Bis(diaziridine) derivatives as photocrosslinkers for the treatment of corneal ectasia

Abstract

The present disclosure features bis(diaziridine) derivatives of formula (I) (1-a) or (1-b) that produce crosslinks in the cornea in response to exposure to electromagnetic radiation (e.g., UV-light). The compounds can be used, for example, to treat a subject (e.g., a human) suffering from a disease, disorder, or condition in which an abnormal shape of the cornea (e.g., corneal thinning, e.g., bilateral corneal thinning, e.g., bilateral thinning of the central, paracentral, or peripheral cornea; or corneal steepening (e.g., bulge)) contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition. Non-limiting examples of such diseases, disorders, or conditions include: (i) corneal ectatic diseases; (ii) vision conditions; (iii) diseases, disorders, or conditions that are sequelae to or coexist with any of the above or any of the disclosed herein. More specific non-limiting examples of such diseases, disorders or conditions include keratoconus, corneal sphericity, pellucid marginal degeneration, corneal ectasia (e.g., post-operative ectasia, such as post-LASIK ectasia), Terrien marginal degeneration, myopia, hyperopia, astigmatism, irregular astigmatism and presbyopia. In some embodiments, the claimed methods can be performed without adding or supplementing oxygen levels, which is advantageous in some applications. Preferred exemplary compounds are, for example, bis(diaziridine) amino acid derivatives, such as Example 1: #imgabs0#

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 796,803, filed on January 25, 2019, which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure features chemical entities (e.g., compounds or pharmaceutically acceptable salts and / or hydrates and / or prodrugs of compounds) that produce crosslinks in the cornea in response to exposure to electromagnetic radiation. The present disclosure also features compositions comprising the chemical entities and other methods of using and preparing the same. The chemical entities can be used, for example, to treat subjects (e.g., humans) suffering from a disease, disorder, or condition in which an abnormal shape of the cornea (e.g., corneal thinning, e.g., bilateral corneal thinning, e.g., bilateral thinning of the central, paracentral, or peripheral cornea; or corneal steepening (e.g., bulging)) causes the pathology and / or symptoms and / or progression of the disease, disorder, or condition. Non-limiting examples of such diseases, disorders, or conditions include: (i) corneal ectatic diseases; (ii) vision conditions; and (iii) sequelae or diseases, disorders, or conditions that coexist with any of the above or any of the disclosed herein. More specific non-limiting examples of such diseases, disorders or conditions include keratoconus, keratosphericity, pellucid marginal degeneration, corneal ectasia (e.g., post-operative ectasia, such as post-LASIK ectasia), Terrien marginal degeneration, myopia, hyperopia, astigmatism, irregular astigmatism and presbyopia.

[0004] background

[0005] Various eye diseases, such as myopia, keratoconus, and hyperopia, involve an abnormal shape of the cornea. For example, laser-assisted in situ keratomileusis (LASIK) is one of several corrective treatments that reshape the cornea so that light passing through it is properly focused onto the retina at the back of the eye. The success of a specific treatment to address the abnormal shape of the cornea depends on the stability of the structural changes in the cornea after the treatment is applied.

[0006] Although the treatment can initially achieve the desired corneal remodeling, if the collagen fibrils in the cornea continue to change after the desired remodeling is achieved, the desired effect of remodeling the cornea may be at least partially weakened or reversed. For example, due to the thinning and weakening of the cornea caused by LASIK surgery, a complication called post-LASIK ectasia may occur. In the post-LASIK ectasia, the cornea gradually becomes steeper (protuberance). In order to strengthen and stabilize the structure of the cornea after remodeling, some treatments can also induce crosslinking in the corneal tissue. For example, a photosensitizer (such as riboflavin) is applied to the cornea as a crosslinking agent. Once the crosslinking agent is applied to the cornea, the crosslinking agent is activated by a light source (such as ultraviolet (UV) light), so that the crosslinking agent absorbs enough energy, thereby releasing free oxygen radicals (such as singlet oxygen) and / or other free radicals in the cornea. Once released, the free radicals form covalent bonds between the corneal collagen fibrils, thereby crosslinking the corneal collagen fibrils and strengthening and stabilizing the corneal structure.

[0007] Due to the favorable structural changes caused by the crosslinking agent, the crosslinking agent can be used as the main aspect of some treatments. For example, crosslinking agents can be used to treat keratoconus. Crosslinking therapy can also be used to induce corneal refractive changes to correct myopia, hyperopia, astigmatism, irregular astigmatism, presbyopia and other diseases.

[0008] U.S. Patent Application Publication No. 2011 / 0237999, filed March 18, 2011, U.S. Patent Application Publication No. 2012 / 0215155, filed April 3, 2012, U.S. Patent Application Publication No. 2014 / 0343480, filed May 19, 2014, U.S. Patent Application Publication No. 2013 / 0060187, filed October 31, 2012, International Patent Application Publication No. 2011 / 130356, filed April 13, 2011 No. 2015 / 130944, filed on February 26, 2015, and International Patent Application No. 2016 / 090016, filed on December 2, 2015, describe systems and compositions (e.g., riboflavin or riboflavin phosphate eye drops) that can produce cross-linking activity in the cornea with or without removal of corneal epithelial cells in the treatment of ocular diseases, such as keratoconus (e.g., progressive keratoconus) or corneal ectasia after refractive surgery. VISCOUS (riboflavin 5′-phosphate 20% dextran eye drops) 0.146% and (Riboflavin 5′-phosphate eye drops) 0.146% is suitable for KXL TM A photoenhancer of a system for corneal collagen cross-linking to treat progressive keratoconus.

[0009] U.S. Patent Application Publication No. 20160083352 discloses diaziridine compounds as photocrosslinkers, for example, for use in electronic and optoelectronic devices. SUMMARY OF THE INVENTION

[0011] The present disclosure features chemical entities (e.g., compounds or pharmaceutically acceptable salts and / or hydrates and / or prodrugs of compounds) that produce crosslinks in the cornea in response to exposure to electromagnetic radiation. The present disclosure also features compositions comprising the chemical entities and other methods of using and preparing the same. The chemical entities can be used, for example, to treat subjects (e.g., humans) suffering from a disease, disorder, or condition in which an abnormal shape of the cornea (e.g., corneal thinning, e.g., bilateral corneal thinning, e.g., bilateral thinning of the central, paracentral, or peripheral cornea; or corneal steepening (e.g., bulging)) causes the pathology and / or symptoms and / or progression of the disease, disorder, or condition. Non-limiting examples of such diseases, disorders, or conditions include: (i) corneal ectatic diseases; (ii) vision conditions; and (iii) sequelae or diseases, disorders, or conditions that coexist with any of the above or any of the disclosed herein. More specific non-limiting examples of such diseases, disorders or conditions include keratoconus, keratosphericity, pellucid marginal degeneration, corneal ectasia (e.g., post-operative ectasia, such as post-LASIK ectasia), Terrien marginal degeneration, myopia, hyperopia, astigmatism, irregular astigmatism, and presbyopia. In some embodiments, the claimed methods can be performed without adding or supplementing oxygen levels, which is advantageous in some applications.

[0012] In one aspect, the characteristic chemical entity comprises a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0013]

[0014] Among them A 1 , B 1 , and B 2 As defined here.

[0015] In one aspect, the characteristic chemical entity comprises a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0016]

[0017] Among them A 1 , B 1 , and B 2 As defined here.

[0018] In one aspect, the characteristic chemical entity comprises a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0019]

[0020] Where E 1 、F 1 , G 1 , H 1 , J 1 , L 1 、M 1 , Q 1 , B 1 and B 2 As defined here.

[0021] In one aspect, the invention provides pharmaceutical compositions comprising a chemical entity described herein (eg, a compound generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound) and one or more pharmaceutically acceptable excipients.

[0022] In one aspect, a method of producing crosslinks in the cornea is characterized by contacting the cornea with a chemical entity as described herein (e.g., a compound or a pharmaceutically acceptable salt thereof, or a composition comprising the compound or a pharmaceutically acceptable salt thereof) and applying electromagnetic radiation to the cornea. The method may include, for example, applying the chemical entity to the cornea of ​​a subject (e.g., a human) suffering from a disease, disorder, or condition in which an abnormal shape of the cornea (e.g., corneal thinning, e.g., bilateral corneal thinning, e.g., bilateral thinning of the central, paracentral, or peripheral cornea; or corneal steepening (e.g., bulge)) causes the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., keratoconus, spherical keratoconus, pellucid marginal degeneration, corneal ectasia (e.g., postoperative ectasia, e.g., post-LASIK ectasia), Terrien marginal degeneration, myopia, hyperopia, astigmatism, irregular astigmatism, and presbyopia); and applying electromagnetic radiation to the cornea. Methods may include, but are not limited to, providing refractive correction to the cornea (eg, by imparting mechanical rigidity) as well as strengthening and stabilizing the structure of the cornea.

[0023] In another aspect, the method of treating a disease, disorder or condition is characterized in that an abnormal shape of the cornea (e.g., corneal thinning, e.g., bilateral corneal thinning, e.g., bilateral thinning of the central, paracentral or peripheral cornea; or corneal steepening (e.g., bulge)) contributes to the pathology and / or symptoms and / or progression of the disease, disorder or condition. The method comprises administering a chemical entity described herein (e.g., a compound generally or specifically described herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same) in an amount effective to treat the disease, disorder or condition.

[0024] In another aspect, a method for treating a disease, disorder or condition is characterized in that an abnormal shape of the cornea (e.g., corneal thinning, e.g., bilateral corneal thinning, e.g., bilateral thinning of the central, paracentral or peripheral cornea; or corneal steepening (e.g., bulge)) causes the pathology and / or symptoms and / or progression of the disease, disorder or condition. The method comprises administering to the cornea of ​​a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound generally or specifically described herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same); and applying electromagnetic radiation to the cornea.

[0025] A non-limiting example of such diseases, disorders, and conditions is a corneal ectatic disease. In certain embodiments, the corneal ectatic disease is keratoconus. In certain embodiments, the corneal ectatic disease is keratospheric keratoconus. In certain embodiments, the corneal ectatic disease is pellucid marginal degeneration. In certain embodiments, the corneal ectatic disease is corneal ectasia (e.g., post-operative ectasia, such as post-LASIK ectasia). In certain embodiments, the corneal ectatic disease is Terrien marginal degeneration.

[0026] Another non-limiting example of such diseases, disorders, and conditions is a vision condition. In certain embodiments, the vision condition is myopia. In certain embodiments, the vision condition is hyperopia. In certain embodiments, the vision condition is myopia. In certain embodiments, the vision condition is hyperopia. In certain embodiments, the vision condition is astigmatism. In certain embodiments, the vision condition is irregular astigmatism. In certain embodiments, the vision condition is presbyopia.

[0027] Implementations may include one or more of the following advantageous features.

[0028] In some embodiments, the claimed methods can be performed without adding or supplementing oxygen levels, which can be advantageous in some applications.

[0029] In some embodiments, the chemical entities and compositions described herein can be applied to the cornea without prior removal of corneal epithelial cells, thereby improving patient comfort.

[0030] In some embodiments, the chemical entities and compositions described herein can be cross-linked in the cornea using relatively short durations of electromagnetic radiation.

[0031] Other implementations include what is described in the detailed description and / or claims.

[0032] Other definitions

[0033] In order to promote the understanding of the disclosure set forth herein, a plurality of other terms are defined below. Generally, the nomenclature used herein and the laboratory procedures of organic chemistry, medicinal chemistry and pharmacology described herein are well-known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art to which this paper belongs. Each patent, application, disclosed application and other publications and attached appendix mentioned in the entire specification are incorporated herein by reference in their entirety.

[0034] As used herein, the term "acceptable" with respect to a formulation, composition or ingredient means having no persistent detrimental effect on the general health of the subject being treated.

[0035] As used herein, the term "effective amount" or "therapeutically effective amount" means that a sufficient amount of a chemical entity (e.g., a compound described generally or specifically herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same) is administered to alleviate to some extent one or more symptoms of the disease or condition being treated. Results include reduction and / or alleviation of signs, symptoms, or causes of disease, or any other desired changes in a biological system. For example, an "effective amount" for therapeutic use is an amount comprising a compound disclosed herein to provide a clinically significant alleviation of disease symptoms. In any case, any appropriate technique (e.g., a dose escalation study) may be used to determine a suitable "effective" amount.

[0036] The term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash, eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson, ed., CRC Press LLC: Boca Raton, FL, 2009).

[0037] The term "pharmaceutically acceptable salt" refers to a preparation of a compound that does not cause significant irritation to the organism to which it is administered and does not eliminate the biological activity and properties of the compound. In some cases, a pharmaceutically acceptable salt is obtained by reacting a compound described herein with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In some cases, a salt is formed by reacting a compound having an acidic group described herein with a base, such as an ammonium salt, an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt, such as a calcium salt or a magnesium salt, a salt of an organic base, such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and a salt formed with an amino acid, such as arginine, lysine, and the like, or by other methods previously determined. There is no specific limitation on the pharmacologically acceptable salt, as long as it can be used in medicine. Examples of salts formed with bases of the compounds described herein include the following: salts formed with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salts formed with organic bases such as methylamine, ethylamine and ethanolamine; salts formed with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may be acid addition salts, specifically exemplified by addition salts formed with the following acids: inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid: organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

[0038] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersants, suspending agents and / or thickening agents. Pharmaceutical compositions facilitate administration of compounds to an organism. There are a variety of techniques for administering compounds in the art, including but not limited to rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary and topical administration.

[0039] The term "subject" may refer to an animal, including but not limited to a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, e.g., to refer to a mammalian subject, e.g., a human subject.

[0040] In the context of treating a disease, disorder or condition, the term "treat," ...

[0041] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0042] The term "alkyl" refers to a hydrocarbon chain which may be straight or branched and contains the indicated number of carbon atoms. -10 Indicates that the group may have 1 to 10 (inclusive) carbon atoms. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl.

[0043] The term "haloalkyl" refers to an alkyl group wherein one or more hydrogen atoms are replaced by independently selected halogens.

[0044] The term "alkoxy" refers to an -O-alkyl group (eg, -OCH3).

[0045] The term "haloalkoxy" refers to an -O-haloalkyl group (eg, -OCF3).

[0046] The term "alkylene" refers to a branched or unbranched divalent alkyl group (eg, -CH2-).

[0047] The term "arylene" and the like refers to the divalent form of the ring system, here a divalent aryl.

[0048] The term "alkenyl" refers to a hydrocarbon chain that may be straight or branched and has one or more carbon-carbon double bonds. The alkenyl moiety contains the specified number of carbon atoms. For example, C 2-6 It means that the group may have 2 to 6 (inclusive) carbon atoms.

[0049] The term "alkynyl" refers to a hydrocarbon chain which may be straight or branched and has one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C 2-6 It means that the group may have 2 to 6 (inclusive) carbon atoms.

[0050] The term "aryl" refers to a 6-carbon monocyclic, 10-carbon bicyclic or 14-carbon tricyclic aromatic ring system, wherein 0, 1, 2, 3 or 4 atoms of each ring may be substituted with a substituent, and the ring containing the monocyclic group is aromatic, and at least one of the fused rings containing the bicyclic or tricyclic group is aromatic, such as tetrahydronaphthyl. Examples of aryl also include phenyl, naphthyl, etc.

[0051] The term "cycloalkyl" as used herein includes saturated cyclic hydrocarbon groups having 3 to 10 carbons, preferably 3 to 8 carbons, more preferably 3 to 6 carbons, wherein the cycloalkyl group may be optionally substituted. Preferred cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0052] The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms being selected from O, N or S (e.g., carbon atoms and 1-3, 1-6 or 1-9 heteroatoms of N, O or S for the monocyclic, bicyclic or tricyclic ring, respectively), wherein 0, 1, 2, 3 or 4 atoms of each ring may be substituted with substituents, and the ring in which the monocyclic group is contained is aromatic, and at least one of the fused rings in which the bicyclic or tricyclic group is contained is aromatic, but need not necessarily be a ring containing heteroatoms, such as tetrahydroisoquinolinyl. Exemplary heteroaryl systems are derived from, but are not limited to, the following ring systems: pyrrole, furan, thiophene, imidazole, pyrazole, oxazole (= [1,3] oxazole), isoxazole (= [1,2] oxazole), thiazole (= [1,3] thiazole), isothiazole (= [1,2] thiazole), [1,2,3] triazole, [1,2,4] triazole, [1,2,4] oxadiazole, [1,3,4] oxadiazole, [1,2,4] thiadiazole, [1,3,4] thiadiazole, tetrazole, pyridine, pyridazine , pyrimidine, pyrazine, [1,2,3]triazine, [1,2,4]triazine, [1,3,5]triazine, indole, isoindole, benzofuran, benzothio[1,3]benzoxazole, [1,3]benzothiazole, benzimidazole, indazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, various naphthyridines, such as [1,8]naphthyridine, various thienopyridines, such as thieno[2,3-b]pyridine, and purines.

[0053] The term "heterocyclyl" refers to a non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms being selected from O, N or S (e.g., carbon atoms and 1-3, 1-6 or 1-9 heteroatoms of N, O or S for monocyclic, bicyclic or tricyclic rings, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted with substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.

[0054] In addition, the atoms constituting the compounds of the present embodiments are intended to include all isotopic forms of such atoms. As used herein, isotopes include those atoms having the same atomic number but different mass numbers. As a general example and not limitation, isotopes of hydrogen include tritium and deuterium, while isotopes of carbon include 13 C and 14 C.

[0055] The details of one or more embodiments of the invention are set forth in the following description and in the appendix, which is expressly considered a part of this disclosure. Other features and advantages will also be apparent from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0057] The present disclosure features chemical entities (e.g., compounds or pharmaceutically acceptable salts and / or hydrates and / or prodrugs of compounds) that produce crosslinks in the cornea in response to exposure to electromagnetic radiation. The present disclosure also features compositions comprising the chemical entity and other methods of using and preparing the same. The chemical entity can be used, for example, to treat a subject (e.g., a human) suffering from a disease, disorder, or condition in which an abnormal shape of the cornea (e.g., corneal thinning, e.g., bilateral corneal thinning, e.g., bilateral thinning of the central, paracentral, or peripheral cornea; or corneal steepening (e.g., bulging)) causes the pathology and / or symptoms and / or progression of the disease, disorder, or condition. Non-limiting examples of such diseases, disorders, or conditions include: (i) corneal ectasia disorders; (ii) vision conditions; (iii) sequelae or diseases, disorders, or conditions coexisting with any of the above or any of the disclosed herein. More specific non-limiting examples of such diseases, disorders or conditions include keratoconus, keratosphericity, pellucid marginal degeneration, corneal ectasia (e.g., post-operative ectasia, such as post-LASIK ectasia), Terrien marginal degeneration, myopia, hyperopia, astigmatism, irregular astigmatism, and presbyopia. In some embodiments, the claimed methods can be performed without adding or supplementing oxygen levels, which is advantageous in some applications.

[0058] Compounds of formula (I)

[0059] In one aspect, the disclosure features compounds of formula (I):

[0060]

[0061] or a pharmaceutically acceptable salt thereof,

[0062] in:

[0063] L A and L B Each is independently C1-C5 alkylene, which is optionally substituted by 1-3 R a replace;

[0064] A is a moiety that enhances delivery of the compound to the corneal stroma (e.g., through the intact corneal epithelium) and / or enhances binding of the compound to corneal collagen;

[0065] B 1 and B 2 Each independently is -Z 1 -Z2 -Z 3 ,in:

[0066] ·Z 1 It is C 1-3 Alkylene, which is optionally substituted by 1 to 4 R a replace;

[0067] ·Z 2 is a bond, -N(R d )-, -O- or -S-; and

[0068] ·Z 3 Is a halogen, H or C 1-7 Alkyl, which is optionally substituted by 1-4 R a replace;

[0069] Each occurrence of R a Independently selected from the group consisting of: -OH; -SH; -F; -Cl; -Br; -NR e R f ; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 0-2 (C 1-4 alkyl); cyano; -NR'C(=NR')NR'R"; and C 3-6 Cycloalkyl, which is optionally substituted by 1-4 independently selected R b replace;

[0070] Each occurrence of R b Independently selected from the group consisting of: -OH; -SH; -F; -Cl; -Br; -NR e R f ; C 1-4 Alkyl; C 1-4 Haloalkyl; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); oxo; -S(O) 1-2 (NR'R");-S(O) 0-2 (C 1-4 alkyl); cyano; -NR'C(=NR')NR'R"; and C 3-6Cycloalkyl, which is optionally substituted by 1-4 independently selected C 1-4 Alkyl substitution;

[0071] Each occurrence of R b Independently selected from the group consisting of H, C 1-6 Alkyl; C 3-6 Cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 Alkoxy;

[0072] Each occurrence of R e and R f Independently selected from the group consisting of: H; C 1-6 Alkyl; C 3-6 Cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 Alkoxy; and

[0073] Each occurrence of R' and R" is independently selected from the group consisting of H and C 1-4 or R' and R" together with the nitrogen atom to which they are attached form a ring containing 3-8 ring atoms, wherein the ring contains: (a) 1-7 ring carbon atoms, each carbon atom being replaced by 1-2 independently selected from H and C 1-3 (b) 0-3 ring heteroatoms (except the nitrogen atom connected to R' and R "), each of which is independently selected from N (R d ), O and S.

[0074] Variable A

[0075] In some embodiments of Formula (I), A is a moiety that enhances delivery of the compound to the corneal stroma (e.g., through the intact corneal epithelium) and / or enhances binding of the compound to corneal collagen;

[0076] In some embodiments of Formula (I), A is a moiety that enhances delivery of the compound through the intact corneal epithelium to the corneal stroma and / or enhances binding of the compound to corneal collagen.

[0077] In some embodiments of Formula (I), A is a moiety (eg, a small molecule moiety) that is capable of penetrating corneal epithelial cells.

[0078] In some embodiments, A is a peptide moiety.

[0079] In certain embodiments, A is linked to L at the N-terminus. A and connected to L at the C-terminus B In certain other embodiments of Formula (I), A is linked to L at the C-terminus. A and connected to L at the N-terminus B .

[0080] In some embodiments, A is a peptide portion taken from a decorin sequence that binds collagen. In some of the aforementioned embodiments, A is a peptide portion taken from a decorin sequence that binds type I collagen (e.g., A is a peptide portion taken from a decorin sequence SYIRIADTNIT, reported in J. Biol. Chem. 2007, 282, 16062, which is incorporated herein by reference in its entirety). As a non-limiting example of the aforementioned embodiments, A may include a peptide portion of the sequence RIAD.

[0081] In certain embodiments, A is a peptide portion taken from the asporin sequence (e.g., A is a peptide portion taken from the asporin sequence HIRIAEAKLT, reported in J. Biol. Chem. 2007, 282, 16062, which is incorporated herein by reference in its entirety). As a non-limiting example of the foregoing embodiments, A may be a peptide portion of the sequence RIAE.

[0082] In certain embodiments, A is a peptide portion taken from a biglycan sequence (eg, A is a peptide portion taken from the asporidin sequence NYLRISEAKLT, reported in J. Biol. Chem. 2007, 282, 16062, which is incorporated herein by reference in its entirety).

[0083] In certain embodiments, A is a moiety that binds alucan and / or fibromodulin.

[0084] Variable L A and L B

[0085] In some embodiments of Formula (I), L A and L B Each is independently C1-C3 alkylene, which is optionally substituted by 1-3 R a replace.

[0086] In some of the foregoing embodiments, LA and L B are each independently C1-C3 alkylene, which is optionally substituted by 1 R a replace.

[0087] As a non-limiting example of the foregoing embodiment, L A and L B and are each independently an unsubstituted C1-C3 alkylene group (eg, an unsubstituted C2-C3 alkylene group, eg, unsubstituted ethylene or propylene).

[0088] Variable B 1 and B 2

[0089] In some embodiments of Formula (I), B 1 and B 2 Each independently is -Z 1 -Z 3 (i.e., Z 2 is key).

[0090] In some embodiments of Formula (I), Z 3 is H, halogen or C 1-3 alkyl.

[0091] In some embodiments of Formula (I), Z 3 Is H or C 1-3 Alkyl (e.g., Z 3 It can be H).

[0092] In some embodiments of Formula (I), Z 3 is a halogen (e.g., Z 3 It can be F).

