibiting the growth of K-ras mutant human pancreatic cancer cell lines.

[0334] Example 11: Exemplary compound inhibits VEGF expression Pathological angiogenesis is a hallmark of cancer. Tumor growth and metastasis depend heavily on the development of new blood vessels. Vascular endothelial growth factor (VEGF) is the most important molecule involved in angiogenesis. VEGF promotes tumor angiogenesis, and without sufficient blood supply, tumors cannot grow beyond a critical size. Pathological angiogenesis is also important in diabetic retinopathy (a common cause of blindness). VEGF plays a crucial role in diabetic retinopathy and is a therapeutic target.

[0335] The effects of compounds 2, 5, and 6 on VEGF production were examined. For example, SKOV-3 ovarian cancer cells cultured in culture were treated with compound 5 at 1x IC50. 50 Treatment lasted up to 24 hours. Secreted VEGF was measured in the culture medium by ELISA (R&D Systems). Compound 5 time-dependently inhibited VEGF-A levels, reaching 80% at 6 hours and 100% at 24 hours. Similar results were obtained using other ovarian cancer cell lines. For example, at 24 hours, the reduction in secreted VEGF-A relative to the corresponding controls was: OVCAR3 = 100%, A2780 = 86%, A2780cis = 100%, and A2780ADR = 100%. Compared to the control, compound 5 inhibited VEGF-B by 90-92%. The anti-VEGF activity of compound 5 was as strong in drug-resistant cell lines as in drug-sensitive cell lines. Compound 6 gave similar results.

[0336] Example 12: Exemplary compound inhibits the activation of mutant K-Ras The unexpected property of the compounds of this invention is that they strongly inhibit the activation of mutant K-Ras. This effect may be particularly useful in cancer types characterized by K-Ras mutations, such as, for example, pancreatic cancer, lung cancer, and ovarian cancer. Figure 18A The inhibition of K-Ras activation by compound 6 is shown.

[0337] Notably and surprisingly, exemplary compound 5 does not inhibit the activation of mutant K-Ras through the mechanism by which compound 6 inhibits the activation of mutant K-Ras, but rather by inhibiting its palmitoylation. Figure 18B This is a lipid modification required to drive Ras action in cancer. This property of compound 5 is not shared by, for example, compound 6 or sulinic acid phosphate.

[0338] Example 13: Exemplary compound reaches the posterior chamber of the eye The biodistribution of the compound of formula ADY was determined after topical application to the eyes of New Zealand white rabbits in the form of in vivo eye drops. The biodistribution of the compound of formula ADY can also be determined after topical application to human cadaver eyes, which were stored on ice and used within 2 hours of removal from the donor. The anterior surface of the human eye (corresponding to an area slightly larger than the palpebral fissure) was brought into direct contact with the formulation of the present invention and incubated at 37°C for approximately 10 minutes. The eye was then rinsed with 10% dimethyl sulfoxide (DMSO) to remove residual PS from the ocular surface without damaging ocular tissue, and incubated in PBS for 60 minutes. At specific time intervals, ocular tissue was dissected and the levels of the compound of formula ADY were determined by HPLC.

[0339] The pharmacokinetics and biodistribution of compounds 1, 2, and 5 in rabbit eyes were determined. These compounds were each dissolved in phosphate-buffered saline (PBS) and used as eye drops. The eye drops were sterilized by filtration through a 0.2 μm membrane prior to administration to rabbits. New Zealand rabbits were administered 25 μl of each of the three eye drops every 5 minutes, and euthanized after 1 or 3 hours. Eyes were harvested, ocular tissue and lacrimal glands were dissected, homogenized, and the test compounds were extracted with acetonitrile and analyzed by HPLC as described in the compound synthesis section herein. Compounds 1 and 2 were detected at 328 nm, and compound 5 at 260 nm. The results obtained are shown in Table 7. All three compounds reached the posterior chamber of the eye unexpectedly, easily, and rapidly. Table 7: Drug levels in rabbit eye tissue ND: Not detected; NA: Not measured