[0093] In some embodiments of Formula (I), Z 1 It is C 1-3 Alkylene, which is optionally composed of 1-3 independently selected R a Replace (for example, Z 1 It can be methylene, CHF or CF2).

[0094] In certain embodiments, Z 1 is unsubstituted C 1-3 Alkylene (eg, CH2).

[0095] In certain embodiments, Z 1 is unsubstituted C 1-3 Alkylene; and Z 3 It's H.

[0096] In certain embodiments, Z 1is C substituted with 1-2 independently selected halogens (e.g., F) 1-3 Alkylene.

[0097] In certain embodiments, B 1 and B 2 Each independently selected from CH3, CHR a , CH(R a )2 and C(R a )2-halogen.

[0098] As a non-limiting example of the foregoing embodiment, B 1 and B 2 Each may independently be CH3, CHF2, CH2F and CF3 (eg, CH3).

[0099] Compounds of formula (Ia)

[0100] In another aspect, the disclosure features compounds of formula (Ia):

[0101]

[0102] Among them A 1 It is C2-C 20 Alkylene, which is substituted by 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, 1) R 1 interval;

[0103] B 1 and B 2 Each independently is -Z 1 -Z 2 -Z 3 ,in:

[0104] ·Z 1 It is C 1-3 Alkylene, which is optionally substituted by 1 to 4 R a replace;

[0105] ·Z 2 is a bond, -N(R d )-, -O- or -S-; and

[0106] ·Z 3 Is a halogen, H or C 1-7 Alkyl, which is optionally substituted by 1-4 R a replace;

[0107] Each occurrence of R 1 is a divalent group independently selected from:

[0108] ·-N(R d1 )-;

[0109] ·-N(R 3 )-;

[0110] -O-;

[0111] ·S(O) p , where p is 0, 1 or 2;

[0112] C(=O);

[0113] C(=S);

[0114] ·CHR 2 ;

[0115] ·C(R 2 )2;

[0116] -C(=O)CH(R 2 )N(R d1 )-;and

[0117] -C(=O)CH(R 2 )CH2N(R d1 )-;

[0118] Each occurrence of R 2 Independently selected from the following group:

[0119] (i)R a ;

[0120] (ii) C1-C6 alkyl, which is optionally substituted with 1 to 3 R a replace;

[0121] (iii)L 2 -heterocyclyl, wherein the heterocyclyl contains 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N(R d ), O and S, wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace,

[0122] (iv)L 2 -C6-C 10 Aryl, which is optionally substituted by 1 to 4 R c replace;

[0123] (v)L 2 -heteroaryl, wherein the heteroaryl contains 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(R d ), O and S, and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c Replacement; and

[0124] (vi) H; or

[0125] (vii) -C(=O)CH(R 2 )N(R d1 )-R in the group 2 and R d1 to form a ring containing 5-8 ring atoms, wherein the ring includes: (a) 3-6 ring carbon atoms (excluding CH(R) 2 ), each carbon atom is replaced by 1-2 independently selected from H and C 1-3 (b) 0-3 ring heteroatoms (except for R d1 connected nitrogen atoms), each of which is independently selected from N(R d1 ), O and S;

[0126] Each occurrence of R 3 Independently selected from the following group:

[0127] (i) C1-C6 alkyl, which is optionally substituted with 1 to 3 R a replace;

[0128] (ii) L 3 -heterocyclyl, wherein the heterocyclyl contains 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N(R d ), O and S, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace,

[0129] (iii)L 3 -C6-C 10 Aryl, which is optionally substituted by 1 to 4 R c Replacement; and

[0130] (iv)L 3 -heteroaryl, wherein the heteroaryl contains 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(R d ), O and S, and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace;

[0131] Each occurrence of R a Independently selected from the group consisting of: -OH; -SH; -F; -Cl; -Br; -NR e R f ; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)(C1-4 alkyl); -C(=O)OH; -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 0-2 (C 1-4 alkyl); cyano; -NR'C(=NR')NR'R"; and C 3-6 Cycloalkyl, which is optionally substituted by 1-4 independently selected R b replace;

[0132] Each occurrence of R b Independently selected from the group consisting of: -OH; -SH; -F; -Cl; -Br; -NR e R f ; C 1-4 Alkyl; C 1-4 Haloalkyl; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); oxo; -S(O) 1-2 (NR'R"');-S(O) 0-2 (C 1-4 alkyl); cyano; -NR'C(=NR')NR'R"; and C 3-6 Cycloalkyl, which is optionally substituted by 1-4 independently selected C 1-4 Alkyl substitution;

[0133] Each occurrence of R c Independently selected from the group consisting of: -OH; -SH; -F; -Cl; -Br; -NR e R f ; C 1-4 Alkyl; C 1-4 Haloalkyl; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 0-2 (C 1-4 alkyl); cyano; -NR'C(=NR')NR'R"; and C 3-6 Cycloalkyl, which is optionally substituted by 1-4 independently selected C 1-4 Alkyl substitution;

[0134] Each occurrence of R bIndependently selected from the group consisting of H, C 1-6 Alkyl; C 3-6 Cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 Alkoxy;

[0135] Each occurrence of R e and R f Independently selected from the group consisting of: H; C 1-6 Alkyl; C 3-6 Cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 Alkoxy; and

[0136] Each occurrence of R' and R" is independently selected from the group consisting of H and C 1-4 or R' and R" together with the nitrogen atom to which they are attached form a ring containing 3-8 ring atoms, wherein the ring contains: (a) 1-7 ring carbon atoms, each carbon atom being replaced by 1-2 independently selected from H and C 1-3 (b) 0-3 ring heteroatoms (except the nitrogen atom connected to R' and R "), each of which is independently selected from N (R d ), O and S;

[0137] Each occurrence of R d1 Independently selected from the group consisting of: H; C 1-6 Alkyl; C 3-6 Cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 Alkoxy; or -C(=O)CH(R 2 )N(R d1 )-R in the group 2 and R d1 Combined to form a ring as defined above containing 5 to 8 ring atoms;

[0138] and

[0139] L 2 and L 3 is independently a bond at each occurrence, or is optionally substituted with 1-3 groups independently selected from oxo and R a C1-C6 alkylene substituted with a substituent.

[0140] Variable A 1

[0141] In some embodiments of Formula (Ia), A 1 is C4-C8 alkylene, which is substituted by 1-4 (e.g., 1, 2-3, 3-4, 2, 3 or 4) independently selected R 1 interval.

[0142] In certain embodiments, A 1 is C4-C6 alkylene, which is substituted by 1-4 (e.g., 1, 2-3, 3-4, 2, 3 or 4) independently selected R 1 interval.

[0143] In certain embodiments, A 1 R selected by 1 independently 1 interval.

[0144] In certain embodiments, A 1 R selected by 2-3 (e.g., 2 or 3) independently 1 interval.

[0145] In certain embodiments, A 1 R selected by 3-4 (e.g., 3 or 4) independently 1 interval.

[0146] In certain embodiments, A 1 1-3 independently selected R 1 interval.

[0147] In certain embodiments, A 1 R selected by 2-4 independent 1 interval.

[0148] Variable R 1

[0149] In some embodiments of Formula (Ia), one R 1 are independently -C(=O)CH(R 2 )N(R d1 )-or-N(R 3 )-(For example, an R1 is -C(=O)CH(R 2 )N(R d1 )-; or an R 1 Yes-N(R 3 )-)).

[0150] In some of the foregoing embodiments, the other R 1 The groups are each independently selected from the following group: -N(R d1 )-、(C=O)、-O-、S(O) p 、-C(=O)CH(R 2 )N(R d1 )- and -C(=O)CH(R 2 )CH2N(R d1 )-.

[0151] As a non-limiting example of the aforementioned embodiment, other R 1 The groups may be independently selected from the following groups: -N(H)-, (C=O), -O-, S(O)2, -C(=O)CH(R 2 )N(H)- and -C(=O)CH2CH2N(H)-.

[0152] Variable R 2 and R 3

[0153] In some embodiments of Formula (Ia), R 2 For H.

[0154] In some embodiments of Formula (Ia), R 2 is a C1-C6 alkyl group, which is optionally substituted by 1-3 R a replace.

[0155] In certain embodiments, R 2 is a C1-C4 alkyl group, which is optionally substituted by 1-2 R a Replaced (e.g., by 1 R a substituted C1-C4 alkyl).

[0156] In certain of the foregoing embodiments (when R 2 When it is C1-C4 alkyl, it is optionally substituted by 1-2 R a Replaced (e.g., by 1 R a Substituted C1-C4 alkyl)), each R a Independently selected from: -OH; -SH; -NR e R f ; -C(=O)O(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); -S(O)1-2 (NR'R");-S(O) 0-2 (C 1-4 alkyl); cyano; and -NR'C(=NR')NR'R".

[0157] As a non-limiting example of the foregoing embodiment, R a can be independently selected from the group consisting of -NH2, -OH, -SH, -SMe, -NH(C=NH)NH2, CO2H and CO2NH2 (e.g., R a may be each independently selected from -NH2, -OH, -NH(C=NH)NH2, CO2H and CO2NH2).

[0158] In some embodiments of Formula (Ia), R 2 for:

[0159] L 2 -C6-C 10 Aryl, which is optionally substituted by 1 to 4 R c replace; or

[0160] L 2 -heteroaryl, wherein the heteroaryl contains 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(R d ), O and S, and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace.

[0161] In certain embodiments, R 2 YesL 2 -phenyl, wherein the phenyl group is optionally substituted by 1-2 R c replace.

[0162] In certain embodiments, R 2 YesL 2 -heteroaryl, wherein the heteroaryl contains 5-9 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(R d ), O and S, and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-2 independently selected R c replace.

[0163] As a non-limiting example of the foregoing embodiment, R 2 Can be L 2 -Indolyl or L 2 -imidazolyl, wherein the indolyl or imidazolyl is optionally substituted with 1-2 independently selected R c replace.

[0164] In certain of the foregoing embodiments (when R2 For L 2 -C6-C 10 When aryl, it is optionally substituted by 1 to 4 R c Replace; or L 2 -heteroaryl, wherein the heteroaryl contains 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(R d ), O and S, wherein one or more of the heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c Replace), each R c is independently selected from -OH; -SH; -F; -Cl; -Br; -NR e R f ; C 1-4 Alkyl; C 1-4 Haloalkyl; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 0-2 (C 1-4 alkyl); cyano; - and C 3-6 Cycloalkyl, which is optionally substituted by 1-4 independently selected C 1-4 Alkyl substitution.

[0165] As a non-limiting example of the foregoing embodiment, R c Can be independently selected from -OH, F, -NR e R f , C 1-4 Alkyl; and C 1-4 Haloalkyl (e.g., R c is OH).

[0166] In certain embodiments, L 2 is optionally replaced by 1-3 R a (e.g., unsubstituted) substituted C 1-6 (For example, C 1-4 )alkylene.

[0167] In some embodiments of Formula (Ia), each occurrence of R 2 Independently selected from:

[0168] H;

[0169] C1-C6 alkyl is optionally substituted with 1-2 substituents selected from -NH2, -OH, -SH, -SMe, -NH(C=NH)NH2, CO2H and CO2NH2;

[0170] (C1-C6 alkylene)-phenyl, optionally substituted with 1-2 -OH groups;

[0171] (C1-C6 alkylene)-indolyl; and

[0172] (C1-C6 alkylene)-imidazolyl; or

[0173] ·-CH(R 2 )N(R d1 )-R in the group 2 and R d1 , combine to form a pyrrolidine ring.

[0174] In certain embodiments, each occurrence of R 2 Independently selected from:

[0175] H;

[0176] C1-C6 alkyl is optionally substituted with 1-2 substituents selected from -NH2, -OH, -NH(C=NH)NH2, CO2H and CO2NH2; and

[0177] ·(C1-C6 alkylene)-imidazolyl.

[0178] As a non-limiting example of the foregoing implementation, each occurrence of R 2 Can be independently selected from:

[0179] H;

[0180] ·

[0181] and

[0182] ·

[0183] In some embodiments of Formula (Ia), each occurrence of R 3 Independently selected from:

[0184] C1-C6 alkyl is optionally substituted with 1-2 substituents selected from -NH2, -OH, -SH, -SMe, -NH(C=NH)NH2, CO2H and CO2NH2;

[0185] (C1-C6 alkylene)-phenyl, optionally substituted with 1-2 -OH groups;

[0186] (C1-C6 alkylene)-indolyl; and

[0187] ·(C1-C6 alkylene)-imidazolyl.

[0188] In some embodiments of Formula (Ia), R 3 is a C1-C6 alkyl group, which is optionally substituted by 1-3 R a replace.

[0189] In certain embodiments, R 3 is a C1-C4 alkyl group, which is optionally substituted by 1-2 R a Replaced (e.g., by 1 R a substituted C1-C4 alkyl).

[0190] In certain of the foregoing embodiments (when R 3 When it is C1-C4 alkyl, it is optionally substituted by 1-2 R a Replaced (e.g., by 1 R a Substituted C1-C4 alkyl)), R a Each independently selected from: -OH; -SH; -NR e R f ; -C(=O)O(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 0-2 (C 1-4 alkyl); cyano; and -NR'C(=NR')NR'R".

[0191] As a non-limiting example of the foregoing embodiment, R a can be independently selected from the group consisting of -NH2, -OH, -SH, -SMe, -NH(C=NH)NH2, CO2H and CO2NH2 (e.g., R a can be independently selected from -NH2, -OH, -NH(C=NH)NH2, CO2H and CO2NH2; for example, R a may be independently selected from -NH2 and CO2H).

[0192] In some embodiments of Formula (Ia), R 3 YesL 3 -C6-C 10 Aryl, which is optionally substituted by 1 to 4 R c replace; or

[0193] L 3 -heteroaryl, wherein the heteroaryl contains 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(R d ), O and S, and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace.

[0194] In certain embodiments, R 3 YesL 3 -phenyl, wherein the phenyl group is optionally substituted by 1-2 R c replace.

[0195] In certain embodiments, R 3 YesL 3 -heteroaryl, wherein the heteroaryl contains 5-8 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(R d ), O and S, and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-2 independently selected R c replace.

[0196] As a non-limiting example of the foregoing embodiment, R 3 Can be L 3 -Indolyl or L 3 -imidazolyl, wherein the indolyl or imidazolyl is optionally substituted with 1-2 independently selected R c replace.

[0197] In certain of the foregoing embodiments (when R 3 For L 2 -C6-C 10 When aryl, it is optionally substituted by 1 to 4 R c or L 3 -heteroaryl substituted, wherein the heteroaryl contains 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(R d ), O and S, wherein one or more of the heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c Replace), each R c is independently selected from -OH; -SH; -F; -Cl; -Br; -NR e R f ; C 1-4 Alkyl; C 1-4 Haloalkyl; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 0-2 (C 1-4 alkyl); cyano; - and C 3-6 Cycloalkyl, which is optionally substituted by 1-4 independently selected C 1-4 Alkyl substitution.

[0198] As a non-limiting example of the foregoing embodiment, Rc Can be independently selected from -OH, F, -NR e R f , C 1-4 Alkyl; and C 1-4 Haloalkyl (e.g., R c is OH).

[0199] In certain embodiments, L 3 is optionally replaced by 1-3 R a (e.g., unsubstituted) substituted C 1-6 (For example, C 1-4 )alkylene.

[0200] In certain embodiments, L 3 is a C substituted with an oxo group 1-6 (For example, C 1-4 As a non-limiting example, L 3 Can be

[0201] In certain embodiments, L 3 is the key.

[0202] In certain embodiments, each occurrence of R 3 Independently selected from:

[0203] C1-C6 alkyl, optionally substituted with 1-2 substituents selected from -NH2, -OH, -NH(C=NH)NH2, CO2H and CO2NH2; and

[0204] ·(C1-C6 alkylene)-imidazolyl.

[0205] As a non-limiting example of the foregoing implementation, each occurrence of R 3 Can be independently selected from:

[0206] ·

[0207] and

[0208] ·

[0209] In certain embodiments, each occurrence of R 3 Independently selected from: C1-C6 alkyl, optionally substituted with 1-2 substituents selected from -NH2, -OH, -NH(C=NH)NH2, CO2H and CO2NH2.

[0210] As a non-limiting example of the foregoing implementation, each occurrence of R 3Can be independently selected from:

[0211] In some embodiments, each occurrence of R 3 Independently selected from: L 3 -heterocyclyl, wherein the heterocyclyl contains 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N(R d ), O and S, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace.

[0212] In certain embodiments, each occurrence of R 3 Independently selected from: L 3 -heterocyclyl, wherein the heterocyclyl contains 4-6 (e.g., 5-6) ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N(R d ), O and S, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-2 independently selected R b substituted (for example, the heterocyclyl group can be pyrrolidinyl, piperidinyl or morpholinyl).

[0213] In certain of these embodiments, L 3 is the key.

[0214] In certain embodiments (when each occurrence of R 3 Independently selected from: L 3 -heterocyclyl, wherein the heterocyclyl contains 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N(R d ), O and S, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b Replacement), L 3 It is C 1-6 Alkyl, optionally with 1-3 independently selected R a (e.g., unsubstituted) substituted.

[0215] In certain embodiments (when each occurrence of R 3 Independently selected from: L 3 -heterocyclyl, wherein the heterocyclyl contains 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N(R d ), O and S, wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b Replacement), L 3 It is C 1-6 (For example, C 1-4 ) alkylene, which is substituted with an oxo group (for example, it can be ).

[0216] As a non-limiting example, R 3 Can be selected from:

[0217]

[0218] Variable B 1 and B 2

[0219] In some embodiments of Formula (Ia), B 1 and B 2 Each independently is -Z 1 -Z 3 (i.e., Z 2 is key).

[0220] In some embodiments of Formula (Ia), Z 3 is H, halogen or C 1-3 alkyl.

[0221] In some embodiments of Formula (Ia), Z 3 Is H or C 1-3 Alkyl (e.g., Z 3 It can be H).

[0222] In some embodiments of Formula (Ia), Z 3 is a halogen (e.g., Z 3 It can be F).

[0223] In some embodiments of Formula (Ia), Z 1 It is C 1-3 Alkylene, which is optionally composed of 1-3 independently selected R a Replace (for example, Z 1 It can be methylene, CHF or CF2).

[0224] In certain embodiments, Z 1 is unsubstituted C 1-3 Alkylene (eg, CH2).

[0225] In certain embodiments, Z 1 is unsubstituted C 1-3 Alkylene; and Z 3 It's H.

[0226] In certain embodiments, Z 1 is C substituted with 1-2 independently selected halogens (e.g., F) 1-3 Alkylene.

[0227] In certain embodiments, B 1 and B2 Each independently selected from CH3, CHR a , CH(R a )2 and C(R a )2-halogen.

[0228] As a non-limiting example of the foregoing embodiment, B 1 and B 2 Each may independently be CH3, CHF2, CH2F or CF3 (eg, CH3).

[0229] Variable R d1

[0230] In some embodiments of Formula (Ia), each occurrence of R d1 Independently selected from the group consisting of: each occurrence of R d1 Independently selected from the group consisting of: H; C 1-6 Alkyl; C 3-6 Cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 (NR'R"); and -S(O) 1-2 (C 1-4 alkyl); or -C(=O)CH(R 2 )N(R d1 )-R in the group 2 and R d1 Combined to form a ring as defined above containing 5 to 8 ring atoms.

[0231] In certain embodiments, each occurrence of R d1 Independently selected from the following group: H, C 1-6 Alkyl; and C 3-6 Cycloalkyl.

[0232] In certain embodiments, each occurrence of R d1 It's H.

[0233] Compound of formula (Ib)

[0234] In another aspect, the disclosure features compounds of formula (Ib):

[0235]

[0236] or a pharmaceutically acceptable salt thereof,

[0237] in,

[0238] B 1 and B 2 Each independently is -Z1 -Z 2 -Z 3 ,in:

[0239] ·Z 1 It is C 1-3 Alkylene, which is optionally substituted by 1 to 4 R a replace;

[0240] ·Z 2 is a bond, -N(R d )-, -O- or -S-; and

[0241] ·Z 3 is H, halogen or C 1-7 Alkyl, which is optionally substituted by 1-4 R a replace;

[0242] E 1 、F 1 , G 1 , H 1 , J 1 , L 1 、M 1 and Q 1 Each independently selected from:

[0243] ·key;

[0244] ·Optionally 1-3 R a Substituted C1-C6 alkylene; and

[0245] ·R 1 ;

[0246] Each occurrence of R 1 Independently selected from the following group:

[0247] ·-N(R d1 )-;

[0248] ·-N(R 3 )-;

[0249] -O-;

[0250] ·S(O) p , where p is 0, 1 or 2;

[0251] C(=O);

[0252] C(=S);

[0253] ·CHR 2 ;

[0254] ·C(R 2 )2

[0255] -C(=O)CH(R 2 )N(R d1 )-;and

[0256] -C(=O)CH(R 2 )CH2N(R d1 )-;

[0257] The condition is E 1 and F 1 At least one of them is C1-C6 alkylene, which is optionally replaced by 1-3 R a Replace; and the condition is F 1 , G 1 , H 1 , J 1 , L 1 and M 1 1-4 of them are independently selected R 1 ;

[0258] Each occurrence of R 2 Independently selected from the following group:

[0259] (i)R a ;

[0260] (ii) C1-C6 alkyl, which is optionally substituted with 1 to 3 R a replace;

[0261] (iii)L 2 -heterocyclyl, wherein the heterocyclyl contains 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N(R d ), O and S; and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace,

[0262] (iv)L 2 -C6-C 10 Aryl, which is optionally substituted by 1 to 4 R c replace;

[0263] (v)L 2 -heteroaryl, wherein the heteroaryl contains 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(R d ), O and S, and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c Replacement; and

[0264] (vi) H; or

[0265] (vii) -C(=O)CH(R 2 )N(Rd1 )-R in the group 2 and R d1 to form a ring containing 5-8 ring atoms, wherein the ring includes: (a) 3-6 ring carbon atoms (excluding CH(R) 2 ), each carbon atom is replaced by 1-2 independently selected from H and C 1-3 (b) 0-3 ring heteroatoms (except for R d1 connected nitrogen atoms), each of which is independently selected from N(R d1 ), O and S;

[0266] Each occurrence of R 3 Independently selected from the following group:

[0267] (i) C1-C6 alkyl, which is optionally substituted with 1 to 3 R a replace;

[0268] (ii) L 3 -heterocyclyl, wherein the heterocyclyl contains 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N(R d ), O and S, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace,

[0269] (iii)L 3 -C6-C 10 Aryl, which is optionally substituted by 1 to 4 R c Replacement; and

[0270] (iv)L 3 -heteroaryl, wherein the heteroaryl contains 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(R d ), O and S, and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace;

[0271] Each occurrence of R a Independently selected from the group consisting of: -OH; -SH; -F; -Cl; -Br; -NR e R f ; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 0-2 (C1-4 alkyl); cyano; -NR'C(=NR')NR'R"; and C 3-6 Cycloalkyl, which is optionally substituted by 1-4 independently selected R b replace;

[0272] Each occurrence of R b Independently selected from the group consisting of: -OH; -SH; -F; -Cl; -Br; -NR e R f ; C 1-4 Alkyl; C 1-4 Haloalkyl; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); oxo; -S(O) 1-2 (NR'R");-S(O) 0-2 (C 1-4 alkyl); cyano; -NR'C(=NR')NR'R"; and C 3-6 Cycloalkyl, which is optionally substituted by 1-4 independently selected C 1-4 Alkyl substitution;

[0273] Each occurrence of R c Independently selected from the group consisting of: -OH; -SH; -F; -Cl; -Br; -NR e R f ; C 1-4 Alkyl; C 1-4 Haloalkyl; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 0-2 (C 1-4 alkyl); cyano; -NR'C(=NR')NR'R"; and C 3-6 Cycloalkyl, which is optionally substituted by 1-4 independently selected C 1-4 Alkyl substitution;

[0274] Each occurrence of R d Independently selected from the group consisting of HC 1-6 Alkyl; C 3-6 Cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4alkyl); -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 Alkoxy;

[0275] Each occurrence of R e and R f Independently selected from the group consisting of: H; C 1-6 Alkyl; C 3-6 Cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 Alkoxy; and

[0276] Each occurrence of R' and R" is independently selected from the group consisting of H and C 1-4 or R' and R" together with the nitrogen atom to which they are attached form a ring containing 3-8 ring atoms, wherein the ring contains: (a) 1-7 ring carbon atoms, each carbon atom being replaced by 1-2 independently selected from H and C 1-3 (b) 0-3 ring heteroatoms (except the nitrogen atom connected to R' and R "), each of which is independently selected from N (R d ), O and S.

[0277] Each occurrence of R d1 Independently selected from the group consisting of H, C 1-6 Alkyl; C 3-6 Cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 Alkoxy; or -C(=O)CH(R 2 )N(R d1 )-R in the group 2 and R d1 Combined to form a ring as defined above containing 5 to 8 ring atoms;

[0278] and

[0279] L 2 and L 3is independently a bond at each occurrence, or is optionally substituted with 1-3 groups independently selected from oxo and R a C1-C6 alkylene substituted with a substituent.

[0280] In some embodiments of Formula (Ib), F 1 , G 1 , H 1 , J 1 , L 1 and M 1 1-4 of them are independently selected R 1 .

[0281] In certain embodiments, F 1 , G 1 , H 1 , J 1 , L 1 and M 1 1-3 (e.g., 2-3) of which are each independently selected R 1 .

[0282] In some of the foregoing embodiments, F 1 , G 1 , H 1 , J 1 , L 1 and M 1 1-2 (e.g., 1 or 2) of which are each independently selected R 1 .

[0283] In some of the foregoing embodiments, F 1 , G 1 , H 1 , J 1 , L 1 and M 1 2-3 (e.g., 2 or 3) of which are each independently selected R 1 .

[0284] In some of the foregoing embodiments, F 1 , G 1 , H 1 , J 1 , L 1 and M 1 2-4 (e.g., 2, 3, or 4) of which are each independently selected R 1 .

[0285] Variable H 1 and J 1

[0286] In some embodiments of Formula (Ib), H 1and J 1 Each independently selected from the following group:

[0287] ·key;

[0288] ·Optionally 1-3 R a Substituted C1-C6 alkylene;

[0289] ·-N(R d1 )-;

[0290] ·-N(R 3 )-;

[0291] -O-;

[0292] ·S(O) p , where p is 0, 1 or 2;

[0293] C(=O);

[0294] C(=S);

[0295] ·CHR 2 ;

[0296] -C(=O)CH(R 2 )N(R d1 )-;and

[0297] -C(=O)CH(R 2 )CH2N(R d1 )-.

[0298] In certain embodiments, H 1 and J 1 Each independently selected from the following group:

[0299] ·key;

[0300] ·-N(R d1 )-,

[0301] -O-;

[0302] ·S(O) p , where p is 0, 1 or 2;

[0303] C(=O);

[0304] C(=S);

[0305] ·CHR 2 ;

[0306] -C(=O)CH(R 2 )N(R d1 )-;and

[0307] -C(=O)CH(R 2 )CH2N(R d1 )-.

[0308] In some embodiments of Formula (Ib), H 1 and J 1 One of them is independently -C(=O)CH(R 2 )N(R d1 )-(For example, J 1 -C(=O)CH(R 2 )N(R d1 )-).

[0309] In some of the foregoing embodiments, H 1 and J 1 The other of is independently selected from the group consisting of:

[0310] ·key;

[0311] ·-N(R d1 )-,

[0312] -O-;

[0313] ·S(O) p , where p is 0, 1 or 2;

[0314] C(=O);

[0315] C(=S);

[0316] ·CHR 2 ;

[0317] -C(=O)CH(R 2 )N(R d1 )-;and

[0318] -C(=O)CH(R 2 )CH2N(R d1 )-.

[0319] In certain of the foregoing embodiments (when H 1 and J 1 One of them is independently -C(=O)CH(R 2 )N(R d1 )-time (for example, J 1 -C(=O)CH(R 2 )N(R d1 )-)), H 1 and J 1 The other of d1 )- and -O- (e.g., H 1 Can be a bond; or H1 Can be -N(R d1 )(e.g., -N(H)-)).

[0320] In some embodiments of Formula (Ib), H 1 and J 1 One of them is independently -N(R 3 )-or-N(R d1 )-. In certain of the foregoing embodiments, H 1 and J 1 One of them is independently -N(R 3 )-.

[0321] In certain of the foregoing embodiments (when H 1 and J 1 One of them is independently -N(R 3 )-or-N(R d1 )-time), H 1 and J 1 The other of is independently selected from:

[0322] ·key;

[0323] -O-;

[0324] ·S(O) p , where p is 0, 1 or 2;

[0325] C(=O);

[0326] C(=S);

[0327] ·CHR 2 ;

[0328] -C(=O)CH(R 2 )N(R d1 )-;and

[0329] -C(=O)CH(R 2 )CH2N(R d1 )-.

[0330] As a non-limiting example of the aforementioned embodiment (when H 1 and J 1 One of them is independently -N(R 3 )-or-N(R d1 )-time), H 1 and J 1 The other of may be a bond or C(=O).

[0331] Variable E 1 and Q 1

[0332] In some embodiments of Formula (Ib), E 1 and Q 1 Each is an independently selected C1-C6 alkylene group, which is optionally substituted by 1-3 R a replace.

[0333] In some of the foregoing embodiments, E 1 and Q 1 Each is an independently selected C1-C4 alkylene group, which is optionally substituted by 1-3 R a replace.

[0334] As a non-limiting example of the foregoing embodiment, E 1 and Q 1 and C2-C4 alkylene groups (eg, C2-C3 alkylene groups, eg, C2 alkylene groups).

[0335] Variable F 1

[0336] In some embodiments of Formula (Ib), F 1 Select from the following group:

[0337] ·key;

[0338] ·Optionally 1-3 R a Substituted C1-C6 alkylene;

[0339] ·-N(R d1 )-;

[0340] ·-N(R 3 )-;

[0341] -O-;

[0342] ·S(O) p , where p is 0, 1 or 2;

[0343] C(=O);

[0344] C(=S);

[0345] ·CHR 2 ;

[0346] -C(=O)CH(R 2 )N(R d1 )-;and

[0347] -C(=O)CH(R 2 )CH2N(R d1 )-.

[0348] In certain embodiments, F 1Selected from bonds, -N(R d1 )- (e.g., -N(H)-), -O-, and -S-.

[0349] In certain embodiments, F 1 is the key.

[0350] In certain embodiments, F 1 -N(R d1 )-(e.g., -N(H)-),

[0351] In certain embodiments, F 1 It is -O-.

[0352] In certain embodiments, F 1 For -S-.

[0353] Variable G 1

[0354] In some embodiments of Formula (Ib), G 1 Select from the following group:

[0355] ·key;

[0356] ·Optionally 1-3 R a Substituted C1-C6 alkylene;

[0357] ·-N(R d1 )-;

[0358] ·-N(R 3 )-;

[0359] -O-;

[0360] ·S(O) p , where p is 0, 1 or 2;

[0361] C(=O);

[0362] C(=S);

[0363] ·CHR 2 ;

[0364] -C(=O)CH(R 2 )N(R d1 )-;and

[0365] -C(=O)CH(R 2 )CH2N(R d1 )-.

[0366] In certain embodiments, G 1 Select from the following group:

[0367] ·key;

[0368] -O-;

[0369] ·S(O) p , where p is 0, 1 or 2;

[0370] C(=O);

[0371] C(=S);

[0372] ·CHR 2 ;

[0373] -C(=O)CH(R 2 )N(R d1 )-;and

[0374] -C(=O)CH(R 2 )CH2N(R d1 )-.

[0375] In certain embodiments, G 1 is the key.

[0376] In certain embodiments, G 1 S(O) p , where p=1 or 2 (eg, p=2).

[0377] Variable M 1

[0378] In some embodiments of Formula (Ib), M 1 Select from the following group:

[0379] ·key;

[0380] ·Optionally 1-3 R a Substituted C1-C6 alkylene;

[0381] ·-N(R d1 )-;

[0382] ·-N(R 3 )-;

[0383] -O-;

[0384] ·S(O) p , where p is 0, 1 or 2;

[0385] C(=O);

[0386] C(=S);

[0387] ·CHR 2 ;

[0388] -C(=O)CH(R2 )N(R d1 )-;and

[0389] -C(=O)CH(R 2 )CH2N(R d1 )-.

[0390] In certain embodiments, M 1 Select from the following group:

[0391] ·key;

[0392] -O-;

[0393] ·S(O) p , where p is 0, 1 or 2;

[0394] C(=O);

[0395] C(=S);

[0396] ·CHR 2 ;

[0397] -C(=O)CH(R 2 )N(R d1 )-;and

[0398] -C(=O)CH(R 2 )CH2N(R d1 )-.

[0399] In certain embodiments, M 1 is the key.

[0400] Variable L 1

[0401] In some embodiments of Formula (Ib), L 1 Select from the following group:

[0402] ·key;

[0403] ·Optionally 1-3 R a Substituted C1-C6 alkylene;

[0404] ·-N(R d1 )-;

[0405] ·-N(R 3 )-;

[0406] -O-;

[0407] ·S(O) p , where p is 0, 1 or 2;

[0408] C(=O);

[0409] C(=S);

[0410] ·CHR 2 ;

[0411] -C(=O)CH(R 2 )N(R d1 )-;and

[0412] -C(=O)CH(R 2 )CH2N(R d1 )-.

[0413] In certain embodiments, L 1 Select from the following group:

[0414] ·key;

[0415] -O-;

[0416] ·S(O) p , where p is 0, 1 or 2;

[0417] C(=O);

[0418] C(=S);

[0419] ·CHR 2 ;

[0420] -C(=O)CH(R 2 )N(R d1 )-;and

[0421] -C(=O)CH(R 2 )CH2N(R d1 )-.

[0422] In certain embodiments, L 1 is the key.

[0423] In certain embodiments, L 1 -C(=O)CH(R 2 )(CH2)N(R d1 )-(For example, R 2 =H).

[0424] In certain embodiments, L 1 It is C(=O).

[0425] In certain embodiments, L 1 -C(=O)CH(R 2 )N(R d1 )-.

[0426] Variable R 2 and R3

[0427] In some embodiments of Formula (Ib), R 2 For H.

[0428] In some embodiments of Formula (Ib), R 2 is a C1-C6 alkyl group, which is optionally substituted by 1-3 R a replace.

[0429] In certain embodiments, R 2 is a C1-C4 alkyl group, which is optionally substituted by 1-2 R a Replaced (e.g., by 1 R a substituted C1-C4 alkyl).

[0430] In certain of the foregoing embodiments (when R 2 When it is C1-C4 alkyl, it is optionally substituted by 1-2 R a Replaced (e.g., by 1 R a Substituted C1-C4 alkyl)), R a Each independently selected from: -OH; -SH; -NR e R f ; -C(=O)O(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 0-2 (C 1-4 alkyl); cyano; and -NR'C(=NR')NR'R".

[0431] As a non-limiting example of the foregoing embodiment, R a can be independently selected from the group consisting of -NH2, -OH, -SH, -SMe, -NH(C=NH)NH2, CO2H and CO2NH2 (e.g., R a may be each independently selected from -NH2, -OH, -NH(C=NH)NH2, CO2H and CO2NH2).

[0432] In some embodiments of Formula (Ib), R 2 for

[0433] L 2 -C6-C 10 Aryl, which is optionally substituted by 1 to 4 R c replace; or

[0434] L 2 -heteroaryl, wherein the heteroaryl contains 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(Rd ), O and S, and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace.

[0435] In certain embodiments, R 2 YesL 2 -phenyl, wherein the phenyl group is optionally substituted by 1-2 R c replace.

[0436] In certain embodiments, R 2 YesL 2 -heteroaryl, wherein the heteroaryl contains 5-8 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(R d ), O and S, and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-2 independently selected R c replace.

[0437] As a non-limiting example of the foregoing embodiment, R 2 Can be L 2 -Indolyl or L 2 -imidazolyl, wherein the indolyl or imidazolyl is optionally substituted with 1-2 independently selected R c replace.

[0438] In certain of the foregoing embodiments (when R 2 For L 2 -C6-C 10 When aryl, it is optionally substituted by 1 to 4 R c or L 2 -heteroaryl substituted, wherein the heteroaryl contains 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(R d ), O and S, wherein one or more of the heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c Replace), each R c is independently selected from -OH; -SH; -F; -Cl; -Br; -NR e R f ; C 1-4 Alkyl; C 1-4 Haloalkyl; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 0-2 (C 1-4 alkyl); cyano; - and C 3-6Cycloalkyl, which is optionally substituted by 1-4 independently selected C 1-4 Alkyl substitution.

[0439] As a non-limiting example of the foregoing embodiment, R c Can be independently selected from -OH, F, -NR e R f , C 1-4 Alkyl; and C 1-4 Haloalkyl (e.g., R c is OH).

[0440] In certain embodiments, L 2 is optionally replaced by 1-3 R a (e.g., unsubstituted) substituted C 1-6 (For example, C 1-4 )alkylene.

[0441] In some embodiments of Formula (Ib), each occurrence of R 2 Independently selected from:

[0442] H;

[0443] C1-C6 alkyl, optionally substituted with 1-2 substituents selected from -NH2, -OH, -SH, -SMe, -NH(C=NH)NH2, CO2H and CO2NH2;

[0444] (C1-C6 alkylene)-phenyl, optionally substituted with 1-2 -OH groups;

[0445] (C1-C6 alkylene)-indolyl; and

[0446] (C1-C6 alkylene)-imidazolyl; or

[0447] ·-CH(R 2 )N(R d1 )-R in the group 2 and R d1 , combine to form a pyrrolidine ring.

[0448] In certain embodiments, each occurrence of R 2 Independently selected from:

[0449] H;

[0450] C1-C6 alkyl, optionally substituted with 1-2 substituents selected from -NH2, -OH, -NH(C=NH)NH2, CO2H and CO2NH2; and

[0451] ·(C1-C6 alkylene)-imidazolyl.

[0452] As a non-limiting example of the foregoing implementation, each occurrence of R 2 Can be independently selected from:

[0453] H;

[0454] · and

[0455] ·

[0456] In some embodiments of Formula (Ib), each occurrence of R 3 Independently selected from:

[0457] C1-C6 alkyl, optionally substituted with 1-2 substituents selected from -NH2, -OH, -SH, -SMe, -NH(C=NH)NH2, CO2H and CO2NH2;

[0458] (C1-C6 alkylene)-phenyl, optionally substituted with 1-2 -OH groups;

[0459] (C1-C6 alkylene)-indolyl; and

[0460] ·(C1-C6 alkylene)-imidazolyl.

[0461] In some embodiments of Formula (Ib), R 3 is a C1-C6 alkyl group, which is optionally substituted by 1-3 R a replace.

[0462] In certain embodiments, R 3 is a C1-C4 alkyl group, which is optionally substituted by 1-2 R a Replaced (e.g., by 1 R a substituted C1-C4 alkyl).

[0463] In certain of the foregoing embodiments (when R 3 When it is C1-C4 alkyl, it is optionally substituted by 1-2 R a Replaced (e.g., by 1 R a Substituted C1-C4 alkyl)), R a Each independently selected from: -OH; -SH; -NR e R f ; -C(=O)O(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 0-2 (C 1-4 alkyl); cyano; and -NR'C(=NR')NR'R".

[0464] As a non-limiting example of the foregoing embodiment, R a can be independently selected from: -NH2, -OH, -SH, -SMe, -NH(C=NH)NH2, CO2H and CO2NH2 (for example, R a can be independently selected from -NH2, -OH, -NH(C=NH)NH2, CO2H and CO2NH2; for example, R a may be independently selected from -NH2 and CO2H).

[0465] In some embodiments of Formula (Ib), R 3 YesL 3 -C6-C 10 Aryl, which is optionally substituted by 1 to 4 R c replace; or

[0466] L3-heteroaryl, wherein the heteroaryl contains 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(R d ), O and S, and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace.

[0467] In certain embodiments, R 3 YesL 3 -phenyl, wherein the phenyl group is optionally substituted by 1-2 R c replace.

[0468] In certain embodiments, R 3 YesL 3 -heteroaryl, wherein the heteroaryl contains 5-8 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(R d ), O and S, and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-2 independently selected R c replace.

[0469] As a non-limiting example of the foregoing embodiment, R 3 Can be L 3 -Indolyl or L 3 -imidazolyl, wherein the indolyl or imidazolyl is optionally substituted with 1-2 independently selected R c replace.

[0470] In certain of the foregoing embodiments (when R 3 For L 2 -C6-C 10 When aryl, it is optionally substituted by 1 to 4 R c or L 3-heteroaryl substituted, wherein the heteroaryl contains 5-10 ring atoms, of which 1-4 ring atoms are heteroatoms, each independently selected from N, N(R d ), O and S, wherein one or more of the heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c Replace), each R c is independently selected from -OH; -SH; -F; -Cl; -Br; -NR e R f ; C 1-4 Alkyl; C 1-4 Haloalkyl; C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)OH; -CON(R')(R"); -S(O) 1-2 (NR'R");-S(O) 0-2 (C 1-4 alkyl); cyano; - and C 3-6 Cycloalkyl, which is optionally substituted by 1-4 independently selected C 1-4 Alkyl substitution.

[0471] As a non-limiting example of the foregoing embodiment, R c Can be independently selected from -OH, F, -NR e R f , C 1-4 Alkyl; and C 1-4 Haloalkyl (e.g., R c is OH).

[0472] In certain embodiments, L 3 is optionally replaced by 1-3 R a (e.g., unsubstituted) substituted C 1-6 (For example, C 1-4 ).

[0473] In certain embodiments, L 3 is a C substituted with an oxo group 1-6 (For example, C 1-4 As a non-limiting example of the foregoing, L 3 Can be

[0474] In certain embodiments, L 3 is the key.

[0475] In certain embodiments, each occurrence of R 3 Independently selected from:

[0476] C1-C6 alkyl, optionally substituted with 1-2 substituents selected from -NH2, -OH, -NH(C=NH)NH2, CO2H and CO2NH2; and

[0477] ·(C1-C6 alkylene)-imidazolyl.

[0478] As a non-limiting example of the foregoing implementation, each occurrence of R 3 Can be independently selected from:

[0479] ·

[0480] and

[0481] ·

[0482] In certain embodiments, each occurrence of R 3 Independently selected from: C1-C6 alkyl optionally substituted with 1-2 substituents selected from -NH2, -OH, -NH(C=NH)NH2, CO2H and CO2NH2.

[0483] As a non-limiting example of the foregoing implementation, each occurrence of R 3 Can be independently selected from:

[0484] In some embodiments, each occurrence of R 3 Independently selected from: L 3 -heterocyclyl, wherein the heterocyclyl contains 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N(R d ), O and S, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace.

[0485] In certain embodiments, each occurrence of R 3 Independently selected from: L 3 -heterocyclyl, wherein the heterocyclyl contains 4-6 (e.g., 5-6) ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N(R d ), O and S, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-2 independently selected R b substituted (for example, the heterocyclyl group can be pyrrolidinyl, piperidinyl or morpholinyl).

[0486] In certain embodiments (when each occurrence of R 3 Independently selected from: L 3-heterocyclyl, wherein the heterocyclyl contains 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N(R d ), O and S, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b Replacement), L 3 It is C 1-6 Alkyl, optionally with 1-3 independently selected R a (e.g., unsubstituted) substituted.

[0487] In certain embodiments (when each occurrence of R 3 Independently selected from: L 3 -heterocyclyl, wherein the heterocyclyl contains 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N(R d ), O and S, wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b Replacement), L 3 It is C 1-6 (For example, C 1-4 ) alkylene, which is substituted with an oxo group (for example, it can be ).

[0488] As a non-limiting example, R 3 Can be selected from:

[0489]

[0490] Variable R d1

[0491] In some embodiments of Formula (Ib), each occurrence of R d1 Independently selected from the group consisting of: each occurrence of R d1 Independently selected from the group consisting of H, C 1-6 Alkyl; C 3-6 Cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 (NR'R"); and -S(O) 1-2 (C 1-4 alkyl); or -C(=O)CH(R 2 )N(R d1 )-R in the group 2 and R d1 Combined to form a ring as defined above containing 5 to 8 ring atoms.

[0492] In certain embodiments, each occurrence of R d1Independently selected from the following group: H, C 1-6 Alkyl; and C 3-6 Cycloalkyl.

[0493] In certain embodiments, each occurrence of R d1 It's H.

[0494] Variable B 1 and B 2

[0495] In some embodiments of Formula (Ib), B 1 and B 2 Each independently is -Z 1 -Z 3 (i.e., Z 2 is key).

[0496] In some embodiments of Formula (Ib), Z 3 is H, halogen or C 1-3 alkyl.

[0497] In some embodiments of Formula (Ib), Z 3 Is H or C 1-3 Alkyl (e.g., Z 3 It can be H).

[0498] In some embodiments of Formula (Ib), Z 3 is a halogen (e.g., Z 3 It can be F).

[0499] In some embodiments of Formula (Ib), Z 1 It is C 1-3 Alkylene, which is optionally composed of 1-3 independently selected R a Replace (for example, Z 1 It can be methylene, CHF or CF2).

[0500] In certain embodiments, Z 1 is unsubstituted C 1-3 Alkylene (eg, CH2).

[0501] In certain embodiments, Z 1 is unsubstituted C 1-3 Alkylene; and Z 3 It's H.

[0502] In certain embodiments, Z 1 is C substituted with 1-2 independently selected halogens (e.g., F) 1-3 Alkylene.

[0503] In certain embodiments, B 1 and B2 Each independently selected from CH3, CHR a , CH(R a )2 and C(R a )2-halogen.

[0504] As a non-limiting example of the foregoing embodiment, B 1 and B 2 Each can independently be CH3, CHF2, CH2F or CF3.

[0505] Non-limiting combinations of formula (Ib) [1]

[0507] In some embodiments of Formula (Ib), H 1 or J 1 One of them is -C(=O)CH(R 2 )N(R d1 )-;as well as

[0508] E 1 and Q 1 Each is an independently selected C1-C6 alkylene group, which is optionally substituted by 1-3 R a (For example, C 2-4 Alkylene, such as unsubstituted C 2-4 alkylene) substituted.

[0509] In some of the foregoing embodiments, F 1 -N(R d1 )- (e.g., -N(H)-), -O-, or -S-).

[0510] In certain embodiments of [1], the compound of formula (Ib) is a compound of formula (II):

[0511]

[0512] or a pharmaceutically acceptable salt thereof,

[0513] in:

[0514] E 1 and Q 1 Each is an independently selected C1-C6 alkylene group (e.g., C 2-4 Alkylene, such as unsubstituted C 2-4 alkylene), which is optionally substituted by 1 to 3 R a replace;

[0515] F 1 Yes-N(R d1 )- (e.g., -N(H)-), -O-, or -S-; and

[0516] H 1 , G 1 , L 1 and M 1 are each independently selected from:

[0517] ·key:

[0518] ·-N(R d1 )-,

[0519] -O-;

[0520] ·S(O) p , where p is 0, 1 or 2;

[0521] C(=O);

[0522] C(=S);

[0523] ·CHR 2 ;

[0524] -C(=O)CH(R 2 )N(R d1 )-;and

[0525] -C(=O)CH(R 2 )CH2N(R d1 )-.

[0526] [1-1]

[0527] In some embodiments of Formula (II), L 1 and M 1 Each is a key.

[0528] In some embodiments of Formula (II), G 1 and H 1 Each is a key.

[0529] In some embodiments of Formula (II), F 1 -N(R d )-(e.g., NH).

[0530] In certain embodiments, the compound of Formula II is a compound of Formula (II-a):

[0531]

[0532] or a pharmaceutically acceptable salt thereof.

[0533] [1-2]

[0534] In some embodiments of Formula (II), G 1 S(O) p ; and p is 1 or 2.

[0535] In certain of the foregoing embodiments (when G in Formula II 1 S(O) p ; and p is 1 or 2), F 1 It is -O-.

[0536] In certain embodiments (when G in Formula II 1 S(O) p ; when p is 1 or 2; and / or F 1 When -O-, H 1 -N(R d1 )-(e.g., NH).

[0537] In certain embodiments, the compound of formula (II) is a compound of formula (II-b):

[0538]

[0539] or a pharmaceutically acceptable salt thereof.

[0540] [1-3]

[0541] In some embodiments of Formula (II), L 1 -C(=O)CH(R 2 )(CH2)N(R d1 )-.