[0340] The following was demonstrated in an ocular PK / biodistribution study in rats using another exemplary compound (compound 6). Compound 6 (reconstituted in polyethylene glycol 155; Tween 80% 1%; Kolliphor EL 10%, prepared with physiological saline to 100%; pH 7.2) was administered intravenously (iv) at a single dose of 30 mg / kg. Its retinal levels were 4.9 μM and 1 μM at 1 h and 2 h, respectively (corresponding scleral levels were similar, at 3.2 μM and 2.0 μM). When compound 6 was administered intraperitoneally (ip) at a single dose of 100 mg / kg (in corn oil), its retinal levels were detectable at 3 h (3.2 μM) and remained at 2.8 μM at 4 h and 6 h. Similarly, following a single topical application, 3% of compound 6 (formulated in 16% vitamin E TPGS, 3.2% mannitol, 1.2% boric acid, and 0.005% polyquad, pH 7.2) produced a retinal level of 2.1 μM at 4 h. The biodistribution of compound 2 in a human eye (recently removed from a deceased donor and kept on ice until several hours after application) was also assessed. In this study, compound 2 was dissolved in pure water; its pH was adjusted to 4.8 ± 0.1, and its osmolarity was adjusted to 290 mOsm. The final concentration of compound 2 was 10% (w / v).

[0341] The anterior surface of each eye was brought into contact with a solution of compound 2 at 37°C; the solution level was approximately 3 mm above the corneal rim. After 1 minute or 10 minutes, the eyes were thoroughly rinsed with PBS, incubated for 1 hour, and the retina, choroid, aqueous humor, ciliary body, iris, and cornea were dissected and collected for HPLC analysis. As shown in the table below, compound 2 indeed reached the posterior segment of the eye.

[0342] Example 14: In vivo inhibition of oxygen-induced retinopathy by exemplary compounds Several animal models have been explored to understand retinal vascular development. The mouse model of oxygen-induced retinopathy is the most widely used and has played a crucial role in our understanding of retinal angiogenesis and in the development of therapies such as anti-vascular endothelial growth factor injections for wet age-related macular degeneration. In this model, the retina exhibits widespread central vascular occlusion, with pathological neovascularization forming around the junction of vascular and avascular areas, reflecting oxygen-induced retinopathy in humans.

[0343] Starting on day 7 postnatal (P7), C57BL / 6 mice were housed in 75 ± 2% oxygen and introduced into room air on P12 after intravitreal injection of 1 μl of 1% Compound 6 solution or a medium. On P17, the pups were euthanized, both eyes were enucleated and fixed with 4% paraformaldehyde (PFA). After several intermediate steps, the retina was obtained and further fixed overnight with 4% PFA. After appropriate washing, the retina was incubated overnight with 10 μg / ml FITC-conjugated anti-agglutinin antibody, and retinal patches were prepared on slides and evaluated by fluorescence microscopy. The areas of avascular, neovascularized, and the entire retina were determined using ImageJ software.

[0344] As shown in Figure 19, compared with the control group treated with the mediator, treatment with compound 6 significantly reduced the central avascular area (75% inhibition; p<0.001) and peripheral neovascularization (51% inhibition; p<0.04) in these mice, restoring the retinal vascular system to normal.

[0345] Consistent with these findings, compound 6 demonstrated an ability to inhibit angiogenesis in vitro when used in the following assays ( Figure 20 (a) Tube formation assays using cultured human vascular endothelial cells (HUVECs) (which mimic the remodeling phase of angiogenesis), in which both compounds significantly inhibited the formation of capillary-like structures (also known as tubes), for example, compound 6 at 30 μM inhibited branching points by 97% (p<0.001); and (b) chicken embryo chorioallantoic membrane assays, an established model for studying neovascularization, in which compound 5 reduced neovascularization by 21% (58±4.9 to 46±2.1; p<0.04) and compound 6 reduced it by 37% (42.6±8.2 to 27±1.5; p<0.03).

[0346] In another study, the same mouse model of oxygen-induced retinopathy described above was used. In this study, mice were treated daily from day 12 to day 17 with an aqueous solution of compound 2 (pH = 4.6, molar osmolality = 282 mOsm; concentration = 10% w / v). Compound 2 was administered as one drop of ophthalmic solution to each eye every two hours throughout the day, for a total of five administrations per day. At the end of the study, the mice were euthanized, and their retinas were dissected and studied using an anti-lectin I antibody, isolectin B4 (Vector Laboratories), via immunofluorescence assay, and evaluated as described above.