[0542] In certain of the foregoing embodiments (when L in Formula (II) 1 -C(=O)CH(R 2 )(CH2)N(R d1 )-time), M 1 , G 1 and H 1 Each is a key.

[0543] In certain of the foregoing embodiments (when L in Formula II 1 -C(=O)CH(R 2 )(CH2)N(R d1 )-; and / or M in formula (II) 1 , G 1 and H 1 Each is a key), F 1 is -O- or -N(R d1 )- (e.g., -N(H)-).

[0544] In certain embodiments, the compound of formula (II) is a compound of formula (II-c1) or (II-c2):

[0545]

[0546] or a pharmaceutically acceptable salt thereof.

[0547] [1-4]

[0548] In some embodiments of Formula (II), L 1 It is C(=O).

[0549] In certain of the foregoing embodiments (when L in Formula (II) 1 When C(=O) is 1 , G 1 and H 1 Each is a key.

[0550] In certain of the foregoing embodiments (when L in Formula (II) 1 is C(=O); and / or M in formula (II) 1 , G 1 and H 1 Each is a key), F 1 is -O- or -N(R d1 )-.

[0551] In certain embodiments, the compound of formula (II) is a compound of formula (II-d):

[0552]

[0553] or a pharmaceutically acceptable salt thereof.

[0554] [1-5]

[0555] In some embodiments of Formula (II), L 1 -C(=O)CH(R 2 )N(R d1 )-.

[0556] In some of the foregoing embodiments, M 1 , G 1 and H 1 Each is a key.

[0557] In certain embodiments (e.g., when L 1 -C(=O)CH(R 2 )N(R d1 )-and / or M 1 , G 1 and H 1 Each is a key), F 1 is -O- or -N(R d1 )- (e.g., -N(H)-).

[0558] In certain embodiments, the compound of formula (II) is of formula (II-e):

[0559]

[0560] or a pharmaceutically acceptable salt thereof.

[0561] As a non-limiting example of the foregoing embodiment, the compound has the following formula:

[0562]

[0563]

[0564] In some embodiments of Formula (Ib), H 1 and J 1 One of them is -N(R 3 )-or-N(R d1 )-(For example, H 1 and J 1 One of them is -N(R 3 )-).

[0565] In certain of the foregoing embodiments, the compound of formula (Ib) is a compound of formula (III):

[0566]

[0567] or a pharmaceutically acceptable salt thereof.

[0568] In certain embodiments of Formula (III), E 1 and Q 1 Each is an independently selected C1-C6 alkylene (e.g., C2-C4 alkylene, C2-C3 alkylene, C2 alkylene, e.g., unsubstituted C2 alkylene), which is optionally substituted by 1-3 R a replace.

[0569] In some of the foregoing embodiments, F 1 and M 1 Each is a key.

[0570] In certain embodiments, G 1 and L 1 Each independently selected from:

[0571] ·key;

[0572] -O-;

[0573] ·S(O) p , where p is 0, 1 or 2;

[0574] C(=O);

[0575] C(=S);

[0576] ·CHR 2 ;

[0577] -C(=O)CH(R 2 )N(R d1 )-;and

[0578] -C(=O)CH(R 2 )CH2N(R d1 )-.

[0579] As a non-limiting example of the foregoing implementation, G 1 and L 1 Each is a key.

[0580] In certain of the aforementioned embodiments of [2], H 1 is the key.

[0581] In certain of the aforementioned embodiments of [2], H 1 Yes (C=O).

[0582] In certain embodiments of [1] (including [1-1]-[1-4]) and [2], each occurrence of R 2 As defined in claims 40-42.

[0583] In certain embodiments of [1] (including [1-1]-[1-4]) and [2], each occurrence of R 2 Independently selected from:

[0584] H;

[0585] C1-C6 alkyl, optionally substituted with 1-2 substituents selected from -NH2, -OH, -SH, -SMe, -NH(C=NH)NH2, CO2H and CO2NH2;

[0586] (C1-C6 alkylene)-phenyl, optionally substituted with 1-2 -OH groups;

[0587] (C1-C6 alkylene)-indolyl; and

[0588] (C1-C6 alkylene)-imidazolyl; or

[0589] ·-CH(R 2 )N(R d1 )-R in the group 2 and R d1 , combine to form a pyrrolidine ring.

[0590] In certain embodiments of [1] (including [1-1]-[1-4]) and [2], each occurrence of R 2 Independently selected from:

[0591] H;

[0592] C1-C6 alkyl, optionally substituted with 1-2 substituents selected from -NH2, -OH, -NH(C=NH)NH2, CO2H and CO2NH2; and

[0593] ·(C1-C6 alkylene)-imidazolyl.

[0594] In certain embodiments of [1] (including [1-1]-[1-4]) and [2], each occurrence of R 2 Independently selected from:

[0595] H;

[0596] · and

[0597] ·

[0598] In certain embodiments of [1] (including [1-1]-[1-4]) and [2], each occurrence of R 3 As defined in claims 43-45.

[0599] In certain embodiments of [1] (including [1-1]-[1-4]) and [2], each occurrence of R 3 Independently selected from:

[0600] C1-C6 alkyl, optionally substituted with 1-2 substituents selected from -NH2, -OH, -SH, -SMe, -NH(C=NH)NH2, CO2H and CO2NH2;

[0601] (C1-C6 alkylene)-phenyl, optionally substituted with 1-2 -OH groups;

[0602] (C1-C6 alkylene)-indolyl; and

[0603] ·(C1-C6 alkylene)-imidazolyl.

[0604] In certain embodiments of [1] (including [1-1]-[1-4]) and [2], each occurrence of R 3 Independently selected from:

[0605] C1-C6 alkyl is optionally substituted with 1-2 substituents selected from -NH2, -OH, -NH(C=NH)NH2, CO2H and CO2NH2; and

[0606] ·(C1-C6 alkylene)-imidazolyl.

[0607] In certain embodiments of [1] (including [1-1]-[1-4]) and [2], each occurrence of R 3 Independently selected from:

[0608] · and

[0609] ·

[0610] As a non-limiting example of the foregoing implementation, each occurrence of R 3 Can be independently selected from the following groups:

[0611] In certain embodiments of [1] (including [1-1]-[1-4]) and [2], each occurrence of R 3 Independently selected from: L 3 -heterocyclyl, wherein the heterocyclyl contains 3-10 ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N(R d ), O and S, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace.

[0612] In certain embodiments of [1] (including [1-1]-[1-4]) and [2], each occurrence of R 3 Independently selected from: L 3 -heterocyclyl, wherein the heterocyclyl contains 4-6 (e.g., 5-6) ring atoms, of which 1-3 ring atoms are heteroatoms, each independently selected from N(R d ), O and S, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-2 independently selected R b substituted (for example, the heterocyclyl group can be pyrrolidinyl, piperidinyl or morpholinyl).

[0613] In certain embodiments of [1] (including [1-1] to [1-4]) and [2] (when R 3 For: L 3 -heterocyclic group), L 3 In certain other embodiments, L 3 is optionally 1-3 independently selected R a (e.g., unsubstituted) substituted C 1-6 In certain embodiments of [1] (including [1-1] to [1-4]) and [2] (when R 3 For: L3 -heterocyclic group), L 3 C 1-6 (For example, C 1-4 ) alkylene, which is substituted with an oxo group (for example, it can be ).

[0614] In certain embodiments of [1] (including [1-1] to [1-4]) and [2] (when R 3 For: L 3 -heterocyclic group), R 3 Selected from:

[0615]

[0616] In certain embodiments of [1] (including [1-1]-[1-4]) and [2], B 1 and B 2 Each as defined in claims 53-57.

[0617] In certain embodiments of [1] (including [1-1]-[1-4]) and [2], B 1 and B 2 Each independently is -Z 1 -Z 3 (i.e., Z 2 as key).

[0618] In certain embodiments of [1] (including [1-1] to [1-4]) and [2], Z 3 is H, halogen or C 1-3 In certain embodiments of [1] (including [1-1] to [1-4]) and [2], Z 1 is optionally 1-3 independently selected R a Substituted C 1-3 Alkylene.

[0619] In certain embodiments of [1] (including [1-1]-[1-4]) and [2], B 1 and B 2 Each independently selected from CH3, CHR a , CH(R a )2 and C(R a )2-halogen.

[0620] In certain embodiments of [1] (including [1-1]-[1-4]) and [2], B 1 and B 2 Each is independently selected from CH3, CHF2, CH2F and CF3.

[0621] In certain embodiments of [1] (including [1-1]-[1-4]) and [2], each occurrence of R d1 As defined in claims 58-60.

[0622] In certain embodiments of [1] (including [1-1]-[1-4]) and [2], each occurrence of R d1 Independently selected from the group consisting of H, C 1-6 Alkyl; C 3-6 Cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 (NR'R"); and -S(O) 1-2 (C 1-4 alkyl); or -C(=O)CH(R 2 )N(R d1 )-R in the group 2 and R d1 Combined to form a ring as defined above containing 5 to 8 ring atoms.

[0623] In certain embodiments of [1] (including [1-1]-[1-4]) and [2], each occurrence of R d1 Independently selected from the group consisting of H, C 1-6 Alkyl; and C 3-6 As a non-limiting example of the foregoing embodiment, each R d1 It can be H.

[0624] In some embodiments, the compound is selected from the following Table-A1:

[0625] Table A-1

[0626]

[0627]

[0628]

[0629]

[0630]

[0631] or a pharmaceutically acceptable salt thereof.

[0632] Pharmaceutical compositions and administration

[0633] Overview

[0634] In some embodiments, a chemical entity (e.g., a compound or a pharmaceutically acceptable salt and / or hydrate and / or prodrug of a compound) that produces cross-links in the cornea in response to exposure to photoactivating light is administered as a pharmaceutical composition comprising the chemical entity and one or more pharmaceutically acceptable excipients and, optionally, one or more additional therapeutic agents described herein.

[0635] In some embodiments, the pharmaceutical composition is as described in US2018 / 0236077, which is incorporated herein by reference in its entirety.

[0636] In some embodiments, the chemical entities described herein can be administered in combination with one or more delivery agents. Delivery agents include, but are not limited to, anesthetics, analgesics, tension agents, shear thinning agents, viscosity increasing agents, surfactants (e.g., ionic surfactants or nonionic surfactants) or chelating agents. Non-limiting examples of anesthetics may include pilocarpine, procaine, tetracaine or oxybuprocaine. Non-limiting examples of analgesics include menthol, benzyl alcohol or phenylethyl alcohol. Non-limiting examples of tension agents include glycerol, propylene glycol, polyethylene glycol (PEG) -8, ethanol, benzyl alcohol, phenylethyl alcohol or triacetin. Non-limiting examples of shear thinning, viscosity increasing agents include carbomer, polycarbophil, gellan gum, xanthan gum, sodium carboxymethylcellulose or sodium hyaluronate. Non-limiting examples of ionic surfactants include benzalkonium chloride. Non-limiting examples of nonionic surfactants include poloxamer 407, tetronic 1107, tetronic 1304, polysorbate 80, polyethylene glycol (PEG) -40 hydrogenated castor oil, lecithin, polysorbate 60, polyethylene glycol (PEG) -35 castor oil, tocopherol (TPGS), nonoxynol -9 or tyloxapol. Non-limiting examples of chelating agents include ethylenediaminetetraacetic acid (EDTA) or citrate.

[0637] In some embodiments, the chemical entities described herein can be administered to corneal epithelial cells in combination with one or more preparations. In certain embodiments, the preparation increases the permeability of the corneal epithelium. As a non-limiting example of the foregoing, the preparation may include one or more of the following: zinc metalloproteinases, copper metalloproteinases, papain, bromelain, actinidin, ficin (ficain), N-acetylcysteine, ambroxol, carbocysteine ​​or erdosteine. In certain embodiments, one or more preparations may also include one or more anesthetics (e.g., pilocarpine, procaine, tetracaine or oxybuprocaine).

[0638] In some embodiments, the chemical entities described herein can be administered in combination with one or more enhancing agents that are configured to: (i) remove one or more therapeutic agents from the corneal epithelium without diluting the one or more therapeutic agents delivered to the stroma; (ii) close the tight junctions of the epithelium to control the hydration of the cornea; (iii) promote oxidation of one or more therapeutic agents delivered to the stroma; or (iv) further deliver one or more therapeutic agents from the epithelium to the stroma. As non-limiting examples of the foregoing, the enhancing agent may include one or more of the following: a divalent metal salt, one or more pro-oxidants, or one or more glycosaminoglycans.

[0639] In some embodiments, the chemical entities described herein can be administered in combination with one or more post-treatment formulations in response to the application of one or more enhancing formulations, and the one or more post-treatment formulations can include at least one of the following: one or more divalent metal salts, one or more viscosity agents, one or more glycosaminoglycans, or one or more antibiotics.

[0640] In some embodiments, the chemical entity can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tweens, poloxamers or other similar polymer delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or dielectrics, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and lanolin. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilized derivatives may also be used to enhance the delivery of the compounds described herein. Dosage forms or compositions containing the chemical entities described herein in the range of 0.005%-100% may be prepared, with the balance being made up by non-toxic excipients. The contemplated compositions may contain 0.001%-100% of the chemical entities provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, and in yet another embodiment 20-80%. Actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22nd ed. (Pharmaceutical Press, London, England, 2012).

[0641] Routes of administration and composition components

[0642] The composition can be prepared as a liquid solution or suspension; a solid form suitable for adding a liquid to prepare a solution or suspension before administration can also be prepared; and the preparation can also be emulsified. According to the present disclosure, the preparation of such preparations is known to those skilled in the art.

[0643] The composition may be administered topically (eg, intraocularly in the form of topical instillations).

[0644] Pharmaceutical forms suitable for intraocular use include sterile aqueous solutions (e.g., buffers, such as citrate buffer; for example, eye drops, such as 20% dextran eye drops) or dispersions; formulations including sesame oil, peanut oil or propylene glycol aqueous solutions; and sterile powders for the extemporaneous preparation of sterile solutions or dispersions. In general, the form must be sterile and must be fluid to the extent that it is easy to inject. It should also be stable under the conditions of manufacture and storage, and must be able to resist the contaminating action of microorganisms such as bacteria and fungi during storage.

[0645] The carrier can also be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof, and vegetable oils. Suitable fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size in the case of dispersion, and by using a surfactant. The action of microorganisms can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, isotonic agents are preferably included, such as sugars or sodium chloride. The absorption of the composition can be prolonged by using agents that delay absorption, such as aluminum monostearate and gelatin in the composition.

[0646] Sterile solutions are prepared by incorporating the required amount of active compound and, if necessary, the above-mentioned other components into a suitable solvent and then filtering and sterilizing. Generally, the various sterilized active ingredients are incorporated into a sterile carrier containing an alkaline dispersion medium and the above-mentioned other required ingredients to prepare a dispersion. When preparing sterile powders required for preparing sterile solutions, the preferred preparation method is vacuum drying and freeze drying technology to obtain a powder of the active ingredient and any other required ingredients from a previously sterile filtered solution.

[0647] In certain embodiments, the excipient is sterile and generally free of undesirable substances. The composition can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients, such as tablets and capsules, sterility is not required. USP / NF standards are generally sufficient.

[0648] The ophthalmic composition may include, but is not limited to, any one or more of the following: dextran, viscogens (e.g., carboxymethylcellulose, glycerol, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin); preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol and zinc chloride; Alcon Laboratories Inc.), Purite (stabilized chlorine oxide complex; Allergan, Inc.).

[0649] Compositions may include ointments and creams. Ointments are semisolid preparations, typically based on petrolatum or other petroleum derivatives. Creams containing selected active agents are typically viscous liquids or semisolid emulsions, typically oil-in-water or water-in-oil. Cream bases are typically washable and include an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes referred to as the "inner" phase, is typically composed of petrolatum and a fatty alcohol (such as cetyl alcohol or stearyl alcohol); although not necessarily, the aqueous phase typically exceeds the volume of the oil phase and typically includes a wetting agent. Emulsifiers in cream formulations are typically nonionic, anionic, cationic, or amphoteric surfactants. Like other carriers or vehicles, ointment bases should be inert, stable, non-irritating, and insensitive.

[0650] In certain embodiments, the compounds and compositions disclosed herein can be applied to the cornea using an applicator. Non-limiting examples of applicators can include a dropper or a syringe.

[0651] In certain embodiments, the compounds and compositions described herein can be administered in a formulation that allows the compound of the composition to pass through the corneal epithelium to the lower region in the corneal stroma. In other embodiments, the corneal epithelium can be removed or otherwise cut to allow the compound or composition provided herein to be more directly administered to the underlying tissue.

[0652] Thus, in some embodiments, the compounds and compositions described herein are applied directly to the cornea (e.g., without removing or otherwise cutting the corneal epithelium). In other embodiments, the corneal epithelium is removed or otherwise cut prior to applying the compounds and compositions described herein.

[0653] dose

[0654] The dosage can vary according to the patient's needs, the severity of the disease being treated and the specific compound being used. The appropriate dosage for a particular situation can be determined by a technician in the medical field. In some cases, the total dose can be administered in batches or by providing continuous delivery throughout the process.

[0655] In some embodiments, the composition is a solution (e.g., a buffer, such as a citrate buffer; such as an ophthalmic solution, such as a 20% dextran ophthalmic solution) comprising 0.01-100 mg / mL of a chemical entity described herein (e.g., 0.02-50 mg / mL, 0.04-25 mg / mL, 0.08-12.5 mg / mL, 0.16-6.25 mg / mL, 0.2-5 mg / mL). In certain embodiments of the foregoing, the unit dose is 0.001-1 mL (e.g., 0.002-0.5 mL, 0.010-0.25 mL, e.g., 0.020-0.1 mL).

[0656] In some embodiments, the composition is a solution (e.g., a buffer, such as a citrate buffer; e.g., an ophthalmic solution, such as a 20% dextran ophthalmic solution) comprising 0.001%-20% of a chemical entity described herein (e.g., 0.002%-10%, 0.004%-5%, 0.008%-2.5%). In certain embodiments of the foregoing, the unit dose is 0.001-1 mL (e.g., 0.002-0.5 mL, 0.010-0.25 mL, e.g., 0.020-0.2 mL).

[0657] Dosage regimen

[0658] The above dosage can be regularly administered in a specific duration. In some embodiments, the unit dosage can be administered every 1-1200 seconds (e.g., every 2-300 seconds, every 2-150 seconds, every 5-150 seconds, every 5-100 seconds, every 5-10 seconds, every 10-150 seconds, every 50-150 seconds). In some of the aforementioned embodiments, the dosage is administered in a time period of 1-1200 minutes (e.g., 1-600 minutes, 5-120 minutes, 10-120 minutes).

[0659] Treatment

[0660] Overview

[0661] The disclosure features methods for treating a subject (e.g., a human) having a disease, disorder, or condition in which an abnormal shape of the cornea (e.g., corneal thinning, e.g., bilateral corneal thinning, e.g., bilateral thinning of the central, paracentral, or peripheral cornea; or corneal steepening (e.g., bulge)) contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition. In certain embodiments, the methods described herein may include or further include treating one or more disorders associated with, combined with, or sequelae to any one or more disorders described herein.

[0662] In some embodiments, the method further comprises identifying the object.

[0663] In certain embodiments, the chemical entities described herein provide refractive correction to the cornea (e.g., by imparting mechanical rigidity). In certain embodiments, the chemical entities described herein strengthen and stabilize the corneal structure. In certain embodiments, the chemical entities described herein can be used for vision correction.

[0664] method

[0665] In some embodiments, the method comprises administering a compound disclosed herein or a pharmaceutical composition thereof to a cornea of ​​a subject in need thereof; and applying electromagnetic radiation (eg, light) to the cornea, thereby generating crosslinks in the cornea.

[0666] In certain of the foregoing embodiments, the method comprises administering a compound disclosed herein or a pharmaceutical composition thereof to the corneal stroma of a subject in need thereof.

[0667] In certain embodiments, a compound disclosed herein or a pharmaceutical composition thereof is administered to the cornea without removing corneal epithelial cells.

[0668] In some embodiments, the claimed methods can be performed without adding or supplementing oxygen levels, which can be advantageous in some applications.

[0669] In other embodiments, the method further comprises increasing or decreasing O2 concentration on the cornea during irradiation.

[0670] In certain embodiments, the method further comprises administering to the cornea one or more delivery agents, wherein the one or more delivery agents are as described elsewhere herein.

[0671] In certain embodiments, the method further comprises administering to a subject in need thereof (e.g., to the cornea of ​​a subject in need thereof) one or more preparations that increase the permeability of the corneal epithelium, wherein the one or more preparations are as described elsewhere herein.

[0672] In certain embodiments, the method further comprises administering one or more enhancing formulations to the corneal epithelium, wherein the one or more enhancing formulations are configured as one or more of the following:

[0673] (i) removing one or more therapeutic agents from the corneal epithelium without diluting one or more therapeutic agents delivered to the stroma;

[0674] (ii) closing the tight junctions of the epithelium to control corneal hydration;

[0675] (iii) promoting oxidation of one or more therapeutic agents delivered to the matrix; or

[0676] (iv) further delivering one or more therapeutic agents from the epithelium to the stroma,

[0677] wherein the one or more enhancing agents are as described elsewhere herein.

[0678] In certain embodiments, the method further comprises administering one or more post-treatment formulations to a subject in need thereof in response to applying one or more enhancing formulations, wherein the one or more enhancing formulations are as described elsewhere herein.

[0679] Electromagnetic Radiation

[0680] In some embodiments, the electromagnetic radiation applied to the cornea of ​​a subject in need thereof is optical radiation. In certain embodiments, the optical radiation has a suitable wavelength, energy, and duration to cause a reaction (e.g., photoinduced electron transfer and / or fragmentation) of a compound described herein, thereby allowing crosslinking.

[0681] In some embodiments, the wavelength of light can be selected so that it corresponds to or encompasses absorption by a compound described herein and reaches an area of ​​tissue that has been contacted with a compound described herein, e.g., penetrates to an area where a compound described herein is present.

[0682] In some embodiments, the energy of the applied electromagnetic radiation is less than 2000 J / cm 2 In some of the foregoing embodiments, the applied electromagnetic energy is between 1 and 500 J / cm 2 The total energy dose absorbed in the cornea can be described as the effective dose, which is the energy absorbed by the area of ​​the corneal epithelium. For example, the effective dose for the area of ​​the corneal surface can be, for example, 5 J / cm 2 and 20J / cm 2 or 30J / cm 2 Between (e.g., 5.4 J / cm 2 ).

[0683] In some embodiments, the electromagnetic radiation is about 0.1-100 mW / cm 2 (e.g., 1-100 mW / cm 2 In some embodiments, the electromagnetic radiation is applied at an irradiance of about 1-5 mW / cm 2 (For example, 3mW / cm 2 ) irradiance is applied.

[0684] In some embodiments, the electromagnetic radiation has a wavelength in the visible, infrared or ultraviolet spectrum. In some embodiments, the electromagnetic radiation includes radiation with a wavelength from about 300nm to about 800nm ​​(e.g., from 300nm to 700nm). In certain embodiments, the electromagnetic radiation includes ultraviolet A (UVA) light (e.g., wavelength between 350 and 380nm, e.g., 360-370nm, e.g., 365nm). In certain embodiments, the electromagnetic radiation includes visible wavelengths (e.g., wavelength between 400nm and 550nm, e.g., about 452nm). In some embodiments, the electromagnetic radiation is laser radiation. In certain embodiments, the laser radiation is applied with an average power of 1-100mW.

[0685] In some embodiments, the duration of irradiation is between 30 seconds and 1 hour. In certain embodiments, the duration of irradiation is between 1 minute and 1 hour (e.g., 30 minutes).

[0686] In some embodiments, the cornea of ​​the eye can be more extensively treated with a compound or composition described herein; and radiation can be selectively directed to the treated corneal area according to a specific pattern.

[0687] In certain embodiments, one or more mirrors or lenses can be used to direct and focus electromagnetic radiation into a specific pattern on the cornea (eg, at a specific focal plane within the cornea, eg, at a specific depth in the underlying region where cross-linking activity is desired).

[0688] In some embodiments, a specific electromagnetic radiation pattern can be modulated to achieve a desired degree of cross-linking in a selected area of ​​the cornea. For example, the electromagnetic radiation can be delivered according to any combination of wavelength, bandwidth, intensity, power, location, penetration depth, and / or treatment duration (duration of exposure period, duration of dark period, and ratio of exposure period to dark period duration).

[0689] In some embodiments, electromagnetic radiation is delivered using a system containing a digital micromirror device (DMD) to modulate the application of electromagnetic radiation in space and time. In some of the aforementioned embodiments, light is projected in a precise spatial pattern, which is produced by microscopic mirrors in a matrix laid on a semiconductor chip. Each mirror represents one or more pixels in the pattern of projected light. Using DMD, topography-guided crosslinking can be performed. Several different spatial and temporal irradiances and dose distributions can be used for the control of DMD according to the topography. These spatial and temporal dose distributions can be generated using continuous wave irradiation, but can also be modulated by pulsed irradiation, by pulsing the irradiation source under a variable frequency and duty cycle mechanism as described above. Alternatively, the DMD can modulate different frequencies and duty cycles pixel by pixel to obtain maximum flexibility using continuous wave irradiation. Alternatively, a combination of pulsed irradiation and modulated DMD frequency and duty cycle can be combined. This allows a specific amount of spatially determined corneal crosslinking. This spatially determined crosslinking can be combined with dosimetry, interferometry, optical coherence tomography (OCT), corneal topography, etc., for pretreatment planning and / or real-time monitoring and modulation of corneal crosslinking during treatment. Furthermore, preclinical patient information can be combined with finite element biomechanical computer modeling to create patient-specific pretreatment plans.

[0690] In some embodiments, electromagnetic radiation is delivered using multiphoton excitation microscopy. Specifically, instead of delivering a single photon of a specific wavelength to the cornea, multiple photons of longer wavelengths (i.e., lower energy) are delivered, which are combined to induce crosslinking. Advantageously, longer wavelengths are scattered less in the cornea than shorter wavelengths, which allows longer wavelengths of light to penetrate the cornea more efficiently than shorter wavelengths of light. Since the photosensitizer absorbs much less light of longer wavelengths, the shielding effect of incident radiation deeper in the cornea is also reduced compared to conventional short-wavelength irradiation. This allows enhanced control of depth-specific crosslinking. For example, in some embodiments, two photons can be used, each of which carries about half of the energy necessary to excite the molecules of the compounds or compositions disclosed herein to produce the photochemical kinetic reactions further described below. When the compound disclosed herein absorbs two photons simultaneously, it absorbs enough energy to release active free radicals in corneal tissue. Embodiments may also utilize lower energy photons such that a molecule of the compounds disclosed herein must absorb, for example, three, four, or five photons simultaneously to release active free radicals. The probability of nearly simultaneous absorption of multiple photons is low, so a high flux of excitation photons may be required, and a high flux may be delivered by a femtosecond laser.

[0691] In some embodiments, electromagnetic radiation is applied continuously (continuous wave (CW)) or as pulsed radiation. In certain embodiments, this choice has an impact on the amount, rate, and degree of cross-linking. In certain embodiments, when electromagnetic radiation light is applied as pulsed radiation, the duration of the exposure period, the duration of the dark period, and the ratio of the exposure period to the dark period duration have an impact on the resulting corneal hardening. For the same amount or dose of energy delivered, pulsed radiation can be used to produce more or less corneal tissue hardening compared to continuous wave irradiation. Light pulses of appropriate length and frequency can be used to achieve more ideal chemical amplification. For pulsed light therapy, the on / off duty cycle can be between about 1000 / 1 and about 1 / 1000; the irradiance can be about 0.1mW / cm 2 About 1000mW / cm 2 Between average irradiances, the pulse rate may be between about 0.01 Hz and about 1000 Hz or between about 1000 Hz and about 100,000 Hz.

[0692] In some embodiments, pulsed radiation can be delivered by using a DMD, electronically turning on and off the light source 110 and / or using a mechanical or photoelectric (e.g., Pockels cells) shutter or mechanical chopper or rotating aperture. Due to the pixel-specific modulation capability of the DMD and the subsequent stiffness imparted based on the modulation frequency, duty cycle, irradiance and dose delivered to the cornea, a complex biomechanical stiffness pattern of the cornea can be imparted to allow various degrees of refractive correction. For example, these refractive corrections may involve a combination of myopia, hyperopia, astigmatism, irregular astigmatism, presbyopia and complex corneal refractive surface corrections because of ophthalmic diseases such as keratoconus, transparent edge disease, ectasia after laser vision correction surgery and other corneal biomechanical conditions change / degeneration, etc. A specific advantage of the DMD system and method is that it allows randomized asynchronous pulses to form a topographic pattern, creating non-periodic and uniformly occurring irradiation, eliminating the possibility of triggering photosensitive epileptic seizures or flicker vertigo with pulse frequencies between 2Hz and 84Hz.

[0693] Examples of systems and methods for delivering electromagnetic radiation are described in, for example, U.S. Patent Application Publication No. 2011 / 0237999, filed on March 18, 2011, entitled “Systems and Methods for Applying and Monitoring Ophthalmic Treatments,” U.S. Patent Application Publication No. 2012 / 0215155, filed on April 3, 2012, entitled “Systems and Methods for Applying and Monitoring Ophthalmic Treatments,” and U.S. Patent Application Publication No. 2013 / 0245536, filed on March 15, 2013, entitled “Systems and Methods for Corneal Cross-linking with Pulsed Light,” the contents of which are incorporated herein by reference in their entirety.

[0694] oxygen

[0695] In some embodiments, the claimed methods can be performed without added or supplemented oxygen levels, which is advantageous in some applications. In other embodiments, the claimed methods can be performed in the presence of added or supplemented oxygen levels, as described herein, and the claimed methods may further include administering one or more additional therapeutic agents (agents other than the compounds of Formula I described herein), wherein the use of added or supplemented oxygen levels may be beneficial.

[0696] In some embodiments, the concentration of O2 is actively increased or decreased (e.g., increased) during irradiation to control the crosslinking rate. Oxygen can be administered in different ways during the crosslinking process. In some embodiments, a pharmaceutical composition comprising a compound as described herein can be supersaturated with O2. Thus, when the compounds described herein are applied to the eye, a higher concentration of O2 is delivered directly to the cornea along with riboflavin and affects reactions involving O2 when riboflavin is exposed to electromagnetic radiation. According to another approach, a steady state of O2 (at a selected concentration, e.g., >21%) can be maintained on the corneal surface to expose the cornea to a selected amount of O2 and cause O2 to enter the cornea. Example systems and methods for applying oxygen during the cross-linking process are described, for example, in U.S. Patent No. 8,574,277, filed on October 21, 2010, entitled “Eye Therapy,” and U.S. Patent Application Publication No. 2013 / 0060187, filed on October 31, 2012, entitled “Systems and Methods for Corneal Cross-Linking with Pulsed Light,” the contents of which are incorporated herein by reference in their entirety.

[0697] Thus, in some embodiments, the method may further comprise applying a selected concentration of oxygen to the eye, wherein the selected concentration is greater than the concentration of oxygen in the atmosphere.

[0698] Indications

[0699] In some embodiments, the condition, disease or disorder is an ophthalmic disease.

[0700] In some embodiments, the ophthalmic disease comprises decreased corneal stiffness.

[0701] Expansive disease

[0702] In some embodiments, the condition, disease or disorder is a corneal ectatic disorder. Non-limiting examples of ectatic disorders include keratoconus (e.g., keratoconus with a papillary cone, an ellipsoidal cone, or a spherical cone; e.g., progressive keratoconus), spherical keratoconus, pellucid marginal degeneration, corneal ectasia (e.g., postoperative ectasia, such as post-LASIK ectasia), and Terrien's marginal degeneration.

[0703] In certain embodiments, the condition, disease or disorder is corneal ectasia occurring after refractive surgery (e.g., postoperative corneal ectasia). Non-limiting examples of refractive surgery include radial keratotomy (RK), photorefractive keratectomy (PRK), or laser in situ keratomileusis (LASIK).

[0704] In some embodiments, the condition, disease or disorder is bacterial keratitis.

[0705] Vision Condition

[0706] In some embodiments, the disease, disorder or condition is myopia, hyperopia, astigmatism, irregular astigmatism, presbyopia.

[0707] In some embodiments, the ophthalmic disorder is a cataract (eg, nuclear, cortical, posterior polar, secondary, traumatic, or radiation cataract) or a lens disorder.

[0708] Combination therapy

[0709] The present disclosure encompasses monotherapy regimens as well as combination therapy regimens.

[0710] In some embodiments, the methods described herein can further comprise administering one or more additional therapies (eg, one or more additional therapeutic agents and / or one or more treatment regimens) in combination with the compounds described herein.

[0711] In some embodiments, the compounds described herein can be administered in combination with one or more other therapeutic agents. Representative additional therapeutic agents include, but are not limited to, therapeutic agents for the following conditions: inflammation, cataracts, lens disorders, or ectatic disorders, including, but not limited to, keratoconus (e.g., keratoconus with papillary cones, ellipsoidal cones, or spherical cones), spherical keratoconus, pellucid marginal degeneration, corneal ectasia (e.g., postoperative ectasia, such as post-LASIK ectasia), and Terrien marginal degeneration.

[0712] In some embodiments, the one or more additional therapeutic agents include those useful, for example, as cross-linking agents, including those described in U.S. Provisional Patent Application entitled Compounds and Compositions for Eye Treatment, designated by Attorney Docket No. 45387-0003P01, filed on the same day.

[0713] In some embodiments, the one or more additional therapeutic agents include those useful as, for example, cross-linking agents, including those described in U.S. Patent Application Publication No. 2014 / 0343480, filed May 19, 2014, which is incorporated herein by reference in its entirety. Non-limiting examples include:

[0714] Riboflavin (e.g., riboflavin or riboflavin phosphate);

[0715] 2,3-Butanedione;

[0716] Folic acid;

[0717] Quinoxalines (for example, olaquidox);

[0718] Quinolines (for example, chloroquine, hydroxychloroquine, and quinine);

[0719] Dibucaine;

[0720] Methotrexate;

[0721] Menadione; and

[0722] Verteporfin

[0723] and its derivatives.

[0724] Other non-limiting examples of cross-linking agents may include photosensitizers such as Rose Bengal, methylene blue, and N-hydroxypyridine-2-(1H)-thione. Other non-limiting examples of cross-linking agents may also include photosensitizers such as Photofrin.RTM, synthetic di- and dichlorins, phthalocyanines with or without metal substituents, chloroaluminum phthalocyanines with or without various substituents, O-substituted tetraphenylporphyrins, 3,1-meso-tetrakis(o-propionylaminophenyl)porphyrin, verdins, purpurins, tin and zinc derivatives of octaethylpurpurin, etiopurpurin, hydroporphyrins, bacteriochlorins of the tetrakis(hydroxyphenyl)porphyrin series (e.g., protoporphyrins I to protoporphyrin IX, coproporphyrins, uroporphyrins, mesoporphyrins, hematoporphyrins and sapphyrins), chlorins, chlorine 6, mono-1-aspartyl derivatives of chlorine 6, di-1-aspartyl derivatives of chlorine 6, tin ( IV) Chloro-6, meta-tetrahydrophenylchlorin, benzoporphyrin derivatives, benzoporphyrin monoacid derivatives, tetracyanoethylene adducts of benzoporphyrin, dimethyl acetylene dicarboxylate adducts of benzoporphyrin, Diels-Adler adducts, monoacid ring "a" derivatives of benzoporphyrin, sulfonated aluminum PC, sulfonated AlPc, disulfonated, tetrasulfonated derivatives, sulfonated aluminum naphthalocyanines, naphthalocyanines with or without metal substituents and with or without different substituents, chlorophyll, bacteriochlorophyll A, anthraquinones, anthrapyrazoles, aminoanthraquinones, phenoloxazine dyes, thiazines, methylene blue, phenothiazine derivatives, chalcogenapyrylium dyes, cationic selenium and telluropyrylium derivatives selena and tellurapyryliumderivatives, ring-substituted cationic PC, pheophorbide derivatives, natural porphyrins, hematoporphyrins, ALA-induced protoporphyrin IX, endogenous metabolic precursors, 5-aminolevulinic acid, benzonaphthoporphyrazines, cationic imminium salts, tetracyclines, lutetium texaphyrin, texaphyrin, tin-etio-purpurin, porphycenes, benzophenothiazinium, xanthenes, rose bengal bengal), eosin, erythrosine, cyanine, merocyanine 540, selenium-substituted cyanines, flavins, riboflavin, proflavin, quinones, anthraquinones, benzoquinones, naphthaldiimides, naphthalimides, Victoria blue, toluidine blue, dianthraquinones (e.g., hypericin), fullerenes, rhodamine and their photosensitive derivatives.

[0725] In some embodiments, one or more additional agents include a metal (including elemental and ionic forms) (e.g., a metal salt, such as a divalent metal salt). Non-limiting examples include:

[0726] Iron (e.g., iron (II), e.g., FeSO4) (in certain embodiments, the iron additive can be dissolved in a citrate buffer);

[0727] ·copper;

[0728] ·manganese;

[0729] ·chromium;

[0730] ·vanadium;

[0731] ·aluminum;

[0732] ·cobalt;

[0733] ·mercury;

[0734] ·cadmium;

[0735] Nickel; and

[0736] ·arsenic;

[0737] Optionally in combination with hydrogen peroxide.

[0738] In some embodiments, the one or more additional therapeutic agents include, for example, those used as anesthetics. Non-limiting examples include: pilocarpine, proparacaine, tetracaine, or oxybuprocaine.

[0739] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as analgesics. Non-limiting examples include: menthol, benzyl alcohol, or phenylethyl alcohol.

[0740] In some embodiments, the one or more additional therapeutic agents include, for example, those that can be used to increase the permeability of the corneal epithelium. Non-limiting examples include: zinc metalloproteinases, copper metalloproteinases, papain, bromelain, actinidin, ficin, N-acetylcysteine, ambroxol, carbocysteine, or erdosteine.

[0741] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as therapeutic agents for cataracts and / or lens disorders.

[0742] In some embodiments, the one or more additional therapeutic agents include, for example, those useful as antibiotics.

[0743] In some embodiments, the one or more additional therapeutic agents include, for example, those useful in gene therapy.

[0744] In some embodiments, the one or more additional treatment regimens include a treatment regimen for inflammation, cataracts, lens disorders, or ectatic disorders, including but not limited to keratoconus (e.g., keratoconus with papillary cones, ellipsoidal cones, or spherical cones), spherical keratoconus, pellucid marginal degeneration, corneal ectasia (e.g., post-operative ectasia, such as post-LASIK ectasia), and Terrien marginal degeneration.

[0745] In some embodiments, the one or more additional treatment regimens include treatment regimens for myopia, hyperopia, astigmatism, irregular astigmatism, and presbyopia.

[0746] In some embodiments, one or more additional treatment options include ophthalmic surgery. Non-limiting examples include:

[0747] Corneal transplant surgery;

[0748] Cataract surgery;

[0749] Laser surgery;

[0750] Corneal transplantation (eg, penetrating keratoplasty or lamellar keratoplasty);

[0751] Refractive surgery (e.g., photorefractive keratectomy (RK), photorefractive keratectomy (PRK), or laser in situ keratomileusis (LASIK);

[0752] Corneal remodeling; and

[0753] Treatment of corneal lacerations.

[0754] Additional non-limiting examples of the one or more additional treatment regimens include contact lens therapy, amniotic membrane therapy, LASIK therapy, and administration of antibiotics.

[0755] Preparation and biological experiments of compounds

[0756] As will be appreciated by those skilled in the art, methods for synthesizing compounds of the formula described herein will be apparent to those of ordinary skill in the art. Synthetic chemical transformations and protecting group methods (protection and deprotection) useful for synthesizing compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Press (1989); T. W. Greene and R. G. M. Wuts, Protecting Groups in Organic Synthesis, 2nd ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Organic Synthesis Reagents, John Wiley and Sons (1994); L. Paquette, ed., Encyclopedia of Organic Synthesis Reagents, John Wiley and Sons (1995), and subsequent editions thereof.

[0757] In some embodiments, intermediates useful for preparing compounds described herein may be prepared using the chemistry described in any one or more of the following schemes and non-limiting examples.

[0758] Compound preparation

[0759] abbreviation

[0760]

[0761]

[0762] Synthesis Example

[0763] Synthesis of intermediates I-1, I-2, I-3 and I-4

[0764] Intermediates I-1, I-2, I-3 and I-4 were synthesized according to the following scheme:

[0765]

[0766] Compound ii

[0767] Hydroxylamine-O-sulfonic acid (96.27 g, 851 mmol) in dry methanol (200 mL) was added dropwise to a stirred solution of 4-hydroxybutan-2-one (i) (50 g, 567 mmol) in 7M ammonia in methanol (500 mL) at -40°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for at least 5 hours and then at 20°C overnight. The mixture was filtered through Celite TMFilter and remove the solvent under reduced pressure to give compound (ii), which was used directly in the next step without further purification.

[0768] ESI-MS m / z=103.2[M+H] + .

[0769] Intermediate I-1

[0770] Iodine (86.4 g, 340 mmol) was slowly added to compound (ii) (340 mmol) and triethylamine (94.73 mL, 680 mmol) in DCM (1 L) in the dark until a continuous orange-brown color appeared. The resulting mixture was stirred at 20 ° C for 2 hours. Subsequently, the mixture was washed with saturated brine and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography with an elution gradient of 0-30% EtOAc in petroleum ether to obtain a yellow liquid intermediate (I-1) (13 g).

[0771] 1 H NMR: (400 MHz, chloroform-d) δ, ppm 3.55 (t, J = 6.3 Hz, 2H), 1.65 (t, J = 6.3 Hz, 2H), 1.51 (s, 1H), 1.09 (s, 3H).

[0772] Intermediate I-2

[0773] Tosyl chloride (6.1 g, 36 mmol) was added dropwise to a DCM (30 mL) solution of intermediate (I-1) (3 g, 30 mmol). The mixture was stirred at 0 ° C, and triethylamine (6.06 g, 60 mmol) was added dropwise. The mixture was protected from light and warmed to room temperature and stirred for another 5 hours. Subsequently, the mixture was washed with saturated brine, and the organic layer was concentrated and evaporated under reduced pressure. The residue was purified by silica gel chromatography to obtain a colorless oily intermediate (I-2) (5.9 g).

[0774] 1 H NMR: (400 MHz, chloroform-d) δ, ppm 7.89-7.76 (m, 2H), 7.46-7.34 (m, 2H), 3.97 (t, J = 6.4 Hz, 2H), 2.47 (s, 3H), 1.69 (t, J = 6.4 Hz, 2H), 1.02 (s, 3H).

[0775] Compound iv

[0776] Hydroxylamine-O-sulfonic acid (43.83 g, 387.54 mmol) in dry methanol (200 mL) was added dropwise to a stirred solution of 4-oxopentanoic acid (iii) (30 g, 258.36 mmol) in 7M ammonia in methanol (400 mL) at -40°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for at least 5 hours and then at 20°C overnight. The mixture was filtered through Celite TM Filter and remove the solvent under reduced pressure to give compound (iv), which was used directly in the next step without further purification.

[0777] ESI-MS m / z=131.1[M+H] + .

[0778] Intermediate I-3

[0779] To a stirred solution of compound (iv) (40 g, 307.35 mmol) in DCM (400 mL) protected from light at 0°C, TEA (62.20 g, 614.69 mmol) and iodine (78.01 g, 307.35 mmol) were added in batches. The resulting mixture was stirred at 20°C for 2 hours, washed with saturated brine (400 mL), and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography with an elution gradient of 20-40% EtOAc in petroleum ether to give intermediate (I-3) (15.1 g) as a yellow oil.

[0780] Compound vi

[0781] To a stirred DMF solution of 3-[[(tert-butoxy)carbonyl]amino]propionic acid (v) (60 g, 317.11 mmol), N-methoxymethylamine hydrochloride (37.12 g, 380.53 mmol) and TEA (80.22 g, 792.77 mmol) were added HOBT (47.13 g, 348.82 mmol) and EDCl (121.58 g, 634.21 mmol) in portions at 0°C. The mixture was stirred at 20°C for 5 hours and then diluted with water (2 L). The resulting mixture was extracted with EtOAc (3x800 mL), and the combined organic layers were washed with water (3x800 mL), saturated brine (1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica chromatography with an elution gradient of 0-30% EtOAc in petroleum ether to give compound (vi) (63.5 g) as a pale yellow oil.

[0782] ESI-MS m / z=233.2[M+H] + .

[0783] Compound vii

[0784] Under argon atmosphere, 1M methylmagnesium bromide solution in THF (328mL, 328.07mmol) was added dropwise to a 0°C stirred solution of compound (vi) (63.5g, 273.38mmol) in THF (1L). The mixture was stirred at 0°C for 5 hours, then quenched with NH4Cl (1L) aqueous solution and extracted with EtOAc (3x800mL). The combined organic layer was washed with water (3x1L), saturated brine (1L), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an elution gradient of 0-15% EtOAc in petroleum ether to give compound (vii) (24.8g) as a colorless oil.

[0785] ESI-MS m / z=233.2[M+2Na] +

[0786] 1 HNMR: (400 MHz, DMSO-d 6 )δ, ppm 1.37-1.42 (m, 10H), 2.08-2.09 (d, 3H), 2.50-2.57 (m, 2H), 3.08-3.13 (m, 2H), 6.75 (s, 1H).

[0787] Compound viii

[0788] Hydroxylamine-O-sulfonic acid (29.96 g, 264.90 mmol) in dry methanol was added dropwise to a stirred solution of compound (vii) (24.8 g, 132.45 mmol) in 7M ammonia in methanol (300 mL) at -40°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for at least 5 hours and then at 20°C overnight. The mixture was filtered through Celite TM Filter and remove the solvent under reduced pressure to give compound (viii), which was used directly in the next step without further purification.

[0789] ESI-MS m / z=202.3[M+H] + .

[0790] Compound ix

[0791] To a stirred solution of compound (viii) (30 g, 149.05 mmol) in DCM (300 mL) protected from light at 0°C, TEA (30.17 g, 298.11 mmol) and iodine (37.83 g, 149.05 mmol) were added in portions. The resulting mixture was stirred at 20°C for 2 hours, washed with saturated brine (300 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography with an elution gradient of 0-30% EtOAc in petroleum ether to give compound (ix) (13 g) as a yellow oil.

[0792] ESI-MS m / z=200.2[M+H] +

[0793] 1 H NMR: (400 MHz, chloroform-d) δ, ppm 1.05 (s, 3H), 1.45 (s, 9H), 1.58 (q, 2H), 3.05 (s, 2H), 4.60 (s, 1H).

[0794] Intermediate I-4

[0795] To a stirred solution of compound (ix) (5 g, 25.09 mmol) in DCM (30 mL) at 0°C was added TFA (15 mL). The mixture was stirred at 20°C for 2 hours and then concentrated under reduced pressure to give intermediate (I-4) trifluoroacetate salt, which was used in the next step without further purification.

[0796] ESI-MS m / z=197.3[M+H] + .

[0797] Synthesis of Compound 2 (Example 1)

[0798] Example 1 was synthesized according to the following scheme:

[0799]

[0800] Compound 1

[0801] 2-iodoacetic anhydride (354 mg, 6.75 mmol) and DIPEA (1.74 g, 13.5 mmol) were added to the solution of the intermediate (I-4) obtained from compound (ix) (900 mg, 4.5 mmol) in DCM (20 mL) at one time. The mixture was stirred at room temperature for 3 hours in dark, quenched with saturated ammonium chloride and extracted with EtOAc. The combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain compound (1) (1.38 g) as a yellow oil.

[0802] m / z(ES+), [M+H] + =268.

[0803] Compound 2 (Example 1)

[0804] A mixture of compound (1) (1.38 g), intermediate (I-4) (5 mmol) and potassium carbonate (2.78 g) in DMF (20 mL) was stirred at room temperature in the dark for 5 hours. The mixture was diluted with EtOAc (100 mL) and washed with saturated brine and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC column: XBridge ShieldRP18 OBD column 19x250 mm, 10 μm; mobile phase A: 0.05% TFA in water, mobile phase B: MeCN; flow rate: 25 mL / min; gradient: from 2% B to 17% B in 7 minutes; 254 / 220 nm; Rt: 3.81 minutes to obtain compound (2) (Example 1) (173.5 mg) as a yellow solid.