[0347] Figure 21 demonstrates that compound 2 has a major effect on retinopathy. Specifically, compound 2 significantly reduced the avascular area of ​​the retina (mediator = 16.8 ± 1.1 vs. compound 2 = 5.8 ± 0.8; p < 0.0001) and the neovascular area (mediator = 20.7 ± 3.7 vs. compound 2 = 9.9 ± 2.2; p < 0.029). n = 8 groups.

[0348] To describe the state of the prior art to which this invention relates, numerous patent and non-patent publications are cited herein. The entire disclosure of each of these publications is incorporated herein by reference.

[0349] Although certain embodiments of the invention have been described and / or exemplified above, various other embodiments will be apparent to those skilled in the art from the foregoing disclosure. Therefore, the invention is not limited to the specific embodiments described and / or exemplified, but is capable of considerable variations and modifications without departing from the scope and spirit of the appended claims.

[0350] References 1.Prager GW, Braga S, Bystricky B, Qvortrup C, Criscitiello C, Esin E, et al., Global cancer control: responding to the growing burden, rising costs and inequalities in access. ESMO Open2018; 3(2):e000285; 2.Global Burden of Disease Cancer C, Fitzmaurice C, Akinyemiju TF, AllLami FH, Alam T, Alizadeh-Navaei R et al., Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990to 2016:ASystematicAnalysis for the Global Burden of Disease Study.JAMAOncol 2018; 3.Fidler MM,Bray F,Soerjomataram I.The global cancer burden and humandevelopment:Areview.Scand J Public Health 2018;46(1):27-36; 4.Nikolaou M,Pavlopoulou A,Georgakilas AG,Kyrodimos E.The challengeof drug resistance in cancer treatment:a current overview.Clin Exp Metastasis2018;35(4):309-18; 5.Reid BM,Permuth JB,Sellers TA.Epidemiology of ovarian cancer:areview.Cancer Biol Med2017;14(1):9-32; 6.Cortez AJ,Tudrej P,Kujawa KA,Lisowska KM.Advances in ovarian cancertherapy.Cancer Chemother Pharmacol 2018;81(1):17-38; 7.Giornelli GH.Management of relapsed ovarian cancer:areview.Springerplus 2016;5(1):1197; 8.Doubeni CA,Doubeni AR,Myers AE.Diagnosis and Management of OvarianCancer.Am Fam Physician 2016;93(11):937-44; 9.Matulonis UA,Sood AK,Fallowfield L,Howitt BE,Sehouli J,KarlanBY.Ovarian cancer.Nat Rev Dis Primers 2016;2:16061; 10. Duh EJ, Sun JK, Stitt AW. Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight 2017; 2(14); 11. National Institutes of Health. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Statistical summaries: cancer stat fact sheets (ovary) and cancer statistics review (CSR), 1975–2013, http: / / seer.cancer.gov / statistics / summaries.html, 2016; 12. Rosen DG, Yang G, Liu G, Mercado-Uribe I, Chang B, Xiao XS et al., Ovarian cancer: pathology, biology, and disease models. Front Biosci(Landmark Ed) 2009; 14:2089-102; 13. Itamochi H. Targeted therapies in epithelial ovarian cancer: Molecular mechanisms of action. World J Biol Chem 2010; 1(7):209-20; 14. Coward JI, Middleton K, Murphy F. New perspectives on targeted therapy in ovarian cancer. Int J Womens Health 2015; 7:189-203; 15. Westin SN, Herzog TJ, Coleman RL. Investigational agents in development for the treatment of ovarian cancer. Invest New Drugs 2013; 31(1):213-29; 16. Markman M, Walker JL. Intraperitoneal chemotherapy of ovarian cancer: a review, with a focus on practical aspects of treatment. J Clin Oncol 2006;24(6):988-94; 17. Narod S. Can advanced-stage ovarian cancer be cured?Nat Rev Clin Oncol 2016;13(4):255-61; 18. Coleman RL, Monk BJ, Sood AK, Herzog TJ. Latest research and treatment of advanced-stage epithelial ovarian cancer. Nat Rev Clin Oncol 2013;10(4):211-24; 19. Romero I, Bast RC, Jr. Minireview: human ovarian cancer: biology, current management, and paths to personalizing therapy. Endocrinology 2012;153(4):1593-602; 20. Vaughan S, Coward JI, Bast RC, Jr., Berchuck A, Berek JS, Brenton JD et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer 2011;11(10):719-25; 21. Bowtell DD, Bohm S, Ahmed AA, Aspuria PJ, Bast RC, Jr., Beral V et al. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer. Nat Rev Cancer 2015;15(11):668-79; [ PubMed ] 22.Cheng KW,Wong CC,Alston N,Mackenzie GG,Huang L,Ouyang N.Aerosol administration of phospho-sulindac inhibits lung tumorigenesis.MolCancer Ther 2013;12(8):1417-28; 23.Mackenzie GG,Sun Y,Huang L,Xie G,Ouyang N,Gupta RC Phospho-sulindac(OXT-328),a novel sulindac derivative,is safe and effective in coloncancer prevention in mice.Gastroenterology 2010:139(4):1320-32; EMBO Rep 2016:17(10):1374-95: 24.Pakos-Zebrucka K,Koryga I,Mnich K,Ljujic M,Samali A,Gorman AM. Annu Rev Pathol 2015:10:173-94: 25.Oakes SA,Papa FR.The role of endoplasmic reticulum stress in humanpathology. 26.Rigas B,Sun Y.Induction of oxidative stress as a mechanism of action of chemopreventive agents against cancer.Br J Cancer 2008:98(7):1157-60; 27. Sun Y, Huang L, Mackenzie GG, Rigas B. Oxidative stress mediates through apoptosis the anticancer effect of phospho-nonsteroidal anti-inflammatory drugs: implications for the role of oxidative stress in the action of anticancer agents. J Pharmacol Exp Ther 2011; 338(3):775-83; 28. Yokoyama C, Sueyoshi Y, Ema M, Mori Y, Takaishi K, Hisatomi H. Induction of oxidative stress by anticancer drugs in the presence and absence of cells. Oncol Lett 2017; 14(5):6066-70; 29. Lin DTS, Davis NG, Conibear E. Targeting the Ras palmitoylation / depalmitoylation cycle in cancer. Biochem Soc Trans 2017; 45(4):913-21; 30. Olivares AM, Althoff K, Chen GF, Wu S, Morrisson MA, DeAngelis MM et al., Animal Models of Diabetic Retinopathy. Curr Diab Rep 2017; 17(10):93; 31. Kim CB, D'Amore PA, Connor KM. Revisiting the mouse model of oxygen-induced retinopathy. Eye Brain 2016; 8:67-79.