[0805] m / z (ES+), [M+H]+=239

[0806] 1 H NMR: (300MHz, methanol-d4)δ, ppm, 3.82 (t, J=2.3Hz, 2H), 3.23 (t, J=7.3Hz, 2H), 3.15- 2.95 (m, 2H), 1.76 (td, J=8.4, 2.3Hz, 2H), 1.69-1.50 (m, 2H), 1.15-0.97 (m, 6H).

[0807] Synthesis of Compound 6 (Example 2)

[0808] Example 2 was synthesized according to the following scheme:

[0809]

[0810] Compound 3

[0811] DIPEA (0.96 g, 7.5 mmol) was added dropwise to a stirred room temperature solution of intermediate (I-4) obtained from compound (ix) (500 mg, 2.5 mmol), Fmoc-L-Arg (Pbf) -H (1.6 g, 2.5 mmol), HOBT (407 mg, 3 mmol) and EDCI (0.86 g, 5 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 3 hours in the dark, then quenched with water and extracted with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain a yellow oily compound (3) (1.2 g).

[0812] m / z(ES+), [M+H] + =730.

[0813] Compound 4

[0814] Compound (3) (1.2 g, 1.65 mmol) was added to 10% diethylamine in THF (15 mL) and stirred at room temperature for 2 hours in the dark. The mixture was concentrated under reduced pressure to give compound (4), which was used directly in the next step without further purification.

[0815] m / z(ES+), [M+H] + =508.

[0816] Compound 5

[0817] In DMF (15mL), a mixture of compound (4) obtained from compound (3) (1.2g, 1.65mmol), intermediate (I-2) (627.38mg, 2.47mmol) and potassium carbonate (458.7mg, 3.3mmol) was stirred at 55°C in dark for 10 hours. The mixture was diluted with ethyl acetate (50mL) and washed with saturated brine and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain a yellow oily compound (5) (300mg).

[0818] m / z(ES+), [M+H] + =590.

[0819] Compound 6 (Example 2)

[0820] To a solution of compound (5) (300 mg, 0.51 mmol) in DCM (10 mL) stirred at 0°C was added TFA (5 mL). The mixture was stirred at 0°C for 2 hours and then at room temperature for 2 hours under light protection. The mixture was concentrated under reduced pressure and the residue was purified using preparative HPLC, column: Atlantis Prep T3 OBD column 19x150 mm 5μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: from 14% B to 14% B in 10 minutes; 254 / 220nm; Rt: 8.12 minutes. Compound (6) (Example 2) (40.8 mg) was obtained as a colorless oil after freeze drying.

[0821] m / z(ES+), [M+H] + =339

[0822] 1 H NMR: (300MHz, methanol-d4) δ, ppm, 3.80 (t, J=6.4Hz, 1H), 3.25 (d, J=5.7Hz, 5H), 2.99 (d, J=9.4Hz, 2H) , 1.94 (dd, J=10.6, 5.7Hz, 2H), 1.68 (ddq, J=28.6, 15.3, 8.2, 6.3Hz, 6H), 1.07 (d, J=1.1Hz, 6H).

[0823] Synthesis of Compound 10 (Example 3)

[0824] Example 3 was synthesized according to the following scheme:

[0825]

[0826] Compound 7

[0827] DIPEA (0.96 g, 7.5 mmol) was added dropwise to a stirred room temperature solution of intermediate (I-4) obtained from compound (ix) (500 mg, 2.5 mmol), Fmoc-L-Gln(Trt)-OH (1.53 g, 2.5 mmol), HOBt (407 mg, 3 mmol) and EDCI (0.86 g, 5 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 3 hours in the dark, then quenched with water and extracted with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain compound (7) (1.37 g) as a yellow oil.

[0828] m / z(ES+), [M+H] + =692.

[0829] Compound 8

[0830] Compound (7) (1.37 g, 2.92 mmol) was added to 10% diethylamine in THF (15 mL) and stirred at room temperature for 2 hours in the dark. The mixture was concentrated under reduced pressure and the residue was purified using silica gel chromatography to obtain compound (8) (680 mg) as a yellow solid.

[0831] m / z(ES+), [M+H] + =470.

[0832] Compound 9

[0833] A mixture of compound (8) (680 mg, 1.45 mmol), intermediate (I-2) (551 mg, 2.17 mmol) and potassium carbonate (403.1 mg, 2.9 mmol) in DMF (15 mL) was stirred at 55 ° C in the dark for 10 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with saturated brine and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a yellow oily compound (9), which was used directly in the next step without further purification.

[0834] m / z(ES+), [M+H] + =590.

[0835] Compound 10 (Example 3)

[0836] To a solution of compound (9) stirred at 0°C in DCM (10 mL) from the previous step was added TFA (5 mL). The mixture was stirred at 0°C for 2 hours and then at room temperature for 2 hours under light protection. The mixture was concentrated under reduced pressure and the residue was purified using preparative HPLC, column: SunFire C18 OBD column, 5μm, 19mm x 250mm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 25mL / min; gradient: from 10% B to 30% B in 10 minutes; 254 / 220nm; Rt: 8.76 minutes, after freeze-drying, a colorless oily compound (10) (Example 3) (39 mg) was obtained.

[0837] m / z(ES+), [M+H] + =310

[0838] 1H NMR: (400MHz, methanol-d4) δ, ppm, 3.84 (t, J=6.0Hz, 1H), 3.26 (td, J=6.8, 3.5Hz, 2H), 3.00 (td, J=7.5, 3.5Hz, 2 H), 2.54 (q, J=6.5Hz, 2H), 2.21-2.10 (m, 2H), 1.82-1.72 (m, 2H), 1.72-1.51 (m, 2H), 1.09 (d, J=6.7Hz, 5H).

[0839] Synthesis of Compound 14 (Example 4)

[0840] Example 4 was synthesized according to the following scheme:

[0841]

[0842] Compound 11

[0843] DIPEA (0.96 g, 7.5 mmol) was added dropwise to a stirred room temperature solution of intermediate (I-4) obtained from compound (ix) (500 mg, 2.5 mmol), Fmoc-L-Ser(tBu)-OH (960 mg, 2.5 mmol), HOBt (407 mg, 3 mmol) and EDCI (0.86 g, 5 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 3 hours in the dark, then quenched with water and extracted with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide a yellow oily compound (11), which was used in the next step without further purification.

[0844] m / z(ES+), [M+H] + =465.

[0845] Compound 12

[0846] The compound (11) obtained from the previous step was added to 10% diethylamine in THF (15 mL) and stirred at room temperature for 2 hours in the dark. The mixture was concentrated under reduced pressure and the residue was purified using silica gel chromatography to obtain compound (12) (480 mg) as a yellow solid.

[0847] m / z(ES+), [M+H] + =243.

[0848] Compound 13

[0849] A mixture of compound (12) (480 mg, 1.98 mmol), intermediate (I-2) (757 mg, 2.98 mmol) and potassium carbonate (550.4 mg, 3.96 mmol) in DMF (15 mL) was stirred at 55 ° C in the dark for 10 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with saturated brine and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide compound (13), which was used directly in the next step without further purification.

[0850] m / z(ES+), [M+H] + =324.

[0851] Compound 14 (Example 4)

[0852] To a solution of compound (13) stirred at 0°C in DCM (10 mL) from the previous step was added TFA (5 mL). The mixture was stirred at 0°C for 2 hours and then at room temperature for 2 hours under light protection. The mixture was concentrated under reduced pressure and the residue was purified using preparative HPLC, column: SunFire C18 OBD Prep column, 5μm, 19mm x 250mm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 25mL / min; gradient: from 10% B to 30% B in 10 minutes; 254 / 220nm; Rt: 8.38 minutes, after freeze-drying, a colorless oily compound (14) (Example 4) (71 mg) was obtained.

[0853] m / z(ES+), [M+H] + =310

[0854] 1 H NMR: (400MHz, methanol-d4)δ, ppm, 4.02 (q, J=7.1Hz, 1H), 3.95-3.85 (m, 2H), 3.31-3.17 (m, 2H), 3.06 (dd, J=9.6, 7.3Hz, 2H), 1.85-1.71 (m, 2H), 1.71-1.53 ​​(m, 2H), 1.08 (d, J=7.0Hz, 6H).

[0855] Synthesis of Compound 18 (Example 5)

[0856] Example 5 was synthesized according to the following scheme:

[0857]

[0858] Compound 15

[0859] DIPEA (0.96 g, 7.5 mmol) was added dropwise to a stirred room temperature solution of intermediate (I-4) obtained from compound (ix) (500 mg, 2.5 mmol), Fmoc-L-Glu (tBu) -OH.H2O (1.06 g, 2.5 mmol), HOBt (407 mg, 3 mmol) and EDCI (0.86 g, 5 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 3 hours in the dark, then quenched with water and extracted with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain a yellow oily compound (15) (520 mg).

[0860] m / z(ES+), [M+H] + =507.

[0861] Compound 16

[0862] Compound (15) (520 mg, 1.03 mmol) was added to 10% diethylamine in THF (15 mL) and stirred at room temperature for 2 hours in the dark. The mixture was concentrated under reduced pressure to give compound (16), which was used in the next step without further purification.

[0863] m / z(ES+), [M+H] + =285.

[0864] Compound 17

[0865] A mixture of compound (16), intermediate (I-2) (381 mg, 1.5 mmol) and potassium carbonate (278.1 mg, 2 mmol) in DMF (15 mL) obtained from the previous step was stirred at 55 ° C in dark for 10 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with saturated brine and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain a yellow oily compound (17) (150 mg).

[0866] m / z(ES+), [M+H] + =367.

[0867] Compound 18 (Example 5)

[0868] To a solution of compound (17) (150 mg, 0.51 mmol) in DCM (10 mL) stirred at 0°C was added TFA (5 mL). The mixture was stirred at 0°C for 2 hours and then at room temperature for 2 hours under light-shielding conditions. The mixture was concentrated under reduced pressure and the residue was purified using preparative HPLC, column: Atlantis Prep T3 OBD column 19x150mm 5μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: from 20% B to 20% B in 8 minutes; 254 / 220nm; Rt: 7.57 minutes. After freeze-drying, compound (18) (Example 5) (11.3 mg) was obtained as a colorless oil.

[0869] m / z(ES+), [M+H] + =311

[0870] 1 H NMR: (300MHz, methanol-d4) δ, ppm, 3.84 (t, J=6.2Hz, 1H), 3.26 (d, J=6.9Hz, 3H), 3.07-2.94 (m, 2H), 2.52 (td, J=7.2 , 3.2Hz, 2H), 2.18 (dd, J=8.8, 5.6Hz, 2H), 1.83-1.69 (m, 2H), 1.63 (dt, J=13.3, 6.5Hz, 2H), 1.13-1.04 (m, 6H).

[0871] Synthesis of Compound 25 (Example 6)

[0872] Example 6 was synthesized according to the following scheme:

[0873]

[0874] Compound 19

[0875] To a solution of intermediate (I-2) (2.30 g, 9.04 mmol) and tert-butyl 3-aminopropionate (5.25 g, 36.18 mmol) in MeCN (30 mL) stirred at 0°C was added KCO (12.50 g, 90.45 mmol). The mixture was stirred at 60°C for 16 hours and then concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with EtOAc (3x100 mL). The combined organic layers were washed with water (3x100 mL), saturated brine (200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give compound (19) (1.5 g) as a colorless oil.

[0876] ESI-MS m / z=228.5[M+H] + .

[0877] Compound 20

[0878] To a stirred solution of compound (19) (1.50 g, 6.6 mmol) in DCM (10 mL) was added TFA (10 mL). The mixture was stirred at 20°C for 6 hours and then concentrated under reduced pressure to give compound (20), which was used in the next step without further purification.

[0879] ESI-MS m / z=172.2[M+H] + .

[0880] Compound 21

[0881] To a mixture of compound (20) (1 g, 5.84 mmol) and saturated NaHCO3 aqueous solution (50 mL) in 1,4-dioxane (50 mL) stirred at 0°C, di-tert-butyl dicarbonate (1.91 g, 8.75 mmol) was added in portions. Subsequently, the mixture was stirred at 20°C for 16 hours and then concentrated under reduced pressure. The residue was extracted with EtOAc (2x100 mL), the extract was discarded, and the remaining solution was acidified to pH 6 with 1M HCl. The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layer was washed with water (2x300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% formic acid in water, B: MeCN, gradient from 10% to 100% in 25 minutes; detector, UV 200nm, to obtain compound (21) (1g) as a colorless oil.

[0882] ESI-MS m / z=272.3[M+H] + ; 294.2[M+Na] + .

[0883] Compound 22

[0884] To a stirred solution of compound (21) (3 g, 7.29 mmol) in DMF (100 mL) at 0°C were added intermediate (I-1) (0.80 g, 8.02 mmol), DIPEA (1884.68 mg, 14.58 mmol), HOBT (197.04 mg, 1.46 mmol) and EDCI (1471.46 mg, 9.48 mmol). The resulting mixture was stirred at 20°C for 16 hours, then diluted with water (300 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with water (2 x 300 mL), saturated aqueous NaCl (300 mL) solution and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (4:1) to give compound (22) (3 g) as an off-white solid.

[0885] ESI-MS m / z=494[M+H] + ; 516[M+Na] + .

[0886] 1 H NMR: (400MHz, chloroform-d) δ, ppm, 7.79 (d, J=7.5Hz, 2H), 7.63 (dd, J=7.9, 2.8Hz, 2H), 7.43 ( t, J=7.5Hz, 2H), 7.38-7.31 (m, 2H), 5.86 (d, J=8.7Hz, 1H), 4.64 (dt, J=8.9, 4.5Hz, 1H ), 4.48-4.33 (m, 2H), 4.28 (t, J=7.3Hz, 1H), 4.15 (qd, J=7.2, 6.5, 2.0Hz, 2H), 2.95 (d dd, J=84.3, 17.1, 4.5Hz, 2H), 1.72 (td, J=6.3, 3.2Hz, 2H), 1.48 (s, 9H), 1.08 (s, 3H).

[0887] Compound 23

[0888] Diethylamine (15 mL) was added dropwise to a stirred 0°C solution of compound (22) (2 g, 4.05 mmol) in THF (30 ml). The mixture was stirred at 20°C for 4 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) and then with DCM / MeOH (7:1) to give compound (23) (1 g) as a pale yellow oil.

[0889] ESI-MS m / z=272.2[M+H] + .

[0890] Compound 24

[0891] To a stirred solution of compound (23) (600 mg, 2.21 mmol) and compound (21) (600 mg, 2.21 mmol) in DMF (5 mL) at 0°C was added DIPEA (857.44 mg, 6.63 mmol) and HATU (1261.28 mg, 3.32 mmol). The mixture was stirred at 0°C for 2 hours, then diluted with water (50 mL) and extracted with EtOAc (3x30 mL). The combined organic layers were washed with water (3x30 mL), saturated brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% formic acid in water, B: MeCN, 0-100% B in 30 minutes; detector, UV 200 nm to obtain compound (24) (800 mg) as a light yellow oil.

[0892] ESI-MS m / z=525.3[M+H] + ; 547.3[M+Na] + .

[0893] Compound 25 (Example 6)

[0894] 4M HCl in 1,4-dioxane (20 mL) was added dropwise to a solution of compound (24) (800 mg, 1.53 mmol) in 1,4-dioxane (10 mL) stirred at 0° C. The resulting mixture was stirred at 20° C. for 6 hours and then concentrated under reduced pressure to give compound (25) (Example 6) (550 mg) as a pale yellow oil.

[0895] ESI-MS m / z=369.0[M+H] +

[0896] 1 H-NMR: (400MHz, methanol-d4): δ, ppm, 4.85-4.75 (m, 1H), 4.20-4.00 (m, 2H), 3.30 (dt, J=6.4, 3.0Hz, 2H), 3.15-3.00 (m, 2H), 3.00-2.80 (m, 2H), 2.74 (dtd, J=12.6, 6.3, 2.7Hz, 2H), 1.80-1.73 (m, 2H), 1.71 (ddt, J=8.3, 6.7, 2.5Hz, 1H), 1.11 (s, 3H), 1.09-1.01 (m, 3H).

[0897] Synthesis of Compound 29 (Example 7)

[0898] Example 7 was synthesized according to the following scheme:

[0899]

[0900] Compound 26

[0901] EDCI (361 mg, 1.88 mmol) was added to a DCM (15 mL) solution of Fmoc-L-His (Trt) -OH (774.7 mg, 1.25 mmol), intermediate (I-1) (250 mg, 2.5 mmol) and N, N-dimethylaminopyridine (5 mg, 0.125 mmol). The mixture was stirred at room temperature for 2 hours in the dark, then diluted with DCM (50 mL) and washed with water (20 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography to obtain compound (26) (841 mg).

[0902] m / z(ES+), [M+H] + =702.

[0903] Compound 27

[0904] Compound (26) (841 mg, 1.2 mmol) was dissolved in 10% diethylamine in THF (10 mL) and stirred at room temperature for 2 hours in the dark. The mixture was concentrated under reduced pressure and the residue was purified using silica gel chromatography to obtain compound (27) (420 mg) as a yellow solid.

[0905] m / z(ES+), [M+H] + =480.

[0906] 1 H NMR: (300MHz, chloroform-d) δ, ppm, 7.79 (d, J=7.5Hz, 2H), 7.63 (d, J=7.4Hz, 2H), 7.43 (t, J=7.4Hz, 2H), 7.38-7.31 (m, 2H), 4.43 (d, J= 7.8Hz, 3H), 4.25 (t, J=6.9Hz, 1H), 4.11 (t, J=6.3Hz, 2H), 3.15 (s, 2H), 1.73 (t, J=6.2Hz, 3H), 1.65-1.50 (m, 3H), 1.46 (s, 11H).

[0907] Compound 28

[0908] A mixture of compound (27) (420 mg, 0.88 mmol), compound (21) (271 mg, 1.00 mmol), PyBOP (0.91 g, 1.75 mmol) and DIPEA (338.6 mg, 2.63 mmol) in DMF (10 mL) was stirred overnight at room temperature in the dark. The mixture was quenched and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound (28) (490 mg).

[0909] m / z(ES+), [M+H] + =733.

[0910] Compound 29 (Example 7)

[0911] To a 0°C solution of compound (28) (490 mg, 0.67 mmol) in DCM (10 mL) was added TFA (5 mL). The mixture was stirred at 0°C for 2 hours and then at room temperature for 2 hours under light-shielding conditions. The mixture was concentrated under reduced pressure and the residue was purified using preparative HPLC, column: XBridge Prep Phenyl OBD column 19×150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: from 15% B to 15% B in 7 minutes; 254 / 220 nm; Rt: 4.92 minutes. After freeze drying, compound (29) (Example 7) (62.7 mg) was obtained as a colorless oil.

[0912] m / z(ES+), [M+H] + =391.

[0913] 1 H NMR: (300MHz, methanol-d4) δ, ppm, 8.88 (d, J = 1.4Hz, 1H), 7.42 (d, J = 1.4Hz, 1H), 4.87-4.80 (m, 2H), 4.13 (t, J = 6.1Hz, 2H), 3.39 (dd, J = 15.5, 6.0Hz, 1H), 3.30-3.15 (m, 3H), 3.10-2.95 (m, 2H), 2.74 (dt, J=7.3, 3.4Hz, 2H), 1.84-1.65 (m, 4H), 1.08 (d, J=13.2Hz, 6H).

[0914] Synthesis of Compound 33 (Example 8)

[0915] Example 8 was synthesized according to the following scheme:

[0916]

[0917] Compound 30

[0918] EDCI (361 mg, 1.88 mmol) was added to a DCM (15 mL) solution of FFmoc-L-Lys(Boc)-OH (585.7 mg, 1.25 mmol), intermediate (I-1) (250 mg, 2.5 mmol) and N, N-dimethylaminopyridine (5 mg, 0.13 mmol). The mixture was stirred at room temperature for 2 hours in the dark, then diluted with DCM (50 mL) and washed with water (20 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain compound (30) (717 mg).

[0919] m / z(ES+), [M+Na] + =573.

[0920] Compound 31

[0921] Compound (30) (717 mg, 1.31 mmol) was dissolved in 10% diethylamine in THF (10 mL), and the mixture was stirred at room temperature for 2 hours in the dark. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound (31) (240 mg) as a yellow solid.

[0922] m / z(ES+), [M+H] + =329.

[0923] Compound 32

[0924] A solution of compound (31) (240 mg, 0.73 mmol), compound (21) (271 mg, 1.00 mmol), PyBOP (0.76 g, 1.46 mmol) and DIPEA (282 mg, 2.19 mmol) in DMF (10 mL) was stirred overnight at room temperature in the dark. The mixture was quenched with water and extracted with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound (32) (620 mg).

[0925] m / z(ES+), [M+H] + =582.

[0926] Compound 33 (Example 8)

[0927] TFA (5 mL) was added to a 0°C solution of compound (32) (620 mg, 1.07 mmol) in DCM (10 mL). The mixture was stirred at 0°C for 2 hours and then at room temperature for 2 hours under light-shielding conditions. The mixture was concentrated under reduced pressure and the residue was purified using preparative HPLC, column: XBridge Prep Phenyl OBD column 19×150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 20 mL / min; gradient: from 15% B to 15% B in 7 minutes; 254 / 220 nm; Rt: 4.92 minutes. After freeze-drying, compound (33) (Example 8) (47.7 mg) was obtained as a colorless oil.

[0928] m / z(ES+), [M+H] + =382.

[0929] 1 H NMR: (300MHz, methanol-d4) δ, ppm, 4.44 (s, 1H), 4.09 (s, 2H), 2.98 (dt, J=25.9, 7.8Hz, 4H), 2.73 (t, J= 6.0Hz, 2H), 1.94 (s, 1H), 1.85-1.58 (m, 6H), 1.51 (d, J=8.0Hz, 2H), 1.06 (dd, J=9.3, 2.0Hz, 5H).

[0930] Synthesis of Compound 37 (Example 9)

[0931] Example 9 was synthesized according to the following scheme:

[0932]

[0933] Compound 34

[0934] To a stirred solution of (2S)-4-(tert-butoxy)-2-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)-4-oxobutanoic acid (6.23 g, 15.13 mmol) and intermediate (I-4) (1.50 g, 15.13 mmol) in DMF (50 mL) at 0°C was added DIPEA (11.73 g, 90.78 mmol) and HATU (8.63 g, 22.69 mmol) in portions. The mixture was stirred at 0°C for 2 hours, then diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The organic layer was washed with water (2 x 100 mL), saturated brine (100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give compound (34) (2 g) as a pale yellow solid.

[0935] ESI-MS m / z=493[M+H] + ; 515[M+Na] + .

[0936] Compound 35

[0937] To a THF (15 mL) solution of compound (34) (600 mg, 1.25 mmol) stirred at 0°C was added diethylamine (15 mL). The mixture was stirred at 20°C for 4 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc=10:1, and then eluted with DCM / MeOH (10:1) to obtain a light yellow oily compound (35) (300 mg).

[0938] ESI-MS m / z=271.4[M+H] + .

[0939] Compound 36

[0940] To a stirred solution of compound (21) (300 mg, 1.11 mmol) and compound (35) (300 mg, 1.11 mmol) in DMF (5 mL) at 0°C were added DIPEA (428.72 mg, 3.32 mmol) and HATU (630.64 mg, 1.66 mmol) in portions. The mixture was stirred at 0°C for 2 hours, concentrated under reduced pressure, and the residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.5% NH4HCO3 aqueous solution, 0-100 B% in 30 minutes, B: MeCN, detector: UV 200 nm, 60% B to give compound (36) (300 mg) as a colorless oil.

[0941] ESI-MS m / z=524.4[M+H] + ; 546.3[M+Na] + .

[0942] Compound 37 (Example 9)

[0943] A solution of compound (36) (180 mg, 34.40 mmol) in 4M HCl in 1,4-dioxane (4.0 mL) was stirred at 20° C. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.01% aqueous HCl; B: MeCN, gradient from 0% to 100% in 25 minutes; detector, UV 200 nm to give compound (37) (Example 9) (144 mg, 99.78%) as a light yellow semisolid.

[0944] ESI-MS m / z=368.1[M+H] + .

[0945] 1 H-NMR: (400 MHz, methanol-d4): δ, ppm, 4.71 (dd, J = 8.3, 5.3 Hz, 1H), 3.29 (d, J = 6.2 Hz, 2H), 3.17 (hept, J = 6.8 Hz, 2H), 3.08-3.02 (m, 2H), 2.88 (dd, J = 16.9, 5.3 Hz, 1H), 2.79-2.66 (m, 3H), 1.81-1.69 (m, 2H), 1.55 (t, J = 7.1 Hz, 2H), 1.11 (s, 3H), 1.04 (s, 3H).

[0946] Synthesis of Compound 43 (Example 10)

[0947] Example 10 was synthesized according to the following scheme:

[0948]

[0949] Compound 38

[0950] To a stirred solution of intermediate (I-4) (800 mg, 4.10 mmol) and (2S)-6-[[(tert-butoxy)carbonyl]amino]-2-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)hexanoic acid (1920.83 mg, 4.10 mmol) in DMF (10 mL) at 0°C was added DIPEA (3179.01 mg, 24.6 mmol) and HATU (2026.08 mg, 5.33 mmol). The mixture was stirred at 0°C for 2 hours, then diluted with water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL), saturated brine (200 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% NH4HCO3 aqueous solution; B: MeCN, detector: 200nm, 80% B to obtain a light yellow solid compound (38) (1.2g).

[0951] ESI-MS m / z=572.4[M+Na] + .

[0952] Compound 39

[0953] To a solution of compound (38) (600 mg, 1091.56 mmol) in THF (60 mL) was added diethylamine (30 mL). The resulting mixture was stirred at 20°C for 4 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) and then with DCM / MeOH (7:1) to give compound (39) (300 mg) as a colorless oil.

[0954] ESI-MS m / z=328.2[M+H] + .

[0955] Compound 40

[0956] To a stirred solution of compound (21) (248.59 mg, 0.92 mmol) and compound (39) (300 mg, 0.92 mmol) in DMF (5 mL) at 0°C were added DIPEA (355.25 mg, 2.75 mmol) and HATU (522.57 mg, 1.37 mmol). The mixture was stirred at 0°C for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% NH4HCO3 aqueous solution; B: MeCN, detector, 200 nm; gradient from 10% to 80% in 20 minutes to give compound (40) (300 mg) as a colorless oil.

[0957] ESI-MS m / z=581.4[M+H] + .

[0958] Compound 41

[0959] Compound (40) (300 mg) in 4M HCl in 1,4-dioxane (15 mL) was stirred at 20° C. for 6 hours. The resulting mixture was concentrated under reduced pressure to give compound (41), which was used in the next step without further purification.

[0960] ESI-MS m / z=381.3[M+H] + .

[0961] Compound 42

[0962] To a solution of compound (41) (290 mg, 0.76 mmol) and tert-butyl N-[(1E)-[[(tert-butyloxy)carbonyl]amino][(methylsulfanyl)amino]methylene]carbamate (465.51 mg, 1.52 mmol) in DMF (5.00 mL) stirred at 0°C, TEA (0.23 g, 2.27 mmol) and N,N-dimethylaminopyridine (18.62 mg, 0.15 mmol) were added in portions. The mixture was stirred at 20°C overnight and then concentrated under reduced pressure, and the residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% formic acid in water, B: MeCN, detector, UV 254 nm, gradient from 10% to 90% in 25 minutes to give compound (42) (200 mg) as a yellow oil.

[0963] ESI-MS m / z=623.5[M+H] + .

[0964] Compound 43 (Example 10)

[0965] Compound (42) (200 mg, 0.32 mmol) in 4M HCl in 1,4-dioxane (5 mL) was stirred at 20° C. for 6 hours. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.01% aqueous HCl solution B: MeCN; gradient from 0% to 100% in 30 minutes; detector, UV 200 nm to give compound (43) (Example 10) (83 mg) as a light yellow semisolid.

[0966] ESI-MS m / z=423.3[M+H] +

[0967] 1 H NMR: (400MHz, methanol-d4); δ, ppm, 4.25-4.34 (m, 1H), 3.30-3.24 (m, 2H), 3.26-3.09 (m, 4H), 3.09-3.01 (m, 2H), 2.78 (td, J= 6.4, 3.3Hz, 2H), 1.94-1.81(s, 1H), 1.81-1.70(m, 3H), 1.70-1.61(m, 2H), 1.60-1.33(m, 4H), 1.11(s, 3H), 1.05(s, 3H).

[0968] Synthesis of Compound 45 (Example 11)

[0969] Example 11 was synthesized according to the following scheme:

[0970]

[0971] Compound 44

[0972] To a DMF (2 mL) solution of intermediate (I-3) (94.79 mg, 0.74 mmol) and compound (35) (200 mg, 0.74 mmol) stirred at 0° C. were added DIPEA (382.47 mg, 2.96 mmol) and HATU (365.74 mg, 0.96 mmol). The mixture was stirred at 0° C. for 2 hours, concentrated under reduced pressure, and the residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% NH4HCO3 aqueous solution; B: MeCN, 70% B to obtain a light yellow oily compound (44) (300 mg).

[0973] ESI-MS m / z=381.2[M+H] + .

[0974] Compound 45 (Example 11)

[0975] Compound (44) (100 mg, 0.53 mmol) in 4M HCl in dioxane (5 mL) was stirred at 20°C for 6 hours. The resulting mixture was concentrated in vacuo, and the residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.01% formic acid in water; B: MeCN, gradient from 10% to 60% in 20 minutes; detector, UV 200 nm to give compound (45) (Example 11) (53 mg) as a white solid.

[0976] ESI-MS m / z=325.15[M+H] +

[0977] 1 H-NMR: (300MHz, DMSO-d6) δ, ppm, 12.3 (s, 1H), 8.15 (d, J=8.0Hz, 1H), 7.83 (t, J=5.7Hz, 1H), 4.51 (td, J=7.9, 5.8Hz, 1H), 3.07-2.93 (m, 2H), 2 .66 (dd, J=16.4, 5.9Hz, 1H), 2.50-2.38 (m, 1H), 2.03 (dd, J=8.5, 7.1Hz, 2H), 1.61-1.49 (m, 2H), 1.42 (t, J=7.2Hz, 2H), 0.99 (d, J=3.8Hz, 6H).

[0978] Synthesis of Compound 49 (Example 12)

[0979] Example 12 was synthesized according to the following scheme:

[0980]

[0981] Compound 46

[0982] To a solution of intermediate (I-4) (800 mg, 8.07 mmol) and (2S)-4-[[(tert-butoxy)carbonyl]amino]-2-([[(9H-fluoren-9-yl)methoxy]carbonyl]amino)butanoic acid (3.55 g, 8.07 mmol) in DMF (10.00 mL) stirred at 0°C were added DIPEA (3.13 g, 24.21 mmol) and HATU (4.60 g, 12.10 mmol). The mixture was stirred at 0°C for 2 hours, then diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (2 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give compound (46) (1 g) as a white solid.

[0983] ESI-MS m / z=522.3[M+H] + .

[0984] Compound 47

[0985] A solution of compound (46) (1 g, 1.92 mmol) and diethylamine (4 mL) in THF (20 mL) was stirred at 20° C. for 4 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) and then with DCM / MeOH (7:1) to give compound (47) (300 mg) as a pale yellow oil.

[0986] ESI-MS m / z=300.4[M+H] + .

[0987] Compound 48

[0988] To a stirred solution of compound (47) (300 mg, 1.0 mmol) and intermediate (I-3) (128.4 mg, 1.0 mmol) in DMF (5.00 mL) at 0°C was added HATU (495.33 mg, 1.30 mmol) and DIPEA (388.54 mg, 3.01 mmol). The mixture was stirred at 0°C for 2 hours and then concentrated under reduced pressure, and the residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% NH4HCO3 aqueous solution; B: MeCN, detector: UV 200 nm, 0-100% B in 25 minutes, 50% B to give compound (48) (300 mg) as a colorless oil.

[0989] ESI-MS m / z=410.3[M+H] + .

[0990] Compound 49 (Example 12)

[0991] Compound (48) (300 mg, 0.73 mmol) in 4M HCl in dioxane (3 mL) was stirred at 20° C. for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase A: 0.05% NH4HCO3 aqueous solution; B: MeCN, gradient from 10% to 70%; detector, UV 200 nm to give compound (49) (Example 12) (206.8 mg) as a white solid.

[0992] ESI-MS m / z=310.2[M+H] +

[0993] 1 H-NMR: (400 MHz, methanol-d4) δ, ppm, 4.47 (dd, J = 8.4, 5.7 Hz, 1H), 3.19 (td, J = 7.0, 3.1 Hz, 2H), 3.14-2.99 (m, 2H), 2.31-2.11 (m, 3H), 2.07-1.93 (m, 1H), 1.74 (t, J = 7.5 Hz, 2H), 1.63-1.53 ​​(m, 2H), 1.05 (d, J = 3.4 Hz, 6H).

[0994] Synthesis of Compound 52 (Example 13)

[0995] Example 13 was synthesized according to the following scheme:

[0996]

[0997] Compound 50

[0998] To a solution of intermediate (I-2) (2 g, 7.87 mmol) and tert-butyl 2-aminoacetate hydrochloride (3.09 g, 23.59 mmol) in MeCN (20 mL) stirred at room temperature was added K2CO3 (6.53 g, 47.33 mmol). The mixture was stirred at 70°C for 16 hours, then concentrated under reduced pressure, diluted with water (200 mL) and extracted with EtOAc (3x200 mL). The combined organic layers were washed with water (2x300 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EtOAc (3:1) to give compound (50) (1.2 g) as a pale yellow oil.

[0999] ESI-MS m / z=214.3[M+H] + .

[1000] Compound 51

[1001] To a stirred solution of compound (50) (1.2 g, 5.63 mmol) in DMF (10 mL) at 0°C was added NaH (0.68 g, 17.10 mmol) in portions. The mixture was stirred at 0°C for 0.5 hours, and then intermediate (I-2) (1.43 g, 5.63 mmol) in DMF (3 mL) was added dropwise. The resulting mixture was stirred at 20°C for 4 hours, and then quenched with saturated NH4Cl aqueous solution (40 mL) at 0°C. The mixture was extracted with EtOAc (3x30 mL), and the combined organic layers were washed with water (2x40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% NH4HCO3 aqueous solution, B: MeCN, gradient from 0% to 100% in 25 minutes; detector, UV 200nm, to give a light yellow oily compound (51) (300 mg).

[1002] ESI-MS m / z=296.2[M+H] +

[1003] Compound 52 (Example 13)

[1004] Compound (51) (200 mg, 0.68 mmol) in 4M HCl in dioxane (10 mL) was stirred at 20°C for 6 hours. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC using the following conditions: Column: SunFire PrepC18 OBD column 19×150 mm, 5 μm; Mobile phase A: water (0.1% formic acid), Mobile phase B: MeCN; Flow rate: 25 mL / min; Gradient: 5% B to 25% B in 8 minutes; 254 / 220 nm; Rt: 7.23 minutes to give compound (52) (Example 13) (53 mg) as a colorless oil.

[1005] ESI-MS m / z=240.2[M+H] + .

[1006] 1 H-NMR: (300 MHz, methanol-d4): δ, ppm, 3.54 (s, 2H), 3.13-3.01 (m, 4H), 1.79-1.68 (m, 4H), 1.08 (s, 6H).

[1007] Synthesis of Compound 54 (Example 14)

[1008] Example 14 was synthesized according to the following scheme:

[1009]

[1010] Compound 53

[1011] To a stirred solution of compound (50) (300 mg, 1.41 mmol) and intermediate (I-3) (180.23 mg, 1.41 mmol) in DMF (5.00 mL) at 0°C was added DIPEA (545.38 mg, 4.22 mmol) and HATU (802.24 mg, 2.11 mmol). The mixture was stirred at 0°C for 2 hours, then concentrated under reduced pressure, and the residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: NH4HCO3 aqueous solution; B: MeCN, detector, UV 200 nm. 0-100% B, 50% B in 25 minutes to give compound (53) (200 mg) as a pale yellow oil.

[1012] ESI-MS m / z=324.3[M+H] + .

[1013] Compound 54 (Example 14)

[1014] To a solution of compound (53) (200 mg, 0.62 mmol) in 1,4-dioxane stirred at 0°C was added 4M HCl in 1,4-dioxane. The mixture was stirred at 20°C for 6 hours, then concentrated under reduced pressure, and the residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.1% formic acid in water; B: MeCN, gradient from 10% to 70% in 20 minutes; detector, UV 200nm to give compound (54) (Example 14) (50 mg) as a white solid.

[1015] ESI-MS m / z=268.2[M+H] + ,290.1[M+Na] +

[1016] 1H-NMR: (300MHz, DMSO-d6)δ, ppm, 4.11 (s, 1H), 3.91 (s, 1H), 3.25 (dd, J=15.3, 7.7Hz, 2H), 2.27 (t, J=7.5Hz, 1H), 2.08 (dd, J=8.6, 6.3Hz, 1H), 1.72-1.40 (m, 4H), 1.18-0.55 (m, 6H).

[1017] Synthesis of Compound 57 (Example 15)

[1018] Example 15 was synthesized according to the following scheme:

[1019]

[1020] Compound 55

[1021] To a solution of tert-butyl N-(2-aminoethyl)carbamate (630.03 mg, 3.93 mmol) and intermediate (I-2) (500 mg, 1.97 mmol) in MeCN (20 mL) stirred at 0°C was added KCO (543.44 mg, 3.99 mmol) and KI (32.63 mg, 0.2 mmol). The mixture was stirred at 70°C for 16 hours, then concentrated under reduced pressure, diluted with water (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous NaSO, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to give compound (55) (280 mg) as a pale yellow oil.

[1022] ESI-MS m / z=243.3[M+H] + .

[1023] Compound 56

[1024] To a DMF (2 mL) solution of intermediate (I-3) (148.05 mg, 1.16 mmol) and compound (55) (280 mg, 1.16 mmol) stirred at 0°C was added DIPEA (448.01 mg, 3.47 mmol) and HATU (571.15 mg, 1.50 mmol). The mixture was stirred at 20°C for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: NH4HCO3 aqueous solution; B: MeCN, detector: 200 nm, 70% B to obtain a colorless oily compound (56) (270 mg).

[1025] ESI-MS m / z=353.3[M+H] + .

[1026] Compound 57 (Example 15)

[1027] 4M HCl in 1,4-dioxane (6 mL) was added dropwise to a solution of compound (56) (200 mg) in 1,4-dioxane stirred at 0° C. The mixture was stirred at 20° C. for 6 hours and then concentrated in vacuo to give compound (57) (Example 15) (100 mg) as a colorless oil.

[1028] ESI-MS m / z=253.2[M+H] + .

[1029] 1 H-NMR: (300MHz, methanol-d4): δ, ppm, 3.66-3.54 (m, 2H), 3.46-3.32 (m, 2H), 3.23-3.01 (q, J=7.1, 5.9Hz, 2H), 2.28 (q, J=7.5Hz, 2H), 1.81-1.70 (m, 2H), 1.70-1.51 (m, 2H), 1.14-1.01 (m, 6H).

[1030] Synthesis of Compound 60 (Example 16)

[1031] Example 16 was synthesized according to the following scheme:

[1032]

[1033] Compound 58

[1034] To a stirred ethanol solution (50 mL) of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (600 mg, 2.81 mmol) and intermediate (I-4) (278.90 mg, 2.81 mmol) at 0°C was added NaHCO3 (708.88 mg, 8.44 mmol) in batches. The mixture was stirred at 80°C for 16 hours and then concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% formic acid in water; B: MeCN, detector, UV 200nm, 20% B to give a yellow oily compound (58) (500 mg).

[1035] ESI-MS m / z=313.4[M+H] + .

[1036] Compound 59

[1037] To a stirred solution of intermediate (I-3) (236.4 mg, 1.85 mmol) and compound (58) (524 mg, 1.68 mmol) in DMF (5 mL) at 0°C was added DIPEA (650 mg, 5.04 mmol) and HATU (829.07 mg, 2.18 mmol). The mixture was stirred at 0°C for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% formic acid in water, B: MeCN, detector, UV 254 nm, 0-100% B in 30 minutes to give compound (59) (300 mg) as a colorless oil.

[1038] ESI-MS m / z=445.3[M+Na] + .

[1039] Compound 60 (Example 16)

[1040] 4M HCl in 1,4-dioxane (4 mL) was added dropwise to a solution of compound (59) (200 mg, 0.47 mmol) in MeCN stirred at 0°C. The mixture was stirred at 20°C for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% formic acid in water, B: MeCN, detector, UV 200 nm, 0-100% in 25 minutes, 20% B to give compound (60) (Example 16) (100 mg) as a colorless oil.

[1041] ESI-MS m / z=323.2[M+H] +

[1042] 1 H-NMR: (400MHz, methanol-d4): δ, ppm, 8.56 (s, 1H), 3.52 (q, J=7.6Hz, 4H), 3.24 (dd, J=7.2, 4.0Hz, 4H), 2.30 (dt, J=14.6, 7.3Hz, 2H), 1.76 (td, J=7.6, 3.6Hz, 6H), 1.69-1.56 (m, 2H), 1.10-1.01 (m, 6H).

[1043] Synthesis of Compound 64 (Example 17)

[1044] Example 17 was synthesized according to the following scheme:

[1045]

[1046] Compound 61

[1047] To a stirred solution of compound (50) (750 mg) in DCM (15 mL) was added TFA (15 mL) at 20° C. The mixture was stirred at 20° C. for 6 hours and then concentrated under reduced pressure to give compound (61), which was used in the next step without further purification.

[1048] ESI-MS m / z=158.2[M+H] + .

[1049] Compound 62

[1050] To a solution of compound (61) (750 mg, 0.48 mol) in 1,4-dioxane (10 mL) and saturated aqueous NaHCO3 (10 mL) stirred at 0°C was added di-tert-butyl dicarbonate (2.3 g, 10.75 mmol) in portions. The resulting mixture was stirred at 20°C for 16 hours and then neutralized to pH 6-7 with 1M HCl. The aqueous layer was extracted with EtOAc (3 x 50 mL), and the combined organic layers were washed with water (3 x 50 mL), saturated brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% formic acid in water; B: MeCN, 0%-100% gradient in 30 minutes, UV 200 nm to give compound (62) (250 mg) as a pale yellow oil.

[1051] ESI-MS m / z=258.2[M+H] + .

[1052] Compound 63

[1053] To a stirred solution of compound (62) (237.94 mg, 0.93 mmol) and compound (35) (250 mg, 0.93 mmol) in DMF (5 mL) at 0°C, DIPEA (358.57 mg, 2.77 mmol) and HATU (457.12 mg, 1.2 mmol) were added portionwise. The mixture was stirred at 20°C for 2 hours, then concentrated under reduced pressure, and the residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% formic acid in water; B: MeCN, gradient from 0% to 100% in 30 minutes; detector, UV 200 nm, to give compound (63) (380 mg) as a pale yellow oil.

[1054] ESI-MS m / z=510.3[M+H] + .

[1055] Compound 64 (Example 17)

[1056] 4M HCl in 1,4-dioxane (3 mL) was added dropwise to a solution of compound (63) (200 mg, 0.39 mmol) in 1,4-dioxane stirred at 0°C. The mixture was stirred at 20°C for 6 hours and then concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% acetic acid in water; B: MeCN, 20% B to give compound (64) (Example 17) (75 mg) as a white solid.

[1057] ESI-MS m / z=354.2[M+H] +

[1058] 1 H-NMR: (400MHz, methanol-d4): δ, ppm, 4.69 (dd, J=7.6, 5.5Hz, 1H), 3.64-3.51 (m, 2H), 3.17 (h, J=6.5 Hz, 2H), 2.84-2.58 (m, 4H), 1.60 (dt, J=43.4, 7.6Hz, 2H), 1.55 (dt, 2H), 1.06 (d, J=12.6Hz, 6H).

[1059] Synthesis of Compound 68 (Example 18)

[1060] Example 18 was synthesized according to the following scheme:

[1061]

[1062] Compound 65

[1063] To a solution of intermediate (I-2) (1 g, 3.93 mmol) and tert-butyl (2S)-2-amino-3-hydroxypropanoate (633.9 mg, 3.93 mmol) stirred at 0°C in MeCN (100 mL) was added K2CO3 (1.09 g, 7.86 mmol). The mixture was stirred at 60°C for 48 hours, then concentrated under reduced pressure, diluted with water (100 mL) and extracted with EtOAc (3x100 mL). The combined organic layers were washed with water (2x200 mL), dried over anhydrous Na2SO4, and after filtration the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% formic acid in water; B: MeCN, gradient from 10% to 90% in 25 minutes; detector, UV 200 nm. Compound (65) (0.50 g) was obtained as a yellow oil.

[1064] ESI-MS m / z=244.4[M+H] + .

[1065] Compound 66

[1066] TFA (15 mL) was added dropwise to a solution of compound (65) (0.50 g, 2.05 mmol) in DCM (15 ml) stirred at 0° C. The mixture was stirred at 20° C. for 6 hours and then concentrated under reduced pressure to give compound (66), which was used in the next step without further purification.

[1067] ESI-MS m / z=188.2[M+H] + .

[1068] Compound 67

[1069] To a stirred solution of compound (66) (55.38 mg, 0.3 mmol) and compound (35) (80 mg, 0.3 mmol) in DMF (2 mL) at 0°C was added DIPEA (114.74 mg, 0.89 mmol) and HATU (146.28 mg, 0.39 mmol). The mixture was stirred at 0°C for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% formic acid in water; B: MeCN, gradient from 10% to 50% in 20 minutes; detector, UV 200 nm, to give compound (67) (70 mg) as a white solid.

[1070] ESI-MS m / z=440.2[M+H]+ .

[1071] Compound 68 (Example 18)

[1072] 4M HCl in 1,4-dioxane (2 mL) was added dropwise to a stirred solution of compound (67) (70 mg, 0.16 mmol) at 20°C. The mixture was stirred at 20°C for 6 hours and then concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% formic acid in water; B: gradient from 10% to 90% in 25 minutes; detector, UV 200 nm, 15% B to give compound (68) (Example 18) (51 mg) as a white solid.

[1073] ESI-MS m / z=384.2[M+H] + .

[1074] 1 H-NMR: (300MHz, DMSO-d6): δ, ppm, 8.23 ​​(d, J=8.5Hz, 1H), 7.87 (t, J=5.7Hz, 1H), 5.01 (s, 1H), 4.70-4.40 (m, 1H), 3.47 (d, J=6.3Hz, 2H), 3.09 (t, J=6.2 Hz, 1H), 2.99 (q, J=6.7Hz, 2H), 2.69 (dd, J=16.4, 5.5Hz, 1H), 2.62-2.51 (m , 1H), 2.37 (ddt, J=23.5, 12.0, 6.3Hz, 2H), 1.60-1.32 (m, 4H), 1.00 (s, 6H).

[1075] Synthesis of Compound 73 (Example 19)

[1076] Example 19 was synthesized according to the following scheme:

[1077]

[1078] Compound 69

[1079] To a solution of (2S)-2-amino-6-[[(tert-butoxy)carbonyl]amino]hexanoic acid tert-butyl ester (1.19 g, 3.93 mmol) and intermediate (I-2) (1 g, 3.93 mmol) stirred at 0°C in MeCN (100 mL) was added KCO (1.09 g, 7.86 mmol) in portions. The mixture was stirred at 60°C for 48 hours and then concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with EtOAc (3x100 mL). The combined organic layers were washed with water (2x200 mL), dried over anhydrous NaSO, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1 to 3:1) to give compound (69) (1 g) as a pale yellow oil.

[1080] ESI-MS m / z=385.2[M+H] + .

[1081] Compound 70

[1082] TFA (30 mL) was added dropwise to a solution of compound (69) (570 mg) in DCM (30 ml) stirred at 0° C. The mixture was stirred at 20° C. for 6 hours and then concentrated under reduced pressure to give (Compound 70), which was used in the next step without further purification.

[1083] ESI-MS m / z=229.2[M+H] + .