Claims

1. Compound 6 or a pharmaceutically acceptable salt thereof: 。 2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or condition, wherein the medicament comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, wherein the disease or condition is an inflammatory disease or condition, cancer, neurodegenerative disease or condition, cardiovascular disease or condition, eye disease or condition, or angiogenic disease or condition.

4. The use according to claim 3, wherein the medicament further comprises a pharmaceutically acceptable excipient.

5. The use according to claim 3, wherein the cancer is ovarian cancer, colon cancer, leukemia, gastric cancer, lung cancer, pancreatic cancer, or cancer characterized by one or more K-Ras mutations.

6. The use according to claim 3, wherein the cancer is chemically resistant to one or more other therapeutic agents.

7. The use according to claim 3, wherein the treatment comprises inhibiting vascular endothelial growth factor expression.

8. The use as claimed in claim 3, wherein the disease or condition is an eye disease or condition.

9. The use according to claim 3, wherein the disease or condition is diabetic retinopathy.

10. The use as claimed in claim 3, wherein the disease or condition is dry eye disease.

11. The use according to claim 3, wherein the disease or condition is a retinopathy selected from the group consisting of: diabetic retinopathy, retinopathy of prematurity, VEGF retinopathy, age-related macular degeneration, retinal vein occlusion, and hypertensive retinopathy.

12. The use according to any one of claims 3 to 11, wherein the medicament further comprises a therapeutically effective amount of an additional active agent.

13. The use according to claim 12, wherein the additional active agent is selected from the group consisting of antibiotics, cyclosporine, ristatin, and combinations thereof.

14. The use according to any one of claims 3 to 11, wherein the drug is formulated for topical application.

15. The use of claim 14, wherein the drug is formulated for topical application in an eye drop dosage form.

16. The use according to any one of claims 3 to 11, wherein the drug is formulated for intraocular injection.

17. The use according to any one of claims 3 to 11, wherein the drug is formulated for oral administration.

Images