[1084] Compound 71

[1085] To a solution of compound (70) (1 g, 4.38 mmol) in 1,4-dioxane (30 mL) stirred at 0°C was added saturated aqueous NaHCO3 (30 mL) and di-tert-butyl dicarbonate (955.98 mg, 4.38 mmol) in portions. The resulting mixture was stirred at 25°C for 16 hours and then neutralized to pH 6-7 with 1M HCl. The aqueous layer was extracted with EtOAc (3x50 mL), the combined organic layers were washed with water (2x100 mL), dried over anhydrous Na2SO4, and after filtration the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% formic acid in water; B: MeCN, 10% to 50% gradient in 20 minutes; detector, UV 200 nm to obtain compound (71) (200 mg) as a pale yellow oil.

[1086] ESI-MS m / z=329.3[M+H] + .

[1087] Compound 72

[1088] To a stirred solution of compound (71) (170 mg, 0.52 mmol) and compound (35) (153.93 mg, 0.57 mmol) in DMF (3 mL) at 0°C was added HATU (236.19 mg, 0.62 mmol) and DIPEA (200.7 mg, 1.55 mmol) in portions. The mixture was stirred at 0°C for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.05% formic acid in water; B: MeCN, 10% to 80% gradient in 20 minutes; detector, UV 200 nm to obtain compound (72) (100 mg) as a pale yellow oil.

[1089] ESI-MS m / z=581.6[M+H] + .

[1090] Compound 73 (Example 19)

[1091] 4M HCl in 1,4-dioxane (4 mL) was added dropwise to a solution of compound (72) (100 mg, 0.17 mmol) stirred at 20°C in 1,4-dioxane. The mixture was stirred at 20°C for 6 hours and then concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: Column: SunFire C18 OBD Prep Column, 5 μm, 19 mm × 250 mm; mobile phase A: water (0.1% formic acid), mobile phase B: MeCN; flow rate: 25 mL / min; gradient: 1% B to 1% B in 7 min; 200 nm; Rt: 5.6 min) to give compound (73) (Example 19) (34.6 mg) as a white solid.

[1092] ESI-MS m / z=425.25[M+H] +

[1093] 1 H-NMR (300MHz, methanol-d4): δ, ppm, 4.72 (dd, J=8.7, 4.9Hz, 1H), 3.56 (s, 1H), 3.29-3.03 (m, 2H), 2. 97 (t, J=7.1Hz, 2H), 2.86 (m, 4H), 1.89-1.75 (m, 2H), 1.77-1.44 (m, 8H), 1.06 (d, J=5.6Hz, 6H).

[1094] Synthesis of Compound 75 (Example 20)

[1095] Example 20 was synthesized according to the following scheme:

[1096]

[1097] Compound 74

[1098] To the MeCN (20mL) solution of intermediate (I-2) (1.41g, 5.55mmol) stirred at room temperature, intermediate (I-4) (500mg, 5.04mmol) and KCO (2.11g, 15.13mmol) were added in batches. The mixture was stirred at 70 ° C for 16 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (100mL) and extracted with EtOAc (3x100mL). The combined organic layer was washed with water (2x200mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to obtain compound (74), which can be used in the next step without further purification.

[1099] ESI-MS m / z=182.2[M+H] + .

[1100] Compound 75 (Example 20)

[1101] To a stirred 0°C solution of morpholin-4-yl acetic acid (286.47 mg, 1.97 mmol) in DMF (2 mL) was added compound (74) (300 mg, 1.79 mmol), DIPEA (695.62 mg, 5.38 mmol) and HATU (886.82 mg, 2.33 mmol) in portions. The mixture was stirred at 0°C for 2 hours and then concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 column 19x250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeCN; flow rate: 25 mL / min; gradient: 32% B to 40% B in 12 minutes; 220 / 200 nm; Rt: 9.98 minutes) to give compound (75) (Example 20) (16.6 mg) as a colorless oil.

[1102] ESI-MS m / z=309.15[M+H] +

[1103] 1H-NMR: (400 MHz, methanol-d4): δ, ppm, 3.79-3.65 (m, 4H), 3.48-3.38 (m, 2H), 3.31 (s, 2H), 3.23 (s, 2H), 2.51 (t, J = 4.7 Hz, 4H), 1.73-1.63 (m, 2H), 1.58-1.48 (m, 2H), 1.08 (s, 3H), 1.05 (s, 3H).

[1104] Synthesis of Compound 78 (Example 21)

[1105] Example 21 was synthesized according to the following scheme:

[1106]

[1107] Compound 76

[1108] To the MeCN (10 mL) solution of intermediate (I-2) (500 mg, 1.967 mmol) stirred at room temperature, (2S)-3-amino-2-[(tert-butyloxycarbonyl)amino] tert-butyl propionate (511.86 mg, 1.97 mmol) and KCO (815.21 mg, 5.9 mmol) were added in batches. The mixture was stirred at 70 ° C for 16 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (50 mL) and the aqueous layer was extracted with EtOAc (3x50 mL). The combined organic layer was washed with water (2x100 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to obtain compound (76), which can be used in the next step without further purification.

[1109] ESI-MS m / z=343.5[M+H] + .

[1110] Compound 77

[1111] To a solution of compound (76) (800 mg, 2.34 mmol) in DMF (5 mL) stirred at 0° C., intermediate (I-3) (329.27 mg, 2.57 mmol), DIPEA (905.8 mg, 7.01 mmol) and HATU (1065.94 mg, 2.80 mmol) were added portionwise. The mixture was stirred at 0° C. for 2 hours, then concentrated under reduced pressure, and the residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.1% formic acid in water, mobile phase B: MeCN, gradient from 0% to 100% in 30 minutes; detector, UV 220 nm, 70% B to obtain compound (77) (200 mg) as a colorless oil.

[1112] ESI-MS m / z=453.4[M+H] + .

[1113] Compound 78 (Example 21)

[1114] 4M HCl in 1,4-dioxane (20 mL) was added to a 20°C solution of compound (77) (200 mg, 0.44 mmol) in 1,4-dioxane. The mixture was stirred at 20°C for 6 hours and then concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.1% formic acid in water, B: MeCN, detector, UV 200 nm, 10% to 100% gradient in 30 minutes, 20% B to give compound (78) (Example 21) (40.1 mg) as a white solid.

[1115] ESI-MS m / z=297.15[M+H] +

[1116] 1 H-NMR (300MHz, DMSO-d6): δ, ppm, 7.89 (d, J=6.9Hz, 1H), 4.12 (p, J=6.8, 6.4Hz, 1H), 2.99 (dd, J=11. 8, 5.8Hz, 1H), 2.85-2.67 (m, 3H), 2.09 (t, J=7.7Hz, 2H), 1.64-1.47 (m, 4H), 1.01 (d, J=10.1Hz, 6H).

[1117] Synthesis of Compound 81 (Example 22)

[1118] Example 22 was synthesized according to the following scheme:

[1119]

[1120] Compound 79

[1121] 4-aminopiperidine-1-carboxylic acid tert-butyl ester (400mg, 2.0mmol) and K2CO3 (828.07mg, 5.99mmol) are added in batches to MeCN (40mL) solution of intermediate (I-2) (507.88mg, 2.0mmol) stirred at room temperature. The mixture is stirred at 70 ° C for 16 hours, then cooled to room temperature and concentrated under reduced pressure. The residue is diluted with water (50mL) and extracted with EtOAc (3x50mL). The combined organic layer is washed with water (2x100mL), through anhydrous Na2SO4 drying, after filtration, the filtrate is concentrated under reduced pressure to obtain compound (79), which can be used in the next step without further purification.

[1122] ESI-MS m / z=283.3[M+H] + .

[1123] Compound 80

[1124] To a DMF (5 mL) solution of compound (79) (600 mg, 2.13 mmol) stirred at 0°C, intermediate (I-3) (299.47 mg, 2.34 mmol), DIPEA (823.82 mg, 6.37 mmol) and HATU (1.05 g, 2.76 mmol) were added in portions. The mixture was stirred at 0°C for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.1% formic acid in water, B: gradient from 0% to 100% in 30 minutes; detector, UV 220 nm, 60% to obtain compound (80) (300 mg) as a colorless oil.

[1125] ESI-MS m / z=415.3[M+Na] +

[1126] Compound 81 (Example 22)

[1127] 4M HCl in 1,4-dioxane (20 mL) was added dropwise to a solution of compound (80) (300 mg) at room temperature and stirred at 20°C for 4 hours. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.1% formic acid in water, B: MeCN, detector, UV 220 nm, 0% to 100% gradient in 30 minutes, 20% B to give compound (81) (Example 22) (200 mg) as a colorless oil.

[1128] ESI-MS m / z=293.2[M+H] +

[1129] 1 H-NMR (300MHz, methanol-d4): δ, ppm, 8.55 (s, 1H), 4.12-3.95 (m, 1H), 3.51-3.39 (m, 2H), 3.31-3.18 (m, 2H), 3.16-2.95 (m, 2H) )2.37-2.25(m, 1H), 2.25-2.09(m, 2H), 2.01-1.81(m, 3H), 1.73(q, J=7.3Hz, 2H), 1.69-1.48(m, 2H), 1.14-0.99(m, 6H).

[1130] Synthesis of Compound 84 (Example 23)

[1131] Example 23 was synthesized according to the following scheme:

[1132]

[1133] Compound 82

[1134] (3R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (400mg, 2.15mmol) and K2CO3 (890.43mg, 6.44mmol) were added in batches to MeCN (40mL) solution of intermediate (I-2) (600.75mg, 2.36mmol) stirred at room temperature. The mixture was stirred at 70 ° C for 16 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (100mL) and extracted with EtOAc (3x50mL). The combined organic layer was washed with water (2x100mL), dried over anhydrous Na2SO4, and after filtration, the filtrate was concentrated under reduced pressure to obtain compound (82), which can be used in the next step without further purification.

[1135] ESI-MS m / z=257.1[M+H] + .

[1136] Compound 83

[1137] To a DMF (5 mL) solution of intermediate (I-3) (315.12 mg, 2.46 mmol) stirred at 0°C was added compound (82) (600 mg, 2.24 mmol), DIPEA (866.88 mg, 6.71 mmol) and HATU (1, 105.15 mg, 2.91 mmol) in portions. The mixture was stirred at 0°C for 16 hours and then concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.1% formic acid in water, B: MeCN; detector, UV 220 nm, 0% to 100% gradient in 30 minutes, 70% to obtain compound (83) (200 mg) as a colorless oil.

[1138] ESI-MS m / z=412.9[M+H] + .

[1139] Compound 84 (Example 23)

[1140] 4M HCl in 1,4-dioxane (15 mL) was added to a 20°C solution of compound (83) (200 mg, 0.53 mmol) in 1,4-dioxane. The mixture was stirred at 20°C for 4 hours and then concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography using the following conditions: column, C18 silica gel; mobile phase, A: 0.1% formic acid in water, B: MeCN; detector, UV 254 nm, 0% to 100% gradient in 30 minutes, 20% to give compound (84) (Example 23) (100 mg) as a pale yellow oil.

[1141] ESI-MS m / z=279.20[M+H] +

[1142] 1 H-NMR: (300MHz, methanol-d4): δ, ppm, 8.56 (s, 1H), 4.27-3.89 (m, 1H), 3.81-3.62 (m, 1H), 3.54-3.43 (dd, J=12.4, 3.6Hz, 1H), 3.42-3.35 ( t, J=7.7Hz, 4H), 3.21-3.07(m, 1H), 2.41(m, 1H), 2.30-2.10(m, 3H), 1.84-1.72(m, 2H), 1.71-1.51(m, 2H), 1.11(s, 3H), 1.04(s, 3H).

[1143] Methods for evaluating compounds:

[1144] Pig corneal flattening test

[1145] The whole eye of the pig is warmed to room temperature in 4°C saline. The cornea is then de-epithelialized with a blunted surgical blade and the eye is placed in a custom-made removable eye holder in a horizontal position with the cornea facing up. The eye holder is then placed in a closed chamber where the atmosphere, temperature, and humidity can be controlled (usually a 37.0°C water bath). The IOP is maintained at a constant pressure by inserting a blood bank buffered saline line from an IV bag at a standard height through a syringe needle into each eye. 5% Dextran T500 in blood bank buffered saline is dripped onto the corneal surface of each eye every 90 seconds for 2 hours to allow the eyes to stabilize. The dripping of dextran is stopped and the solution of the test compound is allowed to soak into the corneal surface of the test eye through a small rubber O-ring in the center of the cornea that is fixed in place. After the set soaking time (usually 10 minutes), the O-ring is removed and the excess test solution is rinsed off with saline. The test eye is then oriented in a vertical position and the test eye is placed in a fixed position using a syringe. The HR device fine cornea 100 scans to measure the keratometry of the cornea's pre-treatment surface. The eye is then returned to a horizontal position and a specific pattern of 365nm UVA light is applied to the cornea for the desired dosing period. After another 1.5 hours (during which the instillation of 5% dextran is restarted), the eye is oriented back to a vertical position and treated as before. The HR device scans the cornea 100 finely to measure the corneal curvature of the cornea after treatment. A difference map between the corneal images before and after treatment is obtained, and the overall change in corneal curvature (Km) in the central 3mm area is recorded as the change in diopter.

[1146] The following notes further clarify some of the steps in the experiment:

[1147] (1) After the porcine eyeballs were warmed to room temperature in saline, the eyes were either immediately placed in a custom-made removable eye holder with the cornea facing up or first de-epithelialized with a blunted surgical blade and then placed in the holder.

[1148] (2) As used herein, IOP refers to “intraocular pressure.” IOP was maintained by inserting a blood bank buffered saline line from a standard height IV bag through a needle into each eye.

[1149] (3) 0.5%-10% (usually 5%) Dextran T500 in blood bank buffered saline is dripped onto the cornea of ​​each eye every 90 seconds for 2 hours to allow the eye to stabilize. The test eye is then oriented in a vertical position and the The HR device (Fine Cornea 100 Scan) acquires the pre-treatment surface keratometry of the cornea. The eye is then returned to a horizontal position and the dextran drop is replaced with a solution of the test compound (usually 0.22% w / v in saline) held in place by a small rubber O-ring in the center of the cornea.

[1150] (4) After a set soaking time of 5-30 minutes (usually 10 minutes), remove the O-ring and rinse off excess test solution with saline.

[1151] Representative porcine corneal flattening data for selected embodiments of the present disclosure are listed in Table B-1 below*:

[1152] Table B-1.

[1153] Example# Compound# Refractive change (D) 1 Compound 2 -0.32 10 Compound -0.64

[1154] *At 365nm, 30mW / cm 2 Irradiance, continuous wave (CW), duration 8.1 min, 15 J total dose, UVA light was applied in a 4 mm circle in a normal (21% O2) atmosphere at 37.0°C.

[1155] Pig corneal sclerosis test

[1156] The whole globe of the pig is warmed to room temperature in saline at 4°C. The eye is either immediately placed in a custom-made removable eye holder in a horizontal position with the cornea facing up, or the epithelium is first removed with a blunted surgical blade and then placed in the holder. The eye holder is then placed in a closed chamber where the atmosphere, temperature and humidity can be controlled (usually a 37.0°C water bath). The solution of the test compound is fixed in place by a small rubber O-ring in the center of the cornea and then immersed in the corneal surface of the test eye. After a set immersion time (usually 10 minutes), the O-ring is removed and the excess test solution is rinsed off with saline. A specific pattern of UVA light at 365nm is applied to the test eye cornea during the desired dosing cycle. A corneal flap of the desired thickness (usually 200μm) is then removed from the eye using a femtosecond laser (Zeimer, LDV1). The corneal flap was placed in saline at ambient temperature for 20 minutes and then mounted on a biaxial tensiometer (CellScale Biotester 5000, Waterloo, ON) using a biological rake attachment (5 tines, 3.5 mm width). The corneal flap was stretched at a constant rate of 4 μm / s in saline at 37°C until the sample failed. The maximum slope of the force vs. distance curve was calculated and compared with the value obtained with the untreated cornea.

[1157] The following notes further clarify some of the steps in the experiment:

[1158] (1) A solution of the test compound (usually 0.22% w / v in saline) is held in place by a small rubber O-ring in the center of the cornea and then allowed to soak into the corneal surface of the test eye. After a set soaking time of 5-30 minutes (usually 10 minutes), the O-ring is removed and any excess test solution is rinsed off with saline.

[1159] (2) A corneal flap of the desired thickness and diameter (typically 200 μm thick, 8 mm in diameter) was then excised from the eye using a femtosecond laser (Zeimer, LDV1). The corneal flap was placed in saline at ambient temperature for 20 minutes and then mounted on a biaxial tensile tester (CellScale Biotester 5000, Waterloo, ON) in saline or directly mounted on the tester in 5% dextran T500 / saline.

[1160] (3) A Biorake attachment (5 tines, 3.5 mm width) was used to secure the flap, which was stretched at 37°C at a constant rate of 4 μm / s in the X direction (5 N load cell) and the Y direction (10 N load cell).

[1161] (4) The maximum slope of the force-distance curve corresponds to the stiffness value, which is compared with the value obtained for the untreated cornea.

[1162] Representative porcine hardening data** for selected embodiments of the present disclosure are listed below in Table C-1:

[1163] Table C-1.

[1164] Example# Name / ID# Maximum slope 1 Compound 2 11.28 6 Compound 25 <![CDATA[10.88 # ]]> 10 Compound 43 <![CDATA[10.14 # ]]> 13 Compound 52 12.38 14 Compound 54 <![CDATA[10.5 # ,10.66]]> 17 Compound 64 10.13 23 Compound 84 <![CDATA[10.68 # ]]>

[1165] **At 365nm, 30mW / cm 2 Irradiance, continuous wave (CW), duration 8.1 min, 15 J total dose, UVA light was applied in a 9 mm circle in a normal (21% O2) atmosphere at 37.0°C.

[1166] Maximum slope value of untreated cornea = 10.1

[1167] #The eyes were not de-epithelialized before treatment.

[1168] Many embodiments of the present invention have been described. However, it should be understood that various modifications can be made without departing from the spirit and scope of the present invention. Therefore, other embodiments are included within the scope of the appended claims.

Claims

1. A compound of formula II or a pharmaceutically acceptable salt thereof, in: B 1 and B 2 Each independently is -Z 1 -Z 2 -Z 3 ,in: ·Z 1 It is C 1-3 Alkylene; ·Z 2 is a key; and ·Z 3 It is H; E 1 and Q 1 Each is independently C1-C6 alkylene; Each occurrence of R 2 Independently selected from the following group: (i) C1-C6 alkyl, which is replaced by one R a Replacement; and (ii) H; Each occurrence of R a are independently selected from the group consisting of: -C(=O)OH and -NR'C(=NR')NR'R"; Each occurrence of R' and R" is H; Each occurrence of R d1 is H; F 1 Yes-N(R d1 )-, -O- or -S-; and H 1 , G 1 , L 1 and M 1 are each independently selected from: ·key; -C(=O)CH(R 2 )N(R d1 )-;and ·-C(=O)CH(R 2 )CH2N(R d1 )-。 2. The compound according to claim 1, wherein F 1 Yes-N(R d1 )-or-O-;L 1 and M 1 Each is a bond; and G 1 and H 1 Each is a key.

3. The compound according to claim 1, wherein the compound is a compound of formula II-a: or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, wherein The compound is of formula (II-c1) or (II-c2): or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein The compound is of formula (II-e): or a pharmaceutically acceptable salt thereof.

6. The compound as claimed in claim 3, wherein R 2 For H.

7. The compound according to claim 4 or 5, wherein Each occurrence of R 2 Independently selected from: H, 8. The compound of claim 4, wherein R 2 Selected from 9. The compound of claim 5, wherein one R 2 is H, and the other R 2 Selected from 10. The compound of any one of claims 1 to 5, wherein B 1 and B 2 Each is CH3.

11. The compound of claim 6, wherein B 1 and B 2 Each is CH3.

12. The compound of claim 8, wherein B 1 and B 2 Each is CH3.

13. The compound of claim 12, wherein R 2 for 14. The compound of claim 12, wherein R 2 for 15. The compound of claim 9, wherein B 1 and B 2 Each is CH3.

16. The compound of claim 15, wherein R 2 for 17. A compound of formula (III): or a pharmaceutically acceptable salt thereof, in: B 1 and B 2 Each independently is -Z 1 -Z 2 -Z 3 ,in: ·Z 1 It is C 1-3 Alkylene; ·Z 2 is a key; and ·Z 3 It is H; E 1 、F 1 , H 1 , L 1 、M 1 and Q 1 Each independently selected from: Keys; and C1-C6 alkylene; The condition is E 1 and F 1 At least one of them is C1-C6 alkylene; G 1 is C(=O) or a bond; Each occurrence of R 3 Independently selected from the following group: (i) C1-C6 alkyl, which is optionally substituted with 1 R a Replacement; and (ii) L 3 -heterocyclyl, wherein the heterocyclyl contains 5-6 ring atoms, of which 1-3 ring atoms are N(R d ); Each occurrence of R a is -C(=O)OH; Each occurrence of R d is H; and L 3 Each is a key.

18. The compound of claim 17, wherein F 1 , G 1 , H 1 , L 1 and M 1 Each is a key.

19. The compound according to claim 18, wherein Each occurrence of R 3 is a C1-C6 alkyl group, which is replaced by one R a replace.

20. The compound of claim 19, wherein Each occurrence of R 3 Independently selected from:

21. The compound of claim 18, wherein Each occurrence of R 3 Independently selected from: L 3 -heterocyclyl, wherein the heterocyclyl contains 5-6 ring atoms, of which 1-3 ring atoms are N(R d ).

22. The compound of claim 21, wherein R 3 for 23. The compound of claim 19, wherein B 1 and B 2 Each is CH3.

24. The compound of claim 20, wherein B 1 and B 2 Each is CH3.

25. The compound of claim 21, wherein B 1 and B 2 Each is CH3.

26. The compound of claim 22, wherein B 1 and B 2 Each is CH3.

27. The compound of claim 1, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

28. The compound of claim 17, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising the compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

30. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, or the pharmaceutical composition according to claim 29, in the preparation of a medicament for application to the cornea, wherein the use comprises: Electromagnetic radiation is applied to the cornea, thereby creating cross-links in the cornea.

31. The use according to claim 30, wherein The medicament treats one or more corneal ectatic conditions.

32. The use according to claim 31, wherein The one or more corneal ectatic conditions are selected from the group consisting of keratoconus, keratospheric keratoconus, pellucid marginal degeneration, postoperative ectasia, and Tring's marginal degeneration.

33. The use according to claim 32, wherein The corneal ectatic disorder is keratoconus.

34. The use according to claim 33, wherein The keratoconus is progressive keratoconus.

35. The use according to claim 32, wherein The corneal ectatic disorder is post-operative ectasia.

36. The use according to claim 35, wherein The post-operative dilation is post-LASIK dilation.

37. The use according to claim 30, wherein The medication treats a vision condition selected from the group consisting of myopia, hyperopia, astigmatism, and presbyopia.

38. The use according to claim 30, wherein The medication treats irregular astigmatism.

39. The use according to claim 30, wherein The drug is administered directly to the cornea.

40. The use according to claim 39, wherein The drug is administered without removing the corneal epithelium.

41. The use according to claim 30, wherein The electromagnetic radiation includes ultraviolet light.

42. The use according to claim 41, wherein The ultraviolet light is UV-A light.

43. The use according to claim 30, wherein The electromagnetic radiation is laser radiation.

44. The use according to claim 40 or 42, wherein The irradiation duration is 1 to 60 minutes.

45. The use according to claim 41 or 43, wherein The wavelength of the radiation is between 350 and 380 nm.

46. ​​The use according to claim 41 or 43, wherein The wavelength of the radiation is 360-370 nm.

47. The use according to claim 30, wherein The irradiance of the electromagnetic radiation is 0.1 to 100 mW / cm 2 .

48. The use of claim 30, further comprising administering an additional cross-linking agent to the cornea.

49. The use according to claim 48, wherein The additional cross-linking agent is selected from the group consisting of riboflavin, 2,3-butanedione, folic acid, quinoxaline, quinoline, dibucaine, methotrexate, menadione and verteporfin.

50. The use of claim 30, further comprising administering to the cornea one or more additives other than the cross-linking agent.

51. The use according to claim 50, wherein The additive is selected from the group consisting of iron, copper, manganese, chromium, vanadium, aluminum, cobalt, mercury, cadmium, nickel, arsenic, 2,3-butanedione and folic acid.

52. The use of claim 30, further comprising administering an additional ophthalmic treatment for inflammation, cataracts, or lens disorders.

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